研究者詳細 - 岡村　智教

論文 - 岡村　智教

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Associations between Mobile Health Applications and Blood Pressure among Non-Patient Adults: A Systematic Review and Meta-Analysis.

Li Q, Ikeda A, Charvat H, Ohira T, Muraki I, Okamura T, Sato S, Miura M, Kamijima J, Ikeda S, Yamagishi K, Tanigawa T

American journal of hypertension 2026年02月

ISSN 0895-7061

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Independent and combined associations of body mass index and visceral fat area with kidney function decline in a healthy Japanese urban population: a longitudinal study.

Enami MS, Hirata A, Kuwabara K, Miyazaki J, Kubota Y, Nishida Y, Kubo S, Hirata T, Uchida T, Kadota A, Higashiyama A, Sugiyama D, Nishikawa T, Miyamatsu N, Miyamoto Y, Okamura T

BMC nephrology 27 （ 1 ） 96 2026年01月

Background: Obesity has been linked to progressive loss of kidney function, but the independent and combined associations of body mass index (BMI) and visceral fat accumulation remain uncertain in healthy individuals. This study aimed to clarify the longitudinal relationship between BMI, visceral fat area (VFA), and chronic kidney disease (CKD), defined as an estimated glomerular filtration rate based on serum cystatin C (eGFRcys) < 60 mL/min/1.73 m² among the Kobe Study participants targeting healthy urban residents in Japan. Methods: A total of 897 participants (267 men, 630 women) without CKD and with a mean age of 61.4 years were analyzed. VFA was measured using the impedance method, and participants were followed for a median of 8.3 years. Participants were classified into four groups based on baseline BMI (kg/m²) and VFA (cm²): G1 (VFA < 100 and BMI < 25), G2 (VFA < 100 and BMI ≥ 25), G3 (VFA ≥ 100 and BMI < 25), G4 (VFA ≥ 100 and BMI ≥ 25). Multivariable linear regression models were used to estimate adjusted mean annual changes in eGFRcys, and Cox proportional hazards models were applied to calculate hazard ratios (HRs) for incident CKD, adjusting for potential confounders (age, sex, smoking status, alcohol consumption, dyslipidemia, diabetes, hypertension and eGFRcys at baseline). Results: During follow-up, 85 participants (9.5%) developed CKD. The adjusted mean annual decline in eGFRcys was − 2.17% in G1, − 3.29% in G2, − 2.81% in G3, and − 3.81% in G4. Compared with G1, both G3 and G4 showed an elevated risks of CKD incidence (G3: HR 2.40, 95% CI 1.14–5.05; G4: HR 3.89, 95% CI 2.17–6.98), whereas the confidence interval crossed 1 for G2 (HR 0.88, 95% CI 0.12–6.47). Participants in G4 exhibited the steepest decline in kidney function and the highest CKD incidence rate (49.2 per 1,000 person-years). Conclusions: In healthy adults, the combination of elevated BMI and VFA was associated with accelerated kidney function decline. These findings underscore the importance of evaluating visceral fat in addition to BMI for early identification of individuals at increased risk of CKD and enable preventive strategies. Clinical trial number: Not applicable.

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The Japanese Society of Hypertension Guidelines for blood pressure control using digital technologies

Arima H., Itoh H., Ohkubo T., Ohya Y., Kabayama M., Kishi T., Hirawa N., Miura K., Miura S.I., Yamamoto K., Yoshimura C., Rakugi H., Asayama K., Inoue T., Ohishi M., Kusaka M., Goto K., Shimosawa T., Nishiyama A., Hoshide S., Yano Y., Kaneko K., Uesugi F., Shigyo M., Suenaga E., Masujima T., Kawachi S., Okayama A., Miyakawa M., Miyamatsu N., Nakamura K., Saito I., Murakami Y., Ishida M., Kitagawa K., Ohnishi H., Okada H., Fujioka Y., Ogawa Y., Shide K., Inoue S., Naito Y., Tsukahara T., Kakuma T., Yoshida M., Takashima N., Yagita Y., Kuwabara M., Takahashi K., Hozawa A., Eguchi H., Mogi M., Metoki H., Mukoyama M., Mizuno A., Furuhashi M., Fujiyoshi A., Higashi Y., Node K., Toyoda K., Tsuchihashi T., Tamura K., Takemi Y., Sugawara A., Shibata H., Shibata S., Koriyama H., Kario K., Katsuya T., Kai H., Ogura S., Okamura T., Uehara Y., Ichihar A., yamashita S., hosoki S., satoh A., sakamoto Y., koyoshi R., maeda T., Yamazato M., Mori F., Fujii T., Haze T., Niijima T., Sakaguchi T., Kobayashi Y., Kitajima K., Akasaki Y., Akagi Y., Sakima A., Yoshida S., Yamanokuchi T., Morito N., Fujimoto T., Hirata T., Tada K., Takami Y., Takahashi K., Segawa H.

Hypertension Research 2026年

ISSN 09169636

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[Development of quality management checklists for medical facilities conducting workplace cancer screening programs].

Okada Y, Saika K, Tatemichi M, Okamura T, Saitoh E

Sangyo eiseigaku zasshi = Journal of occupational health 2025年12月

ISSN 1341-0725

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Longitudinal study of plasma metabolites during menopause and their associations with later onset of metabolic syndrome.

Miyake A, Iida M, Harada S, Sugiyama D, Matsumoto M, Miyagawa N, Toki R, Edagawa S, Hirata A, Kuwabara K, Okamura T, Sato A, Amano K, Hirayama A, Sugimoto M, Soga T, Tomita M, Arakawa K, Kisu I, Yamagami W, Takebayashi T

The Journal of clinical endocrinology and metabolism 2025年12月

ISSN 0021-972X

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Current Status of Cardiovascular Disease in Japan: Prevention Strategies, Future Challenges, and Fundamental Lessons

Okamura T., Hirata A.

Journal of the American College of Cardiology 86 （ 22 ） 2106 - 2108 2025年12月

ISSN 07351097

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Association of repeated high serum osmolarity with cognitive function in older Japanese adults in a KOBE study subanalysis

Nishikawa T., Miyamatsu N., Higashiyama A., Kubota Y., Nishida Y., Hirata T., Hirata A., Miyazaki J., Tatsumi Y., Sugiyama D., Kuwabara K., Kubo S., Miyamoto Y., Okamura T.

Scientific Reports 15 （ 1 ） 36784 2025年12月

The relationship between serum osmolarity and cognitive function has not been fully characterized. This study aimed to examine the cross-sectional association between repeated high serum osmolarity and cognitive performance among elderly community residents. We performed a subanalysis of the Kobe Orthopedic and Biomedical Epidemiological Study, including residents aged ≥ 75 years who completed the Japanese Montreal Cognitive Assessment (MoCA-J) in 2016–2017 (n = 127), 2018–2019 (n = 71), and 2020 (n = 16). Serum osmolarity was obtained from the data in the 2012–2013 survey and in the 2016–2017 survey. MoCA-J scores were dichotomized at ≤ 22 versus > 22. Multivariate logistic regression adjusted for demographic, lifestyle including daily non-alcohol drink intake, seasonal, and clinical covariates to assess associations between osmolarity status and cognitive group. Among 214 participants (mean age 76.2 ± 1.3 years; 56% female), high osmolarity (≥ 300 mOsm/L) in 2012–2013 was associated with MoCA-J ≤ 22 (OR 2.67, 95% CI 1.29–5.53, p = 0.008). A similar association emerged for 2016–2017 measurements (OR 6.12, 95% CI 1.46–25.61, p = 0.013). Participants with high serum osmolarity at both time points showed a stronger cross-sectional association with lower MoCA-J scores (OR 17.64, 95% CI = 1.8–184.83, p = 0.017). No significant association was observed between daily non-alcoholic drink (NAD) intake and either MoCA-J scores or serum osmotic pressure. Repeated high serum osmolarity was cross-sectionally associated with lower cognitive performance in Japanese community-dwelling older adults. While NAD intake showed no significant association, further research is needed to explore the potential role of serum osmolarity in cognitive health. These findings warrant confirmation in larger prospective studies.

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[Comparison of estimated salt and potassium intake and urinary sodium-to-potassium ratio based on casual urine: A 10-year follow-up of NIPPON DATA2010].

Kitaoka K, Kadota A, Yoshita K, Okami Y, Kondo K, Harada A, Okuda N, Ohkubo T, Okamura T, Miura K

[Nihon koshu eisei zasshi] Japanese journal of public health 2025年10月

ISSN 0546-1766

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Low-Density-Lipoprotein Cholesterol Control and Treatment Status 1 Year after the Initial Health Checkup in Individuals with Referral-Level LDL Cholesterol.

Aoki H, Kitaoka K, Suzuki Y, Kaneko H, Okada A, Takeda N, Morita H, Hiroi Y, Node K, Furui Y, Okamura T, Miura K, Yasunaga H, Takeda N

Journal of atherosclerosis and thrombosis 33 （ 2 ） 204 - 215 2025年09月

ISSN 1340-3478

Aims: Despite strong recommendations for medical consultation, the treatment status and low-density lipoprotein cholesterol (LDL-C) levels at 1-year follow-up of individuals with referral-level LDL-C identified in health checkups remain unclear. We evaluated the treatment status and 1-year LDL-C control among individuals identified in health checkups as requiring early medical consultation due to LDL-C levels of ≥ 180 mg/dL. Methods: We conducted a nationwide cohort study including health checkup data for individuals aged 20–74 years. We identified 102,049 individuals (median age: 48 years; male: 66.8%) with uncontrolled LDL-C (≥ 180 mg/dL) at baseline, who had no prior lipid-lowering therapy. Poisson regression with robust error variance was used to assess factors associated with uncontrolled LDL-C at 1 year. Results: Among individuals with LDL-C ≥ 180 mg/dL at baseline, 56,147 (55.0%) visited a medical institution within 3 months of the checkup, and 13,124 (12.9%) were prescribed lipid-lowering medications at 1 year. At 1 year follow-up, 49,260 (48.3%) still had LDL-C ≥ 180 mg/dL. Factors associated with persistent LDL-C ≥ 180 mg/dL at 1 year included obesity (RR: 1.07, [95% CI: 1.06–1.09]), 10 mg/dL increase in LDL-C at baseline (1.11 [1.10–1.11]), smoking (1.05 [1.04–1.07]), alcohol consumption (0.95 [0.94–0.97]), poor sleep quality (1.02 [1.01–1.03]), and skipping breakfast ≥ 3 times per week (1.07 [1.05–1.08]). Conclusions: Despite being classified as requiring early medical intervention, only half of individuals with LDL-C ≥ 180 mg/dL visited a physician within 3 months, and nearly half continued to have uncontrolled LDL-C at 1 year. Strategies to facilitate timely medical visits and appropriate lipid management in health checkup-identified cases are warranted.

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Effectiveness of recommendations in promoting the use of Mobile health applications in health guidance: a randomized controlled trial.

Onoue T, Nishida K, Nakata Y, Hayashi F, Marutani M, Sakane N, Moriguchi J, Muto S, Kato K, Masuda I, Okamura T, Matsuzaki K, Kawamura T, Tsushita K

Journal of occupational health 67 （ 1 ） 2025年07月

ISSN 1341-9145

Objectives: Use of commercially available mobile health (mHealth) applications in supporting lifestyle improvements has become popular in recent years. However, the effectiveness of advice promoting the use of such applications based on individual behavioral goals in a health guidance setting remains unclear. This study explored how guiding participants of the Specific Health Guidance (SHG) program, a Japanese public health initiative to prevent cardiovascular disease, to use commercially available mHealth applications impacted their application usage, lifestyle habits, and cardiovascular risk factors. Methods: In this multicenter, randomized, open-label, parallel-group comparison study, 156 individuals with a history of SHG participation and who were engaged in the Motivational Health Guidance program (a type of SHG) in 2021 were assigned to intervention (n = 76) or control (n = 80) groups. Whereas both groups received standard guidance, the intervention group also received recommendations for mHealth applications based on their individual behavioral goals. The participants' application usage, behavioral changes, and body weight were assessed after 3 months, with health checkup data evaluated after 1 year. Results: The proportion of mHealth application users after 3 months was significantly higher in the intervention group (68.4%) than in the control group (40.0%). The intervention group also reported a significantly greater weekly frequency of mHealth application usage. Moreover, the intervention group reported a significantly decreased change in triglyceride levels after 1 year compared with the control group. Conclusions: Recommending commercially available mHealth applications in a health guidance setting significantly increased the number of mHealth application users and their frequency of use.

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Association of Social Participation with Cardiovascular Risk Factors: A Systematic Review.

Miura M, Ikeda A, Sato S, Muraki I, Okamura T, Ohira T, Miyazaki J, Ishihara M, Okamoto K, Kamijima J, Li Q, Ikeda S, Yamagishi K, Tanigawa T

Journal of atherosclerosis and thrombosis 32 （ 8 ） 897 - 910 2025年05月

ISSN 1340-3478

Aim: Although social participation, defined as involvement in social activities, may be beneficial for cardiovascular health, evidence about the association remains limited. This systematic review summarized the relationship between social participation and cardiovascular risk factors. Methods: Original articles of longitudinal observational studies published in English before January 1, 2024, were searched via PubMed, Scopus, and Cochrane Library. Two investigators selected eligible literature for four health outcomes: hypertension, diabetes, dyslipidemia, and obesity. Results: Eight articles (including duplicates) covering cohort studies were included. The results indicated that social participation is associated with lower hypertension risk, but gender differences may exist in the association between social participation and hypertension. Two articles from a Japanese cohort study were found on diabetes, both of which reported significant preventive association with social participation. The only study on dyslipidemia showed a higher hyperlipidemia risk among women, but not men, with social participation. Two studies on the risk of obesity showed inconsistent results, with one reporting the association between social participation and maintenance of smaller waist circumference only among men, while the other found no association with body mass index. Conclusions: There is some evidence of the association between social participation and better cardiovascular health outcomes. However, evidence on gender differences and validation of the methodology for measuring social participation was still lacking.

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Serum Total Cholesterol and Fatal Subarachnoid Hemorrhage in 120,000 Japanese: A Pooled Analysis of Data from 12 Cohorts.

Satoh A, Arima H, Tanaka-Mizuno S, Fujiyoshi A, Kadota A, Miura K, Ueshima H, Okamura T, Murakami Y, EPOCH JAPAN Research Group

Journal of atherosclerosis and thrombosis 32 （ 11 ） 1425 - 1433 2025年05月

ISSN 1340-3478

Aim: The aim of this study was to clarify the association between serum total cholesterol and fatal subarachnoid hemorrhage in Japanese men and women. Methods: The study involved a pooled analysis of individual data from 12 well-qualified cohort studies conducted in Japan. The participants were classified according to their serum total cholesterol levels: ＜4.14 mmol/L (＜160 mg/dL), 4.14–4.64 mmol/L (160–180 mg/dL), 4.65–5.16 mmol/L (180–199 mg/dL), 5.17–5.68 mmol/L (200–219 mg/dL), 5.69–6.20 mmol/L (220–239 mg/dL), and ≥ 6.21 mmol/L (≥ 240 mg/dL). The outcome of the analysis was death from subarachnoid hemorrhage. Results: A total of 120,973 participants (70,947 women and 50,026 men) aged 18–96 years at baseline underwent follow-up for a median of 12.7 years, and 261 participants died from subarachnoid hemorrhage during this period. In women, both low (＜5.69 mmol/L [＜220 mg/dL]) and high (≥ 6.21 mmol/L [≥ 240 mg/ dL]) serum total cholesterol levels were significantly associated with a higher risk of fatal subarachnoid hemorrhage compared with the reference group (5.69–6.20 mmol/L [220–239 mg/dL]). These associations remained significant after adjustment for confounding factors. In contrast, no associations were observed in men. Conclusion: Both low and high serum total cholesterol levels were associated with a higher risk of fatal subarachnoid hemorrhage in 70,947 female participants from 12 cohort studies throughout Japan.

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Cross-Sectional Association between Sedentary Behavior and Physical Inactivity with Cardiometabolic Risk Factors among Japanese: The NIPPON DATA2010.

Ohashi M, Miyagawa N, Yanagita M, Okuda N, Fujiyoshi A, Ohkubo T, Kadota A, Okami Y, Kondo K, Harada A, Okamura T, Ueshima H, Okayama A, Miura K, NIPPON DATA2010 Research Group

Journal of atherosclerosis and thrombosis 32 （ 10 ） 1328 - 1346 2025年05月

ISSN 1340-3478

Aim: Sedentary behavior and physical inactivity increase the risk of cardiometabolic diseases. It is important to evaluate physical activity in daily life and understand the influence of these factors on cardiometabolic diseases in the Japanese population, which tends to have a prolonged sitting time. We examined the association between sedentary behavior and physical inactivity, characterized by extended television (TV) viewing and low step counts, which are easily monitored and modifiable, and cardiometabolic risk factors in the Japanese population. Methods: This cross-sectional study included 2,531 Japanese adults (1,087 men and 1,444 women) 20–91 years old, randomly selected throughout Japan. TV viewing was assessed using a self-reported questionnaire, and step counts were measured using pedometers. Cardiometabolic risk factors were determined using physical examinations or blood samples. The association between sedentary behavior and physical inactivity with each risk factor was examined using a cross-sectional analysis with multivariate-adjusted logistic regression models. Results: In both sexes, longer TV viewing positively correlated with low high-density lipoprotein (HDL) cholesterol and high triglycerides (TG). In women, TV viewing time is associated with obesity and increased abdominal circumference (AC). Conversely, in men, lower step counts were positively associated with obesity and increased AC, low HDL cholesterol, and high TG levels. Conclusions: The association between prolonged TV viewing and cardiometabolic risk factors was more pronounced in women than in men, whereas the influence of lower step counts was stronger in men than in women. These findings contribute to the improvement of cardiovascular health by monitoring and managing individual screen times and step counts in daily life.

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Genome-wide association study of plasma amino acids and Mendelian randomization for cardiometabolic traits.

Toki R, Fushiki S, Kojima S, Sutoh Y, Otsuka-Yamasaki Y, Harada S, Iida M, Hirata A, Miyagawa N, Matsumoto M, Edagawa S, Miyake A, Kuwabara K, Hirayama A, Sugimoto M, Sato A, Amano K, Soga T, Tomita M, Arakawa K, Kinoshita K, Sakurai-Yageta M, Tamiya G, Ohmomo H, Shimizu A, Okamura T, Takebayashi T

Scientific reports 15 （ 1 ） 14569 2025年04月

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = − 0.040, SE = 0.011), diastolic BP (β = − 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.

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A Randomized Clinical Trial of ICT-based Interventions for Sodium and Potassium Regulation in Healthy Adults.

Yano Y, Kitaoka K, Ohkubo T, Okamura T, Kanegae H, Yoshita K, Tsukinoki R, Okami Y, Node K, Rakugi H, Itoh H, Miura K

American journal of hypertension 38 （ 8 ） 588 - 594 2025年04月

ISSN 0895-7061

BACKGROUND: There is limited knowledge regarding effective strategies, including information and communication technology (ICT)-based interventions, to reduce sodium intake and increase potassium intake in healthy individuals. METHODS: We conducted a 3-month randomized controlled trial involving healthy adult employees with spot urine sodium-to-potassium ratios (spot UNa/UK) ≥4.0 or estimated 24-hour salt intake ≥10g. Estimated 24-hour UNa and UK were calculated using the Tanaka formula. Participants were assigned to one of four groups: (i) online education, where participants monitored their spot UNa/UK and received feedback from dieticians (n = 84); (ii) messaging, with similar self-monitoring and dietician messages (n = 84); (iii) self-learning, provided with an educational leaflet (n = 87); and (iv) a control group (n = 87). The primary outcome was the change in spot UNa/UK ratios, and secondary outcomes included changes in estimated 24-hour UNa and UK. The trial protocol specified a hierarchical order for testing the interventions, anticipating the highest efficacy in the online education group. RESULTS: After the intervention, the online education group showed a decrease in spot UNa/UK ratios (mean -0.9 (95% CI: -1.8 to 0.0), P = 0.052) compared to the control group. The increase in estimated 24-hour UK excretion was larger in online education compared to the control group (mean + 2.5 mmol/day (95% CI: -0.3 to 5.3), P = 0.085). The difference in estimated 24-hour UNa excretion between the online education and control groups was -4.3 mmol/day (95% CI: -15.5 to 6.9, P = 0.45). CONCLUSIONS: Combining self-monitoring of sodium and potassium intake with ICT-based interventions, including online nutritional education, was associated with a modest reduction in the estimated ratios of sodium and potassium intake in healthy individuals.

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Atherosclerotic Cardiovascular Disease Risk Prediction Models in China, Japan, and Korea: Implications for East Asians?

Nguyen P.K., Zhao D., Okamura T., Chang Kim H., Wong N.D., Yang E.

JACC: Asia 5 （ 3 ） 333 - 349 2025年03月

ISSN 2772-3747

The management of atherosclerotic cardiovascular disease (ASCVD) in the United States is currently based upon large epidemiological studies in primarily non-Hispanic White subjects. Although this strategy provides a uniform approach that is simpler to implement, it may result in inappropriately targeting certain Asian populations for treatment based on inaccurate ASCVD risk estimation. In this state-of-the-art review, we detail the similarities and differences in the prevalence of ASCVD and its risk factors among Chinese, Japanese, and Korean people living in the United States and in their native countries. We highlight the limitations of current risk calculators when applied to East Asian immigrants and summarize risk stratification approaches in China, Japan, and Korea. Our review underscores the need to disaggregate registry, cohort, and clinical trial data by East Asian subgroups, to actively engage these populations in research, and to initiate studies to better define ASCVD risk in East Asian people living in the United States.

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All-Cause and Cause-Specific Mortality Associated with Long-Term Exposure to Fine Particulate Matter in Japan: The Ibaraki Prefectural Health Study

Michikawa, T; Nishiwaki, Y; Asakura, K; Okamura, T; Takebayashi, T; Hasegawa, S; Milojevic, A; Minami, M; Taguri, M; Takeuchi, A; Ueda, K; Sairenchi, T; Yamagishi, K; Iso, H; Irie, F; Nitta, H

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 32 （ 8 ） 982 - 993 2025年01月

ISSN 1340-3478

Aims: Long-term exposure to fine particulate matter (PM2.5) is causally associated with mortality and cardiovascular disease. However, in terms of cardiovascular cause-specific outcomes, there are fewer studies about stroke than about coronary heart disease, particularly in Asia. Furthermore, there remains uncertainty regarding the PM2.5-respiratory disease association. We examined whether long-term exposure to PM2.5 is associated with all-cause, cardiovascular and respiratory disease mortality in Japan. Methods: We used data of 46,974 participants (19,707 men; 27,267 women), who were enrolled in 2009 and followed up until 2019, in a community-based prospective cohort study (the second cohort of the Ibaraki Prefectural Health Study). We estimated PM2.5 concentrations using the inverse distance weighing methods based on ambient air monitoring data, and assigned each participant to administrative area level concentrations. A Cox proportional hazard model was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality. Results: During the average follow-up of 10 years, we confirmed 2,789 all-cause deaths. All outcomes including stroke mortality did not significantly increase as the PM2.5 concentration increased. For non-malignant respiratory disease mortality, the multivariable adjusted HR per 1 µg/m3 increase in the PM2.5 concentration was 1.09 (95% CI = 0.97–1.23). Conclusions: In this population exposed to PM2.5 at concentrations of 8.3–13.1 µg/m3, there was no evidence that long-term exposure to PM2.5 had adverse effects on mortality. Weak evidence of positive association observed for non-malignant respiratory disease mortality needs further studies in other populations.

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Comprehensive assessment of the impact of blood pressure, body mass index, smoking, and diabetes on healthy life expectancy in Japan: NIPPON DATA90.

Tsukinoki R, Murakami Y, Hayakawa T, Kadota A, Harada A, Kita Y, Okayama A, Miura K, Okamura T, Ueshima H

Journal of epidemiology 35 （ 8 ） 349 - 54 2025年01月

ISSN 0917-5040

Background: Healthy life expectancy (HLE) is a population health indicator that is widely used in developed countries, but little is known about its relationships with combinations of non-communicable disease risk factors. This study was conducted to examine HLE at age 65 years according to combinations of blood pressure levels, body mass index, smoking status, and diabetes mellitus (DM) in a Japanese population. Methods: In a nationwide cohort study (NIPPON DATA90), data on these risk factors were obtained from participants in 1990 through physical examinations, blood tests, interviews, and questionnaires. Subsequently, participants aged ≥65 years underwent surveys on activities of daily living in 1995 and 2000, and multistate life tables were used to calculate combination-specific HLEs and their 95% confidence intervals (CIs). Results: The study population comprised 6,569 participants (men: 2,797; women: 3,772) who were followed until 2010. HLE at age 65 years in men with grade II/III hypertension, obesity, current smoker status, and DM (HLE 12.9; 95% CI, 12.9–13.0 years) was 9.7 years shorter than men without these risk factors (HLE 22.6; 95% CI, 22.4–22.8 years). Similarly, HLE at age 65 years in women with grade II/III hypertension, obesity, current smoker status, and DM (HLE 16.2; 95% CI, 15.9–16.5 years) was 10.1 years shorter than women without these risk factors (HLE 26.3; 95% CI, 26.3–26.3 years). Conclusion: The large discrepancies in HLEs underscore the impact of non-communicable disease risk factors, which should be considered when formulating health interventions to improve HLE in Japanese older adults.

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Association between employment status and long-term changes in psychological stress across the COVID-19 pandemic period in Japan: NIPPON DATA2010.

Abe M, Arima H, Okuda N, Taniguchi H, Satoh A, Nishi N, Aono N, Higashiyama A, Suzuki H, Okami Y, Kondo K, Kitaoka K, Kadota A, Okamura T, Ohkubo T, Okayama A, Miura K, NIPPON DATA Research Group

Journal of occupational health 67 （ 1 ） 2025年01月

ISSN 1341-9145

Objectives: There is a growing interest in understanding the long-term impact of employment status on psychological stress. We aimed to explore the association between socioeconomic status and psychological stress over a long-term follow-up period across the COVID-19 pandemic, employing the Kessler 6-Item Psychological Distress Scale (K6). Methods: We evaluated K6 scores from the 2021 follow-up survey of NIPPON DATA2010 using a self-administered questionnaire. The association between employment status and changes in K6 scores over 11 years was examined. Multiple regression analyses were used to estimate both crude and adjusted differences in K6 score changes across various socioeconomic factors including employment category, annual household income, marital status, and household size. Analyses were stratified by age, gender, and prefectural population size. Results: This study included 1532 participants with an average age of 54.9 years. Over 11 years (2010–2021), participants in both gender and age groups showed increases in mean K6 scores (men: 2.79 to 3.06; women: 3.15 to 3.56; <65 years: 3.27 to 3.47; ≥65 years: 2.37 to 3.08). Nonemployed participants, particularly homemakers, showed significantly greater increases in K6 scores, compared with full-time employees, especially among women, younger individuals, and those in densely populated areas, with a significant interaction with age. Conclusions: Nonemployed individuals, especially homemakers, experienced greater psychological stress over the past 11 years than did their fully employed counterparts. Public interventions, including strengthened social connections and telemental health services, may help mitigate these disparities, enhance mental well-being, and foster a sense of belonging.

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Long-term risk of cardiovascular mortality according to age group and blood pressure categories of the latest guideline

Satoh M., Ohkubo T., Miura K., Harada A., Tsutsui A., Hozawa A., Shimizu Y., Ishikawa S., Kokubo Y., Okamura T., Murakami Y.

Hypertension Research 48 （ 4 ） 1428 - 1433 2025年

ISSN 09169636

This study examined the association between the latest blood pressure (BP) classification and cardiovascular disease (CVD) mortality risk, using data from 70,570 individuals across 10 Japanese cohorts. Participants were stratified by age (40–64 and 65–89 years) and antihypertensive treatment use. BP was classified according to the 2019 Japanese Society of Hypertension Guidelines. During a follow-up period of approximately 10 years, 2304 CVD deaths occurred. Cox models demonstrated that CVD mortality risk increased stepwise with the BP category, with this association being especially pronounced in patients aged 40–64 years, where the Grade I hypertension group showed the highest population-attributable fraction (PAF). When the treated participants were included in the hypertension group, the overall PAF for CVD mortality was 41.1%. Similar patterns were observed for CVD subtype mortality risk, with hypertension showing particularly high PAFs for intracerebral hemorrhage. These findings highlight the importance of early-stage prevention and management of hypertension. (Figure presented.)

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Associations between mental health and lifestyle changes during the COVID-19 pandemic in a general Japanese population: NIPPON DATA2010.

Aono N, Higashiyama A, Suzuki H, Fujiyoshi A, Abe M, Satoh A, Arima H, Nishi N, Kadota A, Ohkubo T, Okamura T, Okuda N, Okayama A, Miura K

Environmental health and preventive medicine 30 28 2025年

ISSN 1342-078X

BACKGROUND: Deterioration in lifestyle associated with poor mental health could be an important concern during the coronavirus disease 2019 (COVID-19) pandemic. However, few studies have investigated the association between mental health status and lifestyle changes during the pandemic in nationwide Japanese general population. METHODS: This cross-sectional study was conducted using the data among 1,546 participants of the follow-up study of NIPPON DATA2010 in 2021. Recent mental status, as assessed using the Kessler 6 (K6) scale, and lifestyle changes compared to before the pandemic were determined using self-reported questionnaires. Some lifestyle changes such as decreased physical activity were defined as undesirable, whereas others such as decreased alcohol drinking were defined as desirable. The participants were divided into three groups based on the K6 scores: the K6<5, 5≤K6<9, and K6≥9 groups. The odds ratios (ORs) and 95% confidence intervals (CIs) of the K6 groups for each lifestyle change compared with that in the K6<5 group were estimated after adjusting for possible confounders. RESULTS: The ORs of the K6≥9 group for all undesirable lifestyle changes were significantly high, especially increased alcohol drinking (OR 4.64; 95% CI, 2.71-7.93), and decreased physical activity (OR 4.63; 95% CI, 3.29-6.52). Among the desirable changes, the OR of the 5≤K6<9 group was significantly high for increased eating home cooking. CONCLUSIONS: Poor mental health showed a significant association with undesirable lifestyle changes, especially increased alcohol drinking and decreased physical activity, in a nationwide general Japanese population during the COVID-19 pandemic.

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[Effect of the combination of "weight gain of more than 10 kg since age 20" and obesity on the new onset of diabetes mellitus].

Naruse H, Kuwabara K, Hirata A, Imai Y, Sugiyama D, Funamoto M, Okamura T

[Nihon koshu eisei zasshi] Japanese journal of public health 72 （ 3 ） 199 - 207 2024年12月

ISSN 0546-1766

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Progression of aortic calcification among Japanese in Japan and white and Japanese Americans: a prospective cohort study

Li, MY; Fujiyoshi, A; Willcox, BJ; Li, JT; Kadota, A; Kadowaki, S; Seto, T; Kadowaki, T; Chang, YF; Evans, R; Miura, K; Edmundowicz, D; Okamura, T; Masaki, KH; Ueshima, H; Sekikawa, A

EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING 26 （ 2 ） 273 - 279 2024年11月

ISSN 2047-2404

Aims Continued low mortality from coronary heart disease in Japan, despite deleterious changes in traditional risk factors, remains unexplained. Since aortic calcification (AC) was an early predictor of cardiovascular mortality, we compared the progression and incidence of AC between Japanese in Japan, white Americans, and third-generation Japanese Americans in the ERA JUMP cohort. We examined whether higher blood levels of marine-derived n-3 fatty acids (FAs) in Japanese than in Americans accounted for the difference. Methods Men (n = 700) aged 40–49 years (252 Japanese in Japan, 238 white, and 210 Japanese Americans) were examined at baseline and results and 4–7 years later. AC was evaluated from the aortic arch to the iliac bifurcation with computed tomography and quantified by the Agatston method. Robust linear regression and linear mixed models were used to compare the progression of AC. Multivariable logistic regression models were fitted to compare the incidence of AC (AC ≥ 50 at follow-up) among those with baseline AC < 50. Japanese in Japan had a significantly slower progression of AC than white and Japanese Americans after adjusting for age, baseline AC, follow-up time, and traditional risk factors. White Americans had a significantly higher incidence of AC than Japanese in Japan [OR = 4.61 (95% CI, 1.27–16.82)]. Additional adjustment for blood levels of n-3 FAs accounted for the difference in AC incidence but not progression. Conclusion Japanese in Japan had a significantly slower progression and lower incidence of AC than white Americans. High levels of marine-derived n-3 FAs in Japanese in Japan partly accounted for the difference in incidence.

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Evaluation of Medication Adherence Among Prevalent Users in Hypertension, Dyslipidemia, and Diabetes Using Health Insurance Claims: A Population-Based Cohort Study in Japan

Matsumoto, M; Harada, S; Ikuta, H; Iida, M; Kato, S; Sata, M; Shibuki, T; Ishibashi, Y; Miyagawa, N; Hisamatsu, M; Hirata, A; Kuwabara, K; Takeuchi, A; Sugiyama, D; Suzuki, S; Nakamura, T; Okamura, T; Takebayashi, T

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY 33 （ 8 ） e5855 2024年08月

ISSN 1053-8569

Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined. Methods: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression. Results: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications. Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support.

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Risk Factors for Heart Failure and Coronary Artery Disease Mortality Based on the National Vital Statistics During a 25-Year Follow-up in Japan　- NIPPON DATA90.

Kubo K, Hirata A, Kadota A, Harada A, Nakamura Y, Hayakawa T, Takashima N, Fujiyoshi A, Okami Y, Kita Y, Okayama A, Miura K, Ueshima H, Okamura T, NIPPON DATA90 Research Group

Circulation journal : official journal of the Japanese Circulation Society 88 （ 9 ） 1478 - 1487 2024年07月

ISSN 1346-9843

Background: Prevention of heart failure (HF) is a public health issue. Using the National Vital Statistics, we explored risk factors for HF and coronary artery disease (CAD) mortality. Methods and Results: Altogether, 7,556 Japanese individuals aged ≥30 years in 1990 were followed over 25 years; of these, 139 and 154 died from HF and CAD, respectively. In multivariable Cox proportional hazard analysis, common risk factors for CAD and HF mortality were hypertension (hazard ratio [HR] 1.48 [95% confidence interval {CI} 1.00–2.20] and 2.31 [95% CI 1.48–3.61], respectively), diabetes (HR 2.52 [95% CI 1.63–3.90] and 2.07 [95% CI 1.23–3.50], respectively), and current smoking (HR 2.05 [95% CI 1.27–3.31) and 1.86 [95% CI 1.10–3.15], respectively). Specific risk factors for CAD were male sex, chronic kidney disease, history of cardiovascular disease, and both abnormal T and Q waves, with HRs (95% CIs) of 1.75 (1.05–2.92), 1.78 (1.19–2.66), 2.50 (1.62–3.88), and 11.4 (3.64–36.0), respectively. Specific factors for HF were current drinking (HR 0.43; 95% CI 0.24–0.78) and non-high-density lipoprotein cholesterol (non-HDL-C; HR 0.81; 95% CI 0.67–0.98). There was an inverse association between non-HDL-C and HF in those aged ≥65 years (HR 0.71; 95% CI 0.56–0.90), but not in those aged <65 years. Conclusions: We identified common risk factors for HF and CAD deaths; a history of cardiovascular disease was a specific risk for CAD.

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[Validity assessment of self-reported medication use in a pharmacoepidemiologic study by comparison with prescription record review].

Yajima R, Matsumoto M, Iida M, Harada S, Shibuki T, Hirata A, Kuwabara K, Miyagawa N, Nakamura T, Okamura T, Takebayashi T

[Nihon koshu eisei zasshi] Japanese journal of public health 71 （ 8 ） 430 - 437 2024年06月

ISSN 0546-1766

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A Novel Risk Score for Major Bleeding in Japanese Patients with Non-Valvular Atrial Fibrillation: The J-RISK AF Study.

Akao M, Tomita H, Nakai M, Kodani E, Suzuki S, Hayashi K, Sawano M, Goya M, Yamashita T, Fukuda K, Tsuda T, Isobe M, Toyoda K, Miyamoto Y, Okamura T, Sasahara Y, Okumura K, J-RISK AF Research Group

Journal of atherosclerosis and thrombosis 31 （ 11 ） 1591 - 1606 2024年05月

ISSN 1340-3478

Aim: Oral anticoagulants (OACs) reduce the risk of ischemic stroke but may increase the risk of major bleeding in patients with non-valvular atrial fibrillation (NVAF). Various risk scores, such as HAS-BLED, ATRIA, ORBIT, and DOAC, have been proposed to assess the risk of major bleeding in patients with NVAF receiving OACs. However, limited data are available regarding bleeding risk stratification in Japanese patients with NVAF. Methods: Of the 16,098 NVAF patients from the J-RISK AF study, the combined data of the five major AF registries in Japan (J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry), we analyzed 11,539 patients receiving OACs (median age, 71 years old; women, 29.6%; median CHA2DS2-VASc score, 3). Results: During the 2-year follow-up period, major bleeding occurred in 274 patients (1.3% per patient-year). In a multivariate Cox proportional hazards analysis, an advanced age, hypertension (systolic blood pressure ≥ 150 mmHg), bleeding history, anemia, thrombocytopenia, and concomitant antiplatelet agents were significantly associated with a higher incidence of major bleeding. We developed a novel risk stratification system, HED-[EPA]2-B3 score, which had a better predictive performance for major bleeding (C-statistics 0.67, [95% confidence interval, 0.63-0.70]) than the HAS-BLED (0.64, [0.60-0.67], P for difference 0.02) and ATRIA (0.63, [0.60-0.66], P for difference ＜0.01) scores. Furthermore, it was non-significantly higher than the ORBIT (0.65, [0.62-0.68], P for difference 0.07) and DOAC (0.65, [0.62-0.68], P for difference 0.17) scores. Conclusion: Our novel risk stratification system, the HED-[EPA]2-B3 score, may be useful for identifying Japanese patients receiving OACs at a risk of major bleeding.

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Low-density lipoprotein particle profiles compared with standard lipids measurements in the association with asymptomatic intracranial artery stenosis.

Vu T, Yano Y, Pham HKT, Mondal R, Ohashi M, Kitaoka K, Moniruzzaman M, Torii S, Shiino A, Tsuji A, Hisamatsu T, Okamura T, Kondo K, Kadota A, Watanabe Y, Nozaki K, Ueshima H, Miura K

Scientific reports （Scientific Reports） 14 （ 1 ） 10765 2024年05月

ISSN 2045-2322

The Shiga Epidemiological Study of Subclinical Atherosclerosis was conducted in Kusatsu City, Shiga, Japan, from 2006 to 2008. Participants were measured for LDL-p through nuclear magnetic resonance technology. 740 men participated in follow-up and underwent 1.5 T brain magnetic resonance angiography from 2012 to 2015. Participants were categorized as no-ICAS, and ICAS consisted of mild-ICAS (1 to < 50%) and severe-ICAS (≥ 50%) in any of the arteries examined. After exclusion criteria, 711 men left for analysis, we used multiple logistic regression to examine the association between lipid profiles and ICAS prevalence. Among the study participants, 205 individuals (28.8%) had ICAS, while 144 individuals (20.3%) demonstrated discordance between LDL-c and LDL-p levels. The discordance “low LDL-c–high LDL-p” group had the highest ICAS risk with an adjusted OR (95% CI) of 2.78 (1.55–5.00) in the reference of the concordance “low LDL-c–low LDL-p” group. This was followed by the concordance “high LDL-c–high LDL-p” group of 2.56 (1.69–3.85) and the discordance “high LDL-c–low LDL-p” group of 2.40 (1.29–4.46). These findings suggest that evaluating LDL-p levels alongside LDL-c may aid in identifying adults at a higher risk for ICAS.

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[Development of a new method for assessing the availability of low-sodium foods in Japan].

Hayabuchi H, Takemi Y, Ohta M, Sakata I, Sakaguchi K, Kubo A, Yoshita K, Kitaoka K, Okami Y, Ohkubo T, Okamura T, Node K, Miura K

[Nihon koshu eisei zasshi] Japanese journal of public health 71 （ 7 ） 366 - 375 2024年03月

ISSN 0546-1766

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Correction: Universal health coverage in the context of population ageing: catastrophic health expenditure and unmet need for healthcare.

Okamoto S, Sata M, Rosenberg M, Nakagoshi N, Kamimura K, Komamura K, Kobayashi E, Sano J, Hirazawa Y, Okamura T, Iso H

Health economics review 14 （ 1 ） 20 2024年03月

ISSN 2191-1991

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Real-World Clinical Profile of Patients Prescribed Evolocumab in Japan.

Sheng F, Wang AY, Miyawaki K, Tsuchiya T, Osada N, Miller R, Fu Z, Okamura T

Circulation journal : official journal of the Japanese Circulation Society 88 （ 10 ） 1629 - 1636 2024年03月

ISSN 1346-9843

Background: Real-world utilization data for evolocumab, the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to be introduced in Japan in 2016, to date are limited. This study aimed to clarify the current real-world patient user profiles of evolocumab based on large-scale health claims data. Methods and Results: This retrospective database study examined patients from a health administrative database (MDV database) who initiated evolocumab between April 2016 (baseline) and November 2021. Characteristics and clinical profiles of this patient population are described. In all, 4,022 patients were included in the final analysis. Most evolocumab prescriptions occurred in the outpatient setting (3,170; 78.82%), and 940 patients (23.37%) had a recent diagnosis of familial hypercholesterolemia. Common recent atherosclerotic cardiovascular disease events at baseline included myocardial infarction (1,633; 40.60%), unstable angina (561; 13.95%), and ischemic stroke (408; 10.14%). Comorbidity diseases included hypertension (2,504; 62.26%), heart failure (1,750; 43.51%), diabetes (1,199; 29.81%), and chronic kidney disease (297; 7.38%). Among the lipid-lowering regimens concomitant with evolocumab, ezetimibe+statin was used most frequently (1,281; 31.85%), followed by no concomitant lipid-lowering regimen (1,190; 29.59%), statin (950; 23.62%), and ezetimibe (601; 14.94%). The median evolocumab treatment duration for all patients was 260 days (interquartile range 57-575 days). Conclusions: This study provides real-world insights into evolocumab utilization in Japan for optimizing patient care and adherence to guideline-based therapies to better address hypercholesterolemia in Japan.

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Mortality from major causes and lifestyles by proportions of public assistance recipients among 47 prefectures in Japan: Ecological panel data analysis from 1999 to 2016.

Nishi N, Kitaoka K, Tran Ngoc Hoang P, Okami Y, Kondo K, Sata M, Kadota A, Nakamura M, Yoshita K, Okamura T, Ojima T, Miura K

Preventive medicine reports （Preventive Medicine Reports） 39 102635 2024年03月

ISSN 2211-3355

Objective: Comprehensive investigations of correlations between subnational socioeconomic factors and trends in mortality and lifestyle are important for addressing public health problems. Methods: Forty-seven prefectures in Japan were divided into quartiles based on the proportion of public assistance recipients (PPAR). Age-standardized mortality from all causes, cancer, heart disease, and stroke in each prefecture were averaged for these quartiles in 2000, 2005, 2010, and 2015. Data from the National Health and Nutrition Survey were obtained for the following periods: 1999–2001, 2003–2005, 2007–2009, 2012, and 2016. Body mass index (BMI), intake of total energy, vegetable and salt, step count, and prevalence of current smoking and drinking for individuals aged 40–69 years age range were standardized for each prefecture and averaged by quartile. A two-way analysis of variance was used to assess differences in mortality and lifestyle across different years or periods, and quartiles. Results: Mortality rates decreased, with the first (lowest) quartile showing the lowest rates, across all causes, cancer and heart diseases in both sexes. BMI exhibited an increase in men, whereas, BMI in women and other lifestyle factors in both sexes, excluding smoking and drinking in women, exhibited a decrease. BMI, vegetable and salt intake, total energy intake in men, and smoking in women varied across quartiles. Lower quartiles exhibited lower BMI and smoking prevalence but higher energy, vegetables, and salt intake. Conclusions: PPAR exhibited favorable trends and significant differences in mortality related to all causes, cancer and heart disease across both sexes, along with BMI among women.

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Relationship Between Hemoglobin Concentration and Cardiovascular Disease Mortality in a 25-Year Follow-up Study of a Japanese General Population　- NIPPON DATA90.

Kawashima M, Hisamatsu T, Harada A, Kadota A, Kondo K, Okami Y, Hayakawa T, Kita Y, Okayama A, Ueshima H, Okamura T, Miura K, NIPPON DATA90 Research Group

Circulation journal : official journal of the Japanese Circulation Society （Circulation journal : official journal of the Japanese Circulation Society） 88 （ 5 ） 742 - 750 2024年02月

ISSN 1346-9843

BACKGROUND: Deviations of hemoglobin from normal levels may be a factor in cardiovascular disease (CVD) risk; however, conclusive evidence is lacking. In addition, preclinical conditions may influence hemoglobin concentrations, but studies focusing on reverse causation are limited. Thus, we examined the relationship between hemoglobin concentrations and CVD mortality risk, considering reverse causation.Methods and Results: In a prospective cohort representative of the general Japanese population (1990-2015), we studied 7,217 individuals (mean age 52.3 years; 4,219 women) without clinical CVD at baseline. Participants were categorized into sex-specific hemoglobin quintiles (Q1-Q5) and data were analyzed using the Cox proportional hazards model adjusted for possible confounders. During a 25-year follow-up, 272 men and 334 women died from CVD. Adjusted hazard ratios for CVD mortality across sex-specific quintiles, using Q3 as the reference, were significantly higher for Q1 (1.40; 95% confidence interval [CI] 1.08-1.82) and Q5 (1.49; 95% CI 1.14-1.96), and remained significant after excluding deaths within the first 5 years of follow-up to consider reverse causation (1.35 [95% CI 1.02-1.79] and 1.45 [95% CI 1.09-1.94], respectively). A similar U-shaped association was seen between transferrin saturation levels and CVD mortality, but after excluding deaths within the first 5 years the association was significant only for Q1. CONCLUSIONS: Low and high hemoglobin concentrations were associated with an increased risk of CVD mortality.

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Association of Nonalcoholic Fatty Liver Disease with Arterial Stiffness and its Metabolomic Profiling in Japanese Community-Dwellers.

Hirata A, Harada S, Iida M, Kurihara A, Fukai K, Kuwabara K, Kato S, Matsumoto M, Sata M, Miyagawa N, Toki R, Edagawa S, Sugiyama D, Sato A, Hirayama A, Sugimoto M, Soga T, Tomita M, Okamura T, Takebayashi T

Journal of atherosclerosis and thrombosis （Journal of atherosclerosis and thrombosis） 31 （ 7 ） 1031 - 1047 2024年02月

ISSN 1340-3478

AIMS: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites. METHODS: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted. RESULTS: NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09-0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI. CONCLUSIONS: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

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Universal health coverage in the context of population ageing: catastrophic health expenditure and unmet need for healthcare.

Okamoto S, Sata M, Rosenberg M, Nakagoshi N, Kamimura K, Komamura K, Kobayashi E, Sano J, Hirazawa Y, Okamura T, Iso H

Health economics review （Health Economics Review） 14 （ 1 ） 8 2024年01月

ISSN 2191-1991

Background: Universal health coverage means that all people can access essential health services without incurring financial hardship. Even in countries with good service coverage and financial protection, the progress towards universal health coverage may decelerate or be limited with respect to the growing older population. This study investigates the incidence/prevalence, determinants, and consequences of catastrophic health expenditure (CHE) and unmet need for healthcare and assesses the potential heterogeneity between younger (≤ 64 years) and older people (65 years≤). Methods: Utilising an annual nationally representative survey of Japanese aged 20 years and over, we estimated the incidence of CHE and unmet need for healthcare using disaggregated estimates by household members’ age (i.e. ≤64 years vs. 65 years≤) between 2004 and 2020. Using a fixed-effects model, we assessed the determinants of CHE and unmet need along with the consequences of CHE. We also assessed the heterogeneity by age. Results: Households with older members were more likely to have their healthcare needs met but experienced CHE more so than households without older members. The financial consequences of CHE were heterogeneous by age, suggesting that households with older members responded to CHE by reducing food and social expenditures more so than households without older members reducing expenditure on education. Households without older members experienced an income decline in the year following the occurrence of CHE, while this was not found among households with older members. A U-shaped relationship was observed between age and the probability of experiencing unmet healthcare need. Conclusions: Households with older members are more likely to experience CHE with different financial consequences compared to those with younger members. Unmet need for healthcare is more common among younger and older members than among their middle-aged counterparts. Different types and levels of health and financial support need to be incorporated into national health systems and social protection policies to meet the unique needs of individuals and households.

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Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

Harada S, Iida M, Miyagawa N, Hirata A, Kuwabara K, Matsumoto M, Okamura T, Edagawa S, Kawada Y, Miyake A, Toki R, Akiyama M, Kawai A, Sugiyama D, Sato Y, Takemura R, Fukai K, Ishibashi Y, Kato S, Kurihara A, Sata M, Shibuki T, Takeuchi A, Kohsaka S, Sawano M, Shoji S, Izawa Y, Katsumata M, Oki K, Takahashi S, Takizawa T, Maruya H, Nishiwaki Y, Kawasaki R, Hirayama A, Ishikawa T, Saito R, Sato A, Soga T, Sugimoto M, Tomita M, Komaki S, Ohmomo H, Ono K, Otsuka-Yamasaki Y, Shimizu A, Sutoh Y, Hozawa A, Kinoshita K, Koshiba S, Kumada K, Ogishima S, Sakurai-Yageta M, Tamiya G, Takebayashi T

Journal of epidemiology 34 （ 8 ） 393 - 401 2024年01月

ISSN 0917-5040

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women’s health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

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Reliability of Time-Series Plasma Metabolome Data over 6 Years in a Large-Scale Cohort Study

Miyake A., Harada S., Sugiyama D., Matsumoto M., Hirata A., Miyagawa N., Toki R., Edagawa S., Kuwabara K., Okamura T., Sato A., Amano K., Hirayama A., Sugimoto M., Soga T., Tomita M., Arakawa K., Takebayashi T., Iida M.

Metabolites （Metabolites） 14 （ 1 ） 2024年01月

ISSN 2218-1989

Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys—at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies.

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A population-based urinary and plasma metabolomics study of environmental exposure to cadmium.

Ishibashi Y, Harada S, Eitaki Y, Kurihara A, Kato S, Kuwabara K, Iida M, Hirata A, Sata M, Matsumoto M, Shibuki T, Okamura T, Sugiyama D, Sato A, Amano K, Hirayama A, Sugimoto M, Soga T, Tomita M, Takebayashi T

Environmental health and preventive medicine 29 22 2024年

ISSN 1342-078X

Background: The application of metabolomics-based profiles in environmental epidemiological studies is a promising approach to refine the process of health risk assessment. We aimed to identify potential metabolomics-based profiles in urine and plasma for the detection of relatively low-level cadmium (Cd) exposure in large population-based studies. Method: We analyzed 123 urinary metabolites and 94 plasma metabolites detected in fasting urine and plasma samples collected from 1,412 men and 2,022 women involved in the Tsuruoka Metabolomics Cohort Study. Regression analysis was performed for urinary N-acetyl-beta-D-glucosaminidase (NAG), plasma, and urinary metabolites as dependent variables, and urinary Cd (U-Cd, quartile) as an independent variable. The multivariable regression model included age, gender, systolic blood pressure, smoking, rice intake, BMI, glycated hemoglobin, low-density lipoprotein cholesterol, alcohol consumption, physical activity, educational history, dietary energy intake, urinary Na/K ratio, and uric acid. Pathway-network analysis was carried out to visualize the metabolite networks linked to Cd exposure. Result: Urinary NAG was positively associated with U-Cd, but not at lower concentrations (Q2). Among urinary metabolites in the total population, 45 metabolites showed associations with U-Cd in the unadjusted and adjusted models after adjusting for the multiplicity of comparison with FDR. There were 12 urinary metabolites which showed consistent associations between Cd exposure from Q2 to Q4. Among plasma metabolites, six cations and one anion were positively associated with U-Cd, whereas alanine, creatinine, and isoleucine were negatively associated with U-Cd. Our results were robust by statistical adjustment of various confounders. Pathway-network analysis revealed metabolites and upstream regulator changes associated with mitochondria (ACACB, UCP2, and metabolites related to the TCA cycle). Conclusion: These results suggested that U-Cd was associated with metabolites related to upstream mitochondrial dysfunction in a dose-dependent manner. Our data will help develop environmental Cd exposure profiles for human populations.

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Seasonal variation in vascular dehydration risk: insights from the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study

Nishikawa, T; Miyamatsu, N; Higashiyama, A; Kubota, Y; Nishida, Y; Hirata, T; Hirata, A; Miyazaki, J; Sugiyama, D; Kuwabara, K; Kubo, S; Miyamoto, Y; Okamura, T

ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE 29 62 2024年

ISSN 1342-078X

Background: Dehydration, a risk factor for ischemic cerebrovascular diseases, is common in summer; however, the incidence of ischemic diseases is not necessarily higher in summer. Therefore, this study aimed to clarify the relationships between serum osmolarity, hematocrit, daily non-alcohol drink (NAD) intake and factors such as season and age as risk factors for dehydration. Method: Participants (703 women and 306 men) in the follow-up survey, in 2012 and 2013, of the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) Study, consisting of healthy individuals living in Kobe, Japan, were categorized into two groups based on the examination month: the warmer and colder seasons. Multivariate analyses were conducted to examine disparities in serum osmolarity, hematocrit, and NAD intake between these two groups. Results: The colder season was found to be negatively correlated with serum osmolarity and NAD intake, but positively correlated with hematocrit, even after adjusting for relevant factors. Age was independently associated with serum osmolarity, but not with hematocrit and NAD intake. Conclusions: This study suggests that intra-vascular volume depletion is more likely in the colder season despite lower serum osmolarity compared to the warmer season. Age-related increases in serum osmolarity without a corresponding rise in water intake may contribute to this. These findings support the importance of addressing dehydration in the colder season, particularly in older adults.

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Association between alcohol intake and death from cardiovascular diseases and its subtypes stratified by dyslipidemia in Japanese men: 20-years follow-up of NIPPON DATA90

Hirata, T; Hirata, A; Torii, S; Takashima, N; Kadota, A; Choudhury, SR; Okayama, A; Miura, K; Okamura, T

ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE 29 61 2024年

ISSN 1342-078X

Background: The association between alcohol consumption and atherosclerotic cardiovascular disease (ASCVD) was controversial, and no previous studies have shown the impact of dyslipidemia on the association. We aimed to clarify the association between alcohol consumption and death from cardiovascular disease (CVD) and its subtypes and the impact of dyslipidemia on the association. Methods: We conducted a 20-year cohort study to clarify the association between alcohol intake and death from CVD and its subtypes in 2,909 Japanese men. We estimated the hazard ratio (HR) and 95% confidence intervals (CIs) for current drinkers with non-drinkers as the reference, after adjusting for potential confounders using Cox proportional hazards models. We also investigated the association between alcohol consumption and ASCVD or CVD death stratified by the presence or absence of dyslipidemia. Results: During 50,782 person-years of follow-up period, 223 participants died from total CVD, 110 participants died from ASCVD, and 25 participants died from cerebral hemorrhage. Current drinkers with 1 gou/day were significantly associated with lower risk of ASCVD (HR: 0.60, 95%CI: 0.37–0.98), which is more apparent in those without dyslipidemia, and current drinkers with ²3 gou/day were significantly associated with higher risk of cerebral hemorrhage (HR: 4.13, 95%CI: 1.12–15.19). Conclusions: Small amounts of alcohol drinking were associated with lower risk of ASCVD in Japanese men, especially those without dyslipidemia. Meanwhile, excessive alcohol drinking was associated with higher risk of cerebral hemorrhage. Our findings suggest that it is important for current Japanese drinkers to reduce alcohol consumption for preventing ASCVD or cerebral hemorrhage.

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Influence of previous health guidance history: impact and limitations of a single health guidance session.

Hayase A, Onoue T, Nishida K, Nakata Y, Hayashi F, Marutani M, Sakane N, Okamura T, Matsuzaki K, Kawamura T, Tsushita K

Environmental and occupational health practice 6 （ 1 ） 2024年

Objectives: Metabolic syndrome (MS) is a significant health concern in the working-age population. Since 2008, Japan has mandated health insurers to implement Specific Health Checkups to identify individuals with MS and preliminary groups, making Specific Health Guidance (SHG) compulsory for these groups. People receiving SHG multiple times is increasing as it is conducted as an annual public program. Therefore, we evaluated the influence of a health guidance history on the effectiveness of subsequent guidance. Methods: Using data from 10,191 participants in the 2017 Motivational Health Guidance (a type of SHG involving a single session), this longitudinal study assessed the changes in health checkup findings from 2017 to 2018. Participants were categorized based on their previous year’s (2016) SHG eligibility and participation: Group 1 (n = 3,903) met the 2016 SHG criteria and participated, Group 2 (n = 2,305) met the criteria but did not participate, and Group 3 (n = 3,983) had no MS risk factors and did not need to participate in the 2016 SHG. Results: The entire cohort and Groups 2 and 3 exhibited significant weight loss after 1 year. Group 1 showed a significant negative association, with a 3% (odds ratio [OR] 0.64; 95% confidence interval [CI], 0.55–0.75) and 5% body weight loss (OR 0.66; 95% CI, 0.54–0.81) than Group 3. Men in Group 1 showed a significant association with new-onset MS (OR 2.56; 95% CI, 1.93–3.40). Conclusions: The findings suggest that participants with a history of health guidance in the previous year may have low rates of achieving weight loss and a high incidence of new-onset MS after 1 year.

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Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022.

Okamura T, Tsukamoto K, Arai H, Fujioka Y, Ishigaki Y, Koba S, Ohmura H, Shoji T, Yokote K, Yoshida H, Yoshida M, Deguchi J, Dobashi K, Fujiyoshi A, Hamaguchi H, Hara M, Harada-Shiba M, Hirata T, Iida M, Ikeda Y, Ishibashi S, Kanda H, Kihara S, Kitagawa K, Kodama S, Koseki M, Maezawa Y, Masuda D, Miida T, Miyamoto Y, Nishimura R, Node K, Noguchi M, Ohishi M, Saito I, Sawada S, Sone H, Takemoto M, Wakatsuki A, Yanai H

Journal of atherosclerosis and thrombosis （Journal of atherosclerosis and thrombosis） 31 （ 6 ） 641 - 853 2023年12月

ISSN 1340-3478

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High blood pressure and colorectal cancer mortality in a 29-year follow-up of the Japanese general population: NIPPON DATA80.

Hisamatsu T, Kadota A, Hayakawa T, Kita Y, Harada A, Okami Y, Kondo K, Ohkubo T, Okamura T, Okayama A, Ueshima H, Miura K, NIPPON DATA80 Research Group

Hypertension research : official journal of the Japanese Society of Hypertension （Hypertension Research） 47 （ 1 ） 206 - 214 2023年11月

ISSN 0916-9636

Onco-hypertension has been proposed, although associations of high blood pressure (BP) with cancer risk remain inconsistent. We examined associations of high BP with risk of mortality from stomach, lung, colorectal, liver, and pancreatic cancers independent of possible confounders in an analysis that excluded deaths within the first 5 years of follow-up to consider the reverse causality. In a prospective cohort representative of the general Japanese population (1980–2009), we studied 8088 participants (mean age, 48.2 years; 56.0% women) without clinical cardiovascular disease or antihypertensive medication at baseline. Fine-Gray competing risks regression was used to estimate hazard ratios for 10 mmHg higher BP adjusted for confounders including smoking, alcohol-drinking, obesity, and diabetes mellitus. During 29-year follow-up, 159 (2.0%), 159 (2.0%), 89 (1.1%), 86 (1.1%), and 68 (0.8%) participants died from stomach, lung, colorectal, liver, and pancreatic cancers, respectively. We observed a positive association of high BP with risk of colorectal cancer mortality but not with mortality risks from any other cancers. The association with colorectal cancer mortality for systolic and diastolic BP was evident in those aged 30–49 years (hazard ratios 1.43 [95% confidence interval, 1.22–1.67] and 1.86 [1.32–2.62], respectively) but not in those aged 50–59 years and ≥60 years (P for age interaction <0.01 for systolic and diastolic BP). The associations with colorectal cancer mortality were similar in the analyses stratified by smoking, alcohol-drinking, obesity, and diabetic status. In conclusion, high BP among young to middle-aged adults was independently associated with risk of colorectal cancer mortality later in life. [Figure not available: see fulltext.].

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Metabolomics profiles alterations in cigarette smokers and heated tobacco product users.

Harada S, Ohmomo H, Matsumoto M, Sata M, Iida M, Hirata A, Miyagawa N, Kuwabara K, Kato S, Toki R, Edagawa S, Sugiyama D, Sato A, Hirayama A, Sugimoto M, Soga T, Tomita M, Shimizu A, Okamura T, Takebayashi T

Journal of epidemiology 34 （ 9 ） 403 - 410 2023年11月

ISSN 0917-5040

Background: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment. Methods: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey. Results: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels. Conclusion: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

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Association of Pro-Inflammatory Diet with Long-Term Risk of All-Cause and Cardiovascular Disease Mortality: NIPPON DATA80.

Ganbaatar G, Okami Y, Kadota A, Ganbaatar N, Yano Y, Kondo K, Harada A, Okuda N, Yoshita K, Okamura T, Okayama A, Ueshima H, Miura K, NIPPON DATA80 Research Group

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 31 （ 3 ） 326 - 343 2023年10月

ISSN 1340-3478

Aim: A pro-inflammatory diet may increase the risk of cardiovascular disease (CVD) and all-cause mortality. However, this remains inconclusive as there is yet no study using a dietary record method that has been conducted in a large general population. Furthermore, an underestimation of the pro-inflammatory diet may exist due to the unmeasured effect of salt intake. Thus, in this study, we aimed to examine how pro-inflammatory diet is associated with the long-term risk of all-cause and CVD mortality in a representative Japanese population. Methods: A national nutrition survey was conducted throughout Japan in 1980. After considering the exclusion criteria, 9284 individuals (56% women aged 30–92 years) were included in this study. In total, 20 dietary parameters derived from 3-day weighed dietary records were used to calculate the dietary inflammatory index (DII). The causes of death were monitored until 2009. The Cox proportional hazards model was used to determine multivariable-adjusted hazard ratios (HRs). Stratified analysis according to salt intake level was also performed. Results: Compared with the lowest quartile of DII, multivariable-adjusted HRs (95% confidence intervals) in the highest quartile were 1.28 (1.15, 1.41), 1.35 (1.14, 1.60), 1.48 (1.15, 1.92), 1.62 (1.11, 2.38), and 1.34 (1.03, 1.75) for all-cause mortality, CVD mortality, atherosclerotic CVD mortality, coronary heart disease mortality, and stroke mortality, respectively. Stratified analysis revealed stronger associations among individuals with higher salt intake. Conclusions: As per our findings, a pro-inflammatory diet was determined to be positively associated with the long-term risk of all-cause and CVD mortality in a representative Japanese population. Thus, considering both salt intake and pro-inflammatory diet is deemed crucial for a comprehensive assessment of CVD risk.

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Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes An Individual-Participant Data Meta-Analysis

Grams, ME; Coresh, J; Matsushita, K; Ballew, SH; Sang, YY; Surapaneni, A; de Pinho, NA; Anderson, A; Appel, LJ; Ärnlöv, J; Azizi, F; Bansal, N; Bell, S; Bilo, HJG; Brunskill, NJ; Carrero, JJ; Chadban, S; Chalmers, J; Chen, J; Ciemins, E; Cirillo, M; Ebert, N; Evans, M; Ferreiro, A; Fu, EL; Fukagawa, M; Green, JA; Gutierrez, OM; Herrington, WG; Hwang, SJ; Inker, LA; Iseki, K; Jafar, T; Jassal, SK; Jha, V; Kadota, A; Katz, R; Köttgen, A; Konta, T; Kronenberg, F; Lee, BJ; Lees, J; Levin, A; Looker, HC; Major, R; Cohen, CM; Mieno, M; Miyazaki, M; Moranne, O; Muraki, I; Naimark, D; Nitsch, D; Oh, W; Pena, M; Purnell, TS; Sabanayagam, C; Satoh, M; Sawhney, S; Schaeffner, E; Schöttker, B; Shen, JI; Shlipak, MG; Sinha, S; Stengel, B; Sumida, K; Tonelli, M; Valdivielso, JM; van Zuilen, AD; Visseren, FLJ; Wang, AYM; Wen, CP; Wheeler, DC; Yatsuya, H; Yamagata, K; Yang, JW; Young, A; Zhang, HT; Zhang, L; Levey, AS; Gansevoort, RT

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 330 （ 13 ） 1266 - 1277 2023年10月

ISSN 0098-7484

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Trends in mortality from major causes and lifestyle factors by per capita prefectural income: Ecological panel data analysis from 1995 to 2016 in Japan

Nishi N., Kitaoka K., Tran Ngoc Hoang P., Okami Y., Kondo K., Sata M., Kadota A., Nakamura M., Yoshita K., Okamura T., Ojima T., Miura K.

Preventive Medicine Reports （Preventive Medicine Reports） 35 102348 2023年10月

ISSN 2211-3355

In Japan, trends in mortality and lifestyle have not been fully investigated according to subnational socioeconomic factors. Forty-seven prefectures (subnational units) were divided into quartiles by annual per capita prefectural income. Age-standardized mortality from all causes, cancer, heart disease, and stroke was averaged by quartile in 1995, 2000, 2005, 2010, and 2015. Data from the National Health and Nutrition Survey were obtained for periods 1 (1995–1997), 2 (1999–2001), 3 (2003–2005), 4 (2007–2009), 5 (2012), and 6 (2016). Body mass index (BMI), the intake of vegetables and salt, the number of steps, and the prevalence of current smoking and drinking for the 40–69-year age range were standardized by 10-year age groups in the 2010 Japanese population and were averaged by quartile. Differences in mortality and lifestyle by year and period, and quartile were tested using a two-way analysis of variance. Mortality decreased in both sexes and mortality in men from all causes, cancer, and stroke differed by quartile, with mortality highest in the first (lowest) quartile. BMI in men and smoking prevalence in women increased, whereas remaining lifestyle factors except for the prevalence of drinking decreased in women. BMI and the number of steps in both sexes and current smoking prevalence in women differed by quartile, with lower quartiles showing a higher BMI and fewer step counts. In conclusion, favorable trends and significant differences in mortality from all causes, cancer, and stroke in men and BMI in women were observed by per capita prefectural income level.

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Smoking is associated with impaired long-term quality of life in elderly people: a 22-year cohort study in NIPPON-DATA 90.

Liu Y, Okamura T, Hirata A, Sato Y, Hayakawa T, Kadota A, Kondo K, Ohkubo T, Miura K, Okayama A, Ueshima H

Journal of epidemiology （Journal of epidemiology） 34 （ 6 ） 265 - 269 2023年09月

ISSN 0917-5040

BACKGROUND: Whether smoking is associated with worse quality of life (QoL) or not is relatively controversial. The current study is to investigate the relationship between smoking and subjective QoL in a long cohort study. METHODS: The NIPPON DATA 90 project collected 8,383 community residents in 300 randomly selected areas as baseline data in 1990, administered four follow-up QoL surveys, and evaluated mortality statistics. We conducted multinomial logistic regression analysis to compare past smokers and current smokers to never smokers, with impaired QoL and mortality as outcomes. RESULTS: In four follow-ups, QoL data was collected from 2,035, 2,252, 2,522, and 3,280 participants in 1995, 2000, 2005, and 2012, respectively. In the 1995 follow-up, current smoking at baseline was not associated with worse QoL. In 2000 and 2005 follow-ups, smoking was significantly associated with worse QoL (odds ratio [OR] 2.1; 95% confidence interval [CI], 1.33-3.36 and OR 2.29; 95% CI, 1.38-3.80, respectively). In the 2012 follow-up, smoking was not associated with QoL. Sensitivity analysis did not change the result significantly. CONCLUSION: In this study we found that baseline smoking was associated with worse QoL in long-follow-up.

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Alcohol Consumption and Cerebral Small- and Large-Vessel Diseases: A Mendelian Randomization Analysis.

Hisamatsu T, Tabara Y, Kadota A, Torii S, Kondo K, Yano Y, Shiino A, Nozaki K, Okamura T, Ueshima H, Miura K, SESSA Research Group

Journal of atherosclerosis and thrombosis （Journal of atherosclerosis and thrombosis） 31 （ 2 ） 135 - 147 2023年08月

ISSN 1340-3478

AIMS: It remains inconclusive regarding alcohol intake and stroke risk because determining risk factors depends on the specific pathogenesis of stroke. We used the variant rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) as an instrument to investigate the causal role of alcohol intake in cerebral small- and large-vessel diseases. METHODS: We studied 682 men (mean age, 70.0 years), without stroke, in a cross-sectional Mendelian randomization analysis. We assessed small-vessel diseases (SVDs), which comprised lacunar infarcts, white matter hyperintensities (WMHs), and cerebral microbleeds, and large intracranial artery stenosis (ICAS) on brain magnetic resonance imaging. RESULTS: The median (25%tiles, 75%tiles) alcohol consumption by ALDH2-rs671 inactive A allele (n=313 [45.9%]) and non-A allele (n=369 [54.1%]) carriers was 3.5 (0.0, 16.0) and 32.0 (12.9, 50.0) g/day, respectively. Non-A allele carriers had higher prevalent hypertension and lower low-density lipoprotein cholesterol concentrations than A allele carriers. In age-adjusted ordinal logistic regression for graded burden, odds ratios (95% confidence intervals) for total SVDs, lacunar infarcts, WMHs, cerebral microbleeds, and ICAS in non-Aallele carriers were 1.46 (1.09-1.94), 1.41 (0.95-2.08), 1.39 (1.05-1.85), 1.69 (1.06-2.69), and 0.70 (0.50-0.98), respectively, compared with A allele carriers. These associations attenuated to statistical non-significance after considering covariates and amount of alcohol intake. CONCLUSIONS: Our findings suggest a positive association of alcohol consumption with risk of cerebral SVDs and its inverse association with risk of large-vessel disease through intermediaries, such as hypertension or low-density lipoprotein cholesterol. These findings provide insight into potential causal mechanisms linking alcohol consumption with stroke risk.

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Prevalence of Allergic Diseases across All Ages in Japan: A Nationwide Cross- Sectional Study Employing Designated Allergic Disease Medical Hospital Network

Ito, Y; Kato, T; Yoshida, K; Takahashi, K; Fukutomi, Y; Nagao, M; Fukuie, T; Matsuzaki, H; Gotoh, M; Tanaka, A; Konno, S; Tezuka, J; Nakamura, Y; Adachi, Y

JMA JOURNAL 6 （ 2 ） 165 - 174 2023年04月

ISSN 2433-328X

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Marital status, household size, and lifestyle changes during the first COVID-19 pandemic: NIPPON DATA2010

Abe M., Arima H., Satoh A., Okuda N., Taniguchi H., Nishi N., Higashiyama A., Suzuki H., Kadota A., Ohkubo T., Ueshima H., Miura K., Okayama A., Saitoh S., Sakata K., Hozawa A., Nakamura Y., Okamura T., Murakami Y., Ojima T., Nakagawa H., Kita Y., Nakamura Y., Miyamatsu N., Hayakawa T., Yoshita K., Miyamoto Y., Watanabe M., Takashima N., Fujiyoshi A., Kodama K., Kasagi F., Kiyohara Y., Ninomiya T.

PLoS ONE （PLoS ONE） 18 （ 3 March ） 2023年03月

Stay-at-home strategies taken during the COVID-19 pandemic changed our lifestyle drastically. Although marital status and household size are important social determinants of health that affect lifestyle, their impacts on lifestyle during the pandemic are still unclear. We aimed to evaluate the association between marital status, household size, and lifestyle changes during the first pandemic in Japan. Questionnaire surveys on lifestyle changes from before to during the first COVID-19 pandemic were conducted on October 2020 in Japan. Classified into age groups, multivariable logistic regression analysis was performed to examine the combined association of marital status and household size on lifestyle, adjusted for potential confounders including socioeconomic factors. In our prospective cohort study, 1928 participants were included. Among older participants, the singles living alone were likely to perceive more unhealthy lifestyle changes (45.8%), compared with the married (33.2%), and significantly associated with at least one unhealthy change [adjusted odds ratio (OR): 1.81, 95% confidence interval (CI): 1, 18-2.78], mainly due to decreased physical activity and increased alcohol consumption. Meanwhile, the younger participants showed no significant association between marital status, household size, and unhealthy changes, while those living alone had 2.87 times higher odds of weight gain (≥ 3 kg) than the married (adjusted OR: 2.87, 95% CI: 0.96-8.54) during the pandemic. Our findings suggest that older singles living alone are potentially vulnerable subgroups to drastic social changes which warrant special attention to prevent adverse health outcomes and additional burden on health systems in the following future.

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[Determinants of salt taste threshold among urban residents: the KOBE study].

Wakako M, Sata M, Kubota Y, Nishida Y, Kubo S, Higashiyama A, Hirata T, Kadota A, Hirata A, Miyazaki J, Kawahara M, Kuwabara K, Sugiyama D, Miyamatsu N, Miyamoto Y, Okamura T

[Nihon koshu eisei zasshi] Japanese journal of public health 70 （ 5 ） 300 - 310 2023年02月

ISSN 0546-1766

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Association between proprotein convertase subtilisin/kexin type 9 (PCSK9) and subclinical cerebrovascular disease in the community.

Kunimura A, Yano Y, Hisamatsu T, Torii S, Kondo K, Kadota A, Fujiyoshi A, Okamura T, Watanabe Y, Shiino A, Nozaki K, Ueshima H, Miura K, SESSA research group

European journal of neurology （European Journal of Neurology） 30 （ 5 ） 1327 - 1334 2023年02月

ISSN 1351-5101

Background and purpose: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new target for reducing low-density lipoprotein cholesterol and incident cardiovascular disease, including stroke. However, the clinical relevance of circulating PCSK9 levels has been poorly elucidated in the general population, particularly in association with subclinical cerebrovascular disease including cerebral small vessel disease (CSVD) and intracranial artery stenosis (ICAS). Methods: In community-dwelling Japanese men (n = 526) aged 46–82 years without a history of cardiovascular disease, the associations of serum PCSK9 levels with the prevalence of CSVD and ICAS were assessed using magnetic resonance imaging. CSVD included lacunar infarction, deep and subcortical white matter hyperintensity, periventricular hyperintensity and cerebral microbleeds. Results: The median (interquartile range) age at baseline and serum PCSK9 levels were 69 (63–74) years and 240 (205–291) ng/ml, respectively. After adjusting for traditional cardiovascular risk factors including low-density lipoprotein cholesterol, multivariable Poisson regression with robust error variance revealed a significant association between PCSK9 levels (per 1 SD) and ICAS (relative risks 1.18, 95% confidence interval 1.02–1.37). Multivariable ordinal logistic regression for ICAS, with stenosis graded as mild (<50%) or moderate–severe (≥50%), revealed a similar association (common odds ratio 1.31, 95% confidence interval 1.04–1.64). However, no significant association was observed between serum PCSK9 levels and CSVD. Conclusions: Higher circulating PCSK9 levels were independently associated with an ICAS prevalence but not with CSVD prevalence. The quantification of circulating PCSK9 levels may help to identify individuals at high risk for cerebrovascular disease in the general population.

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The association between sleep parameters and sarcopenia in Japanese community-dwelling older adults.

Shibuki T, Iida M, Harada S, Kato S, Kuwabara K, Hirata A, Sata M, Matsumoto M, Osawa Y, Okamura T, Sugiyama D, Takebayashi T

Archives of gerontology and geriatrics （Archives of Gerontology and Geriatrics） 109 104948 2023年01月

ISSN 0167-4943

Purpose: This study aimed to examine the association between sleep duration and quality and sarcopenia, assessed by factors such as low muscle mass (LMM), low muscle strength (LMS), and low physical performance (LPP) among older community-dwellers in Japan. Methods: In this cross-sectional study, a total of 2,069 (men, 902; women, 1,167) participants aged 65 to 80 years were included. Sarcopenia and each low physical function were defined using the definitions of the Asian Working Groups of Sarcopenia 2019. Sleep duration was stratified into three categories: short sleep (<6 h), normal sleep (6-8 h), and long sleep (>8 h). Sleep quality was classified into two groups based on 8-item Athens Insomnia Scale score: insomnia (≥6), and non-insomnia (<6). We analyzed the association between sleep parameters and sarcopenia, including low physical functions, by logistic regression analysis. Results: Compared to normal sleepers, long sleepers had a positive association with sarcopenia (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.25-3.58). In particular, long sleep was strongly associated with LMS (OR 1.77, 95%CI 1.07-2.94) and LPP (OR 1.90, 95%CI 1.25-2.88). On the other hand, poor sleep quality was not associated with sarcopenia in long sleepers, but in normal sleepers. Conclusions: Long sleep was associated with sarcopenia, including LMS and LPP. However, in long sleepers, insomnia was not associated with sarcopenia or any of its components.

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Fatty liver index predicts the development of hypertension in a Japanese general population with and without dysglycemia.

Wu D, Hirata A, Hirata T, Imai Y, Kuwabara K, Funamoto M, Sugiyama D, Okamura T

Hypertension research : official journal of the Japanese Society of Hypertension （Hypertension Research） 46 （ 4 ） 879 - 886 2023年01月

ISSN 0916-9636

Fatty liver has been suggested to be associated with the development of hypertension. However, whether this association is related to glycemia has not been elucidated. Therefore, we investigated whether the fatty liver index (FLI) predicts the development of hypertension among individuals with and without dysglycemia in a general Japanese population. A total of 3114 participants (1036 males and 2078 females) without hypertension who underwent a Specific Health Checkup in the fiscal year 2013 were followed up until 2018. The participants were divided into six groups based on FLI tertiles (low, moderate, or high) and whether they had dysglycemia. We estimated the hazard ratios (HRs) of each group by sex using the Cox proportional hazard model. Models were adjusted for age, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, and alcohol consumption and further adjusted for systolic blood pressure (SBP). During the mean follow-up period of 2.8 years, 160 of the 3114 participants developed hypertension. Using the low FLI group with normoglycemia as a reference, the HR for incident hypertension was increased in the high FLI group with and without dysglycemia in both sexes after adjusting for confounders, except SBP (HR [95% confidence interval]: male: 1.52 (1.06–2.17) in normoglycemia and 2.05 (1.43–2.92) in dysglycemia, and female: 1.86 (1.43–2.42) in normoglycemia and 2.98 (2.19–4.07) in dysglycemia). Furthermore, in females, this association was observed after adjusting for SBP. We concluded that FLI was independently associated with an increased risk of incident hypertension in individuals with and without dysglycemia. [Figure not available: see fulltext.].

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Offering on-site mammography in workplaces improved screening rates: Cluster randomized controlled trial.

Shima A, Tanaka H, Okamura T, Nishikawa T, Morino A, Godai K, Tatsumi Y, Kawahara M, Kiyohara M, Kawatsu Y, Kimura T, Miyamatsu N

Journal of occupational health （Journal of occupational health） 65 （ 1 ） e12389 2023年01月

ISSN 1341-9145

OBJECTIVES: Despite evidence of breast cancer screening efficacy, the screening rate has remained less than 50% in Japan. This study aimed to evaluate the effect of an environmental approach offering on-site mammography in workplaces. METHODS: Supermarket stores were randomly assigned into two groups, the intervention group (leaflet and mammography) and the control group (leaflet). From May to July 2018, participants in the intervention group were given a leaflet informing them of the subsidies for breast cancer screening and offered the opportunity to have mammography in their workplaces. Participants in the control group were given the same leaflet, but had to arrange their own screening outside the workplace. The primary outcome was the breast cancer screening rate in 2018. The odds ratio (OR) and 95% confidence interval (CI) for having screening in the intervention group compared with the control group were estimated using multilevel logistic regression. RESULTS: We analyzed data from 1624 participants (mean age 53 years) from 25 supermarket stores (intervention: 8 stores, control: 17 stores). Among participants who had not attended screening in the previous year, the screening rate was 7% in the control group and 53% in the intervention group, with an adjusted OR (95% CI) of 14.22 (8.97-22.54). The effect was greater in those who had never attended screening before. CONCLUSION: In a worksite-based cluster randomized controlled trial in Japanese supermarket stores, an environmental approach offering mammography in workplaces substantially increased the breast cancer screening rate within 1 year (UMIN000030465).

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Determinants of double product: a cross-sectional study of urban residents in Japan.

Nakagoshi N, Kubo S, Nishida Y, Kuwabara K, Hirata A, Sata M, Higashiyama A, Kubota Y, Hirata T, Tatsumi Y, Kawamura K, Miyazaki J, Miyamatsu N, Sugiyama D, Miyamoto Y, Okamura T

Environmental health and preventive medicine （Environmental Health and Preventive Medicine） 28 （ 1 ） 37 2023年

ISSN 1342-078X

Background: The current study aimed to investigate the determinants of high double product (DP) by evaluating the association between resting DP, which is calculated as systolic blood pressure (SBP) multiplied by heart rate (HR), and blood test results and lifestyle factors. Methods: This research included 973 participants in the baseline survey of the KOBE study, which included a cohort of urban residents. The possible DP determinants were identified by examining the association between lifestyle factors and laboratory findings and DP by analyzing covariance adjusted for sex and age. Logistic regression analysis was performed with high DP (SBP © HR ² 9145 mmHg beats/min or quintile according to sex) as outcome and DP determinants as independent variables. Results: Age, hematocrit, and gamma-glutamyl transferase (log) level were positively associated with a high DP in both men and women. In addition, a high DP was positively associated with Homeostatic Model Assessment for Insulin Resistance score in women alone. Meanwhile, the amount of exercise was negatively associated with a high DP in men alone. Conclusions: High DP values at rest were associated with insulin resistance, gamma-glutamyl transferase, and the amount of exercise in participants without underlying disease.

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Correction to: Determinants of double product: a cross-sectional study of urban residents in Japan.

Nakagoshi N, Kubo S, Nishida Y, Kuwabara K, Hirata A, Sata M, Higashiyama A, Kubota Y, Hirata T, Tatsumi Y, Kawamura K, Miyazaki J, Miyamatsu N, Sugiyama D, Miyamoto Y, Okamura T

Environmental health and preventive medicine 28 74 2023年

ISSN 1342-078X

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Predicting habitual water intake from lifestyle questions

Tanaka H., Mizuma K., Nakamura Y., Hirata A., Miyazaki J., Suzuki K., Seta H., Watanabe H., Suzuki T., Watanabe R., Murayama N., Okamura T., Nakamura S.

European Review for Medical and Pharmacological Sciences （European Review for Medical and Pharmacological Sciences） 27 （ 18 ） 8829 - 8841 2023年

ISSN 11283602

– OBJECTIVE: Previous studies have used selective recall and descriptive dietary record methods, requiring considerable effort for assessing food and water intake. This study created a simplified lifestyle questionnaire to predict habitual water intake (SQW), accurately and quickly assessing the habitual water intake. We also evaluated the validity using descriptive dietary records as a cross-sectional study. SUBJECTS AND METHODS: First, we used crowdsourcing and machine learning to collect data, predict water intake records, and create questionnaires. We collected 305 lifestyle-related questions as predictor variables and selective recall methods for assessing water intake as an outcome variable. Random forests were used for the machine learning models because of their interpretability and accurate estimation. Random forest and single regression correlation analysis were augmented by the synthetic minority oversampling that trained the model. We separated the data by sex and evaluated our model using unseen hold-out testing data, predicting the individual and overall habitual water intake from various sources, including non-alcoholic beverages, alcohol, and food. RESULTS: We found a 0.60 Spearman’s correlation coefficient for total water intake between the predicted and the selective recall method values, reflecting the target value to be achieved. This question set was then used for feasibility tests. The descriptive dietary record method helped to obtain a ground-truth value. We categorized the data by gender, season, and source: non-alcoholic beverages, alcohol, food, and total water intake, and the correlation was confirmed. Consequently, our results showed a Pearson’s correlation coefficient of 0.50 for total water intake between the predicted and the selective recall method values. CONCLUSIONS: We hypothesize that dissemination of SQW can lead to better health management by easily determining the habitual water intake.

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Dietary Factors, Dietary Patterns, and Cardiovascular Disease Risk in Representative Japanese Cohorts: NIPPON DATA80/90.

Kondo K, Miura K, Okamura T, Okayama A, Ueshima H, NIPPON DATA80/90 Research Group

Journal of atherosclerosis and thrombosis （Journal of atherosclerosis and thrombosis） 30 （ 3 ） 207 - 219 2022年11月

ISSN 1340-3478

Diet is one of the most important factors affecting healthy life expectancy through the onset of cardiovascular disease (CVD) risk as well as various chronic diseases. Because dietary habits and disease structure differ depending on the country, region, and/or race, evidence from each population is required. NIPPON DATA80/90 is a long-term cohort study of a representative Japanese population that participated in national nutrition surveys. Among the many findings of this cohort study, a dietary pattern with higher intake of fruits, vegetables, fish (n-3 polyunsaturated fatty acids), and dietary fiber and lower intake of salt as well as sodium-to-potassium ratio was found to be associated with a lower risk of CVD mortality. The results from our cohort study would be useful for effectively preventing CVD. This article reviews the published studies from the NIPPON DATA80/90 to highlight the significant findings that may be used to develop risk prevention strategies for CVD.

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Small High-Density Lipoprotein and Omega-3 Fatty Acid Intake Differentiates Japanese and Japanese-Americans: The INTERLIPID Study.

Okami Y, Chan Q, Miura K, Kadota A, Elliott P, Masaki K, Okayama A, Okuda N, Yoshita K, Miyagawa N, Okamura T, Sakata K, Saitoh S, Sakurai M, Nakagawa H, Stamler J, Ueshima H, INTERMAP and INTERLIPID Research Groups.

Journal of atherosclerosis and thrombosis （Journal of atherosclerosis and thrombosis） 30 （ 8 ） 884 - 906 2022年11月

ISSN 1340-3478

AIM: To identify the most differentiated serum lipids, especially concerning particle size and fractions, between Japanese living in Japan and Japanese-Americans in Hawaii, in the absence of possible genetic confounders, and cross-sectionally examine the associated modifiable lifestyle factors. METHODS: Overall, 1,241 (aged 40-59 years) Japanese living in Japan and Japanese-Americans in Hawaii were included. We quantified 130 serum lipid profiles (VLDL 1-5, IDL, LDL 1-6, high-density lipoprotein [HDL] 1-4, and their subfractions) using Bruker's 1H-nuclear magnetic resonance spectrometer for the primary outcome. Modifiable lifestyle factors included body mass index (BMI), physical activity, alcohol and smoking habits, and 70 nutrient parameters. We evaluated the different lipids between the groups using partial least squares-discriminant analysis and association between extracted lipids and lifestyle factors using multivariable linear regression analysis. RESULTS: Concentrations of HDL4, HDL with the smallest particle size, were lower in Japanese than in Japanese-Americans of both sexes. Higher fish-derived omega-3 fatty acid intake and lower alcohol intake were associated with lower HDL4 concentrations. A 1% higher kcal intake of total omega-3 fatty acids was associated with a 9.8-mg/dL lower HDL4. Fish-derived docosapentaenoic acid, eicosapentaenoic acid, and docosahexaenoic acid intake were inversely associated with HDL4 concentration. There was no relationship between country, sex, age, or BMI. CONCLUSIONS: Japanese and Japanese-Americans can be differentiated based on HDL4 concentration. High fish intake among the Japanese may contribute to their lower HDL4 concentration. Thus, HDL particle size may be an important clinical marker for coronary artery diseases or a fish consumption biomarker.

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Impact of baseline blood pressure on adverse outcomes in Japanese patients with non-valvular atrial fibrillation: the J-RISK AF.

Kodani E, Tomita H, Nakai M, Akao M, Suzuki S, Hayashi K, Sawano M, Goya M, Yamashita T, Fukuda K, Ogawa H, Tsuda T, Isobe M, Toyoda K, Miyamoto Y, Miyata H, Okamura T, Sasahara Y, Okumura K, J-RISK AF Research Group

European heart journal open （European Heart Journal Open） 2 （ 6 ） oeac081 2022年11月

Aims This study aimed to investigate the impact of baseline blood pressure (BP) on adverse outcomes in patients with atrial fibrillation (AF), using a pooled analysis performed on data from J-RISK AF, a large-scale cohort of Japanese patients with AF. ..................... Methods and results Of the 16 918 patients from five major AF registries including the J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry, 15 019 non-valvular AF (NVAF) patients with baseline BP values (age, 70.0 ± 11.0 years; men, 69.1%) were analysed. Incidence rates of adverse events were evaluated between patients divided into baseline systolic BP quartiles or at 150 mmHg. During the follow-up period of 730 days, ischaemic stroke, major bleeding, all-cause death, and cardiovascular death occurred in 277, 319, 718, and 275 patients, respectively. Hazard ratios (HRs) for ischaemic stroke and major bleeding were comparable among the quartiles, whereas HRs for all-cause and cardiovascular deaths in the lowest quartile with systolic BP <114 mmHg were significantly higher [HR 1.43, 95% confidence interval (CI) 1.13–1.81; and HR 1.47, 95% CI 1.01–2.12, respectively] than in the third quartile, even after adjusting for known confounding factors. In patients with a systolic BP of ≥150 mmHg, adjusted HR for major bleeding was significantly higher than that of <150 mmHg (HR 1.64, 95% CI 1.12–2.40). Conclusion In Japanese patients with NVAF, a baseline systolic BP <114 mmHg was significantly associated with higher all-cause and cardiovascular mortality. In contrast, a systolic BP ≥150 mmHg was an independent risk factor for major bleeding.

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Association between visceral fat accumulation and decline in the estimated glomerular filtration rate based on cystatin C in the Japanese urban population: the KOBE study.

Tanabe A, Hirata A, Kuwabara K, Kubo S, Higashiyama A, Hirata T, Sugiyama D, Nishida Y, Kubota Y, Kadota A, Nishikawa T, Miyamatsu N, Miyamoto Y, Okamura T

Endocrine journal （Endocrine journal） 70 （ 1 ） 97 - 106 2022年10月

ISSN 0918-8959

Although metabolic syndrome, including visceral fat accumulation, causes kidney and cardiovascular diseases, the impact of visceral fat accumulation on mild decreased renal function remains unclear. This study examines the association between visceral fat area (VFA) measured by bioimpedance methods and the estimated glomerular filtration rate based on serum cystatin C (eGFRcys) in the Japanese urban population. This community-based cross-sectional study enrolled 952 individuals (287 men, 665 women) who participated in the second follow-up survey of the Kobe Orthopedic and Biomedical Epidemiological (KOBE) study. We compared the multivariate-adjusted means of eGFRcys among VFA quartile groups by gender using the analysis of covariance. Models were adjusted for age, high blood pressure, hypercholesterolemia, glucose intolerance, smoking, and alcohol use, and further adjusted for body mass index (BMI). The highest VFA quartile group had lower eGFRcys than the lowest VFA quartile group after adjusted for cardiometabolic risk factors, except for BMI (93.1 [95% confidence interval (CI), 90.1-96.2] vs. 82.1 [95% CI, 79.1-85.0] in men and 95.8 [95% CI, 94.1-97.5] vs. 89.4 [95% CI, 87.8-90.9] in women). Moreover, further adjustment for BMI revealed a similar result in men (93.5 [95% CI, 89.8-97.2] vs. 81.6 [95% CI, 77.9-85.3]), while no significant association was found in women. This study suggests a significant association between increased VFA levels and lower eGFRcys levels independent of cardiometabolic risk factors, such as glucose intolerance and hypercholesterolemia in men and women, as well as independent of BMI in men.

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Impact of hypertension and diabetes on the onset of chronic kidney disease in a general Japanese population.

Kaneyama A, Hirata A, Hirata T, Imai Y, Kuwabara K, Funamoto M, Sugiyama D, Okamura T

Hypertension research : official journal of the Japanese Society of Hypertension （Hypertension Research） 46 （ 2 ） 311 - 320 2022年09月

ISSN 0916-9636

Hypertension (HT) and diabetes mellitus (DM) are both major risk factors for chronic kidney disease (CKD); however, few studies have examined the impacts of the combination of HT and DM on CKD development in general populations. We aimed to explore whether HT or DM contributes more to CKD development in a Japanese community. A total of 5823 individuals without a history of CKD who underwent specific health checkups in fiscal year 2013 were monitored until the end of March 2018. Participants were categorized as having neither HT nor DM (none group), either HT or DM, and both (HT + DM). We calculated the hazard ratios (HRs) for developing CKD in each category using Cox proportional hazards models after adjusting for age, dyslipidemia, smoking, and alcohol drinking and with the none group as the reference. We also estimated the population attributable fraction (PAF) for CKD development in populations with either HT or DM or both. During a mean follow-up of 3.0 years, 759 individuals developed CKD, with HRs of 1.56 with a 95% confidence interval (CI) [1.33, 1.83], 1.22 with a 95% CI [0.86, 1.75], and 2.83 with a 95% CI [2.22, 3.63] for the HT only, DM only and HT + DM categories, respectively. Sex-specific analysis showed similar findings. The PAFs for CKD (14.1% and 17.2% for men and women, respectively) were the highest among participants with HT only. We concluded that in this Japanese community, HT contributed more than DM to CKD development; hence, managing hypertension is important to prevent CKD as well as diabetes.

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Relationship between Serum Proprotein Convertase Subtilisin/Kexin Type 9 Concentration and Prevalence of Coronary Artery Calcium in a Community-Based Sample of Japanese Men.

Kunimura A, Miura K, Segawa H, Torii S, Kondo K, Hisamatsu T, Kadota A, Fujiyoshi A, Yano Y, Nakagawa Y, Okamura T, Ueshima H, SESSA research group.

Journal of atherosclerosis and thrombosis （Journal of atherosclerosis and thrombosis） 30 （ 7 ） 767 - 777 2022年09月

ISSN 1340-3478

AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for reducing low-density lipoprotein cholesterol (LDL-C) and cardiovascular events in high-risk patients. However, the influence of circulating PCSK9 concentration on atherosclerotic plaque formation in the general population remains unknown. We assessed the relationship between serum PCSK9 concentration and coronary artery calcium (CAC) prevalence in the general population. METHODS: Community-dwelling Japanese men (n=622) aged 46-82 years without a history of cardiovascular disease and lipid-lowering medications were included. Serum PCSK9 concentration and CAC score were measured using the Agatston method, and the multivariable analysis was used to assess their association. CAC was defined as an Agatston score of ＞10. We conducted further analysis stratified by age (＜60, 60-69, and ≥ 70 years). RESULTS: The average age, LDL-C, and median serum PCSK9 concentration were 68 years, 122 mg/dL, and 240 ng/mL, respectively. After multivariable adjustment for traditional cardiovascular risk factors, no significant association was observed between serum PCSK9 concentration and CAC prevalence (adjusted relative risk [aRR] 1.05, 95% confidence interval [CI] 0.97-1.13). With age stratification, serum PCSK9 concentration was significantly associated with CAC prevalence in men aged ＜60 years (aRR 1.38, 95% CI 1.01-1.88) but not in men aged 60-69 years (aRR 0.96, 95% CI 0.85-1.10) or ≥ 70 years (aRR 1.08, 95% CI 0.99-1.19). CONCLUSIONS: A higher serum PCSK9 concentration was associated with a higher CAC prevalence in men aged ＜60 years, which was independent of traditional cardiovascular risk factors.

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Reliable Information from Health Professionals Encourages Urban Japanese Mothers' Continued Participation in Health Checkups.

Tsukinoki R, Murakami Y, Imamura H, Okamura T

Healthcare (Basel, Switzerland) （Healthcare (Switzerland)） 10 （ 8 ） 2022年08月

ISSN 2227-9032

We examined mothers’ health information sources and their relationships with continued participation in health checkups among urban Japanese mothers. Participants were 152 mothers below 40 years old with one or more children under 12 years old. We collected data at a children’s festival in Tokyo in 2019. A self-administered questionnaire was used to collect information regarding health checkups, trusted sources of information regarding mother’s health, and anthropological variables. Continued participation in health checkups was defined as participating in health checkups almost every year during the past five years. Logistic regression analysis was used to adjust for health insurance, mothers’ age, number of children, and current medical history. the sources of mothers’ health information trusted by over 20% of mothers in the two groups were “family”, “friends”, “Web/SNS”, and “healthcare professionals.” However, continued participation in health checkups was significantly associated with only the source of health information from “healthcare professionals” (odds ratio: 2.8 [95% confidence interval: 1.26–6.31], p = 0.01). These findings suggest that reliable information from health professionals encourages urban Japanese mothers’ continued participation in health checkups among Japanese mothers under 40 years old who have children under 12 years of age.

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Alcohol consumption and subclinical and clinical coronary heart disease: A Mendelian randomization analysis.

Hisamatsu T, Miura K, Tabara Y, Sawayama Y, Kadowaki T, Kadota A, Torii S, Kondo K, Yano Y, Fujiyoshi A, Yamamoto T, Nakagawa Y, Horie M, Kimura T, Okamura T, Ueshima H, SESSA and ACCESS Research Groups.

European journal of preventive cardiology （European Journal of Preventive Cardiology） 29 （ 15 ） 2006 - 2014 2022年07月

ISSN 2047-4873

Aims: The potential effect of alcohol consumption on coronary heart disease (CHD) remains unclear. We used the variant rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) as an instrument to investigate the causal role of alcohol intake in subclinical and clinical CHD. Methods: We conducted two Mendelian randomization studies: a cross-sectional study of coronary artery calcification (CAC) on computed tomography of 1029 healthy men (mean age, 63.8 years) and a case-control study of 421 men with CHD [acute coronary syndrome (ACS) or stable angina pectoris] who underwent coronary revascularization and 842 age-matched male controls. Results: In the CAC study, medians (25%tiles, 75%tiles) of alcohol consumption by ALDH2-rs671 ∗2 homozygotes [n = 86 (8.4%)], ∗1∗2 heterozygotes [n = 397 (38.5%)], and ∗1 homozygotes [n = 546 (53.1%)] were 0.0 (0.0, 0.0), 28.0 (0.0, 129.0), and 224.0 (84.0, 350.0) g/week, respectively. In age-adjusted Poisson regression with robust error variance, compared with ∗2 homozygotes, relative risks for prevalent CAC score >0, ≥100, and ≥300 in ∗1 homozygotes were 1.29 (95% confidence interval, 1.06-1.57), 1.76 (1.05-2.96), and 1.81 (0.80-4.09), respectively. In age-adjusted ordinal logistic regression for CAC distributions, we observed higher odds among ∗1 homozygotes [odds ratio, 2.19 (1.39-3.46)] and even among ∗1∗2 heterozygotes [1.77 (1.11-2.82)] compared with ∗2 homozygotes. In the case-control study, conditional logistic regression revealed lower prevalence of ∗1 homozygotes among men with CHD [odds ratio, 0.54 (0.35-0.82)], especially ACS [0.46 (0.27-0.77)], than controls. Conclusion: Our findings indicate a positive association of alcohol consumption with CAC burden but an inverse association with clinical CHD, especially ACS.

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An Accelerated Failure Time Cure Model with Shifted Gamma Frailty and Its Application to Epidemiological Research.

Aida H, Hayashi K, Takeuchi A, Sugiyama D, Okamura T

Healthcare (Basel, Switzerland) （Healthcare (Switzerland)） 10 （ 8 ） 2022年07月

ISSN 2227-9032

Survival analysis is a set of methods for statistical inference concerning the time until the occurrence of an event. One of the main objectives of survival analysis is to evaluate the effects of different covariates on event time. Although the proportional hazards model is widely used in survival analysis, it assumes that the ratio of the hazard functions is constant over time. This assumption is likely to be violated in practice, leading to erroneous inferences and inappropriate conclusions. The accelerated failure time model is an alternative to the proportional hazards model that does not require such a strong assumption. Moreover, it is sometimes plausible to consider the existence of cured patients or long-term survivors. The survival regression models in such contexts are referred to as cure models. In this study, we consider the accelerated failure time cure model with frailty for uncured patients. Frailty is a latent random variable representing patients’ characteristics that cannot be described by observed covariates. This enables us to flexibly account for individual heterogeneities. Our proposed model assumes a shifted gamma distribution for frailty to represent uncured patients’ heterogeneities. We construct an estimation algorithm for the proposed model, and evaluate its performance via numerical simulations. Furthermore, as an application of the proposed model, we use a real dataset, Specific Health Checkups, concerning the onset of hypertension. Results from a model comparison suggest that the proposed model is superior to existing alternatives.

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Effect of diabetes and prediabetes on the development of disability and mortality among middle-aged adult Japanese: a 22-year follow-up of NIPPON DATA90.

Tran Ngoc Hoang P, Kadota A, Yuichiro Y, Akiko H, Takehito H, Shohei O, Miyagawa N, Kondo K, Nagako O, Kita Y, Okayama A, Yukihiro F, Maegawa H, Miura K, Okamura T, Ueshima H, NIPPON DATA90 Research Group.

Journal of diabetes investigation （Journal of Diabetes Investigation） 13 （ 11 ） 1897 - 1904 2022年06月

ISSN 2040-1116

Aims/Introduction: To examine the association between diabetes and prediabetes at baseline, and disability, mortality over a 22-year period among middle-aged Japanese adults. Materials and Methods: Participants consisted of 1,788 adults aged 45–64 years at baseline from the cohort study National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 1990 (NIPPON DATA90). Disability, defined as having a decline in activities of daily living (ADL), was assessed by a modified Katz questionnaire at four time points. Disability and death without disability for 22-year follow up were used as outcomes to test the association with a diagnosis of diabetes or prediabetes at baseline, using multinomial logistic regression. Adjusted odds ratios (ORs) were obtained from four models that contained appropriate adjustment factors, such as age, sex, smoking status, drinking status, body mass index and cardiovascular risk factors (hypertension, hypercholesterolemia, triglycerides, low serum high-density lipoprotein), at baseline. Results: In the present study, 334 participants (18.7%) reported at least one disability, and 350 (19.6%) were reported dead without observation of disability during follow up. Adjusting sex and other risk factors, participants with diabetes and prediabetes had a higher risk for disability (OR 1.43, 95% confidence interval [CI] 1.07–1.91 and OR 1.66, 95% CI 1.10–2.50, respectively) and for mortality (OR 1.56, 95% CI 1.16–2.08 and OR 1.77, 95% CI 1.18–2.65, respectively) than individuals with normal glucose tolerance. Conclusions: In middle-aged Japanese adults, individuals with diabetes and prediabetes were more likely to be associated with disability and mortality. Our findings suggest that prediabetes and diabetes in middle-aged adults should be paid more attention, and requires more intervention to prevent disability and mortality in later life.

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Ono T, Kato S, Kokubo Y, Hasegawa Y, Kosaka T, Maeda Y, Okamura T, Miyamoto Y, Ikebe K

International journal of environmental research and public health （International Journal of Environmental Research and Public Health） 19 （ 11 ） 2022年05月

ISSN 1661-7827

We examined whether the number of teeth could be a surrogate marker for metabolic syndrome (MetS) risk in cross-section. A total of 3771 individuals from the general urban Japanese population (1690 men, 2081 women; mean age 67.1 ± 11.0 years) participated in this study. Participants were diagnosed with MetS with three or more components hypertension, hyperglycemia, lipid metabolism abnormality, and abnormal abdominal girth. Questionnaires were administered to determine the number of teeth, smoking status, drinking status, and past illnesses. To clarify the relationships between the number of teeth and the presence of MetS components, we divided subjects into two groups: those with less than 20 residual teeth and those with 20 or more, then statistical analyses (Mantel-Haenszel tests and logistic regression analysis) were performed. MetS were higher for those with ≤19 teeth than those with ≥20 teeth when examining all participants and women-only groups. Hyperglycemia, low HDL cholesterol, high triglycerides, and diagnosis with MetS were all significantly higher in the ≤19 teeth group for both sexes combined and for women. These results suggest that less than 20 teeth may be a surrogate marker for MetS risk, but further studies on gender differences and pathological background are needed.

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Accumulated unhealthy behaviours and insomnia in Japanese dwellers with and without cardiovascular risk factors: a cross-sectional study.

Kato S, Harada S, Iida M, Kuwabara K, Sugiyama D, Takeuchi A, Sata M, Matsumoto M, Kurihara A, Hirata A, Okamura T, Takebayashi T

BMJ open （BMJ Open） 12 （ 4 ） e052787 2022年04月

ISSN 2044-6055

Objectives To date, the association between accumulated unhealthy behaviours and insomnia in individuals stratified according to the presence or absence of major cardiovascular risk factors is unclear. This study aimed to examine the effect of accumulated unhealthy behaviours on insomnia in Japanese dwellers. Design Cross-sectional study. Setting Baseline data between April 2012 and March 2015. Participants Our study used cross-sectional data among Japanese aged 35-74 years in a rural community (N=9565), the attendees of annual municipal or work site health check-up programmes. Main outcome measures Insomnia was assessed by Athens Insomnia Scale, which was set at 6 points and greater; other scales were given. Participants were categorised into three groups by their number of unhealthy behaviours (no exercise habit, smoking, alcohol drinking, skipping breakfast and obesity): 0-1, 2-3, 4 or more. The association between accumulated unhealthy behaviours and insomnia was estimated by logistic regression analysis. Further analysis was done after stratification of cardiovascular risk factors assessed by anthropometrics and clinical biochemistry measurements. Results The overall prevalence of insomnia was 13.3% for men and 19.3% for women. Men with unhealthy behaviour factors were more likely to have insomnia after adjusting for potential confounders, compared with the least unhealthy group (trend p=0.013). Women with four or more unhealthy behaviour factors were more likely to have insomnia, compared with the lowest groups (OR 1.175, 95% CI 1.077 to 1.282). Insomnia has an association with the unhealthy behaviours among men without cardiovascular risk factors (lowest groups: OR 1.133, 95% CI 1.037 to 1.238, trend p=0.026). Women without hypertension were more likely to have suspected insomnia, compared with the lowest group (OR 1.215, 95% CI 1.101 to 1.341). Conclusion The results showed accumulated unhealthy behaviours were associated with increased risk of insomnia in Japanese dwellers. For healthy population without cardiovascular risk factors, unhealthy behaviours should be considered as background conditions for insomnia.

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Trends in Prevalence, Treatment, and Control of Hypertension According to 40-Year-Old Life Expectancy at Prefectures in Japan from the National Health and Nutrition Surveys

Sata M., Okamura T., Nishi N., Kadota A., Nakamura M., Kondo K., Okami Y., Kitaoka K., Ojima T., Yoshita K., Miura K.

Nutrients （Nutrients） 14 （ 6 ） 2022年03月

The prevalence of hypertension has been decreasing in Japan due to improved medical treatment and a decrease in dietary salt intake. However, disparities in the prevalence, treatment, and control of hypertension are expected to occur in different regions. This study aimed to investigate the trends in the prevalence, treatment, and control of hypertension at the prefectural level of life expectancy among Japanese population. We used data from the National Health and Nutrition Survey and analysed the individual survey information of individuals aged 40–69 years by dividing it into six terms, i.e., 1995–1997, 1999–2001, 2003–2005, 2007–2009, 2012, and 2016. Prefectures were classified into four groups according to their 40-year-old life expectancy in 2000. Outcome values were standardised to the population by 10-year age groups in 2010, and they were tested by two-way analysis of variance according to six terms and life expectancies. The prevalence of hypertension tended to decrease, especially among women, whereas the treatment and control tended to improve from the first to the sixth period in both men and women. The prevalence and treatment of hypertension in men with longer life expectancy tended to be lower than that in other groups, and there was no obvious difference in the control. In women, there were no obvious differences in the prevalence, treatment, or control. Reducing the prevalence of hypertension by improving lifestyle factors, such as high salt intake in each prefecture with a relatively short life expectancy, may be important to resolve the disparity in life expectancy among prefectures.

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Metabolic profiling of charged metabolites in association with menopausal status in Japanese community-dwelling midlife women: Tsuruoka Metabolomic Cohort Study.

Watanabe K, Iida M, Harada S, Kato S, Kuwabara K, Kurihara A, Takeuchi A, Sugiyama D, Okamura T, Suzuki A, Amano K, Hirayama A, Sugimoto M, Soga T, Tomita M, Kobayashi Y, Banno K, Aoki D, Takebayashi T

Maturitas （Maturitas） 155 54 - 62 2022年01月

研究論文（学術雑誌）, ISSN 0378-5122

Background: Emerging evidence has shown that charged metabolites, such as amino acids, may play an important role in the pathogenesis of various metabolic disorders, many of which women in the postmenopausal period are at high risk of developing. This study examined the metabolic profile of middle-aged Japanese women to investigate alterations in charged metabolites induced by menopausal transition. Methods: The participants were 1193 female residents aged 40–60 at the baseline survey of the Tsuruoka Metabolomics Cohort Study. We investigated the cross-sectional association of menopausal status with 94 metabolomic biomarkers assayed in fasting plasma samples via capillary electrophoresis time-of-flight mass spectrometry using linear regression analysis. Results: Among the participants, 529 were premenopausal, 132 were in menopausal transition (MT), and 532 were postmenopausal. Significant differences were found in age, blood pressure, glucose and lipid levels, and smoking and drinking habits among the three groups. The concentrations of 5 metabolites in the MT group and 15 metabolites in the postmenopausal group were significantly higher than those in the premenopausal group after adjusting for confounding factors. When classified into pathways, these metabolites were related to the tricarboxylic cycle, urea cycle, and homocysteine metabolism, some of which are linked to arteriosclerosis. Conclusion: Multiple charged metabolites were associated with women's menopausal status, showing a gradual increase as women shifted from pre-, to peri-, to postmenopause. These findings might reflect the early changes behind the increased risk of dyslipidemia, diabetes, cardiovascular disease, and osteoporosis in later life.

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Predictors of lower limb fractures in general Japanese: NIPPON DATA90.

Saito Y, Miura K, Arima H, Hayakawa T, Takashima N, Kita Y, Okuda N, Fujiyoshi A, Iwahori T, Miyagawa N, Kondo K, Torii S, Kadota A, Ohkubo T, Okayama A, Okamura T, Ueshima H, NIPPON DATA90 Research Group.

PloS one （PLoS ONE） 17 （ 2 ） e0261716 2022年

研究論文（学術雑誌）, ISSN 1932-6203

Objective This study aimed to investigate the incidence rates and predictors of lower limb fractures in a general Japanese population. Methods NIPPON DATA is a nationwide, long-term, prospective cohort study of individuals who participated in the National Cardiovascular Survey Japan and the National Nutrition Survey in 1990. Overall, 3,134 individuals (1,827 women, 1,307 men) who participated in follow-up assessments in 1995, 2000, and/or 2006 were included in the present analysis. The outcomes of this study were lower limb fractures (including proximal femur fractures). Results The mean age at baseline was 63.8 years in women and 63.1 years in men. The average body mass index (BMI) was 23.3 kg/m2 in women and 22.9 kg/m2 in men. During a mean follow- up of 12.1 years, 271 total lower limb fractures were observed. In women, older age, lower BMI, and less intake of vegetables were associated with increased risks of proximal femur fractures. With regard to the outcome of total lower limb fractures, less intake of vegetables and regular exercise were significant predictors in women. Calcium intake was not significantly associated with proximal femur or total lower limb fractures. There were no significant predictors of proximal femur or total lower limb fractures in men, except for age. Conclusions Aging was a significant risk factor for proximal femur and total lower limb fractures in both men and women. With regard to modifiable risk factors, low BMI and low intake of vegetables were associated with increased risks of proximal femur and/or total lower limb fractures in the general population of Japanese women.

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A Strategy for Further Wellness for All: A Population Approach to Prevent Cardiovascular Diseases in Japan.

Okamura T

Journal of nutritional science and vitaminology （Journal of Nutritional Science and Vitaminology） 68 （ Supplement ） S104 - S106 2022年

ISSN 0301-4800

A population approach may be effective in reducing cardiovascular disease (CVD) in the entire population. In Japan, the first public population approach is Health Japan 21 from 2000 to 2012. In 2013, it was revised as Health Japan 21 (the second term), which was promoting the health of all citizens until 2022. In the final assessment, although a significant decrease in age-adjusted CVD mortality was observed, it is unclear why these findings occurred. An assessment system for a population approach for CVD needs to be developed in Japan.

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Effect of Chronic Kidney Disease or Anemia or Both on Cardiovascular Mortality in a 25-Year Follow-Up Study of Japanese General Population (From NIPPON DATA90)

Kubo K., Okamura T., Sugiyama D., Hisamatsu T., Hirata A., Kadota A., Kondo K., Hirata T., Higashiyama A., Hayakawa T., Miyamoto Y., Okayama A., Miura K., Ueshima H.

American Journal of Cardiology （American Journal of Cardiology） 184 1 - 6 2022年

ISSN 00029149

The relation between chronic kidney disease (CKD) and cardiovascular disease (CVD) in the general population is well elucidated. In patients with CKD, anemia is associated with adverse outcomes. However, the effects of CKD and anemia on CVD in the general population remains poorly explored, especially in Asian populations. This study aimed to investigate the effect of CKD and/or anemia on CVD mortality in a long-term cohort study involving Japanese community dwellers. We assessed 7,339 participants (aged ≥30 years) with no CVD history. These participants were divided into 4 categories according to their CKD (estimated glomerular filtration rate <60 or urine protein >1+ by dipstick qualitative test) and/or anemia (hemoglobin: <13 g/100 ml [men], <12 g/100 ml [women]) statuses. For each category, we calculated the hazard ratios (HRs) of CVD mortality by using the Cox proportional hazards model after adjusting for age, body mass index, hypertension, diabetes, dyslipidemia, smoking, and alcohol drinking. Within 25 years of follow-up, 637 participants died because of CVD. The HRs of CVD in patients with CKD only, anemia only, and both were 1.27, 1.59, and 2.60 (95% confidence intervals [CI] 1.06 to 1.53, 1.34 to 1.90, and 1.80 to 3.76) in men and 1.42, 1.08, and 2.00 (95% CI 1.19 to 1.69, 0.99 to 1.18, and 1.54 to 2.60) in women, respectively. In conclusion, CKD with anemia is associated with an increased risk for CVD mortality in a general population in Japan.

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Lifestyle behaviors associated with the initiation of renal replacement therapy in Japanese patients with chronic kidney disease: a retrospective cohort study using a claims database linked with specific health checkup results

Hara A., Hirata T., Okamura T., Kimura S., Urushihara H.

Environmental Health and Preventive Medicine （Environmental Health and Preventive Medicine） 26 （ 1 ） 102 2021年12月

研究論文（学術雑誌）, ISSN 1342078X

Background: Chronic kidney disease (CKD) is an independent risk factor for progression to an end-stage renal disease requiring dialysis or kidney transplantation. We investigated the association of lifestyle behaviors with the initiation of renal replacement therapy (RRT) among CKD patients using an employment-based health insurance claims database linked with specific health checkup (SHC) data. Methods: This retrospective cohort study included 149,620 CKD patients aged 40–74 years who underwent a SHC between April 2008 and March 2016. CKD patients were identified using ICD-10 diagnostic codes and SHC results. We investigated lifestyle behaviors recorded at SHC. Initiation of RRT was defined by medical procedure claims. Lifestyle behaviors related to the initiation of RRT were identified using a Cox proportional hazards regression model with recency-weighted cumulative exposure as a time-dependent covariate. Results: During 384,042 patient-years of follow-up by the end of March 2016, 295 dialysis and no kidney transplantation cases were identified. Current smoking (hazard ratio: 1.87, 95% confidence interval, 1.04─3.36), skipping breakfast (4.80, 1.98─11.62), and taking sufficient rest along with sleep (2.09, 1.14─3.85) were associated with the initiation of RRT. Conclusions: Among CKD patients, the lifestyle behaviors of smoking, skipping breakfast, and sufficient rest along with sleep were independently associated with the initiation of RRT. Our study strengthens the importance of monitoring lifestyle behaviors to delay the progression of mild CKD to RRT in the Japanese working generation. A substantial portion of subjects had missing data for eGFR and drinking frequency, warranting verification of these results in prospective studies.

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Prediction of Lifetime Risk of Cardiovascular Disease Deaths Stratified by Sex in the Japanese Population.

Imai Y, Mizuno Tanaka S, Satoh M, Hirata T, Murakami Y, Miura K, Waki T, Hirata A, Sairenchi T, Irie F, Sata M, Ninomiya T, Ohkubo T, Ishikawa S, Miyamoto Y, Ohnishi H, Saitoh S, Tamakoshi A, Yamada M, Kiyama M, Iso H, Sakata K, Nakagawa H, Okayama A, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention From Observational Cohorts in Japan (EPOCH‐Japan) Research Group *.

Journal of the American Heart Association （Journal of the American Heart Association） 10 （ 23 ） e021753 2021年11月

研究論文（学術雑誌）

BACKGROUND: Lifetime risk is an informative estimate for driving lifestyle and behavioral changes especially for young adults. The impact of composite risk factors for cardiovascular disease on lifetime risk stratified by sex has not been investigated in the Japanese population, which has a much lower mortality of coronary heart disease compared with the Western population. We aimed to estimate lifetime risk of death from cardiovascular disease attributable to traditional risk factors. METHODS AND RESULTS: We analyzed pooled individual data from the Evidence for Cardiovascular Prevention from Observational Cohorts in a Japanese cohort study. A modified Kaplan– Meier approach was used to estimate the remaining lifetime risk of cardiovascular death. In total, 41 002 Japanese men and women with 537 126 person-years of follow-up were included. The lifetime risk at the index-age of 45 years for those with optimal risk factors (total cholesterol <4.65 mmol/L, systolic blood pressure <120 mm Hg, diastolic blood pressure <80 mm Hg, absence of diabetes, and absence of smoking habit) was lower compared with the highest risk profile of ≥2 risk factors (6.8% [95% CI, 0%–11.9%] versus 19.4% [16.7%– 21.4%] for men and 6.9% [1.2%–11.5%] versus 15.4% [12.6%–18.1%] for women). CONCLUSIONS: The magnitude and the number of risk factors were progressively associated with increased lifetime risk even in individuals in early adulthood who tend to have low short-term risk. The degree of established cardiovascular risk factors can be converted into lifetime risk. Our findings may be useful for risk communication in the early detection of future cardiovascular disease risk.

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Risk Classification for Metabolic Syndrome and the Incidence of Cardiovascular Disease in Japan With Low Prevalence of Obesity: A Pooled Analysis of 10 Prospective Cohort Studies.

Iso H, Cui R, Takamoto I, Kiyama M, Saito I, Okamura T, Miyamoto Y, Higashiyama A, Kiyohara Y, Ninomiya T, Yamada M, Nakagawa H, Sakurai M, Shimabukuro M, Higa M, Shimamoto K, Saito S, Daimon M, Kayama T, Noda M, Ito S, Yokote K, Ito C, Nakao K, Yamauchi T, Kadowaki T

Journal of the American Heart Association （Journal of the American Heart Association） 10 （ 23 ） e020760 2021年11月

研究論文（学術雑誌）

BACKGROUND: It is uncertain whether risk classification under the nationwide program on screening and lifestyle modification for metabolic syndrome captures well high-risk individuals who could benefit from lifestyle interventions. We examined the validity of risk classification by linking the incidence of cardiovascular disease (CVD). CONCLUSIONS: Similar CVD excess and attributable risks among individuals with metabolic syndrome components in the absence and presence of obesity/overweight imply the need for lifestyle modification in both high-risk groups. METHODS AND RESULTS: Individual-level data of 29 288 Japanese individuals aged 40 to 74 years without a history of CVD from 10 prospective cohort studies were used. Metabolic syndrome was defined as the presence of high abdominal obesity and/ or overweight plus risk factors such as high blood pressure, high triglyceride or low high-density lipoprotein cholesterol levels, and high blood glucose levels. The risk categories for lifestyle intervention were information supply only, motivation-support intervention, and intensive support intervention. Sex-and age-specific hazard ratios and population attributable fractions of CVD, which were also further adjusted to consider non– high density lipoprotein cholesterol levels, were estimated with reference to nonobese/overweight individuals, using Cox proportional hazard regression. Since the reference category included those with risk factors, we set a supernormal group (nonobese/overweight with no risk factor) as another reference. We documented 1023 incident CVD cases (565 men and 458 women). The adjusted CVD risk was 60% to 70% higher in men and women aged 40 to 64 years receiving an intensive support intervention, and 30% higher in women aged 65 to 74 years receiving a motivation-support intervention, compared with nonobese/overweight individuals. The population attributable fractions in men and women aged 40 to 64 years receiving an intensive support intervention were 17.7% and 6.6%, respectively, while that in women aged 65 to 74 years receiving a motivation-support intervention was 9.4%. Compared with the supernormal group, nonobese/overweight individuals with risk factors had similar hazard ratios and population attributable fractions as individuals with metabolic syndrome.

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Changes in smoking habits and behaviors following the introduction and spread of heated tobacco products in Japan and its effect on FEV1 decline: a longitudinal cohort study.

Harada S, Sata M, Matsumoto M, Iida M, Takeuchi A, Kato S, Hirata A, Kuwabara K, Shibuki T, Ishibashi Y, Sugiyama D, Okamura T, Takebayashi T

Journal of epidemiology （Journal of epidemiology） 32 （ 4 ） 180 - 187 2021年10月

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: Heated tobacco product (HTP) use in Japan has rapidly increased. Despite this rapid spread, little is known about the health effects of HTP use. We conducted a longitudinal cohort study to investigate the change in smoking habits following the spread of HTP use and its effect on forced expiratory volume in 1 second (FEV1) decline. METHODS: Participants consisted of a resident population (n = 2,612; mean age, 67.7 years) with FEV1 measurement in 2012-2014 and 2018-2019, and a worksite population (n = 722; mean age 49.3 years) without FEV1 data. Participants were categorized as combustible cigarette-only smokers, HTP-only users, dual users, past smokers, and never smokers. The association between smoking group and the change in smoking consumption over a mean 5.6 years was examined. Differences in annual FEV1 change between smoking groups were examined in the resident population. RESULTS: Prevalence of HTP-only and dual users in 2018-2019 was 0.8% and 0.6% in the resident population, and 5.0% and 1.9% in the worksite population, respectively. The overall number of tobacco products smoked/used increased in dual users compared to baseline, but not in others. Annual FEV1 decline in dual users tended to be greater than that in cigarette-only smokers (16; 95% confidence interval, -34 to 2 mL/year after full adjustment). Participants switching to HTP-only use 1.7 years before had a similar FEV1 decline as cigarette-only smokers. CONCLUSIONS: HTP use, including dual use, is prevalent even in a rural region of Japan. Dual users appear to smoke/use tobacco products more and have a greater FEV1 decline. Tobacco policy should consider dual use as high-risk.

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Impact of resting heart rate on cardiovascular mortality according to serum albumin levels in a 24-year follow-up study on a general Japanese population: NIPPON DATA80.

Liu Y, Hirata A, Okamura T, Sugiyama D, Hirata T, Kadota A, Kondo K, Ohkubo T, Miura K, Okayama A, Ueshima H

Journal of epidemiology （Journal of epidemiology） 33 （ 5 ） 227 - 235 2021年09月

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: Elevated resting heart rate (RHR) is associated with an increased risk of cardiovascular disease (CVD) and all-cause mortality. However, the findings of cohort studies differed. Thus, the impact of RHR on CVD mortality might be different according to the background of the population. Therefore, we examined the relationship of RHR and CVD mortality according to serum albumin (ALB) levels in a Japanese general population. METHODS: In total, 8,363 individuals without a history of CVD were followed for 24.0 years. The participants were divided into four groups according to the quartiles of RHR (Q1-Q4), and they were further classified into the high and low ALB groups based on a median value of 44 g/L. We estimated the multivariable-adjusted hazard ratios (HRs) of CVD mortality in each RHR group based on ALB levels, and the interaction between RHR and ALB groups on CVD mortality was evaluated. RESULTS: We found no significant association between RHR and CVD mortality. However, the Q4 of RHR was significantly associated with an increased risk for CVD mortality (HR 1.27; 95% confidence interval [CI], 1.02-1.57) in participants with a low ALB level. Meanwhile, the Q4 of RHR was significantly correlated with a decreased risk for CVD morality in those with a high ALB level (HR 0.61; 95% CI, 0.47-0.79) after adjusting for covariates. A significant interaction between RHR and ALB for CVD mortality was shown (P < 0.001). CONCLUSION: The impact of RHR on CVD mortality differed according to ALB levels in a general Japanese population.

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Serum modified high-density lipoprotein and risk of atherosclerotic cardiovascular disease in a Japanese community-based nested case-control study.

Sata M, Kakino A, Hirata A, Iida M, Usami Y, Harada S, Fujita Y, Kohsaka S, Izawa Y, Sawano M, Oki K, Sugiyama D, Takahashi S, Takebayashi T, Sawamura T, Okamura T

European journal of preventive cardiology 29 （ 5 ） e193 - e195 2021年09月

研究論文（学術雑誌）, ISSN 2047-4873

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Smoking, blood pressure, and body mass index to estimate healthy life expectancy: NIPPON DATA90

Tsukinoki Rumi, Hayakawa Takehito, Kadota Aya, Murakami Yoshitaka, Miura Katsuyuki, Okayama Akira, Okamura Tomonori, Ueshima Hirotsugu

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 50 2021年09月

研究論文（学術雑誌）, ISSN 0300-5771

Relationship of higher-level functional capacity on long-term mortality in Japanese population: NIPPON DATA90

Nagata Hideki, Miura Katsuyuki, Tanaka Sachiko, Kadota Aya, Hayakawa Takehito, Takashima Naoyuki, Kita Yoshikuni, Kondo Keiko, Okayama Akira, Okamura Tomonori, Ueshima Hirotsugu

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 50 2021年09月

研究論文（学術雑誌）, ISSN 0300-5771

Impact of overweight on diabetes prevalence: 20-year trends in National Health and Nutrition Survey, Japan

Sata Mizuki, Sugiyama Daisuke, Hirata Takumi, Horie Saki, Takimoto Hidemi, Okamura Tomonori

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 50 206 - 206 2021年09月

研究論文（学術雑誌）, ISSN 0300-5771

Disease Burden and Universal Health Coverage Monitoring

Okamoto Shohei, Shimmmei Keita, Okamura Tomonori

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 50 2021年09月

研究論文（学術雑誌）, ISSN 0300-5771

Change of smoking habits by introducing and spreading heated tobacco products in Japan

Harada Sei, Sata Mizuki, Matsumoto Minako, Takeuchi Ayano, Iida Miho, Kato Suzuka, Hirata Aya, Kuwabara Kazuyo, Sugiyama Daisuke, Okamura Tomonori, Takebayashi Toru

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 50 93 - 93 2021年09月

研究論文（学術雑誌）, ISSN 0300-5771

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Association between environmental cadmium exposure and plasma and urinary metabolite profiles in Japanese cohort study

Ishibashi Yoshiki, Harada Sei, Eitaki Yoko, Iida Miho, Kurihara Ayako, Hirata Aya, Shibuki Takuma, Okamura Tomonori, Hirayama Akiyoshi, Sugimoto Masahiro, Soga Tomoyoshi, Tomita Masaru, Takebayashi Toru

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY 50 2021年09月

研究論文（学術雑誌）, ISSN 0300-5771

Erratum to "Validity Assessment of Self-reported Medication Use for Hypertension, Diabetes, and Dyslipidemia in a Pharmacoepidemiologic Study by Comparison With Health Insurance Claims" [J Epidemiol (2020) doi:10.2188/jea.JE20200089. Epub ahead of print.].

Matsumoto M, Harada S, Iida M, Kato S, Sata M, Hirata A, Kuwabara K, Takeuchi A, Sugiyama D, Okamura T, Takebayashi T

Journal of epidemiology 31 （ 9 ） 520 - 521 2021年07月

研究論文（学術雑誌）, ISSN 0917-5040

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Relationship of higher-level functional capacity with long-term mortality in Japanese older people: NIPPON DATA90.

Nagata H, Miura K, Tanaka S, Kadota A, Hayakawa T, Kondo K, Fujiyoshi A, Takashima N, Kita Y, Okayama A, Okamura T, Ueshima H

Journal of epidemiology （Journal of Epidemiology） 33 （ 3 ） 136 - 141 2021年07月

研究論文（学術雑誌）, ISSN 0917-5040

Background: Basic and instrumental activities of daily living (BADL and IADL, respectively) are known predictors of mortality. However, the relationship between higher-level functional capacity (HLFC) and mortality and related sex differences have rarely been investigated. Methods: A prospective population-based cohort study was conducted in 1,824 older residents (≥65 years) with independent BADL from 300 randomly selected areas in Japan from 1995, and the participants were followed up until 2010. Using the Cox proportional hazards model, the relationship between HLFC and mortality risk was investigated, with adjustment for possible confounders. HLFC was assessed using the Tokyo Metropolitan Institute of Gerontology Index of Competence. Baseline data were collected using a questionnaire or by home-visit interviews. Results: During an average 12.2-year follow-up, all-cause death was observed in 836 (45.8%) participants. Impaired HLFC was significantly associated with mortality (hazard ratio [HR] 1.37; 95% confidence interval [CI], 1.13–1.65). Lower social role was significantly associated with higher mortality risk in men (HR 1.38; 95% CI, 1.13–1.68). Lower IADL and intellectual activity were significantly associated with higher mortality risk in women (HR 1.50; 95% CI, 1.15–1.95 and HR 1.46; 95% CI, 1.19–1.79, respectively). The relationship between HLFC and mortality risk showed a similar tendency among cardiovascular diseases, stroke, cancer, and pneumonia. Conclusion: Impaired HLFC was associated with a high risk of all-cause mortality among community-dwelling older people with independent BADL. In particular, social role in men and IADL and intellectual activity in women were associated with long-term mortality risk.

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Association between socioeconomic status and physical inactivity in a general Japanese population: NIPPON DATA2010

Sumimoto Y., Yanagita M., Miyamatsu N., Okuda N., Nishi N., Nakamura Y., Nakamura K., Miyagawa N., Miyachi M., Kadota A., Ohkubo T., Okamura T., Ueshima H., Okayama A., Miura K.

PLoS ONE （PLoS ONE） 16 （ 7 July ） e0254706 2021年07月

研究論文（学術雑誌）, ISSN 1932-6203

Background: Lower socioeconomic status (SES) may be related to inactivity lifestyle; however, the association between SES and physical inactivity has not been sufficiently investigated in Japan. Methods: The study population is the participants of NIPPON DATA2010, which is a prospective cohort study of the National Health and Nutrition Survey 2010 in Japan. They were residents in 300 randomly selected areas across Japan. This study included 2,609 adults. Physical activity was assessed by physical activity index (PAI) calculated from activity intensity and time. The lowest tertile of PAI for each 10-year age class and sex was defined as physical inactivity. Multivariable logistic regression analyses were conducted to examine the association of SES (employment status, educational attainment, living status, and equivalent household expenditure (EHE)) with physical inactivity. Results: In the distribution of PAI by age classes and sex, the highest median PAI was aged 30-39 years among men (median 38.6), aged 40-49 years among women (38.0), and median PAI was decreased with increasing age. Multivariable-adjusted model shows that not working was significantly associated with physical inactivity after adjustment for age in all age groups and sexes. Not living with spouse for adult women and elderly men was significantly associated with physical inactivity compared to those who living with spouse. However, neither educational attainment nor EHE had any significant associations with physical inactivity. Conclusions: The result indicated that physical inactivity was associated with SES in a general Japanese population. SES of individuals need to be considered in order to prevent inactivity lifestyle.

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The Risk of Fasting Triglycerides and its Related Indices for Ischemic Cardiovascular Diseases in Japanese Community Dwellers: the Suita Study.

Higashiyama A, Wakabayashi I, Okamura T, Kokubo Y, Watanabe M, Takegami M, Honda-Kohmo K, Okayama A, Miyamoto Y

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 12 ） 1275 - 1288 2021年05月

研究論文（学術雑誌）, ISSN 1340-3478

Aim: A prospective cohort study in a Japanese urban general population was performed to investigate whether triglyceride (TG) and its related indices were associated with the risk for the incidence of ischemic cardiovascular disease (CVD) after the adjustment for low-density lipoprotein cholesterol (LDL-C) in Asian community dwellers. Methods: A 15.1-year prospective cohort study was performed in 6,684 Japanese community dwellers aged 30–79 years without a history of CVD and whose fasting TG levels were ＜400 mg/dL. After adjusting for covariates, including LDL-C, the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the deciles (D) of TG and those of 1-standard deviation (SD) increment of log-transformed TG (1-SD of TG) according to LDL-C level (≥ 140 and ＜140 mg/dL) for ischemic CVD incidence were estimated. The multivariable-adjusted HRs and 95%CIs of the quintiles (Q) of TG, TG/HDL-C, and the cardiometabolic index (CMI) for ischemic CVD were also estimated. Results: In 101,230 person-years, 464 ischemic CVD cases occurred. For D10 of TG, the HR (95%CI) was 1.56 (1.05–2.32), and for 1-SD of TG, it was 1.30 (1.00–1.70) in participants with LDL-C ＜140 mg/dL and 1.07 (0.77–1.50) in those with LDL-C ≥ 140 mg/dL. For Q5 of the CMI, the multivariable-adjusted HR was higher than those of TG and TG/HDL-C. Conclusions: Fasting TG was an independent predictor for ischemic CVD incidence after adjusting for LDL-C in Japanese community dwellers with TG ＜400 mg/dL. Among TG, TG/HDL-C, and the CMI, the CMI could be the most powerful predictor for ischemic CVD.

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Combined Impact Of Chronic Kidney Disease And Hypertension On Lifetime Risk Of Cardiovascular Disease Death: A Pooled Analysis Of Data From The Evidence For Cardiovascular Prevention From Observational Cohorts In Japan Study

Imai Yukiko, Sakurai Masaru, Hideaki Nakagawa, Hirata Aya, Murakami Yoshitaka, Tanaka Sachiko, Kiyohara Yutaka, Ninomiya Toshiharu, Ishikawa Shizukiyo, Saitoh Shigeyuki, Irie Fujiko, Sairenchi Toshimi, Kiyama Masahiko, Miura Katsuyuki, Ueshima Hirotsugu, Okamura Tomonori

CIRCULATION 143 2021年05月

研究論文（学術雑誌）, ISSN 0009-7322

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Relationship of urinary liver-type fatty acid-binding protein with cardiovascular risk factors in the Japanese population without chronic kidney disease: Sasayama study.

Kubota Y, Higashiyama A, Marumo M, Konishi M, Yamashita Y, Okamura T, Miyamoto Y, Wakabayashi I

BMC nephrology （BMC Nephrology） 22 （ 1 ） 189 2021年05月

研究論文（学術雑誌）

Background: Urinary liver-type fatty acid-binding protein (L-FABP) is a well-known marker of proximal tubular impairment. We evaluated the relationship between cardiovascular disease (CVD) risk factors and levels of L-FABP in a cross-sectional community-based study. Participants with normoalbuminuria and normal estimated glomerular filtration rate (eGFR), that is, non-chronic kidney disease (non-CKD), were enrolled in this study. To the best of our knowledge, this is the first study to focus on the association between CVD risk factors and a proximal tubular marker in the Japanese general population with normoalbuminuria and normal eGFR. Methods: The present study is part of the Sasayama study. The participants included 1000 community residents (447 men and 553 women) aged 40–64 years without a history of CVD or renal dysfunction. Out of these participants 375 men and 477 women, defined as non-CKD, were included for further analysis. In each sex, the highest quintile group was considered to have high-normal L-FABP levels. A multiple logistic regression model was used to evaluate the relationship between risk factors for CVD and high-normal L-FABP levels in the non-CKD participants. We performed a similar analysis using the high-normal urinary albumin to creatinine ratio (UACR) as a dependent variable instead of L-FABP. Results: Among the non-CKD participants, in the highest quintile group (Q5, top 20%), L-FABP was ≥2.17 μg/gCre in men and ≥ 2.83 μg/gCre in women. In women, the multivariate odds ratio was 3.62 (1.45–9.00) for high-normal L-FABP in the presence of diabetes mellitus (DM) compared with that in the group without DM. However, the relationship between DM and the UACR level was not significant. In men, DM was significantly associated with high-normal UACR. However, the relationship with L-FABP levels was not significant. Conclusions: The presence of DM was more strongly related to high-normal L-FABP levels than to high-normal UACR in women even at the stage of normoalbuminuria and normal eGFR. Our results were also consistent with the findings of a previous study where women were more prone to nonalbuminuric renal impairment compared to men, although further studies are required to confirm the results.

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Association between socioeconomic status and prolonged television viewing time in a general Japanese population: NIPPON DATA2010.

Sumimoto Y, Yanagita M, Miyamatsu N, Okuda N, Nishi N, Nakamura Y, Nakamura K, Miyagawa N, Miyachi M, Kadota A, Ohkubo T, Okamura T, Ueshima H, Okayama A, Miura K, for NIPPON DATA2010 Research Group.

Environmental health and preventive medicine （Environmental Health and Preventive Medicine） 26 （ 1 ） 57 2021年05月

研究論文（学術雑誌）, ISSN 1342-078X

Background: It has been pointed out that prolonged television (TV) viewing is one of the sedentary behaviors that is harmful to health; however, the association between socioeconomic status (SES) and prolonged TV viewing time has not been sufficiently investigated in Japan. Methods: The study population are the participants of NIPPON DATA2010, which is a prospective cohort study of the National Health and Nutrition Survey 2010 in Japan. They were residents in 300 randomly selected areas across Japan. This study included 2752 adults. SES was classified according to the employment status, educational attainment, living status, and equivalent household expenditure (EHE). Prolonged TV viewing time was defined as more than or equal to 4 h of TV viewing per day. Multivariable logistic regression analyses were conducted to examine the association of SES with prolonged TV viewing time. Results: The mean TV viewing time was 2.92 h in all participants. Of 2752 participants, 809 (29.4%) prolonged TV viewing, and the mean TV viewing time of them was 5.61 h. The mean TV viewing time in participants without prolonged TV viewing time was 1.81 h. The mean TV viewing time was prolonged as age classes increased and significantly longer in aged ≥60 years. Prolonged TV viewing time was associated with not working for all age classes and sexes. Only among women, education attainment and living status were also associated with prolonged TV viewing time. For education attainment, the lower the received years of education, the higher odds ratios (OR) of prolonged TV viewing time. For living status, in women aged <60 years, living with others had a significantly higher OR compared to living with spouse. On the other hand, in women aged ≥60 years, living alone had a significantly higher OR. EHE did not have any significant associations with prolonged TV viewing time. Conclusions: In a general Japanese population, it should be noted that the association between SES and prolonged TV viewing time differed by age and sex. Particularly, it must draw attention to the prolonged TV viewing in elderly. The intervention in order to shorten TV viewing time needs to consider these attributes.

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Comparison of the Japan Society of Clinical Chemistry reference method and CDC method for HDL and LDL cholesterol measurements using fresh sera

Kayamori Y., Nakamura M., Kishi K., Miida T., Nishimura K., Okamura T., Hirayama S., Ohmura H., Yoshida H., Ai M., Tanaka A., Sumino H., Murakami M., Inoue I., Teramoto T., Yokoyama S.

Practical Laboratory Medicine （Practical Laboratory Medicine） 25 e00228 2021年05月

研究論文（学術雑誌）, ISSN 2352-5517

Objectives: In 2009, the Japan Society of Clinical Chemistry (JSCC) recommended a reference method for the measurement of serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. This automated method uses cholesterol esterase-cholesterol dehydrogenase to measure cholesterol levels in fractions obtained after ultracentrifugation and dextran sulfate/magnesium chloride precipitation. In the present study, using fresh samples, we compared the LDL-C and HDL-C levels measured using this method with those measured using the traditional Centers for Disease Control and Prevention (CDC)-beta-quantification (BQ) method. Design: and methods: Using both the JSCC and CDC-BQ methods, LDL-C/HDL-C levels were measured in 47 non-diseased and 126 diseased subjects, whose triglyceride levels were lower than 11.29 mmol/L (1000 mg/dL). Results: For LDL-C, the equation of the line representing the correlation between the two methods was y = 0.991x + 0.009 mmol/L; r = 0.999; and Sy/x = 0.025 mmol/L, where x is the mean LDL-C level measured using the CDC-BQ method. Similarly, for HDL-C, the equation of the line representing the correlation between the two methods was y = 0.988x + 0.041 mmol/L, r = 0.999, and Sy/x = 0.019 mmol/L, where x is the mean HDL-C level measured using the CDC-BQ method. Conclusions: The JSCC method agreed with the CDC-BQ method in cases of both non-diseased and diseased subjects, including those with dyslipidemia.

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EFFECT OF ACCUMULATED UNHEALTHY BEHAVIORS ON INSOMNIA(A)over-cap(SIC).LIFESTYLE-RELATED DISEASE DIFFERENCES IN A JAPANESE COMMUNITY POPULATION

Kato Suzuka, Harada Sei, Iida Miho, Kuwabara Kazuyo, Sugiyama Daisuke, Takeuchi Ayano, Hirata Aya, Sata Mizuki, Matsumoto Minako, Kurihara Ayako, Okamura Tomonori, Takebayashi Toru

SLEEP 44 A128 - A128 2021年05月

研究論文（学術雑誌）, ISSN 0161-8105

Reliability of urinary charged metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry.

Ishibashi Y, Harada S, Takeuchi A, Iida M, Kurihara A, Kato S, Kuwabara K, Hirata A, Shibuki T, Okamura T, Sugiyama D, Sato A, Amano K, Hirayama A, Sugimoto M, Soga T, Tomita M, Takebayashi T

Scientific reports （Scientific Reports） 11 （ 1 ） 7407 2021年04月

研究論文（学術雑誌）, ISSN 2045-2322

Currently, large-scale cohort studies for metabolome analysis have been launched globally. However, only a few studies have evaluated the reliability of urinary metabolome analysis. This study aimed to establish the reliability of urinary metabolomic profiling in cohort studies. In the Tsuruoka Metabolomics Cohort Study, 123 charged metabolites were identified and routinely quantified using capillary electrophoresis-mass spectrometry (CE-MS). We evaluated approximately 750 quality control (QC) samples and 6,720 participants’ spot urine samples. We calculated inter- and intra-batch coefficients of variation in the QC and participant samples and technical intraclass correlation coefficients (ICC). A correlation of metabolite concentrations between spot and 24-h urine samples obtained from 32 sub-cohort participants was also evaluated. The coefficient of variation (CV) was less than 20% for 87 metabolites (70.7%) and 20–30% for 19 metabolites (15.4%) in the QC samples. There was less than 20% inter-batch CV for 106 metabolites (86.2%). Most urinary metabolites would have reliability for measurement. The 96 metabolites (78.0%) was above 0.75 for the estimated ICC, and those might be useful for epidemiological analysis. Among individuals, the Pearson correlation coefficient of 24-h and spot urine was more than 70% for 59 of the 99 metabolites. These results show that the profiling of charged metabolites using CE-MS in morning spot human urine is suitable for epidemiological metabolomics studies.

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A Novel Risk Stratification System for Ischemic Stroke in Japanese Patients With Non-Valvular Atrial Fibrillation.

Okumura K, Tomita H, Nakai M, Kodani E, Akao M, Suzuki S, Hayashi K, Sawano M, Goya M, Yamashita T, Fukuda K, Ogawa H, Tsuda T, Isobe M, Toyoda K, Miyamoto Y, Miyata H, Okamura T, Sasahara Y, J-RISK AF Research Group.

Circulation journal : official journal of the Japanese Circulation Society （Circulation Journal） 85 （ 8 ） 1254 - + 2021年03月

研究論文（学術雑誌）, ISSN 1346-9843

Background: Recently, identification of independent risk factors for ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients was made by analyzing the 5 major Japanese registries: J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and the Hokuriku-Plus AF Registry. Methods and Results: The predictive value of the risk scheme in Japanese NVAF patients was assessed. Of 16,918 patients, 12,289 NVAF patients were analyzed (mean follow up, 649±181 days). Hazard ratios (HRs) of each significant, independent risk factor were determined by using adjusted Cox-hazard proportional analysis. Scoring system for ischemic stroke was created by transforming HR logarithmically and was estimated by c-statistic. During the 21,820 person-years follow up, 241 ischemic stroke events occurred. Significant risk factors were: being elderly (aged 75-84 years [E], HR=1.74), extreme elderly (≥85 years [EE], HR=2.41), having hypertension (H, HR=1.60), previous stroke (S, HR=2.75), type of AF (persistent/permanent) (T, HR=1.59), and low body mass index <18.5 kg/m2(L, HR=1.55) after adjusting for oral anticoagulant treatment. The score was assigned as follows: 1 point to H, E, L, and T, and 2 points to EE and S (HELT-E2S2score). The C-statistic, using this score, was 0.681 (95% confidence interval [CI]=0.647-0.714), which was significantly higher than those using CHADS2(0.647; 95% CI=0.614-0.681, P=0.027 for comparison) and CHA2DS2-VASc scores (0.641; 95% CI=0.608-0.673, P=0.008).

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Association of the Estimated Coronary Artery Incidence Risk According to the Japan Atherosclerosis Society Guidelines 2017 with Cardio-Ankle Vascular Index.

Sata M, Okamura T, Harada S, Sugiyama D, Kuwabara K, Hirata A, Takeuchi A, Iida M, Kato S, Matsumoto M, Kurihara A, Takebayashi T

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 12 ） 1266 - 1274 2021年03月

研究論文（学術雑誌）, ISSN 1340-3478

Aims: The categories in the comprehensive lipid and risk management guidelines were proposed by the Japan Atherosclerosis Society (JAS Guidelines 2017), which adopted the estimated 10 year absolute risk of coronary artery disease (CAD) incidence in the Suita score. We examined whether those categories were concordant with the degree of arterial stiffness. Methods: In 2014, the cardio-ankle vascular index (CAVI), an arterial stiffness parameter, was measured in 1,972 Japanese participants aged 35–74 years in Tsuruoka City, Yamagata Prefecture, Japan. We examined the mean CAVI and the proportion and odds ratios (ORs) of CAVI ≥ 9.0 on the basis of the following three management classifications using the analysis of variance and logistic regression: “Category I (Low risk),” “Category II (Middle risk),” and “Category III (High risk).” Results: The mean CAVI and proportion of CAVI ≥ 9.0 were 8.6 and 34.8% among males and 8.1 and 18.3% among females, respectively. The mean CAVI and proportion of CAVI ≥ 9.0 were associated with an estimated 10 year absolute risk for CAD among males and females, excluding High risk for females. These results were similar to the management classification by the guideline: the multivariable-adjusted ORs (95% confidence intervals) of CAVI ≥ 9.0 among Category II and Category III compared with those among Category I were 2.96 (1.61–5.43) and 7.33 (4.03–13.3) for males and 3.99 (2.55–6.24) and 3.34 (2.16–5.16) for females, respectively. Conclusions: The risk stratification, which was proposed in the JAS Guidelines 2017, is concordant with the arterial stiffness parameter.

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Alcohol drinking and brain morphometry in apparently healthy community-dwelling Japanese men

Syaifullah A.H., Shiino A., Fujiyoshi A., Kadota A., Kondo K., Ito T., Segawa H., Moniruzzaman M., Waki T., Miyagawa N., Tooyama I., Ueshima H., Miura K., Horie M., Nakagawa Y., Yamamoto T., Nakano Y., Ogawa E., Maegawa H., Morino K., Miyazawa I., Watanabe Y., Nozaki K., Andoh A., Tsuru T., Ogita H., Miyamatsu N., Nakamura Y., Torii S., Kadowaki T., Kadowaki S., Suzuki S., Kunimura A., Higashiyama A., Okamura T., Azuma K., Sawamura T., Igase M., Tabara Y., Sekikawa A., Barinas-Mitchell E.J.M., Edmundowicz D., Ohkubo T., Hozawa A., Murakami Y., Okuda N., Arima H., Satoh A., Kita Y., Hisamatsu T., Yanagita M., Abbott R.D., Ohno S., Takashima N., Zaid M., Saito Y.

Alcohol （Alcohol） 90 57 - 65 2021年02月

研究論文（学術雑誌）, ISSN 07418329

© 2020 Elsevier Inc. The clinical implications of alcohol consumption have been extensively examined; however, its effects on brain structures in apparently healthy community-dwellers remain unclear. Therefore, we investigated the relationship between alcohol consumption and brain gray matter volume (GMV) in community-dwelling Japanese men using voxel-based morphometry (VBM). We recruited cognitively intact Japanese men, aged 40–79 years, from a population-based cohort in Shiga, Japan. Brain magnetic resonance imaging was performed, on average, 2 years after demographic and medical information was obtained in 2010–2014. A multivariable linear regression analysis of 639 men was conducted to elucidate the relationship between the amount of alcohol consumed and GMV. VBM statistics were analyzed by threshold-free cluster enhancement with a family-wise error rate of <0.05. The results obtained demonstrated that the amount of alcohol consumed was associated with lower GMV. The VBM analysis showed lower GMV within the parahippocampal, entorhinal, cingulate, insular, temporal, and frontal cortices and cerebellum in very heavy drinkers (≥42 ethanol g/day) than in non-drinkers. Furthermore, alcohol consumption was associated with a higher white matter lesion volume. These results suggest subclinical structural changes similar to alcohol-related neurological diseases.

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Relationship between non-fasting triglycerides and cardiovascular disease mortality in a 20-year follow-up study of a Japanese general population: NIPPON DATA90.

Hirata A, Okamura T, Hirata T, Sugiyama D, Ohkubo T, Okuda N, Kita Y, Hayakawa T, Kadota A, Kondo K, Miura K, Okayama A, Ueshima H

Journal of epidemiology （Journal of Epidemiology） 32 （ 7 ） 303 - 313 2021年01月

研究論文（学術雑誌）, ISSN 0917-5040

Background: Non-fasting triglycerides (TG) are considered a better predictor of cardiovascular disease (CVD) than fasting TG. However, the effect of non-fasting TG on fatal CVD events remains unclear. In the present study, we aimed to explore the relationship between non-fasting TG and CVD mortality in a Japanese general population. Methods: A total of 6,831 participants without a history of CVD, in which those who had a blood sampling over 8 hours or more after a meal were excluded, were followed for 18.0 years. We divided participants into seven groups according to non-fasting TG levels: ≤59 mg=dL, 60–89 mg=dL, 90–119 mg=dL, 120–149 mg=dL, 150–179 mg=dL, 180–209 mg=dL, and ≥210 mg=dL, and estimated the multivariable-adjusted hazard ratios (HRs) of each TG group for CVD mortality after adjusting for potential confounders, including high density lipoprotein cholesterol. Additionally, we performed analysis stratified by age <65 and ≥65 years. Results: During the follow-up period, 433 deaths due to CVD were detected. Compared with a non-fasting TG of 150–179 mg=dL, non-fasting TG ≥210 mg=dL was significantly associated with increased risk for CVD mortality (HR 1.56: 95% CI, 1.01–2.41). Additionally, lower levels of non-fasting TG were also significantly associated with increased risk for fatal CVD. In participants aged ≥65 years, lower levels of non-fasting TG had a stronger impact on increased risk for CVD mortality, while higher levels of non-fasting TG had a stronger impact in those aged <65 years. Conclusion: In a general Japanese population, we observed a U-shaped association between non-fasting TG and fatal CVD events.

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Tracking Pattern of Total Cholesterol Levels from Childhood to Adolescence in Japan.

Osawa E, Asakura K, Okamura T, Suzuki K, Fujiwara T, Maejima F, Nishiwaki Y

Journal of atherosclerosis and thrombosis （Journal of atherosclerosis and thrombosis） 29 （ 1 ） 38 - 49 2021年01月

研究論文（学術雑誌）, ISSN 1340-3478

AIMS: This study aimed to evaluate the tracking pattern of serum total cholesterol (TC) levels among Japanese children using data collected continuously for 9 years and examine the relationship between childhood and adulthood TC levels. METHODS: TC levels of 2,608 first grade primary school children enrolled during 1981-2014 from two Japanese towns were measured during annual health check-ups. Nine-year trajectories of estimated TC levels stratified by TC quartiles in the first grade were analyzed using a mixed effects model. Adulthood TC levels were measured in participants who underwent health check-ups in the same area. RESULTS: Overall, 1,322 boys and 1,286 girls in the first grade of a primary school were followed for 9 years. Trajectories of TC levels during the period stratified by TC quartiles in the first grade differed significantly and did not cross each other for both sexes. Childhood data of 242 adult participants were linked with their adulthood data; the mean of age was late 20s for both sexes. The average TC levels in adulthood increased from the first to the fourth quartile in the first grade. Additionally, trajectories of TC levels differed between boys and girls. The later the admission year, the more elevated the TC levels in girls. CONCLUSION: Among Japanese children, TC levels were strongly tracked from childhood to adolescence for 9 years, and elevated TC levels in childhood were related to elevated TC levels in adulthood. Maintaining appropriate TC levels during childhood may be important to prevent future coronary artery diseases.

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Validity of a selective recall method for assessing water intake and its relationship with hydration status

Uchida T., Nakamura Y., Tanaka H., Nakamura S., Okamura T., Watanabe H., Murayam N.

EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES （European Review for Medical and Pharmacological Sciences） 25 （ 21 ） 6623 - 6632 2021年

ISSN 1128-3602

OBJECTIVE: We previously established a descriptive dietary record method that accurately quantifies habitual water intake from food and beverages, to ascertain the relationship between water intake and health. Here, we verified the validity of a selective recall method, which is easy for users to answer and analyze. PATIENTS AND METHODS: Japanese men and women aged 20-44 years (n = 16) and 45-64 years (n = 16) participated over three working days and one non-working day. The day following each of the surveyed days, participants collected their first morning urine for urinalysis and completed a selective recall and descriptive dietary record questionnaire. RESULTS: The two methods of determining water intake were positively correlated (r = 0.94, p < 0.0001). Water intake volumes from non-alcoholic beverages (r = 0.94, p < 0.0001), alcoholic beverages (r = 1.00, p < 0.0001), and food (r = 0.72, p < 0.0001), calculated using the two methods, exhibited strong correlation. No correlation was observed between urinalysis parameters and total water intake. A significant, negative correlation was observed between urine osmolarity and total water intake in men (r = -0.55, p = 0.0011) and women (r = -0.51, p = 0.0032) aged 20-44 years. CONCLUSIONS: Selective recall is a valid method for assessing water intake from food and beverages.

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Development of a Cardiovascular Disease Risk Prediction Model Using the Suita Study, a Population-Based Prospective Cohort Study in Japan (vol 27, pg 1160, 2020)

Nakai Michikazu, Watanabe Makoto, Kokubo Yoshihiro, Nishimura Kunihiro, Higashiyama Aya, Takegami Misa, Nakao Yoko M., Okamura Tomonori, Miyamoto Yoshihiro

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 28 （ 3 ） 304 - 304 2021年

研究論文（学術雑誌）, ISSN 1340-3478

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Prevalence, Characteristics, and Impact of Frailty in Patients with Functional Tricuspid Regurgitation.

Saji M, Yoshikawa T, Takayama M, Izumi Y, Takamisawa I, Okamura T, Shimizu H, Lim DS, Latib A, Isobe M, Fukuda K

International heart journal （International Heart Journal） 62 （ 6 ） 1280 - 1286 2021年

研究論文（学術雑誌）, ISSN 1349-2365

Little is known as regards frailty in patients with functional tricuspid regurgitation (FTR). Thus, in this study, we aimed to investigate the prevalence, characteristics, and impact of frailty on patients with severe FTR. This prospective study included 110 consecutive patients with severe FTR who were assessed via transtho-racic echocardiography at an outpatient clinic. Patients were dichotomized using short physical performance bat-tery (SPPB). To better understand the whole picture of frailty in patients with FTR, other frailty scales were also assessed (frailty checklist, clinical frailty scale, gait speed, and Columbia frailty scale). The primary end-point was the combination of all-cause mortality and heart failure hospitalization. According to each definition of frailty, 28%-46% were identified to be frail. Those with SPPB score of < 9 were older, had greater New York Heart Association (NYHA) functional classification, and had lower albumin level and estimated glomerular filtration rate compared with those with SPPB score of ≥9. They also have smaller tricuspid valve coaptation depth and worse right ventricular fractional area change (RV-FAC) than those with SPPB score of ≥9 despite having similar TR severity. The primary endpoint at 1 year was noted in 31% of patients. The SPPB score has excellent discriminatory performance for predicting the primary endpoint (area under the curve 0.82, 95% confidence interval [CI] 0.76-0.91) in receiver operating characteristic analysis and was independently associated with the primary endpoint after adjustment in multivariate analysis (adjusted haz-ard ratio 0.81, 95% CI, 0.73-0.90; P < 0.001). Frailty has been widely prevalent in the elderly patient population with FTR; in fact, it has been deter-mined to be strong parameter for poor outcomes.

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Validity Assessment of Self-reported Medication Use for Hypertension, Diabetes, and Dyslipidemia in a Pharmacoepidemiologic Study by Comparison With Health Insurance Claims.

Matsumoto M, Harada S, Iida M, Kato S, Sata M, Hirata A, Kuwabara K, Takeuchi A, Sugiyama D, Okamura T, Takebayashi T

Journal of epidemiology （Journal of Epidemiology） 31 （ 9 ） 495 - 502 2020年12月

研究論文（学術雑誌）, ISSN 0917-5040

Background: Although self-reported questionnaires are widely employed in epidemiologic studies, their validity has not been sufficiently assessed. The aim of this study was to evaluate the validity of a self-reported questionnaire on medication use by comparison with health insurance claims and to identify individual determinants of discordance in the Tsuruoka Metabolomics Cohort Study. Methods: Participants were 2,472 community-dwellers aged 37 to 78 years from the Tsuruoka Metabolomics Cohort Study. Information on lifestyle and medications was collected through a questionnaire. Sensitivity and specificity were determined using health insurance claims from November 2014 to March 2016, which were used as a standard. Potential determinants of discordance were assessed using multivariable logistic regression. Results: The self-reported questionnaire on medication use showed high validity. Sensitivity and specificity were 0.95 (95% CI, 0.93–0.96) and 0.97 (95% CI, 0.96–0.98) for antihypertensive medications, 0.94 (95% CI, 0.91–0.97) and 0.98 (95% CI, 0.98–0.99) for diabetes medications, and 0.84 (95% CI, 0.82–0.87) and 0.98 (95% CI, 0.97–0.99) for dyslipidemia medications, respectively. Males without high education and those who currently smoke cigarettes were found to be associated with discordant reporting which affected sensitivity, especially those with medication use for dyslipidemia. Conclusions: In this population-based cohort study, we found that the self-reported questionnaire on medication use was a valid measure to capture regular medication users. Sensitivity for dyslipidemia medications was lower than those for the other medications. Type of medication, sex, education years, and smoking status influenced discordance, which affected sensitivity in self-reporting.

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Risk Factors That Most Accurately Predict Coronary Artery Disease Based on the Duration of Follow-up　- NIPPON DATA80.

Okami Y, Ueshima H, Nakamura Y, Kondo K, Kadota A, Okuda N, Ohkubo T, Miyamatsu N, Okamura T, Miura K, Okayama A, NIPPON DATA80 Research Group.

Circulation journal : official journal of the Japanese Circulation Society （Circulation journal : official journal of the Japanese Circulation Society） 85 （ 6 ） 908 - 913 2020年12月

研究論文（学術雑誌）, ISSN 1346-9843

BACKGROUND: This study assessed sex-specific time-associated changes in the impact of risk factors on coronary artery disease (CAD) mortality in a general population over long-term follow-up.Methods and Results:A prospective longitudinal cohort study was conducted on representative Japanese populations followed up for 29 years. Data from 8,396 participants (3,745 men, 4,651 women) were analyzed. The sex-specific multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of 4 risk factors (smoking, diabetes, serum total cholesterol [TC], and systolic blood pressure [SBP]) for CAD mortality were calculated at baseline and at 10, 15, 20, 25, and 29 years of follow-up. In men, smoking (HR 3.23; 95% CI 1.16-9.02) and a 1-SD increase in TC (HR 1.82; 95% CI 1.29-2.57) were strongly associated with a higher risk of CAD in the first 10 years, but this association decreased over time. Diabetes (HR 2.30; 95% CI 1.37-3.85) and a 1-SD increase in SBP (HR 1.23; 95% CI 1.00-1.50) were strongly correlated with a higher risk of CAD after 29 years). In women, diabetes was correlated with CAD after 20 years (HR 2.53; 95% CI 1.19-5.36) and this correlation persisted until after 29 years (HR 2.47; 95% CI 1.40-4.35). CONCLUSIONS: The duration of follow-up needed for the accurate assessment of risk factors for CAD mortality varies according to risk factor and sex.

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Physique at Birth and Cardiovascular Disease Risk Factors in Japanese Urban Residents: the KOBE Study.

Umemoto K, Kubo S, Nishida Y, Higashiyama A, Kawamura K, Kubota Y, Hirata T, Hirata A, Sata M, Kuwabara K, Miyazaki J, Kadota A, Iida M, Sugiyama D, Miyamatsu N, Miyamoto Y, Okamura T

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 29 （ 2 ） 188 - 199 2020年12月

研究論文（学術雑誌）, ISSN 1340-3478

Aim: This study investigated the relationship between birth physique and cardiovascular risk factors in Japanese urban residents aged 40 years and more. Methods: A self-administered questionnaire on birth physique was performed among 624 individuals (165 men and 459 women) who participated in the KOBE study. We examined whether self-reported birth physique and available recorded birth weights matched for 72 participants. Then the association between birth physique and risk factors for all participants was examined by gender. Body size at birth in the questionnaire (large, medium, small) was set as an exposure and laboratory values from the baseline survey (2010-2011) were used as outcomes. Results: Mean (standard deviation) recorded birth weight of 72 participants was 3665 (318), 3051 (300), and 2653 (199) g, in the large, medium, and small group, respectively. In the analysis for all participants, odds ratio for having both hypertension and impaired glucose tolerance were significantly higher in the small versus large birth weight group, which was 7.42 (95% CI 1.75–31.50) for men and 4.44 (95% CI 1.14–17.30) for women after adjusting for age, body mass index, smoking/alcohol/exercise habits, and menstrual status in women. Similar results were observed in participants with recorded birth weight. Conclusions: The present study indicates that individuals with small physique at birth might be at higher risk for hypertension and impaired glucose tolerance in middle age compared to those with large birth weight.

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Association of Red Meat Intake with the Risk of Cardiovascular Mortality in General Japanese Stratified by Kidney Function: NIPPON DATA80.

Segawa H, Kondo K, Kadota A, Yamauchi H, Ohno S, Tanaka-Mizuno S, Okuda N, Miyagawa N, Arima H, Okamura T, Miura K, Okayama A, Ueshima H, The Nippon Data Research Group

Nutrients （Nutrients） 12 （ 12 ） 1 - 10 2020年11月

研究論文（学術雑誌）

The consumption of red meat has been recommended for individuals with reduced kidney function. However, red meat intake was recently suspected to increase cardiovascular disease (CVD) risk. We evaluated the association of red meat intake with CVD mortality risk in Japanese with/without reduced kidney function. Overall, 9112 participants of a Japanese national survey in 1980, aged ≥30 years, were followed for 29 years. Red meat intake was assessed using weighed dietary record. Cox proportional hazards models were used to estimate the hazard ratio (HR) of CVD mortality according to sex-specific tertiles of red meat intake. We also performed stratified analyses with/without reduced kidney function defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m . Red meat intake was not associated with CVD mortality risk in men and women. In stratified analyses, the HR of the highest compared with the lowest tertile of red meat intake was lower only in women with reduced kidney function (0.67, 95% confidence interval 0.46–0.98). In conclusion, there were no clear associations between red meat intake and CVD mortality risk in Japanese population; however, a higher intake of red meat was associated with lower risk of future CVD mortality in women with reduced kidney function. 2

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Exercise Habits Are Associated with Improved Long-Term Mortality Risks in the Nationwide General Japanese Population: A 20-Year Follow-Up of the NIPPON DATA90 Study.

Takatsuji Y, Ishiguro A, Asayama K, Ohkubo T, Miura K, Kadota A, Yanagita M, Fujiyoshi A, Arima H, Miyagawa N, Takashima N, Kita Y, Hayakawa T, Kikuya M, Nakamura Y, Okayama A, Okamura T, Ueshima H, NIPPON DATA90 Research Group.

The Tohoku journal of experimental medicine （The Tohoku journal of experimental medicine） 252 （ 3 ） 253 - 262 2020年11月

研究論文（学術雑誌）, ISSN 0040-8727

Exercise habits are known as a protective factor for a variety of diseases and thus recommended worldwide; however, few studies have examined long-term effects of exercise habits on mortality. We continuously monitored death status in a nationwide population sample of 7,709 eligible persons from the National Integrated Project for Prospective Observation of Noncommunicable Disease and its Trends in the Aged in 1990 (NIPPON DATA90), for which baseline data were obtained in 1990. To investigate the long-term impact of baseline exercise habits, we calculated the relative risk of non-exercisers (participants without regular voluntary exercise habits) in reference to exercisers (those with these habits) for all-cause or cause-specific mortality using a Cox proportional hazard model, in which the following confounding factors were appropriately adjusted: sex, age, body mass index, total energy intake, smoking, drinking, and history of cardiovascular disease. During a median 20 years of follow-up, 1,747 participants died, 99 of heart failure. The risk for all-cause mortality was 12% higher in non-exercisers than in exercisers (95% confidence interval, 1%-24%), which was also observed for mortality from heart failure, as 68% higher in non-exercisers than in exercises (95% confidence interval, 3%-173%). These associations were similarly observed when the participants were divided to subgroups by sex, age, and the light, moderate, or vigorous intensity of physical activity, without any significant heterogeneities (P > 0.1). The present study has revealed significant impact of exercise habits on long-term mortality risks, supporting worldwide recommendations for improvement of exercise habits.

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Estimation of 10-Year Risk of Death from Coronary Heart Disease, Stroke, and Cardiovascular Disease in a Pooled Analysis of Japanese Cohorts: EPOCH-JAPAN.

Li Y, Yatsuya H, Tanaka S, Iso H, Okayama A, Tsuji I, Sakata K, Miyamoto Y, Ueshima H, Miura K, Murakami Y, Okamura T, EPOCH-JAPAN Research Group.

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 8 ） 816 - 825 2020年10月

研究論文（学術雑誌）, ISSN 1340-3478

Aims: We aimed to develop and validate risk prediction models to estimate the absolute 10-year risk of death from coronary heart disease (CHD), stroke, and cardiovascular disease (CVD). Methods: We evaluated a total of 44,869 individuals aged 40-79 years from eight Japanese prospective cohorts to derive coefficients of risk equations using cohort-stratified Cox proportional hazard regression models. Discrimination (C-index) of the equation was examined in each cohort and summarised using random-effect metaanalyses. Calibration of the equation was assessed using Hosmer-Lemeshow chi-squared statistic. Results: Within a median follow-up of 12.7 years, we observed 765 deaths due to CVD (276 CHDs and 489 strokes). After backward selection, age, sex, current smoking, systolic blood pressure (SBP), proteinuria, prevalent diabetes mellitus, the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDLC), interaction terms of age by SBP, and age by current smoking were retained as predictors for CHD. Sex was excluded in the stroke equation. We did not consider TC/HDLC as a risk factor for the stroke and CVD equations. The pooled C-indices for CHD, stroke, and CVD were 0.83, 0.80, and 0.81, respectively, and the corresponding p-values of the Hosmer-Lemeshow tests were 0.18, 0.003, and 0.25, respectively. Conclusions: Risk equations in the present study can adequately estimate the absolute 10-year risk of death from CHD, stroke, and CVD. Future work will evaluate the system as an education and risk communication tool for primary prevention of CHD and stroke.

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The relationship between serum levels of LOX-1 ligand containing ApoAI as a novel marker of dysfunctional HDL and coronary artery calcification in middle-aged Japanese men.

Hirata A, Kakino A, Okamura T, Usami Y, Fujita Y, Kadota A, Fujiyoshi A, Hisamatsu T, Kondo K, Segawa H, Sawamura T, Miura K, Ueshima H, SESSA Research Group.

Atherosclerosis （Atherosclerosis） 313 20 - 25 2020年09月

研究論文（学術雑誌）, ISSN 0021-9150

© 2020 Elsevier B.V. Background and aims: Dysfunctional high-density lipoprotein (HDL) is a risk factor for cardiovascular disease (CVD) beyond HDL concentrations. Recently, a novel method has been introduced to measure LOX-1 ligand containing apolipoprotein AI (LAA), which is an indicator of various types of modified HDL with binding capacity to LOX-1 and related to impaired anti-atherogenic functions of HDL. This study aimed to examine the relationship between LAA as a novel marker of dysfunctional HDL and coronary artery calcification (CAC). Methods: We selected 910 community-dwelling Japanese men aged 40–79 years without a history of CVD. The odds ratios per 1SD of LAA for the presence of CAC (Agatston score >10) were estimated using logistic regression model adjusted for confounders, including HDL-C or HDL particle (HDL-P) concentration. In addition, we performed further analysis stratified by age (<65 and ≥ 65 years). Results: The mean age of the participants was 63.6 years, and the median LAA was 187.0 ng/mL. The prevalent CAC was 46.2%. The multivariable adjusted odds ratio (95% confidence interval) per 1SD of LAA for CAC was 1.14 (0.96–1.36) for all participants. After stratification by age, multivariable adjusted odds ratios per 1SD of LAA were 1.34 (1.02–1.76) and 0.97 (0.77–1.23) in men aged <65 and ≥ 65 years, respectively. Conclusions: The present study showed that LAA was associated with CAC independent of HDL-C or HDL-P in middle-aged Japanese men. This finding suggests that LAA might be an early marker for CVD events. Future longitudinal studies are warranted.

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Differences between home blood pressure and strictly measured office blood pressure and their determinants in Japanese men.

Kadowaki S, Kadowaki T, Hozawa A, Fujiyoshi A, Hisamatsu T, Satoh A, Arima H, Tanaka S, Torii S, Kondo K, Kadota A, Masaki K, Okamura T, Ohkubo T, Miura K, Ueshima H, SESSA Research Group.

Hypertension research : official journal of the Japanese Society of Hypertension （Hypertension Research） 44 （ 1 ） 80 - 87 2020年08月

研究論文（学術雑誌）, ISSN 0916-9636

© 2020, The Japanese Society of Hypertension. Conventional office blood pressure (OBP) and home blood pressure (HBP) measurements are often inconsistent. The purpose of this research was (1) to test whether strictly measured OBP values with sufficient rest time before measurement (st-OBP) is comparable to HBP at the population level and (2) to ascertain whether there are particular determinants for the difference between HBP and st-OBP at the individual level. Data from a population-based group of 1056 men aged 40–79 years were analyzed. After a five-min rest, st-OBP was measured twice. HBP was measured after a 2-min rest every morning for seven consecutive days. To determine factors related to ΔSBP (HBP minus st-OBP measurements), multiple linear regression analyses and analyses of covariance were performed. While st-OBP and HBP were comparable (136.5 vs. 137.2 mmHg) at the population level, ΔSBP varied with a standard deviation of 13.5 mmHg. Smoking was associated with a larger ΔSBP regardless of antihypertensive usage, and BMI was associated with a larger ΔSBP in participants using antihypertensive drugs. The adjusted mean ΔSBP in the highest BMI tertile category was 4.6 mmHg in participants taking antihypertensive drugs. st-OBP and HBP measurements were comparable at the population level, although the distribution of ΔSBP was considerably broad. Smokers and obese men taking antihypertensive drugs had higher HBP than st-OBP, indicating that their blood pressure levels are at risk of being underestimated. Therefore, this group would benefit from the addition of HBP measurements.

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Guidelines on the Clinical Evaluation of Medicinal Products for Treatment of Dyslipidemia.

Yamashita S, Masuda D, Akishita M, Arai H, Asada Y, Dobashi K, Egashira K, Harada-Shiba M, Hirata K, Ishibashi S, Kajinami K, Kinoshita M, Kozaki K, Kuzuya M, Ogura M, Okamura T, Sato K, Shimano H, Tsukamoto K, Yokode M, Yokote K, Yoshida M

Journal of atherosclerosis and thrombosis 27 （ 11 ） 1246 - 1254 2020年08月

研究論文（学術雑誌）, ISSN 1340-3478

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Estimated 24 h urinary sodium-to-potassium ratio is related to renal function decline: A 6-year cohort study of japanese urban residents

Hattori H., Hirata A., Kubo S., Nishida Y., Nozawa M., Kawamura K., Hirata T., Kubota Y., Sata M., Kuwabara K., Higashiyama A., Kadota A., Sugiyama D., Miyamatsu N., Miyamoto Y., Okamura T.

International Journal of Environmental Research and Public Health （International Journal of Environmental Research and Public Health） 17 （ 16 ） 1 - 12 2020年08月

研究論文（学術雑誌）, ISSN 16617827

© MDPI AG. All rights reserved. The effect of the sodium-to-potassium ratio (Na/K) on renal function within the clinically normal range of renal function are limited. We investigated the effects of an estimated 24 h urinary Na/K (e24hUNa/K) on a 6-year renal function decline among 927 urban Japanese community dwellers with no history of cardiovascular diseases and medication for hypertension, diabetes, or dyslipidemia. We partitioned the subjects into quartiles according to the e24hUNa/K. The estimated glomerular filtration rate (eGFR) was calculated using the chronic kidney disease epidemiology collaboration (CKD/EPI) formula and renal function decline was defined as an absolute value at or above the third quartile of the eGFR decline rate. A multivariable logistic regression model was used for estimation. Compared with the first quartile of the e24hUNa/K, multivariable-adjusted odds ratios (ORs) for eGFR decline in the second, third, and fourth quartiles were 0.96 (95% confidence interval: 0.61–1.51), 1.06 (0.67–1.66), and 1.65 (1.06–2.57), respectively. These results were similar when the simple spot urine Na/K ratio was used in place of the e24hUNa/K. Apparently healthy urban residents with an almost within normal range mean baseline eGFR and high e24hUNa/K ratios had an increased risk for a future decline in renal function. Reducing the Na/K ratio may be important in the prevention of chronic kidney disease in its early stage.

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Long-Term Exposure to Particulate Matter and Mortality from Cardiovascular Diseases in Japan: The Ibaraki Prefectural Health Study (IPHS).

Takeuchi A, Nishiwaki Y, Okamura T, Milojevic A, Ueda K, Asakura K, Takebayashi T, Hasegawa S, Sairenchi T, Irie F, Ota H, Nitta H

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 3 ） 230 - 240 2020年07月

研究論文（学術雑誌）, ISSN 1340-3478

© 2021, Japan Atherosclerosis Society. All rights reserved. Aim: To examine the association between long-term exposure to suspended particulate matter (SPM) and cardiovascular mortality in Japan after controlling for known major confounding factors among a large middle and elderly cohort study in Ibaraki Prefecture, Japan. Methods: We followed 91,808 residents (men 34%) who undertook a national health check-up at age 40–79 years for 17 years (1993–2010). Two different exposure indices were adopted: baseline SPM concentration (in the year 1990) and average SPM concentration for the first (average of 1990 and 1995) and the second half (average of 2005 to 2009) of the study period. Sex-specific adjusted risk ratios (RRs) for cardiovascular mortality were calculated using general mixed Poisson regression models after adjusting the age, BMI, history of diabetes mellitus and hypertension, creatinine, glutamic pyruvic transaminase, total cholesterol, high-density lipoprotein cholesterol, smoking, alcohol, and temperature. The variation between seven medical administration areas was also taken into account as a random effect. Results: Baseline SPM concentration was associated with an increased risk of mortality from all cardiovascular diseases, coronary artery disease, and stroke. The adjusted RRs (95% confidence interval [CI]) per 10 µg/m3 increase in SPM concentration for all cardiovascular mortality were 1.147 (1.014–1.300) for men and 1.097 (0.985–1.222) for women. The point estimate of RR was highest for non-hemorrhagic stroke in men (1.248 [0.991–1.571]), although CI overlapped the unity. The RRs seemed slightly lower in the second half than in the first half, though the CIs widened in the second half. Conclusion: Our results suggest that long-term exposure to SPM is associated with an increased risk of all cardiovascular mortality for men in Ibaraki, Japan.

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Isolated systolic hypertension and 29-year cardiovascular mortality risk in Japanese adults aged 30--49 years.

Hisamatsu T, Miura K, Ohkubo T, Kadota A, Kondo K, Kita Y, Hayakawa T, Kanda H, Okamura T, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Journal of hypertension （Journal of hypertension） 38 （ 11 ） 2230 - 2236 2020年07月

研究論文（学術雑誌）, ISSN 0263-6352

OBJECTIVE: The prognostic implication of isolated systolic hypertension (ISH), defined as SBP at least 140 mmHg and DBP less than 90 mmHg, among young-to-middle-aged adults remains controversial. We examined the association of ISH with cardiovascular disease (CVD) risk in adults aged 30-49 years. METHODS: In a prospective cohort of representative Japanese general populations from the NIPPON DATA80 (1980-2009), we studied 4776 participants (mean age, 39.4 years; 55.4% women) without clinical CVD or antihypertensive medication. Participants were classified as follows: normal blood pressure (BP) (SBP/DBP, <120/<80 mmHg), high-normal BP (120-129/<80 mmHg), elevated BP (130-139/80-89 mmHg), ISH, isolated diastolic hypertension (IDH) (<140/≥90 mmHg), and systolic--diastolic hypertension (SDH) (≥140/≥90 mmHg). RESULTS: ISH was observed in 389 (8.1%) participants. During the 29-year follow-up, 115 participants died of CVD, 28 of coronary heart disease, and 49 of stroke. Cox proportional hazards models adjusted for demographics and CVD risk factors showed that participants with ISH had higher risk of CVD mortality than those with normal BP [hazard ratio (confidence interval), 4.10 (1.87-9.03)]. The magnitude of CVD mortality risk related to ISH was comparable with that related to IDH [3.38 (1.31-8.72)] and not as great as that related to SDH [5.41 (2.63-11.14)]. We found significant associations of ISH with coronary and stroke mortality. The association of ISH with CVD mortality was consistent across men and women and those aged 30-39 and 40-49 years. CONCLUSION: ISH among young-to-middle-aged Japanese adults was independently associated with higher risk of CVD mortality later in life.

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Neurologically favourable outcomes of cardiogenic out-of-hospital cardiac arrest with relation to the type of witness in Japan

Shirakawa K., Kanao K., Saito Y., Doi K., Takuma K., Okamura T., Takebayashi T.

Resuscitation （Resuscitation） 152 97 - 104 2020年07月

研究論文（学術雑誌）, ISSN 03009572

© 2020 Elsevier B.V. Aim: To assess the current situation and neurologically favourable outcomes after out-of-hospital cardiac arrest (OHCA) with respect to the type of witness. Methods: This retrospective observational study used data from the All-Japan Utstein Registry of the Fire and Disaster Management Agency collected between January 1, 2016, and December 31, 2016. Patients with cardiogenic OHCA aged ≥18 years who were witnessed by bystanders were included. The primary outcome measure was a neurologically favourable outcome 1 month after the OHCA. Results: Among the 123,554 patients with OHCA registered between January 1, 2016, and December 31, 2016, 24,856 patients were included. Of them, 15,139 were witnessed by family, and 9717 were witnessed by non-family (friends, 1306; colleagues, 951; passers-by, 997; others, 6463). When witnessed by family, the rate of neurologically favourable outcomes was significantly lower than that when witnessed by non-family (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.41–0.49, P < 0.001). After adjusting for potential confounders, the rate of neurologically favourable outcomes remained lower when OHCA was witnessed by family (OR = 0.88, 95% CI = 0.79–0.99, P = 0.03). However, in subgroup analysis, adjusted ORs for neurologically favourable outcomes were slightly greater for 65–84-year-old women and ≥85-year-old women with family witnesses than for those with non-family witnesses. For all other groups, non-family witnesses outperformed family witnesses. Conclusion: Family-witnessed OHCA events had fewer neurologically favourable outcomes before and after adjusting for confounders. BLS education for family members may lead to improved prognosis of witnessed cardiogenic OHCAs.

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Association between Plasma Metabolites in the Urea Cycle and Diabetic Kidney Disease (DKD) in a Japanese Population

Yamamoto Masahiko, Harada Sei, Okamura Tomonori, Fujihara Kazuya, Yaguchi Yuta, Komatsu Takeshi, Sato Takaaki, Kitazawa Masaru, Yamada Mayuko H., Kaneko Masanori, Osawa Taeko, Matsubayashi Yasuhiro, Yamada Takaho, Kodama Satoru, Sone Hirohito, Takebayashi Toru

DIABETES 69 2020年06月

研究論文（学術雑誌）, ISSN 0012-1797

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A Combination of Blood Pressure and Total Cholesterol Increases the Lifetime Risk of Coronary Heart Disease Mortality: EPOCH-JAPAN.

Satoh M, Ohkubo T, Asayama K, Murakami Y, Sugiyama D, Waki T, Tanaka-Mizuno S, Yamada M, Saitoh S, Sakata K, Irie F, Sairenchi T, Ishikawa S, Kiyama M, Okayama A, Miura K, Imai Y, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH–JAPAN) Research Group.

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 1 ） 6 - 24 2020年04月

研究論文（学術雑誌）, ISSN 1340-3478

© 2021 Japan Atherosclerosis Society. Aim: Lifetime risk (LTR) indicates the absolute risk of disease during the remainder of an individual’s lifetime. We aimed to assess the LTRs for coronary heart disease (CHD) mortality associated with blood pressure (BP) and total cholesterol levels in an Asian population using a meta-analysis of individual participant data because no previous studies have assessed this risk. Methods: We analyzed data from 105,432 Japanese participants in 13 cohorts. Apart from grade 1 and 2–3 hypertension groups, we defined “normal BP” as systolic/diastolic BP ＜130/＜80 mmHg and “high BP” as 130–139/80–89 mmHg. The sex-specific LTR was estimated while considering the competing risk of death. Results: During the mean follow-up period of 15 years (1,553,735 person-years), 889 CHD deaths were recorded. The 10-year risk of CHD mortality at index age 35 years was ≤ 0.11%, but the corresponding LTR was ≥ 1.84%. The LTR of CHD at index age 35 years steeply increased with an increase in BP of participants with high total cholesterol levels [≥ 5.7 mmol/L (220 mg/dL)]. This risk was 7.73%/5.77% (95% confidence interval: 3.53%–10.28%/3.83%–7.25%) in men/women with grade 2–3 hypertension and high total cholesterol levels. In normal and high BP groups, the absolute differences in LTRs between the low and high total cholesterol groups were ≤ 0.25% in men and ≤ 0.40% in women. Conclusions: High total cholesterol levels contributed to an elevated LTR of CHD mortality in hypertensive individuals. These findings could help guide high-risk young individuals toward initiating lifestyle changes or treatments.

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Risk Factors Associated With Ischemic Stroke in Japanese Patients With Nonvalvular Atrial Fibrillation

Okumura K., Tomita H., Nakai M., Kodani E., Akao M., Suzuki S., Hayashi K., Sawano M., Goya M., Yamashita T., Fukuda K., Ogawa H., Tsuda T., Isobe M., Toyoda K., Miyamoto Y., Miyata H., Okamura T., Sasahara Y.

JAMA network open （JAMA network open） 3 （ 4 ） e202881 2020年04月

研究論文（学術雑誌）, ISSN 2574-3805

Importance: Despite the development of risk stratification schemes that have been widely used to determine the risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF), risk stratification schemes in Asian patients with NVAF remain undetermined. Objective: To determine risk factors for ischemic stroke in Japanese patients with NVAF. Design, Setting, and Participants: This cohort study analyzed individual patient data from 5 AF registries in Japan: J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) Registry, Fushimi AF Registry, Shinken Database, Keio Interhospital Cardiovascular Studies (Keio Study), and Hokuriku-Plus AF Registry. Patients with atrial fibrillation were registered from 158 institutions in the J-RHYTHM Registry, 80 in the Fushimi AF Registry, a single hospital in Shinken Database, 11 in the Keio Study, and 19 in the Hokuriku-Plus AF Registry. Patients with valvular AF or lacking data were excluded. Data were collected and integrated in March 2016, and those from the Keio Study were updated in April 2018. Data were analyzed from April 2018 to February 2020. Main Outcomes and Measures: Significant risk factors for ischemic stroke were determined by adjusted Cox proportional hazards analysis. Results: In total, 12 289 patients with NVAF (3758 [31%] female; mean [SD] age 70.2 [11] years) were analyzed with a mean (SD) follow-up period of 649 (181) days (1.8 [0.5] years). During 21 820 person-years of follow-up, 241 cases of ischemic stroke were reported. Risk factors associated with ischemic stroke after adjustment for oral anticoagulant use at enrollment were age (75-84 years: hazard ratio [HR], 1.74; 95% CI, 1.32-2.30; P < .001; and ≥85 years: HR, 2.41; 1.63-3.56; P < .001), hypertension (HR, 1.60; 95% CI, 1.15-2.23; P = .006), previous stroke (HR, 2.75; 95% CI, 2.09-3.62; P < .001), persistent or permanent AF (HR, 1.59; 95% CI, 1.21-2.10; P = .001), and body mass index less than 18.5 (HR, 1.55; 95% CI, 1.05-2.29; P = .03). Neither diabetes nor heart failure were identified as risk factors for ischemic stroke. Conclusions and Relevance: Previous stroke, advanced age, hypertension, persistent or permanent AF, and low body mass index were independent risk factors associated with ischemic stroke in Japanese patients with NVAF.

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Statin Intolerance Clinical Guide 2018.

Kajinami K, Tsukamoto K, Koba S, Inoue I, Yamakawa M, Suzuki S, Hamano T, Saito H, Saito Y, Masuda S, Nakayama T, Okamura T, Yamashita S, Kagawa T, Kaneyama J, Kuriyama A, Tanaka R, Hirata A, Statin Intolerance Clinical Guide Working Group; The Japan Society of Hepatology, Japanese Society of Neurology, Japan Atherosclerosis Society, The Japanese Society for the Study of Xenobiotics

Journal of atherosclerosis and thrombosis 27 （ 4 ） 375 - 396 2020年04月

ISSN 1340-3478

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Echocardiographic Parameters and the Risk of Incident Atrial Fibrillation: The Suita Study

Higashiyama Aya, Kokubo Yoshihiro, Watanabe Makoto, Nakao Yoko Masukata, Okamura Tomonori, Okayama Akira, Miyamoto Yoshihiro

JOURNAL OF EPIDEMIOLOGY （Journal of Epidemiology） 30 （ 4 ） 183 - 187 2020年04月

研究論文（学術雑誌）, ISSN 0917-5040

© 2019 Aya Higashiyama et al. Background: Left atrial dimension (LAD) and other parameters of echocardiography have been reported to be associated with the risk of atrial fibrillation (AF). However, few studies have investigated the associations between echocardiographic parameters and the risk of AF in the Asian general population, which has a low AF incidence. Methods: A prospective cohort study was performed in 1,424 individuals in the Suita study with echocardiographic parameters, including LAD, and no history of AF. After echocardiography, the participants were followed using 12-lead electrocardiography and questionnaires to detect AF incidence. The multivariable-adjusted hazard ratios (HRs) of echocardiographic parameters for AF incidence were estimated after adjustment for the risk factors of the AF risk score. Results: During the median 6.0 years of follow-up, 31 AF cases occurred. The multivariable-adjusted HR of a 1-mm increase in LAD for AF was 1.18 (95% confidence interval [CI], 1.08-1.28). The multivariable-adjusted HR for AF of a 1-standard-deviation increase in LAD was higher than that of left ventricular internal dimensions in diastole, left ventricular mass, ejection fraction, and percent fractional shortening, and it was the only significant factor. In 667 participants with both LAD and LA volume (LAV) measurements, LAD and LAV were independently associated with the risk of AF incidence. Conclusions: LAD on echocardiography was an independent risk factor of incident AF in the Japanese population. LAD might be useful for identifying individuals with a high risk of AF in health check-ups of the general population.

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Electrocardiographic Left Atrial Abnormality and B-Type Natriuretic Peptide in a General Japanese Population: NIPPON DATA2010.

Shoji S, Kohsaka S, Sawano M, Okamura T, Hirata A, Sugiyama D, Ohkubo T, Nakamura Y, Watanabe M, Kadota A, Ueshima H, Okayama A, Miura K, NIPPON DATA2010 Research Group.

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 28 （ 1 ） 34 - 43 2020年03月

研究論文（学術雑誌）, ISSN 1340-3478

© 2021 Japan Atherosclerosis Society. Aims: P-wave terminal force in lead V1 (PTFV1) is an electrocardiogram marker of increased left atrial pressure and may be a noninvasive and early detectable marker for future cardiovascular events in the general population compared to serum B-type natriuretic peptide (BNP) concentration. The clinical significance of PTFV1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV1 and BNP concentrations in a contemporary representative Japanese population. Methods: Among 2,898 adult men and women from 300 randomly selected districts throughout Japan (NIPPON DATA2010), we analyzed 2,556 participants without cardiovascular disease (stroke, myocardial infarction, and atrial fibrillation). Elevated BNP was defined as a value of ≥ 20 pg/mL based on the definition from the Japanese Circulation Society guidelines. Results: In total, 125 (4.9%) participants had PTFV1. Participants with PTFV1 were older with a higher prevalence of hypertension, major electrocardiographic findings, and elevated BNP concentrations (13.5 [6.9, 22.8] versus 7.8 [4.4, 14.5] pg/mL; P＜0.001). After adjustment for confounders, PTFV1 was correlated with elevated BNP (odds ratio, 1.66; 95% confidence interval, 1.05–2.62; P= 0.030). This correlation was consistent among various subgroups and was particularly evident in those aged ＜65 years or those without a history of hypertension. Conclusions: In the contemporary general population cohort, PTFV1 was independently related to high BNP concentration. PTFV1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.

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Relationship between thin physique at 6 years and metabolic disease risks in middle-aged Japanese women: The Suita study

Katsuragi S., Okamura T., Kokubo Y., Watanabe M., Higashiyama A., Ikeda T., Miyamoto Y.

Journal of Obstetrics and Gynaecology Research （Journal of Obstetrics and Gynaecology Research） 46 （ 3 ） 517 - 526 2020年03月

研究論文（学術雑誌）, ISSN 13418076

© 2020 Japan Society of Obstetrics and Gynecology Aim: We previously reported that female babies born small developed cardiovascular risks in middle age. The present study was conducted using the same cohort to examine the relationship between physique at 6 years and the metabolic disease risk in middle age. Methods: Data collected from 721 women aged 41–69 years who underwent a medical examination at a single institution between 2007 and 2008 were retrospectively examined. We collected data from medical examinations and a questionnaire on physique (thin, normal, and fat) at 6 years. The relationship between birthweight and physique at 6 years was investigated. Results: Among females who were born small (< 2500 g), 80%, 16%, and 4% became thin, normal, or fat, respectively, by 6 years. Physique at 6 years had a negative relationship with future triglyceride, fasting glucose, HbA1C, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) levels and a positive relationship with high-density lipoprotein cholesterol levels. Conclusion: Although our findings may be specific to the study population, physique at 6 years had a negative relationship with the metabolic disease risk in middle-aged Japanese women. Insulin and MOMA-IR levels negatively correlated with physique at 6 years, and development from low birthweight infants to childhood obesity was rare in this cohort.

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Elevated Fasting Blood Glucose Levels Are Associated With Lower Cognitive Function, With a Threshold in Non-Diabetic Individuals: A Population-Based Study

Liu Ziyi, Zaid Maryam, Hisamatsu Takashi, Tanaka Sachiko, Fujiyoshi Akira, Miyagawa Naoko, Ito Takahiro, Kadota Aya, Tooyama Ikuo, Miura Katsuyuki, Ueshima Hirotsugu, Hirotsugu Ueshima, Miura Katsuyaki, Horie Minoru, Yamamoto Takashi, Hayashi Hideki, Nakano Yasutaka, Ogawa Emiko, Maegawa Hiroshi, Miyazawa Itsuko, Murata Kiyoshi, Mitsunami Kenichi, Nozaki Kazuhiko, Shiino Akihiko, Tsuru Teruhiko, Ogita Hisakazu, Shimizu Akio, Miyamatsu Naomi, Kita Toru, Kimura Takeshi, Nishio Yoshihiko, Nakamura Yasuyuki, Okamura Tomonori, Sekikawa Akira, Barinas-Mitchell Emma J. M., Edmundowicz Daniel, Ohkubo Takayoshi, Hozawa Atsushi, Murakami Yoshitaka, Okuda Nagako, Arima Hisatomi, Kita Yoshikuni, Higashiyama Aya, Nagasawa Shinya, Azuma Koichiro, Yanagita Masahiko, Abbott Robert D., Takashima Naoyuki, Ohno Seiko, Kadowaki Takashi, Kadowaki Sayaka, Kondo Keiko, Torii Sayuki, Saito Yoshino, Suzuki Sentaro, Satoh Atsushi, Yamazoe Masahiro

JOURNAL OF EPIDEMIOLOGY 30 （ 3 ） 121 - 127 2020年03月

研究論文（学術雑誌）, ISSN 0917-5040

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Relationship between calcium intake and impaired activities of daily living in a Japanese population: NIPPON DATA90.

Kogure M, Tsuchiya N, Narita A, Hirata T, Nakaya N, Nakamura T, Hozawa A, Hayakawa T, Okuda N, Miyagawa N, Kadota A, Ohkubo T, Murakami Y, Sakata K, Miura K, Okayama A, Okamura T, Ueshima H

Journal of epidemiology （Journal of Epidemiology） 31 （ 1 ） 119 - 124 2020年02月

研究論文（学術雑誌）, ISSN 0917-5040

© 2020 Mana Kogure et al. Background: Major reasons for long-term care insurance certification in Japan are stroke, dementia, and fracture. These diseases are reported to be associated with calcium intake. This study examined the association between calcium intake and impaired activities of daily living (ADL) using the data from NIPPON DATA90, consisting of representative sample of the Japanese population. Methods: A population-based nested case-control study was performed. A baseline survey was conducted in 1990, followed by ADL surveys of individuals ≥65 years old in 2000. Individuals with impaired ADL and selected age-and sex-matched controls were then identified. We obtained 132 pairs. Calcium intake was energy-adjusted using the residual method. The association between calcium intake and impaired ADL was examined using conditional logistic regression models. To assess the accuracy of the estimates, we conducted bootstrap analyses. Results: The adjusted odds ratios (ORs) for impaired ADL compared with the group with a calcium intake of <476 mg/day were 0.72 (95% confidence interval [CI], 0.37–1.40) for the 476–606 mg/day group and 0.44 (95% CI, 0.21–0.94) for the ≥607 mg/ day group in 2000 (P for linear trend = 0.03). After the bootstrap analyses, the inverse relationship unchanged (median OR per 100-mg rise in calcium intake, 0.87 [1,000 resamplings]; 95% CI, 0.76–0.97). Conclusions: After bootstrap analyses, calcium intake was inversely associated with impaired ADL 10 years after the baseline survey.

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Development of a Cardiovascular Disease Risk Prediction Model Using the Suita Study, a Population-Based Prospective Cohort Study in Japan.

Nakai M, Watanabe M, Kokubo Y, Nishimura K, Higashiyama A, Takegami M, Nakao YM, Okamura T, Miyamoto Y

Journal of atherosclerosis and thrombosis （Journal of Atherosclerosis and Thrombosis） 27 （ 11 ） 1160 - 1175 2020年02月

研究論文（学術雑誌）, ISSN 1340-3478

© 2020 Japan Atherosclerosis Society. Aim: To construct a risk prediction model for cardiovascular disease (CVD) based on the Suita study, an urban Japanese cohort study, and compare its accuracy against the Framingham CVD risk score (FRS) model. Methods: After excluding participants with missing data or those who lost to follow-up, this study consisted of 3,080 men and 3,470 women participants aged 30–79 years without CVD at baseline in 1989–1999. The main outcome of this study was incidence of CVD, defined as the incidence of stroke or coronary heart disease. Multi-variable Cox proportional hazards models with stepwise selection were used to develop the prediction model. To assess model performance, concordance statistics (C-statistics) and their 95% confidence intervals (CIs) were cal-culated using a bootstrap procedure. A calibration test was also conducted. Results: During a median follow-up period of 16.9 years, 351 men and 241 women developed CVD. We for-mulated risk models with and without electrocardiogram (ECG) data that included age, sex, systolic blood pres-sure, diastolic blood pressure, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, diabetes mellitus, smoking, and urinary protein as risk factors. The C-statistics of the Suita CVD risk models with ECG data (0.782; 95% CI, 0.766–0.799) and without ECG data (0.781; 95% CI, 0.765–0.797) were significantly higher than that of the FRS model (0.768; 95% CI, 0.750–0.785). Conclusions: The Suita CVD risk model is feasible to use and improves predictability of the incidence of CVD relative to the FRS model in Japan.

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Relationship of household salt intake level with long-term all-cause and cardiovascular disease mortality in Japan: NIPPON DATA80

Shima A., Miyamatsu N., Miura K., Miyagawa N., Okuda N., Yoshita K., Kadota A., Suzuki H., Kondo K., Okamura T., Okayama A., Ueshima H., Saitoh S., Sakata K., Hozawa A., Hayakawa T., Nakamura Y., Nishi N., Ohkubo T., Kasagi F., Murakami Y., Izumi T., Matsumura Y., Ojima T., Tamakoshi K., Nakagawa H., Kita Y., Fujiyoshi A., Nakamura Y., Miyamoto Y., Kodama K., Kiyohara Y.

Hypertension Research （Hypertension Research） 43 （ 2 ） 132 - 139 2020年02月

研究論文（学術雑誌）, ISSN 09169636

© 2019, The Japanese Society of Hypertension. In Asian countries, a major source of salt intake is from seasoning or table salt added at home. However, little is known about the adverse effects of salt intake evaluated according to household unit. We investigated the relationship between household salt intake level and mortality from all-cause and cardiovascular diseases (CVDs). Participants included 8702 individuals (56% women) who were living with someone else and who were aged 30–79 years and enrolled in the National Nutritional Survey of Japan in 1980 with a 24-year follow-up. Household nutrient intake was evaluated using a 3-day weighing record method in which all foods and beverages consumed by any of the household members were recorded. The household salt intake level was defined as the amount of salt consumed (g) per 1000 kcal of total energy intake in each household, and its average was 6.25 (2.02) g/1000 kcal. During the follow-up, there were 2360 deaths (787 CVD, 168 coronary heart disease [CHD], and 361 stroke). Cox proportional hazard ratios (HRs) for an increment of 2 g/1000 kcal in household salt intake were calculated and adjusting for sex, age, body mass index, smoking status, alcohol consumption status, self-reported work exertion level, household potassium intake, household saturated fatty acid intake, and household long-chain n-3 polyunsaturated fatty acid intake. The HRs (95% confidence intervals) were 1.07 (1.02, 1.12) for all-cause mortality, 1.11 (1.03, 1.19) for CVD, 1.25 (1.08, 1.44) for CHD, and 1.12 (1.00, 1.25) for stroke. The household salt intake level was significantly associated with long-term risk of all-cause, CVD, CHD, and stroke mortality in a representative Japanese population.

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Relationship between carbohydrate and dietary fibre intake and the risk of cardiovascular disease mortality in Japanese: 24-year follow-up of NIPPON DATA80

Miyazawa I., Miura K., Miyagawa N., Kondo K., Kadota A., Okuda N., Fujiyoshi A., Chihara I., Nakamura Y., Hozawa A., Nakamura Y., Kita Y., Yoshita K., Okamura T., Okayama A., Ueshima H.

European Journal of Clinical Nutrition （European Journal of Clinical Nutrition） 74 （ 1 ） 67 - 76 2020年01月

研究論文（学術雑誌）, ISSN 09543007

© 2019, Springer Nature Limited. Background/Objectives: The association between carbohydrate intake and cardiovascular disease (CVD) risk has been investigated, but whether the quality of carbohydrate is more important than its amount is not known. We examined the associations between intake of dietary fibre (DF), carbohydrate, available carbohydrate, and starch with long-term CVD mortality in a Japanese population. Subjects/Methods: We prospectively followed 8925 participants (3916 men and 5009 women) aged 30–79 years without CVD at baseline who participated in the National Nutrition Survey in Japan. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for CVD mortality by quartiles of exposure variables. Results: During 24 years of follow-up, 823 CVD deaths were observed. In men, the multivariable-adjusted HR for CVD mortality was lower in the highest quartile of DF intake (HR: 0.64; 95% CI: 0.47–0.87; Ptrend = 0.007) compared with the lowest quartile. This association was not significant in women. Multivariable-adjusted HR for total stroke mortality was lower in the highest quartile of DF intake (HR: 0.61; 95% CI: 0.38–0.98; Ptrend = 0.046) compared with the lowest quartile in women. Carbohydrate, available carbohydrate, and starch intake were not associated with CVD mortality. Conclusions: Higher intake of DF was associated significantly with a lower risk of CVD mortality in men and lower risk of stroke mortality in women. Intake of carbohydrate, available carbohydrate, and starch were not associated with the risk of CVD mortality in men or women.

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The perinatal condition around birth and cardiovascular risk factors in the Japanese general population: The suita study

Katsuragi S., Okamura T., Kokubo Y., Watanabe M., Higashiyama A., Ikeda T., Miyamoto Y.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 27 （ 3 ） 204 - 214 2020年

研究論文（学術雑誌）, ISSN 13403478

© 2019 Japan Atherosclerosis Society. Aim: To investigate the relationship between perinatal condition around birth and cardiovascular risk in later life. Methods: Retrospective data were examined from 1241 city dwellers (521 men, 720 women; age 41–69 years) who had undergone medical examination at a single institution including blood tests and physical measurements from 2007 to 2008. The questionnaire was conducted to determine how perinatal factors affect their lives later. We also selected and studied a total of 28 individuals (12 men and 16 women) specifically about the conformity rate of the breastfeeding method between participants’ memories and what was written in the maternal and child health handbooks. Results: The conformity rate of the breastfeeding method between a self-questionnaire and his/her maternal and child health handbook was well correlated (r =0.73; p＜0.025). Among the data in women who were born at home, HbA1C levels (5.36±0.03 vs. 5.25±0.05 mg/dL, p=0.03) and low-density lipoprotein cholesterol (136.0±1.4 vs. 129.3±2.5 mg/dL, p=0.04) were higher than women who were born at the hospital. Women raised by formula showed higher low-density lipoprotein cholesterol levels than women fed breast milk or a mixture of breast milk and formula (150.2±4.8 vs. 138.7±3.7, 142.5±2.6 mg/dL, p =0.04). Fasting blood glucose levels at an adult time in men and women born through breech presentation were higher than those by the cephalic presentation (123.2±7.8 vs. 106.8±1.2 mg/dL, p=0.03). Conclusion: The study proposed that some perinatal conditions around birth such as delivery place, presenting part, and lactation affected especially Japanese women’s cardiovascular risks between ages 41 and 69 years.

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Hypercholesterolemia and lifetime risk of coronary heart disease in the general japanese population: Results from the suita cohort study

Sugiyama D., Turin T.C., Yeasmin F., Rumana N., Watanabe M., Higashiyama A., Takegami M., Kokubo Y., Okamura T., Miyamoto Y.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 27 （ 1 ） 60 - 70 2020年

研究論文（学術雑誌）, ISSN 13403478

© 2020 Japan Atherosclerosis Society This article is distributed under the terms of the latest ver. Lifetime risk (LTR) is a measure of disease burden, which presents the probability of occurrence of a specific disease in the remaining lifetime of a group of people for a given index age. This measure is useful for presenting the risk dynamics of a disease at the population level, which constitutes important public health information toward prevention. To date, there have been no studies investigating the LTR for coronary heart diseases (CHDs) in relation to hypercholesterolemia in Asian populations. Therefore, we estimated the LTR of CHDs according to serum low-density lipoprotein cholesterol (LDL-C). Methods: The participants included in this study were 2,559 men and 2,848 women, enrolled in the Suita Cohort Study of urban residents followed up from 1989 to 2007 for a total of 69,823 person-years. We estimated the sex-and index-age-specific LTR for the first CHD event among participants with or without hypercholesterolemia (LDL-C ≥ 160 mg/dL), accounting for the competing risk for mortality. Results: For men with hypercholesterolemia, the LTR was 47.2% (95% confidence interval [CI]: 29.3–65.1%) and 44.5% (95% CI: 21.4–68.5%) for those aged 45 and 75, respectively. The LTRs of women with hypercholesterolemia were also higher than of those without hypercholesterolemia. However, their LTRs were lower for all index ages compared to men. These results did not differ for hypercholesterolemia defined by non-high-density lipoprotein cholesterol. Conclusions: The presence of hypercholesterolemia increases the LTR for CHDs in the Japanese population, especially in men. This estimate can be used in preventive knowledge translation efforts at the population level.

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Dietary inflammatory index positively associated with high-sensitivity C-reactive protein level in Japanese from NIPPON data2010

Yang Y., Hozawa A., Kogure M., Narita A., Hirata T., Nakamura T., Tsuchiya N., Nakaya N., Ninomiya T., Okuda N., Kadota A., Ohkubo T., Okamura T., Ueshima H., Okayama A., Miura K.

Journal of Epidemiology （Journal of Epidemiology） 30 （ 2 ） 98 - 107 2020年

研究論文（学術雑誌）, ISSN 09175040

© 2019 Yunqing Yang et al. Background: It has been reported that chronic inflammation may play an important role in the pathogenesis of several serious diseases and could be modulated by diet. Recently, the Dietary Inflammatory Index (DII®) was developed to assess the inflammatory potential of the overall diet. The DII has been reported as relevant to various diseases but has not been validated in Japanese. Thus, in the present study, we analyzed the relationship between DII scores and high-sensitivity C-reactive protein (hs-CRP) levels in a Japanese population. Methods: Data of the National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 2010 (NIPPON DATA2010), which contained 2,898 participants aged 20 years or older from the National Health and Nutrition Survey of Japan (NHNS2010), were analyzed. Nutrient intakes derived from 1-day semi-weighing dietary records were used to calculate DII scores. Energy was adjusted using the residual method. Levels of hs-CRP were evaluated using nephelometric immunoassay. Multiple linear regression analyses were performed. Results: After adjusting for age, sex, smoking status, BMI, and physical activity, a significant association was observed between DII scores and log(CRP+1) (standard regression coefficient = 0.05, P < 0.01). Although it was not statistically significant, the positive association was consistently observed in almost all age-sex subgroups and the non-smoker subgroup. Conclusions: The current study confirmed that DII score was positively associated with hs-CRP in Japanese.

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Electrocardiographic ST-T Abnormities Are Associated with Stroke Risk in the REGARDS Study

Sawano M., Yuan Y., Kohsaka S., Inohara T., Suzuki T., Okamura T., Howard G., Howard V.J., Judd S., Soliman E.Z., Cushman M.

Stroke （Stroke） 51 （ 4 ） 1100 - 1106 2020年

研究論文（学術雑誌）, ISSN 00392499

© 2020 Lippincott Williams and Wilkins. All rights reserved. Background and Purpose-In previous studies, isolated nonspecific ST-segment and T-wave abnormalities (NSSTTAs), a common finding on ECGs, were associated with greater risk for incident coronary artery disease. Their association with incident stroke remains unclear. Methods-The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a population-based, longitudinal study of 30 239 white and black adults enrolled from 2003 to 2007 in the United States. NSSTTAs were defined from baseline ECG using the standards of Minnesota ECG Classification (Minnesota codes 4-3, 4-4, 5-3, or 5-4). Participants with prior stroke, coronary heart disease, and major and minor ECG abnormalities other than NSSTTAs were excluded from analysis. Multivariable Cox proportional hazards regression was used to examine calculate hazard ratios of incident ischemic stroke by presence of baseline NSSTTAs. Results-Among 14 077 participants, 3111 (22.1%) had NSSTTAs at baseline. With a median of 9.6 years follow-up, 106 (3.4%) with NSSTTAs had ischemic stroke compared with 258 (2.4%) without NSSTTAs. The age-adjusted incidence rates (per 1000 person-years) of stroke were 2.93 in those with NSSTTAs and 2.19 in those without them. Adjusting for baseline age, sex, race, geographic location, and education level, isolated NSSTTAs were associated with a 32% higher risk of ischemic stroke (hazard ratio, 1.32 [95% CI, 1.05-1.67]). With additional adjustment for stroke risk factors, the risk of stroke was increased 27% (hazard ratio, 1.27 [95% CI, 1.00-1.62]) and did not differ by age, race, or sex. Conclusions-Presence of NSSTTAs in persons with an otherwise normal ECG was associated with a 27% increased risk of future ischemic stroke.

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Reference intervals of serum non-cholesterol sterols by gender in healthy Japanese individuals

Yoshida H., Tada H., Ito K., Kishimoto Y., Yanai H., Okamura T., Ikewaki K., Inagaki K., Shoji T., Bujo H., Miida T., Yoshida M., Kuzuya M., Yamashita S.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 27 （ 5 ） 409 - 417 2020年

研究論文（学術雑誌）, ISSN 13403478

© 2020, Japan Atherosclerosis Society. All rights reserved. Aims: The present study was conducted to establish a practical method for measuring non-cholesterol sterols and reference intervals of serum levels. Methods: Healthy subjects (109 men and 151 women), four patients with sitosterolemia, and 10 heterozygous mutation carriers of ABCG5/ABCG8 genes were investigated. Then, three non-cholesterol sterols (sitosterol, campesterol, and lathosterol) of fasting serum samples were measured via a practical and highly sensitive gas chromatography (GC) method with 0.2 µg/mL as the lower limit of quantification. The coefficient of variation (CV) values for within-run reproducibility were 3.06%, 1.89%, and 1.77% for lathosterol, campesterol, and sitosterol, respectively. The CV values for between-run reproducibility were 2.81%, 2.06%, and 2.10% for lathosterol, campesterol, and sitosterol, respectively. Results: The serum levels of sitosterol and campesterol were significantly higher in women than in men, whereas the serum levels of lathosterol were significantly higher in men than in women. Because of these gender difference, the determination of reference intervals of the three sterol values was performed by considering gen-der. The reference intervals of sitosterol, campesterol, and lathosterol were 0.99–3.88, 2.14–7.43, and 0.77–3.60 µg/mL in men and 1.03–4.45, 2.19–8.34, and 0.64–2.78 µg/mL in women, respectively. The serum levels of sitosterol and campesterol were higher in patients with sitosterolemia (94.3±47.3 and 66.3±36.6 µg/mL, respectively) than in healthy subjects. Conclusion: These results demonstrate a practical and highly sensitive GC method to measure non-cholesterol sterol levels and gender-segregated reference intervals of sitosterol, campesterol, and lathosterol in Japanese healthy subjects.

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Impact of hypertension stratified by diabetes on the lifetime risk of cardiovascular disease mortality in Japan: a pooled analysis of data from the Evidence for Cardiovascular Prevention from Observational Cohorts in Japan study

Imai Y., Hirata T., Saitoh S., Ninomiya T., Miyamoto Y., Ohnishi H., Murakami Y., Iso H., Tanaka S., Miura K., Tamakoshi A., Yamada M., Kiyama M., Ueshima H., Ishikawa S., Okamura T.

Hypertension Research （Hypertension Research） 2020年

研究論文（学術雑誌）, ISSN 09169636

© 2020, The Japanese Society of Hypertension. Lifetime risk is an informative estimate to motivate people to change lifestyle behaviors, especially from a younger age, in public health education. The impact of the combination of hypertension and diabetes on the lifetime risk of cardiovascular mortality has not been investigated in Asian populations. A pooled analysis of individual data from nine cohorts was performed. A total of 57,339 Japanese men and women were eligible for the analysis. We used the modified Kaplan–Meier approach and estimated the remaining lifetime risk of cardiovascular mortality starting from the index age of 35 years. Participants were classified into four categories defined by hypertension and diabetes. The lifetime risk was increased in the order of those without either risk, those without hypertension but with diabetes, those with hypertension but without diabetes, and those with both risks. The lifetime risk of cardiovascular mortality at the 35-year index age was as follows: 7.8% in men and 6.2% in women for those without either hypertension or diabetes, 13.2% in men and 9.5% in women for those without hypertension but with diabetes, 17.2% in men and 11.7% in women for those with hypertension but without diabetes, and 19.4% in men and 15% in women for those with both risks. These findings reinforce the need for a life-course perspective in the management of hypertension and diabetes from a younger age.

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Electrocardiographic ST-T Abnormities Are Associated with Stroke Risk in the REGARDS Study

Sawano M., Yuan Y., Kohsaka S., Inohara T., Suzuki T., Okamura T., Howard G., Howard V.J., Judd S., Soliman E.Z., Cushman M.

Stroke （Stroke） 51 （ 4 ） 1100 - 1106 2020年

研究論文（学術雑誌）, ISSN 00392499

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Reference intervals of serum non-cholesterol sterols by gender in healthy Japanese individuals

Yoshida H., Tada H., Ito K., Kishimoto Y., Yanai H., Okamura T., Ikewaki K., Inagaki K., Shoji T., Bujo H., Miida T., Yoshida M., Kuzuya M., Yamashita S.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 27 （ 5 ） 409 - 417 2020年

研究論文（学術雑誌）, ISSN 13403478

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Imai Y., Hirata T., Saitoh S., Ninomiya T., Miyamoto Y., Ohnishi H., Murakami Y., Iso H., Tanaka S., Miura K., Tamakoshi A., Yamada M., Kiyama M., Ueshima H., Ishikawa S., Okamura T.

Hypertension Research （Hypertension Research） 2020年

研究論文（学術雑誌）, ISSN 09169636

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[The search for a predictor of deterioration of the nonspecific stress index K6 among urban residents: The KOBE study].

Taya H, Kuwabara K, Higashiyama A, Sugiyama D, Hirata A, Sata M, Hirata T, Nishida Y, Kubo S, Kubota Y, Kadota A, Miyamatsu N, Nishimura K, Miyamoto Y, Okamura T

[Nihon koshu eisei zasshi] Japanese journal of public health 67 （ 8 ） 509 - 517 2020年

研究論文（学術雑誌）, ISSN 0546-1766

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Acceleration of opportunistic atrial fibrillation screening for elderly patients in routine primary care.

Suzuki A, Okamura T, Sasaki M, Matsuoka H, Ikeda Y, Takahashi A, Akiyama S, Ono F, Yoshihara N, Akita Study group.

PloS one （PLoS ONE） 15 （ 12 ） e0244240 2020年

研究論文（学術雑誌）, ISSN 1932-6203

Cardio-embolic ischemic stroke caused by atrial fibrillation is more severe compared with other types of stroke, such as lacunar infarction and atherothrombotic infarction in patients without atrial fibrillation. Therefore, it is important to prevent cardio-embolic ischemic stroke by detecting atrial fibrillation early in at-risk patients and administering appropriate anticoagulation therapy. This prospective observational study aimed to evaluate the effectiveness of opportunistic atrial fibrillation screening at 12 primary clinics in Japan. The study included a 12-month pre-campaign period and a 12-month campaign period. During the campaign period, an awareness campaign was conducted to encourage physicians to be mindful of screening patients aged 65 years for atrial fibrillation by checking their pulses and performing subsequent electrocardiography when an irregular pulse was detected. The primary outcome was the proportion of patients with newly diagnosed atrial fibrillation. A sub-analysis focusing on first-time outpatients was performed. There were 9921 and 10,282 patients with no history of atrial fibrillation in the pre-campaign and campaign periods, respectively. In the whole population, the proportion of patients with newly diagnosed atrial fibrillation was 0.9% throughout the pre-campaign and campaign periods. In the sub-analysis limited to first-time outpatients, the detection proportion increased from 1.6% to 1.9% during the campaign period. In terms of age stratification, a large increase in detection was observed, especially among patients aged 65–74 years (detection increased from 0.9% to 1.5%) and 85 years (detection increased from 2.9% to 3.3%) during the campaign period. Our findings suggest the feasibility of opportunistic atrial fibrillation screening in routine primary care practice in Japan. Of note, our findings suggest that opportunistic atrial fibrillation screening targeting first-time outpatients may be of clinical value.

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[Association of the combined estimated 24-h urinary Na/K ratio and body mass index with blood pressure: Cross-sectional data from the KOBE study].

Nozawa M, Kuwabara K, Kubota Y, Nishida Y, Kubo S, Hirata T, Higashiyama A, Hirata A, Hattori H, Sata M, Kadota A, Sugiyama D, Miyamatsu N, Miyamoto Y, Okamura T

[Nihon koshu eisei zasshi] Japanese journal of public health 67 （ 10 ） 722 - 733 2020年

研究論文（学術雑誌）, ISSN 0546-1766

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Lipoprotein particles and coronary artery calcium in middle-aged US-White and Japanese men

Mahajan H., Zaid M., MacKey R., Kadota A., Vishnu A., Fujiyoshi A., Vasudha A., Hisamatsu T., Evans R., Okamura T., Miura K., Kuller L., Ueshima H., Sekikawa A.

Open Heart （Open Heart） 6 （ 2 ） e001119 2019年12月

研究論文（学術雑誌）, ISSN 2398595X

© © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. Objective This cross-sectional study examined whether contrasting distributions of nuclear magnetic resonance (NMR)-measured lipoproteins contribute to differences in the prevalence of subclinical atherosclerosis measured using coronary artery calcium (CAC) between the two groups of middle-aged males: the US-residing Caucasian (US-White) and Japan-residing Japanese (Japanese). Methods In a population-based study of 570 randomly selected asymptomatic men aged 40-49 years (270 US-White and 300 Japanese), we examined the relationship between race/ethnicity, NMR-measured lipoproteins and CAC (measured by Electron Beam CT and quantified using the Agatston method) using multivariable robust Poisson regression adjusting for traditional and novel risk factors for coronary heart disease (CHD). Results The US-White compared with the Japanese had significantly different NMR-measured lipoprotein particle distributions. The US-White had a significantly higher prevalence of CAC≥10 (CAC-prevalence) compared with the Japanese adjusting for CHD risk factors (prevalence ratio (PR)=2.10; 95% CI=1.24 to 3.48), and this difference was partially attenuated (∼18%) with further adjustment for lipoprotein levels (PR=1.73; 95% CI=1.02 to 3.08). There was no reclassification improvement with further addition of lipoproteins particle concentrations/size to a model that already included traditionally measured lipids (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), cardiovascular risk factors, and inflammatory markers (net reclassification improvement index=-2% to 3%). Conclusions Variations in the distribution of NMR-measured lipoprotein particles partially accounted for the difference in the CAC-prevalence between middle-aged US-White and Japanese men.

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Association of Electrocardiographic Left Atrial Abnormality and B-type Natriuretic Peptide in a Large Japanese Cohort: A Report From the Nippon Data2010 Research Group

Shoji Satoshi, Kohsaka Shun, Sawano Mitsuaki, Okamura Tomonori, Hirata Aya, Sugiyama Daisuke, Ohkubo Takayoshi, Nakamura Yasuyuki, Watanabe Makoto, Kadota Aya, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

CIRCULATION 140 2019年11月

研究論文（学術雑誌）, ISSN 0009-7322

Double Product Privilege in Predicting All-cause and Cardiovascular Disease Mortality Compare to Heart Rate and Blood Pressure Separately, the Nippon-data 80 Study

Liu Yiwei, Sugiyama Daisuke, Hirata Aya, Miura Katsuyuki, Ueshima Hirotsugu, Kadota Aya, Ohkubo Takayoshi, Okayama Akita, Kondo Keiko, Okamura Tomonori

CIRCULATION 140 2019年11月

研究論文（学術雑誌）, ISSN 0009-7322

Serum modified HDL was associated with cardiovascular disease in a Japanese community-based cohort

Okamura T., Sata M., Iida M., Kakino A., Harada S., Hirata A., Usami Y., Sugiyama D., Sawamura T., Takabayashi T.

EUROPEAN JOURNAL OF PUBLIC HEALTH 29 361 - 361 2019年11月

研究論文（学術雑誌）, ISSN 1101-1262

Presence of intimate family and cancer screening behavior: a cross-sectional study of 4237 workers

Miyamatsu N., Shima A., Morino A., Azuma S., Ichikawa M., Godai K., Kawatsu Y., Nishikawa T., Tanaka H., Okamura T.

EUROPEAN JOURNAL OF PUBLIC HEALTH 29 320 - 320 2019年11月

研究論文（学術雑誌）, ISSN 1101-1262

Being conscious of water intake positively associated with sufficient non-alcohol drink intake regardless of seasons and reasons in healthy Japanese; the KOBE study: A cross sectional study

Nishikawa T., Miyamatsu N., Higashiyama A., Kubota Y., Nishida Y., Hirata T., Sugiyama D., Kuwabara K., Kubo S., Miyamoto Y., Okamura T.

International Journal of Environmental Research and Public Health （International Journal of Environmental Research and Public Health） 16 （ 21 ） 2019年11月

研究論文（学術雑誌）, ISSN 16617827

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. The present study sought to clarify if being conscious of water intake (CWI) is associated with sufficient non-alcohol drink (NAD) intake. We used data of healthy participants without diabetes, aged 40–74 years, in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. The association between being CWI and NAD intake was evaluated by multivariate linear regression analyses after adjusting for age, sex, surveyed months (seasons), alcohol drinking, health-awareness life habits, socioeconomic factors, serum osmolarity, estimated daily salt intake, and reasons for NAD intake. Among 988 (698 women and 290 men) participants eligible for the present analyses, 644 participants (65.2%) were CWI and 344 participants (34.8%) were not CWI (non-CWI). The most popular reason for being CWI was to avoid heat stroke in summer and to prevent ischemic cerebral stroke in winter. The CWI group took more NAD, especially decaffeinated beverages, than the non-CWI group (1846.7 ± 675.1 mL/day vs. 1478.0 ± 636.3 ml/day, p < 0.001). There was a significant association between being CWI and NAD intake in multivariate linear regression analyses ever after adjusting for the relevant variables (β = 318.1, p < 0.001). These findings demonstrated CWI, regardless of the reasons and the seasons, was associated with high NAD intake in Japanese healthy population.

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Association between dyslipidemia and plasma levels of branched-chain amino acids in the Japanese population without diabetes mellitus

Fukushima K., Harada S., Takeuchi A., Kurihara A., Iida M., Fukai K., Kuwabara K., Kato S., Matsumoto M., Hirata A., Akiyama M., Tomita M., Hirayama A., Sato A., Suzuki C., Sugimoto M., Soga T., Sugiyama D., Okamura T., Takebayashi T.

Journal of Clinical Lipidology （Journal of Clinical Lipidology） 13 （ 6 ） 932 - 939.e2 2019年11月

研究論文（学術雑誌）, ISSN 19332874

© 2019 National Lipid Association Background: Branched-chain amino acids (BCAAs) play a key role in energy homeostasis. Objective: We aimed to investigate the association between plasma BCAA levels and dyslipidemia in the Japanese population without diabetes mellitus. Methods: This cross-sectional study included 4952 participants without diabetes mellitus, enrolled in the Tsuruoka Metabolomic Cohort Study. Plasma BCAA levels were measured by capillary electrophoresis–mass spectrometry. Correlations between lipid and BCAA profiles were evaluated by sex-stratified multiple linear regression analyses, after adjusting for confounders. Logistic regression was used to identify associations between BCAAs and metabolic dyslipidemia (MD) defined as triglyceride levels ≥150 mg/dL, high-density lipoprotein cholesterol levels ≤40 mg/dL for men and ≤50 mg/dL for women, or low-density lipoprotein cholesterol (LDL-C) levels ≥140 mg/dL. Results: In both sexes, the levels of individual BCAAs and the total BCAA levels correlated positively with triglyceride levels and negatively with high-density lipoprotein cholesterol levels. Valine, leucine, and total BCAA levels were weakly and positively correlated with LDL-C levels. Increased BCAA levels showed positive associations with MD. However, associations between BCAAs and elevated LDL-C levels were unclear. Furthermore, the associations between BCAA levels and MD regardless of fasting blood sugar (FBS) levels (high or low). Although valine, leucine, and total BCAA levels were weakly associated with elevated LDL-C levels in the high-FBS group, no such association was observed in the low-FBS group. Conclusions: BCAAs might be associated with MD independently of the FBS level and might play an important role in lipid metabolism and dyslipidemia.

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Age-related and seasonal change in serum osmolarity and water intake in a healthy population

Nishikawa T., Miyamatsu N., Higashiyama A., Nishida Y., Kubota Y., Hirata T., Sugiyama D., Kuwabara K., Miyamoto Y., Okamura T.

EUROPEAN JOURNAL OF PUBLIC HEALTH 29 2019年11月

研究論文（学術雑誌）, ISSN 1101-1262

Impact of care coordination on oral anticoagulant therapy among patients with atrial fibrillation in routine clinical practice in Japan: A prospective, observational study

Ono F., Akiyama S., Suzuki A., Ikeda Y., Takahashi A., Matsuoka H., Sasaki M., Okamura T., Yoshihara N.

BMC Cardiovascular Disorders （BMC Cardiovascular Disorders） 19 （ 1 ） 235 2019年10月

研究論文（学術雑誌）

© 2019 The Author(s). Background: Care coordination between general practitioners (GPs) and cardiovascular specialists is expected to play a key role in establishing appropriate oral anticoagulant (OAC) treatment in atrial fibrillation (AF) patients. The aim of this study was to assess the impact of care coordination on oral anticoagulant therapy in the management of AF in Japan. Methods: This study was a multi-center, single-arm, prospective cohort study with retrospective chart and claims data review for historical controls. The study included three study periods: a 12-month pre-campaign period; a 12-month campaign period for AF screening and care coordination; and a 3-month post-campaign period for follow-up of care coordination. During the campaign period, patients aged ≥65 years who attended participating GP clinics underwent opportunistic AF screening by GPs under the campaign. At the discretion of the GP, newly diagnosed AF patients after the screening were referred to a cardiovascular specialist for care coordination. To assess the impact of care coordination and evaluate the effects of the campaign, implementation of care coordination, antithrombotic therapies, and patient-reported outcomes were compared between patients with and without care coordination, and between patients during the pre-campaign and campaign periods. Results: There were 86 newly diagnosed AF patients during the pre-campaign period and 90 during the campaign period. The percentage of patients with care coordination increased from 3.5% (3/86) in the pre-campaign period to 14.4% (n = 13/90) during the campaign period. The percentage of patients who received OAC therapies, according to the definition from the Japanese AF medication guideline, increased from 55.8% (48/86) to 71.1% (64/90) during the campaign period regardless of care coordination. Younger patients were referred to cardiovascular specialists for care coordination. Implementation of OAC therapy did not differ between patients with and without care coordination. Adherence to OAC therapy was low regardless of care coordination. Conclusions: This GP-targeted campaign was effective at raising awareness regarding the implementation of care coordination and appropriate OAC therapy at local clinical practices in Japan. Improvement of adherence to OAC therapy in elderly patients is a critical issue, and measures such as education programs targeted to patients and healthcare professionals should be undertaken.

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Explaining the decline in coronary heart disease mortality rates in Japan: Contributions of changes in risk factors and evidence-based treatments between 1980 and 2012

Ogata S., Nishimura K., Guzman-Castillo M., Sumita Y., Nakai M., Nakao Y.M., Nishi N., Noguchi T., Sekikawa A., Saito Y., Watanabe T., Kobayashi Y., Okamura T., Ogawa H., Yasuda S., Miyamoto Y., Capewell S., O'Flaherty M.

International Journal of Cardiology （International Journal of Cardiology） 291 183 - 188 2019年09月

研究論文（学術雑誌）, ISSN 01675273

© 2019 The Authors Background: We aimed to quantify contributions of changes in risks and uptake of evidence-based treatment to coronary heart disease (CHD) mortality trends in Japan between 1980 and 2012. Methods: We conducted a modelling study for the general population of Japan aged 35 to 84 years using the validated IMPACT model incorporating data sources like Vital Statistics. The main outcome was difference in the number of observed and expected CHD deaths in 2012. Results: From 1980 to 2012, age-adjusted CHD mortality rates in Japan fell by 61%, resulting in 75,700 fewer CHD deaths in 2012 than if the age and sex-specific mortality rates had remained unchanged. Approximately 56% (95% uncertainty interval [UI]: 54–59%) of the CHD mortality decrease, corresponding to 42,300 (40,900–44,700) fewer CHD deaths, was attributable to medical and surgical treatments. Approximately 35% (28–41%) of the mortality fall corresponding to 26,300 (21,200–31,000) fewer CHD deaths, was attributable to risk factor changes in the population, 24% (20–29%) corresponding to 18,400 (15,100–21,900) fewer and 11% (8–14%) corresponding to 8400 (60,500–10,600) fewer from decreased systolic blood pressure (8.87 mm Hg) and smoking prevalence (14.0%). However, increased levels of cholesterol (0.28 mmol/L), body mass index (BMI) (0.68 kg/m2), and diabetes prevalence (1.6%) attenuated the decrease in mortality by 2% (1–3%), 3% (2–3%), and 4% (1–6%), respectively. Conclusions: Japan should continue their control policies for blood pressure and tobacco, and build a strategy to control BMI, diabetes, and cholesterol levels to prevent further CHD deaths.

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THE IMPACT OF DISTRIBUTION SHIFTS IN A POPULATION'S CARDIOVASCULAR RISK FACTORS ON HEALTHY LIFE EXPECTANCY IN JAPAN

Tsukinoki R., Murakami Y., Miura K., Okamura T., Kadota A., Hayakawa T., Okayama A., Ueshima H.

JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH 73 A57 - A57 2019年09月

研究論文（学術雑誌）, ISSN 0143-005X

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DEVELOPMENT OF A CARDIOVASCULAR DISEASE RISK PREDICTION MODEL FOR POPULATION HEALTH PLANNING IN JAPAN: EPOCH-JAPAN STUDY

Murakami Y., Okamura T., Miura K., Ueshima H.

JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH 73 A91 - A91 2019年09月

研究論文（学術雑誌）, ISSN 0143-005X

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Variation in process quality measures of diabetes care by region and institution in Japan during 2015–2016: An observational study of nationwide claims data

Sugiyama T., Imai K., Ihana-Sugiyama N., Tanaka H., Yanagisawa-Sugita A., Sasako T., Higashi T., Okamura T., Yamauchi T., Ueki K., Ohsugi M., Kadowaki T.

Diabetes Research and Clinical Practice （Diabetes Research and Clinical Practice） 155 107750 2019年09月

研究論文（学術雑誌）, ISSN 01688227

© 2019 The Authors Aims: To calculate process quality measures of diabetes care in Japan using nationwide exclusive claims database. Methods: Using the National Database of health insurance claims during 2015–2016, the proportions of outpatients who received recommended examinations at least annually among those with regular antidiabetic medication were calculated as quality indicators, reported altogether and by prefecture and institutional certification (from the Japan Diabetes Society). Distributions of institutional-level quality indicators were also reported. Results: Among 4,154,452 outpatients, 96.7% underwent HbA1c or glycated albumin examination. Retinopathy examination was conducted among 46.5% of patients [prefecture (range): 37.5%–51.0%, institutional certification: 44.8% (without) vs. 59.8% (with)]. Urinary qualitative examination was conducted among 67.3% of patients at institutions with <200 beds (prefecture: 54.1%–81.9%, institutional certification: 66.8% vs. 92.8%), whereas urinary quantitative albumin or protein examination was conducted among 19.4% of patients (prefecture: 10.8%–31.6%, institutional certification: 18.7% vs. 54.8%). Distributions of institutional-level quality indicators showed that most institutions without institutional certification seldomly order urinary quantitative examination. Conclusions: Although the quality indicator for glycaemic control examination was favourable, some aspects of diabetes care were suboptimal and varied greatly by prefecture and institution; individual and organisational efforts to improve quality of diabetes care would be needed in Japan.

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The association of home and accurately measured office blood pressure with coronary artery calcification among general Japanese men

Satoh A., Arima H., Hozawa A., Ohkubo T., Hisamatsu T., Kadowaki S., Kadota A., Fujiyoshi A., Miyagawa N., Zaid M., Torii S., Okamura T., Sekikawa A., Miura K., Ueshima H.

Journal of Hypertension （Journal of Hypertension） 37 （ 8 ） 1676 - 1681 2019年08月

研究論文（学術雑誌）, ISSN 02636352

© 2019 Wolters Kluwer Health, Inc. All rights reserved. Objective:We conducted a cross-sectional study to clarify whether home blood pressure (HBP) is more strongly associated with coronary artery calcification (CAC) than accurately measured office blood pressure (OBP) among the general population of Japanese men.Methods:We analyzed the data of 919 Japanese male participants who were randomly selected from general population (mean age 64.5 years). OBP was measured twice consecutively by a trained nurse using electrical device after 5 min of complete rest alone in a sitting position in a silent room. The participants were asked to measure HBP with an electrical device once in the morning during 7 consecutive days. CAC was assessed using computed tomography. Presence of CAC was defined as Agatston score at least 10. We calculated odds ratios for the presence of CAC per one SD higher OBP and HBP adjusted for age and other cardiovascular risk factors.Results:The mean systolic OBP (SD) and HBP (SD) were 136.8 (19.0) and 137.2 (18.5) mmHg, respectively, without statistical difference between the two (P = 0.595). OBP and HBP were highly correlated (r = 0.74 P < 0.001). CAC was found in 454 (49.4%) participants. Multivariable-adjusted odds ratios [95% confidence interval (CI)] for the presence of CAC were comparable between OBP (1.32, 95% CI: 1.12-1.56) and HBP (1.35, 95% CI: 1.14-1.60) (P heterogeneity = 0.813).Conclusion:The strength of association of accurately measured OBP with CAC was comparable with that of HBP among randomly selected male general population aged 40-79 years.

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Daily habit of water intake in patients with cerebral infarction before its onset; Comparison with a healthy population: A cross-sectional study

Nishikawa T., Miyamatsu N., Higashiyama A., Hojo M., Nishida Y., Fukuda S., Hirata T., Ichiura K., Kubota Y., Kubo S., Ueba T., Kadota A., Sugiyama D., Okamura T.

Cerebrovascular Diseases （Cerebrovascular Diseases） 47 （ 3-4 ） 143 - 150 2019年07月

研究論文（学術雑誌）, ISSN 10159770

© 2019 S. Karger AG, Basel. Background: While water intake is frequently recommended to prevent cerebral infarction (CI), only few studies have been published on this topic. Objectives: This study retrospectively estimated the daily non-alcohol drink (NAD) intake in CI patients before CI onset and compared it with NAD in healthy subjects. Methods: We performed a cross-sectional study on CI patients in 3 hospitals and healthy subjects in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. Data from 1,287 subjects (274 CI patients and 1,013 healthy subjects) were used for the analyses. By dividing the CI patients into "increased", "unchanged", and "decreased" groups according to their current NAD intake, we compared the NAD intake between these 3 groups and healthy subjects by analyses of covariance and the post hoc test, adjusting for sex, age, surveyed month, body mass index, alcohol drinking history, and smoking history. Under the assumption that the NAD intake in the "unchanged" group was equal to the NAD intake before CI onset, the OR of less NAD intake for CI adjusting for the relevant variables in the "unchanged" group and the healthy subjects was calculated; the cut-off point was chosen using Youden's index. Results: The mean age (mean ± SD) of the participants was 62.8 ± 9.3 years. One hundred and fifty-one patients (36 women) were included in the "increased" group; 105 (30 women), in the "unchanged" group; 18 (2 women), in the "decreased" group; and 1,013 (706 women), in the "healthy" group. The mean NAD intake was 1,702.5 ± 670.2 mL in the "increased" group, 1,494.2 ± 611.2 mL in the "unchanged" group, 1,268.0 ± 596.1 mL in the "decreased" group, and 1,720.6 ± 686.0 mL in the "healthy" group. After adjusting for the relevant variables, a significant difference in NAD intake between the groups was observed (F = 6.1, p < 0.001), and a post hoc test demonstrated significant differences (p < 0.05) in NAD intake between the "healthy" and "unchanged" groups, and between the "increased" and "unchanged" groups. The OR of less NAD intake (<1,570 mL/day, chosen using Youden's index) for CI was 2.48 (95% CI 1.52-4.07). Conclusion: This study showed that daily NAD intake before CI onset in CI patients was less than that in healthy persons, indicating that sufficient intake of NAD may be protective for CI.

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Association of alcohol consumption with fat deposition in a community-based sample of Japanese men: The Shiga epidemiological study of subclinical atherosclerosis (SESSA)

Sumi M., Hisamatsu T., Fujiyoshi A., Kadota A., Miyagawa N., Kondo K., Kadowaki S., Suzuki S., Torii S., Zaid M., Sato A., Arima H., Terada T., Miura K., Ueshima H., Horie M., Nakano Y., Yamamoto T., Hayashi H., Ogawa E., Maegawa H., Miyazawa I., Murata K., Mitsunami K., Nozaki K., Tooyama I., Shiino A., Tsuru T., Ogita H., Shimizu A., Miyamatsu N., Kita T., Kimura T., Nishio Y., Nakamura Y., Okamura T., Sekikawa A., Barinas-Mitchell E.J., Edmundowicz D., Ohkubo T., Hozawa A., Miyagi S., Murakami Y., Okuda N., Kita Y., Higashiyama A., Nagasawa S., Azuma K., Yanagita M., Abbott R.D., Ohno S., Takashima N., Kadowaki T., Saito Y., Ito T., Satoh A., Yamazoe M.

Journal of Epidemiology （Journal of Epidemiology） 29 （ 6 ） 205 - 212 2019年06月

研究論文（学術雑誌）, ISSN 09175040

© 2018 Masaki Sumi et al. Background: Excessive alcohol intake has been shown to be associated with cardiovascular disease via metabolic pathways. However, the relationship between alcohol intake and obesity has not been fully elucidated. We aimed to examine the association of alcohol consumption with fat deposition and anthropometric measures. Methods: From 2006–2008, we conducted a cross-sectional study in a population-based sample of Japanese men aged 40 through 79 years. Areas of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were calculated using computed tomography imaging. Based on a questionnaire, we classified participants into five groups according to weekly alcohol consumption, excluding former drinkers: Non-drinkers (0 g=week), 0.1–160.9, 161–321.9, 322–482.9, and ≥483 g=week. Multivariable linear regression was used to estimate adjusted means of obesity indices for each group. Results: We analyzed 998 men (mean age and body mass index [BMI], 63.8 years and 23.6 kg=m2, respectively). Higher weekly alcohol consumption was strongly and significantly associated with higher abdominal VAT area, percentage of VAT, and VATto- SAT ratio (all P for trend <0.001), and also with waist circumferences and waist-to-hip ratio (P for trend = 0.042 and 0.007, respectively). These associations remained significant after further adjustment for BMI, whereas alcohol consumption had no significant association with abdominal SAT area. Conclusions: Higher alcohol consumption was associated with higher VAT area, VAT%, and VAT-to-SAT ratio, independent of confounders, including BMI, in general Japanese men. These results suggest that alcohol consumption may have a potential adverse effect on visceral fat deposition.

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The impact of sex on risk of cardiovascular disease and all-cause mortality in adults with or without diabetes mellitus: A comparison between the U.S. and Japan

Liu L., Miura K., Kadota A., Fujiyoshi A., Gracely E., Xue F., Liu Z., Takashima N., Miyagawa N., Ohkubo T., Arima H., Okayama A., Okamura T., Ueshima H.

Journal of Diabetes and its Complications （Journal of Diabetes and its Complications） 33 （ 6 ） 417 - 423 2019年06月

研究論文（学術雑誌）, ISSN 10568727

© 2019 Elsevier Inc. Aims: To test a hypothesis that women with diabetes mellitus (DM)versus those without DM had a significantly higher risk of heart disease (HD), stroke and all-cause mortality than their male counterparts in the U.S. as well as in Japan. Methods: We analyzed two nationally representative datasets, one from the U.S. NHANES III cohort (n = 13,169), and the other from the Japan NIPPON DATA90 cohort (n = 7445). Hazard ratios (HRs)of DM for risk of mortality and sex-DM interaction effect on mortality were analyzed prospectively using Cox's proportional hazards regression models. Results: Patients with DM had significantly higher mortality from HD, stroke and all-cause mortality in the U.S. and in Japan. However, the HRs of DM versus non-DM for HD and all-cause mortality were significantly higher in women compared to men in the U.S. (sex-DM interaction: HR = 1.59, p = 0.01, and 1.24, p = 0.045 for HD and all-cause mortality), but the sex-DM interaction effect was not statistically significant in the Japanese cohort. Discussion: Patients with DM had a significantly higher risk of mortality than those without DM in the U.S. and Japan. However, women with DM versus those without DM had a higher relative risk of HD and all-cause mortality than their counterparts in men in the U.S, but this sex difference by DM status was not observed in the Japanese cohort. Whether the sex-difference effect of DM on HD and all-cause mortality is due to a difference in metabolic disorders between the two populations warrants consideration and further studies.

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Socioeconomic and lifestyle factors associated with depressive tendencies in general Japanese men and women: NIPPON DATA2010

Suzuki H., Kadota A., Okuda N., Hayakawa T., Nishi N., Nakamura Y., Arima H., Miyagawa N., Satoh A., Miyamatsu N., Yanagita M., Yatsuya H., Yamagata Z., Ohkubo T., Okamura T., Ueshima H., Okayama A., Miura K.

Environmental Health and Preventive Medicine （Environmental Health and Preventive Medicine） 24 （ 1 ） 37 2019年05月

研究論文（学術雑誌）, ISSN 1342078X

© 2019 The Author(s). Background: The gender-specific characteristics of individuals at an increased risk of developing depression currently remain unclear despite a higher prevalence of depression in women than in men. This study clarified socioeconomic and lifestyle factors associated with an increased risk of subclinical depression in general Japanese men and women. Methods: Study participants were residents not receiving psychiatric treatments in 300 sites throughout Japan in 2010 (1152 men, 1529 women). Multivariable-adjusted odds ratios (OR) and 95% confidence intervals (95%CIs) for socioeconomic factors and lifestyle factors were calculated using a logistic regression analysis. Results: Risk of depressive tendencies was significantly higher in men who were single and living alone (OR, 3.27; 95% CI, 1.56-6.88) than those married. The risk was significantly lower in women who were not working and aged ≥ 60 years (OR, 0.39; 95% CI, 0.22-0.68) and higher in men who were not working and aged < 60 years (OR, 3.57; 95%CI, 1.31-9.72) compared with those who were working. Current smoking was also associated with a significantly increased risk of depressive tendencies in women (OR, 2.96; 95% CI, 1.68-5.22) but not in men. Conclusions: Socioeconomic and lifestyle factors were associated with an increased risk of depressive tendencies in general Japanese. Related factors were different by sex.

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Higher serum uric acid level is inversely associated with renal function assessed by cystatin C in a Japanese general population without chronic kidney disease: The KOBE study

Kubo S., Nishida Y., Kubota Y., Higashiyama A., Sugiyama D., Hirata T., Miyamatsu N., Tanabe A., Hirata A., Tatsumi Y., Kadota A., Kuwabara K., Nishikawa T., Miyamoto Y., Okamura T.

BMC Nephrology （BMC Nephrology） 20 （ 1 ） 117 2019年04月

研究論文（学術雑誌）, ISSN 1471-2369

© 2019 The Author(s). Background: Although several epidemiological studies have suggested that high serum uric acid (SUA) levels are related to a decline in kidney function, only a few studies have investigated using cystatin C to calculate estimated glomerular filtration rate (eGFR). We aimed to clarify the relationship between SUA levels and kidney function assessed by cystatin C in a Japanese general community population without chronic kidney disease (CKD). Methods: We conducted a community-based cross-sectional study that included 1086 healthy participants, aged 40-74 years, without CKD and not undergoing treatment of hyperuricemia, who had participated in the baseline survey of the Kobe Orthopedic and Biomedical Epidemiological (KOBE) study. The preconditions for participation in this study were no past histories of cardiovascular disease or cancer, and not undergoing treatment for diabetes, hypertension, or dyslipidemia. We classified the participants into quartiles stratified by sex according to their SUA level and then examined the relationship with eGFR. The odds ratios for having a low eGFR, defined as the lowest quartile of eGFR (i.e., ≤78.4 mL/min/1. 73m 2 ) was estimated according to SUA quartiles (men, Q1 ≤ 5.0, Q2 5.1-5.9, Q3 6.0-6.6, and Q4 ≥ 6.7; women, Q1 ≤ 3.8, Q2 3.9-4.3, Q3 4.4-4.9, and Q4 ≥ 5.0 mg/dL) after adjustment for age, body mass index, systolic blood pressure, HbA1c, high and low density lipoprotein cholesterol, and smoking and drinking habits. The adjusted mean of each quartile was also calculated. Results: Multivariable-adjusted means of eGFR showed a graded decrease in higher SUA quartiles (men, Q1 90.5, Q2 88.0, Q3 83.5, and Q4 82.0; women, Q1 95.7, Q2 91.3, Q3 89.2, and Q4 86.7). In addition, the multivariable-adjusted odds ratios for having a lower eGFR (95% confidence interval) for each SUA quartile compared with Q1 was Q2 2.29 (0.98, 5.35), Q3 4.94 (2.04, 11.97), and Q4 8.01 (3.20, 20.04) for men, and was Q2 2.20 (1.12, 4.32), Q3 2.68 (1.39, 5.20), and Q4 4.96 (2.62, 9.41) for women. Conclusions: There was a graded inverse relationship between mild elevations in SUA levels and eGFR assessed by cystatin C in an apparently healthy Japanese population without CKD. This association was similar in both men and women.

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Associations of Overweight, Obesity, and Underweight With High Serum Total Cholesterol Level Over 30 Years Among the Japanese Elderly: NIPPON DATA 80, 90, and 2010

Shibata Yosuke, Ojima Toshiyuki, Nakamura Mieko, Kuwabara Kazuyo, Miyagawa Naoko, Saito Yoshino, Nakamura Yasuyuki, Kiyohara Yutaka, Nakagawa Hideaki, Fujiyoshi Akira, Kadota Aya, Ohkubo Takayoshi, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki, Ueshima Hirotsugu, Miura Katsuyuki, Okayama Akira, Okamura Tomonori, Okayama Akira, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Okamura Tomonori, Saitoh Shigeyuki, Sakata Kiyomi, Hozawa Atsushi, Hayakawa Takehito, Nakamura Yosikazu, Nishi Nobuo, Okuda Nagako, Okamura Tomonori, Murakami Yoshitaka, Ohkubo Takayoshi, Kasagi Fumiyoshi, Izumi Toru, Matsumura Yasuhiro, Ojima Toshiyuki, Tamakoshi Koji, Nakagawa Hideaki, Kita Yoshikuni, Miura Katsuyuki, Kadota Aya, Miyamatsu Naomi, Nakamura Yasuyuki, Yoshita Katsushi, Miyamoto Yoshihiro, Kodama Kazunori, Kiyohara Yutaka

JOURNAL OF EPIDEMIOLOGY （Journal of Epidemiology） 29 （ 4 ） 133 - 138 2019年04月

研究論文（学術雑誌）, ISSN 0917-5040

© 2018 Yosuke Shibata et al. Background: The trend of association between overweight and high serum total cholesterol (TC) among the elderly is unclear. In addition, there is little evidence of risk of underweight for high TC. Therefore, we examined the trend of association of overweight or underweight with high TC among Japanese elderly people using nationwide population-based data. Methods: Data of the National Survey on Circulatory Disorders and National Health and Nutrition Survey for 1980, 1990, 2000, and 2010 were used in the analysis. High TC was defined as 220mg=dL and above. For participants aged =50 years, sex-specific odds ratios (ORs) of overweight or underweight compared with normal body mass index participants for high TC were calculated using a logistic regression model adjusted for age, smoking, drinking, exercise, food, and treatment of hyperlipidemia. Results: A total of 5,734, 4,673, 5,059, and 2,105 participants enrolled in these surveys in 1980, 1990, 2000, and 2010, respectively. Although overweight was positively and significantly associated with high TC in 1980, the association has gradually weakened since (ORs in 1980 and 2010 were 2.44; 95% confidence interval [CI], 1.83-3.24 and 0.92; 95% CI, 0.66-1.27 among men and 1.43; 95% CI, 1.18-1.72 and 1.08; 95% CI, 0.81-1.44 among women, respectively). While underweight was inversely and significantly associated with high TC in 1980, the association also gradually weakened among women (ORs in 1980 and 2010 were 0.28; 95% CI, 0.12-0.60 and 0.37; 95% CI, 0.10-1.28 among men and 0.39; 95% CI, 0.26-0.57 and 0.96; 95% CI, 0.58-1.57 among women, respectively). Conclusions: These findings provide evidence that high TC prevention efforts must expand the target to not only overweight but also to normal and underweight people.

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One-year weight loss maintenance outcomes following a worksite-based weight reduction program among Japanese men with cardiovascular risk factors

Tsukinoki R., Okamura T., Okuda N., Kadota A., Murakami Y., Yanagita M., Miyamatsu N., Miura K., Ueshima H.

Journal of Occupational Health （Journal of Occupational Health） 61 （ 2 ） 189 - 196 2019年03月

研究論文（学術雑誌）, ISSN 13419145

© 2019 Japan Society for Occupational Health. Objectives: Worksite-based programs present a simple and effective approach to facilitate weight reduction in employees. Despite the importance of 1-year weight loss maintenance, studies have generally focused on the short-term effects of weight reduction programs. In addition, little is known about the long-term weight maintenance outcomes in Asian populations. We examined the long-term maintenance effects of a worksite-based weight reduction program among Japanese men with cardiovascular risk factors. Methods: The study sample comprised 58 overweight men with cardiovascular risk factors who had voluntarily participated in a randomized crossover trial involving a 3-month weight reduction program. Participants were followed up for 1 year after the trial concluded, and both groups were merged for the analysis. We compared the changes in body weight before the post-trial follow-up and after 12 months to examine the long-term maintenance effects of the program. Changes in other cardiovascular risk factors (eg, waist circumference, blood pressure, lipid measures, and diabetes-related measures) were also examined. Results: Both groups of study participants achieved weight loss during the weight reduction program. Total 53 participants (91.4%) completed the 12-month post-trial follow-up. There were no significant changes in mean body weight (mean: -0.11, 95% confidence interval: -0.7-0.49 kg) and other cardiovascular risk factors between the beginning and end of the follow-up period. Conclusions: This study showed that the worksite-based weight reduction program not only enabled short-term weight loss, but that the participants were able to successfully maintain their weight for 1 year after the program without any supplementary interventions.

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Association of blood pressure with estimates of 24-h urinary sodium and potassium excretion from repeated single-spot urine samples

Trang Thi Minh Nguyen, Miura Katsuyuki, Tanaka-Mizuno Sachiko, Tanaka Taichiro, Nakamura Yasuyuki, Fujiyoshi Akira, Kadota Aya, Tamaki Junko, Takebayashi Toru, Okamura Tomonori, Ueshima Hirotsugu

HYPERTENSION RESEARCH （Hypertension Research） 42 （ 3 ） 411 - 418 2019年03月

研究論文（学術雑誌）, ISSN 0916-9636

© 2018, The Japanese Society of Hypertension. While the association between 24-h urinary sodium and potassium excretion with blood pressure is well established, the relationships of these ions to spot urine measurements are unclear. Our purpose is to assess the association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. Spot urine and blood pressure were collected annually during a 5-year period from 4360 Japanese workers with ages ranging from 19 to 55 years. Estimates of 24-h sodium and potassium excretion were based on Tanaka’s formula. Overall, a single standard deviation increase in the estimated sodium excretion (36.5 mmol/day) was associated with a 1.3 mmHg higher systolic blood pressure and a 0.8 mmHg higher diastolic blood pressure (P < 0.001). A single standard deviation increase in estimated potassium excretion (8.9 mmol/day) was associated with a 1.1 mmHg lower systolic blood pressure and a 0.7 mmHg lower diastolic blood pressure (P < 0.001). As a combined measure of the excretion of both electrolytes, the estimated 24-h sodium-to-potassium ratio was positively associated with both blood pressures (P < 0.001). Associations of blood pressure with sodium and the sodium-to-potassium ratio increased with age and were stronger in men compared to women. Associations with potassium and the sodium-to-potassium ratio were stronger in individuals who were overweight. The findings provide evidence for an association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. As convenient measures of dietary intake for each electrolyte, repeated spot urine samples may be useful for assessing hypertension risk, especially in men, older individuals, and overweight individuals.

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Impact of Hypertension on Hospitalizations for Cardiovascular Diseases in a Worksite Population: An Epidemiologic Study Using Claims Data for Workers

Fukushima Ayako, Khabtheni Wafa, Guelfucci Florent, Onishi Yoshie, Sugiyama Daisuke, Okamura Tomonori, Toumi Mondher

AMERICAN JOURNAL OF HYPERTENSION （American Journal of Hypertension） 32 （ 3 ） 298 - 307 2019年03月

研究論文（学術雑誌）, ISSN 0895-7061

© 2018 American Journal of Hypertension, Ltd. All rights reserved. BACKGROUND Few of studies investigated the effect of antihypertensives among working population. We aimed to describe the impact of hypertension with and without antihypertensives on hospitalizations because of cardiovascular diseases (CVDs) in the Japanese working population. METHODS This retrospective study included adults aged 40-64 years whose systolic and diastolic blood pressure (BP) readings taken between 2008 and 2015 were available in the Japanese claims database. Individuals were categorized as treated (T) or untreated (UT) depending on their hypertension treatment history. Time to first CVD-related hospitalization was compared among individuals with different BP levels using Cox models that included baseline characteristics with either baseline BP level or a time-dependent variable reflecting BP changes over time. RESULTS Of 740,784 UT individuals (male: 61.9%, mean age: 47.9 years), 2,121 individuals were hospitalized due to a CVD over a 957.3-day average follow-up. Among 72,828 T individuals (male: 74.3%, mean age: 53.7 years), the corresponding figure was 470 individuals over an 813.4-day average follow-up. The risk of hospitalization increased with baseline hypertension severity among UT (hazard ratios [HRs] = 1.93, 2.82, and 6.32 for grade 1, grade 2, and grade 3, respectively; P < 0.0001, reference: Optimal) but not among T individuals. UT individuals with hypertension at any given time had a significantly higher probability of hospitalization compared to nonhypertensive individuals (HR = 1.74, P < 0.0001). CONCLUSIONS This study adds quantitative evidence on the impact of hypertension on the risk of CVD-related hospitalization in the Japanese working population. It suggests that antihypertensive treatment had beneficial effects in this relatively young, working population aged 40-64 years.

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Longitudinal Trajectories of Fasting Plasma Glucose and Risks of Cardiovascular Diseases in Middle Age to Elderly People Within the General Japanese Population: The Suita Study

Ogata Soshiro, Watanabe Makoto, Kokubo Yoshihiro, Higashiyama Aya, Nakao Yoko M., Takegami Misa, Nishimura Kunihiro, Nakai Michikazu, Kiyoshige Ed, Hosoda Kiminori, Okamura Tomonori, Miyamoto Yoshihiro

JOURNAL OF THE AMERICAN HEART ASSOCIATION （Journal of the American Heart Association） 8 （ 3 ） e010628 2019年02月

研究論文（学術雑誌）, ISSN 2047-9980

Background Few previous studies used information on changes in fasting plasma glucose ( FPG ) assessed at multiple points in time in relationship to cardiovascular disease ( CVD ) incidence. The present study aimed to identify subgroups of FPG trajectories with assessing CVD incidence. Methods and Results The present study was based on the Suita study, a population-based cohort study in Japan. The primary outcome was incidence of the first CVD events consisting of stroke and coronary heart diseases between 1989 and 2013. The main exposure was FPG assessed every 2 years. We used joint latent class mixed models to derive FPG trajectories over time while evaluating cumulative incidence of CVD , and categorized participants into several subgroups based on those trajectories and cumulative incidence. We observed 356 and 243 CVD events during the median follow-up of 17.2 and 20.2 years among 3120 men and 3482 women, respectively. The joint latent mixed models found 3 subgroups in men and 2 subgroups in women. Of the 3 subgroups in men, 1 subgroup had FPG levels that increased sharply (96.5-205.0 mg/dL from aged 40 to 80 years) and higher CVD cumulative incidence. Of the 2 subgroups in women, 1 subgroup had FPG levels that increased sharply (97.7-190.5 mg/dL from aged 40 to 80 years) and tended to have slightly higher CVD incidence compared with the other subgroup. Conclusion It can be important to manage CVD risk factors especially for people whose FPG trajectories sharply increased to prevent CVD .

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Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium

Inker L., Grams M., Levey A., Coresh J., Cirillo M., Collins J., Gansevoort R., Gutierrez O., Hamano T., Heine G., Ishikawa S., Jee S., Kronenberg F., Landray M., Miura K., Nadkarni G., Peralta C., Rothenbacher D., Schaeffner E., Sedaghat S., Shlipak M., Zhang L., van Zuilen A., Hallan S., Kovesdy C., Woodward M., Levin A., Astor B., Appel L., Greene T., Chen T., Chalmers J., Arima H., Perkovic V., Yatsuya H., Tamakoshi K., Li Y., Hirakawa Y., Matsushita K., Grams M., Sang Y., Polkinghorne K., Chadban S., Atkins R., Djurdjev O., Liu L., Zhao M., Wang F., Wang J., Ebert N., Martus P., Tang M., Heine G., Emrich I., Seiler S., Zawada A., Nally J., Navaneethan S., Schold J., Shlipak M., Sarnak M., Katz R., Hiramoto J., Iso H., Yamagishi K., Umesawa M., Muraki I., Fukagawa M., Maruyama S., Hasegawa T., Fujii N., Wheeler D., Emberson J.

American Journal of Kidney Diseases （American Journal of Kidney Diseases） 73 （ 2 ） 206 - 217 2019年02月

研究論文（学術雑誌）, ISSN 02726386

© 2018 National Kidney Foundation, Inc. Rationale & Objective: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. Study Design: Cross-sectional individual participant-level analyses in a global consortium. Setting & Study Populations: 17 CKD and 38 general population and high-risk cohorts. Selection Criteria for Studies: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. Data Extraction: Data were obtained and analyzed between July 2015 and January 2018. Analytical Approach: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. Results: The CKD cohorts (n = 254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n = 1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59 mL/min/1.73 m 2 ), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30 mg/g). Limitations: Variations in study era, health care delivery system, typical diet, and laboratory assays. Conclusions: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

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Having few remaining teeth is associated with a low nutrient intake and low serum albumin levels in middle-aged and older Japanese individuals: findings from the NIPPON DATA2010

Nakamura Mieko, Ojima Toshiyuki, Nagahata Tomomi, Kondo Imako, Ninomiya Toshiharu, Yoshita Katsushi, Arai Yusuke, Ohkubo Takayoshi, Murakami Keiko, Nishi Nobuo, Murakami Yoshitaka, Takashima Naoyuki, Okuda Nagako, Kadota Aya, Miyagawa Naoko, Kondo Keiko, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE （Environmental Health and Preventive Medicine） 24 （ 1 ） 1 2019年01月

研究論文（学術雑誌）, ISSN 1342-078X

© 2019 The Author(s). Background: Oral health is thought to be associated with diet quality, and socioeconomic status (SES) affects both oral health and diet. The aim of this study was to investigate the association between the number of teeth and dietary intake as well as nutritional biomarker, considering the subjects' SES. Methods: We conducted a cross-sectional analysis of data from 2049 individuals aged ≥ 50 years from the National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 2010. The number of remaining teeth was categorized into age-specific quartiles (Q1 to Q4). We assessed the adjusted means and 95% confidence intervals for dietary variables by the number of teeth using analysis of covariance. Stratified analyses by SES were also conducted. Results: The intake of grain products was 31 g higher, and those of vegetables and meat were 30 g and 8 g lower, respectively, in Q1 (fewer teeth) than in Q4 (more teeth). Carbohydrate intake was higher whereas protein, minerals (potassium, magnesium, and zinc), vitamins (vitamins A, E, B 1 , B 6 , β-carotene, and folic acid), and dietary fiber intakes were lower among individuals with fewer teeth. Adjusted mean serum albumin levels were low in Q1. The associations between the number of teeth and dietary intake were more evident in individuals with a low SES. Conclusions: Having few remaining teeth was associated with a low nutrient intake and low serum albumin levels in middle-aged and older Japanese adults, and these associations were more evident in individuals with low SES.

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Lifetime Risk of Stroke and Coronary Heart Disease Deaths According to Blood Pressure Level: EPOCH-JAPAN (Evidence for Cardiovascular Prevention From Observational Cohorts in Japan)

Satoh Michihiro, Ohkubo Takayoshi, Asayama Kei, Murakami Yoshitaka, Sugiyama Daisuke, Yamada Michiko, Saitoh Shigeyuki, Sakata Kiyomi, Irie Fujiko, Sairenchi Toshimi, Ishikawa Shizukiyo, Kiyama Masahiko, Ohnishi Hirofumi, Miura Katsuyuki, Imai Yutaka, Ueshima Hirotsugu, Okamura Tomonori, Iso Hiroyasu, Kitamura Akihiko, Ninomiya Toshiharu, Kiyohara Yutaka, Nakagawa Hideaki, Nakayama Takeo, Okayama Akira, Sairenchi Toshimi, Tamakoshi Akiko, Tsuji Ichiro, Miyamoto Yoshihiro, Ishikawa Shizukiyo, Yatsuya Hiroshi, Okamura Tomonori

HYPERTENSION （Hypertension） 73 （ 1 ） 52 - 59 2019年01月

研究論文（学術雑誌）, ISSN 0194-911X

© 2018 American Heart Association, Inc. Lifetime risk (LTR) provides an absolute risk assessment during the remainder of one's life. Few studies have focused on the LTRs of stroke and coronary heart disease (CHD), categorized by fine blood pressure in Asian populations. We aimed to assess it using a large database of a meta-analysis with the individual participant data. The present meta-analysis included 107 737 Japanese (42.4% men; mean age, 55.1 years) from 13 cohorts. During the mean follow-up of 15.2±5.3 years (1 559 136 person-years), 1922 died from stroke and 913 from CHD. We estimated risks after adjusting for competing risk of death other than the outcome of interest. The 10-year risk of stroke and CHD deaths at index age of 35 years was ≤1.9% and ≤0.3%, respectively. The LTRs of stroke death at the index age of 35 years (men/women) were 6.1%/4.8% for optimal, 5.7%/6.3% for normal, and 6.6%/6.0% for high-normal blood pressure groups, and 9.1%/7.9% for grade 1, 14.5%/10.3% for grade 2, and 14.6%/14.3% for grade 3 hypertension groups. The LTRs of CHD death similarly elevated with an increase in blood pressure but were lower (≤7.2%) than those of stroke death. In conclusion, blood pressure was clearly associated with an elevated LTR of stroke or CHD death, although the LTR of CHD death was one-half of that of stroke death in an Asian population. These results would help young people with hypertension to adopt a healthy lifestyle or start antihypertensive therapy early.

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Okami Yukiko, Ueshima Hirotsugu, Nakamura Yasuyuki, Kondo Keiko, Kadota Aya, Okuda Nagako, Okamura Tomonori, Miura Katsuyuki, Fujiyoshi Akira, Hozawa Atsushi, Kadota Aya, Kasagi Fumiyoshi, Nakagawa Hideaki, Toyoshima Hideaki, Yanagawa Hiroshi, Yoshita Katsushi, Kodama Kazunori, Ueda Kazuo, Sakata Kiyomi, Tamakoshi Koji, Okuda Nagako, Miyamatsu Naomi, Nishi Nobuo, Saitoh Shigeyuki, Tokudome Shinkan, Okubo Takayoshi, Hayakawa Takehito, Izumi Toru, Ojima Toshiyuki, Matsumura Yasuhiro, Miyamoto Yoshihiro, Kita Yoshikuni, Murakami Yoshitaka, Nakamura Yoshikazu, Kiyohara Yutaka

CIRCULATION JOURNAL （Circulation Journal） 83 （ 1 ） 147 - + 2019年01月

研究論文（学術雑誌）, ISSN 1346-9843

© 2019, Japanese Circulation Society. All rights reserved. Background: In recent years, individuals with high serum total cholesterol (TC) have been more likely to modify their diet by reducing their intake of dietary lipids. The aim of this study was to investigate time-related changes in the relationships between the Keys score, dietary lipids, and TC between 1980 and 2010 in representative Japanese populations. Methods and Results: We used 3 cross-sectional cohort studies conducted among Japanese representative populations in 1980, 1990, and 2010 (NIPPON DATA80/90/2010) for the analyses. We analyzed data for 10,365, 7,714, and 2,657 participants, respectively, in each dataset. The relationships between TC and the Keys score (calculated by dietary lipids, cholesterol, and energy intake)/ dietary lipids were examined. In men, a 1-unit higher Keys score correlated with 0.92 mg/dL and 0.64 mg/dL TC in 1980 and 1990, respectively, but not in 2010. In women, a 1-unit higher Keys score correlated with 0.70 mg/dL and 0.74 mg/dL TC in 1980 and 1990, respectively, but with 0.33 mg/dL in 2010. In men and women, dietary cholesterol, saturated fatty acid (SFA), and trans fatty acid (TFA) levels were positively associated with TC concentrations in 1980 and 1990, but not in 2010. Conclusions: In these representative Japanese populations, a higher Keys score as well as dietary cholesterol, SFA, and TFA levels correlated with higher TC concentrations in 1980/1990, but the relationships were weaker or not observed in 2010.

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Vegetable protein intake was inversely associated with cardiovascular mortality in a 15-year follow-up study of the general Japanese population

Kurihara A., Okamura T., Sugiyama D., Higashiyama A., Watanabe M., Okuda N., Kadota A., Miyagawa N., Fujiyoshi A., Yoshita K., Ohkubo T., Okayama A., Miura K., Ueshima H.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 26 （ 2 ） 198 - 206 2019年

研究論文（学術雑誌）, ISSN 13403478

© 2019 Japan Atherosclerosis Society. Aim: To examine the relationship between the intake of dietary vegetable protein and CVD mortality in a 15-year follow-up study of a representative sample of the Japanese population. Methods: A total of 7,744 participants aged 30 years or older (3,224 males and 4,520 females) who were free of CVD at baseline were included in this analysis. Vegetable protein intake (% energy) was assessed using a threeday semi-weighed dietary record at baseline. Multivariable-adjusted hazard ratios (HRs) were calculated using Cox’s proportional hazards model after adjusting for confounding factors. Results: The total person-years studied were 107,988 with a mean follow-up period of 13.9 years. There were 1,213 deaths during the follow-up period, among which 354 (29.2%) were due to CVD. Vegetable protein intake was associated inversely with CVD and cerebral hemorrhage mortality, with the HRs for a 1% energy increment in vegetable protein intake being 0.86 (95% CI, 0.75-0.99) and 0.58 (95% CI, 0.35-0.95), respectively. In the subgroup analysis of participants with or without hypertension, the inverse association between vegetable protein intake and CVD mortality was more evident in the nonhypertensive group, with the HRs for CVD and stroke being 0.68 (95% CI, 0.50- 0.94) and 0.50 (95% CI, 0.30-0.84), respectively. Conclusions: Vegetable protein intake may prevent future CVD, particularly in nonhypertensive subjects in the Japanese population. However, further studies are necessary to examine the biological mechanisms of this effect.

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Household Salt Intake Level is Associated With All-Cause, Cardiovascular and Stroke Mortality: A 24-Year Follow-Up of Nippon Data80

Shima Azusa, Miyamatsu Naomi, Miura Katsuyuki, Miyagawa Naoko, Okuda Nagako, Nishi Nobuo, Yoshita Katsushi, Kadota Aya, Suzuki Harumitsu, Kondo Keiko, Okamura Tomonori, Okayama Akira, Ueshima Hirotsugu

CIRCULATION 139 2019年

研究論文（学術雑誌）, ISSN 0009-7322

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Differences Between Coronary Artery Calcification and Aortic Artery Calcification in Relation to Cardiovascular Disease Risk Factors in Japanese Men

Kimani Cecilia, Kadota Aya, Miura Katsuyuki, Fujiyoshi Akira, Zaid Maryam, Kadowaki Sayaka, Hisamatsu Takashi, Arima Hisatomi, Horie Minoru, Ueshima Hirotsugu, Yamamoto Takashi, Maegawa Hiroshi, Murata Kiyoshi, Nozaki Kazuhiko, Shiino Akihiko, Toyama Ikuo, Tsuru Teruhiko, Ogita Hisakazu, Takashima Naoyuki, Kadowaki Takashi, Miyamatsu Naomi, Miyagawa Naoko, Torii Sayuki, Hayashi Hideki, Nakano Yasutaka, Ogawa Emiko, Miyazawa Itsuko, Shimizu Akio, Abbott Robert D., Kondo Keiko, Suzuki Sentaro, Ito Takahiro, Andoh Akira, Kunimura Ayako, Nishio Yoshihiko, Mitsunami Kenichi, Kita Toru, Kimura Takeshi, Tabara Yasuharu, Nakamura Yasuyuki, Okamura Tomonori, Sekikawa Akira, Barinas-Mitchell Emma J. M., Ohkubo Takayoshi, Kita Yoshikuni, Murakami Yoshitaka, Hozawa Atsushi, Okuda Nagako, Higashiyama Aya, Ohno Seiko, Nagasawa Shinya, Yamazo Masahiro, Saito Yoshino, Edmundowicz Daniel, Satoh Atsushi, Azuma Koichiro, Yanagita Masahiko, Sawamura Tatsuya, Igase Michiya

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 26 （ 5 ） 452 - 464 2019年

研究論文（学術雑誌）, ISSN 1340-3478

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Cardiovascular risk assessment chart by dietary factors in Japan: NIPPON DATA80

Kondo K., Miura K., Tanaka-Mizuno S., Kadota A., Arima H., Okuda N., Fujiyoshi A., Miyagawa N., Yoshita K., Okamura T., Okayama A., Ueshima H.

Circulation Journal （Circulation Journal） 83 （ 6 ） 1254 - 1260 2019年

研究論文（学術雑誌）, ISSN 13469843

© 2019, Japanese Circulation Society. All rights reserved. Background: Many studies show that dietary factors such as vegetables, fruit, and salt are associated with cardiovascular disease (CVD) risk. However, a risk assessment chart for CVD mortality according to combinations of dietary factors has not been established. Methods and Results: Participants were 9,115 men and women aged 30–79 years enrolled in the National Nutritional Survey of Japan in 1980 with a 29-year follow-up. Dietary intake was assessed using a 3-day weighed dietary record at baseline. Cox regression models were used to estimate the hazard ratio (HR) of CVD mortality stratified by vegetables, fruit, fish, and salt consumption. HRs of CVD mortality according to combinations of dietary factors were color coded on an assessment chart. Higher intakes of vegetables, fruit, and fish, and lower salt intake were associated with lower CVD mortality risk. HRs calculated from combinations of dietary factors were displayed using 5 colors corresponding to the magnitude of the HR. People with the lowest intake of vegetables, fruit, and fish, and higher salt intake had a HR of 2.87 compared with those with the highest intake of vegetables, fruit, and fish, and lower salt intake. Conclusions: Vegetables, fruit, fish, and salt intake were independently associated with CVD mortality risk. The assessment chart generated could be used in Japan as an educational tool for CVD prevention.

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Association of work situation with cardiovascular disease mortality risk among working-age Japanese men: A 20-year follow-up of NIPPON DATA90

Okuda N., Kadota A., Nishi N., Miura K., Ohkubo T., Miyagawa N., Satoh A., Kita Y., Hayakawa T., Takashima N., Fujiyoshi A., Okayama A., Okamura T., Ueshima H.

Circulation Journal （Circulation Journal） 83 （ 7 ） 1506 - 1513 2019年

研究論文（学術雑誌）, ISSN 13469843

© 2019, Japanese Circulation Society. All rights reserved. Background: Several cohort studies have demonstrated an association between socioeconomic status (SES) and health outcomes in Japan. As long-term employment is common in Japan, the size of the company may be related to cardiovascular disease (CVD) mortality risk. We examined the association of employment conditions with CVD mortality risk among working-age Japanese men (30–59 years, n=2,091). Methods and Results: We used 20-year follow-up data from NIPPON DATA90, for which baseline data were obtained from the 4th National Survey on Circulatory Disorders in 1990. Participants were classified into 4 groups: 3 strata for indefinite-term employees according to company size (large company/public office, moderate-sized, or small), and the self-employed/administrator group. Multivariable-adjusted hazard ratios (HRs) were adjusted for age, lifestyle, and CVD risk factors. Smokers were more common, habitual exercise was less common, and the average systolic blood pressure was higher among indefinite-term employees of small companies compared with employees at large companies/public offices. There was no significant difference in the total CVD mortality risk between indefinite-term employees and self-employed/administrator participants. The age-adjusted HR (95% confidence interval) for total CVD using indefinite-term employees of large companies/public office as a reference was 2.53 (1.12, 5.69) for employees of small companies. Conclusions: Working as an indefinite-term employee at a small company in Japan was significantly associated with elevated risk of CVD mortality among Japanese men.

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Association between body mass index and all-cause death in japanese population: Pooled individual participant data analysis of 13 cohort studies

Hozawa A., Hirata T., Yatsuya H., Murakami Y., Kuriyama S., Tsuji I., Sugiyama D., Satoh A., Tanaka-Mizuno S., Miura K., Ueshima H., Okamura T.

Journal of Epidemiology （Journal of Epidemiology） 29 （ 12 ） 457 - 463 2019年

研究論文（学術雑誌）, ISSN 09175040

© 2018 Atsushi Hozawa et al. Background: We sought to investigate the optimal values of BMI for the lowest risk of all-cause death and whether the optimal BMI differs according to smoking status in large-scale pooled analysis of 13 Japanese cohorts. Methods: Data from 179,987 participants of 13 well-qualified cohort studies conducted throughout Japan were used for our analysis. A cohort-stratified Cox proportional hazard model was used. P values for interactions were calculated based on the cross product of BMI and age, sex, or smoking status. Results: In the entire study population, all-cause mortality risk was lowest when the BMI was 22.0–24.9 kg=m2. This was also the case for selected healthy participants (never smoked, baseline total cholesterol level ≥4.1 mmol=L; the first 5 years of follow-up data were excluded). No effect modification of age, sex, or smoking status was observed. Regardless of their BMI, never smokers always had a lower all-cause mortality risk than did current smokers even with an ideal BMI in terms of mortality risk. Conclusion: A BMI of 22–24.9 kg=m2 correlated with the lowest risk of mortality, regardless of whether all participants or selected healthy participants were analyzed. The fact that smoking was more strongly associated with mortality than obesity emphasizes the urgency for effective anti-smoking programs.

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A novel cell-free, non-fluorescent method to measure lox-1-binding activity corresponding to the functional activity of hdl

Kakino A., Usami Y., Horiuchi S., Fujita Y., Kotani K., Chen C., Okamura T., Sawamura T.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 26 （ 11 ） 947 - 958 2019年

研究論文（学術雑誌）, ISSN 13403478

©2019 Japan Atherosclerosis Society. Aims: A functional abnormality in high-density lipoprotein (HDL) particles rather than a quantitative abnormality in HDL cholesterol levels has been suggested to promote atherosclerosis. The modification of HDL may underlie functional changes to HDL such as gaining the ability to bind and activate the lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1). We aimed to develop a novel method for measuring modified HDL on the basis of its binding to LOX-1. Methods: We designed a LOX-1 binding–based enzyme-linked immunosorbent assay (ELISA) with recombinant LOX-1 and anti-apoAI antibody. A lipid-free standard was devised by making a chimeric fusion protein containing anti-LOX-1 antibody and human apoAI fragment. We used this system to detect modified HDL, designated as LOX-1 ligand containing apoAI (LAA). Results: With our ELISA system, we detected HDL modified by copper oxidation, hypochlorous acid, 4-hydroxynonenal, and potassium cyanate, but not native HDL. Upon oxidation, HDL showed increased LOX-1 binding activity and decreased cholesterol efflux and paraoxonase-1 activities. In the ELISA, the chimeric fusion protein standard showed minimal variation in reference binding curves in contrast to copper-oxidized HDL preparations, suggesting better quality control of the chimeric fusion protein as the standard for measuring modified HDL activity. LAA was detectable in the plasma of healthy individuals and of mice fed a high-fat diet. Conclusion: We have developed a novel ELISA by using recombinant LOX-1 and anti-apoAI antibody to measure the activity of modified HDL in plasma.

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Anthropometric Obesity Indices were Stronger than CT-Based Indices in Associations with Carotid Intima-Media Thickness in Japanese Men

Liu Yuyan, Fujiyoshi Akira, Arima Hisatomi, Kadota Aya, Kadowaki Sayaka, Hisamatsu Takashi, Miyazawa Itsuko, Kondo Keiko, Tooyama Ikuo, Miura Katsuyuki, Ueshima Hirotsugu, Horie Minoru, Nakano Yasutaka, Yamamoto Takashi, Ogawa Emiko, Maegawa Hiroshi, Murata Kiyoshi, Mitsunami Kenichi, Nozaki Kazuhiko, Shiino Akihiko, Araki Isao, Tsuru Teruhiko, Toyama Ikuo, Ogita Hisakazu, Kurita Souichi, Maeda Toshinaga, Miyamatsu Naomi, Kita Toru, Kimura Takeshi, Nishio Yoshihiko, Nakamura Yasuyuki, Okamura Tomonori, Sekikawa Akira, Barinas-Mitchell Emma J. M., Edmundowicz Daniel, Ohkubo Takayoshi, Hozawa Atsushi, Okuda Nagako, Higashiyama Aya, Nagasawa Shinya, Kita Yoshikuni, Murakami Yoshitaka, Takashima Naoyuki, Kadowaki Takashi, Abbott Robert D., Ohno Seiko, Zaid Maryam, Miyagawa Naoko, Torii Sayuki, Saito Yoshino, Suzuki Sentaro, Ito Takahiro

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 26 （ 12 ） 1102 - 1114 2019年

研究論文（学術雑誌）, ISSN 1340-3478

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Carotid Intima-Media Thickness and Plaque in Apparently Healthy Japanese Individuals with an Estimated 10-Year Absolute Risk of CAD Death According to the Japan Atherosclerosis Society (JAS) Guidelines 2012: The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) (vol 20, pg 755, 2013)

Kadota Aya, Miura Katsuyuki, Okamura Tomonori, Fujiyoshi Akira, Ohkubo Takayoshi, Kadowaki Takashi, Takashima Naoyuki, Hisamatsu Takashi, Nakamura Yasuyuki, Kasagi Fumiyoshi, Maegawa Hiroshi, Kashiwagi Atsunori, Ueshima Hirotsugu

JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 26 （ 8 ） 746 - 746 2019年

研究論文（学術雑誌）, ISSN 1340-3478

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Employment and health after retirement in Japanese men

Okamoto Shohei, Okamura Tomonori, Komamura Kohei

BULLETIN OF THE WORLD HEALTH ORGANIZATION （Bulletin of the World Health Organization） 96 （ 12 ） 826 - 833 2018年12月

研究論文（学術雑誌）, ISSN 0042-9686

© 2018, World Health Organization. All rights reserved. Objective To estimate the average treatment effect of working past the current retirement age on the health of Japanese men. Methods We used publicly available data from the National Survey of Japanese Elderly, extracting a sample of 1288 men who were 60 years or older. Survey respondents were followed-up for at most 15 years for the onset of four health outcomes: death, cognitive decline, stroke and diabetes. By using the propensity score method, we adjusted for the healthy worker effect by incorporating economic, sociodemographic and health data in the form of independent variables. By calculating the differences in times to a health outcome between those in employment and those not employed, we estimated the average treatment effects on health of being in paid work past retirement age. Findings Compared with those not employed, those in employment lived 1.91 years longer (95% confidence interval, CI: 0.70 to 3.11), had an additional 2.22 years (95% CI: 0.27 to 4.17) before experiencing cognitive decline, and had a longer period before the onset of diabetes and stroke of 6.05 years (95% CI: 4.44 to 7.65) and 3.35 years (95% CI: 1.42 to 5.28), respectively. We also observed differences between employees and the self-employed: the self-employed had longer life expectancies than employees. In terms of years to onset of diabetes or stroke, however, we only observed significant benefits to health of being an employee but not self-employed. Conclusion Our study found that being in employment past the current age of retirement had a positive impact on health.

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Response to the letter entitled "Extremely high levels of high-density lipoprotein cholesterol and increased risk of cardiovascular mortality"

Hirata Aya, Okamura Tomonori

JOURNAL OF CLINICAL LIPIDOLOGY 12 （ 6 ） 1551 - 1551 2018年12月

研究論文（学術雑誌）, ISSN 1933-2874

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The Japanese Society of Hypertension-Digest of plan for the future.

Node K, Kishi T, Tanaka A, Itoh H, Rakugi H, Ohya Y, Miura K, Okamura T, Ishimitsu T, Ichihara A, Ito M, Ohishi M, Ohkubo T, Kai H, Kashihara N, Kario K, Saitoh S, Tsuchihashi T, Nakamura S, Nishiyama A, Hasebe N, Higaki J, Tamura K, Kawano Y, Yatabe T, Ito S, JSH Future Plan Working Group and Executive Board Members

Hypertension research : official journal of the Japanese Society of Hypertension 41 （ 12 ） 989 - 990 2018年12月

ISSN 0916-9636

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Cardiometabolic index as a useful discriminator for the risk of increased arterial stiffness.

Wakabayashi I, Marumo M, Kubota Y, Higashiyama A, Miyamoto Y, Okamura T

Clinica chimica acta; international journal of clinical chemistry 486 42 - 43 2018年11月

ISSN 0009-8981

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Difference in water intake between persons with a history of cerebral infarction and healthy persons

Nishikawa T., Miyamatsu N., Higashiyama A., Hojo M., Nishida Y., Fukuda S., Ichiura K., Kubo S., Ueba T., Okamura T.

EUROPEAN JOURNAL OF PUBLIC HEALTH 28 326 - 326 2018年11月

研究論文（学術雑誌）, ISSN 1101-1262

Corrigendum to "Lipoprotein-associated phospholipase A2 is related to risk of subclinical atherosclerosis but is not supported by Mendelian randomization analysis in a general Japanese population." [Atherosclerosis 246 (March 2016) 141-147].

Ueshima H, Kadowaki T, Hisamatsu T, Fujiyoshi A, Miura K, Ohkubo T, Sekikawa A, Kadota A, Kadowaki S, Nakamura Y, Miyagawa N, Okamura T, Kita Y, Takashima N, Kashiwagi A, Maegawa H, Horie M, Yamamoto T, Kimura T, Kita T, ACCESS and SESSA Research Groups

Atherosclerosis 278 336 2018年11月

ISSN 0021-9150

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LIFETIME RISK OF STROKE AND CORONARY HEART DISEASE DEATH ACCORDING TO BLOOD PRESSURE LEVEL: EVIDENCE FOR CARDIOVASCULAR PREVENTION FROM OBSERVATIONAL COHORTS IN JAPAN

JOURNAL OF HYPERTENSION 36 E92 - E93 2018年10月

研究論文（学術雑誌）, ISSN 0263-6352

Association between impairment of salty taste recognition and masked hypertension based on home blood pressure in Japanese residents: the KOBE study

Kubota Y., Higashiyama A., Sugiyama D., Nishida Y., Kubo S., Hirata T., Kadota A., Miyamatsu N., Wakabayashi I., Miyamoto Y., Okamura T.

Hypertension Research （Hypertension Research） 41 （ 9 ） 756 - 762 2018年09月

研究論文（学術雑誌）, ISSN 09169636

© 2018, The Japanese Society of Hypertension. Excessive salt intake is an established risk factor for hypertension. We conducted a cross-sectional study to examine the association between salty taste recognition and estimated salt intake and masked hypertension in a healthy Japanese normotensive population. The participants were 892 apparently healthy community residents (246 men and 646 women) aged between 40 and 74 years with blood pressure below 140/90 mm Hg. Salty taste recognition was assessed using a salt-impregnated taste strip. Daily salt intake was calculated as estimated 24 h urinary sodium excretion using spot urine tests. Each participant performed home blood pressure measurements for a minimum of 5 days per week. The participants were classified into three groups according to their salty taste recognition threshold evaluated by the salt concentrations of the taste strips (0.6%, 0.8%, and ≥ 1.0%). In women, the multivariate odds ratio (95% confidence interval) for masked hypertension (≥ 135/85 mm Hg) was 2.98 (1.16–7.64) in the ≥ 1.0% group compared with that in the 0.6% group. In men, the proportion of masked hypertension in the ≥ 1.0% group did not differ from that in the 0.6% group, and no correlation was identified between estimated daily salt intake and the salty taste recognition threshold. In conclusion, impairment of salty taste recognition was associated with masked hypertension in women even with normal blood pressure in the clinical setting.

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Pooled analysis of the associations between body mass index, total cholesterol, and liver cancer-related mortality in Japan

Ukawa S., Tamakoshi A., Murakami Y., Kiyohara Y., Yamada M., Nagai M., Satoh A., Miura K., Ueshima H., Okamura T., Imai Y., Ohkubo T., Irie F., Iso H., Kitamura A., Ninomiya T., Nakagawa H., Nakayama T., Okayama A., Sairenchi T., Saitoh S., Sakata K., Tsuji I., Kiyama M., Miyamoto Y., Ishikawa S., Yatsuya H.

Asian Pacific Journal of Cancer Prevention （Asian Pacific Journal of Cancer Prevention） 19 （ 8 ） 2089 - 2095 2018年08月

研究論文（学術雑誌）, ISSN 15137368

© 2018 Asian Pacific Organization for Cancer Prevention. Objective: We employed a large-scale pooled analysis to investigate the association of liver cancer-related mortality with being overweight/obese and total cholesterol (TC) levels, since limited and inconsistent data on these associations exist in Japan. Methods: A total of 59,332 participants (23,853 men and 35,479 women) from 12 cohorts without a history of cancer who were followed for a median of 14.3 years were analyzed. A sex-specific stratified Cox proportional hazards model adjusted for age and other potential confounders was used to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for liver cancer-related mortality. Results: A total of 447 participants (266 men and 181 women) died of liver cancer within the follow-up period. Individuals classified as having a high BMI (≥25.0 kg/m2) and low TC levels (< 160 mg/dL) had a significantly increased risk for liver cancer-related mortality (HR 7.05, 95% CI 4.41-11.26 in men; HR 8.07, 95% CI 4.76-13.67 in women) when compared with those in the intermediate BMI (18.5-24.9 kg/m2) and TC (160-219 mg/dL) categories. These associations remained after limiting the follow-up duration to > 5 years. Conclusion: Being overweight/obese, combined with low TC levels, was strongly associated with liver cancer-related mortality in the EPOCH-JAPAN.

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ALCOHOL AND CARDIOVASCULAR DISEASE, ITS RISK FACTORS, AND OTHER HEALTH DISORDERS IN THE COMMUNITY

Higashiyama A., Miyamoto Y., Wakabayashi I., Okamura T.

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 42 69A - 69A 2018年08月

研究論文（学術雑誌）, ISSN 0145-6008

EARLY DETECTION OF PERIPHERAL ARTERY ISCHEMIA IN HEALTHY MALE SMOKERS BY AN ANKLE BRACHIAL INDEX AFTER EXERCISE: SASAYAMA STUDY

Kubota Y., Higashiyama A., Marumo M., Konishi M., Yamashita Y., Okamura T., Miyamoto Y., Wakabayashi I.

ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 42 26A - 26A 2018年08月

研究論文（学術雑誌）, ISSN 0145-6008

Serum modified high density lipoprotein levels assessed by a novel assay was associated with coronary artery calcification in an apparently healthy population

Okamura T., Kakino A., Miura K., Fujiyoshi A., Kadota A., Fujita Y., Zaid M., Usami Y., Hisamastu T., Horiuchi S., Kunimura A., Sugiyama D., Kondo K., Sawamura T., Ueshima H.

EUROPEAN HEART JOURNAL 39 4 - 4 2018年08月

研究論文（学術雑誌）, ISSN 0195-668X

The association of coronary artery calcification progression, albuminuria and estimated glomerular filtration rate among general population

Kadota A., Miura K., Fujiyoshi A., Hisamatsu T., Kadowaki S., Zaid M., Miyagawa N., Kondo K., Kunimura A., Okamura T., Ueshima H.

EUROPEAN HEART JOURNAL 39 895 - 895 2018年08月

研究論文（学術雑誌）, ISSN 0195-668X

Spreading Awareness of Stroke through School-Based Education: A Pooled Analysis of Three Community-Based Studies

Hino T., Yokota C., Nishimura K., Nakai M., Kato S., Kuwabara K., Takekawa H., Arimizu T., Tomari S., Wada S., Ohnishi H., Toyoda K., Okamura T., Minematsu K.

Journal of Stroke and Cerebrovascular Diseases （Journal of Stroke and Cerebrovascular Diseases） 27 （ 7 ） 1810 - 1814 2018年07月

研究論文（学術雑誌）, ISSN 10523057

© 2018 National Stroke Association Background: Advancing school-based education is a promising means to spread knowledge pertaining to stroke. The aim of the current study was to clarify whether stroke lessons provided by schoolteachers could deliver stroke knowledge to children (aged 9-11 years) and their parents, at a similar level to when taught by medical staff. Methods: Schoolteachers conducted lessons on stroke for school children using the educational materials we prepared (i.e., the teacher group; 1051 children and 719 parents). This was compared with our previous data from Akashi city and Tochigi prefecture, in which the stroke lessons were conducted by medical staff (i.e., the medical group; 1031 children and 756 parents). Three campaigns were conducted between September 2014 and May 2016. Each child was given education materials to take home to discuss stroke with their parents. The children and their parents answered questionnaires on stroke knowledge, at baseline, immediately after the lesson, and at 3 months after the lesson. Results: Compared with the time point before the lesson, both children and parents instructed by the teacher group showed significant increases in the scores about stroke symptoms and risk factors, immediately and at 3 months after the lesson (P <.001). The combined analysis for the group instructed by medical personnel showed no significant differences in the stroke knowledge scores between the 2 groups at 3 months. Conclusions: Teacher-led lessons, using our educational material, adequately delivered knowledge of stroke to children and parents, in a manner that was similar to when medical staff delivered this information.

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Sex differences in impact of coronary artery calcification to predict coronary artery disease

Nakao Yoko M., Miyamoto Yoshihiro, Higashi Masahiro, Noguchi Teruo, Ohishi Mitsuru, Kubota Isao, Tsutsui Hiroyuki, Kawasaki Tomohiro, Furukawa Yutaka, Yoshimura Michihiro, Morita Hideaki, Nishimura Kunihiro, Kada Akiko, Goto Yoichi, Okamura Tomonori, Tei Chuwa, Tomoike Hitonobu, Naito Hiroaki, Yasuda Satoshi

HEART （Heart） 104 （ 13 ） 1118 - 1124 2018年07月

研究論文（学術雑誌）, ISSN 1355-6037

© 2018 BMJ Publishing Group. All Rights Reserved. Objective to assess sex-specific differences regarding use of conventional risks and coronary artery calcification (cac) to detect coronary artery disease (caD) using coronary ct angiography (ccta). Methods the nationwide gender-specific atherosclerosis Determinants estimation and ischemic cardiovascular Disease Prospective cohort study is a prospective, multicentre, nationwide cohort study. candidates with suspected caD aged 50–74 years enrolled from 2008 to 2012. the outcome was obstructive caD defined as any stenosis ≥50% by ccta. We constructed logistic regression models for obstructive caD adjusted for conventional risks (clinical model) and cac score. improvement in discrimination beyond risks was assessed by c-statistic; net reclassification index (nri) for caD probability of low (<30%), intermediate (30%–60%) and high (≥60%); and risk stratification capacity. results among 991 patients (456 women, 535 men; 65.2 vs 64.4 years old), women had lower cac scores (median, 4 vs 60) and lower caD prevalence (21.7% vs 37.0%) than men. cac significantly improved model discrimination compared with clinical model in both sexes (0.66–0.79 in women vs 0.61–0.83 in men). the nri for women was 0.33, which was much lower than that for men (0.71). adding cac to clinical model had a larger benefit in terms of moving an additional 43.3% of men to the most determinant categories (high or low risk) compared with −1.4% of women. Conclusions the addition of cac to a prediction model based on conventional variables significantly improved the classification of risk in suspected patients with caD, with sex differences influencing the predictive ability.

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THE SERUM HIGH LDL CHOLESTEROL LEVELS AND LIFETIME RISK OF CORONARY HEART DISEASE IN A JAPANESE GENERAL POPULATION: SUITA STUDY

Sugiyama Dasuke, Turin Tanvir C., Afzal Arfan R., Rumana Nahid, Wanatabe Makoto, Higashiyama Aya, Takegami Misa, Kokubo Yoshiro, Okamura Tomonori, Miyamoto Yoshihiro

ATHEROSCLEROSIS SUPPLEMENTS 32 77 - 77 2018年06月

研究論文（学術雑誌）, ISSN 1567-5688

Association Between Glycemic Control and Incident Stroke　- Overview From an Epidemiologic Study.

Hirata T, Okamura T

Circulation journal : official journal of the Japanese Circulation Society 82 （ 6 ） 1499 - 1500 2018年05月

ISSN 1346-9843

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Overweight or underweight and the risk of decline in activities of daily living in a 22-year cohort study of a Japanese sample

Okamoto S., Okamura T., Sugiyama D., Hayakawa T., Nakamura Y., Miyagawa N., Kurita S., Takashima N., Ohkubo T., Kadota A., Fujiyoshi A., Miura K., Okayama A., Ueshima H.

Geriatrics and Gerontology International （Geriatrics and Gerontology International） 18 （ 5 ） 799 - 805 2018年05月

研究論文（学術雑誌）, ISSN 1444-1586

© 2018 Japan Geriatrics Society Aim: The present study aimed to clarify the association between body mass index (BMI) and the activities of daily living (ADL). Although BMI is likely to be concerned regarding the relationship with specific diseases or mortality, few studies have focused on the relationship of BMI and ADL. Methods: A total of 3353 Japanese participants of a 22-year cohort study from 1990 to 2012 aged 45–74 years at baseline were divided into four groups according to their BMI levels: ≤18.5, 18.5–21.9 (reference), 22.0–24.9 and ≥25.0 kg/m 2 . Outcomes were becoming dependent in ADL (including death after ADL decline) and death without observation of ADL decline as a competing risk. Sex-specific multinomial logistic regression analysis was carried out in 2017 to estimate the odds ratios (OR) after adjusting for age, smoking, alcohol drinking, hypertension, hypercholesterolemia, diabetes and serum albumin. Results: After multivariable adjustment, though the relationship between BMI and risk of ADL decline was U-shaped among women, only those with BMI ≥25.0 showed a higher risk for ADL decline (OR 1.39, 95% CI 1.01–1.92) compared with the reference. The OR for death without observation of ADL decline was significantly lower for men with BMI ≥25.0 (OR 0.70, 95% CI 0.50–0.98). Conclusions: This study suggests being overweight is a good predictor of future decline in ADL for women, whereas men with BMI 22.0–24.9 had lower risks of ADL decline. Appropriate management of weight in older women could prevent disabilities. Geriatr Gerontol Int 2018; 18: 799–805.

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International Comparison of Abdominal Fat Distribution among Four Populations

Kadowaki Sayaka, Miura Katsuyuki, Kadowaki Takashi, Fujiyoshi Akira, El-Saed Aiman, Masaki Kamal H., Okamura Tomonori, Edmundowicz Daniel, Rodriguez Beatriz L., Nakamura Yasuyuki, Barinas-Mitchell Emma J.M., Kadota Aya, Willcox Bradley J., Abbott Robert D., Kuller Lewis H., Choo Jina, Shin Chol, Ueshima Hirotsugu, Sekikawa Akira

Metabolic Syndrome and Related Disorders 16 （ 4 ） 166 - 173 2018年05月

ISSN 1540-4196

Background: Abdominal fat distribution varies across groups with different races or environments. Whether environmental factors, apart from racial differences, affect abdominal fat distribution is unknown. Methods: We compared the abdominal fat distribution of four groups; different races with similar environments (Caucasians vs. Japanese Americans), different environments with an identical race (Japanese Americans vs. Japanese), and similar races with similar environments (Japanese vs. Koreans). A population-based sample of 1212 men aged 40-49 were analyzed: 307 Caucasians and 300 Japanese Americans in the United States, 310 Japanese in Japan, and 295 Koreans in Korea. We compared the proportion of visceral adipose tissue area to total abdominal adipose tissue area (VAT%) and other factors that can affect abdominal fat distribution (smoking, alcohol use, physical activity levels, and metabolic factors). Results: VAT% was significantly higher in Japanese and Koreans than in Japanese Americans and Caucasians (50.0, 48.5, 43.2, 41.0%, respectively, P < 0.001). Even after adjustment for possible confounders, the significant VAT% difference remained in comparing groups with identical race but different environments (i.e., Japanese vs. Japanese Americans). In contrast, comparing groups with different races but similar environments (i.e., Caucasians vs. Japanese Americans), VAT% was not significantly different. Comparing groups with similar races and similar environments (i.e., Japanese vs. Koreans), VAT% did not significantly differ. Conclusions: Environmental differences, apart from racial differences, affect the difference in abdominal fat distribution across different groups in middle-aged men.

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Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH–JAPAN study

Hirata A., Sugiyama D., Watanabe M., Tamakoshi A., Iso H., Kotani K., Kiyama M., Yamada M., Ishikawa S., Murakami Y., Miura K., Ueshima H., Okamura T., Okamura T., Imai Y., Ohkubo T., Irie F., Iso H., Kitamura A., Ninomiya T., Kiyohara Y., Miura K., Murakami Y., Nakagawa H., Nakayama T., Okayama A., Sairenchi T., Saitoh S., Sakata K., Tamakoshi A., Tsuji I., Yamada M., Miyamoto Y., Ishikawa S., Yatsuya H.

Journal of Clinical Lipidology （Journal of Clinical Lipidology） 12 （ 3 ） 674 - 684.e5 2018年05月

研究論文（学術雑誌）, ISSN 19332874

© 2018 National Lipid Association Background: The effect of very high or extremely high levels of high-density lipoprotein cholesterol (HDL-C) on cardiovascular disease (CVD) is not well described. Although a few recent studies have reported the adverse effects of extremely high levels of HDL-C on CVD events, these did not show a statistically significant association between extremely high levels of HDL-C and cause-specific CVD mortality. In addition, Asian populations have not been studied. Objective: We examine the impact of extremely high levels of HDL-C on cause-specific CVD mortality using pooled data of Japanese cohort studies. Methods: We performed a large-scale pooled analysis of 9 Japanese cohorts including 43,407 participants aged 40–89 years, dividing the participants into 5 groups by HDL-C levels, including extremely high levels of HDL-C ≥2.33 mmol/L (≥90 mg/dL). We estimated the adjusted hazard ratio of each HDL-C category for all-cause death and cause-specific deaths compared with HDL-C 1.04–1.55 mmol/L (40–59 mg/dL) using a cohort-stratified Cox proportional hazards model. Results: During a 12.1-year follow-up, 4995 all-cause deaths and 1280 deaths due to overall CVD were identified. Extremely high levels of HDL-C were significantly associated with increased risk of atherosclerotic CVD mortality (hazard ratio = 2.37, 95% confidence interval: 1.37–4.09 for total) and increased risk for coronary heart disease and ischemic stroke. In addition, the risk for extremely high HDL-C was more evident among current drinkers. Conclusion: We showed extremely high levels of HDL-C had an adverse effect on atherosclerotic CVD mortality in a pooled analysis of Japanese cohorts.

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International Comparison of Abdominal Fat Distribution among Four Populations: The ERA-JUMP Study

Kadowaki S., Miura K., Kadowaki T., Fujiyoshi A., El-Saed A., Masaki K., Okamura T., Edmundowicz D., Rodriguez B., Nakamura Y., Barinas-Mitchell E., Kadota A., Willcox B., Abbott R., Kuller L., Choo J., Shin C., Ueshima H., Sekikawa A.

Metabolic Syndrome and Related Disorders （Metabolic Syndrome and Related Disorders） 16 （ 4 ） 166 - 173 2018年05月

研究論文（学術雑誌）, ISSN 15404196

© 2018, Mary Ann Liebert, Inc. Background: Abdominal fat distribution varies across groups with different races or environments. Whether environmental factors, apart from racial differences, affect abdominal fat distribution is unknown. Methods: We compared the abdominal fat distribution of four groups; different races with similar environments (Caucasians vs. Japanese Americans), different environments with an identical race (Japanese Americans vs. Japanese), and similar races with similar environments (Japanese vs. Koreans). A population-based sample of 1212 men aged 40-49 were analyzed: 307 Caucasians and 300 Japanese Americans in the United States, 310 Japanese in Japan, and 295 Koreans in Korea. We compared the proportion of visceral adipose tissue area to total abdominal adipose tissue area (VAT%) and other factors that can affect abdominal fat distribution (smoking, alcohol use, physical activity levels, and metabolic factors). Results: VAT% was significantly higher in Japanese and Koreans than in Japanese Americans and Caucasians (50.0, 48.5, 43.2, 41.0%, respectively, P < 0.001). Even after adjustment for possible confounders, the significant VAT% difference remained in comparing groups with identical race but different environments (i.e., Japanese vs. Japanese Americans). In contrast, comparing groups with different races but similar environments (i.e., Caucasians vs. Japanese Americans), VAT% was not significantly different. Comparing groups with similar races and similar environments (i.e., Japanese vs. Koreans), VAT% did not significantly differ. Conclusions: Environmental differences, apart from racial differences, affect the difference in abdominal fat distribution across different groups in middle-aged men.

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Data on alcohol consumption and coronary artery calcification among asymptomatic middle-aged men for the ERA-JUMP study

Mahajan H., Choo J., Masaki K., Fujiyoshi A., Guo J., Hisamatsu T., Evans R., Shangguan S., Willcox B., Okamura T., Vishnu A., Barinas-Mitchell E., Ahuja V., Miura K., Kuller L., Shin C., Ueshima H., Sekikawa A.

Data in Brief （Data in Brief） 17 1091 - 1098 2018年04月

研究論文（学術雑誌）, ISSN 2352-3409

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Heterogeneity of Absolute/Relative Measures of Cardiovascular Mortality Among Cohorts in an Individual Participant Data Meta-Analysis: An EPOCH-JAPAN Study

Murakami Yoshitaka, Okamura Tomonori, Miura Katsuyuki, Ueshima Hirotsugu

CIRCULATION 137 2018年03月

研究論文（学術雑誌）, ISSN 0009-7322

Trajectories of Stroke Risk Factors Before Stroke Onset With a 24-year Follow-up of Japanese People Living in an Urban Area: The Suita Study

Ogata Soshiro, Nakamura Fumiaki, Nishimura Kunihiro, Watanabe Makoto, Kokubo Yoshihiro, Higashiyama Aya, Takegami Misa, Nakao Yoko M., Nakai Michikazu, Okamura Tomonori, Miyamoto Yoshihiro

CIRCULATION 137 2018年03月

研究論文（学術雑誌）, ISSN 0009-7322

Left Atrial Dilatation Predicts The Incidence Of Persistent Atrial Fibrillation In Japanese General Population; The Suita Study

Higashiyama Aya, Watanabe Makoto, Kokubo Yoshihiro, Okamura Tomonori, Okayama Akira, Miyamoto Yoshihiro

CIRCULATION 137 2018年03月

研究論文（学術雑誌）, ISSN 0009-7322

Cardiovascular risk and blood pressure lowering treatment among elderly individuals

Asayama Kei, Ohkubo Takayoshi, Satoh Atsushi, Tanaka Sachiko, Higashiyama Aya, Murakami Yoshitaka, Yamada Michiko, Saitoh Shigeyuki, Okayama Akira, Miura Katsuyuki, Ueshima Hirotsugu, Miyamoto Yoshihiro, Okamura Tomonori

Journal of Hypertension 36 （ 2 ） 410 - 418 2018年02月

ISSN 0263-6352

Objective: There is little evidence to support an increased risk of blood pressure (BP) elevation among elderly individuals receiving antihypertensive drug treatment. Methods: To clarify the impact on BP level and residual cardiovascular risk in treated elderly individuals, we analysed individual participant data of 26 133 residents aged 60-89 years from seven Japanese general populations and cross-classified participants by age category, 60-74 (young-old) versus 75-89 years (old-old), and by usage of antihypertensive medication at baseline survey (1980-1995). Results: During a median follow-up period of 12.7 years, 2451 cardiovascular deaths were observed. Multivariable-Adjusted hazard ratios of cardiovascular mortality in treated participants compared with untreated participants were 1.30 [95% confidence intervals, 1.16-1.46) and 1.35 (95% confidence interval, 1.16-1.56) in young-old and old-old participants, respectively. Irrespective of antihypertensive medication, the risk increase of total cardiovascular and stroke mortality with elevation of BP was significant among young-old (P ≤ 0.0013), but not significant among old-old participants (P ≥ 0.061). Conclusion: Although impact on BP was more evident among young-old than old-old individuals, clinicians who prescribe antihypertensive medication to elderly patients should consider that such patients require further monitoring.

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Cardiovascular risk and blood pressure lowering treatment among elderly individuals: Evidence for Cardiovascular Prevention from Observational Cohorts in Japan

Asayama K., Ohkubo T., Satoh A., Tanaka S., Higashiyama A., Murakami Y., Yamada M., Saitoh S., Okayama A., Miura K., Ueshima H., Miyamoto Y., Okamura T.

Journal of Hypertension （Journal of Hypertension） 36 （ 2 ） 410 - 418 2018年02月

研究論文（学術雑誌）, ISSN 02636352

© 2018 Wolters Kluwer Health, Inc. All rights reserved. Objective: There is little evidence to support an increased risk of blood pressure (BP) elevation among elderly individuals receiving antihypertensive drug treatment. Methods: To clarify the impact on BP level and residual cardiovascular risk in treated elderly individuals, we analysed individual participant data of 26 133 residents aged 60-89 years from seven Japanese general populations and cross-classified participants by age category, 60-74 (young-old) versus 75-89 years (old-old), and by usage of antihypertensive medication at baseline survey (1980-1995). Results: During a median follow-up period of 12.7 years, 2451 cardiovascular deaths were observed. Multivariable-Adjusted hazard ratios of cardiovascular mortality in treated participants compared with untreated participants were 1.30 [95% confidence intervals, 1.16-1.46) and 1.35 (95% confidence interval, 1.16-1.56) in young-old and old-old participants, respectively. Irrespective of antihypertensive medication, the risk increase of total cardiovascular and stroke mortality with elevation of BP was significant among young-old (P ≤ 0.0013), but not significant among old-old participants (P ≥ 0.061). Conclusion: Although impact on BP was more evident among young-old than old-old individuals, clinicians who prescribe antihypertensive medication to elderly patients should consider that such patients require further monitoring.

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Guidelines for Diagnosis and Treatment of Familial Hypercholesterolemia 2017.

Harada-Shiba M, Arai H, Ishigaki Y, Ishibashi S, Okamura T, Ogura M, Dobashi K, Nohara A, Bujo H, Miyauchi K, Yamashita S, Yokote K, Working Group by Japan Atherosclerosis Society for Making Guidance of Familial Hypercholesterolemia

Journal of atherosclerosis and thrombosis 25 （ 8 ） 751 - 770 2018年01月

ISSN 1340-3478

Statement 1. Familial hypercholesterolemia (FH) is an autosomal hereditary disease with the 3 major clinical features of hyper-LDL-cholesterolemia, premature coronary artery disease and tendon and skin xanthomas. As there is a considerably high risk of coronary artery disease (CAD), in addition to early diagnosis and intensive treatment, family screening (cascade screening) is required (Recommendation level A) 2. For a diagnosis of FH, at least 2 of the following criteria should be satisfied: ① LDL-C ≥180 mg/dL, ② Tendon/skin xanthomas, ③ History of FH or premature CAD within 2nd degree blood relatives (Recommendation level A) 3. Intensive lipid-lowering therapy is necessary for the treatment of FH. First-line drug should be statins. (Rec-ommendation level A, Evidence level 3) 4. Screening for CAD as well as asymptomatic atherosclerosis should be conducted periodically in FH patients. (Recommendation level A) 5. For homozygous FH, consider LDL apheresis and treatment with PCSK9 inhibitors or MTP inhibitors. (Rec-ommendation level A) 6. For severe forms of heterozygous FH who have resistant to drug therapy, consider PCSK9 inhibitors and LDL apheresis. (Recommendation level A) 7. Refer FH homozygotes as well as heterozygotes who are resistant to drug therapy, who are children or are pregnant or have the desire to bear children to a specialist. (Recommendation level A).

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Macronutrient Intake and Socioeconomic Status

Sakurai Masaru, Nakagawa Hideaki, Kadota Aya, Yoshita Katsushi, Nakamura Yasuyuki, Okuda Nagako, Nishi Nobuo, Miyamoto Yoshihiro, Arima Hisatomi, Ohkubo Takayoshi, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S17 - S22 2018年01月

ISSN 0917-5040

BACKGROUND: This study examined the relationships among household income, other SES indicators, and macronutrient intake in a cross-sectional study of a representative Japanese population.METHODS: In 2010, we established a cohort of participants in the National Health and Nutrition Survey (NHNS) from 300 randomly selected areas throughout Japan. A total of 2,637 participants (1,145 men and 1,492 women) were included in the study. Data from NHNS2010 and the Comprehensive Survey of Living Conditions 2010 (CSCL2010) were merged, and relationships among macronutrient intake and SES were evaluated. Additionally, socioeconomic factors associated with a risk of a higher carbohydrate/lower fat intake beyond dietary recommendations were evaluated.RESULTS: Household income was positively associated with fat intake (P = 0.001 for men and <0.001 for women) and inversely associated with carbohydrate intake (P = 0.003 for men and <0.001 for women) after adjustments for age and other SES variables. Similar relationships were observed between equivalent household expenditure (EHE) and macronutrient intake; however, these relationships were weaker than those of household income. Older age was the factor most strongly associated with a high carbohydrate/low fat intake, followed by household income, EHE, education levels, and occupation type.CONCLUSIONS: Older age was the factor most strongly associated with a high carbohydrate/low fat intake, and some aspects of SES, such as household income, EHE, education levels, and occupation type, were independently associated with an imbalanced macronutrient intake. SES may affect the health status of individuals through the intake of macronutrients.

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Relationship Between Socioeconomic Status and the Prevalence of Underweight, Overweight or Obesity in a General Japanese Population

Nakamura Tomiyo, Nakamura Yasuyuki, Saitoh Shigeyuki, Okamura Tomonori, Yanagita Masahiko, Yoshita Katsushi, Kita Yoshikuni, Murakami Yoshitaka, Yokomichi Hiroshi, Nishi Nobuo, Okuda Nagako, Kadota Aya, Ohkubo Takayoshi, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S10 - S16 2018年01月

ISSN 0917-5040

BACKGROUND: Socioeconomic status (SES) imbalances in developed and developing countries may result in individuals being overweight and obese. However, few studies have investigated this issue in Japan. We herein examined the relationship between SES and being underweight, overweight or obese according to sex and age groups (20-64 or ≥65 years) in Japan.METHODS: In 2010, we established a cohort of participants in the National Health and Nutrition Survey of Japan. We divided 2,491 participants (1,081 men and 1,410 women) according to the WHO definitions of underweight, overweight or obesity and performed multinomial logistic analyses using BMI <18.5 kg/m2 (underweight), BMI 25.0-29.9 kg/m2 (overweight), and BMI ≥30.0 kg/m2 (obese) versus BMI 18.5-24.9 kg/m2 (normal) as the outcome, with SES groups as the main explanatory variables.RESULTS: In adult men, a lower education level relative to a higher education level was inversely associated with obesity after adjustments for other SESs (odds ratio [OR] 0.41; 95% confidence interval [CI], 0.18-0.96). However, in adult women, lower education level was positively associated with being overweight and obese (OR 1.67; 95% CI, 1.07-2.49 for overweight and OR 2.66; 95% CI, 1.01-7.01 for obese). In adult women, a lower household income was positively associated with being overweight and obese (obese: OR 4.84; 95% CI, 1.36-17.18 for those with a household income <2 million JPY relative to those with ≥6 million JPY).CONCLUSIONS: In adult women, a lower education level and lower household income were positively associated with being overweight or obese. In contrast, in adult men, a lower education level was inversely associated with obesity. Gender and age differences in SESs affect the prevalence of being overweight or obese.

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Relationships among Food Group Intakes, Household Expenditure, and Education Attainment in a General Japanese Population

Nagahata Tomomi, Nakamura Mieko, Ojima Toshiyuki, Kondo Imako, Ninomiya Toshiharu, Yoshita Katsushi, Arai Yusuke, Ohkubo Takayoshi, Murakami Keiko, Nishi Nobuo, Murakami Yoshitaka, Takashima Naoyuki, Okuda Nagako, Kadota Aya, Miyagawa Naoko, Kondo Keiko, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S23 - S28 2018年01月

ISSN 0917-5040

BACKGROUND: A lower socioeconomic status (SES) may be related to the intake of unhealthy food; however, this relationship has not been examined in detail. This study was undertaken to examine relationships among food group intakes and SES in a representative Japanese population.METHODS: This was a cross-sectional study using the baseline data of NIPPON DATA2010, which is a prospective cohort study of the National Health and Nutrition Survey in Japan. A total of 2,898 participants were included in the baseline survey in 2010. The effects of age (<65 years and ≥65 years), equivalent household expenditure (EHE), and education attainment on food group intakes (gram per 1,000 kcal) were analyzed using a two-way analysis of variance.RESULTS: When EHE was lower, cereal intake was higher in men and women. Among men, fish, milk, and alcohol intakes were reduced with lower EHE. Among women, vegetable intake was reduced with lower EHE. In men and women, cereal intake was higher with lower education attainment. In contrast, meat intake was reduced with lower education attainment.CONCLUSIONS: Lower SES was associated with a higher cereal intake and lower vegetable, fish, meat, and milk intakes in a representative Japanese population. Socioeconomic discrepancies need to be considered in order to promote healthier dietary habits.

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Reliability of plasma polar metabolite concentrations in a large-scale cohort study using capillary electrophoresis-mass spectrometry

Harada S., Hirayama A., Chan Q., Kurihara A., Fukai K., Iida M., Kato S., Sugiyama D., Kuwabara K., Takeuchi A., Akiyama M., Okamura T., Ebbels T., Elliott P., Tomita M., Sato A., Suzuki C., Sugimoto M., Soga T., Takebayashi T.

PLoS ONE （PLoS ONE） 13 （ 1 ） e0191230 2018年01月

研究論文（学術雑誌）, ISSN 1932-6203

© 2018 Harada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Cohort studies with metabolomics data are becoming more widespread, however, large-scale studies involving 10,000s of participants are still limited, especially in Asian populations. Therefore, we started the Tsuruoka Metabolomics Cohort Study enrolling 11,002 community-dwelling adults in Japan, and using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography–mass spectrometry. The CE-MS method is highly amenable to absolute quantification of polar metabolites, however, its reliability for large-scale measurement is unclear. The aim of this study is to examine reproducibility and validity of large-scale CE-MS measurements. In addition, the study presents absolute concentrations of polar metabolites in human plasma, which can be used in future as reference ranges in a Japanese population. Methods Metabolomic profiling of 8,413 fasting plasma samples were completed using CE-MS, and 94 polar metabolites were structurally identified and quantified. Quality control (QC) samples were injected every ten samples and assessed throughout the analysis. Inter- and intra-batch coefficients of variation of QC and participant samples, and technical intraclass correlation coefficients were estimated. Passing-Bablok regression of plasma concentrations by CE-MS on serum concentrations by standard clinical chemistry assays was conducted for creatinine and uric acid. Results and conclusions In QC samples, coefficient of variation was less than 20% for 64 metabolites, and less than 30% for 80 metabolites out of the 94 metabolites. Inter-batch coefficient of variation was less than 20% for 81 metabolites. Estimated technical intraclass correlation coefficient was above 0.75 for 67 metabolites. The slope of Passing-Bablok regression was estimated as 0.97 (95% confidence interval: 0.95, 0.98) for creatinine and 0.95 (0.92, 0.96) for uric acid. Compared to published data from other large cohort measurement platforms, reproducibility of metabolites common to the platforms was similar to or better than in the other studies. These results show that our CE-MS platform is suitable for conducting large-scale epidemiological studies.

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Socioeconomic Inequalities in Oral Health among Middle-Aged and Elderly Japanese

Murakami Keiko, Ohkubo Takayoshi, Nakamura Mieko, Ninomiya Toshiharu, Ojima Toshiyuki, Shirai Kayoko, Nagahata Tomomi, Kadota Aya, Okuda Nagako, Nishi Nobuo, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S59 - S65 2018年01月

ISSN 0917-5040

BACKGROUND: Most studies on socioeconomic inequalities in oral health have not considered the effects of behavioral and biological factors and age differences. Furthermore, the nationwide status of inequalities remains unclear in Japan.METHODS: We analyzed data from 2,089 residents aged ≥40 years throughout Japan. The lowest quartile of the number of remaining teeth for each 10-year age category was defined as poor oral health. Behavioral and biological factors included smoking status, obesity, diabetes mellitus, high-sensitivity C-reactive protein, and the use of dental devices. Multiple logistic regression analyses were conducted to examine the associations of educational attainment and equivalent household expenditure (EHE) with oral health, and stratified analyses by age category were also conducted (40-64 years and ≥65 years).RESULTS: Lower education and lower EHE were significantly associated with an increased risk of poor oral health after adjusting for age, sex, employment status, marital and living statuses, and EHE/education; the odds ratio for junior high school education compared with ≥college education was 1.84 (95% confidence interval [CI], 1.36-2.49), and the odds ratio of the lowest compared with the highest EHE quartile was 1.91 (95% CI, 1.43-2.56). Further adjustments for behavioral and biological factors attenuated but did not eliminate these associations. EHE was significantly associated with oral health among elderly adults only, with a significant interaction by age category.CONCLUSIONS: Those with a lower education and those with lower EHE had a significantly higher risk of poor oral health, even after adjustments for behavioral and biological factors.

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Socioeconomic Status and Knowledge of Cardiovascular Risk Factors

Tsuji Masayoshi, Arima Hisatomi, Ohkubo Takayoshi, Nakamura Koshi, Takezaki Toshiro, Sakata Kiyomi, Okuda Nagako, Nishi Nobuo, Kadota Aya, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S46 - S52 2018年01月

ISSN 0917-5040

BACKGROUND: The relationship between socioeconomic status (SES) and knowledge of cardiovascular risk factors remains unknown in a general Japanese population.METHODS: Of 8,815 participants from 300 randomly selected areas throughout Japan, 2,467 participants who were free of cardiovascular disease and who provided information on SES in the National Health and Nutrition Survey of Japan 2010 were enrolled in this cross-sectional analysis. SES was classified according to the employment status, length of education, marital and living statuses, and equivalent household expenditure (EHE). Outcomes were ignorance of each cardiovascular risk factor (hypertension, diabetes, hypercholesterolemia, low high-density lipoprotein [HDL] cholesterol, arrhythmia, and smoking) and insufficient knowledge (number of correct answers <4 out of 6).RESULTS: A short education and low EHE were significantly associated with a greater ignorance of most cardiovascular risk factors. A short education (<10 years) was also associated with insufficient knowledge of overall cardiovascular risk factors: age- and sex-adjusted odds ratios (OR) were 1.92 (95% confidence interval [CI], 1.51-2.45) relative to participants with ≥13 years of education. Low EHE was also associated with insufficient knowledge (age- and sex-adjusted OR 1.24; 95% CI, 1.01-1.51 for the lowest quintile vs the upper 4 quintiles). These relationships remained significant, even after further adjustments for regular exercise, smoking, weekly alcohol consumption, body mass index, hypertension, diabetes mellitus, hypercholesterolemia, and low HDL cholesterol.CONCLUSION: Participants with a short education and low EHE were more likely to have less knowledge of cardiovascular risk factors.

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Socioeconomic Status Associated With Urinary Sodium and Potassium Excretion in Japan

Miyagawa Naoko, Okuda Nagako, Nakagawa Hideaki, Takezaki Toshiro, Nishi Nobuo, Takashima Naoyuki, Fujiyoshi Akira, Ohkubo Takayoshi, Kadota Aya, Okamura Tomonori, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S29 - S34 2018年01月

ISSN 0917-5040

BACKGROUND: Although socioeconomic status (SES) may affect food and nutrient intakes, few studies have reported on sodium (Na) and potassium (K) intakes among individuals with various SESs in Japan. We investigated associations of SES with Na and K intake levels using urinary specimens in a representative Japanese population.METHODS: This was a cross-sectional study of 2,560 men and women (the NIPPON DATA2010 cohort) who participated in the National Health and Nutrition Survey Japan in 2010. Casual urine was used to calculate estimated excretion in 24-hour urinary Na (E24hr-Na) and K (E24hr-K). The urinary sodium-to-potassium (Na/K) ratio was calculated from casual urinary electrolyte values. An analysis of covariance was performed to investigate associations of aspects of SES, including equivalent household expenditure (EHE), educational attainment, and job category, with E24hr-Na, E24hr-K, and the Na/K ratio for men and women separately. A stratified analysis was performed on educational attainment and the job category for younger (<65 years) and older (≥65 years) participants.RESULTS: In men and women, average E24hr-Na was 176.2 mmol/day and 172.3, average E24hr-K was 42.5 and 41.3, and the average Na/K ratio was 3.61 and 3.68, respectively. Lower EHE was associated with a higher Na/K ratio in women and lower E24hr-K in men and women. A shorter education was associated with a higher Na/K ratio in women and younger men, and lower E24hr-K in older men and women.CONCLUSION: Lower EHE and a shorter education were associated with a lower K intake and higher Na/K ratio estimated from casual urine specimens in Japanese men and women.

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Spreading Awareness of Stroke through School-Based Education

Hino Tenyu, Yokota Chiaki, Nishimura Kunihiro, Nakai Michikazu, Kato Suzuka, Kuwabara Kazuyo, Takekawa Hidehiro, Arimizu Takuro, Tomari Shinya, Wada Shinichi, Ohnishi Hideyuki, Toyoda Kazunori, Okamura Tomonori, Minematsu Kazuo

Journal of Stroke and Cerebrovascular Diseases 2018年01月

ISSN 1052-3057

Background: Advancing school-based education is a promising means to spread knowledge pertaining to stroke. The aim of the current study was to clarify whether stroke lessons provided by schoolteachers could deliver stroke knowledge to children (aged 9-11 years) and their parents, at a similar level to when taught by medical staff. Methods: Schoolteachers conducted lessons on stroke for school children using the educational materials we prepared (i.e., the teacher group; 1051 children and 719 parents). This was compared with our previous data from Akashi city and Tochigi prefecture, in which the stroke lessons were conducted by medical staff (i.e., the medical group; 1031 children and 756 parents). Three campaigns were conducted between September 2014 and May 2016. Each child was given education materials to take home to discuss stroke with their parents. The children and their parents answered questionnaires on stroke knowledge, at baseline, immediately after the lesson, and at 3 months after the lesson. Results: Compared with the time point before the lesson, both children and parents instructed by the teacher group showed significant increases in the scores about stroke symptoms and risk factors, immediately and at 3 months after the lesson (P < .001). The combined analysis for the group instructed by medical personnel showed no significant differences in the stroke knowledge scores between the 2 groups at 3 months. Conclusions: Teacher-led lessons, using our educational material, adequately delivered knowledge of stroke to children and parents, in a manner that was similar to when medical staff delivered this information.

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The National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 2010 (NIPPON DATA2010)

Kadota Aya, Okuda Nagako, Ohkubo Takayoshi, Okamura Tomonori, Nishi Nobuo, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 2018年01月

ISSN 0917-5040

BACKGROUND: The structure and risk factors for cardiovascular diseases (CVD) in Japan may change because lifestyle, particularly nutrition, socioeconomic status, and medical care, which affect CVD, may markedly change over time. Therefore, a new prospective cohort study on a representative general Japanese population based on national surveys is required.METHODS: In November 2010, the baseline survey of the National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 2010 (NIPPON DATA2010) was performed with the National Health and Nutrition Survey of Japan (NHNS2010) in 300 randomly selected districts throughout Japan. The survey included a questionnaire, electrocardiogram, urinalysis, and blood biomarkers added to the NHNS2010 examinations. Physical measurements, blood biomarkers, and dietary data were also obtained in NHNS2010. Socioeconomic factors were obtained by merging with the Comprehensive Survey of Living Conditions 2010 (CSLC2010) dataset. Participants are followed annually for the incidence of diabetes mellitus, CVD events (acute coronary events, heart failure, atrial fibrillation, and stroke), and cause-specific mortality. The activities of daily living are followed every 5 years.RESULTS: A total of 2,898 individuals aged 20 years or older agreed to participate in the baseline survey of NIPPON DATA2010. The participation rate was 74.6%. Of these, data from NHNS2010 was merged for 2,891 participants (1,236 men and 1,655 women). The data of 2,807 participants were also merged with CSLC2010 data.CONCLUSIONS: We established NIPPON DATA2010 as a cohort study on a representative general Japanese population that covers all of Japan.

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Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals

Hirata Aya, Sugiyama Daisuke, Watanabe Makoto, Tamakoshi Akiko, Iso Hiroyasu, Kotani Kazuhiko, Kiyama Masahiko, Yamada Michiko, Ishikawa Shizukiyo, Murakami Yoshitaka, Miura Katsuyuki, Ueshima Hirotsugu, Okamura Tomonori

Journal of Clinical Lipidology 2018年01月

ISSN 1933-2874

Background: The effect of very high or extremely high levels of high-density lipoprotein cholesterol (HDL-C) on cardiovascular disease (CVD) is not well described. Although a few recent studies have reported the adverse effects of extremely high levels of HDL-C on CVD events, these did not show a statistically significant association between extremely high levels of HDL-C and cause-specific CVD mortality. In addition, Asian populations have not been studied. Objective: We examine the impact of extremely high levels of HDL-C on cause-specific CVD mortality using pooled data of Japanese cohort studies. Methods: We performed a large-scale pooled analysis of 9 Japanese cohorts including 43,407 participants aged 40-89 years, dividing the participants into 5 groups by HDL-C levels, including extremely high levels of HDL-C ≥2.33 mmol/L (≥90 mg/dL). We estimated the adjusted hazard ratio of each HDL-C category for all-cause death and cause-specific deaths compared with HDL-C 1.04-1.55 mmol/L (40-59 mg/dL) using a cohort-stratified Cox proportional hazards model. Results: During a 12.1-year follow-up, 4995 all-cause deaths and 1280 deaths due to overall CVD were identified. Extremely high levels of HDL-C were significantly associated with increased risk of atherosclerotic CVD mortality (hazard ratio = 2.37, 95% confidence interval: 1.37-4.09 for total) and increased risk for coronary heart disease and ischemic stroke. In addition, the risk for extremely high HDL-C was more evident among current drinkers. Conclusion: We showed extremely high levels of HDL-C had an adverse effect on atherosclerotic CVD mortality in a pooled analysis of Japanese cohorts.

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Fatty liver index predicts incident diabetes in a Japanese general population with and without impaired fasting glucose

Hirata A., Sugiyama D., Kuwabara K., Hirata T., Tsutatani H., Funamoto M., Watanabe K., Miyamatsu N., Okamura T.

Hepatology Research （Hepatology Research） 48 （ 9 ） 708 - 716 2018年01月

研究論文（学術雑誌）, ISSN 1386-6346

© 2018 The Japan Society of Hepatology Aim: Fatty liver is associated with the development of diabetes. However, to our knowledge, no study has examined the relationship between the fatty liver index (FLI), calculated scores of hepatic steatosis, and the development of diabetes among individuals without impaired fasting glucose (IFG). We aimed to examine whether FLI predicts the development of diabetes in individuals with and without IFG in a Japanese general population. Methods: We selected 1498 men and 2941 women who participated in Specific Health Checkups in Japan. We divided all participants into six groups according to tertiles of FLI (low, moderate, and high) and the presence or absence of IFG, by sex. We calculated hazard ratios for incident diabetes for each group using a Cox proportional hazard model, adjusting for potential confounders. Results: During a mean follow-up period of 3.0 years, 176 cases of diabetes in men and 320 cases in women were identified. Compared with the low FLI group without IFG, the high FLI group without IFG was significantly associated with incident diabetes in both men (hazard ratio, 1.90; 95% confidence interval, 1.08–3.36) and women (hazard ratio, 1.72; 95% confidence interval, 1.18–2.51). All IFG groups were significantly associated with incident diabetes regardless of FLI levels. Conclusions: Our results showed that FLI is associated with the development of diabetes regardless of sex and the presence or absence of IFG, and that it may be a useful predictor of future risk of incident diabetes even in individuals without IFG.

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Association between glycemic control and incident stroke ― Overview from an epidemiologic study

Hirata Takumi, Okamura Tomonori

Circulation Journal 82 （ 6 ） 1499 - 1500 2018年01月

ISSN 1346-9843

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Association between impairment of salty taste recognition and masked hypertension based on home blood pressure in Japanese residents

Kubota Yoshimi, Higashiyama Aya, Sugiyama Daisuke, Nishida Yoko, Kubo Sachimi, Hirata Takumi, Kadota Aya, Miyamatsu Naomi, Wakabayashi Ichiro, Miyamoto Yoshihiro, Okamura Tomonori

Hypertension Research 2018年01月

ISSN 0916-9636

Excessive salt intake is an established risk factor for hypertension. We conducted a cross-sectional study to examine the association between salty taste recognition and estimated salt intake and masked hypertension in a healthy Japanese normotensive population. The participants were 892 apparently healthy community residents (246 men and 646 women) aged between 40 and 74 years with blood pressure below 140/90 mm Hg. Salty taste recognition was assessed using a salt-impregnated taste strip. Daily salt intake was calculated as estimated 24 h urinary sodium excretion using spot urine tests. Each participant performed home blood pressure measurements for a minimum of 5 days per week. The participants were classified into three groups according to their salty taste recognition threshold evaluated by the salt concentrations of the taste strips (0.6%, 0.8%, and ≥ 1.0%). In women, the multivariate odds ratio (95% confidence interval) for masked hypertension (≥ 135/85 mm Hg) was 2.98 (1.16–7.64) in the ≥ 1.0% group compared with that in the 0.6% group. In men, the proportion of masked hypertension in the ≥ 1.0% group did not differ from that in the 0.6% group, and no correlation was identified between estimated daily salt intake and the salty taste recognition threshold. In conclusion, impairment of salty taste recognition was associated with masked hypertension in women even with normal blood pressure in the clinical setting.

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Association of alcohol consumption and aortic calcification in healthy men aged 40–49 years for the ERA JUMP Study

Atherosclerosis （Atherosclerosis） 268 84 - 91 2018年01月

研究論文（学術雑誌）, ISSN 0021-9150

© 2017 Elsevier B.V. Background and aims Several studies have reported a significant inverse association of light to moderate alcohol consumption with coronary heart disease (CHD). However, studies assessing the relationship between alcohol consumption and atherosclerosis have reported inconsistent results. The current study was conducted to determine the relationship between alcohol consumption and aortic calcification. Methods We addressed the research question using data from the population-based ERA-JUMP Study, comprising of 1006 healthy men aged 40–49 years, without clinical cardiovascular diseases, from four race/ethnicities: 301 Whites, 103 African American, 292 Japanese American, and 310 Japanese in Japan. Aortic calcification was assessed by electron-beam computed tomography and quantified using the Agatston method. Alcohol consumption was categorized into four groups: 0 (non-drinkers), ≤1 (light drinkers), >1 to ≤3 (moderate drinkers) and >3 drinks per day (heavy drinkers) (1 drink = 12.5 g of ethanol). Tobit conditional regression and ordinal logistic regression were used to investigate the association of alcohol consumption with aortic calcification after adjusting for cardiovascular risk factors and potential confounders. Results The study participants consisted of 25.6% nondrinkers, 35.3% light drinkers, 23.5% moderate drinkers, and 15.6% heavy drinkers. Heavy drinkers [Tobit ratio (95% CI) = 2.34 (1.10, 4.97); odds ratio (95% CI) = 1.67 (1.11, 2.52)] had significantly higher expected aortic calcification score compared to nondrinkers, after adjusting for socio-demographic and confounding variables. There was no significant interaction between alcohol consumption and race/ethnicity on aortic calcification. Conclusions Our findings suggest that heavy alcohol consumption may be an independent risk factor for atherosclerosis.

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Corrigendum to “Lipoprotein-associated phospholipase A2 is related to risk of subclinical atherosclerosis but is not supported by Mendelian randomization analysis in a general Japanese population.” [Atherosclerosis 246 (March 2016) 141–147]

Ueshima Hirotsugu, Kadowaki Takashi, Hisamatsu Takashi, Fujiyoshi Akira, Miura Katsuyuki, Ohkubo Takayoshi, Sekikawa Akira, Kadota Aya, Kadowaki Sayaka, Nakamura Yasuyuki, Miyagawa Naoko, Okamura Tomonori, Kita Yoshikuni, Takashima Naoyuki, Kashiwagi Atsunori, Maegawa Hiroshi, Horie Minoru, Yamamoto Takashi, Kimura Takeshi, Kita Toru

Atherosclerosis 2018年01月

ISSN 0021-9150

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Differences in Lifestyle Improvements With the Intention to Prevent Cardiovascular Diseases by Socioeconomic Status in a Representative Japanese Population

Goryoda Sayuri, Nishi Nobuo, Hozawa Atsushi, Yoshita Katsushi, Arai Yusuke, Kondo Keiko, Miyagawa Naoko, Hayakawa Takehito, Fujiyoshi Akira, Kadota Aya, Ohkubo Takayoshi, Okamura Tomonori, Okuda Nagako, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S35 - S39 2018年01月

ISSN 0917-5040

BACKGROUND: The relationships among socioeconomic status and lifestyle improvements have not yet been examined in a representative Japanese population.METHODS: We analyzed data from 2,647 participants (1,087 men and 1,560 women) who participated in NIPPON DATA2010. This survey inquired about lifestyle improvements and socioeconomic status. Education was categorized as low (≤9 years), middle (10-12 years), and high (≥13 years). Marital status was categorized as married, divorced, widowed, and never married/other. A multivariable logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of lifestyle improvements with the intention of preventing cardiovascular diseases for educational attainment and marital status, with adjustments for age and awareness of cardiovascular disease risk factors.RESULTS: Overall, 1,507 (56.9%) participants practiced prevention and improvements in hypertension, diabetes, elevated cholesterol, and metabolic syndrome, and the OR of lifestyle improvements was significantly higher with a high education than with a low education in men (OR 2.86; 95% CI, 1.96-4.17) and women (OR 2.36; 95% CI, 1.67-3.33). The number of participants who practiced prevention and improvements in hypertension, diabetes, elevated cholesterol, and metabolic syndrome was significantly lower in divorced than in married men (OR 0.46; 95% CI, 0.22-0.95) and women (OR 0.53; 95% CI, 0.33-0.86).CONCLUSIONS: Specific differences caused by educational attainment and marital status may exist in lifestyle improvements.

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Factors Related to Participation in Health Examinations for Japanese National Health Insurance

Imamura Haruhiko, Kogure Mana, Kita Yoshikuni, Nakagawa Hideaki, Hozawa Atsushi, Okamura Tomonori, Murakami Yoshitaka, Nishi Nobuo, Okuda Nagako, Kadota Aya, Ohkubo Takayoshi, Ueshima Hirotsugu, Okayama Akira, Miura Katsuyuki

Journal of Epidemiology 28 S53 - S58 2018年01月

ISSN 0917-5040

BACKGROUND: This study investigated relationships among socioeconomic factors and participation in health examinations for Japanese National Health Insurance (NHI) using a representative Japanese population.METHODS: We used the linkage database of NIPPON DATA2010 and Comprehensive Survey of Living Conditions 2010. Participants with NHI aged 40-74 years were included in the analysis. Prevalence ratios (PRs) for participation in health examinations in the past year were set as an outcome. Participant characteristics, including sex, age, socioeconomic factors (educational attainment, employment, equivalent household expenditure [EHE], house ownership, and marital status), laboratory measures, and lifestyle were included in an age-stratified modified Poisson regression analysis to examine relationships.RESULTS: The number of study participants was 812, and 564 (69.5%) participated in health examinations in the past year. Among those aged 40-64 years, there was no significant PR for socioeconomic factors. Among those aged 65-74 years, high (≥13 years) educational attainment (adjusted PR, 1.22; 95% confidence interval [CI], 1.05-1.41) and house ownership (PR 1.40; 95% CI, 1.11-1.77) were positively associated with participation, while high (4th quartile) EHE (PR 0.84; 95% CI, 0.73-0.97) was negatively associated.CONCLUSION: These results suggest that high educational attainment, house ownership, and low EHE were positive factors for participation in health examinations among those aged 65-74 years.

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The National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 2010 (NIPPON DATA2010): Objectives, Design, and Population Characteristics

Kadota A., Okuda N., Ohkubo T., Okamura T., Nishi N., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S2 - S9 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: The structure and risk factors for cardiovascular diseases (CVD) in Japan may change because lifestyle, particularly nutrition, socioeconomic status, and medical care, which affect CVD, may markedly change over time. Therefore, a new prospective cohort study on a representative general Japanese population based on national surveys is required.METHODS: In November 2010, the baseline survey of the National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged 2010 (NIPPON DATA2010) was performed with the National Health and Nutrition Survey of Japan (NHNS2010) in 300 randomly selected districts throughout Japan. The survey included a questionnaire, electrocardiogram, urinalysis, and blood biomarkers added to the NHNS2010 examinations. Physical measurements, blood biomarkers, and dietary data were also obtained in NHNS2010. Socioeconomic factors were obtained by merging with the Comprehensive Survey of Living Conditions 2010 (CSLC2010) dataset. Participants are followed annually for the incidence of diabetes mellitus, CVD events (acute coronary events, heart failure, atrial fibrillation, and stroke), and cause-specific mortality. The activities of daily living are followed every 5 years.RESULTS: A total of 2,898 individuals aged 20 years or older agreed to participate in the baseline survey of NIPPON DATA2010. The participation rate was 74.6%. Of these, data from NHNS2010 was merged for 2,891 participants (1,236 men and 1,655 women). The data of 2,807 participants were also merged with CSLC2010 data.CONCLUSIONS: We established NIPPON DATA2010 as a cohort study on a representative general Japanese population that covers all of Japan.

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Socioeconomic Status Associated With Urinary Sodium and Potassium Excretion in Japan: NIPPON DATA2010

Miyagawa N., Okuda N., Nakagawa H., Takezaki T., Nishi N., Takashima N., Fujiyoshi A., Ohkubo T., Kadota A., Okamura T., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S29 - S34 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: Although socioeconomic status (SES) may affect food and nutrient intakes, few studies have reported on sodium (Na) and potassium (K) intakes among individuals with various SESs in Japan. We investigated associations of SES with Na and K intake levels using urinary specimens in a representative Japanese population.METHODS: This was a cross-sectional study of 2,560 men and women (the NIPPON DATA2010 cohort) who participated in the National Health and Nutrition Survey Japan in 2010. Casual urine was used to calculate estimated excretion in 24-hour urinary Na (E24hr-Na) and K (E24hr-K). The urinary sodium-to-potassium (Na/K) ratio was calculated from casual urinary electrolyte values. An analysis of covariance was performed to investigate associations of aspects of SES, including equivalent household expenditure (EHE), educational attainment, and job category, with E24hr-Na, E24hr-K, and the Na/K ratio for men and women separately. A stratified analysis was performed on educational attainment and the job category for younger (<65 years) and older (≥65 years) participants.RESULTS: In men and women, average E24hr-Na was 176.2 mmol/day and 172.3, average E24hr-K was 42.5 and 41.3, and the average Na/K ratio was 3.61 and 3.68, respectively. Lower EHE was associated with a higher Na/K ratio in women and lower E24hr-K in men and women. A shorter education was associated with a higher Na/K ratio in women and younger men, and lower E24hr-K in older men and women.CONCLUSION: Lower EHE and a shorter education were associated with a lower K intake and higher Na/K ratio estimated from casual urine specimens in Japanese men and women.

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Socioeconomic Status and Knowledge of Cardiovascular Risk Factors: NIPPON DATA2010

Tsuji M., Arima H., Ohkubo T., Nakamura K., Takezaki T., Sakata K., Okuda N., Nishi N., Kadota A., Okamura T., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S46 - S52 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: The relationship between socioeconomic status (SES) and knowledge of cardiovascular risk factors remains unknown in a general Japanese population.METHODS: Of 8,815 participants from 300 randomly selected areas throughout Japan, 2,467 participants who were free of cardiovascular disease and who provided information on SES in the National Health and Nutrition Survey of Japan 2010 were enrolled in this cross-sectional analysis. SES was classified according to the employment status, length of education, marital and living statuses, and equivalent household expenditure (EHE). Outcomes were ignorance of each cardiovascular risk factor (hypertension, diabetes, hypercholesterolemia, low high-density lipoprotein [HDL] cholesterol, arrhythmia, and smoking) and insufficient knowledge (number of correct answers <4 out of 6).RESULTS: A short education and low EHE were significantly associated with a greater ignorance of most cardiovascular risk factors. A short education (<10 years) was also associated with insufficient knowledge of overall cardiovascular risk factors: age- and sex-adjusted odds ratios (OR) were 1.92 (95% confidence interval [CI], 1.51-2.45) relative to participants with ≥13 years of education. Low EHE was also associated with insufficient knowledge (age- and sex-adjusted OR 1.24; 95% CI, 1.01-1.51 for the lowest quintile vs the upper 4 quintiles). These relationships remained significant, even after further adjustments for regular exercise, smoking, weekly alcohol consumption, body mass index, hypertension, diabetes mellitus, hypercholesterolemia, and low HDL cholesterol.CONCLUSION: Participants with a short education and low EHE were more likely to have less knowledge of cardiovascular risk factors.

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Socioeconomic Inequalities in Oral Health among Middle-Aged and Elderly Japanese: NIPPON DATA2010

Murakami K., Ohkubo T., Nakamura M., Ninomiya T., Ojima T., Shirai K., Nagahata T., Kadota A., Okuda N., Nishi N., Okamura T., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S59 - S65 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: Most studies on socioeconomic inequalities in oral health have not considered the effects of behavioral and biological factors and age differences. Furthermore, the nationwide status of inequalities remains unclear in Japan.METHODS: We analyzed data from 2,089 residents aged ≥40 years throughout Japan. The lowest quartile of the number of remaining teeth for each 10-year age category was defined as poor oral health. Behavioral and biological factors included smoking status, obesity, diabetes mellitus, high-sensitivity C-reactive protein, and the use of dental devices. Multiple logistic regression analyses were conducted to examine the associations of educational attainment and equivalent household expenditure (EHE) with oral health, and stratified analyses by age category were also conducted (40-64 years and ≥65 years).RESULTS: Lower education and lower EHE were significantly associated with an increased risk of poor oral health after adjusting for age, sex, employment status, marital and living statuses, and EHE/education; the odds ratio for junior high school education compared with ≥college education was 1.84 (95% confidence interval [CI], 1.36-2.49), and the odds ratio of the lowest compared with the highest EHE quartile was 1.91 (95% CI, 1.43-2.56). Further adjustments for behavioral and biological factors attenuated but did not eliminate these associations. EHE was significantly associated with oral health among elderly adults only, with a significant interaction by age category.CONCLUSIONS: Those with a lower education and those with lower EHE had a significantly higher risk of poor oral health, even after adjustments for behavioral and biological factors.

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Relationships among Food Group Intakes, Household Expenditure, and Education Attainment in a General Japanese Population: NIPPON DATA2010

Nagahata T., Nakamura M., Ojima T., Kondo I., Ninomiya T., Yoshita K., Arai Y., Ohkubo T., Murakami K., Nishi N., Murakami Y., Takashima N., Okuda N., Kadota A., Miyagawa N., Kondo K., Okamura T., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S23 - S28 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: A lower socioeconomic status (SES) may be related to the intake of unhealthy food; however, this relationship has not been examined in detail. This study was undertaken to examine relationships among food group intakes and SES in a representative Japanese population.METHODS: This was a cross-sectional study using the baseline data of NIPPON DATA2010, which is a prospective cohort study of the National Health and Nutrition Survey in Japan. A total of 2,898 participants were included in the baseline survey in 2010. The effects of age (<65 years and ≥65 years), equivalent household expenditure (EHE), and education attainment on food group intakes (gram per 1,000 kcal) were analyzed using a two-way analysis of variance.RESULTS: When EHE was lower, cereal intake was higher in men and women. Among men, fish, milk, and alcohol intakes were reduced with lower EHE. Among women, vegetable intake was reduced with lower EHE. In men and women, cereal intake was higher with lower education attainment. In contrast, meat intake was reduced with lower education attainment.CONCLUSIONS: Lower SES was associated with a higher cereal intake and lower vegetable, fish, meat, and milk intakes in a representative Japanese population. Socioeconomic discrepancies need to be considered in order to promote healthier dietary habits.

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Relationship Between Socioeconomic Status and the Prevalence of Underweight, Overweight or Obesity in a General Japanese Population: NIPPON DATA2010

Nakamura T., Nakamura Y., Saitoh S., Okamura T., Yanagita M., Yoshita K., Kita Y., Murakami Y., Yokomichi H., Nishi N., Okuda N., Kadota A., Ohkubo T., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S10 - S16 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: Socioeconomic status (SES) imbalances in developed and developing countries may result in individuals being overweight and obese. However, few studies have investigated this issue in Japan. We herein examined the relationship between SES and being underweight, overweight or obese according to sex and age groups (20-64 or ≥65 years) in Japan.METHODS: In 2010, we established a cohort of participants in the National Health and Nutrition Survey of Japan. We divided 2,491 participants (1,081 men and 1,410 women) according to the WHO definitions of underweight, overweight or obesity and performed multinomial logistic analyses using BMI <18.5 kg/m2 (underweight), BMI 25.0-29.9 kg/m2 (overweight), and BMI ≥30.0 kg/m2 (obese) versus BMI 18.5-24.9 kg/m2 (normal) as the outcome, with SES groups as the main explanatory variables.RESULTS: In adult men, a lower education level relative to a higher education level was inversely associated with obesity after adjustments for other SESs (odds ratio [OR] 0.41; 95% confidence interval [CI], 0.18-0.96). However, in adult women, lower education level was positively associated with being overweight and obese (OR 1.67; 95% CI, 1.07-2.49 for overweight and OR 2.66; 95% CI, 1.01-7.01 for obese). In adult women, a lower household income was positively associated with being overweight and obese (obese: OR 4.84; 95% CI, 1.36-17.18 for those with a household income <2 million JPY relative to those with ≥6 million JPY).CONCLUSIONS: In adult women, a lower education level and lower household income were positively associated with being overweight or obese. In contrast, in adult men, a lower education level was inversely associated with obesity. Gender and age differences in SESs affect the prevalence of being overweight or obese.

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Macronutrient Intake and Socioeconomic Status: NIPPON DATA2010

Sakurai M., Nakagawa H., Kadota A., Yoshita K., Nakamura Y., Okuda N., Nishi N., Miyamoto Y., Arima H., Ohkubo T., Okamura T., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S17 - S22 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: This study examined the relationships among household income, other SES indicators, and macronutrient intake in a cross-sectional study of a representative Japanese population.METHODS: In 2010, we established a cohort of participants in the National Health and Nutrition Survey (NHNS) from 300 randomly selected areas throughout Japan. A total of 2,637 participants (1,145 men and 1,492 women) were included in the study. Data from NHNS2010 and the Comprehensive Survey of Living Conditions 2010 (CSCL2010) were merged, and relationships among macronutrient intake and SES were evaluated. Additionally, socioeconomic factors associated with a risk of a higher carbohydrate/lower fat intake beyond dietary recommendations were evaluated.RESULTS: Household income was positively associated with fat intake (P = 0.001 for men and <0.001 for women) and inversely associated with carbohydrate intake (P = 0.003 for men and <0.001 for women) after adjustments for age and other SES variables. Similar relationships were observed between equivalent household expenditure (EHE) and macronutrient intake; however, these relationships were weaker than those of household income. Older age was the factor most strongly associated with a high carbohydrate/low fat intake, followed by household income, EHE, education levels, and occupation type.CONCLUSIONS: Older age was the factor most strongly associated with a high carbohydrate/low fat intake, and some aspects of SES, such as household income, EHE, education levels, and occupation type, were independently associated with an imbalanced macronutrient intake. SES may affect the health status of individuals through the intake of macronutrients.

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Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017

Kinoshita M., Yokote K., Arai H., Iida M., Ishigaki Y., Ishibashi S., Umemoto S., Egusa G., Ohmura H., Okamura T., Kihara S., Koba S., Saito I., Shoji T., Daida H., Tsukamoto K., Deguchi J., Dohi S., Dobashi K., Hamaguchi H., Hara M., Hiro T., Biro S., Fujioka Y., Maruyama C., Miyamoto Y., Murakami Y., Yokode M., Yoshida H., Rakugi H., Wakatsuki A., Yamashita S., Okamura T., Daida H., Ninomiya T., Hozawa A., Yokode M., Iida M., Hasegawa K., Hara M., Yamato H., Shoji T., Abe T., Emoto M., Kashihara N., Saiki A., Tomiyama H., Hashimoto J., Hosomi N., Yamazaki Y., Bujo H., Inoue I., Inoue S., Koba S., Sawada S., Sone H., Hiro S., Funabashi T., Matsumoto M., Ohtsuki T., Kitagawa K., Kitazono T., Terayama Y., Tomimoto H., Toyoda K., Harada-Shiba M., Arai H., Ishibashi S., Nohara A., Ohta T., Ogura M., Ohtake A.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 25 （ 9 ） 846 - 984 2018年

研究論文（学術雑誌）, ISSN 13403478

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Imamura H., Kogure M., Kita Y., Nakagawa H., Hozawa A., Okamura T., Murakami Y., Nishi N., Okuda N., Kadota A., Ohkubo T., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S53 - S58 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: This study investigated relationships among socioeconomic factors and participation in health examinations for Japanese National Health Insurance (NHI) using a representative Japanese population.METHODS: We used the linkage database of NIPPON DATA2010 and Comprehensive Survey of Living Conditions 2010. Participants with NHI aged 40-74 years were included in the analysis. Prevalence ratios (PRs) for participation in health examinations in the past year were set as an outcome. Participant characteristics, including sex, age, socioeconomic factors (educational attainment, employment, equivalent household expenditure [EHE], house ownership, and marital status), laboratory measures, and lifestyle were included in an age-stratified modified Poisson regression analysis to examine relationships.RESULTS: The number of study participants was 812, and 564 (69.5%) participated in health examinations in the past year. Among those aged 40-64 years, there was no significant PR for socioeconomic factors. Among those aged 65-74 years, high (≥13 years) educational attainment (adjusted PR, 1.22; 95% confidence interval [CI], 1.05-1.41) and house ownership (PR 1.40; 95% CI, 1.11-1.77) were positively associated with participation, while high (4th quartile) EHE (PR 0.84; 95% CI, 0.73-0.97) was negatively associated.CONCLUSION: These results suggest that high educational attainment, house ownership, and low EHE were positive factors for participation in health examinations among those aged 65-74 years.

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Differences in Lifestyle Improvements With the Intention to Prevent Cardiovascular Diseases by Socioeconomic Status in a Representative Japanese Population: NIPPON DATA2010

Goryoda S., Nishi N., Hozawa A., Yoshita K., Arai Y., Kondo K., Miyagawa N., Hayakawa T., Fujiyoshi A., Kadota A., Ohkubo T., Okamura T., Okuda N., Ueshima H., Okayama A., Miura K.

Journal of epidemiology （Journal of epidemiology） 28 （ Suppl 3 ） S35 - S39 2018年

研究論文（学術雑誌）, ISSN 0917-5040

BACKGROUND: The relationships among socioeconomic status and lifestyle improvements have not yet been examined in a representative Japanese population.METHODS: We analyzed data from 2,647 participants (1,087 men and 1,560 women) who participated in NIPPON DATA2010. This survey inquired about lifestyle improvements and socioeconomic status. Education was categorized as low (≤9 years), middle (10-12 years), and high (≥13 years). Marital status was categorized as married, divorced, widowed, and never married/other. A multivariable logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of lifestyle improvements with the intention of preventing cardiovascular diseases for educational attainment and marital status, with adjustments for age and awareness of cardiovascular disease risk factors.RESULTS: Overall, 1,507 (56.9%) participants practiced prevention and improvements in hypertension, diabetes, elevated cholesterol, and metabolic syndrome, and the OR of lifestyle improvements was significantly higher with a high education than with a low education in men (OR 2.86; 95% CI, 1.96-4.17) and women (OR 2.36; 95% CI, 1.67-3.33). The number of participants who practiced prevention and improvements in hypertension, diabetes, elevated cholesterol, and metabolic syndrome was significantly lower in divorced than in married men (OR 0.46; 95% CI, 0.22-0.95) and women (OR 0.53; 95% CI, 0.33-0.86).CONCLUSIONS: Specific differences caused by educational attainment and marital status may exist in lifestyle improvements.

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Associations of high-density lipoprotein particle and high-density lipoprotein cholesterol with alcohol intake, smoking, and body mass index: The INTERLIPID study

Zaid M., Miura K., Okayama A., Nakagawa H., Sakata K., Saitoh S., Okuda N., Yoshita K., Choudhury S., Rodriguez B., Masaki K., Willcox B., Miyagawa N., Okamura T., Chan Q., Elliott P., Stamler J., Ueshima H.

Circulation Journal （Circulation Journal） 82 （ 10 ） 2557 - 2565 2018年

研究論文（学術雑誌）, ISSN 13469843

© 2018, Japanese Circulation Society. All rights reserved. Background: Recently, high-density lipoprotein particles (HDL-P) have been found to be more strongly inversely associated with coronary artery disease (CAD) risk than their counterpart, HDL cholesterol (HDL-C). Given that lifestyle is among the first targets in CAD prevention, we compared the associations of HDL-P and HDL-C with selected lifestyle factors. Methods and Results: We examined 789 Japanese participants of the INTERLIPID Study: men (n=386) and women (n=403) aged 40–59 years in 1996–1998. Participants treated for dyslipidemias were excluded. Lifestyle factors included alcohol intake, smoking amount, and body mass index (BMI). Multivariable linear regression was used for cross-sectional analyses of these factors with HDL-P, HDL-C, HDL-P size subclasses (small, medium and large) and mean HDL-P size. In men, higher alcohol intake was associated with higher HDL-P and higher HDL-C. The associations of alcohol, however, were strongest with HDL-P. A higher smoking amount tended to be associated with lower HDL-P and HDL-C. In contrast, BMI was not associated with HDL-P, but was strongly inversely associated with HDL-C. While alcohol intake favored larger mean HDL-P size, smoking and BMI favored a lipid profile with smaller HDL-P subclasses and overall smaller mean HDL-P size. Similar, but generally weaker results were observed in women. Conclusions: Although both HDL-P and HDL-C are parameters of HDL, they have different associations with alcohol, smoking and BMI.

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Associations between socioeconomic status and the prevalence and treatment of hypercholesterolemia in a general Japanese population: NIPPON DATA2010

Fujiyoshi N., Arima H., Satoh A., Ojima T., Nishi N., Okuda N., Kadota A., Ohkubo T., Hozawa A., Nakaya N., Fujiyoshi A., Okamura T., Ueshima H., Okayama A., Miura K., Saitoh S., Sakata K., Hayakawa T., Yanagawa H., Nakamura Y., Kasagi F., Murakami Y., Izumi T., Matsumura Y., Tokudome S., Toyoshima H., Nakagawa H., Kita Y., Miyamatsu N., Nakamura Y., Yoshita K., Miyamoto Y., Kodama K., Kiyohara Y., Ueda K.

Journal of Atherosclerosis and Thrombosis （Journal of Atherosclerosis and Thrombosis） 25 （ 7 ） 606 - 620 2018年

研究論文（学術雑誌）, ISSN 13403478

© 2018 Japan Atherosclerosis Society. Aim: To investigate associations between socioeconomic status (SES) and the prevalence and treatment status of hypercholesterolemia in a general Japanese population. Methods: In 2010, we established a cohort study of 2417 adults (age 20-91 yr) from 300 randomly selected areas across Japan who participated in the National Health and Nutrition Survey of Japan. We cross-sectionally examined an association between SES and (1) prevalence of hypercholesterolemia in 2417 participants (999 men and 1418 women) and (2) not receiving medication for hypercholesterolemia in 654 participants (215 men and 439 women). SES included employment status, marital status, length of education, and household expenditures. Hypercholesterolemia was defined as a total serum cholesterol level of ≥ 6.21 mmol/L (240 mg/dL) or the use of lipid-lowering medications. Results: The overall prevalence of hypercholesterolemia was 21.5% in men and 31.0% in women. In men, the lowest quintile of household expenditures was associated with a higher prevalence of hypercholesterolemia (28.3%) compared with the upper 4 quintiles (19.9%) (multivariable-adjusted odds ratio 1.66; 95% confidence interval [CI] 1.16-2.38). Among participants with hypercholesterolemia, 55.4% of men and 55.1% of women were not receiving medication. Unmarried men were more likely to be untreated (75.0%) than married men (50.9%) (multivariable-adjusted odds ratio 2.53; 95%CI 1.05-6.08). SES had no significant effects in women. Conclusion: In a general population of Japanese men, low household expenditures were associated with a higher prevalence of hypercholesterolemia, and unmarried men with hypercholesterolemia were less likely to receive medication.

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Re-evaluation of the associations of egg intake with serum total cholesterol and cause-specific and total mortality in Japanese women

Nakamura Y., Okamura T., Kita Y., Okuda N., Kadota A., Miura K., Okayama A., Ueshima H.

European Journal of Clinical Nutrition （European Journal of Clinical Nutrition） 72 （ 6 ） 1 - 7 2017年12月

研究論文（学術雑誌）, ISSN 0954-3007

© 2017 Macmillan Publishers Limited, part of Springer Nature. Background/objective: Egg intake was associated with serum total cholesterol adjusted for age (aTCH) and total mortality in women, but not in men, using data from NIPPON DATA (ND) 80 which followed up for 14 years. Re-evaluation of these associations in a different cohort is needed. Subject/methods: We analyzed the associations of egg intake with aTCH and cause-specific and total mortality using the ND90 data set with a 15-year follow-up. A nutritional examination was done at the baseline in 1990 using the food-frequency method and by weighed food records. We followed 4686 female participants (ages ≥30 years), with no history of stroke or myocardial infarction (mean age 52.8 years) for 15 years. Results: The participants were divided into 5 egg intake groups (<1/w, 1-2/w, 1/2d, 1/d, and ≥2/d). There were 203, 1462, 1594, 1387, and 40 women in each group, respectively. Egg intake was not associated with aTCH (P = 0.886). There were 183 cardiovascular disease (CVD), 210 cancer, and 599 total mortality cases during follow-up. Cox analysis, adjusted for background factors, found egg intake was directly associated with total and cancer mortality (HR in the ≥2/d vs.The 1 egg/d group: Total, 2.05 (95% CI: 1.20-3.52); cancer, 3.20 (1.51-6.76)), and that cancer mortality in the 1-2/w group was significantly less than that in the 1 egg/d group (0.68 (0.47-0.97)). Egg intake was not associated with CVD mortality. Conclusions: Egg intake was associated with cancer and total mortality. Reducing egg intake may have some definitive health benefits in women in Japan, at least.

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Effects of a school-based stroke education program on stroke-related knowledge and behaviour modification-school class based intervention study for elementary school students and parental guardians in a Japanese rural area.

Kato S, Okamura T, Kuwabara K, Takekawa H, Nagao M, Umesawa M, Sugiyama D, Miyamatsu N, Hino T, Wada S, Arimizu T, Takebayashi T, Kobashi G, Hirata K, Yokota C, Minematsu K

BMJ open 7 （ 12 ） e017632 2017年12月

研究論文（学術雑誌）, ISSN 2044-6055

OBJECTIVES: This study aimed to determine the effect of a stroke education programme on elementary school students and their parental guardians in a rural area in Japan that has high stroke mortality.DESIGN: School class based intervention study.SETTING: Eleven public elementary schools in Tochigi Prefecture, Japan.PARTICIPANTS: 268 students aged 11-12 years and 267 parental guardians.INTERVENTIONS: Students received lessons about stroke featuring animated cartoons and were instructed to communicate their knowledge about stroke to their parental guardians using material (comic books) distributed in the lessons. Stroke knowledge (symptoms, risk factors and attitude towards stroke) and behavioural change for risk factors were assessed at baseline, immediately after the programme and at 3 months. We also evaluated behavioural change for risk factors among parental guardians.RESULTS: The percentage of students with all correct answers for stroke symptoms, risk factors and the recommended response to stroke was significantly increased at 3 months P<0.001). We observed a significant increase in the percentage of guardians who chose all correct symptoms (P<0.001: 61.0% vs 85.4%) and risk factors (P<0.001: 41.2% vs 59.9%) at 3 months compared with baseline. The percentage of parental guardians with a high behavioural response to improving risk factors was significantly increased at 3 months compared with baseline (P<0.001).CONCLUSIONS: In a rural population with high stroke mortality, stroke education can improve knowledge about stroke in elementary school students and their parental guardians.ETHICS AND DISSEMINATION: We conducted the intervention as a part of compulsory education; this study was not a clinical trial. This study was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (M27-026).

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Detection of Subclinical Peripheral Artery Ischemia in Healthy Male Smokers by an Ankle-Brachial Index after Exercise

Kubota Yoshimi, Higashiyama Aya, Marumo Mikio, Konishi Masami, Yamashita Yoshiko, Tashiro Chikara, Okamura Tomonori, Miyamoto Yoshihiro, Wakabayashi Ichiro

Angiology 68 （ 9 ） 769 - 775 2017年10月

ISSN 0003-3197

We investigated the relationship between smoking and the risk of nonnormal (≤0.99) ankle-brachial index (ABI) at rest and after ankle plantar flexion exercise in healthy male community dwellers. A cross-sectional study was performed including 228 Japanese men aged 40 to 64 years without a history of cardiovascular diseases. Participants were classified as never, ex-, and current smokers. We estimated the multivariate-adjusted odds ratios (ORs) for nonnormal ABI of ex- and current smokers in relation to never smokers after adjusting for age and other confounding factors. At rest, the prevalence of nonnormal ABI was not significantly different by smoking status. After exercise, the prevalence of nonnormal ABI increased from 1.8% to 11.5% in ex-smokers and from 3.8% to 17.0% in current smokers, while the prevalence did not significantly change in never smokers. The multivariate-adjusted OR for nonnormal ABI after ankle plantar flexion exercise, in relation to never smokers, was 3.85 (95% confidence interval [CI]: 0.79-18.9) for ex-smokers and 6.97 (95% CI: 1.32-36.7) for current smokers. Our results suggest that ABI after ankle plantar flexion exercise is useful for early detection of subclinical peripheral artery ischemia in male smokers without typical symptoms.

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Detection of Subclinical Peripheral Artery Ischemia in Healthy Male Smokers by an Ankle-Brachial Index After Exercise: Sasayama Study.

Kubota Y, Higashiyama A, Marumo M, Konishi M, Yamashita Y, Tashiro C, Okamura T, Miyamoto Y, Wakabayashi I

Angiology 68 （ 9 ） 769 - 775 2017年10月

研究論文（学術雑誌）, ISSN 0003-3197

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Detection of Subclinical Peripheral Artery Ischemia in Healthy Male Smokers by an Ankle-Brachial Index After Exercise: Sasayama Study.

Kubota Y, Higashiyama A, Marumo M, Konishi M, Yamashita Y, Tashiro C, Okamura T, Miyamoto Y, Wakabayashi I

Angiology 68 （ 9 ） 769 - 775 2017年10月

研究論文（学術雑誌）, ISSN 0003-3197

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Risk of stroke and heart failure attributable to atrial fibrillation in middle-aged and elderly people: Results from a five-year prospective cohort study of Japanese community dwellers.

Ohsawa M, Okamura T, Tanno K, Ogasawara K, Itai K, Yonekura Y, Konishi K, Omama S, Miyamatsu N, Turin TC, Morino Y, Itoh T, Onoda T, Sakata K, Ishibashi Y, Makita S, Nakamura M, Tanaka F, Kuribayashi T, Ohta M, Okayama A

Journal of epidemiology 27 （ 8 ） 360 - 367 2017年08月

研究論文（学術雑誌）, ISSN 0917-5040

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Risk of stroke and heart failure attributable to atrial fibrillation in middle-aged and elderly people: Results from a five-year prospective cohort study of Japanese community dwellers.

Journal of epidemiology 27 （ 8 ） 360 - 367 2017年08月

研究論文（学術雑誌）, ISSN 0917-5040

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Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Song Ci, Burgess Stephen, Eicher John D., O'Donnell Christopher J., Johnson Andrew D., Huang Jie, Sabater-Lleal Maria, Asselbergs Folkert W., Tregouet David, Shin So Youn, Ding Jingzhong, Baumert Jens, Oudot-Mellakh Tiphaine, Folkersen Lasse, Smith Nicholas L., Williams Scott M., Ikram Mohammad A., Kleber Marcus E., Becker Diane M., Truong Vinh, Mychaleckyj Josyf C., Tang Weihong, Yang Qiong, Sennblad Bengt, Moore Jason H., Williams Frances M.K., Dehghan Abbas, Silbernagel Günther, Schrijvers Elisabeth M.C., Smith Shelly, Karakas Mahir, Tofler Geoffrey H., Silveira Angela, Navis Gerjan J., Lohman Kurt, Chen Ming Huei, Peters Annette, Goel Anuj, Hopewell Jemma C., Chambers John C., Saleheen Danish, Lundmark Per, Psaty Bruce M., Strawbridge Rona J., Boehm Bernhard O., Carter Angela M., Meisinger Christa, Peden John F., Bis Joshua C., Okamura Tomonori

Journal of the American Heart Association 6 （ 6 ） 2017年06月

ISSN 2047-9980

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.

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Birthweight and cardiovascular risk factors in a Japanese general population.

Katsuragi S, Okamura T, Kokubo Y, Ikeda T, Miyamoto Y

The journal of obstetrics and gynaecology research 43 （ 6 ） 1001 - 1007 2017年06月

研究論文（学術雑誌）, ISSN 1341-8076

Aim: This study was conducted to examine whether babies born small develop cardiovascular problems in later life. Methods: Data were examined retrospectively for 1241 city dwellers (men 521, women 720) aged 40–69 years who received a medical examination at a single institution. Blood tests, physical measurements, and a questionnaire survey regarding birth weight (small, medium, large), medication history and lifestyle (alcohol consumption, smoking, exercise) was administered. We selected 28 persons (12 men and 16 women) from and studied the rate of conformity between the participants’ memory (small, medium, large) and the actual birth weight recorded in their maternal and child health handbook (< 2500, 2500–3500, > 3500 g). Results: Participants’ recall of their birth weight correlated well with the weight recorded in the maternal notebook (r = 0.73; P < 0.025). Low-density lipoprotein (P < 0.05), and total cholesterol (P < 0.01) levels in men, and systolic (P < 0.05) and diastolic (P < 0.05) blood pressure in women were significantly inversely related to birth weight when controlling for age, body mass index, medication, and lifestyle. The percentage of women born small, medium, and large taking antidiabetic agents was 17.8%, 2.9% and 0% (P < 0.05), respectively. Conclusion: A low birth weight was associated with high low-density lipoprotein and total cholesterol levels in men, and hypertension and diabetes mellitus in women aged 40–69.

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Left ventricular hypertrophy by electrocardiogram as a predictor of success in home blood pressure control: HOMED-BP study.

Tanabe A, Asayama K, Hanazawa T, Watabe D, Nomura K, Okamura T, Ohkubo T, Imai Y

Hypertension research : official journal of the Japanese Society of Hypertension 40 （ 5 ） 504 - 510 2017年05月

研究論文（学術雑誌）, ISSN 0916-9636

Few studies have focused on the effect of organ damage on achievement of long-term home blood pressure (BP) control. Based on the nationwide home BP-based trial data, we aimed to investigate the factors associated with home BP control, in particular, left ventricular hypertrophy (LVH) using the electrocardiogram in patients who started antihypertensive drug treatment. According to the trial protocol, we defined BP as controlled when systolic home BP reached specified targets (125-134 mm Hg in usual control (UC), n=1261; <125 mm Hg in tight control (TC), n=1288). At baseline, before drug treatment started, the mean Sokolow-Lyon voltage was 2.57±0.87 mV, and the mean Cornell product was 1573±705 mm·ms. The numbers of patients who achieved the target BP level in the UC and TC groups were 892 (70.7%) and 576 (44.7%), respectively. In both the UC and TC groups, systolic home BP at baseline was significantly lower in patients who achieved target levels than in those who did not achieve target levels (P<0.0001). Sokolow-Lyon voltage was significantly lower in patients who achieved target levels than in those who did not (P≤0.0055). The Cornell product levels in each group were similar (P≥0.12), although significantly different between patients who did or did not achieve the target level when the UC and TC groups were combined for analysis (P=0.031). Sokolow-Lyon voltage was significantly associated with achievement of home BP control in the multivariable-adjusted model (odds ratio, 1.13; 95% confidence intervals, 1.02-1.26; P=0.015), but Cornell product was not (P=0.13). These results indicate the difficulty of sufficient antihypertensive treatment when untreated patients had target organ damage, that is, LVH diagnosed by Sokolow-Lyon voltage.

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Fasting but not casual blood glucose is associated with pancreatic cancer mortality in Japanese: EPOCH-JAPAN.

Nagai M, Murakami Y, Tamakoshi A, Kiyohara Y, Yamada M, Ukawa S, Hirata T, Tanaka S, Miura K, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN) Research Group.

Cancer causes & control : CCC 28 （ 6 ） 1 - 9 2017年03月

研究論文（学術雑誌）, ISSN 0957-5243

Purpose: The dose–response relationship between fasting blood glucose levels and risk of pancreatic cancer has been investigated, but the association between casual blood glucose levels and pancreatic cancer death has not been examined. We examined the association between casual and fasting blood glucose levels and death due to pancreatic cancer in Japanese. Methods: We performed a pooled analysis of the individual Japanese including 46,387 participants aged 40–79 years from ten cohorts. Participants were classified into five groups: low normal, middle normal, high normal, prediabetes (casual blood glucose 140–199 mg/dl, or fasting blood glucose 110–125 mg/dl), and diabetes (casual blood glucose ≥200 mg/dl, fasting blood glucose ≥126 mg/dl, or anti-diabetic drug use). Low normal, middle normal, and high normal were defined according to tertiles of casual or fasting normal blood glucose levels. Hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer mortality were estimated stratifying casual and fasting blood glucose by cohort-stratified Cox proportional hazards regression analysis, with low normal (casual blood glucose <94 mg/dl, or fasting blood glucose <90 mg/dl) as a reference. Results: Fasting blood glucose showed a dose–response relationship with pancreatic cancer mortality (p for trend = 0.005). After adjusting for covariates, HRs (95% CIs) were 2.83 (1.18–6.76) for prediabetes and 3.96 (1.56–10.08) for diabetes. However, there were no significant associations with casual blood glucose. These tendencies were observed after the exclusion of participants who were censored for the first 5 years of follow-up. Conclusions: Fasting blood glucose is a better predictor of pancreatic cancer death than casual blood glucose.

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Impacts of chronic kidney disease and diabetes on cardiovascular mortality in a general Japanese population: A 20-year follow-up of the NIPPON DATA90 study.

Hirata A, Okamura T, Sugiyama D, Kuwabara K, Kadota A, Fujiyoshi A, Miura K, Okuda N, Ohkubo T, Okayama A, Ueshima H, NIPPON DATA90 and 2010 Research Group.

European journal of preventive cardiology 24 （ 5 ） 505 - 513 2017年03月

研究論文（学術雑誌）, ISSN 2047-4873

Background Studies have shown significant associations of chronic kidney disease (CKD) and diabetes mellitus (DM) with cardiovascular disease (CVD) mortality. The impact on the general population is an important public health issue. However, the population attributable fraction (PAF) of CVD because of CKD and/or DM in a general population is uncertain. Methods We followed 7229 participants (age: ≥30 years) with no history of CVD in a Japanese community. We divided participants into four categories according to CKD and/or DM and calculated hazard ratios (HRs) of CVD mortality for each category using a Cox proportional hazards model adjusted for age, dyslipidemia, smoking and alcohol consumption. In addition, PAFs of CVD were estimated among populations with CKD and/or DM. Results During 20-year follow-up, 488 participants died. HRs for CVD were 1.63 [95% confidence interval (CI): 1.16-2.30] with DM only, 1.42 (95% CI: 1.08-1.86) with CKD only and 2.37 (95% CI: 1.40-4.01) with CKD + DM. In men, the corresponding HRs for CVD were 1.88 (95% CI: 1.19-2.97), 1.71 (95% CI: 1.15-2.56) and 3.26 (95% CI: 1.69-6.30), respectively; the corresponding PAFs of CVD were 4.1%, 5.1% and 2.9%, respectively. PAFs for CVD among women were lower than those in men, 1.6% for DM only, 2.0% for CKD only and 0.7% for CKD + DM. Conclusions PAFs of CVD mortality due to CKD and/or DM were not so high in past 20 years; however, they might increase in the future because of recent increase in prevalence of these in Japanese population.

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Increased childhood BMI is associated with young adult serum uric acid levels: a linkage study from Japan.

Kuwahara E, Murakami Y, Okamura T, Komatsu H, Nakazawa A, Ushiku H, Maejima F, Nishigaki Y, Nishiwaki Y

Pediatric research 81 （ 2 ） 293 - 298 2017年02月

研究論文（学術雑誌）, ISSN 0031-3998

Background:Growth pattern in early life is one of the most important factors affecting the pathogenesis of metabolic-associated diseases. The associations between serum uric acid (SUA) and hypertension, kidney disease, and coronary heart disease have been recognized. We investigated the association between increased BMI during childhood and adult SUA levels in Japan.Methods:We included 298 children with health examination data between 1981 and 2002 who had also undergone physical examinations after reaching early adulthood (approximately 27 y old). Subjects were divided into sex-specific tertiles based on the difference in their BMI (DBMI) over a 6-y period (6-12 y of age). The association between the three DBMI groups and SUA in adults was analyzed.Results:The predicted average SUA level in adults from the high DBMI group was 5.32 mg/dl after adjustment for related factors in a combined sex analysis. This was significantly higher than among the low DBMI group.Conclusion:Excessive BMI increases during childhood led to young adult SUA elevation even after adjusting for several factors. Lifestyle in early life may be a strong predictor of future uric acid metabolism and the resulting disease risk.

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Significant inverse association of equol-producer status with coronary artery calcification but not dietary isoflavones in healthy Japanese men.

Ahuja V, Miura K, Vishnu A, Fujiyoshi A, Evans R, Zaid M, Miyagawa N, Hisamatsu T, Kadota A, Okamura T, Ueshima H, Sekikawa A

The British journal of nutrition 117 （ 2 ） 260 - 266 2017年01月

研究論文（学術雑誌）, ISSN 0007-1145

Equol, a metabolite of the dietary isoflavone daidzein, is produced by the action of gut bacteria in some individuals who are termed as equol-producers. It is proposed to have stronger atheroprotective properties than dietary isoflavones. We examined a cross-sectional association of dietary isoflavones and equol-producer status with coronary artery calcification (CAC), a biomarker of coronary atherosclerosis, among men in Japan. A population-based sample of 272 Japanese men aged 40-49 years recruited from 2004 to 2007 was examined for serum isoflavones, serum equol, CAC and other factors. Equol-producers were classified as individuals having a serum level of equol >83 nm. The presence of CAC was defined as a coronary Ca score ≥10 Agatston units. The associations of dietary isoflavones and equol-producers with CAC were analysed using multiple logistic regression. The median of dietary isoflavones, equol and CAC were 512·7 (interquartile range (IQR) 194·1, 1170·0), 9·1 (IQR 0·10, 33·1) and 0·0 (IQR 0·0, 1·0) nm, respectively. Prevalence of CAC and equol-producers was 9·6 and 16·0 %, respectively. Dietary isoflavones were not significantly associated with CAC. After multivariable adjustment, the OR for the presence of CAC in equol-producers compared with equol non-producers was 0·10 (95 % CI 0·01, 0·90, P<0·04). Equol-producers had significantly lower CAC than equol non-producers, but there was no significant association between dietary isoflavones and CAC, suggesting that equol may be a key factor for atheroprotective properties of isoflavones in Japanese men. This finding must be confirmed in larger studies or clinical trials of equol that is now available as a dietary supplement.

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Is Childhood Exposure to Parental Smoking a Risk Factor for Future Cardiovascular Disease?

Michikawa T, Okamura T

Journal of atherosclerosis and thrombosis 24 （ 12 ） 1204 - 1205 2017年01月

研究論文（学術雑誌）, ISSN 1340-3478

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Risk for metabolic diseases in normal weight individuals with visceral fat accumulation: a cross-sectional study in Japan.

Tatsumi Y, Nakao YM, Masuda I, Higashiyama A, Takegami M, Nishimura K, Watanabe M, Ohkubo T, Okamura T, Miyamoto Y

BMJ open 7 （ 1 ） e013831 2017年01月

研究論文（学術雑誌）, ISSN 2044-6055

Objective To investigate the association between visceral fat area (VFA) and metabolic syndrome (Mets) among normal weight Japanese. Design A cross-sectional study. Setting The health check-up centre of the Takeda Hospital group in Kyoto, Japan. Methods This study involved 1674 men and 1448 women aged 30-74years who underwent medical check-ups in 2012 in the health check-up centre. They were stratified by Body Mass Index (BMI cut-off for obesity is set at 23.0kg/m² for Asians): normal weight 18.5-22.9kg/m² or higher weight ≥23.0kg/m². The age-adjusted ORs of the 2nd to 4th groups of sex-specific VFA quartiles compared with the 1st quartile for a Mets component clustering were estimated. The clustering was having two or more of the following factors: High blood pressure, high fasting blood glucose (FBG), low high-density lipoprotein cholesterol (HDL-C) and high triglycerides. Statistical analyses were conducted in 2016. Results Participants in the 2nd to 4th VFA quartiles had significantly higher clustering risks; ORs were 3.4 (1.5 to 8.0), 6.3 (2.8 to 14.2) and 9.3 (4.2 to 20.7) for normal weight participants, and 1.7 (1.2 to 2.6), 2.6 (1.8 to 3.9) and 6.0 (4.1 to 8.8) for higher weight participants, respectively. The ORs of the 4th VFA quartile for Mets components were significantly higher; ORs for normal weight participants were 2.1 (1.5 to 3.0) (high blood pressure), 2.4 (1.4 to 4.2) (high FBG), 5.2 (2.1 to 12.9) (low HDL-C) and 12.0 (5.7 to 25.3) (high triglycerides), and higher weight participants were 3.9 (2.8 to 5.5), 4.1 (2.8 to 6.2), 3.9 (2.2 to 6.9) and 5.0 (3.4 to 7.4), respectively. Conclusions Among participants with normal weight, as well as those of higher weight, dose-dependent responses were observed between VFA and risk for Mets components and the clustering among Japanese adults. VFA may be useful information for interventions to improve metabolic risk factors in people with normal weight.

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Risk of stroke and heart failure attributable to atrial fibrillation in middle-aged and elderly people

Ohsawa Masaki, Okamura Tomonori, Tanno Kozo, Ogasawara Kuniaki, Itai Kazuyoshi, Yonekura Yuki, Konishi Kazuki, Omama Shinichi, Miyamatsu Naomi, Turin Tanvir Chowdhury, Morino Yoshihiro, Itoh Tomonori, Onoda Toshiyuki, Sakata Kiyomi, Ishibashi Yasuhiro, Makita Shinji, Nakamura Motoyuki, Tanaka Fumitaka, Kuribayashi Toru, Ohta Mutsuko, Okayama Akira

Journal of Epidemiology 27 （ 8 ） 360 - 367 2017年

ISSN 0917-5040

Background: The relative and absolute risks of stroke and heart failure attributable to atrial fibrillation (AF) have not been sufficiently examined. Methods: A prospective study of 23,731 community-dwelling Japanese individuals was conducted. Participantswere divided into two groups based on the presence or absence of prevalent AF (n = 338 and n = 23,393, respectively). Excess events (EE) due to AF and relative risks (RRs) determined using the non-AF group as the reference for incident stroke and heart failurewere estimated using Poisson regression stratified by age groups (middle-aged: 40-69 years old; elderly: 70 years of age or older) after adjustment for sex and age. Results: There were 611 cases of stroke and 98 cases of heart failure during the observation period (131,088 person-years). AF contributed to a higher risk of stroke both in middle-aged individuals (EE 10.4 per 1000 person-years;RR4.88;95%confidenceinterval [CI],2.88-8.29) andelderlyindividuals (EE18.3per1000 personyears; RR 3.05; 95% CI, 2.05-4.54). AFalso contributed to a higher risk of heart failure in middle-aged individuals (EE 3.7 per 1000 person-years; RR 8.18; 95% CI, 2.41-27.8) and elderly individuals (EE 15.4 per 1000 personyears; RR 7.82; 95% CI, 4.11-14.9). Results obtained from multivariate-adjusted analysis were similar (stroke: EE 8.9 per 1000 person-years; RR 4.40; 95% CI, 2.57-7.55 inmiddle-aged and EE 17.4 per 1000 person-years; RR 2.97; 95% CI, 1.99-4.43 in elderly individuals; heart failure: EE 3.1 per 1000 person-years; RR 7.22; 95% CI, 2.06-25.3 in middle-aged and EE 14.1 per 1000 person-years; RR 7.41; 95% CI, 3.86-14.2 in elderly individuals). Conclusions: AF increased the risk of stroke by the same magnitude as that reported previously in Western countries. AF increased the RR of heart failure more than that in Western populations.

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Associations of socioeconomic status with prevalence, awareness, treatment, and control of hypertension in a general Japanese population: NIPPON DATA2010.

Satoh A, Arima H, Ohkubo T, Nishi N, Okuda N, Ae R, Inoue M, Kurita S, Murakami K, Kadota A, Fujiyoshi A, Sakata K, Okamura T, Ueshima H, Okayama A, Miura K, NIPPON DATA2010 Research Group.

Journal of hypertension 35 （ 2 ） 401 - 408 2017年

研究論文（学術雑誌）, ISSN 0263-6352

Objective: To investigate associations between socioeconomic status (SES) and prevalence, awareness, treatment, and control of hypertension in Japan's general population. Methods: In 2010, we established a cohort of participants in the National Health and Nutrition Survey of Japan. The cohort included 2623 adults from 300 randomly selected areas across Japan. Using baseline data, four crosssectional analyses were performed: association of SES with prevalent hypertension in 2623 participants; association of SES with unawareness of hypertension and with no treatment in 1282 hypertensive patients; and association of SES with uncontrolled hypertension in 720 treated hypertensive patients. SES was classified according to employment status, length of education, marital and living status, and household expenditure. Results: The overall prevalence of hypertension was 48.9%. Among hypertensive participants, the proportions of unawareness and no treatment were 33.1 and 43.8%, respectively. Target blood pressure levels were not achieved among 61.2% of treated hypertensive patients. Hypertension was more prevalent in the unmarried and living alone group than in the married group (odds ratio 1.76; 95% confidence interval 1.26-2.44), after adjustment for age, sex, BMI, smoking, alcohol consumption, habitual exercise, history of cardiovascular diseases, diabetes mellitus, hypercholesterolemia, dietary sodium, and potassium intake. SES was not clearly associated with unawareness, no treatment, nor poor control of hypertension. Conclusion: Being unmarried and living alone was associated with increased prevalence of hypertension. There was no clear association of SES with unaware, untreated, and uncontrolled hypertension.

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Age-specific impact of diabetes mellitus on the risk of cardiovascular mortality: An overview from the evidence for Cardiovascular Prevention from Observational Cohorts in the Japan Research Group (EPOCH-JAPAN).

Hirakawa Y, Ninomiya T, Kiyohara Y, Murakami Y, Saitoh S, Nakagawa H, Okayama A, Tamakoshi A, Sakata K, Miura K, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention From Observational Cohorts in Japan Research Group (EPOCH-JAPAN).

Journal of epidemiology 27 （ 3 ） 123 - 129 2017年

研究論文（学術雑誌）, ISSN 0917-5040

Background: Diabetes mellitus is a strong risk factor for cardiovascular disease. However, the age-specific association of diabetes with cardiovascular risk, especially in the elderly, remains unclear in non-Western populations. Methods: A pooled analysis was conducted using 8 cohort studies (mean follow-up period, 10.3 years) in Japan, combining the data from 38,854 individual participants without history of cardiovascular disease. In all, 1867 of the participants had diabetes, defined based on the 1998 World Health Organization criteria. The association between diabetes and the risk of death from cardiovascular disease, coronary heart disease (CHD), and stroke was estimated using a stratified Cox model, accounting for variability of baseline hazard functions among cohorts. Results: During the follow-up, 1376 subjects died of cardiovascular disease (including 268 of coronary heart disease and 621 of stroke). Diabetes was associated with an increased risk of cardiovascular death after multivariable adjustment (hazard ratio [HR] 1.62; 95% confidence interval [CI], 1.35-1.94). Similarly, diabetes was a risk factor for CHD (HR 2.13; 95% CI, 1.47-3.09) and stroke (HR 1.40; 95% CI, 1.05-1.85). In the age-stratified analysis of the risk of cardiovascular death, the relative effects of diabetes were consistent across age groups (p for heterogeneity = 0.18), whereas the excess absolute risks of diabetes were greater in participants in their 70s and 80s than in younger subjects. Conclusions: The management of diabetes is important to reduce the risk of death from cardiovascular disease, not only in midlife but also in late life, in the Japanese population.

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Association between lifestyle factors assessed by standard question items of specific health checkup and the incidence of metabolic syndrome and hypertension in community dwellers: A five-year cohort study of National Health Insurance beneficiaries in Habikino City.

Tsutatani H, Funamoto M, Sugiyama D, Kuwabara K, Miyamatsu N, Watanabe K, Okamura T

[Nihon koshu eisei zasshi] Japanese journal of public health 64 （ 5 ） 258 - 269 2017年

研究論文（学術雑誌）, ISSN 0546-1766

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Relationship between health promotion volunteer experience and medical costs: Hoken-hodouin activities in Suzaka, Nagano.

Imamura H, Murakami Y, Okamura T, Nishiwaki Y

[Nihon koshu eisei zasshi] Japanese journal of public health 64 （ 1 ） 25 - 35 2017年

研究論文（学術雑誌）, ISSN 0546-1766

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Tsutatani H, Funamoto M, Sugiyama D, Kuwabara K, Miyamatsu N, Watanabe K, Okamura T

[Nihon koshu eisei zasshi] Japanese journal of public health 64 （ 5 ） 258 - 269 2017年

研究論文（学術雑誌）, ISSN 0546-1766

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Relationship between health promotion volunteer experience and medical costs: Hoken-hodouin activities in Suzaka, Nagano.

Imamura H, Murakami Y, Okamura T, Nishiwaki Y

[Nihon koshu eisei zasshi] Japanese journal of public health 64 （ 1 ） 25 - 35 2017年

研究論文（学術雑誌）, ISSN 0546-1766

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Diabetes and lifetime risk of coronary heart disease.

Turin TC, Okamura T, Rumana N, Afzal AR, Watanabe M, Higashiyama A, Nakao YM, Nakai M, Takegami M, Nishimura K, Kokubo Y, Okayama A, Miyamoto Y

Primary care diabetes 11 （ 5 ） 461 - 466 2016年12月

研究論文（学術雑誌）, ISSN 1751-9918

Introduction: Epidemiological estimate lifetime risk (LTR) is a measure that expresses the probability of disease in the remaining lifetime for individuals of a specific index age. These estimates can be useful for general audience targeted knowledge translation activities against diabetes. There are only a few reports on lifetime of impact of diabetes on coronary heart disease (CHD) events. Methods: The Suita Study, a cohort study of cardiovascular diseases (CVD), was established in 1989. We included all participants who were CVD free at baseline. Age (in years) was used as the time scale. Age-specific incidence rates were calculated with person-year method within ten-year bands. We estimated the sex and index-age specific LTR of first-ever CHD with taking the competing risk of death into account. Results: We followed 5559 participants without CHD history during 1989-2007 for 71,745.4 person-years. At age 40 years the competing risk of death adjusted LTR for all CHD were 16.61% for men without diabetes and 21.06% for men with diabetes. Therefore the LTD for CHD was higher by 4.45% for men with diabetes compared to men without. The competing risk adjusted LTR of CHD at 40 years of aged women was 9.18% for without diabetes and 14.21% for with diabetes. This increased LTR of CHD for diabetic patients were observed among both men and women across all index ages. Conclusion: In this urban community based population we observed that diabetes has significant effect on the residual LTR of CHD among both men and women of middle age. This easy understandable knowledge can be used as important indexes to assist public health education and planning.

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Diabetes and lifetime risk of stroke and subtypes in an urban middle-aged population.

Turin TC, Okamura T, Rumana N, Afzal AR, Watanabe M, Higashiyama A, Nakao YM, Nakai M, Takegami M, Nishimura K, Kokubo Y, Okayama A, Miyamoto Y

Journal of diabetes and its complications 31 （ 5 ） 831 - 835 2016年11月

研究論文（学術雑誌）, ISSN 1056-8727

Aims: Lifetime risk (LTR) is defined as the cumulative probability of developing a disease in one's remaining lifetime from a given index age. The impact of diabetes on the LTR of stroke events in Asians, where stroke incidence is higher than for Westerners, has not been estimated yet. These estimates can be useful for diabetes knowledge translation activities. Methods: All participants who were stroke-free at baseline in the Suita Study, a cohort study of cardiovascular diseases in Japan, were included in the study sample. Age, in years, was used as the time-scale. Age-specific incidence rates were calculated using the person-years method within five-year bands. We estimated the sex- and index-age-specific LTR of first-ever stroke accounting for the competing risk of death. Results: In this cohort study, we followed 5515 participants from 1989 to 2007 for 71,374.23 person-years. At age 40, the LTRs, adjusted for competing risk of death, for all strokes were 15.98% for men without diabetes and 26.64% for men with diabetes. The LTR for stroke was 10.66% higher for men with diabetes than men without diabetes. For women of same index age, the LTR of stroke was 17.29% and 30.72% with diabetes and without diabetes, respectively. The difference in LTR between persons with diabetes and without diabetes was 13.43%. This increased LTR of strokes for persons with diabetes was observed among both men and women across all index ages. Similar results were observed for cerebral infarction stroke subtype. Conclusions: In this urban community-based population we observed that diabetes has a significant effect on the residual LTR of stroke for both men and women of middle age. This knowledge can be used to inform public health education and planning.

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A pooled analysis of the association of isolated low levels of high-density lipoprotein cholesterol with cardiovascular mortality in Japan.

Hirata T, Sugiyama D, Nagasawa SY, Murakami Y, Saitoh S, Okayama A, Iso H, Irie F, Sairenchi T, Miyamoto Y, Yamada M, Ishikawa S, Miura K, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN) Research Group.

European journal of epidemiology 32 （ 7 ） 1 - 11 2016年10月

研究論文（学術雑誌）, ISSN 0393-2990

Low levels of serum high-density lipoprotein cholesterol (HDL-C) have been shown to be associated with increased risk of coronary heart disease (CHD). However, because this is usually observed in the context of other lipid abnormalities, it is not known whether isolated low serum HDL-C levels are an independent risk factor for CHD. We performed a large pooled analysis in Japan using data from nine cohorts with 41,206 participants aged 40–89 years who were free of cardiovascular disease at baseline. We divided participants into three groups: isolated low HDL-C, non-isolated low HDL-C, and normal HDL-C. Cohort-stratified Cox proportional hazards models were used to estimate multivariate-adjusted hazard ratios (HRs) for death due to CHD, ischemic stroke, and intracranial cerebral hemorrhage; during a 12.9-year follow-up, we observed 355, 286, and 138 deaths, respectively, in these groups. Non-isolated low HDL-C was significantly associated with increased risk of CHD compared with normal HDL-C (HR 1.37, 95 % confidence interval (CI) 1.04–1.80); however, isolated low HDL-C was not. Although isolated low HDL-C was significantly associated with decreased risk of CHD (HR 0.51, 95 % CI 0.29–0.89) in women, it was significantly associated with increased risk of intracranial cerebral hemorrhage in all participants (HR 1.62, 95 % CI 1.04–2.53) and in men (HR 2.00, 95 % CI 1.04–3.83). In conclusion, isolated low HDL-C levels are not associated with increased risk of CHD in Japan. CHD risk may, therefore, be more strongly affected by serum total cholesterol levels in this population.

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Metabolic Profiling of Total Physical Activity and Sedentary Behavior in Community-Dwelling Men.

Fukai K, Harada S, Iida M, Kurihara A, Takeuchi A, Kuwabara K, Sugiyama D, Okamura T, Akiyama M, Nishiwaki Y, Oguma Y, Suzuki A, Suzuki C, Hirayama A, Sugimoto M, Soga T, Tomita M, Takebayashi T

PloS one 11 （ 10 ） e0164877 2016年10月

研究論文（学術雑誌）, ISSN 1932-6203

Objective: Physical activity is known to be preventive against various non-communicable diseases. We investigated the relationship between daily physical activity level and plasma metabolites using a targeted metabolomics approach in a population-based study. Methods: A total of 1,193 participants (male, aged 35 to 74 years) with fasting blood samples were selected from the baseline survey of a cohort study. Information on daily total physical activity, classified into four levels by quartile of metabolic equivalent scores, and sedentary behavior, defined as hours of sitting per day, was collected through a self-administered questionnaire. Plasma metabolite concentrations were quantified by capillary electrophoresis mass spectrometry method. We performed linear regression analysis models with multivariable adjustment and corrected p-values for multiple testing in the original population (n = 808). The robustness of the results was confirmed by replication analysis in a separate population (n = 385) created by random allocation. Results: Higher levels of total physical activity were associated with various metabolite concentrations, including lower concentrations of amino acids and their derivatives, and higher concentrations of pipecolate (FDR p <0.05 in original population). The findings persisted after adjustment for age, body mass index, smoking, alcohol intake, and energy intake. Isoleucine, leucine, valine, 4-methyl-2-oxoisopentanoate, 2-oxoisopentanoate, alanine, and proline concentrations were lower with a shorter sitting time. Conclusions: Physical activity is related to various plasma metabolites, including known biomarkers for future insulin resistance or type 2 diabetes. These metabolites might potentially play a key role in the protective effects of higher physical activity and/or less sedentary behavior on non-communicable diseases.

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Relationship between non-high-density lipoprotein cholesterol and the long-term mortality of cardiovascular diseases: NIPPON DATA 90.

Ito T, Arima H, Fujiyoshi A, Miura K, Takashima N, Ohkubo T, Kadota A, Hayakawa T, Kita Y, Miyagawa N, Okayama A, Okamura T, Ueshima H, NIPPON DATA90 Research Group.

International journal of cardiology 220 262 - 267 2016年10月

研究論文（学術雑誌）, ISSN 0167-5273

Background Non-high-density lipoprotein (HDL) cholesterol level, generally less affected by fasting status or serum triglyceride levels, may be useful for predicting future cardiovascular events in daily clinical practice. This study aimed to investigate the role of non-HDL cholesterol in the development of fatal coronary events and stroke in the general Japanese population. Methods and results From the NIPPON DATA 90 prospective cohort study, 8383 participants were followed up for 20 years since 1990. After exclusion of 666 cases without lipid or covariates data, 561 cases who were 75 years old or older, 274 cases with history of cardiovascular disease, and 181 cases with lipid-lowering treatment, 6701 participants were included in this analysis. Non-HDL cholesterol was defined as total cholesterol minus HDL cholesterol. Outcomes were death from coronary heart disease and stroke. During the period, 69 participants died from coronary heart disease and 112 from stroke. Compared with participants with non-HDL cholesterol level

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Casual serum triglyceride as a predictor of premature type 2 diabetes mellitus: an 8-year cohort study of middle-aged Japanese workers.

Nishikawa T, Okamura T, Shima A, Kawatsu Y, Sugiyama D, Kadota A, Morimoto A, Tatsumi Y, Godai K, Miyamatsu N

Diabetology international 7 （ 3 ） 252 - 258 2016年09月

ISSN 2190-1678

Background: The utility of casual serum triglyceride (TG) as a predictor of type 2 diabetes mellitus (DM) is unclear, especially during the most productive years. Methods: Participants were 3271 workers (913 men and 2358 women, age 20–57) without DM at baseline. They underwent consecutive annual medical check-ups for 8 years. The association between newly diagnosed DM and casual serum TG level was determined by classifying the participants into 4 groups according to casual serum TG level at baseline: below 50 mg/dL (group A), 50–100 mg/dL (group B), 100–150 mg/dL (group C), and ≥150 mg/dL (group D). The effects of casual serum TG level in combination with sex, obesity, or serum glucose level on newly diagnosed DM were also evaluated. Results: A total of 222 newly diagnosed type 2 DM cases with a mean age of 50 years old were observed during the follow-up period, i.e., 10/406 in group A, 66/1534 in group B, 58/712 in group C, and 88/619 in group D. Compared with group A, the odds ratio (ORs) for newly diagnosed DM (after adjusting for DM-associated factors) was found to increase with casual serum TG level: 1.38 (group B), 1.79 (group C), and 2.36 (group D). Moreover, the OR for newly diagnosed DM was higher in participants with high casual serum TG levels who were also male (OR 2.46), obese (OR 4.18), or had a high serum glucose level (OR 6.96) than in the reference group. Conclusions: Serum TG level ≥150 mg/dL when fasting or nonfasting is a significant predictor of type 2 diabetes in middle-aged Japanese workers.

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Validation of the european SCORE risk chart in the healthy middle-aged Japanese.

Sawano M, Kohsaka S, Okamura T, Inohara T, Sugiyama D, Watanabe M, Nakamura Y, Higashiyama A, Kadota A, Okud N, Murakami Y, Ohkubo T, Fujiyoshi A, Miura K, Okayama A, Ueshima H, National Integrated Project for Prospective Observation of Non-Communicable Disease and its Trends in the Aged (NIPPON DATA 80) Research Group.

Atherosclerosis 252 116 - 121 2016年09月

研究論文（学術雑誌）, ISSN 0021-9150

Background and aims The European Society of Cardiology developed prediction models (SCORE) for low- and high-risk populations in the European countries. However, whether or not these models are valid in different ethnicities is unknown. We aimed to evaluate the performance of the low-risk SCORE model in the general Japanese population. Methods Healthy middle-aged Japanese participating in the NIPPON DATA80 cohort had been observed. The predicted 10-year cardiovascular death risk was calculated using the low-risk SCORE model for the overall population as well as for each gender individually. The model performance of the low-risk SCORE model was evaluated with the Harrel's c-statistics for discrimination and the Grønnesby and Borgan goodness-of-fit test for calibration. Results A total of 4842 participants aged 40–64 years old and 47,606 person-years were evaluated in our study. 203 (4.19%) died within the ten-years of follow-up and 44 (0.91%) CV deaths were observed. The low-risk SCORE model in the overall population had reasonable discrimination (c statistics 0.72, 95% CI 0.71–0.73) but poor calibration (R², 0.67, Chi-square value 6.15, p = 0.01). Discrimination was reasonable in both men (c statistics 0.71, 95% CI 0.69–0.73) and women (c statistics 0.71, 95% CI 0.70–0.73). However, calibration was poor in men (R², 0.22, Chi-square value 0.749, p = 0.38) compared to women (R², 0.96, Chi-square value 1.39, p = 0.24). Conclusions Although the low-risk SCORE model performs reasonably well in women, the SCORE models generally overestimated the risk of cardiovascular death risk in the Japanese general population.

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Does the flushing response modify the relationship between alcohol intake and hypertension in the Japanese population? NIPPON DATA2010.

Kogure M, Tsuchiya N, Hozawa A, Nakaya N, Nakamura T, Miyamatsu N, Tanaka H, Wakabayashi I, Higashiyama A, Okuda N, Takashima N, Fujiyoshi A, Kadota A, Ohkubo T, Okamura T, Ueshima H, Okayama A, Miura K

Hypertension research : official journal of the Japanese Society of Hypertension 39 （ 9 ） 670 - 679 2016年09月

研究論文（学術雑誌）, ISSN 0916-9636

The influence of alcohol intake on hypertension may vary depending on the flushing response, but this relationship has not been confirmed. The relationship between alcohol intake and hypertension was examined according to the flushing response in a representative sample of the Japanese population. Participants in the National Health and Nutrition Survey in 2010 were asked to participate in the baseline survey of NIPPON DATA2010. Here, we investigated the relationship between alcohol intake and hypertension according to the flushing response. Statistical analyses were performed in a cross-sectional manner using multiple logistic regression models after adjusting for age, body mass index, smoking status, present illness of diabetes mellitus and present illness of dyslipidemia. Of the 1139 men and 1263 women, 659 and 463, respectively, had hypertension. Among the men, alcohol intake was positively associated with hypertension, regardless of the flushing response (P for linear trend both <0.05). This positive relationship was observed for both users and non-users of antihypertensive drugs. No interaction with the flushing response was observed (P for interaction=0.360). In women, although the direction differed between flushers and non-flushers, the association between alcohol intake and hypertension was not significant, regardless of flushing response. In conclusion, In Japanese men, alcohol intake was positively associated with hypertension in a manner that was not influenced by the flushing response.

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Dietary sodium-to-potassium ratio as a risk factor for stroke, cardiovascular disease and all-cause mortality in Japan

Okayama Akira, Okuda Nagako, Miura Katsuyuki, Okamura Tomonori, Hayakawa Takehito, Akasaka Hiroshi, Ohnishi Hirofumi, Saitoh Shigeyuki, Arai Yusuke, Kiyohara Yutaka, Takashima Naoyuki, Yoshita Katsushi, Fujiyoshi Akira, Zaid Maryam, Ohkubo Takayoshi, Ueshima Hirotsugu

BMJ Open 6 （ 7 ） e011632 2016年07月

ISSN 2044-6055

OBJECTIVES: To evaluate the impact of dietary sodium and potassium (Na-K) ratio on mortality from total and subtypes of stroke, cardiovascular disease (CVD) and all causes, using 24-year follow-up data of a representative sample of the Japanese population.SETTING: Prospective cohort study.PARTICIPANTS: In the 1980 National Cardiovascular Survey, participants were followed for 24 years (NIPPON DATA80, National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged). Men and women aged 30-79 years without hypertensive treatment, history of stroke or acute myocardial infarction (n=8283) were divided into quintiles according to dietary Na-K ratio assessed by a 3-day weighing dietary record at baseline. Age-adjusted and multivariable-adjusted HRs were calculated using the Mantel-Haenszel method and Cox proportional hazards model.PRIMARY OUTCOME MEASURES: Mortality from total and subtypes of stroke, CVD and all causes.RESULTS: A total of 1938 deaths from all causes were observed over 176 926 person-years. Na-K ratio was significantly and non-linearly related to mortality from all stroke (p=0.002), CVD (p=0.005) and total mortality (p=0.001). For stroke subtypes, mortality from haemorrhagic stroke was positively related to Na-K ratio (p=0.024). Similar relationships were observed for men and women. The observed relationships remained significant after adjustment for other risk factors. Quadratic non-linear multivariable-adjusted HRs (95% CI) in the highest quintile versus the lowest quintile of Na-K ratio were 1.42 (1.07 to 1.90) for ischaemic stroke, 1.57 (1.05 to 2.34) for haemorrhagic stroke, 1.43 (1.17 to 1.76) for all stroke, 1.39 (1.20 to 1.61) for CVD and 1.16 (1.06 to 1.27) for all-cause mortality.CONCLUSIONS: Dietary Na-K ratio assessed by a 3-day weighing dietary record was a significant risk factor for mortality from haemorrhagic stroke, all stroke, CVD and all causes among a Japanese population.

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Dietary sodium-to-potassium ratio as a risk factor for stroke, cardiovascular disease and all-cause mortality in Japan: the NIPPON DATA80 cohort study.

Okayama A, Okuda N, Miura K, Okamura T, Hayakawa T, Akasaka H, Ohnishi H, Saitoh S, Arai Y, Kiyohara Y, Takashima N, Yoshita K, Fujiyoshi A, Zaid M, Ohkubo T, Ueshima H, NIPPON DATA80 Research Group.

BMJ open 6 （ 7 ） e011632 2016年07月

研究論文（学術雑誌）

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Dietary sodium-to-potassium ratio as a risk factor for stroke, cardiovascular disease and all-cause mortality in Japan: the NIPPON DATA80 cohort study.

Okayama A, Okuda N, Miura K, Okamura T, Hayakawa T, Akasaka H, Ohnishi H, Saitoh S, Arai Y, Kiyohara Y, Takashima N, Yoshita K, Fujiyoshi A, Zaid M, Ohkubo T, Ueshima H, NIPPON DATA80 Research Group.

BMJ open 6 （ 7 ） e011632 2016年07月

研究論文（学術雑誌）

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Prognostic significance of endogenous erythropoietin in long-term outcome of patients with acute decompensated heart failure.

Nagai T, Nishimura K, Honma T, Higashiyama A, Sugano Y, Nakai M, Honda S, Iwakami N, Okada A, Kawakami S, Kanaya T, Asaumi Y, Aiba T, Nishida Y, Kubota Y, Sugiyama D, Okamura T, Noguchi T, Kusano K, Ogawa H, Yasuda S, Anzai T, NaDEF investigators.

European journal of heart failure 18 （ 7 ） 803 - 813 2016年07月

研究論文（学術雑誌）, ISSN 1388-9842

Aims: Although previous reports suggest that an elevated endogenous erythropoietin (EPO) level is associated with worse clinical outcomes in chronic heart failure (HF) patients, the prognostic implication of EPO in patients with acute decompensated HF (ADHF) and underlying mechanisms of the high EPO level in severe HF patients who have a poor prognosis remain unclear. Methods and results: We examined 539 consecutive ADHF patients with EPO measurement on admission from our registry. During a median follow-up period of 329 days, a higher EPO level on admission was independently associated with worse clinical outcomes [hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.06–1.48, P = 0.008], and haemoglobin level was the strongest determinant of EPO level (P <0.001), whereas estimated glomerular filtration rate (eGFR) was not significant in multivariate regression analysis. In the anaemic subgroup of 318 patients, a higher EPO level than expected on the basis of their haemoglobin level was related to increased adverse events (HR 1.63, 95% CI 1.05–2.49, P = 0.028). Moreover, estimated plasma volume excess rate was positively associated with EPO level (P = 0.003), and anaemic patients with a higher than expected EPO level tended to have a higher estimated plasma volume excess rate and plasma lactate level, and lower systemic oxygen saturation level with the preservation of the reticulocyte production index than those with a lower than expected EPO level. Conclusion: A high EPO level predicts long-term worse clinical outcomes in ADHF patients, independent of anaemia and impaired renal function. Anaemia and hypoxia due to severe congestion may synergistically contribute to a high EPO level in high-risk HF patients.

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Impact of hypertension on the lifetime risk of coronary heart disease.

Turin TC, Okamura T, Afzal AR, Rumana N, Watanabe M, Higashiyama A, Nakao YM, Nakai M, Takegami M, Nishimura K, Kokubo Y, Okayama A, Miyamoto Y

Hypertension research : official journal of the Japanese Society of Hypertension 39 （ 7 ） 548 - 551 2016年07月

研究論文（学術雑誌）, ISSN 0916-9636

The lifetime risk estimate conveys the probability of disease in the remaining lifetime for an index age. These estimates may be useful for general audience-targeted knowledge translation activities against hypertension. There are only a few reports on the impact of hypertension on the lifetime risk of cardiovascular events. The Suita Study, a cohort study of urban residents, was established in 1989. We included all participants who were coronary heart disease (CHD) free at baseline. Age (in years) was used as the timescale. Age-specific incidence rates were calculated with the person-year method within 5-year bands. We estimated the sex- and index-age-specific lifetime risk of first-ever CHD, taking the competing risk of death into account. We followed 5834 participants from 1989 to 2007 for a total of 75 387.5 person-years. At age 45 years, the competing risk of death-adjusted lifetime risk for all CHD for men was 14.12% for normotensive men and 26.95% for hypertensive men. The competing risk of death-adjusted lifetime risk for all CHD at 45 years of age for women was 6.21% for normotensive women and 14.85% for hypertensive women. This increased lifetime risk of CHD for hypertensive patients was observed among both men and women across all index ages. Although the overall lifetime risk of CHD was lower than in the Western population, hypertension showed a significant effect on the residual lifetime risk of CHD among Japanese middle-aged men and women. This easy-to-understand knowledge may be used as an important index to assist public health education and planning.

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Erratum to: Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men.

Harada S, Takebayashi T, Kurihara A, Akiyama M, Suzuki A, Hatakeyama Y, Sugiyama D, Kuwabara K, Takeuchi A, Okamura T, Nishiwaki Y, Tanaka T, Hirayama A, Sugimoto M, Soga T, Tomita M

Environmental health and preventive medicine 21 （ 4 ） 283 - 284 2016年07月

研究論文（学術雑誌）, ISSN 1342-078X

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Erratum to: Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men.

Harada S, Takebayashi T, Kurihara A, Akiyama M, Suzuki A, Hatakeyama Y, Sugiyama D, Kuwabara K, Takeuchi A, Okamura T, Nishiwaki Y, Tanaka T, Hirayama A, Sugimoto M, Soga T, Tomita M

Environmental health and preventive medicine 21 （ 4 ） 283 - 284 2016年07月

研究論文（学術雑誌）, ISSN 1342-078X

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NIPPON DATA (National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged)

Okamura Tomonori

Nihon rinsho. Japanese journal of clinical medicine 74 Pt 1 685 - 690 2016年06月

ISSN 0047-1852

[NIPPON DATA (National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged)].

Okamura T

Nihon rinsho. Japanese journal of clinical medicine 74 Suppl 4 Pt 1 685 - 90 2016年06月

研究論文（学術雑誌）, ISSN 0047-1852

[NIPPON DATA (National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged)].

Okamura T

Nihon rinsho. Japanese journal of clinical medicine 74 Suppl 4 Pt 1 685 - 90 2016年06月

研究論文（学術雑誌）, ISSN 0047-1852

Independent Prognostic Value of Single and Multiple Non-Specific 12-Lead Electrocardiographic Findings for Long-Term Cardiovascular Outcomes: A Prospective Cohort Study.

Sawano M, Kohsaka S, Okamura T, Inohara T, Sugiyama D, Shiraishi Y, Watanabe M, Nakamura Y, Higashiyama A, Kadota A, Okuda N, Murakami Y, Ohkubo T, Fujiyoshi A, Miura K, Okayama A, Ueshima H, NIPPON DATA 80/90 Research Group.

PloS one 11 （ 6 ） e0157563 2016年06月

研究論文（学術雑誌）, ISSN 1932-6203

Aims The long-term prognostic effect of non-specific 12-lead electrocardiogram findings is unknown. We aimed to evaluate the cumulative prognostic impact of axial, structural, and repolarization categorical abnormalities on cardiovascular death, independent from traditional risk scoring systems such as the Framingham risk score and the NIPPON DATA80 risk chart. Methods and Results A total of 16,816 healthy men and women from two prospective, longitudinal cohort studies were evaluated. 3,794 (22.6%) individuals died during a median follow-up of 15 years (range, 2.0-24 years). Hazard ratios for cardiovascular death, all-cause death, coronary death and stroke death were calculated for the cumulative and independent axial, structural, and repolarization categorical abnormalities adjusted for the Framingham risk score and the NIPPON DATA80 risk chart. Individuals with two or more abnormal categories had a higher risk of cardiovascular death after adjustment for Framingham risk score (men: HR 4.27, 95%CI 3.35-5.45; women: HR 4.83, 95%CI 3.76-6.22) and NIPPON DATA80 risk chart (men: HR 2.39, 95%CI 1.87-3.07; women: HR 2.04, 95%CI 1.58-2.64). Conclusion Cumulative findings of axial, structural, and repolarization abnormalities are significant predictors of long-term cardiovascular death in asymptomatic, healthy individuals independent of traditional risk stratification systems.

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Cross-sectional association between exposure to particulate matter and inflammatory markers in the Japanese general population: NIPPON DATA2010.

Michikawa T, Okamura T, Nitta H, Nishiwaki Y, Takebayashi T, Ueda K, Kadota A, Fujiyoshi A, Ohkubo T, Ueshima H, Okayama A, Miura K, NIPPON DATA2010 Research Group.

Environmental pollution (Barking, Essex : 1987) 213 460 - 467 2016年06月

研究論文（学術雑誌）, ISSN 0269-7491

A suggestive mechanism behind the association between particulate matter and cardiovascular disease is inflammatory response. Earlier population-based studies investigating the association between particulate matter and inflammatory biological markers, in particular C-reactive protein (CRP), showed inconsistent results. In addition, evidence from the Asian population, in which CRP levels are typically lower than those observed in Western populations, was sparse. We examined the cross-sectional association between short- and long-term exposure to particulate matter and inflammatory markers, including high-sensitivity CRP (hs-CRP) and white blood cell (WBC) count, in a representative population of Japanese community dwellers (NIPPON DATA2010). We analysed data from 2360 participants (1002 men and 1358 women), aged 20 years or older, who resided in 300 randomly selected districts (222 public health centre areas) throughout Japan. We used background concentrations of suspended particulate matter (SPM, defined as particles with a 100% cut-off level at 10 μm aerodynamic diameter) and co-pollutants within the public health centre area. A logistic regression model was applied to estimate odds ratios (ORs) of elevated hs-CRP (> 0.3 mg/dl) or WBC (> 9000/μl). Since smoking is an important confounding factor, we firstly included this in the models, and additionally conducted the analyses after excluding current smokers. The one-month average concentration of SPM was positively associated with hs-CRP (OR per 10 μg/m³ increase in SPM = 1.42, 95% confidence interval = 1.00-2.04), and high exposure to SPM on the day of blood draw was associated with increased WBC count, after excluding current smokers (OR = 1.13, 1.01-1.28). Similar association patterns were observed for ozone. In conclusion, exposure to particulate matter was associated with inflammatory markers in the general Japanese population. Systemic inflammation may play a role in the link between particulate matter and cardiovascular disease.

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Impact of Flushing Response on the Relationship between Alcohol Consumption and Gamma-glutamyl Transpeptidase: the KOBE study.

Hirata T, Higashiyama A, Kubota Y, Sugiyama D, Kuwabara K, Tatsumi Y, Hirata A, Nishida Y, Kadota A, Imano H, Nishikawa T, Miyamatsu N, Miyamoto Y, Okamura T

Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 51 （ 3 ） 173 - 183 2016年06月

研究論文（学術雑誌）, ISSN 1341-8963

Impact of Flushing Response on the Relationship between Alcohol Consumption and Gamma-glutamyl Transpeptidase: the KOBE study.

Hirata T, Higashiyama A, Kubota Y, Sugiyama D, Kuwabara K, Tatsumi Y, Hirata A, Nishida Y, Kadota A, Imano H, Nishikawa T, Miyamatsu N, Miyamoto Y, Okamura T

Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 51 （ 3 ） 173 - 183 2016年06月

研究論文（学術雑誌）, ISSN 1341-8963

Relationship between outpatient visit frequency and hypertension control: a 9-year occupational cohort study.

Shima A, Tatsumi Y, Ishizaki T, Godai K, Kawatsu Y, Okamura T, Nishikawa T, Morimoto A, Morino A, Miyamatsu N

Hypertension research : official journal of the Japanese Society of Hypertension 39 （ 5 ） 376 - 381 2016年05月

研究論文（学術雑誌）, ISSN 0916-9636

The purpose of this study was to investigate the relationship between the frequency of outpatient visits and hypertension control as determined from health insurance records. This 9-year cohort study in Japan was based on 518 participants with hypertension who underwent health checkups in 2004. Participants were aged 35-56 years and none had a history of cardiovascular or cerebrovascular disease. All were covered by the same employee health insurer. Mean annual outpatient visit days at a hospital/clinic during the 9-year period were classified within four quartiles (Q1, Q2, Q3, Q4). Uncontrolled hypertension was defined as a systolic blood pressure (BP) ≥140 mm Hg and a diastolic BP ≥90 mm Hg. Logistic regression analysis was used to estimate the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of uncontrolled hypertension in groups Q1, Q2 and Q3 vs. Q4. The median (25th-75th percentile) annual outpatient visit days was 9.4 (4.0-15.5). Uncontrolled hypertension was observed in 62.4% of the participants in 2013. The multivariable-adjusted ORs and 95% CIs for uncontrolled hypertension in Q1, Q2 and Q3 vs. Q4 were 4.03 (2.28-7.12), 1.67 (0.99-2.81) and 1.44 (0.86-2.41), respectively. Uncontrolled hypertension increased significantly as the number of outpatient visits decreased (P for trend

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Dietary tofu intake and long-term risk of death from stroke in a general population

Nguyen H., Miyagawa N., Miura K., Okuda N., Yoshita K., Arai Y., Nakagawa H., Sakata K., Ojima T., Kadota A., Takashima N., Fujiyoshi A., Ohkubo T., Abbott R., Okamura T., Okayama A., Ueshima H.

Clinical Nutrition （Clinical Nutrition） 37 （ 1 ） 182 - 188 2016年04月

研究論文（学術雑誌）, ISSN 0261-5614

© 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism Background & aim: Although dietary soy intake is linked with health benefits, a relation with stroke has not been established. The present study examined the association between the intake of tofu, the richest source of dietary soy, with stroke mortality in a general population cohort of Japanese men and women. Methods: Data comprise 9244 Japanese enrolled in the National Nutrition Survey of Japan in 1980. Participants were free of cardiovascular disease and followed for 24 years. Dietary intake was estimated from 3-day weighed food records. Multivariable Cox regression models were used to estimate hazard ratios across levels of tofu intake. Results: During follow-up, there were 417 deaths due to stroke (88 cerebral hemorrhage [CH], 245 cerebral infarction [CI], and 84 of other subtypes). Among all men, and in women aged 65 years or more, tofu intake was unrelated to each form of stroke. For young women (<65 years of age), a significantly lower risk of CH in the top versus bottom quartile of tofu intake was observed (Multivariable-adjusted HR = 0.26, 95% CI: 0.08–0.85). Conclusions: In this large prospective study with long follow-up of Japanese men and women, consumption of tofu was unrelated to the risk of stroke except for CH in women <65 years of age. Whether the association in younger women is real or due to chance alone warrants further study.

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Profiling of plasma metabolites in postmenopausal women with metabolic syndrome.

Iida M, Harada S, Kurihara A, Fukai K, Kuwabara K, Sugiyama D, Takeuchi A, Okamura T, Akiyama M, Nishiwaki Y, Suzuki A, Hirayama A, Sugimoto M, Soga T, Tomita M, Banno K, Aoki D, Takebayashi T

Menopause (New York, N.Y.) 23 （ 7 ） 749 - 58 2016年04月

研究論文（学術雑誌）, ISSN 1072-3714

OBJECTIVE:: The aim of the study was to investigate the associations of amino acids and other polar metabolites with metabolic syndrome (MetS) in postmenopausal women in a lean Asian population. METHODS:: The participants were 1,422 female residents enrolled in a cohort study from April to August 2012. MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III modified for Japanese women. Associations were examined between MetS and 78 metabolites assayed in fasting plasma samples using capillary electrophoresis-mass spectrometry. Replication analysis was performed to confirm the robustness of the results in a separate population created by random allocation. RESULTS:: Analysis was performed for 877 naturally postmenopausal women, including 594 in the original population and 283 in the replication population. The average age, body mass index, and levels of high- and low-density lipoprotein cholesterol of the entire population were 64.6 years, 23.0?kg/m, 72.1?mg/dL, and 126.1?mg/dL, respectively. There was no significant difference in low-density lipoprotein cholesterol levels between women with and without MetS. Thirteen metabolites were significantly related to MetS: multiple plasma amino acids were elevated in women with MetS, including branched-chain amino acids, alanine, glutamate, and proline; and alpha-aminoadipate, which is generated by lysine degradation, was also significantly increased. CONCLUSIONS:: Our large-scale metabolomic profiling indicates that Japanese postmenopausal women with MetS have abnormal polar metabolites, suggesting altered catabolic pathways. These results may help to understand metabolic disturbance, including in persons with normal body mass index and relatively high levels of high-density lipoprotein cholesterol, and may have clinical utility based on further studies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

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Relationship between Non-High-Density Lipoprotein Cholesterol and Low-Density Lipoprotein Cholesterol in the General Population.

Kuwabara K, Harada S, Sugiyama D, Kurihara A, Kubota Y, Higashiyama A, Hirata T, Nishida Y, Kawasaki M, Takebayashi T, Okamura T

Journal of atherosclerosis and thrombosis 23 （ 4 ） 477 - 490 2016年04月

研究論文（学術雑誌）, ISSN 1340-3478

Aim: The Japan Atherosclerosis Society (JAS) Guidelines for Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases for Japanese 2012 version have set a non-high-density lipoprotein cholesterol (non-HDL-C)-management target of low-density lipoprotein cholesterol (LDL-C) + 30 mg/ dL. However, the actual difference between non-HDL-C and LDL-C is not clear. Therefore, we evaluated its joint distribution and assessed the validity of this criterion in the general Japanese population. Methods: We used baseline cross-sectional data of 4,110 participants from two studies; the KOBE Study (n=1,108) and the Tsuruoka Metabolomic Cohort Study (n= 3,002). To evaluate whether the difference between LDL-C and non-HDL-C in the general population match that of the current guidelines, we classified LDL-C levels into four groups according to the JAS Guideline and evaluated its agreement with the corresponding non-HDL-C group. Analysis was also done using six groups (the previous four groups plus the upper and lower cut-off values). Results: The mean difference (mg/dL) between the non-HDL-C and LDL-C (for the KOBE Study and Tsuruoka Metabolomic Cohort Study, respectively) was 19.6 and 24.1 (p <0.001) for men and 15.9 and 18.3 (p <0.001) for women. In both the cohort studies, the difference was lower than 30 mg/dL. It was especially small among individuals with normal triglyceride levels. Conclusions: In the general Japanese population, the difference between non-HDL-C and LDL-C was lower than the expected difference of 30 mg/dL. Changes to the criteria for non-HDL-C target levels may be considered in the future.

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Association of Total Energy Intake with 29-Year Mortality in the Japanese: NIPPON DATA80.

Nagai M, Ohkubo T, Miura K, Fujiyoshi A, Okuda N, Hayakawa T, Yoshita K, Arai Y, Nakagawa H, Nakamura K, Miyagawa N, Takashima N, Kadota A, Murakami Y, Nakamura Y, Abbott RD, Okamura T, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Journal of atherosclerosis and thrombosis 23 （ 3 ） 339 - 354 2016年03月

研究論文（学術雑誌）, ISSN 1340-3478

Aim: In animals, dietary energy restriction is reported to increase longevity, whereas in humans, all cohort studies from Western countries have not shown an association between the low energy intake and longevity. We examined the association between total energy intake and longevity in Japan where dietary pattern is different from that in the West. Methods: A total of 7,704 Japanese aged 30–69 years were followed from 1980 to 2009. Participants were divided into the quintiles of total energy (kcal/day. based on data collected from the National Nutrition Survey. Hazard ratios and 95% confidence intervals (CIs. were derived through the use of Cox proportional hazards models to compare the risk of death across and between the quintiles. Results: There was a significant association between increased energy intake and all-cause mortality risk in only men (P for linear trend=0.008). In cause-specific analysis, compared with the lowest quintile, there was rise in coronary heart disease (CHD. mortality among men (HR; 2.63, 95%CI; 0.95–7.28, P for linear trend 0.016. and women (HR; 2.91, 95%CI; 1.02–8.29, P for linear trend 0.032. and cancer mortality among men (HR; 1.50, 95%CI; 0.999–2.24, P for linear trend 0.038. in the top quintile. Conclusion: We observed significant associations of high energy intake with all-cause and cancer mortality among men and with CHD mortality among men and women. Further studies are needed to confirm the benefits of caloric restriction.

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Lipoprotein-associated phospholipase A2 is related to risk of subclinical atherosclerosis but is not supported by Mendelian randomization analysis in a general Japanese population.

Atherosclerosis 246 141 - 147 2016年03月

研究論文（学術雑誌）, ISSN 0021-9150

Objective: Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is an enzyme predominantly bound to low-density lipoprotein (LDL). Lp-PLA₂ is recognized as playing a key role in inflammatory processes and the development of atherosclerosis. This study aimed to investigate whether Lp-PLA₂ is related to subclinical atherosclerosis, independently from traditional risk factors, in a general Japanese population by analyses of both the observational study and Mendelian randomization using V279F polymorphism. Methods and results: We cross-sectionally examined community-based sample of 929 Japanese men aged 40-79 years, without statin treatment, who were randomly selected from the resident registration. Multiple regression analyses of Lp-PLA₂ activity and concentration were undertaken separately for men aged 40-49 years and 50-79 years, to clarify interactions of age and Lp-PLA₂. Lp-PLA₂ activity for men aged 50-79 years was significantly and positively related to intima-media thickness (IMT) (P = 0.013) and plaque index (P = 0.008) independent of traditional risk factors including small LDL particles, but not to coronary artery calcification (CAC) score. Associations with Lp-PLA₂ concentration were qualitatively similar to those of activity. Corresponding relationships were not observed in men aged 40-49 years. Mendelian randomization analyses based on V279F genotype did not show any significant associations with subclinical atherosclerosis, although the homozygote and heterozygote of V279F showed low Lp-PLA₂ activity and concentration. Conclusions: Lp-PLA₂ activity in Japanese men aged 50-79 years was associated significantly and positively with IMT and plaque in the carotid artery but Mendelian randomization did not support that Lp-PLA₂ is a causative factor for subclinical atherosclerosis.

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Calibration between the Estimated Probability of the Risk Assessment Chart of Japan Atherosclerosis Society and Actual Mortality Using External Population: Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN).

Nakai M, Miyamoto Y, Higashiyama A, Murakami Y, Nishimura K, Yatsuya H, Saitoh S, Sakata K, Iso H, Miura K, Ueshima H, Okamura T, EPOCH-JAPAN Research Group.

Journal of atherosclerosis and thrombosis 23 （ 2 ） 176 - 195 2016年02月

研究論文（学術雑誌）, ISSN 1340-3478

Aim: In Japan Atherosclerosis Society guidelines for the prevention of atherosclerotic cardiovascular diseases 2012 (JAS2012), NIPPON DATA80 risk assessment chart (ND80RAC) was adopted to estimate the 10-year probability of coronary artery disease (CAD) mortality. However, there was no comparison between the estimated mortality calculated by ND80RAC and actual mortality in external populations. Accordingly, we used the large pooled database of cohorts in Japan, EPOCH-JAPAN, as an external population.Methods:The participants of EPOCH-JAPAN without a history of cardiovascular disease (15,091 men and 18,589 women aged 40–74 years) were analyzed based on sex. The probability of a 10-year risk of CAD/stroke mortality was estimated by ND80RAC. The participants were divided into both decile of their estimated mortality and three categories according to JAS2012. The calibration between the mean estimated mortality and the actual mortality was performed by the Hosmer and Lemeshow (H-L) test.Results: In both sexes, the estimated CAD mortality was higher than the actual mortality, particularly in higher deciles of estimated mortality, and the estimated stroke mortality was almost concordant with the actual mortality in low/moderate deciles of estimated mortality. As for the categories according to JAS2012, the estimated CAD mortality was higher than the actual mortality in both sexes; actual mortality in Category III was lower than that in Category II in women. However, it increased in the ascending order of category when we excluded the presence of diabetes from Category III.Conclusions: The estimated CAD mortality by ND80RAC tended to be higher than the actual mortality in the population in which the baseline survey was more recently performed.

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The Associations of C-Reactive Protein with Serum Levels of Polyunsaturated Fatty Acids and Trans Fatty Acids Among Middle-Aged Men from Three Populations

El-Saed A., Masaki K., Okamura T., Evans R. W., Nakamura Y., Willcox B. J., Lee S., Maegawa H., Seto T. B., Choo J., Fujiyoshi A., Miura K., Kuller L. H., Ueshima H., Sekikawa A.

Journal of Nutrition, Health and Aging 20 （ 1 ） 16 - 21 2016年01月

ISSN 1279-7707

BACKGROUND: C-reactive protein (CRP) and many fatty acids (FAs) have been linked to cardiovascular disease. Associations of serum CRP with FAs in different populations have not been established.METHODS: Participants were 926 men aged 40-49 (2002-2006) from a population-based sample; 310 Whites from Pennsylvania, U.S., 313 Japanese from Shiga, Japan, and 303 Japanese Americans from Hawaii, U.S. Serum CRP (mg/L) was measured using immunosorbent assay while serum FAs (%) were measured using capillary-gas-liquid chromatography.RESULTS: Whites had CRP (mg/L) levels higher than Japanese with Japanese Americans in-between (age-adjusted geometric mean "GM" 0.96, 0.38, 0.66, respectively). Whites had also higher levels of total n-6 FAs (%) and trans fatty acids (TFAs) but lower levels of marine-derived n-3 FAs compared to Japanese (41.78 vs. 35.05, 1.04 vs. 0.58, and 3.85 vs. 9.29, respectively). Japanese Americans had FAs levels in-between the other two populations. Whites had significant inverse trends between CRP and tertiles of total n-6 FAs (GM 1.20, 0.91 and 0.80; p=0.002) and marine-derived n-3 FAs (GM 1.22, 1.00 and 0.72; pCONCLUSIONS: With the exception of consistent inverse association of CRP with total n-6 FAs, there are considerable variations across the three populations in the associations of CRP with different FAs.

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The associations of C-reactive protein with serum levels of polyunsaturated fatty acids and trans fatty acids among middle-aged men from three populations

El-Saed A., Masaki K., Okamura T., Evans R. W., Nakamura Y., Willcox B. J., Lee S., Maegawa H., Seto T. B., Choo J., Fujiyoshi A., Miura K., Kuller L. H., Ueshima H., Sekikawa Akira

Journal of Nutrition, Health and Aging 20 （ 1 ） 16 - 21 2016年01月

ISSN 1279-7707

Background: C-reactive protein (CRP) and many fatty acids (FAs) have been linked to cardiovascular disease. Associations of serum CRP with FAs in different populations have not been established. Methods: Participants were 926 men aged 40-49 (2002-2006) from a population-based sample; 310 Whites from Pennsylvania, U.S., 313 Japanese from Shiga, Japan, and 303 Japanese Americans from Hawaii, U.S. Serum CRP (mg/L) was measured using immunosorbent assay while serum FAs (%) were measured using capillary-gasliquid chromatography. Results: Whites had CRP (mg/L) levels higher than Japanese with Japanese Americans in-between (age-adjusted geometric mean “GM” 0.96, 0.38, 0.66, respectively). Whites had also higher levels of total n-6 FAs (%) and trans fatty acids (TFAs) but lower levels of marine-derived n-3 FAs compared to Japanese (41.78 vs. 35.05, 1.04 vs. 0.58, & 3.85 vs. 9.29, respectively). Japanese Americans had FAs levels in-between the other two populations. Whites had significant inverse trends between CRP and tertiles of total n-6 FAs (GM 1.20, 0.91 & 0.80; p=0.002) and marine-derived n-3 FAs (GM 1.22, 1.00 & 0.72; p

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Hypertension and lifetime risk of stroke.

Turin TC, Okamura T, Afzal AR, Rumana N, Watanabe M, Higashiyama A, Nakao Y, Nakai M, Takegami M, Nishimura K, Kokubo Y, Okayama A, Miyamoto Y

Journal of hypertension 34 （ 1 ） 116 - 122 2016年01月

研究論文（学術雑誌）, ISSN 0263-6352

Background: The lifetime risk (LTR) articulates the probability of disease in the residual lifetime for an index age. These estimates can be useful for general audience-targeted knowledge translation activities against hypertension. There are only a few reports on lifetime of impact of hypertension on stroke events in Asians in whom stroke incidence is higher than Westerners. Methods: The Suita Study, a cohort study of cardiovascular diseases in Japan, was established in 1989. We included all participants who were stroke free at baseline. Age (in years) was used as the time scale. Age-specific incidence rates were calculated with person-year method within 10-year bands. We estimated the sex and index-age specific LTR of first-ever stroke with taking the competing risk of death into account. Results: We followed 5783 men and women during 1989-2007 for 74 933 person-years. During the follow-up period, 276 (149 men and 127 women) participants had incident stroke. Of them, majority were cerebral infarction; 166 (102 men and 64 women). The LTR of stroke, accounted for competing risk of death, at 45 years of age for men without hypertension was 17.21% and it was 32.79% for hypertensive men. Among the hypertensive patients, participants with stage 2 or greater hypertension had higher LTR of stroke than the participants with stage 1 hypertension. This increased LTR of stroke for hypertensive patients were also observed among women and across all index ages for stroke. Conclusion: In this urban community-based population, we observed that hypertension has significant effect on the residual LTR of stroke among both men and women of middle age, specifically for ischemic stroke.

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Epidemiologic studies for cardiovascular disease in Japan

Okamura Tomonori

Respiration and Circulation 64 （ 1 ） 7 2016年01月

ISSN 0452-3458

Set up and prospect of new cohort studies

Nishida Yoko, Okamura Tomonori, Harada Sei, Takebayashi Toru

Respiration and Circulation 64 （ 1 ） 71 - 77 2016年01月

ISSN 0452-3458

Serum level of LOX-1 ligand containing ApoB is associated with increased carotid intima-media thickness in Japanese community-dwelling men, especially those with hypercholesterolemia LOX-1 ligand and IMT in Japanese.

Okamura T, Miura K, Sawamura T, Kadota A, Hisamatsu T, Fujiyoshi A, Miyamatsu N, Takashima N, Miyagawa N, Kadowaki T, Ohkubo T, Murakami Y, Nakamura Y, Ueshima H, SESSA Research Group.

Journal of clinical lipidology 10 （ 1 ） 172 - 180e1 2016年01月

研究論文（学術雑誌）, ISSN 1933-2874

Background The serum level of LOX-1 ligand containing ApoB (LAB) may reflect atherogenicity better than usual lipid parameters; however, the relationship between LAB and carotid intima-media thickness (IMT) was not clear even in Asian populations. Methods A total of 992 community-dwelling Japanese men, aged 40 to 79 years, were enrolled in the present study. Serum LAB levels were measured by enzyme-linked immunosorbent assays (ELISAs) with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody. Results Serum LAB levels (median [interquartile range], μg cs/L) were 5341 μg cs/L (4093-7125). The mean average IMT of the common carotid artery was highest in the fourth LAB quartile (842 μm) compared with the first quartile (797 μm) after adjustment for age, high-density lipoprotein cholesterol, triglyceride, body mass index, hypertension, diabetes, high sensitivity C-reactive protein, smoking, and alcohol drinking. However, this statistically significant difference was lost after further adjustment for total cholesterol (TC). After stratification using the combination of median LAB and hypercholesterolemia (serum TC ≥ 6.21 mmol/L and/or lipid-lowering medication), the adjusted mean average IMT (standard error) in the high LAB/hypercholesterolemia group was 886 μm (12.7), 856 μm (16.7) in the low LAB/hypercholesterolemia group, and 833 μm (8.4) in the low LAB/normal cholesterol group (P =.004). After further adjustment for TC, mean average IMT in the high LAB group was significantly higher than that measured in the low LAB group in hypercholesterolemic participants not taking lipid-lowering medication. Conclusion Serum LAB was associated with an increased carotid IMT in Japanese men, especially those with hypercholesterolemia.

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Underweight Young Women Without Later Weight Gain Are at High Risk for Osteopenia After Midlife: The KOBE Study.

Tatsumi Y, Higashiyama A, Kubota Y, Sugiyama D, Nishida Y, Hirata T, Kadota A, Nishimura K, Imano H, Miyamatsu N, Miyamoto Y, Okamura T

Journal of epidemiology 26 （ 11 ） 572 - 578 2016年

研究論文（学術雑誌）, ISSN 0917-5040

Background: Although underweight young women are targets for interventions to prevent low bone mineral density (BMD), the relationship between change in body mass index (BMI) from youth to older age and BMD has not been widely investigated in community dwellers. Methods: In 749 healthy Japanese women aged 40-74 years, BMD was measured by quantitative ultrasound and anthropometric measurements, and BMI was calculated from body weight and height. The BMI of participants at age 20 years was estimated by self-reported body weight and their present height. They were classified into four groups according to the presence of underweight (BMI <18.5 kg/m²) at 20 and/or at present. Logistic regression models were used to estimate multivariate-adjusted odds ratios (ORs) of the presence of underweight at 20 and/or at present for osteopenia (BMD T score <-1 standard deviations) compared with participants with BMI ≥18.5 kg/m² both at 20 and at present. Results: The participants who were underweight both at 20 and at present had a higher OR for osteopenia compared with those with BMI ≥18.5 kg/m² at 20 and at present (OR 3.94; 95% confidence interval [CI], 1.97-7.89). Those underweight only at present also had significantly increased OR of developing osteopenia (OR 2.95; 95% CI, 1.67-5.24). The OR of those underweight only at 20 was 0.87 (95% CI, 0.51-1.48). Conclusions: Current underweight was associated with increased risk for osteopenia among Japanese women, especially in those who were underweight both at 20 and at present. To prevent low BMD in the future, maintaining appropriate body weight might be effective for young underweight women.

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Effects of a Public Education Campaign on the Association Between Knowledge of Early Stroke Symptoms and Intention to Call an Ambulance at Stroke Onset: The Acquisition of Stroke Knowledge (ASK) Study.

Nishikawa T, Okamura T, Nakayama H, Miyamatsu N, Morimoto A, Toyoda K, Suzuki K, Toyota A, Hata T, Yamaguchi T

Journal of epidemiology 26 （ 3 ） 115 - 122 2016年

研究論文（学術雑誌）, ISSN 0917-5040

Background: An immediate ambulance call offers the greatest opportunity for acute stroke therapy. Effectively using ambulance services requires strengthening the association between knowledge of early stroke symptoms and intention to call an ambulance at stroke onset, and encouraging the public to use ambulance services. Methods: The present study utilized data from the Acquisition of Stroke Knowledge (ASK) study, which administered multiple-choice, mail-in surveys regarding awareness of early stroke symptoms and response to a stroke attack before and after a 2-year stroke education campaign in two areas subject to intensive and moderate intervention, as well as in a control area, in Japan. In these three areas, 3833 individuals (1680, 1088 and 1065 participants in intensive intervention, moderate intervention, and control areas, respectively), aged 40 to 74 years, who responded appropriately to each survey were included in the present study. Results: After the intervention, the number of correctly identified symptoms significantly associated with intention to call an ambulance (P <0.05) increased (eg, from 4 to 5 correctly identified symptoms), without increasing choice of decoy symptoms in the intensive intervention area. Meanwhile, in other areas, rate of identification of not only correct symptoms but also decoy symptoms associated with intention to call an ambulance increased. Furthermore, the association between improvement in the knowledge of stroke symptoms and intention to call an ambulance was observed only in the intensive intervention area (P = 0.009). Conclusions: Our results indicate that intensive interventions are useful for strengthening the association between correct knowledge of early stroke symptoms and intention to call an ambulance, without strengthening the association between incorrect knowledge and intention to call an ambulance.

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Standardized Prevalence Ratios for Atrial Fibrillation in Adult Dialysis Patients in Japan.

Ohsawa M, Tanno K, Okamura T, Yonekura Y, Kato K, Fujishima Y, Obara W, Abe T, Itai K, Ogasawara K, Omama S, Turin TC, Miyamatsu N, Ishibashi Y, Morino Y, Itoh T, Onoda T, Kuribayashi T, Makita S, Yoshida Y, Nakamura M, Tanaka F, Ohta M, Sakata K, Okayama A

Journal of epidemiology 26 （ 5 ） 272 - 276 2016年

研究論文（学術雑誌）, ISSN 0917-5040

Background: While it is assumed that dialysis patients in Japan have a higher prevalence of atrial fibrillation (AF) than the general population, the magnitude of this difference is not known. Methods: Standardized prevalence ratios (SPRs) for AF in dialysis patients (n = 1510) were calculated compared to data from the general population (n = 26 454) living in the same area. Results: The prevalences of AF were 3.8% and 1.6% in dialysis patients and the general population, respectively. In male subjects, these respective values were 4.9% and 3.3%, and in female subjects they were 1.6% and 0.6%. The SPRs for AF were 2.53 (95% confidence interval [CI], 1.88-3.19) in all dialysis patients, 1.80 (95% CI, 1.30-2.29) in male dialysis patients, and 2.13 (95% CI, 0.66-3.61) in female dialysis patients. Conclusions: The prevalence of AF in dialysis patients was twice that in the population-based controls. Since AF strongly contributes to a higher risk of cardiovascular mortality and morbidity in the general population, further longitudinal studies should be conducted regarding the risk of several outcomes attributable to AF among Japanese dialysis patients.

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Serum Uric Acid and Mortality Form Cardiovascular Disease: EPOCH-JAPAN Study.

Zhang W, Iso H, Murakami Y, Miura K, Nagai M, Sugiyama D, Ueshima H, Okamura T, EPOCH-JAPAN GROUP.

Journal of atherosclerosis and thrombosis 23 （ 6 ） 692 - 703 2016年

研究論文（学術雑誌）, ISSN 1340-3478

Aim: To investigate the relationship between serum uric acid levels and cardiovascular disease in Asians. Methods: We examined the above relationship using the data of Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN Study). The data of 36,313 subjects (15,628 men and 20,685 women aged 35 –89 years without histories of stroke, coronary heart disease, or cancer at baseline) were used for the analyses. Sex-specific hazard ratios (HRs) of mortality from cardiovascular disease were estimated according to the quintiles of serum uric acid using Cox hazard models stratified by cohorts. Results: During 441,771 person-years of follow-up, we documented 1,288 cardiovascular deaths. A J-or U-shaped relationship between serum uric acid level and cardiovascular disease mortality was observed. Compared with the lowest quintile of serum uric acid levels, the highest quintile was associated with an increased cardiovascular disease mortality in men [HR: 1.28; 95% confidence interval (CI): 1.01– 1.63] and women (HR: 1.51; 95% CI: 1.14–1.99). However, there was no significant association with mortality from stroke, coronary heart disease or heart failure in both men and women. Conclusion: This large pooled analysis in Japan suggested a J-or U-shaped relationship between serum uric acid levels and cardiovascular mortality. The highest quintile of serum uric acid levels was associated with increased cardiovascular disease mortality in both Japanese men and women.

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Serum γ-glutamyltransferase and Mortality due to Cardiovascular Disease in Japanese Men and Women.

Li Y, Iso H, Cui R, Murakami Y, Yatsuya H, Miura K, Nagasawa SY, Ueshima H, Okamura T, EPOCH-JAPAN Research Group.

Journal of atherosclerosis and thrombosis 23 （ 7 ） 792 - 799 2016年

研究論文（学術雑誌）, ISSN 1340-3478

Aim: Whether the association between serum γ-glutamyltransferase (γ-GTP) levels and total cardiovascular disease (CVD) mortality is independent of alcohol drinking in East Asian populations is not well known. We conducted a pooled analysis of Japanese men and women that enabled an analysis restricted to never-drinkers. Methods: A total of 15,987 men and 25,053 women aged 40-79 years, pooled from seven cohort studies throughout Japan, were followed-up to examine sex-specific relationship between serum γ -GTP levels and total CVD mortality. Cox regression model was used that was adjusted for age, smoking status, body mass index, and systolic blood pressure and serum triglyceride, total cholesterol, aspartate aminotransferase, and alanine aminotransferase levels. Results: During an average follow-up of 8.7 years, we documented 361 and 340 deaths from total CVD, 146 and 168 from stroke, and 101 and 53 from coronary heart disease (CHD) for men and women, respectively. Among the never-drinkers, hazard ratios (HRs) for mortality for one standard deviation of log-γ-GTP for men were 1.89 (1.00-3.58) for stroke, 1.04 (0.57-1.90) for CHD, and 1.43 (1.04-1.96) for total CVD. For women, HRs were 1.28 (1.06-1.54), 1.81 (1.34-2.44), and 1.30 (1.14-1.49), respectively. Conclusion: γ-GTP may be a risk factor for total CVD mortality independent of alcohol drinking status in Japanese men and women.

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The Relationship between Very High Levels of Serum High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in a 20-Year Follow-Up Study of Japanese General Population.

Hirata A, Okamura T, Sugiyama D, Kuwabara K, Kadota A, Fujiyoshi A, Miura K, Okuda N, Ohkubo T, Okayama A, Ueshima H, NIPPON DATA90 Research Group.

Journal of atherosclerosis and thrombosis 23 （ 7 ） 800 - 809 2016年

研究論文（学術雑誌）, ISSN 1340-3478

Aims: There is no community-based cohort study to examine the effect of very high level of highdensity lipoprotein cholesterol (HDL-C) on coronary heart disease (CHD) and other cause-specific mortality. Therefore, we investigated the relationship between HDL-C including very high level and cause-specific mortality in a 20-year cohort study of the representative sample of Japanese. Methods: We followed 7,019 individuals from the Japanese general population (2,946 men and 4,073 women). We defined HDL-C levels as follow: low (HDL-C

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Predicting Coronary Heart Disease Using Risk Factor Categories for a Japanese Urban Population, and Comparison with the Framingham Risk Score: The Suita Study.

Nishimura K, Okamura T, Watanabe M, Nakai M, Takegami M, Higashiyama A, Kokubo Y, Okayama A, Miyamoto Y

Journal of atherosclerosis and thrombosis 23 （ 9 ） 1138 - 9 2016年

研究論文（学術雑誌）, ISSN 1340-3478

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Serum Uric Acid and Mortality Form Cardiovascular Disease: EPOCH-JAPAN Study.

Zhang W, Iso H, Murakami Y, Miura K, Nagai M, Sugiyama D, Ueshima H, Okamura T, EPOCH-JAPAN GROUP.

Journal of atherosclerosis and thrombosis 23 （ 12 ） 1365 - 1366 2016年

研究論文（学術雑誌）, ISSN 1340-3478

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Predicting Coronary Heart Disease Using Risk Factor Categories for a Japanese Urban Population, and Comparison with the Framingham Risk Score: The Suita Study.

Nishimura K, Okamura T, Watanabe M, Nakai M, Takegami M, Higashiyama A, Kokubo Y, Okayama A, Miyamoto Y

Journal of atherosclerosis and thrombosis 23 （ 9 ） 1138 - 9 2016年

研究論文（学術雑誌）, ISSN 1340-3478

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Serum Uric Acid and Mortality Form Cardiovascular Disease: EPOCH-JAPAN Study.

Zhang W, Iso H, Murakami Y, Miura K, Nagai M, Sugiyama D, Ueshima H, Okamura T, EPOCH-JAPAN GROUP.

Journal of atherosclerosis and thrombosis 23 （ 12 ） 1365 - 1366 2016年

研究論文（学術雑誌）, ISSN 1340-3478

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Associations of serum LDL particle concentration with carotid intima-media thickness and coronary artery calcification.

Zaid M, Miura K, Fujiyoshi A, Abbott RD, Hisamatsu T, Kadota A, Arima H, Kadowaki S, Torii S, Miyagawa N, Suzuki S, Takashima N, Ohkubo T, Sekikawa A, Maegawa H, Horie M, Nakamura Y, Okamura T, Ueshima H, SESSA Research Group.

Journal of clinical lipidology 10 （ 5 ） 1195 - 1202.e1 2015年12月

研究論文（学術雑誌）, ISSN 1933-2874

Background: Low-density lipoprotein particle (LDL-P) has recently been found to be a stronger predictor of cardiovascular disease (CVD) than LDL-cholesterol (LDL-C). Objectives: Whether LDL-P is associated with subclinical atherosclerosis, independent of LDL-C, as well as other lipid measures has not been fully examined. We aimed to analyze LDL-P associations with measures of subclinical atherosclerosis. Methods: We examined 870 Japanese men randomly selected from Kusatsu City, Shiga, Japan, aged 40-79 years from 2006-2008, free of clinical CVD and not using lipid-lowering medication. Cross-sectional associations of lipid measures with carotid intima-media thickness (cIMT) and coronary artery calcification (CAC; >0 Agatston score) were examined. Results: LDL-P was significantly positively associated with cIMT and maintained this association after adjustments for LDL-C and other lipid measures. Although these lipid measures were positively associated with cIMT, model adjustment for LDL-P removed any significant relationships. Higher LDL-P was associated with a significantly higher odds ratio of CAC and further adjustment for LDL-C did not affect this relationship. In contrast, the LDL-C association with CAC was no longer significant after adjustment for LDL-P. Other lipid measures attenuated associations of LDL-P with CAC. Likewise, associations of these measures with CAC were attenuated when model adjustments for LDL-P were made. Conclusions: In a community-based sample of Japanese men, free of clinical CVD, LDL-P was a robust marker for subclinical atherosclerosis, independent of LDL-C and other lipid measures. Associations of LDL-C and other lipid measures with either cIMT or CAC were generally not independent of LDL-P.

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Advance in cardiac CT

Yamada Yoshitake, Matsumoto Shunsuke, Suzuki Tatsuya, Hashimoto Masahiro, Okamura Teppei, Sugiura Hiroaki, Jinzaki Masahiro, Yamada Minoru

Respiration and Circulation 63 （ 12 ） 1199 - 1207 2015年12月

ISSN 0452-3458

Erratum

Nagai Masato, Ohkubo Takayoshi, Murakami Yoshitaka, Takashima Naoyuki, Kadota Aya, Miyagawa Naoko, Saito Yoshino, Nishi Nobuo, Okuda Nagako, Kiyohara Yutaka, Nakagawa Hideaki, Nakamura Yoshikazu, Fujiyoshi Akira, Abbott Robert D., Okamura Tomonori, Okayama Akira, Ueshima Hirotsugu, Miura Katsuyuki

Hypertension Research 38 （ 11 ） 798 2015年11月

ISSN 0916-9636

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Secular trends of the impact of overweight and obesity on hypertension in Japan, 1980-2010.

Nagai M, Ohkubo T, Murakami Y, Takashima N, Kadota A, Miyagawa N, Saito Y, Nishi N, Okuda N, Kiyohara Y, Nakagawa H, Nakamura Y, Fujiyoshi A, Abbott RD, Okamura T, Okayama A, Ueshima H, Miura K, NIPPON DATA80/90/2010 Research Group.

Hypertension research : official journal of the Japanese Society of Hypertension 38 （ 11 ） 790 - 795 2015年11月

研究論文（学術雑誌）, ISSN 0916-9636

The prevalence of overweight (body mass index (BMI)=25.0-29.9 kg m - 2) and obesity (≥30.0 kg m - 2) has been increasing over the last several decades in Japan. We examined trends of the impact of overweight and obesity on hypertension (systolic/diastolic blood pressure ≥140/90 mm Hg or antihypertensive drugs use) using four national surveys in Japan, from which the participants were randomly sampled from the entire population. Study participants aged 30-79 years were selected for each survey (10 370 in 1980, 8005 in 1990, 5327 in 2000 and 2547 in 2010). The results showed that the impact of overweight and obesity on hypertension had increased significantly (P=0.040 and 0.006 in men and women, respectively). From 1980 to 2010, the multivariable-adjusted odds ratios for hypertension, comparing overweight and obesity with normal weight (BMI =18.5-24.9 kg m - 2), went from 1.94 (95% confidence intervals: 1.64, 2.28) to 2.82 (2.07, 3.83) in men, and from 2.37 (2.05, 2.73) to 3.48 (2.57, 4.72) in women. Most of the association was observed in overweight participants, as only 3% of the Japanese were obese. In addition to the relationship between excessive BMI and other adverse health conditions, the rise in the association with hypertension increases the urgency in addressing weight control. We need to address the overweight and obesity epidemic.

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Smoking increases the risk of all-cause and cardiovascular mortality in patients with chronic kidney disease.

Nakamura K, Nakagawa H, Murakami Y, Kitamura A, Kiyama M, Sakata K, Tsuji I, Miura K, Ueshima H, Okamura T, EPOCH–JAPAN research group.

Kidney international 88 （ 5 ） 1144 - 1152 2015年11月

研究論文（学術雑誌）, ISSN 0085-2538

Little is known about the magnitude and nature of the combined effect of chronic kidney disease (CKD) and smoking on cardiovascular diseases. We studied this in a Japanese population using a pooled analysis of 15,468 men and 19,154 women aged 40-89 years enrolled in 8 cohort studies. The risk of mortality from all-causes and cardiovascular disease was compared in 6 gender-specific categories of baseline CKD status (non-CKD or CKD) and smoking habits (lifelong never smoked, former smokers, or currently smoking). CKD was defined as a decreased level of estimated glomerular filtration rate (under 60 ml/min per 1.73 m 2) and/or dipstick proteinuria. Hazard ratios were estimated for each category, relative to never smokers without CKD. During the follow-up period (mean 14.8 years), there were 6771 deaths, 1975 of which were due to cardiovascular diseases. In both men and women, current or former smokers with CKD had the first or second highest crude mortality rates from all-cause and cardiovascular diseases among the 6 categories. After adjustment for age and other major cardiovascular risk factors, the hazard ratios in male and female current smokers with CKD were 2.26 (95% confidence interval, 1.95-2.63) and 1.78 (1.36-2.32) for all-causes, and 2.66 (2.04-3.47) and 1.71 (1.10-2.67) for cardiovascular diseases, respectively. Thus, coexistence of CKD and smoking may markedly increase the risk of all-cause and cardiovascular mortality.

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Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men.

Harada S, Takebayashi T, Kurihara A, Akiyama M, Suzuki A, Hatakeyama Y, Sugiyama D, Kuwabara K, Takeuchi A, Okamura T, Nishiwaki Y, Tanaka T, Hirayama A, Sugimoto M, Soga T, Tomita M

Environmental health and preventive medicine 21 （ 1 ） 18 - 26 2015年10月

研究論文（学術雑誌）, ISSN 1342-078X

Objective: Metabolomics is a promising approach to the identification of biomarkers in plasma. Here, we performed a population-based, cross-sectional study to identify potential biomarkers of alcohol intake and alcohol-induced liver injury by metabolomic profiling using capillary electrophoresis-mass spectrometry (CE-MS). Methods: Fasting plasma samples were collected from 896 Japanese men who participated in the baseline survey of the Tsuruoka Metabolomics Cohort Study, and 115 polar metabolites were identified and absolutely quantified by CE-MS. Information on daily ethanol intake was collected through a standardized, self-administered questionnaire. The associations between ethanol intake and plasma concentration of metabolites were examined. Relationships between metabolite concentrations or their ratios and serum liver enzyme levels in the highest ethanol intake group (>46.0 g/day) were then examined by linear regression analysis. Replication analysis was conducted in 193 samples collected from independent population of this cohort. Results: Nineteen metabolites were identified to have an association with daily alcohol consumption both in the original and replication population. Three of these metabolites (threonine, glutamine, and guanidinosuccinate) were found to associate well with elevated levels of serum liver enzymes in the highest ethanol intake group, but not in the non-drinker group. We also found that the glutamate/glutamine ratio had a much stronger relation to serum γ-glutamyltransferase, aspartate transaminase, and alanine transaminase than glutamate or glutamine alone (standardized beta = 0.678, 0.558, 0.498, respectively). Conclusions: We found 19 metabolites associated with alcohol intake, and three biomarker candidates (threonine, guanidinosuccinate and glutamine) of alcohol-induced liver injury. Glutamate/glutamine ratio might also be good biomarker.

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Participants with treated hyperlipidemia may be more health conscious

Hozawa Atsushi, Okamura Tomonori

Journal of Atherosclerosis and Thrombosis 22 （ 10 ） 1025 - 1026 2015年10月

ISSN 1340-3478

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Participants with treated hyperlipidemia may be more health conscious

Hozawa Atsushi, Okamura Tomonori

Journal of Atherosclerosis and Thrombosis 22 （ 10 ） 1030 - 1039 2015年10月

ISSN 1340-3478

Continuous decline in mortality from coronary heart disease in Japan despite a continuous and marked rise in total cholesterol: Japanese experience after the Seven Countries Study.

Sekikawa A, Miyamoto Y, Miura K, Nishimura K, Willcox BJ, Masaki KH, Rodriguez B, Tracy RP, Okamura T, Kuller LH

International journal of epidemiology 44 （ 5 ） 1614 - 1624 2015年10月

研究論文（学術雑誌）, ISSN 0300-5771

Background: The Seven Countries Study in the 1960s showed very low mortality from coronary heart disease (CHD) in Japan, which was attributed to very low levels of total cholesterol. Studies of migrant Japanese to the USA in the 1970s documented increase in CHD rates, thus CHD mortality in Japan was expected to increase as their lifestyle became Westernized, yet CHD mortality has continued to decline since 1970. This study describes trends in CHD mortality and its risk factors since 1980 in Japan, contrasting those in other selected developed countries. Methods: We selected Australia, Canada, France, Japan, Spain, Sweden, the UK and the USA. CHD mortality between 1980 and 2007 was obtained from WHO Statistical Information System. National data on traditional risk factors during the same period were obtained from literature and national surveys. Results: Age-adjusted CHD mortality continuously declined between 1980 and 2007 in all these countries. The decline was accompanied by a constant fall in total cholesterol except Japan where total cholesterol continuously rose. In the birth cohort of individuals currently aged 50-69 years, levels of total cholesterol have been higher in Japan than in the USA, yet CHD mortality in Japan remained the lowest: >67% lower in men and > 75% lower in women compared with the USA. The direction and magnitude of changes in other risk factors were generally similar between Japan and the other countries. Conclusions: Decline in CHD mortality despite a continuous rise in total cholesterol is unique. The observation may suggest some protective factors unique to Japanese.

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Serum polyunsaturated fatty acid composition and serum high-sensitivity C-reactive protein levels in healthy Japanese residents

Kubota Yoshimi, Higashiyama A., Imano H., Sugiyama D., Kawamura K., Kadota A., Nishimura K., Miyamatsu N., Miyamoto Y., Okamura T.

Journal of Nutrition, Health and Aging 19 （ 7 ） 719 - 728 2015年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1279-7707

Background/Objectives: Serum polyunsaturated fatty acid (PUFA) composition reflects dietary intake and is related to risks for cardiovascular diseases. We hypothesized that serum n-3 PUFA composition, especially including long-chain n-3 PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is associated with inflammatory status, which is related to increased risk for cardiovascular diseases. Subjects/Methods: We investigated the relationship between serum PUFA composition and high-sensitivity C-reactive protein (hs-CRP) levels in a cross-sectional study among 1,102 healthy men and women aged 40–74 years who reside in Kobe City. Multiple linear regression models that predict hs-CRP level were prepared to confirm the contribution of serum total n-3 PUFA, long-chain n-3 PUFA, EPA and DHA compositions after adjusting for other PUFAs and atherosclerotic risk factors. Results: The serum n-3 PUFA, particularly long-chain n-3 PUFA, compositions were inversely associated with the hs-CRP levels. The standardized regression coefficient was −0.089 (p < 0.01) for total n-3 PUFA, −0.091 (p < 0.01) for long-chain n-3 PUFA, −0.071 (p = 0.03) for EPA, and −0.068 (p = 0.04) for DHA. The n-6 PUFA compositions were also inversely associated with the hs-CRP levels (−0.169 [p < 0.01] for total n-6 PUFA and −0.159 [p < 0.01] for linoleic acid). Conclusions: The serum n-3 PUFA compositions were inversely related with the hs-CRP levels, similar associations were also observed in n-6 PUFA compositions. Our results suggest that dietary PUFA intake was inversely associated with attenuated inflammation in healthy Japanese population.

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Interaction of Blood Pressure and Body Mass Index With Risk of Incident Atrial Fibrillation in a Japanese Urban Cohort: The Suita Study.

Kokubo Y, Watanabe M, Higashiyama A, Nakao YM, Kobayashi T, Watanabe T, Okamura T, Okayama A, Miyamoto Y

American journal of hypertension 28 （ 11 ） 1355 - 1361 2015年08月

研究論文（学術雑誌）, ISSN 0895-7061

BACKGROUND AND PURPOSE To prevent stroke, strategies for atrial fibrillation (AF) prevention and an early detection of AF by electrocardiogram are essential. However, only a limited prospective studies have examined the risk factors for AF, even in blood pressure (BP) and body mass index (BMI), which are not clear among general populations. We investigated the impacts of BP and BMI on the risk of incident AF in a general population. METHODS A total of 6,906 participants (30-84 years) in the Suita Study were prospectively followed up for incident AF. Participants were diagnosed with AF if AF or atrial flutter was present on an electrocardiogram from a routine health examination (every 2 years) or if AF was indicated as a present illness from health examinations and/or medical records during follow-up. Adjusted Cox proportional hazard ratios (HRs) were calculated. RESULTS During the 12.8-year follow-up, 253 incident AF events occurred. Compared with the systolic BP (SBP) <120mm Hg and normal-weight, the adjusted HRs (95% confidence intervals; CIs) of incident AF in the systolic hypertension and the overweight (BMI ≥ 25kg/m²) groups were 1.74 (1.22-2.49) and 1.35 (1.01-1.80), respectively. Compared with SBP <120mm Hg and normal weight, the adjusted HRs (95% CIs) of incident AF in the SBP = 120-139mm Hg with overweight and the systolic hypertension with normal or overweight were 1.72 (1.01-2.91), 1.66 (1.10-2.50), and 2.31 (1.47-3.65), respectively (P for interaction = 0.04). CONCLUSIONS Systolic prehypertension and overweight are associated with incident AF in Japanese population. The association between SBP and AF may be evident by overweight.

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Relationship of three different types of low-carbohydrate diet to cardiometabolic risk factors in a Japanese population: the INTERMAP/INTERLIPID Study.

Nakamura Y, Ueshima H, Okuda N, Miura K, Kita Y, Miyagawa N, Yoshita K, Nakagawa H, Sakata K, Saitoh S, Okamura T, Okayama A, Choudhry SR, Rodriguez B, Masaki KH, Chan Q, Elliott P, Stamler J

European journal of nutrition 55 （ 4 ） 1515 - 24 2015年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1436-6207

Purpose: Low-carbohydrate diets (LCD) are a popular dietary strategy for weight reduction. The effects of LCD on long-term outcome vary depending on type of LCD, possibly due to the fact that effects on cardiometabolic risk factors may vary with different types of LCD. Accordingly, we studied these relations. Methods: We assessed serum concentrations of high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), high-sensitivity C-reactive protein (CRP), total cholesterol, glycated hemoglobin, and uric acid, and nutrient intakes by standardized methods in men and women ages 40–59 years from four population samples of Japanese in Japan (553 men and 544 women, combined). For people consuming usual, animal-based, and plant-based LCDs, we calculated LCD scores, based on relative level of fat, protein, and carbohydrate, by modifying the methods of Halton et al. Instead of calculating scores based on animal or vegetable fat, we used saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA) + polyunsaturated fatty acids (PUFA). Results: In multivariate regression analyses with adjustment for site, age, sex, BMI, smoking, alcohol intake, physical activity, and years of education, all three LCD scores were significantly positively related to HDLc (all P < 0.001), but not to LDLc. The plant-based LCD score was significantly inversely related to log CRP (coefficient = −0.010, P = 0.018). Conclusions: All three LCD scores were significantly positively related to HDLc. The plant-based LCD score was significantly inversely related to CRP. Carbohydrate intake below 50 % of total energy with higher intakes of vegetable protein and MUFA + PUFA, and lower intakes of SFA may be favorable for reducing cardiometabolic risk factors.

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Relationship of type of work with health-related quality of life.

Kawabe Y, Nakamura Y, Kikuchi S, Suzukamo Y, Murakami Y, Tanaka T, Takebayashi T, Okayama A, Miura K, Okamura T, Fukuhara S, Ueshima H

Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation 24 （ 12 ） 2927 - 32 2015年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0962-9343

Purpose: To examine the relation of work type with health-related quality of life (HRQoL) in healthy workers. Methods: We cross-sectionally examined 4427 (3605 men and 822 women) healthy workers in Japan, aged 19–69 years. We assessed HRQoL based on scores for five scales of the SF-36. Multiple regression was applied to examine the relation of work type (nighttime, shift, day to night, and daytime) with the five HRQoL norm-based scores, lower scores of which indicate poorer health status, adjusted for confounding factors, including sleeping duration. Results: Shiftwork was inversely related to role physical [regression estimate (β) = −2.12, 95 % confidence intervals (CI) −2.94, −1.30, P < 0.001], general health (β = −1.37, 95 % CI −2.01, −0.72, P < 0.001), role emotional (β = −1.24, 95% CI −1.98, −0.50, P < 0.001), and mental health (β = −1.31, 95% CI −2.01, −0.63, P < 0.001) independent of confounding factors, but not to vitality. Day-to-nighttime work was inversely related to all the five HRQoL subscales (Ps 0.012 to <0.001). Conclusion: Shiftwork was significantly inversely related to four out of the five HRQoL, except for vitality, and day-to-nighttime work was significantly inversely related to all five HRQoL, independent of demographic and lifestyle factors.

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Associations between inflammatory markers and subclinical atherosclerosis in middle-aged white, Japanese-American and Japanese men

Nagasawa Shin Ya, Ohkubo Takayoshi, Masaki Kamal, Barinas-Mitchell Emma, Miura Katsuyuki, Seto Todd B., El-Saed Aiman, Kadowaki Takashi, Willcox Bradley J., Edmundowicz Daniel, Kadota Aya, Evans Rhobert W., Kadowaki Sayaka, Fujiyoshi Akira, Hisamatsu Takashi, Bertolet Marianne H., Okamura Tomonori, Nakamura Yasuyuki, Kuller Lewis H., Ueshima Hirotsugu, Sekikawa Akira

Journal of Atherosclerosis and Thrombosis 22 （ 6 ） 590 - 598 2015年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: To examine whether the inflammatory markers C-reactive protein (CRP) and fibrinogen are associated with biomarkers of atherosclerosis [carotid intima-media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians. Methods: Population-based samples of 310 Japanese, 293 Japanese-American and 297 white men 40-49 years of age without clinical cardiovascular disease underwent measurement of IMT, CAC and the CRP and fibrinogen levels as well as other conventional risk factors using standardized methods. Statistical associations between the variables were evaluated using multiple linear or logistic regression models. Results: The Japanese group had significantly lower levels of inflammatory markers and subclinical atherosclerosis than the Japanese-American and white groups (P-values all <0.001). The mean level of CRP was 0.66 vs. 1.11 and 1.47 mg/L, while that of fibrinogen was 255.0 vs. 313.0 and 291.5 mg/dl, respectively. In addition, the mean carotid IMT was 0.61 vs. 0.73 and 0.68 mm, while the mean prevalence of CAC was 11.6% vs. 32.1% and 26.3%, respectively. Body mass index (BMI) showed significant positive associations with both the CRP and fibrinogen levels. Although CRP showed a significant positive association with IMT in the Japanese men, this association became non-significant following adjustment for traditional risk factors or BMI. In all three populations, CRP was not found to be significantly associated with the prevalence of CAC. Similarly, fibrinogen did not exhibit a significant association with either IMT or the prevalence of CAC. Conclusions: The associations between inflammatory markers and subclinical atherosclerosis may merely reflect the strong associations between BMI and the levels of inflammatory markers and incidence of subclinical atherosclerosis in both Eastern and Western populations.

Fruit and vegetable intake and mortality from cardiovascular disease in Japan: a 24-year follow-up of the NIPPON DATA80 Study.

Okuda N, Miura K, Okayama A, Okamura T, Abbott RD, Nishi N, Fujiyoshi A, Kita Y, Nakamura Y, Miyagawa N, Hayakawa T, Ohkubo T, Kiyohara Y, Ueshima H, NIPPON DATA80 Research Group

European journal of clinical nutrition 69 （ 4 ） 482 - 488 2015年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0954-3007

Background/Objectives:There have been few studies on the association of fruit and vegetable (FV) intake with cardiovascular disease (CVD) risk in Asian populations where both dietary habits and disease structure are different from western countries. No study in Asia has found its significant association with stroke. We examined associations of FV intake with mortality risk from total CVD, stroke and coronary heart diseases (CHDs) in a representative Japanese sample.Methods:A total of 9112 participants aged from 24-year follow-up data in the NIPPON DATA80, of which baseline data were obtained in the National Nutrition Survey Japan in 1980, were studied. Dietary data were obtained from 3-day weighing dietary records. Participants were divided into sex-specific quartiles of energy adjusted intake of FV. Multivariate-adjusted hazard ratios (HRs) were calculated between strata of the total of FV intake, fruit intake and vegetable intake. The adjustment included age, sex, smoking, drinking habit and energy adjusted intakes of sodium and some other food groups.Results:Participants with higher FV intake were older, ate more fish, milk and dairy products and soybeans and legumes and ate less meat. Multivariate-adjusted HR (95% confidence interval; P; P for trend) for the highest versus the lowest quartile of the total of FV intake was 0.74 (0.61-0.91; 0.004; 0.003) for total CVD, 0.80 (0.59-1.09; 0.105; 0.036) for stroke and 0.57 (0.37-0.87; 0.010; 0.109) for CHD.Conclusions:The results showed that higher total intake of FVs was significantly associated with reduced risk of CVD mortality in Japan.

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High-density lipoprotein particle concentration and subclinical atherosclerosis of the carotid arteries in Japanese men.

Zaid M, Fujiyoshi A, Miura K, Abbott RD, Okamura T, Takashima N, Torii S, Saito Y, Hisamatsu T, Miyagawa N, Ohkubo T, Kadota A, Sekikawa A, Maegawa H, Nakamura Y, Mitsunami K, Ueshima H, SESSA Research group.

Atherosclerosis 239 （ 2 ） 444 - 450 2015年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

The association of high-density lipoprotein particle (HDL-P) with atherosclerosis may be stronger than that of HDL-cholesterol (HDL-C) and independent of conventional cardiovascular risk factors. Whether associations persist in populations at low risk of coronary heart disease (CHD) remains unclear. This study examines the associations of HDL-P and HDL-C with carotid intima-media thickness (cIMT) and plaque counts among Japanese men, who characteristically have higher HDL-C levels and a lower CHD burden than those in men of Western populations. Methods: We cross-sectionally examined a community-based sample of 870 Japanese men aged 40-79 years, free of known clinical cardiovascular disease (CVD) and not on lipid-lowering medication. Participants were randomly selected among Japanese living in Kusatsu City in Shiga, Japan. Results: Both HDL-P and HDL-C were inversely and independently associated with cIMT in models adjusted for conventional CHD risk factors, including low-density lipoprotein cholesterol (LDL-C) and diabetes. HDL-P maintained an association with cIMT after further adjustment for HDL-C (P<0.01), whereas the association of HDL-C with cIMT was noticeably absent after inclusion of HDL-P in the model. In plaque counts of the carotid arteries, HDL-P was significantly associated with a reduction in plaque count, whereas HDL-C was not. Conclusion: HDL-P, in comparison to HDL-C, is more strongly associated with measures of carotid atherosclerosis in a cross-sectional study of Japanese men. Findings demonstrate that, HDL-P is a strong correlate of subclinical atherosclerosis even in a population at low risk for CHD.

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Combined effect of blood pressure and total cholesterol levels on long-term risks of subtypes of cardiovascular death: Evidence for Cardiovascular Prevention from Observational Cohorts in Japan.

Satoh M, Ohkubo T, Asayama K, Murakami Y, Sakurai M, Nakagawa H, Iso H, Okayama A, Miura K, Imai Y, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention From Observational Cohorts in Japan (EPOCH–JAPAN) Research Group*.

Hypertension (Dallas, Tex. : 1979) 65 （ 3 ） 517 - 524 2015年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0194-911X

No large-scale, longitudinal studies have examined the combined effects of blood pressure (BP) and total cholesterol levels on long-term risks for subtypes of cardiovascular death in an Asian population. To investigate these relationships, a meta-analysis of individual participant data, which included 73 916 Japanese subjects (age, 57.7 years; men, 41.1%) from 11 cohorts, was conducted. During a mean follow-up of 15.0 years, deaths from coronary heart disease, ischemic stroke, and intraparenchymal hemorrhage occurred in 770, 724, and 345 cases, respectively. Cohort-stratified Cox proportional hazard models were used. After stratifying the participants by 4 systolic BP ×4 total cholesterol categories, the group with systolic BP ≥160 mm Hg with total cholesterol ≥5.7 mmol/L had the greatest risk for coronary heart disease death (adjusted hazard ratio, 4.39; P<0.0001 versus group with systolic BP <120 mm Hg and total cholesterol <4.7 mmol/L). The adjusted hazard ratios of systolic BP (per 20 mm Hg) increased with increases in total cholesterol categories (hazard ratio, 1.52; P<0.0001 in group with total cholesterol ≥5.7 mmol/L). Similarly, the adjusted hazard ratios of total cholesterol increased with increases in systolic BP categories (P for interaction ≤0.04). Systolic BP was positively associated with ischemic stroke and intraparenchymal hemorrhage death, and total cholesterol was inversely associated with intraparenchymal hemorrhage, but no significant interactions between BP and total cholesterol were observed for stroke. High BP and high total cholesterol can synergistically increase the risk for coronary heart disease death but not for stroke in the Asian population.

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Serum polyunsaturated fatty acid composition and serum high-sensitivity C-reactive protein levels in healthy Japanese residents

Kubota Yoshimi, Higashiyama A., Imano H., Sugiyama D., Kawamura K., Kadota A., Nishimura K., Miyamatsu N., Miyamoto Y., Okamura T.

Journal of Nutrition, Health and Aging 2015年03月

ISSN 1279-7707

Background/Objectives: Serum polyunsaturated fatty acid (PUFA) composition reflects dietary intake and is related to risks for cardiovascular diseases. We hypothesized that serum n-3 PUFA composition, especially including long-chain n-3 PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is associated with inflammatory status, which is related to increased risk for cardiovascular diseases.Subjects/Methods: We investigated the relationship between serum PUFA composition and high-sensitivity C-reactive protein (hs-CRP) levels in a cross-sectional study among 1,102 healthy men and women aged 40–74 years who reside in Kobe City. Multiple linear regression models that predict hs-CRP level were prepared to confirm the contribution of serum total n-3 PUFA, long-chain n-3 PUFA, EPA and DHA compositions after adjusting for other PUFAs and atherosclerotic risk factors.Results: The serum n-3 PUFA, particularly long-chain n-3 PUFA, compositions were inversely associated with the hs-CRP levels. The standardized regression coefficient was −0.089 (p < 0.01) for total n-3 PUFA, −0.091 (p < 0.01) for long-chain n-3 PUFA, −0.071 (p = 0.03) for EPA, and −0.068 (p = 0.04) for DHA. The n-6 PUFA compositions were also inversely associated with the hs-CRP levels (−0.169 [p < 0.01] for total n-6 PUFA and −0.159 [p < 0.01] for linoleic acid).Conclusions: The serum n-3 PUFA compositions were inversely related with the hs-CRP levels, similar associations were also observed in n-6 PUFA compositions. Our results suggest that dietary PUFA intake was inversely associated with attenuated inflammation in healthy Japanese population.

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Effects of stroke education of junior high school students on stroke knowledge of their parents: Tochigi project.

Matsuzono K, Yokota C, Takekawa H, Okamura T, Miyamatsu N, Nakayama H, Nishimura K, Ohyama S, Ishigami A, Okumura K, Toyoda K, Miyamoto Y, Minematsu K, Tochigi Junior High School Stroke Education Group., Participating Investigators of Tochigi Junior High School Stroke Education Group.

Stroke 46 （ 2 ） 572 - 574 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0039-2499

BACKGROUND AND PURPOSE - : Educating the youth about stroke is a promising approach for spreading stroke knowledge. The aim of this study was to verify communication of stroke knowledge to parents by educating junior high school students about stroke. METHODS - : We enrolled 1127 junior high school students (age, 13-15 years) and their parents in the Tochigi prefecture, Japan. All students received a stroke lesson, watched an animated cartoon, and read the related Manga comic as educational aids. The students took back home the Manga and discussed what they learned with their parents. Questionnaires on stroke knowledge were given to all at baseline and immediately after the lesson. RESULTS - : A total of 1125 students and 915 parents answered the questionnaires. In the students, the frequency of correct answers increased significantly for all questions on stroke symptoms except for headache, and for all questions on risk factors after the lesson. In the parents, the correct answer rates increased for stroke symptoms except for headache and numbness in one side of the body, and for all questions on risk factors except for hypertension. Ninety-one percent of students and 92.7% of parents correctly understood the Face, Arm, Speech, and Time (FAST) mnemonic after the lesson. CONCLUSIONS - : Improvement of stroke knowledge immediately after the stroke lesson was observed in parents as well as their children, which indicated that our teaching materials using the Manga was effective in delivering the stroke knowledge to parents through their children.

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LOX-1 in atherosclerotic disease.

Sawamura T, Wakabayashi I, Okamura T

Clinica chimica acta; international journal of clinical chemistry 440 157 - 163 2015年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-8981

Oxidized low-density lipoprotein (LDL) exhibits various biological activities and accumulates in atheromas. LOX-1 (lectin-like oxidized LDL receptor) is the receptor that mediates oxidized LDL activity in vascular endothelial cells. Activation of LOX-1 results in oxidized LDL-induced endothelial dysfunction and hyperlipidemia-induced vascular lipid deposition. We hypothesized that LOX-1 is a candidate risk factor beyond LDL cholesterol (LDLC) and developed a novel assay to quantify LOX-1 ligand containing apoB (LAB). In men from the United States, serum LAB showed a significant positive association with carotid intima-media thickness, independent of LDLC. LAB and the LOX index (obtained by multiplying LAB by sLOX-1) were significantly associated with the incidence of coronary artery disease and ischemic stroke after adjusting for confounding factors, including non-HDL cholesterol. sLOX-1 is thought to be a better biomarker for early diagnosis of acute coronary syndrome than traditional biomarkers, including troponin T. LAB was associated with various atherosclerotic risk factors such as smoking, obesity, diabetes, diastolic hypertension, hypertriglyceridemia, and metabolic syndrome. Measurement of the soluble form of LOX-1 (sLOX-1) and LAB seems to be useful for evaluating the state and risk of atherosclerosis and atherosclerosis-related diseases. Further prospective studies using large populations and randomized clinical trials on sLOX-1, LAB, and the LOX index are needed.

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HDL cholesterol performance using an ultracentrifugation reference measurement procedure and the designated comparison method.

Nakamura M, Yokoyama S, Kayamori Y, Iso H, Kitamura A, Okamura T, Kiyama M, Noda H, Nishimura K, Nakai M, Koyama I, Dasti M, Vesper HW, Teramoto T, Miyamoto Y

Clinica chimica acta; international journal of clinical chemistry 439 185 - 190 2015年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-8981

Background: Accurate high-density lipoprotein cholesterol (HDL-C) measurements are important for management of cardiovascular diseases. The US Centers for Disease Control and Prevention (CDC) and Cholesterol Reference Method Laboratory Network (CRMLN) perform ultracentrifugation (UC) reference measurement procedure (RMP) to value assign HDL-C. Japanese CRMLN laboratory (Osaka) concurrently runs UC procedure and the designated comparison method (DCM). Osaka performance of UC and DCM was examined and compared with CDC RMP. Methods: CDC RMP involved UC, heparin-MnCl₂ precipitation, and cholesterol analysis. CRMLN DCM for samples containing <200mg/dl triglycerides involved 50-kDa dextran sulfate-MgCl₂ precipitation and cholesterol determination. Results: HDL-C regression equations obtained with CDC (x) and Osaka (y) were y=0.992x+0.542 (R²=0.996) for Osaka UC and y=1.004x-0.181 (R²=0.998) for DCM. Pass rates within ±1mg/dl of the CDC target value were 91.9 and 92.1% for Osaka UC and DCM, respectively. Biases at 40mg/dl HDL-C were +0.22 and -0.02mg/dl for Osaka UC and DCM, respectively. Conclusions: Osaka UC and DCM were highly accurate, precise, and stable for many years, assisting manufacturers to calibrate products for clinical laboratories to accurately measure HDL-C for patients, calculate non-HDL-C, and estimate low-density lipoprotein cholesterol with the Friedewald equation.

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The reasonable reliability of a self-administered food frequency questionnaire for an urban, Japanese, middle-aged population: the Suita study.

Maruyama K, Kokubo Y, Yamanaka T, Watanabe M, Iso H, Okamura T, Miyamoto Y

Nutrition research (New York, N.Y.) 35 （ 1 ） 14 - 22 2015年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0271-5317

Because few studies have developed food frequency questionnaires (FFQ) and examined their reliability for Japanese urban populations, FFQ developed for urban Japanese populations may show reasonable reliability for estimating intakes of nutrients and food groups. Therefore, the objective of this study was to examine the reliability of an FFQ developed for a prospective cohort study in a Japanese urban area. A total of 29 men and 29 women aged 47 to 78 years were selected from participants in the Suita study from February 1997 to February 1998. Seven-consecutive-day dietary records (DR) was collected in each season (28-day DR). The FFQ were administered 3 times in total in each season, except in autumn. We calculated Spearman correlation coefficients to assess the validation of the first and third FFQ compared with 28-day DR and to assess the repeatability for 3-, 6-, and 9-month intervals. Reasonable validity of each FFQ compared with 28-day DR were observed for energy intake and for 27 nutrients, and 11 food groups were selected. Median (range) Spearman rank correlation coefficients for energy-adjusted nutrient and food group intakes of the first FFQ were 0.52 (0.14-0.88) and 0.53 (0.24-0.74), and those of the third FFQ were 0.51 (0.07-0.84) and 0.57 (0.16-0.75), respectively. The repeatability of each interval was relatively good; median (range) Spearman correlation coefficients of nutrients for 3-, 6-, and 9-month intervals were 0.67 (0.40-0.85), 0.63 (0.25-0.93), and 0.62 (0.31-0.87), respectively; those for food groups were 0.58 (0.42-0.76), 0.56 (0.24-0.80), and 0.65 (0.30-0.76), respectively. In conclusion, this FFQ is useful for evaluating the associations of nutrient and food intakes with cardiovascular diseases and their risk factors in Japanese urban populations.

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[Effects of a long-term intervention in a work cafeteria on employee vegetable intake].

Misawa A, Yoshita K, Fukumura T, Tanaka T, Tamaki J, Takebayashi T, Kusaka Y, Nakagawa H, Yamato H, Okayama A, Miura K, Okamura T, Ueshima H, HIPOP-OHP Research Group.

Sangyo eiseigaku zasshi = Journal of occupational health 57 （ 3 ） 97 - 107 2015年

研究論文（学術雑誌）, ISSN 1341-0725

OBJECTIVES: We examined the effects on employee vegetable intake of a long-term intervention in an employee work cafeteria.METHODS: The subjects were approximately 1,200 employees (aged 19-61 years) of an industrial company in Fukui prefecture. We promoted the intake of typical Japanese style meals that combined three elements (staple foods, main dishes and vegetable dishes) to increase vegetables intake. We displayed all items on the menus of the employee cafeteria using three colors (yellow, red and green to denote three elements) to indicate healthy food choices for the maintenance of a healthy food environment. We advised employees to choose meals containing the three elements at the time of payment, for nutritional education (appropriate portion choice: APC). We evaluated the ratio of APC at the same time. To calculate the mean daily intake per person, we carried out a questionnaire survey similar to the "semi-quantitative food frequency questionnaire" and asked about the frequency and approximate intake of vegetables.RESULTS: The APC was 63.5% after one year of intervention, significantly increased to 82.1% after two years (p <0.001), and was 80.0% after three years of intervention (p <0.001). Vegetable intake at breakfast (p <0.001), lunch (p <0.001) and dinner (p = 0.011), and from vegetable juice (p = 0.030) significantly increased after three years of intervention. The consumption of pickles significantly decreased after three years of intervention (p = 0.009). It was estimated that the vegetable intake of men increased from 167.3 to 184.6 g, and that of women from 157.9 to 187.7 g.CONCLUSIONS: Employee estimated vegetable intake was significantly increased and that of pickles was significantly decreased by a long-term intervention (three years) in the employee work cafeteria.

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The relationship between lectin-like oxidized low-density lipoprotein receptor-1 ligands containing apolipoprotein B and the cardio-ankle vascular index in healthy community inhabitants

Sugiyama Daisuke, Higashiyama Aya, Wakabayashi Ichiro, Kubota Yoshimi, Adachi Yoshiko, Hayashibe Akiko, Kawamura Kuniko, Kuwabara Kazuyo, Nishimura Kunihiro, Kadota Aya, Nishida Yoko, Hirata Takumi, Imano Hironori, Miyamatsu Naomi, Miyamoto Yoshihiro, Sawamura Tatsuya, Okamura Tomonori

Journal of Atherosclerosis and Thrombosis 22 （ 5 ） 499 - 508 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aims: Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 ligands containing apolipoprotein B (LAB) and lectin-like oxidized LDL receptor-1 (LOX-1) are known as LOX-1-related modified LDL indicators. These indicators play an important role in the early phase atherosclerosis, but the relationship between these indicators and subclinical atherosclerosis, as represented by the cardioankle vascular index (CAVI), has not been assessed. We herein investigated the association of LOX-1- related modified LDL indicators and the CAVI in healthy, Japanese urban community inhabitants who were considered to be at low risk for cardiovascular disease (CVD). Methods: The participants were 515 healthy Japanese (310 men and 205 women) without a history of CVD, cancer or the use of medication for hypertension, diabetes or dyslipidaemia. To estimate the association between LOX-1-related modified LDL indicators (LAB, soluble form of LOX-1 (sLOX- 1)) and the CAVI, we performed multivariable linear regression analyses with possible confounders such as the serum LDL cholesterol level. Results: The plasma LAB showed a positive association with the CAVI in men (standardized coefficient: 0.11, p= 0.04). This relationship was not observed in women. On the other hand, no clear association was observed between the CAVI and the plasma sLOX-1 level in either sex. Conclusions: The plasma LAB levels may represent a useful marker for detecting potential atherosclerosis in healthy individuals considered to be at low risk for atherosclerosis and CVD. Further studies are needed to confirm the present findings.

Risk of hypercholesterolemia for cardiovascular disease and the population attributable fraction in a 24-year Japanese cohort study.

Sugiyama D, Okamura T, Watanabe M, Higashiyama A, Okuda N, Nakamura Y, Hozawa A, Kita Y, Kadota A, Murakami Y, Miyamatsu N, Ohkubo T, Hayakawa T, Miyamoto Y, Miura K, Okayama A, Ueshima H, NIPPON DATA 80/90 Research Group.

Journal of atherosclerosis and thrombosis 22 （ 1 ） 95 - 107 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aims: The population-attributable fraction (PAF) is an indicator of the disease burden. In Western countries, the PAF of hypercholesterolemia in cardiovascular disease (CVD) is the highest among that for traditional risk factors; however, data for Asian populations are limited. Methods: A 24-year cohort study was conducted among 9,209 randomly selected participants who were not taking statins. We estimated the hazard ratio (HR) after adjusting for covariates and PAF associated with the serum total cholesterol (TC) levels in relation to CVD mortality. Results: The TC level was found to be positively associated with an increased risk of CVD, coronary heart disease (CHD) and cardiac death (CHD plus heart failure), with an HR of 1.08 (95% confidence interval [CI]: 1.00-1.16), 1.33 (95% CI: 1.14-1.55) and 1.21 (95% CI: 1.08-1.35) for a 1-SD increment in the serum TC level, respectively. Similar positive associations between the TC level and both CHD and cardiac death were observed after classifying the patients by age and sex. Furthermore, the highest serum TC level (≥6.72 mmol/L) was positively associated with CVD death, with an HR of 1.76 (95% CI: 1.25-2.47), as well as both CHD death and cardiac death. In contrast, no significant relationships were observed between the serum TC level and stroke. Meanwhile, the PAF for CVD, CHD, and cardiac deaths due to hypercholesterolemia (serum TC level ≥5.69 mmol/L, defined by the Japan Atherosclerosis Society) was 1.7%, 10.6% and 5.6%, respectively. Conclusions: The estimated PAF of CVD death due to hypercholesterolemia is moderately high, but lower than that for other risk factors, such as hypertension.

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Association between serum long-chain n-3 and n-6 polyunsaturated fatty acid profiles and glomerular filtration rate assessed by serum creatinine and cystatin C levels in Japanese community-dwellers.

Higashiyama A, Kubota Y, Marumo M, Konishi M, Yamashita Y, Nishimura K, Fukuda Y, Okamura T, Wakabayashi I

Journal of epidemiology 25 （ 4 ） 303 - 311 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: Plasma concentration of n-3 polyunsaturated fatty acids (PUFAs) has been reported to be associated with renal function in Western populations. However, few studies have investigated the association between serum long-chain n-3 and n-6 PUFA profiles and renal function in a Japanese population with high marine-derived longchain n-3 PUFA intake. Methods: A cross-sectional study was performed in 549 Japanese rural community-dwellers aged 40 to 64 years. In adjusted analysis of covariance, we assessed the relationship between estimated glomerular filtration rate (eGFR) and tertiles of serum long-chain n-3 and n-6 PUFA profiles ([eicosapentaenoic acid {EPA} + docosahexaenoic acid {DHA}]:arachidonic acid [AA]). GFR was estimated by Japanese specific equations using serum creatinine and cystatin C (eGFR<inf>cre</inf> and eGFR<inf>cys</inf>). Using multivariate-adjusted linear regression models, we also assessed the relationships between eGFRs and several n-3 and n-6 PUFAs, which have been suggested to be associated with renal function. Results: In all participants, higher dietary fish intake as assessed by a semi-quantitative questionnaire was associated with higher serum value of (EPA+DHA):AA. Participants in the higher (EPA+DHA):AA tertiles had nonsignificantly higher eGFR<inf>cre</inf> and significantly higher eGFR<inf>cys</inf> (P = 0.016). In addition, eGFR<inf>cys</inf> in T2+T3 of (EPA+DHA):AA was significantly higher than that in T1 (adjusted mean eGFR<inf>cys</inf>, T1: 87 ml/min/1.73m2, T2+T3: 91 ml/min/1.73m2; P < 0.01). Among the PUFAs, only (EPA+DHA) was significantly associated with eGFR<inf>cys</inf>. Conclusions: Serum (EPA+DHA):AA, which reflects an individual's fish intake, might be associated with eGFR<inf>cys</inf> in Japanese community-dwellers.

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The relationship between Asian dust events and out-of-hospital cardiac arrests in Japan.

Nakamura T, Hashizume M, Ueda K, Kubo T, Shimizu A, Okamura T, Nishiwaki Y

Journal of epidemiology 25 （ 4 ） 289 - 296 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: Asian dust events are caused by dust storms that originate in the deserts of China and Mongolia and drift across East Asia. We hypothesized that the dust events would increase incidence of out-of-hospital cardiac arrests by triggering acute events or exacerbating chronic diseases. Methods: We analyzed the Utstein-Style data collected in 2005 to 2008 from seven prefectures covering almost the entire length of Japan to investigate the effect of Asian dust events on out-of-hospital cardiac arrests. Asian dust events were defined by the measurement of light detection and ranging. A time-stratified case-crossover analysis was performed. The strength of the association between Asian dust events and out-of-hospital cardiac arrests was shown by odds ratios and 95% confidence intervals in two conditional logistic models. A pooled estimate was obtained from area-specific results by random-effect meta-analysis. Results: The total number of cases of out-of-hospital cardiac arrest was 59 273, of which 35 460 were in men and 23 813 were in women. The total number of event days during the study period was smallest in Miyagi and Niigata and largest in Shimane and Nagasaki. There was no significant relationship between Asian dust events and out-ofhospital cardiac arrests by area in either of the models. In the pooled analysis, the highest odds ratios were observed at lag day 1 in both model 1 (OR 1.07; 95% CI, 0.97-1.19) and model 2 (OR 1.08; 95% CI, 0.97-1.20). However, these results were not statistically significant. Conclusions: We found no evidence of an association between Asian dust events and out-of-hospital cardiac arrests.

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HOMA-IR Values are Associated With Glycemic Control in Japanese Subjects Without Diabetes or Obesity: The KOBE Study.

Hirata T, Higashiyama A, Kubota Y, Nishimura K, Sugiyama D, Kadota A, Nishida Y, Imano H, Nishikawa T, Miyamatsu N, Miyamoto Y, Okamura T

Journal of epidemiology 25 （ 6 ） 407 - 414 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: Several studies have reported that insulin resistance was a major risk factor for the onset of type 2 diabetes mellitus in individuals without diabetes or obesity. We aimed to clarify the association between insulin resistance and glycemic control in Japanese subjects without diabetes or obesity. Methods: We conducted a community-based cross-sectional study including 1083 healthy subjects (323 men and 760 women) in an urban area. We performed multivariate regression analyses to estimate the association between the homeostasis model assessment of insulin resistance (HOMA-IR) values and markers of glycemic control, including glycated haemoglobin (HbA1c), 1,5-anhydroglucitol (1,5-AG), and fasting plasma glucose (FPG) levels, after adjustment for potential confounders. Results: Compared with the lowest tertile of HOMA-IR values, the highest tertile was significantly associated with HbA1c and FPG levels after adjustment for potential confounders, both in men (HbA1c: β = 1.83, P = 0.001; FPG: β = 0.49, P < 0.001) and women (HbA1c: β = 0.82, P = 0.008; FPG: β = 0.39, P < 0.001). The highest tertile of HOMA-IR values was inversely associated with 1,5-AG levels compared with the lowest tertile (β = -18.42, P = 0.009) only in men. Conclusions: HOMA-IR values were associated with markers of glycemic control in Japanese subjects without diabetes or obesity. Insulin resistance may influence glycemic control even in a lean, non-diabetic Asian population.

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Nationwide distribution of cardiovascular practice in Japan - results of Japanese circulation society 2010 annual survey.

Tomoike H, Yokoyama H, Sumita Y, Hanai S, Kada A, Okamura T, Yoshikawa J, Doi Y, Hori M, Tei C, Scientific Committee of the JCS.

Circulation journal : official journal of the Japanese Circulation Society 79 （ 5 ） 1058 - 1067 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-9843

Background: The geographic distribution of cardiovascular (CV) health-care services has not been assessed systematically. Methods and Results: Data of the Japanese Circulation Society (JCS) annual survey were provided to the JCS working group with the permission of the JCS Scientific Committee. The status of CV practice in 2010 was then assessed in 47 prefectures retrospectively, along with national census and gross domestic product (GDP) data. The surveyed indices included resources (hospitals, beds and cardiologists), burden (number of inpatients), and outcome (CV mortality and autopsy) in each prefecture, which correlated well with respective populations or GDP. Inequality of geographic distribution was evident for pediatrics among the 47 prefectures, according to Lorenz curve, Gini coefficient or the maximum/minimum ratio for each index. According to the Gini coefficients, only the number of inpatients (medical or acute myocardial infarction) and beds for the total number of general hospitals or the hospitals surveyed in the present JCS study were lower than expected with regard to GDP. Conclusions: Geographic disparity of CV resources or burden was larger in pediatrics than in CV medicine or surgery. Improvement of equality in CV practice with regard to appropriateness and quality are the coming challenges for the JCS.

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Changes in Waist Circumference and the Incidence of Type 2 Diabetes in Community-Dwelling Men and Women: The Suita Study.

Tatsumi Y, Watanabe M, Nakai M, Kokubo Y, Higashiyama A, Nishimura K, Kobayashi T, Takegami M, Nakao YM, Watanabe T, Okayama A, Okamura T, Miyamoto Y

Journal of epidemiology 25 （ 7 ） 489 - 495 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Backgrounds: The association between weight gain and the incidence of type 2 diabetes is well known. The aim of our study was to investigate the relationship between change in waist circumference (WC) and type 2 diabetes incidence. Methods: The participants in the Suita Study, a population-based cohort study in an urban area of Japan, underwent a baseline survey between 1989 and 1994 (Exam 1) and were examined at follow-up every 2 years. We performed a 9.3-year cohort study of 946 men and 1327 women with no history of diabetes who underwent Exam 1 and Exam 2 (between 1997 and 1999). Participants were stratified by sex and median WC at Exam 1, and, in each stratum, participants were further classified into three categories by tertile of WC change per year between Exam 1 and Exam 2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for type 2 diabetes incidence were calculated by Cox proportional hazard models. The endpoints were first diagnosis of type 2 diabetes or March 2011. Results: During follow-up, 287 participants developed type 2 diabetes. In both sexes with median WC or higher, participants in the highest tertile of WC change had a significantly higher risk of developing type 2 diabetes. Multivariable adjusted HRs were 1.84 (95% CI, 1.10-3.08) in men and 2.30 (95% CI, 1.31-4.04) in women. No significant association was observed among participants with WC below median. Conclusions: Preventing WC gain is important in preventing type 2 diabetes in the Japanese population, especially among individuals with a relatively high WC.

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Alcohol consumption, hospitalization and medical expenditure: a large epidemiological study on the medical insurance system in Japan.

Nakamura K, Okuda N, Okamura T, Miura K, Nishimura K, Yasumura S, Sakata K, Hidaka H, Okayama A

Alcohol and alcoholism (Oxford, Oxfordshire) 50 （ 2 ） 236 - 243 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0735-0414

Aims: This study investigated the relationship between alcohol drinking habits and the onset of high medical expenditure in a Japanese male population. Methods: The cohort comprised 94,307 male beneficiaries 40-69 years of age of the Japanese medical insurance system, who had daily alcohol drinking habits. The likelihood of incurring high medical expenditure, defined as the ≥90th percentile of the medical expenditure distribution in the study population 1 year after baseline, as well as the likelihood of undergoing hospitalization that year were compared among the participants grouped according to their alcohol consumption amount (<2, 2-3.9, 4-5.9, ≥6 drinks/day). Results: Participants who ranked in the top 10% medical expenditure group within the 1 year after baseline each incurred at least 2152 euros/year. The top 10% medical expenditure group accounted for 61.1% of the total medical expenditure in the study population. The odds ratios (95% confidence intervals) for ranking in the top 10% group during the 1-year period, compared with the <2 drinks (23 g of alcohol)/day group, were 1.08 (1.02-1.15) for 2-3.9 drinks/day, 1.11 (1.05-1.19) for 4-5.9 drinks/day, and 1.31 (1.18-1.45) for ≥6 drinks/day after adjustment for age, body mass index, and smoking and exercise habits. The adjusted odds ratios for undergoing hospitalization were 1.11 (1.04-1.19), 1.14 (1.06-1.24) and 1.39 (1.24-1.56), respectively. Conclusion: The likelihood of incurring high medical expenditure and undergoing hospitalization increased with daily alcohol consumption amount.

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Relative and absolute risks of all-cause and cause-specific deaths attributable to atrial fibrillation in middle-aged and elderly community dwellers.

Ohsawa M, Okamura T, Ogasawara K, Ogawa A, Fujioka T, Tanno K, Yonekura Y, Omama S, Turin TC, Itai K, Ishibashi Y, Morino Y, Itoh T, Miyamatsu N, Onoda T, Kuribayashi T, Makita S, Yoshida Y, Nakamura M, Tanaka F, Ohta M, Sakata K, Okayama A

International journal of cardiology 184 （ 1 ） 692 - 698 2015年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0167-5273

Background: The relative and absolute risks of outcomes other than all-cause death (ACD) attributable to atrial fibrillation (AF) stratified age have not been sufficiently investigated. Methods: A prospective study of 23,634 community dwellers aged 40 years or older without organic cardiovascular disease (AF = 335, non-AF = 23,299) was conducted. Multivariate-adjusted rates, rate ratios (RRs) and excess deaths (EDs) for ACD, cardiovascular death (CVD) and non-cardiovascular death (non-CVD), and sexand age-adjusted RR and ED in middle-aged (40 to 69) and elderly (70 years or older) for ACD, CVD, non-CVD, sudden cardiac death (SCD), stroke-related death (Str-D), neoplasm-related death (NPD), and infectionrelated death (IFD) attributable to AF were estimated using Poisson regression. Results: Multivariate-adjusted analysis revealed that AF significantly increased the risk of ACD (RR [95% confidence interval]:1.70 [1.23-2.95]) and CVD (3.86 [2.38-6.27]), but not non-CVD. Age-stratified analysis revealed that AF increased the risk of Str-D in middle-aged (14.5 [4.77-44.3]) and elderly individuals (4.92 [1.91-12.7]), SCD in elderly individuals (3.21 [1.37-7.51]), and might increase the risk of IFD in elderly individuals (2.02 [0.80-4.65], p = 0.098). The RR of CVD was higher in middle-aged versus elderly individuals (RRs, 6.19 vs. 3.57) but the absolute risk difference was larger in elderly individuals (EDs: 7.6 vs. 3.0 per 1000 person-years). Conclusions: Larger absolute risk differences for ACD and CVD attributable to AF among elderly people indicate that the absolute burden of AF is higher in elderly versus middle-aged people despite the relatively small RR.

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Long-term outcomes associated with prolonged PR interval in the general Japanese population.

Hisamatsu T, Miura K, Fujiyoshi A, Okamura T, Ohkubo T, Nagasawa SY, Horie M, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

International journal of cardiology 184 （ 1 ） 291 - 293 2015年

研究論文（学術雑誌）, ISSN 0167-5273

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Associations between Inflammatory Markers and Subclinical Atherosclerosis in Middle-aged White, Japanese-American and Japanese Men: The ERA-JUMP Study.

Nagasawa SY, Ohkubo T, Masaki K, Barinas-Mitchell E, Miura K, Seto T, El-Saed A, Kadowaki T, Willcox BJ, Edmundowicz D, Kadota A, Evans RW, Kadowaki S, Fujiyoshi A, Hisamatsu T, Bertolet MH, Okamura T, Nakamura Y, Kuller LH, Ueshima H, Sekikawa A, ERA-JUNP Study Group.

Journal of atherosclerosis and thrombosis 22 （ 6 ） 590 - 8 2015年

研究論文（学術雑誌）, ISSN 1340-3478

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The Relationship between Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Ligands Containing Apolipoprotein B and the Cardio-Ankle Vascular Index in Healthy Community Inhabitants: The KOBE Study.

Sugiyama D, Higashiyama A, Wakabayashi I, Kubota Y, Adachi Y, Hayashibe A, Kawamura K, Kuwabara K, Nishimura K, Kadota A, Nishida Y, Hirata T, Imano H, Miyamatsu N, Miyamoto Y, Sawamura T, Okamura T

Journal of atherosclerosis and thrombosis 22 （ 5 ） 499 - 508 2015年

研究論文（学術雑誌）, ISSN 1340-3478

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Associations between Inflammatory Markers and Subclinical Atherosclerosis in Middle-aged White, Japanese-American and Japanese Men: The ERA-JUMP Study.

Journal of atherosclerosis and thrombosis 22 （ 6 ） 590 - 8 2015年

研究論文（学術雑誌）, ISSN 1340-3478

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Sugiyama D, Higashiyama A, Wakabayashi I, Kubota Y, Adachi Y, Hayashibe A, Kawamura K, Kuwabara K, Nishimura K, Kadota A, Nishida Y, Hirata T, Imano H, Miyamatsu N, Miyamoto Y, Sawamura T, Okamura T

Journal of atherosclerosis and thrombosis 22 （ 5 ） 499 - 508 2015年

研究論文（学術雑誌）, ISSN 1340-3478

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Cumulative impact of axial, structural, and repolarization ECG findings on long-term cardiovascular mortality among healthy individuals in Japan: National Integrated Project for Prospective Observation of Non-Communicable Disease and its Trends in the Aged, 1980 and 1990.

Inohara T, Kohsaka S, Okamura T, Watanabe M, Nakamura Y, Higashiyama A, Kadota A, Okuda N, Murakami Y, Ohkubo T, Miura K, Okayama A, Ueshima H, NIPPON DATA 80/90 Research Group.

European journal of preventive cardiology 21 （ 12 ） 1501 - 1508 2014年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2047-4873

Methods and Results: Community-dwelling Japanese residents from the National Integrated Project for Perspective Observation of Non-Communicable Disease and its Trends in the Aged, 1980-2004 and 1990-2005 (NIPPON DATA80 and 90), were included in this study. Baseline ECG findings were classified using the Minnesota Code and categorized into axial (left axis deviation, clockwise rotation), structural (left ventricular hypertrophy, atrial enlargement), and repolarization (minor and major ST-T changes) abnormalities. The hazard ratios of the cumulative impacts of ECG findings on long-term CVD death were estimated by stratified Cox proportional hazard models, including adjustments for cohort strata. In all, 16,816 participants were evaluated. The average age was 51.2 ±13.5 years; 42.7% participants were male. The duration of follow up was 300,924 person-years (mean 17.9±5.8 years); there were 1218 CVD deaths during that time. Overall, 4203 participants (25.0%) had one or more categorical ECG abnormalities: 3648 (21.7%) had a single abnormality, and 555 (3.3%) had two or more. The risk of CVD mortality increased as the number of abnormalities accumulated (single abnormality HR 1.29, 95% CI 1.13-1.48; ≥2 abnormalities HR 2.10, 95% CI 1.73-2.53).Conclusions: Individual ECG abnormalities had an additive effect in predicting CVD outcome risk in our large-scale cohort study.Aims: Various cohort studies have shown a close association between long-term cardiovascular disease (CVD) outcomes and individual electrocardiographic (ECG) abnormalities such as axial, structural, and repolarization changes. The combined effect of these ECG abnormalities, each assumed to be benign, has not been thoroughly investigated.

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Low-carbohydrate diets and cardiovascular and total mortality in Japanese: a 29-year follow-up of NIPPON DATA80.

Nakamura Y, Okuda N, Okamura T, Kadota A, Miyagawa N, Hayakawa T, Kita Y, Fujiyoshi A, Nagai M, Takashima N, Ohkubo T, Miura K, Okayama A, Ueshima H, NIPPON DATA Research Group.

The British journal of nutrition 112 （ 6 ） 916 - 924 2014年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0007-1145

Long-term safety of consuming low-carbohydrate diets (LCD) in Asian populations, whose carbohydrate intake is relatively high, is not known. In the present study, the association of LCD with CVD and total mortality was assessed using data obtained in the NIPPON DATA80 (National Integrated Project for Prospective Observation of Non-communicable Disease and Its Trends in the Aged 1980) during 29 years of follow-up. At baseline in 1980, data were collected from study participants aged ≥30 years from randomly selected areas in Japan. LCD scores were calculated based on the percentage of energy as carbohydrate, fat and protein, estimated by 3d weighed food records. A total of 9200 participants (56% women, mean age 51 years) were followed up. During the follow-up, 1171 CVD deaths (52% in women) and 3443 total deaths (48% in women) occurred. The multivariable-adjusted hazard ratio (HR) for CVD mortality using the Cox model comparing the highest v. lowest deciles of LCD score was 0·60 (95% CI 0·38, 0·94; P_trend=0·021) for women and 0·78 (95% CI 0·58, 1·05; P_trend=0·079) for women and men combined; the HR for total mortality was 0·74 (95% CI 0·57, 0·95; P_trend=0·029) for women and 0·87 (95% CI 0·74, 1·02; P_trend=0·090) for women and men combined. None of the associations was statistically significant in men. No differential effects of animal-based and plant-fish-based LCD were observed. In conclusions, moderate diets lower in carbohydrate and higher in protein and fat are significantly inversely associated with CVD and total mortality in women.

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Blood pressure, low-density lipoprotein cholesterol, and incidences of coronary artery disease and ischemic stroke in Japanese: the Suita study.

Tsukinoki R, Okamura T, Watanabe M, Kokubo Y, Higashiyama A, Nishimura K, Takegami M, Murakami Y, Okayama A, Miyamoto Y

American journal of hypertension 27 （ 11 ） 1362 - 1369 2014年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0895-7061

BACKGROUND Blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) are risk factors for coronary artery disease (CAD) and ischemic stroke. However, the hazards of their coexistence are not fully understood in Asian populations. We investigated whether the relationship between BP and cardiovascular disease (CVD) outcomes are modified by LDL-C level in a Japanese population.METHODS Individuals aged 30-79 years (n = 5,151) were classified into 6 groups according to LDL-C levels (<140 and ≥140mg/dL or lipid medication) and BP levels (optimal BP, prehypertension, and hypertension; reference: low LDL-C and optimal BP). Hazard ratios (HRs) were calculated after adjusting for age, high-density lipoprotein cholesterol, diabetes, smoking status, and alcohol consumption. The effect modification of LDL-C on BP-CVD association was assessed using likelihood ratio tests.RESULTS There were 264 CAD and 215 ischemic stroke events during 13 years of follow-up. With low LDL-C, the HRs of prehypertension and hypertension for CAD were 2.01 and 4.71, respectively. Similar trends of HRs were observed with high LDL-C (optimal BP = 2.09, prehypertension = 3.45, hypertension = 5.94). However, the HRs for ischemic stroke did not differ between normal and high LDL-C levels at the same BP level. The apparent effect modification of LDL-C was not observed in the BP-CVD association in either CAD (P = 0.48) or ischemic stroke (P = 0.39).CONCLUSIONS The HRs for CAD in prehypertensive and hypertensive groups were higher than those in the optimal BP group at the same LDL-C levels in a Japanese population; however, there was no statistical effect modification of LDL-C on the BP-CAD association.

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Hypertension and medical expenditure in the Japanese population: Review of prospective studies.

Nakamura K, Okamura T, Miura K, Okayama A

World journal of cardiology 6 （ 7 ） 531 - 8 2014年07月

研究論文（学術雑誌）

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Hypertension and medical expenditure in the Japanese population: Review of prospective studies.

Nakamura K, Okamura T, Miura K, Okayama A

World journal of cardiology 6 （ 7 ） 531 - 8 2014年07月

研究論文（学術雑誌）

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Lipoprotein particle profiles compared with standard lipids in association with coronary artery calcification in the general Japanese population.

Hisamatsu T, Fujiyoshi A, Miura K, Ohkubo T, Kadota A, Kadowaki S, Kadowaki T, Yamamoto T, Miyagawa N, Zaid M, Torii S, Takashima N, Murakami Y, Okamura T, Horie M, Ueshima H, SESSA Research Group.

Atherosclerosis 236 （ 2 ） 237 - 243 2014年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Objective: The utility of lipoprotein particle profiles measured by nuclear magnetic resonance (NMR) spectroscopy beyond standard serum lipids remains inconclusive. Furthermore, few studies have compared NMR measurements with standard lipids in association with coronary artery calcification (CAC) in Japanese, where the coronary atherosclerotic burden is low. We examined whether NMR-based lipoprotein particle profiles are associated with CAC, and compared them with standard lipid and lipid ratios in the Japanese general population. Methods and Results: We conducted a cross-sectional study in 851 men aged 40-79 years without cardiovascular diseases and lipid-lowering therapies. Adjusted odds ratios (ORs) (95% confidence intervals) for the top versus the bottom quartile of NMR-measured particle concentrations were 2.01 (1.24-3.23) for low-density lipoprotein (LDL-P), 1.04 (0.62-1.75) for high-density lipoprotein (HDL-P), 1.82 (1.13-2.95) for very-low-density lipoprotein (VLDL-P), and 1.92 (1.18-3.17) for LDL-P/HDL-P ratio. Similarly adjusted ORs of NMR-measured particle sizes were 0.59 (0.36-0.97) for LDL-P, 0.66 (0.40-1.10) for HDL-P, and 0.67 (0.40-1.12) for VLDL-P. The corresponding ORs were 1.82 (1.14-2.90) for total cholesterol (TC), 2.06 (1.28-3.30) for low-density lipoprotein cholesterol (LDL-C), 0.56 (0.34-0.91) for high-density lipoprotein cholesterol (HDL-C), 2.02 (1.24-3.29) for triglycerides, 2.08 (1.29-3.36) for non-high-density lipoprotein cholesterol (non-HDL-C), 2.27 (1.37-3.78) for TC/HDL-C ratio, and 1.73 (1.06-2.85) for LDL-C/HDL-C ratio. After mutual adjustment for total LDL-P concentration and TC/HDL-C ratio or non-HDL-C, LDL-P was no longer associated, whereas TC/HDL-C ratio remained significantly associated with CAC. Conclusions: In community-based Japanese men, the overall association of CAC with NMR-measured lipoprotein indices is comparable, but not superior, to that with standard lipids.

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Validation of homogeneous assays for HDL-cholesterol using fresh samples from healthy and diseased subjects.

Miida T, Nishimura K, Okamura T, Hirayama S, Ohmura H, Yoshida H, Miyashita Y, Ai M, Tanaka A, Sumino H, Murakami M, Inoue I, Kayamori Y, Nakamura M, Nobori T, Miyazawa Y, Teramoto T, Yokoyama S

Atherosclerosis 233 （ 1 ） 253 - 259 2014年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Background: High-density lipoprotein-cholesterol (HDL-C) is a negative risk factor for cardiovascular events. Although several homogeneous HDL-C assays are available, their accuracy has not been validated, particularly in subjects with disease. We aimed to clarify whether HDL-C concentrations measured by homogeneous assays [HDL-C (H)] agree with those determined by the reference measurement procedures [HDL-C (RMP)] using ultracentrifugation and precipitation with heparin-manganese reagent in fresh clinical samples. Methods: HDL-C concentrations in samples from 48 healthy subjects and 119 subjects with disease were determined using 12 homogeneous assays and RMPs. Results: All reagents showed excellent intra- and inter-assay CVs (<2.23%) for two pooled sera. Furthermore, the mean bias was within ±1.0% in nine reagents using samples from healthy subjects and in eight reagents using samples from subjects with disease. In a single HDL-C (H) determination, the total error requirement of the National Cholesterol Education Program (95% of results<13%) was fulfilled in nine reagents using samples from healthy subjects and six reagents in those from subjects with disease. Error component analysis revealed that only one reagent exceeded ±10% total error in samples from healthy subjects, whereas four reagents exceeded this error in samples from subjects with disease. Correlations between HDL-C (H) and HDL-C (RMP) revealed that the slopes were within 1.00±0.06 in six reagents in healthy subjects, and eight reagents in subjects with disease. Conclusions: Except for three reagents, HDL-C (H) agrees well with HDL-C (RMP) in subjects with common disease, but not in those with extremely low HDL-C or abnormal HDL composition. © 2014 The Authors.

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Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80.

Miyagawa N, Miura K, Okuda N, Kadowaki T, Takashima N, Nagasawa SY, Nakamura Y, Matsumura Y, Hozawa A, Fujiyoshi A, Hisamatsu T, Yoshita K, Sekikawa A, Ohkubo T, Abbott RD, Okamura T, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Atherosclerosis 232 （ 2 ） 384 - 389 2014年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Background: Dietary intake of long-chain n-3 PUFA (LCn3FA) among Japanese is generally higher than that in Western populations. However, little is known whether an inverse association of LCn3FA with cardiovascular disease (CVD) risk exists in a population with higher LCn3FA intake. Objective: To investigate the association between LCn3FA intake and the long-term risk of CVDs in a Japanese general population. Methods: We followed-up a total of 9190 individuals (56.2% women, mean age 50.0 years) randomly selected from 300 areas across Japan and free from CVDs at baseline. Dietary LCn3FA intake was estimated using household weighed food records. Cox models were used to calculate multivariate-adjusted hazard ratios (HR) and confidence intervals (CI) according to sex specific quartiles of LCn3FA intake. Results: During 24-year follow-up (192,897 person-years), 879 cardiovascular deaths were observed. The median daily intake of LCn3FA was 0.37%kcal (0.86g/day). Adjusted HR for CVD mortality was lower in the highest quartile of LCn3FA intake (HR 0.80; 95% CI 0.66-0.96) compared with the lowest quartile, and the trend was statistically significant (P=0.038). The similar but statistically non-significant trends were observed for coronary heart disease death and stroke death. In analyses by age groups, the inverse associations of LCn3FA intake with the risk of total CVD death and stroke death were significant in younger individuals (30-59 years at baseline). Conclusion: LCn3FA intake was inversely and independently associated the long-term risk of total CVD mortality in a representative sample of Japanese with high LCn3FA intake. © 2013 Elsevier Ireland Ltd.

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Steeper increases in body mass index during childhood correlate with blood pressure elevation in adolescence: a long-term follow-up study in a Japanese community.

Kuwahara E, Asakura K, Nishiwaki Y, Komatsu H, Nakazawa A, Ushiku H, Maejima F, Nishigaki Y, Hasegawa T, Okamura T, Takebayashi T

Hypertension research : official journal of the Japanese Society of Hypertension 37 （ 2 ） 179 - 184 2014年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0916-9636

The aim of this study was to clarify the relationship between long-term changes in body mass index (BMI) during childhood and adolescent blood-pressure levels in a general Japanese population. We used health report data from 900 Japanese children between 1983 and 2007. After adjusting for baseline BMI and other confounding factors multivariate linear regression analyses were performed to examine the relationship between changes in BMI (ΔBMI) over a 6-year period (6-12 years) and blood pressure once children reached ages 14 or 15. Sub-group analyses were also performed to ascertain the relationship between ΔBMI and blood pressure at 9th grade for children who had been in the bottom BMI tertile at 1st grade. Endpoint blood-pressure levels in boys (systolic and diastolic) and girls (systolic) from the group whose BMIs increased the most were significantly higher than those from the group whose BMIs increased the least (P<0.05, analysis of variance). After adjustment for baseline BMI and school-entrance year, the former group showed higher blood pressure at the endpoint than the latter (P<0.05, multiple regression analysis). Further adjustment for baseline blood pressure also showed similar results in a combined-sex analysis (n=592). Higher ΔBMI was associated with higher SBP 9 even in children whose BMI was in the lowest tertile at baseline after adjustment for sex and school-entrance year (P=0.02, multiple regression analysis). Steeper BMI increases during primary school lead to adolescent increases in blood pressure even if baseline BMI is low. Growth during childhood should be carefully managed. © 2014 The Japanese Society of Hypertension All rights reserved.

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Effect size and cost-effectiveness estimates of breast and cervical cancer screening reminders by population size through complete enumeration of Japanese local municipalities.

Komoto S, Nishiwaki Y, Okamura T, Tanaka H, Takebayashi T

BMC public health 14 （ 1 ） 43 2014年01月

研究論文（学術雑誌）, 共著, 査読有り

Background: Client reminders are known to increase cancer screening attendance rates. However, there are significant costs associated with them, and their effect by population size is unknown. Methods. In 2007 and 2008, the Japanese Government surveyed breast and cervical cancer screening in every municipality in Japan. From the results, we selected all 1,464 municipalities that carried out both screening types. We examined whether changes in screening attendance rates between 2007 and 2008 were associated with client reminders, number of public health nurses per 100,000 population, financial strength index, and 2007 attendance rates for different population sizes. We then calculated cost-effectiveness estimates of client reminders by population size and screening type. Results: Client reminders were associated with increased attendance rates in populations <100,000. For populations of 50,000-100,000, there was a 2.76% increase in breast cancer screening (95% CI: 0.41, 5.11), and a 2.25% increase in cervical cancer screening (95% CI: 0.89, 3.61). The incremental cost per additional attendance was higher in populations <50,000 than in populations of 50,000-100,000 (breast, $100 versus $54; cervical, $149 versus $67 respectively). Conclusions: Client reminders for breast and cervical cancer screening increased attendance rates in smaller municipalities in Japan. © 2014 Komoto et al.; licensee BioMed Central Ltd.

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[Series: Clinical study from Japan and its reflections; LOX-1 ligands containing apolipoprotein B and carotid intima-media thickness in middle-aged community-dwelling US Caucasian and Japanese men].

Okamura T, Sekikawa A, Sawamura T, Ueshima H

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 （ 1 ） 173 - 80 2014年01月

研究論文（学術雑誌）, ISSN 0021-5384

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[Series: Clinical study from Japan and its reflections; LOX-1 ligands containing apolipoprotein B and carotid intima-media thickness in middle-aged community-dwelling US Caucasian and Japanese men].

Okamura T, Sekikawa A, Sawamura T, Ueshima H

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 （ 1 ） 173 - 80 2014年01月

研究論文（学術雑誌）, ISSN 0021-5384

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Impact of metabolic syndrome on the risk of cardiovascular disease mortality in the United States and in Japan.

Liu L, Miura K, Fujiyoshi A, Kadota A, Miyagawa N, Nakamura Y, Ohkubo T, Okayama A, Okamura T, Ueshima H

The American journal of cardiology 113 （ 1 ） 84 - 89 2014年01月

研究論文（学術雑誌）, 査読有り, ISSN 0002-9149

The United States has a higher prevalence of metabolic syndrome (MS) and cardiovascular disease (CVD) mortality than Japan, but it is unknown how much of the difference in MS accounts for the mortality difference. The aim of this study was to examine the impact of MS on the excess CVD mortality in the United States compared with that in Japan. Data from the United States Third National Health and Nutrition Examination Survey (NHANES III; n = 12,561) and the Japanese National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in Aged (NIPPON DATA; n = 7,453) were analyzed. MS was defined as ≥3 of 5 risk factors (obesity, high blood pressure, decreased high-density lipoprotein cholesterol, elevated glycosylated hemoglobin, and elevated triglycerides). The results show that after a median of 13.8 years of follow-up in the United States, 1,683 patients died from CVD (11.75 per 1,000 person-years), and after a median of 15 years of follow-up in Japan, 369 patients died from CVD (3.56 per 1,000 person-years). The age-adjusted prevalence of MS was 26.7% in the United States and 19.3% in Japan. Of 5 MS factors, obesity, high blood pressure, elevated triglycerides, and glycosylated hemoglobin in the United States, and high blood pressure and elevated glycosylated hemoglobin in Japan were significant risk factors for CVD mortality. Estimates of 13.3% and 44% of the excess CVD mortality for the United States could be explained by the higher prevalence of MS and MS plus baseline CVD history than in Japan. In conclusion, the present study is the first to quantitatively demonstrate that MS and MS plus baseline CVD history may significantly contribute to the explanation of excess CVD mortality in the United States compared with Japan. © 2014 Elsevier Inc. All rights reserved.

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Vegetarian diets and blood pressure: a meta-analysis.

Yokoyama Y, Nishimura K, Barnard ND, Takegami M, Watanabe M, Sekikawa A, Okamura T, Miyamoto Y

JAMA internal medicine 174 （ 4 ） 577 - 587 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2168-6106

IMPORTANCE Previous studies have suggested an association between vegetarian diets and lower blood pressure (BP), but the relationship is not well established. OBJECTIVE To conduct a systematic review and meta-analysis of controlled clinical trials and observational studies that have examined the association between vegetarian diets and BP. DATA SOURCES MEDLINE andWeb of Science were searched for articles published in English from 1946 to October 2013 and from 1900 to November 2013, respectively. STUDY SELECTION All studiesmet the inclusion criteria of the use of (1) participants older than 20 years, (2) vegetarian diets as an exposure or intervention, (3) mean difference in BP as an outcome, and (4) a controlled trial or observational study design. In addition, none met the exclusion criteria of (1) use of twin participants, (2) use of multiple interventions, (3) reporting only categorical BP data, or (4) reliance on case series or case reports. DATA EXTRACTION AND SYNTHESIS Data collected included study design, baseline characteristics of the study population, dietary data, and outcomes. The data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Net differences in systolic and diastolic BP associated with the consumption of vegetarian diets were assessed. RESULTS Of the 258 studies identified, 7 clinical trials and 32 observational studiesmet the inclusion criteria. In the 7 controlled trials (a total of 311 participants; mean age, 44.5 years), consumption of vegetarian diets was associated with a reduction in mean systolic BP (?4.8 mmHg; 95%CI, ?6.6 to ?3.1; P < .001; I2 = 0; P = .45 for heterogeneity) and diastolic BP (?2.2 mmHg; 95%CI, ?3.5 to ?1.0; P < .001; I2 = 0; P = .43 for heterogeneity) compared with the consumption of omnivorous diets. In the 32 observational studies (a total of 21 604 participants; mean age, 46.6 years), consumption of vegetarian diets was associated with lower mean systolic BP (?6.9mmHg; 95%CI, ?9.1 to ?4.7; P < .001; I2 = 91.4; P < .001 for heterogeneity) and diastolic BP (?4.7mmHg; 95%CI, ?6.3 to ?3.1; P < .001; I2 = 92.6; P < .001 for heterogeneity) compared with the consumption of omnivorous diets. CONCLUSIONS AND RELEVANCE Consumption of vegetarian diets is associated with lower BP. Such diets could be a useful nonpharmacologic means for reducing BP. Copyright © 2014 American Medical Association. All rights reserved.

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Relationship between shift work and clustering of the metabolic syndrome diagnostic components.

Kawabe Y, Nakamura Y, Kikuchi S, Murakami Y, Tanaka T, Takebayashi T, Okayama A, Miura K, Okamura T, Ueshima H

Journal of atherosclerosis and thrombosis 21 （ 7 ） 703 - 711 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: To examine the relationship between the type of work and the number of metabolic syndrome diagnostic componentsS (MetS-DC), as well as the risk of MetS, with adjustment for lifestyle habits in Japanese workers. Methods: We examined the baseline data from 4,427 participants (81.4% male) aged 19 to 69 years old. The physical activity of each participant was classified according to the International Physical Activity Questionnaire (IPAQ). We defined the four MetS-DC in this study as follows: 1) high blood pressure (BP): systolic BP ≥ 130 mmHg, or diastolic BP ≥ 85 mmHg, or the use of antihypertensive drugs; 2) dyslipidemia: high-density lipoprotein-cholesterol concentration <40 mg/dl or triglyceride concentration ≥ 150 mg/dl, or on medication for dyslipidemia; 3) dysglycemia: fasting blood sugar level ≥ 110 mg/dl, or if less than eight hours after meals ≥ 140 mg/dl, or on medication for diabetes mellitus; 4) overweight: a body mass index ≥ 25 kg/m2. We defined MetS as overweight plus two or more of the MetS-DC. Results: There were 3,094 subjects in the daytime work group, 73 in the fixed nighttime work group, 1,017 in the shift work group and 243 in the day-to-night work group. The Poisson regression analysis revealed that fixed nighttime (regression coefficient [b] = -0.233, P=0.028) and shift work (b=0.098, P=0.034) independently contributed to the number of MetS-DC, compared to daytime work. The multivariate logistic analysis not including sleep hours in the model showed that shift work was positively related to MetS (odd ratio = 1.47, P<0.01). Conclusion: Shift work were significantly associated with the number of MetS-DC, and was related to risk of MetS compared to daytime work.

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Worksite wellness for the primary and secondary prevention of cardiovascular disease in Japan: the current delivery system and future directions.

Okamura T, Sugiyama D, Tanaka T, Dohi S

Progress in cardiovascular diseases 56 （ 5 ） 515 - 521 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0033-0620

In the Japanese workplace, employers are required to provide annual health checkups for workers in accordance with the "Industrial Safety and Health Law," which also mandates that an occupational physician be assigned to companies employing at least 50 workers. The annual medical examination includes testing for the early detection of cardiovascular risk factors such as hypertension, dyslipidemia, diabetes, and the metabolic syndrome. This approach has successfully contributed to the extremely low incidence of coronary artery disease among Japanese workers. However, problems such as poor health and the low rate of participation in health checkups among small-scale companies still persist. Furthermore, although most wellness delivery systems in Japan employ strategies targeting high-risk individuals, instituting a strategy addressing the broader population irrespective of screening may be effective in reducing disease risk in the overall population. As a future direction, we should therefore develop practical methods for implementing a population strategy. © 2014 Elsevier Inc.

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High long-chain n-3 fatty acid intake attenuates the effect of high resting heart rate on cardiovascular mortality risk: a 24-year follow-up of Japanese general population.

Hisamatsu T, Miura K, Ohkubo T, Yamamoto T, Fujiyoshi A, Miyagawa N, Kadota A, Takashima N, Okuda N, Yoshita K, Kita Y, Murakami Y, Nakamura Y, Okamura T, Horie M, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Journal of cardiology 64 （ 3 ） 218 - 224 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0914-5087

Background: Increased resting heart rate (RHR) independently predicts cardiovascular mortality. Meanwhile, long-chain n-3 fatty acids (LCn3FAs) have a cardioprotective effect. Our aim was to evaluate whether higher LCn3FAs intake attenuates the elevated risk of cardiovascular mortality associated with increased RHR. Methods: We conducted a population-based 24-year prospective cohort study of Japanese, whose LCn3FAs intake is relatively high. Study participants included 8807 individuals aged 30-95 years from randomly selected areas across Japan without cardiovascular diseases and anti-hypertensive drugs at baseline. The primary endpoint was cardiovascular mortality, and the secondary endpoints were cardiac and stroke mortality during 24 years of follow-up. Individual dietary LCn3FAs intake was estimated from household-based 3-day weighed food records. RHR was obtained from 3 consecutive R-wave intervals on 12-lead electrocardiography. Cox models were used to estimate the multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) adjusting for possible confounders. Results: During the follow-up period, 617 cardiovascular deaths were observed. The median daily intake of LCn3FAs was 0.37% kcal (0.86. g/day). The interaction between dietary LCn3FAs intake and RHR in the risk of cardiovascular mortality was statistically significant (p= 0.033). The risk of cardiovascular mortality was significantly higher in the low-intake group (<0.37%. kcal) with an RHR >85. beats/min (bpm) [hazard ratio (HR), 1.67; 95% confidence interval (CI), 1.15-2.43], but not in the high-intake group (≥0.37%. kcal) with an RHR >85. bpm (HR, 0.92; 95% CI, 0.61-1.38), compared with those in the high-intake group with an RHR <70. bpm. Similar results were observed with stroke mortality, but not with cardiac mortality. Conclusions: The risk of cardiovascular mortality associated with increased RHR is elevated in participants with low dietary LCn3FAs intake, but not in participants with high dietary LCn3FAs intake in a representative Japanese general population. These results suggest that high dietary LCn3FAs intake may prevent cardiovascular mortality associated with increased RHR.

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Women. Executive Summary of the Japan Atherosclerosis Society (JAS) Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases in Japan―2012 Version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K, Japan Atherosclerosis Society Committee for Epidemiology and Clinical Management of Atherosclerosis.

Journal of atherosclerosis and thrombosis 21 （ 4 ） 291 - 295 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Chronic kidney disease.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 21 （ 3 ） 173 - 174 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Cerebrovascular diseases.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 21 （ 3 ） 175 - 179 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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The elderly.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 21 （ 3 ） 180 - 185 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Cardiovascular risk with and without antihypertensive drug treatment in the Japanese general population: participant-level meta-analysis.

Asayama K, Satoh M, Murakami Y, Ohkubo T, Nagasawa SY, Tsuji I, Nakayama T, Okayama A, Miura K, Imai Y, Ueshima H, Okamura T, Evidence for Cardiovascular Prevention From Observational Cohorts in Japan (EPOCH-JAPAN) Research Group.

Hypertension (Dallas, Tex. : 1979) 63 （ 6 ） 1189 - 1197 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0194-911X

To evaluate the cardiovascular mortality risk in association with blood pressure level among people with and without antihypertensive treatment, we performed the participant-level meta-analysis that included 39 705 Japanese from 6 cohorts (58.4% women; mean age, 60.1 years; 20.4% treated). Multivariable-adjusted Cox models were used to analyze the risk of cardiovascular mortality and its subtypes among 6 blood pressure levels according to recent guidelines, optimal to Grade 3 hypertension, and the usage of antihypertensive medication at baseline. During median 10.0 years of follow-up, there were 2032 cardiovascular deaths (5.1 per 1000 person-years), of which 410 deaths were coronary heart disease, 371 were heart failure, and 903 deaths were stroke. Treated participants had significantly higher risk for cardiovascular mortality (hazard ratios, 1.50; 95% confidence intervals, 1.36-1.66), coronary heart disease (hazard ratios, 1.53; confidence intervals, 1.23-1.90), heart failure (hazard ratios, 1.39; confidence intervals, 1.09-1.76), and stroke (hazard ratios, 1.48; confidence intervals, 1.28-1.72) compared with untreated people. Among untreated participants, the risks increased linearly with an increment of blood pressure category (P≤0.011). The risk increments per blood pressure category were higher in young participants (<60 years; 22% to 79%) than those in old people (≥60 years; 7% to 15%) with significant interaction for total cardiovascular, heart failure, and stroke mortality (P≤0.026). Among treated participants, the significant linear association was also observed for cardiovascular mortality (P=0.0003), whereas no stepwise increase in stroke death was observed (P=0.19). The risks of cardiovascular mortality were ≈1.5-fold high in participants under antihypertensive medication. More attention should be paid to the residual cardiovascular risks in treated patients. © 2014 American Heart Association, Inc.

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Predicting coronary heart disease using risk factor categories for a Japanese urban population, and comparison with the framingham risk score: the suita study.

Nishimura K, Okamura T, Watanabe M, Nakai M, Takegami M, Higashiyama A, Kokubo Y, Okayama A, Miyamoto Y

Journal of atherosclerosis and thrombosis 21 （ 8 ） 784 - 798 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: The Framingham risk score (FRS) is one of the standard tools used to predict the incidence of coronary heart disease (CHD). No previous study has investigated its efficacy for a Japanese population cohort. The purpose of this study was to develop new coronary prediction algorithms for the Japanese population in the manner of the FRS, and to compare them with the original FRS.Methods: Our coronary prediction algorithms for Japanese were based on a large population-based cohort study (Suita study). The study population comprised 5,521 healthy Japanese. They were followed-up for 11.8 years on average, and 213 cases of CHD were observed. Multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model.Results: Our coronary prediction algorithms for Japanese patients were based on a large population-based cohort study (the Suita study). A multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model. The C-statistics showed that the new model had better accuracy than the original and recalibrated Framingham scores. The net reclassification improvement (NRI) by the Suita score with the inclusion of CKD was 41.2% (P＜0.001) compared with the original FRS. The recalibration of the FRS slightly improved the efficiency of the prediction, but it was still worse than the Suita score with the CKD model. The calibration analysis suggested that the original FRS and the recalibrated FRS overestimated the risk of CHD in the Japanese population. The Suita score with CKD more accurately predicted the risk of CHD.Conclusion: The FRS and recalibrated FRS overestimated the 10-year risk of CHD for the Japanese population. A predictive score including CKD as a coronary risk factor for the Japanese population was more accurate for predicting CHD than the original Framingham risk scores in terms of the C-statics and NRI.

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Diagnosis of atherosclerosis. Executive Summary of the Japan Atherosclerosis Society (JAS) Guidelines for the Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases in Japan―2012 Version.

Journal of atherosclerosis and thrombosis 21 （ 4 ） 296 - 298 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Comparison of HOMA-IR, HOMA-β% and disposition index between US white men and Japanese men in Japan: the ERA JUMP study.

Ahuja V, Kadowaki T, Evans RW, Kadota A, Okamura T, El Khoudary SR, Fujiyoshi A, Barinas-Mitchell EJ, Hisamatsu T, Vishnu A, Miura K, Maegawa H, El-Saed A, Kashiwagi A, Kuller LH, Ueshima H, Sekikawa A, ERA JUMP Study Group.

Diabetologia 58 （ 2 ） 265 - 271 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0012-186X

Aims/hypothesis: At the same level of BMI, white people have less visceral adipose tissue (VAT) and are less susceptible to developing type 2 diabetes than Japanese people. No previous population-based studies have compared insulin resistance and insulin secretion between these two races in a standardised manner that accounts for VAT. We compared HOMA-IR, HOMA of beta cell function (HOMA-β%) and disposition index (DI) in US white men and Japanese men in Japan.Methods: We conducted a population-based, cross-sectional study, comprising 298 white men and 294 Japanese men aged 40–49 years without diabetes. Insulin, glucose, VAT and other measurements were performed at the University of Pittsburgh. We used ANCOVA to compare geometric means of HOMA-IR, HOMA-β% and DI, adjusting for VAT and other covariates.Results: White men had higher HOMA-IR, HOMA-β% and DI than Japanese men, and the difference remained significant (p < 0.01) after adjusting for VAT (geometric mean [95% CI]): 3.1 (2.9, 3.2) vs 2.5 (2.4, 2.6), 130.8 (124.6, 137.3) vs 86.7 (82.5, 91.0), and 42.4 (41.0, 44.0) vs 34.8 (33.6, 36.0), respectively. Moreover, HOMA-IR, HOMA-β% and DI were significantly higher in white men even after further adjustment for BMI, impaired fasting glucose and other risk factors.Conclusions/interpretation: The higher VAT-adjusted DI in white men than Japanese men may partly explain lower susceptibility of white people than Japanese people to developing type 2 diabetes. The results, however, should be interpreted with caution because the assessment of insulin indices was made using fasting samples and adjustment was not made for baseline glucose tolerance. Further studies using formal methods to evaluate insulin indices are warranted.

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Statements.

Journal of atherosclerosis and thrombosis 21 （ 4 ） 299 - 303 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Long chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese men in Japan and white men in the USA: population based prospective cohort study.

Sekikawa A, Miura K, Lee S, Fujiyoshi A, Edmundowicz D, Kadowaki T, Evans RW, Kadowaki S, Sutton-Tyrrell K, Okamura T, Bertolet M, Masaki KH, Nakamura Y, Barinas-Mitchell EJ, Willcox BJ, Kadota A, Seto TB, Maegawa H, Kuller LH, Ueshima H, ERA JUMP Study Group.

Heart (British Cardiac Society) 100 （ 7 ） 569 - 573 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1355-6037

Objective: To determine whether serum concentrations of long chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in the incidence rate of coronary artery calcification (CAC) between Japanese men in Japan and white men in the USA. Methods: In a population based, prospective cohort study, 214 Japanese men and 152 white men aged 40.49 years at baseline (2002.2006) with coronary calcium score (CCS)=0 were re-examined for CAC in 2007.2010. Among these, 175 Japanese men and 113 white men participated in the follow-up exam. Incident cases were defined as participants with CCS≥10 at follow-up. A relative risk regression analysis was used to model the incidence rate ratio between the Japanese and white men. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline. Results: Mean (SD) serum percentage of LCn3PUFA was >100% higher in Japanese men than in white men (9.08 (2.49) vs 3.84 (1.79), respectively, p<0.01). Japanese men had a significantly lower incidence rate of CAC compared to white men (0.9 vs 2.9/100 personyears, respectively, p<0.01). The incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% CI 0.150 to 0.690; p<0.01). After adjusting for age, systolic blood pressure, low density lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant (0.262, 95% CI 0.094 to 0.731; p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376, 95% CI 0.090 to 1.572; p=0.18). Conclusions: LCn3PUFAs significantly contributed to the difference in the incidence of CAC between Japanese and white men.

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Metabolic syndrome.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 21 （ 1 ） 1 - 5 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Diabetes mellitus. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan--2012 version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 21 （ 2 ） 93 - 98 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Familial hypercholesterolemia.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K, Harada-Shiba M, Arai H, Bujo H, Nohara A, Ohta T, Oikawa S, Okada T, Wakatsuki A

Journal of atherosclerosis and thrombosis 21 （ 1 ） 6 - 10 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Other types of primary hyperlipoproteinemia(hyperlipidemia). Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan--2012 version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 21 （ 2 ） 82 - 85 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Coronary artery disease. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan--2012 version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 21 （ 2 ） 86 - 92 2014年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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High risks of all-cause and cardiovascular deaths in apparently healthy middle-aged people with preserved glomerular filtration rate and albuminuria: A prospective cohort study.

Ohsawa M, Fujioka T, Ogasawara K, Tanno K, Okamura T, Turin TC, Itai K, Ogawa A, Yoshida Y, Omama S, Onoda T, Nakamura M, Makita S, Ishibashi Y, Tanaka F, Kuribayashi T, Ohta M, Sakata K, Okayama A

International journal of cardiology 170 （ 2 ） 167 - 172 2013年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0167-5273

Background The reason why coexistence of preserved estimated glomerular filtration rate (eGFR) and albuminuria contributes to a high risk of death and which cause of death increases all-cause mortality have not been elucidated. Methods A total of 16,759 participants aged 40 to 69 years with normal or mildly reduced eGFR (45-119 ml/min/1.73 m²) were enrolled and divided into six groups (group 1, eGFR: 90-119 without albuminuria; group 2, eGFR: 90-119 with albuminuria; group 3, eGFR: 60-89 without albuminuria (reference); group 4, eGFR: 60-89 with albuminuria; group 5, eGFR: 45-59 without albuminuria; group 6, eGFR: 45-59 with albuminuria) based on GFR estimated by using the CKD-EPI study equation modified by a Japanese coefficient and albuminuria (urine albumin-creatinine ratio ≥ 30 mg/g). Outcomes included all-cause death (ACD), cardiovascular death (CVD) and neoplasm-related death (NPD). Multivariable-adjusted mortality rate ratios (RR) and their 95% confidence intervals (CIs) in the groups were estimated by Poisson's regression analysis. Results The highest risk of ACD (RR (95% CIs): 3.95 (2.08-7.52)), CVD (7.15 (2.25-22.7)) and NPB (3.25 (1.26-8.38)) was observed in group 2. Subjects in group 2 were relatively young and had the highest levels of body mass index, blood pressure and HbA_1c and the highest prevalence of diabetes and metabolic syndrome. Conclusion Coexistence of preserved eGFR and albuminuria increases risks for ACD, CVD and NPD. Relatively young metabolic persons having both preserved eGFR and albuminuria should be considered as a very high-risk population. © 2013 Elsevier Ireland Ltd.

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The economic and medical costs of alcohol consumption in Japan.

Kanda H, Okamura T

The West Indian medical journal 62 （ 9 ） 785 - 6 2013年12月

ISSN 0043-3144

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Long-term outcome of healthy participants with atrial premature complex: a 15-year follow-up of the NIPPON DATA 90 cohort.

Inohara T, Kohsaka S, Okamura T, Watanabe M, Nakamura Y, Higashiyama A, Kadota A, Okuda N, Ohkubo T, Miura K, Okayama A, Ueshima H, NIPPON DATA 80/90 Research Group.

PloS one 8 （ 11 ） e80853 2013年11月

研究論文（学術雑誌）, 共著, 査読有り

Background: Atrial premature complexes (APC) are among the most frequently encountered electrocardiographic abnormalities. However, their prognostic value among healthy individuals is unclear. This study aimed to clarify the role of APC in predicting cardiovascular events in a large Japanese community cohort using long-term follow-up data. Methods: National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1990-2005, (NIPPON DATA 90) was a large cohort study of cardiovascular disease (CVD) in Japan. A total of 7692 otherwise healthy participants with no history of myocardial infarction, stroke, atrial fibrillation, or atrial flutter were enrolled (men, 41.5%; mean age, 52.5 ± 13.7 years). Results: A total of 64 (0.8%) participants had at least one beat of APC on screening 12-lead electrocardiogram. During the follow-up of 14.0 ± 2.9 years (total, 107,474 patient-years), 338 deaths occurred due to CVD. The association between APC and CVD outcome was assessed using Cox proportional hazard models. Cox regression analysis revealed that the presence of APC was an independent predictor for CVD deaths (HR: 2.03, 95% CI: 1.12-3.66, P = 0.019). The association of APC on CVD death was more evident in participants with hypertension (P-value for interaction, 0.03). Conclusions: APC recorded during the screening electrocardiogram are significantly associated with an increased risk of CVD deaths in a Japanese community-dwelling population and are a strong prognostic factor for hypertensive participants. © 2013 Inohara et al.

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HbA1c and the risks for all-cause and cardiovascular mortality in the general Japanese population: NIPPON DATA90.

Sakurai M, Saitoh S, Miura K, Nakagawa H, Ohnishi H, Akasaka H, Kadota A, Kita Y, Hayakawa T, Ohkubo T, Okayama A, Okamura T, Ueshima H, NIPPON DATA90 Research Group.

Diabetes care 36 （ 11 ） 3759 - 3765 2013年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0149-5992

Objective - Associations between HbA_1c and cardiovascular diseases (CVD) have been reported mainly in Western countries. It is not clear whether HbA_1c measurements are useful for assessing CVD mortality risk in East Asian populations. Research Design and Methods - The risk for cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. A total of 7,120 participants (2,962men and 4,158 women; mean age 52.3 years) free of previous CVD were followed for 15 years. Adjusted hazard ratios (HRs) and 95% CIs among categories of HbA_1c (<5.0%, 5.0-5.4%, 5.5-5.9%, 6.0-6.4%, and ≥6.5%) for participants without treatment for diabetes and HRs for participants with diabetes were calculated using a Cox proportional hazards model. Results - During the study, there were 1,104 deaths, including 304 from CVD, 61 from coronary heart disease, and 127 from stroke (78 from cerebral infarction, 25 from cerebral hemorrhage, and 24 from unclassified stroke). Relations to HbA_1c with all-cause mortality and CVD death were graded and continuous, and multivariate-adjusted HRs for CVD death in participants with HbA_1c 6.0-6.4% and ≥6.5%were 2.18 (95% CI 1.22-3.87) and 2.75 (1.43-5.28), respectively, compared with participants with HbA_1c <5.0%. Similar associations were observed between HbA_1c and death from coronary heart disease and death from cerebral infarction. Conclusions - High HbA_1c levels were associated with increased risk for all-cause mortality and death from CVD, coronary heart disease, and cerebral infarction in general East Asian populations, as in Western populations. © 2013 by the American Diabetes Association.

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Association of total marine fatty acids, eicosapentaenoic and docosahexaenoic acids, with aortic stiffness in Koreans, whites, and Japanese Americans.

Sekikawa A, Shin C, Masaki KH, Barinas-Mitchell EJ, Hirooka N, Willcox BJ, Choo J, White J, Evans RW, Fujiyoshi A, Okamura T, Miura K, Muldoon MF, Ueshima H, Kuller LH, Sutton-Tyrrell K, ERA JUMP Study Group.

American journal of hypertension 26 （ 11 ） 1321 - 7 2013年11月

研究論文（学術雑誌）, ISSN 0895-7061

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Association of total marine fatty acids, eicosapentaenoic and docosahexaenoic acids, with aortic stiffness in Koreans, whites, and Japanese Americans.

American journal of hypertension 26 （ 11 ） 1321 - 7 2013年11月

研究論文（学術雑誌）, ISSN 0895-7061

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Effects of intensive and moderate public education on knowledge of early stroke symptoms among a Japanese population: the Acquisition of Stroke Knowledge study.

Morimoto A, Miyamatsu N, Okamura T, Nakayama H, Toyoda K, Suzuki K, Toyota A, Hata T, Yamaguchi T

Stroke 44 （ 10 ） 2829 - 2834 2013年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0039-2499

Background and Purpose-To assess the effects of intensive and moderate public education on knowledge of early stroke symptoms among a general Japanese population. Methods-Information on early stroke symptoms was distributed by leaflet 12× and by booklet twice in an intensive intervention area >22 months, and by leaflet and booklet once each in a moderate intervention area. No distribution occurred in the control area. Before and after the intervention, a mailed survey was conducted in the 3 areas. A total of 2734 individuals, aged 40 to 74 years, who did not select all 5 correct symptoms of stroke in the preintervention survey were eligible for our analysis. Results-The numbers of correct answers selected about stroke symptoms did not differ significantly among the 3 areas in the preintervention survey (P=0.156). In the postintervention survey, the proportions of participants who selected sudden 1-sided numbness or weakness (94.2% in the intensive intervention area, 88.3% in the moderate intervention area, and 89.2% in the control area P<0.001) and sudden severe headache (76.8%, 70.1%, and 70.4%, respectively P<0.001) differed significantly among the 3 areas. After adjustment for confounding factors, the multivariable-adjusted odds ratios (95% confidence intervals) for correctly choosing all 5 symptoms were 1.35 (1.07-1.71) in the intensive intervention area and 0.96 (0.74-1.24) in the moderate intervention area compared with the control area. Conclusions-Our findings suggest that frequent distribution of leaflets and booklets significantly improved the short-term knowledge of community residents about early symptoms of stroke. © 2013 American Heart Association, Inc.

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A cross-sectional association of obesity with coronary calcium among Japanese, Koreans, Japanese Americans, and U.S. whites.

Fujiyoshi A, Sekikawa A, Shin C, Masaki K, David Curb J, Ohkubo T, Miura K, Kadowaki T, Kadowaki S, Kadota A, Edmundowicz D, Shah A, Evans RW, Bertolet M, Choo J, Willcox BJ, Okamura T, Maegawa H, Murata K, Kuller LH, Ueshima H, ERA JUMP (Electron-Beam Tomography, Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort) Study Group.

European heart journal cardiovascular Imaging 14 （ 9 ） 921 - 927 2013年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2047-2404

AimsConflicting evidence exists regarding whether obesity is independently associated with coronary artery calcium (CAC), a measure of coronary atherosclerosis. We examined an independent association of obesity with prevalent CAC among samples of multi-ethnic groups whose background populations have varying levels of obesity and coronary heart disease (CHD).Methods and resultsWe analysed a population-based sample of 1212 men, aged 40-49 years free of clinical cardiovascular disease recruited in 2002-06; 310 Japanese in Japan (JJ), 294 Koreans in South Korea (KN), 300 Japanese Americans (JA), and 308 Whites in the USA (UW). We defined prevalent CAC as an Agatston score of ≥10. Prevalent CAC was calculated by tertile of the body mass index (BMI) in each ethnic group and was plotted against the corresponding median of tertile BMI. Additionally, logistic regression was conducted to examine whether an association of the BMI was independent of conventional risk factors. The median BMI and crude prevalence of CAC for JJ, KN, JA, and UW were 23.4, 24.4, 27.4, and 27.1 (kg/m²); 12, 11, 32, and 26 (%), respectively. Despite the absolute difference in levels of BMI and CAC across groups, higher BMI was generally associated with higher prevalent CAC in each group. After adjusting for age, smoking, alcohol, hypertension, lipids, and diabetes mellitus, the BMI was positively and independently associated with prevalent CAC in JJ, KN, UW, but not in JA.ConclusionIn this multi-ethnic study, obesity was independently associated with subclinical stage of coronary atherosclerosis among men aged 40-49 years regardless of the BMI level. © 2013 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013.

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Serum leptin and total dietary energy intake: the INTERLIPID Study.

Nakamura Y, Ueshima H, Okuda N, Murakami Y, Miura K, Kita Y, Okamura T, Okayama A, Turin TC, Choudhry SR, Rodriguez B, David Curb J, Stamler J

European journal of nutrition 52 （ 6 ） 1641 - 1648 2013年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1436-6207

Purpose: It has been hypothesized that leptin-induced appetite suppression is impaired in obese individuals, but little human evidence is available documenting this. We investigated relations between serum leptin and total energy intake using INTERLIPID/INTERMAP data on Japanese-Americans in Hawaii and Japanese in Japan. Methods: Serum leptin and nutrient intakes were examined by standardized methods in men and women aged 40-59 years from two population samples, one Japanese-American in Hawaii (88 men, 94 women), the other Japanese in central Japan (123 men, 111 women). Multiple linear regression analyses stratified by BMI category (<25 kg/m², 25-29.9 kg/m², and ≥30 kg/m²) with adjustment for possible confounders were used to examine the relation between log-leptin and total dietary energy intake. Results: In multivariate regression analyses, in those with BMI < 25 kg/m² and in those with BMI between 25 and 29.9 kg/m², log-leptin was not significantly related to total dietary energy intake; in those with BMI ≥ 30 kg/m², it was significantly inversely related to total dietary energy intake (P = 0.029), independent of body weight and physical activity. Physical activity score was significantly positively related to total dietary energy intake only in participants with BMI < 25 kg/m ² (P < 0.001). Conclusion: Leptin was significantly inversely associated with dietary energy intake in obese persons, but not in overweight and normal-weight persons. © Springer-Verlag 2012.

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Correlation of a self-report and direct measure of physical activity level in the electron-beam tomography and risk assessment among Japanese and US Men in the post World War II birth cohort (ERA JUMP) study.

Berger MA, Shin C, Storti KL, Curb JD, Kriska AM, Arena VC, Choo J, Ueshima H, Okamura T, Miura K, Seto TB, Masaki K, El-Saed A, Sekikawa A

Journal of epidemiology 23 （ 6 ） 411 - 417 2013年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: Physical activity (PA) is complex and a difficult behavior to assess as there is no ideal assessment tool(s) that can capture all contexts of PA. Therefore, it is important to understand how different assessment tools rank individuals. We examined the extent to which self-report and direct assessment PA tools yielded the same ranking of PA levels. Methods: PA levels were measured by the Modifiable Activity Questionnaire (MAQ) and pedometer at baseline among 855 white (W), African-American (AA), Japanese-American (JA), and Korean (K) men (mean age 45.3 years) in 3 geographic locations in the ERA JUMP study. Results: Korean men were more active than W, AA, and JA men, according to both the MAQ and pedometer (MAQ total PA [mean ± SD]: 41.6 ± 17.8, 20.9 ± 9.9, 20.0 ± 9.1, and 29.4 ± 10.3 metabolic equivalent [MET] hours/week, respectively; pedometer: 9584.4 ± 449.4, 8363.8 ± 368.6, 8930.3 ± 285.6, 8335.7 ± 368.6 steps/day, respectively). Higher levels of total PA in Korean men, as shown by MAQ, were due to higher occupational PA. Spearman correlations between PA levels reported on the MAQ and pedometer indicated positive associations ranging from rho = 0.29 to 0.42 for total activity, rho = 0.13 to 0.35 for leisure activity, and rho = 0.10 to 0.26 for occupational activity. Conclusions: The 2 assessment methods correlated and were complementary rather than interchangeable. The MAQ revealed why Korean men were more active. In some subpopulations it may be necessary to assess PA domains other than leisure and to use more than 1 assessment tool to obtain a more representative picture of PA levels. © 2013 Marie A. Berger et al.

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The prevalence of aortic calcification in Japanese compared to white and Japanese-American middle-aged men is confounded by the amount of cigarette smoking.

El-Saed A, Curb JD, Kadowaki T, Okamura T, Sutton-Tyrrell K, Masaki K, Seto TB, Takamiya T, Choo J, Edmundowicz D, Evans RW, Fujiyoshi A, Nakamura Y, Miura K, Shin C, Kuller LH, Ueshima H, Sekikawa A

International journal of cardiology 167 （ 1 ） 134 - 139 2013年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0167-5273

Background: The prevalence of coronary artery calcification (CAC) in Japanese men is lower than in white and Japanese-American men. It is unclear if aortic calcification (AC) strongly linked to smoking is also lower in Japanese men who have many times higher smoking prevalence compared to US men. Methods: We conducted a population-based study of 903 randomly-selected men aged 40-49 years: 310 Japanese men in Kusatsu, Japan, 301 white men in Allegheny County, US, and 292 Japanese men in Hawaii, US (2002-2006). The presence of AC was assessed by electron-beam tomography. AC was defined as Agatston aortic calcium scores (AoCaS) > 0 and ≥ 100. Results: Japanese (35.8%) had significantly less AoCaS > 0 compared to both white (68.8%, p < 0.001) and Japanese-American (62.3%, p < 0.001) but similar AoCaS ≥ 100 (19.4%, 18.3%, 22.6%, respectively, p = 0.392). The pack-years of smoking, which was highest in Japanese, was the most important single associate of AC in all populations. Additionally age, low-density-lipoprotein cholesterol (LDL-C), and triglycerides in Japanese; body-mass index (BMI) in white; and BMI, LDL-C, hypertension, diabetes, and lipid medications in Japanese-American were independent associates of AC. The risk of AC using either cut points adjusted for pack-years of smoking and additional risk factors was lower in Japanese compared to both white and Japanese-American. AC and CAC had moderately positive and significant correlations in Japanese (r = 0.26), white (r = 0.39), and Japanese-American (r = 0.45). Conclusions: The prevalence of AC defined both > 0 and ≥ 100 was significantly lower in Japanese than in white and Japanese-American men after adjusting for cigarette smoking and additional risk factors. © 2011 Elsevier Ireland Ltd.

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Prediction of cardiovascular disease mortality by proteinuria and reduced kidney function: pooled analysis of 39,000 individuals from 7 cohort studies in Japan.

Nagata M, Ninomiya T, Kiyohara Y, Murakami Y, Irie F, Sairenchi T, Miura K, Okamura T, Ueshima H, EPOCH-JAPAN Research Group.

American journal of epidemiology 178 （ 1 ） 1 - 11 2013年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0002-9262

There are limited studies addressing whether proteinuria and estimated glomerular filtration rate (eGFR) are independently associated with cardiovascular disease in Asia. Using data from 7 prospective cohorts recruited between 1980 and 1994 in Japan, we assessed the influence of proteinuria (≥1+ on dipstick) and reduced eGFR on the risk of cardiovascular disease mortality in 39,405 participants (40-89 years) without kidney failure. During a 10.1-year follow-up, 1,927 subjects died from cardiovascular disease. Proteinuria was associated with a 1.75-fold (95% confidence interval (CI): 1.44, 2.11) increased risk of cardiovascular disease mortality after adjustment for potential confounding factors. Additionally, the multivariate-adjusted hazard ratio of cardiovascular disease mortality increased linearly with lower eGFR levels (P_trend < 0.001): Subjects with eGFR of <45 mL/minute/1.73 m² had a 2.22-fold (95% CI: 1.60, 3.07) greater risk of cardiovascular disease mortality than those with eGFR of ≥90 mL/minute/1.73 m². Subjects with both proteinuria and eGFR of <45 mL/minute/1.73 m² had a 4.05-fold (95% CI: 2.55, 6.43) higher risk of cardiovascular disease mortality compared with those with neither of these risk factors. There was no evidence of interaction in the relationship between proteinuria and lower eGFR (P_interaction = 0.77). The present results suggest that proteinuria and lower eGFR are independent risk factors for cardiovascular disease mortality in the Japanese population. © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

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LOX-1 ligands containing apolipoprotein B and carotid intima-media thickness in middle-aged community-dwelling US Caucasian and Japanese men.

Okamura T, Sekikawa A, Sawamura T, Kadowaki T, Barinas-Mitchell E, Mackey RH, Kadota A, Evans RW, Edmundowicz D, Higashiyama A, Nakamura Y, Abbott RD, Miura K, Fujiyoshi A, Fujita Y, Murakami Y, Miyamatsu N, Kakino A, Maegawa H, Murata K, Horie M, Mitsunami K, Kashiwagi A, Kuller LH, Ueshima H, ERA JUMP Study Group.

Atherosclerosis 229 （ 1 ） 240 - 245 2013年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Objective: The serum level of LOX-1 ligand containing ApoB (LAB) may reflect atherogenicity better than LDL cholesterol (LDLC), total LDL particles and usual measurement of oxidized LDL. The association between LAB and intima-media thickness (IMT) of carotid artery was investigated by ultrasound in US and Japan men. Methods: Participants were 297 US Caucasian and 310 Japanese men, aged 40-49 years without past history of cardiovascular disease. Serum LAB levels were measured by ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody. Results: Serum LAB levels [median (interquartile range), μg/L] were 1321 (936, 1730) in US Caucasians and 940 (688, 1259) in Japanese. For Caucasian men, average IMT was higher in higher LAB quartile, which was 0.653, 0.667, 0.688, and 0.702. mm, respectively (p for trend. =. 0.02). Linear regression analysis showed serum LAB was significantly associated with IMT after adjustment for LDLC or total LDL particles in addition to other traditional or novel risk factors for atherosclerosis such as C-reactive protein. However, there was no significant relationship between LAB and IMT in Japanese men. Conclusion: Serum LAB, a new candidate biomarker for residual risk, was associated with an increased carotid IMT in US Caucasian men independently of various risk factors; however, ethnic difference should be clarified in the future. © 2013 Elsevier Ireland Ltd.

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Prognostic values of bundle branch blocks for cardiovascular mortality in Japanese (24year follow-up of NIPPON DATA80).

Nakamura Y, Okamura T, Inohara T, Kohsaka S, Watanabe M, Higashiyama A, Kadota A, Okuda N, Ohkubo T, Nagasawa SY, Miura K, Okayama A, Ueshima H, NIPPON DATA 80 Research Group.

Journal of electrocardiology 46 （ 4 ） 360 - 365 2013年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-0736

Aims Left bundle branch block (LBBB) is generally considered to be associated with a poorer prognosis in comparison with normal controls. However, there are some studies that showed no difference in prognosis of LBBB in comparison with normal controls. Methods and Results We studied prognostic values of BBBs on cardiovascular disease (CVD) and total mortality using the NIPPON DATA80 database with a 24-year follow-up. At the baseline in 1980, data were collected on study participants, ages 30 years and over, from randomly selected areas in Japan. We followed 9,090 participants (44% men, mean age 51). During the 24 year follow-up, there were 886 CVD, and 2,597 total mortality cases. Among participants, 0.2% of them were in LBBB, 1.3% in RBBB, 4.3% in other ventricular conduction defect (VCD) groups. The multivariate-adjusted hazard ratio (HR) using the Cox model including biochemical and other ECG variables revealed that LBBB was significantly positively associated with CVD (HR = 2.71, 95% confidence intervals [CI]: 1.35-5.45, P = 0.005), and total (HR = 2.07, 95%CI: 1.26-3.39, P = 0.004) mortality in men and women combined compared to participants without VCD. RBBB and other VCDs did not carry any significant risk for CVD or total mortality. Conclusions We found significant positive associations of LBBB with CVD and total mortality independent of confounding factors including other ECG changes. © 2013 Elsevier Inc.

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Interaction between dietary marine-derived n-3 fatty acids intake and J-point elevation on the risk of cardiac death: a 24-year follow-up of Japanese men.

Hisamatsu T, Miura K, Ohkubo T, Yamamoto T, Fujiyoshi A, Miyagawa N, Kadota A, Takashima N, Okuda N, Matsumura Y, Yoshita K, Kita Y, Murakami Y, Nakamura Y, Okamura T, Horie M, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Heart (British Cardiac Society) 99 （ 14 ） 1024 - 1029 2013年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1355-6037

Objective: Higher marine-derived n-3 fatty acids (MDn3FAs) intake reduces the risk of sudden cardiac death via antiarrhythmic effects. The article evaluates whether MDn3FAs intake attenuates the increased risk of cardiac death associated with J-point elevation (JPE), characterised by an elevation of QRS-ST junction (J-point) ≥0.1 mV on electrocardiography. Design: A prospective population-based cohort study. Setting: The National Survey on Circulatory Disorders and the National Nutrition Survey of Japan. Participants: A total of 4348 community-dwelling men (mean age 49.3 years), without cardiovascular diseases at baseline, from randomly selected areas across Japan. Main outcome measures: Cardiac death (200 men) during the 24-year follow-up. Results: Dietary MDn3FAs intake was assessed using a dietary method to estimate individual intake of household-based weighed food records for 3 days. Cox models were used to calculate HRs and 95% CIs adjusted for possible confounding factors. JPE was present in 340 participants (7.8%). The median daily intake of MDn3FAs was 0.35%kcal (0.92 g/day). The risk of cardiac death was significantly higher in participants with JPE than in those without JPE in the low intake group (<0.35%kcal; adjusted HR 3.51; 95% CI 1.84 to 6.73; p<0.001), but not in the high intake group (≥0.35%kcal; adjusted HR 1.09; 95% CI 0.56 to 2.16; p=0.795). The interaction between dietary MDn3FAs intake and JPE on the risk of cardiac death was statistically significant (p=0.006). Conclusions: The increased risk of cardiac death associated with JPE may be attenuated by higher dietary MDn3FAs intake.

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Concordance of CKD stages in estimation by the CKD-EPI equation and estimation by the MDRD equation in the Japanese general population: the Iwate KENCO Study.

Ohsawa M, Tanno K, Itai K, Turin TC, Okamura T, Ogawa A, Ogasawara K, Fujioka T, Onoda T, Yoshida Y, Omama S, Ishibashi Y, Nakamura M, Makita S, Tanaka F, Kuribayashi T, Koyama T, Sakata K, Okayama A

International journal of cardiology 165 （ 2 ） 377 - 379 2013年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0167-5273

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Treated and untreated hypertension, hospitalization, and medical expenditure: an epidemiological study in 314622 beneficiaries of the medical insurance system in Japan.

Nakamura K, Miura K, Nakagawa H, Okamura T, Okuda N, Nishimura K, Yasumura S, Sakata K, Hidaka H, Okayama A

Journal of hypertension 31 （ 5 ） 1032 - 1042 2013年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0263-6352

Lippincott Williams &Wilkins.OBJECTIVE: This study investigated the effect of hypertension on hospitalization risk and medical expenditure according to treatment status in a Japanese population. METHODS: A total of 314 622 beneficiaries of the medical insurance system in Japan, aged 40-69 years, without a history of cardiovascular, cerebrovascular, or end-stage renal disease were classified into seven blood pressure categories. These categories were used to compare the risk of undergoing hospitalization in the 1 year after the baseline survey and to examine the percentage of inpatient medical expenditure attributable to overall hypertension relative to total medical expenditure in the study population. RESULTS: During the follow-up period, 6.6% of men and 5.1% of women were hospitalized. In men and women aged 40-54 years, cases of hypertension, especially grade 3 untreated hypertension, led to more frequent hospitalization, compared with optimal blood pressure. Individuals who were hospitalized, especially long-term, incurred considerably higher medical expenditure compared with those who were not hospitalized, regardless of their hypertension status. In women aged 55-69 years, there was little variation in hospitalization risk across blood pressure categories. The inpatient medical expenditure attributable to overall hypertension represented 7.2 and 6.9% of the total medical expenditure for men aged 40-54 and 55-69 years, whereas it represented 2.8 and 3.8% for women, respectively. CONCLUSION: Although cases of hypertension were an economic burden especially in men, grade 3 untreated hypertension was more likely to incur extremely high medical expenditure as a result of hospitalization, compared with other cases. © 2013 Wolters Kluwer Health

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Ethnic difference in liver fat content

Azuma Koichiro, Curb J. David, Kadowaki Takashi, Edmundowicz Daniel, Kadowaki Sayaka, Masaki Kamal H., El-Saed Aiman, Nishio Yoshihiko, Seto Todd B., Okamura Tomonori, Cetinel Cemal, Kadota Aya, Sutton-Tyrrell Kim, Miura Katsuyuki, Evans Rhobert W., Takamiya Tomoko, Maegawa Hiroshi, Miljkovic Iva, Kuller Lewis H., Ueshima Hirotsugu, Kelley David E., Sekikawa Akira

Obesity Research and Clinical Practice 7 （ 3 ） 2013年05月

共著, 査読有り, ISSN 1871-403X

Background: We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW). Objective: We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat. Design: To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables. Results: Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p < 0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p < 0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population. Conclusions: Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver. © 2011 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

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Public awareness of early symptoms of stroke and information sources about stroke among the general Japanese population: the Acquisition of Stroke Knowledge Study.

Miyamatsu N, Okamura T, Nakayama H, Toyoda K, Suzuki K, Toyota A, Hata T, Hozawa A, Nishikawa T, Morimoto A, Ogita M, Morino A, Yamaguchi T

Cerebrovascular diseases (Basel, Switzerland) 35 （ 3 ） 241 - 249 2013年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1015-9770

Background: It is important that the general population be aware of the early symptoms, since it has been shown that early arrival to hospitals leads better prognosis of stroke patients. However, the general population is not well informed about the early symptoms of stroke. This study was conducted to clarify which stroke symptoms are less well known and which information sources are related to awareness of stroke symptoms. Methods: A multiple-choice, mail-in survey involving 5,540 randomly selected residents, aged 40-74 years, of 3 cities in Japan was conducted. Their knowledge about stroke symptoms and their information sources were surveyed; information sources were classified as mass media (television/newspaper/radio) and personal communication sources (posters/leaflets/internet/health professionals/family and/or friends). 'Awareness' was defined as selecting all 5 of the correct stroke symptoms from among 10 listed symptoms with decoy choices. The estimated fraction of the possible impact due to each source on the whole population was also calculated by odds ratios (ORs) and the proportion of respondents who selected each source (Pe). The combined effects of mass media and personal communication sources on awareness were also assessed. Results: Of the 5,540 residents, only 23% selected all 5 correct symptoms. Visual disturbance was the least known of the 5 symptoms (35%). All sources were positively related to awareness, with ORs (Pe) of: television, 1.58 (72.5%); newspaper, 1.79 (48.0%); radio, 1.74 (13.3%); posters, 1.73 (7.6%); leaflets, 1.50 (24.7%); Internet, 1.66 (5.6%); health professionals, 1.33 (34.8%), and family/friends, 1.21 (44.6%). The estimated fraction of the possible impact due to each source was higher for mass media (television, 0.31 and newspaper, 0.28) than personal communication sources (Internet, 0.04 and leaflets, 0.12). Mass media only and mass media/personal communication sources were significantly associated (ORs: 1.66, 2.75, respectively). Conclusions: As a single method of public education, television could be the most effective strategy. Moreover, the combined approach involving mass media and personal communication sources might have a synergistic effect. Less well-known symptoms, such as visual disturbances, should be noted in public education campaigns. Copyright © 2013 S. Karger AG, Basel.

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Alcohol consumption and cardiovascular disease incidence in men with and without hypertension: the Suita study.

Higashiyama A, Okamura T, Watanabe M, Kokubo Y, Wakabayashi I, Okayama A, Miyamoto Y

Hypertension research : official journal of the Japanese Society of Hypertension 36 （ 1 ） 58 - 64 2013年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0916-9636

The relationship between alcohol consumption and the risk for cardiovascular disease (CVD) is U-shaped, whereas alcohol drinking is linearly associated with blood pressure, and the CVD risk also increases linearly according to blood pressure level. Accordingly, we investigated the net effect of alcohol consumption and hypertension on CVD and its subtypes in this study. A 13-year prospective study of 2336 Japanese men who were free from CVD was performed; ex-drinkers were excluded. The participants were divided into eight groups classified by the combination of the presence of hypertension (systolic/diastolic blood pressure ≥140/90 mm Hg) and alcohol consumption (never-, current-(light, moderate and heavy) drinkers). Multivariate-adjusted hazard ratios (HRs) for the incidence of CVD, coronary artery disease (CAD) and stroke due to the combination of hypertension and alcohol consumption were calculated and compared with non-hypertensive never-drinkers. The HRs for CVD and its subtypes were higher in hypertensives than those in non-hypertensives; in hypertensives without medication for hypertension, the relationship between alcohol consumption and the risks for CVD and CAD was U-shaped, with the highest and most significant increase in never-drinkers. The risk for total stroke was the highest in heavy-drinkers, which was significant. In non-hypertensives, there was no evident increase or decrease in the HRs for CVD and its subtypes in drinkers. Accordingly, controlling blood pressure is important to prevent CVD. In hypertensives, heavy drinking should be avoided to prevent CVD, although light-to-moderate drinking could be protective for CAD. Furthermore, in non-hypertensives, drinkers may need to continuously monitor their blood pressure. © 2013 The Japanese Society of Hypertension All rights reserved.

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Influence of cigarette smoking on coronary artery and aortic calcium among random samples from populations of middle-aged Japanese and Korean men.

Hirooka N, Kadowaki T, Sekikawa A, Ueshima H, Choo J, Miura K, Okamura T, Fujiyoshi A, Kadowaki S, Kadota A, Nakamura Y, Maegawa H, Kashiwagi A, Masaki K, Sutton-Tyrrell K, Kuller LH, Curb JD, Shin C.

J Epidemiol Community Health 67 （ 2 ） 119-24, 2013. 2013年

研究論文（学術雑誌）, 共著, 査読有り

The clustering of cardiovascular disease risk factors and their impacts on annual medical expenditure in Japan: community-based cost analysis using Gamma regression models.

Murakami Y,Okamura T,Nakamura K, Miura K, Ueshima H.

BMJ Open 3 （ 3 ） e002234 2013年

研究論文（学術雑誌）, 共著, 査読有り

Ethnic difference in liver fat content: A cross-sectional observation among Japanese American in Hawaii, Japanese in Japan, and non-Hispanic whites in United States.

Azuma K, Curb JD, Kadowaki T, Edmundowicz D, Kadowaki S, Masaki KH, El-Saed A, Nishio Y, Seto TB, Okamura T, Cetinel C, Kadota A, Sutton-Tyrrell K, Miura K, Evans RW, Takamiya T, Maegawa H, Miljkovic I, Kuller LH, Ueshima H, Kelley DE, Sekikawa A.

Obes Res Clin Pract 7 （ 3 ） e198-205 2013年

研究論文（学術雑誌）, 共著, 査読有り

動脈硬化性疾患の絶対リスクの評価と脂質管理目標．

岡村智教、杉山大典．

日本臨床（日本臨床社） 71 （増刊号3 ） 29-35. 2013年

研究論文（学術雑誌）, 共著

Influence of cigarette smoking on coronary artery and aortic calcium among random samples from populations of middle-aged Japanese and Korean men

Hirooka Nobutaka, Kadowaki Takashi, Sekikawa Akira, Ueshima Hirotsugu, Choo Jina, Miura Katsuyuki, Okamura Tomonori, Fujiyoshi Akira, Kadowaki Sayaka, Kadota Aya, Nakamura Yasuyuki, Maegawa Hiroshi, Kashiwagi Atsunori, Masaki Kamal, Sutton-Tyrrell Kim, Kuller Lewis H., Curb J. David, Shin Chol

Journal of Epidemiology and Community Health 67 （ 2 ） 119 - 124 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0143-005X

Background: Cigarette smoking is a risk factor of coronary heart disease. Vascular calcification such as coronary artery calcium (CAC) and aortic calcium (AC) is associated with coronary heart disease. The authors hypothesised that cigarette smoking is associated with coronary artery and aortic calcifications in Japanese and Koreans with high smoking prevalence. Methods: Random samples from populations of 313 Japanese and 302 Korean men aged 40e49 years were examined for calcification of the coronary artery and aorta using electron beam CT. CAC and AC were quantified using the Agatston score. The authors examined the associations of cigarette smoking with CAC and AC after adjusting for conventional risk factors and alcohol consumption. Current and past smokers were combined and categorised into two groups using median pack-years as a cut-off point in each of Japanese and Koreans. The never-smoker group was used as a reference for the multiple logistic regression analyses. Results: The ORs of CAC (score $10) for smokers with higher pack-years were 2.9 in Japanese (p<0.05) and 1.3 in Koreans (non-significant) compared with neversmokers. The ORs of AC (score $100) for smokers with higher pack-years were 10.4 in Japanese (p<0.05) and 3.6 in Koreans (p<0.05). Conclusion Cigarette smoking with higher pack-years is significantly associated with CAC and AC in Japanese men, while cigarette smoking with higher pack-years is significantly associated with AC but not significantly with CAC in Korean men.

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Absolute risk of cardiovascular disease and lipid management targets.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 9 ） 689 - 697 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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The clustering of cardiovascular disease risk factors and their impacts on annual medical expenditure in japan

Murakami Yoshitaka, Okamura Tomonori, Nakamura Koshi, Miura Katsuyuki, Ueshima Hirotsugu

BMJ Open 3 （ 3 ） 2013年

研究論文（学術雑誌）, 共著, 査読有り

Objective: The clustering of cardiovascular disease (CVD) risk factors is a serious threat for increasing medical expenses. The age-specific proportion and distribution of medical expenditure attributable to CVD risk factors, especially focused on the elderly, is thus indispensable for formulating public health policy given the extent of the ageing population in developed countries. Design: Cost analysis using individuals' medical expenses and their corresponding health examination measures. Setting: Shiga prefecture, Japan, from April 2000 to March 2006. Participants: 33 213 participants aged 40 years and over. Main outcome measures: Mean medical expenditure per year. Methods: Gamma regression models were applied to examine how the number of CVD risk factors affects mean medical expenditure. The four CVD risk factors analysed in this study were defined as follows: hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg), hypercholesterolaemia (serum total cholesterol ≥240 mg/dl), high blood glucose (casual blood glucose ≥200 mg/dl) and smoking (current smoker). Sex-specific and age-specific investigations were carried out on the elderly (aged 65 and over) and nonelderly (aged 40-64) populations. Results: The mean medical expenditure (per year) for the no CVD risk-factor group was only 110 000 yen at age 50 (men, 110 708 yen; women, 107 109 yen), but this expenditure was 6-7 times higher for 80-year-olds who have three or four CVD risk factors (men, 603 351 yen; women, 765 673 yen). The total overspend (excess fraction) was larger for the non-elderly (men, 15.4%; women, 11.1%) than that for the elderly (men, 0.1%; women, 5.2%) and largely driven by people with one or two CVD risk factors, except for elderly men. Conclusions: The age-specific proportion and distribution of medical expenditure attributable to CVD risk factors showed that a high-risk approach for the elderly and a population approach for the majority are both necessary to reduce total medical expenditure in Japan.

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Fatty acid intakes and coronary heart disease mortality in Japan

Nakamura Yasuyuki, Kiyohara Yutaka, Okuda Nagako, Okamura Tomonori, Higashiyama Aya, Watanabe Makoto, Kadota Aya, Nagasawa Shin ya, Miyagawa Naoko, Ohkubo Takayoshi, Kita Yoshikuni, Miura Katsuyuki, Okayama Akira, Ueshima Hirotsugu

Current Nutrition and Food Science 9 （ 1 ） 26 - 32 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1573-4013

Associations between dietary fatty acid intakes and risk of coronary heart disease (CHD) are not entirely consistent in prospective studies in the U.S. and Europe. Such studies in Japan are rare. The objective of this study was to examine the association between dietary total, saturated (SFA), and polyunsaturated (PUFA) fatty acids, cholesterol intake and CHD mortality using the dataset of NIPPON DATA90. At the baseline in 1990, we performed blood biochemical measurements and a nutritional survey on participants from 300 randomly selected districts. After exclusion of participants with a history of CHD and/or stroke at the baseline, we followed 7,819 community residents (3,254 men and 4,565 women, age ≥ 30) for 15 years. We estimated individual nutrient intakes among family members by weighed food records in three consecutive representative days. During the follow-up, there were 42 CHD deaths in men and 30 in women. Mean daily SFA and PUFA % calorie intakes were 5.90±1.36%, and 5.59±1.30%, respectively in men, and 6.48±1.53%, and 6.08±1.14% in women. A Cox analysis adjusted for age, vegetable and fruit intakes, and other confounders in women found that SFA intake was significantly associated with CHD mortality (hazards ratio per one quintile increment=1.34, 95% confidence intervals: 1.02-1.74, P=0.03), while no such association was noted in men. No associations were found between other fat intakes and CHD mortality in men or women. In conclusion, SFA intake was positively associated with CHD mortality independent of confounders in women, but not in men. © 2013 Bentham Science Publishers.

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Consumption of dairy products and death from cardiovascular disease in the Japanese General Population

Kondo Imako, Ojima Toshiyuki, Nakamura Mieko, Hayasaka Shinya, Hozawa Atsushi, Saitoh Shigeyuki, Ohnishi Hirofumi, Akasaka Hiroshi, Hayakawa Takehito, Murakami Yoshitaka, Okuda Nagako, Miura Katsuyuki, Okayama Akira, Ueshima Hirotsugu, Okamura Tomonori, Sakata Kiyomi, Nakamura Yosikazu, Matsumura Yasuhiro, Nishi Nobuo, Kasagi Fumiyoshi, Izumi Toru, Tamakoshi Koji, Nakagawa Hideaki, Ohkubo Takayoshi, Kita Yoshikuni, Nakamura Yasuyuki, Yoshita Katsushi, Kadota Aya, Kodama Kazunori, Kiyohara Yutaka

Journal of Epidemiology 23 （ 1 ） 47 - 54 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: Recent Western studies show an inverse association between milk and dairy product intake and cardiovascular disease (CVD). We studied the association between consumption of milk and dairy products and CVD death in Japan. Methods: Men and women aged 30 years or older were followed for 24 years. All had participated in a national nutrition survey in 300 health districts throughout Japan in 1980. The Cox proportional hazards model was used to assess mortality risk according to tertiles of milk and dairy product intake, with the high consumption group as reference. Hazard ratios (HRs) per 100-g/day increase in consumption were also estimated. Results: During the 24-year follow-up period, there were 893 CVD deaths, 174 deaths from coronary heart disease (CHD), and 417 stroke deaths among 9243 participants. For women, the HRs for death from CVD, CHD, and stroke in the low consumption group were 1.27 (95% CI: 0.99-1.58; P for trend = 0.045), 1.67 (0.99-2.80; P = 0.02), and 1.34 (0.94-1.90; P = 0.08), respectively, after adjustment for age, body mass index, smoking status, alcohol drinking habits, history of diabetes, use of antihypertensives, work category, and total energy intake. With each 100-g/day increase in consumption of milk and dairy products, HRs tended to decrease for deaths from CVD (HR, 0.86; 95% CI, 0.74-0.99), CHD (0.73; 0.52-1.03), and stroke (0.81; 0.65-1.01) in women. No significant association was observed in men. Conclusions: Consumption of milk and dairy products was inversely associated with CVD death among women in Japan. © 2012 by the Japan Epidemiological Association.

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Treatment B) drug therapy

Teramoto Tamio, Sasaki Jun, Ishibashi Shun, Birou Sadatoshi, Daida Hiroyuki, Dohi Seitaro, Egusa Genshi, Hiro Takafumi, Hirobe Kazuhiko, Iida Mami, Kihara Shinji, Kinoshita Makoto, Maruyama Chizuko, Ohta Takao, Okamura Tomonori, Yamashita Shizuya, Yokode Masayuki, Yokote Koutaro

Journal of Atherosclerosis and Thrombosis 20 （ 12 ） 850 - 860 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Small dense low-density lipoproteins cholesterol can predict incident cardiovascular disease in an urban Japanese cohort: the Suita study.

Arai H, Kokubo Y, Watanabe M, Sawamura T, Ito Y, Minagawa A, Okamura T, Miyamato Y

Journal of atherosclerosis and thrombosis 20 （ 2 ） 195 - 203 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: Several lines of evidence indicate that small dense low-density lipoproteins (sd-LDL) are more atherogenic than large buoyant LDL; however, few prospective studies have addressed the role of sd-LDL in cardiovascular disease (CVD). We therefore examined the association between sd-LDL cholesterol (sd-LDL-C) and CVD in a Japanese cohort. Methods: An 11.7-year prospective study was performed using a general population aged 30-79 without a history of cardiovascular disease. Direct LDL-C and sd-LDL-C were measured in samples from 2034 participants (968 men and 1066 women). Results: During the follow-up period, there were 116 incident cases of CVD. The multivariableadjusted hazard ratios (HRs) of sd-LDL-C for CVD were calculated using a proportional hazards regression model after adjusting for age, hypertension, diabetes, use of lipid-lowering drugs, body mass index, and current smoking and alcohol drinking, and found that increasing quartiles of sd-LDL-C were associated with increased risk of CVD. We also determined that age and sex-adjusted HRs per 10 mg/dL of sd-LDL-C and HRs for CVD, stroke, cerebral infarction, and coronary artery disease were 1.21 (95% CI: 1.12-1.31), 1.17 (95% CI: 1.05-1.30), 1.15 (95% CI: 1.00-1.33), and 1.29 (95% CI: 1.14-1.45), respectively. Conclusions: It was demonstrated that sd-LDL-C was significantly associated with CVD in a Japanese population, providing evidence of sd-LDL-C as an important biomarker to predict CVD.

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Relation of Serum Leptin and Adiponectin Level to Serum C-Reactive Protein: The INTERLIPID Study.

Nakamura Y, Ueshima H, Okuda N, Miura K, Kita Y, Okamura T, Okayama A, Choudhury SR, Rodriguez B, Masaki KH, Stamler J

International journal of vascular medicine 2013 601364 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2090-2824

Objective. Despite considerable study, the relevance of leptin and adiponectin for atherosclerosis development is still unsettled. We investigated relations of serum leptin and adiponectin to serum C-reactive protein (CRP), using the INTERLIPID dataset on Japanese emigrants living in Hawaii and Japanese in Japan. Design and Methods. Serum leptin, adiponectin, and CRP were measured by standardized methods in men and women of ages 40 to 59 years from two population samples, one Japanese-American in Hawaii (83 men, 89 women) and the other Japanese in central Japan (111 men, 104 women). Participants with CRP >10 mg/L were excluded. Results. Sex-specific multiple linear regression analyses, with log-transformed leptin and adiponectin (log-leptin, log-adipo), site (Hawaii = 1, Japan = 0), SBP, HbA1c, smoking (cigarettes/day), and physical activity index score of the Framingham Offspring Study as covariates, showed that log-leptin directly related and log-adipo inversely related to log-CRP for both sexes (P s < 0.05 to <0.01). Addition to the model of BMI and interaction terms (BMI × log-leptin, BMI × log-adipo, SITE × log-leptin, SITE × log-adipo) resulted in disappearance of statistical significance except for direct relation of log-leptin to log-CRP in men (P = 0.006). Conclusions. Leptin directly related to CRP independent of BMI and other confounding factors in men but not in women. © 2013 Yasuyuki Nakamura et al.

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Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -2012 version.

Journal of atherosclerosis and thrombosis 20 （ 6 ） 517 - 523 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Effect of age on the association between waist-to-height ratio and incidence of cardiovascular disease: the Suita study.

Tatsumi Y, Watanabe M, Kokubo Y, Nishimura K, Higashiyama A, Okamura T, Okayama A, Miyamoto Y

Journal of epidemiology 23 （ 5 ） 351 - 359 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: Waist-to-height ratio (WHtR) has been shown to be a useful screening tool for metabolic syndrome and cardiovascular disease (CVD). We investigated the association of WHtR with CVD incidence by age group. Methods: We conducted a 13.0-year cohort study of Japanese adults (2600 men and 2888 women) with no history of CVD. WHtR was calculated as waist circumference (cm) (WC) divided by height (cm). We stratified participants by sex and age group (30-49, 50-69, ≥70 years). Using the Cox proportional hazards model, we calculated hazard ratios (HRs) and 95% CIs for CVD in relation to WHtR quartile for participants aged 50 to 69 years and 70 years or older. Results: Men aged 50 to 69 years in the highest quartile had significantly increased risks of CVD and coronary heart disease as compared with the lowest quartile; the HRs (95% CI) were 1.82 (1.13-2.92) and 2.42 (1.15-5.12), respectively. Women aged 50 to 69 years in the highest quartile had a significantly increased risk of stroke (HR, 2.43; 95% CI, 1.01-5.85). No significant results were observed in men or women aged 70 years or older. The likelihood ratio test showed that the predictive value of WHtR was greater than that of WC among men aged 50 to 69 years. Conclusions: The association between WHtR and CVD risk differed among age groups. WHtR was useful in identifying middle-aged Japanese at higher risk of CVD and was a better predictor than WC of CVD, especially in men. © 2013 Yukako Tatsumi et al.

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Association between J-point elevation and death from coronary artery disease--15-year follow up of the NIPPON DATA90.

Hisamatsu T, Ohkubo T, Miura K, Yamamoto T, Fujiyoshi A, Miyagawa N, Kadota A, Takashima N, Nagasawa SY, Kita Y, Murakami Y, Okayama A, Horie M, Okamura T, Ueshima H, NIPPON DATA90 Research Group.

Circulation journal : official journal of the Japanese Circulation Society 77 （ 5 ） 1260 - 1266 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-9843

Background: An early repolarization pattern, characterized by an elevation of the QRS-ST junction (J-point) on 12-lead electrocardiography (ECG) is associated with cardiac and sudden death. However, little is known about the prognostic significance of J-point elevation for various disease-specific cardiovascular outcomes, including coronary artery disease (CAD). Methods and Results: To investigate the association between the presence of J-point elevation ≥0.1 mV and various disease-specific cardiovascular outcomes, we conducted a 15-year prospective study in a representative general Japanese population of 7,630 individuals (41% men, mean age 52.4 years) who participated in the National Survey of Circulatory Disorders. Cox models were used to estimate the hazard ratios (HRs) adjusted for possible confounding factors. J-point elevation was present in 264 individuals (3.5%) and was associated with an increased risk of cardiac death (adjusted HR, 2.54; 95% confidence interval [CI] 1.40-4.58; P=0.002) and death from CAD (adjusted HR, 4.66; 95% CI 2.30-9.46; P<0.001). In a subgroup analysis by age, the association between J-point elevation and cardiovascular outcomes was more remarkable in middle-aged (<60 years) than in older individuals (≥60 years) (all P for interaction <0.05). Conclusions: J-point elevation on standard 12-lead ECG was an independent predictor of cardiac death and death from CAD in a representative sample of the general Japanese population, particularly among the middle-aged.

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Treatment A) lifestyle modification

Journal of Atherosclerosis and Thrombosis 20 （ 12 ） 835 - 849 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Other high-risk conditions.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 11 ） 785 - 789 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Comprehensive risk management for the prevention of cardiovascular disease: executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan -- 2012.

Journal of atherosclerosis and thrombosis 20 （ 7 ） 603 - 615 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Carotid intima-media thickness and plaque in apparently healthy Japanese individuals with an estimated 10-year absolute risk of CAD death according to the Japan Atherosclerosis Society (JAS) guidelines 2012: the Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA).

Kadota A, Miura K, Okamura T, Fujiyoshi A, Ohkubo T, Kadowaki T, Takashima N, Hisamatsu T, Nakamura Y, Kasagi F, Maegawa H, Kashiwagi A, Ueshima H, SESSA Research Group., NIPPON DATA80/90 Research Group.

Journal of atherosclerosis and thrombosis 20 （ 10 ） 755 - 766 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: To examine whether subclinical atherosclerosis of the carotid arteries is concordant with the categories in the 2012 atherosclerosis prevention guidelines proposed by the Japan Atherosclerosis Society (JAS guidelines 2012), which adopted the estimated 10-year absolute risk of coronary artery disease (CAD) death in the NIPPON DATA80 Risk Assessment Chart. Methods: Between 2006 and 2008, 868 Japanese men 40 to 74 years of age without a history of cardiovascular disease were randomly selected from Kusatsu City, Japan. The intima media thickness (IMT) and plaque number from the common to internal carotid arteries were investigated using ultrasonography. The absolute risk of CAD death was estimated based on the individual risk factor data, and the mean IMT and plaque number in Categories I, II and III of the guidelines were examined. Results: The estimated 10-year absolute risk of CAD was directly related to the IMT (mean IMT (mean±SD) (mm) for a 10-year absolute risk of ≥2.0% and ≥5.0%: 0.88±0.18 and 0.95±0.19, respectively) and the plaque number. These results are compatible with the categories described by the guidelines (mean IMT (mean±SD) (mm) for Categories I, II, and III: 0.70±0.11, 0.81±0.16 and 0.88±0.18, respectively; mean plaque number: 0.9, 2.1 and 3, respectively). These findings were similar for Category III participants with or without DM and CKD. Conclusions: Subclinical atherosclerosis of the carotid arteries is concordant with the 10-year absolute risk of CAD and the categories in the JAS guidelines 2012.

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Cardiovascular disease risk factors other than dyslipidemia. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan - 2012 version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 10 ） 733 - 742 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Diagnostic criteria for dyslipidemia.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 8 ） 655 - 660 2013年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

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Comparison of predictability of future cardiovascular events between chronic kidney disease (CKD) stage based on CKD epidemiology collaboration equation and that based on modification of diet in renal disease equation in the Japanese general population--Iwate KENCO Study.

Ohsawa M, Tanno K, Itai K, Turin TC, Okamura T, Ogawa A, Ogasawara K, Fujioka T, Onoda T, Yoshida Y, Omama S, Ishibashi Y, Nakamura M, Makita S, Tanaka F, Kuribayashi T, Koyama T, Sakata K, Okayama A

Circulation journal : official journal of the Japanese Circulation Society 77 （ 5 ） 1315 - 25 2013年

研究論文（学術雑誌）, ISSN 1346-9843

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Treatment B) drug therapy: executive summary of the Japan Atherosclerosis Society(JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan--2012 version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 12 ） 850 - 60 2013年

研究論文（学術雑誌）, ISSN 1340-3478

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Treatment A) lifestyle modification: executive summary of the Japan Atherosclerosis Society(JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan--2012 version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 12 ） 835 - 49 2013年

研究論文（学術雑誌）, ISSN 1340-3478

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Ohsawa M, Tanno K, Itai K, Turin TC, Okamura T, Ogawa A, Ogasawara K, Fujioka T, Onoda T, Yoshida Y, Omama S, Ishibashi Y, Nakamura M, Makita S, Tanaka F, Kuribayashi T, Koyama T, Sakata K, Okayama A

Circulation journal : official journal of the Japanese Circulation Society 77 （ 5 ） 1315 - 25 2013年

研究論文（学術雑誌）, ISSN 1346-9843

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Treatment B) drug therapy: executive summary of the Japan Atherosclerosis Society(JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan--2012 version.

Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 12 ） 850 - 60 2013年

研究論文（学術雑誌）, ISSN 1340-3478

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Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K

Journal of atherosclerosis and thrombosis 20 （ 12 ） 835 - 49 2013年

研究論文（学術雑誌）, ISSN 1340-3478

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Long-term risk of BP values above normal for cardiovascular mortality: a 24-year observation of Japanese aged 30 to 92 years.

Takashima N, Ohkubo T, Miura K, Okamura T, Murakami Y, Fujiyoshi A, Nagasawa SY, Kadota A, Kita Y, Miyagawa N, Hisamatsu T, Hayakawa T, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Journal of hypertension 30 （ 12 ） 2299 - 2306 2012年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0263-6352

Lippincott Williams & Wilkins.Objective: In Western populations, blood pressure (BP) measured at baseline has been reported to predict long-term (over 20 years) risk of mortality from cardiovascular diseases (CVDs). However, corresponding evidence is scarce in Asia where stroke is dominant. We investigated the association between baseline BP and 24-year mortality risk due to CVD, in a representative Japanese general population. Methods: We followed up a nationwide sample of 8592 Japanese, aged 30 years or above without a history of CVD and antihypertensive medication at baseline, for 24 years. Hazard ratios for CVD mortality in BP categories defined according to JCN7 criteria were estimated using Cox model adjusted for potential confounding factors with normal BP treated as the reference category. Results: We observed 689 CVD deaths. Hazard ratios for CVD mortality were progressively and significantly increased from the category of prehypertension. Population-attributable fraction (PAF) demonstrated that 43 and 48% of CVD and stroke deaths were explained by non-normal BP at baseline. Hazard ratios and PAF were remarkably higher in younger participants (aged 30-59 years) than those in the elderly (aged 60 years or above). Particularly, in younger men, 81% of CVD deaths were explained by non-normal BP. In sensitivity analysis, participants with antihypertensive medication showed the highest hazard ratio for CVD morality compared with the other categories. Conclusions: BP levels above normal at baseline retained significant relative and absolute risks of CVD and stroke mortality during 24 years. Long-lasting burden of non-normal BP particularly in younger individuals suggests the importance of primary prevention of high BP from younger generation. © 2012 Wolters Kluwer Health

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A nutrient-wide association study on blood pressure.

Tzoulaki I, Patel CJ, Okamura T, Chan Q, Brown IJ, Miura K, Ueshima H, Zhao L, Van Horn L, Daviglus ML, Stamler J, Butte AJ, Ioannidis JP, Elliott P

Circulation 126 （ 21 ） 2456 - 2464 2012年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-7322

BACKGROUND: A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. METHODS AND RESULTS: Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005-2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1-SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. CONCLUSIONS: We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations. © 2012 American Heart Association, Inc.

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A multicenter study on the precision and accuracy of homogeneous assays for LDL-cholesterol: comparison with a beta-quantification method using fresh serum obtained from non-diseased and diseased subjects.

Miida T, Nishimura K, Okamura T, Hirayama S, Ohmura H, Yoshida H, Miyashita Y, Ai M, Tanaka A, Sumino H, Murakami M, Inoue I, Kayamori Y, Nakamura M, Nobori T, Miyazawa Y, Teramoto T, Yokoyama S

Atherosclerosis 225 （ 1 ） 208 - 215 2012年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Background: Homogeneous assays for low-density lipoprotein-cholesterol (LDL-C) have good precision and are pretreatment-free procedures. However, their accuracies have been questioned, especially in diseased subjects. In this study, we aimed to verify whether LDL-C levels determined by homogeneous assays [LDL-C (H)] agree with those determined by a beta-quantification method [LDL-C (BQ)] in fresh clinical samples. Methods: We determined LDL-C levels in 49 non-diseased and 124 diseased subjects whose triglyceride (TG) levels were less than 11.29 mmol/L (1000 mg/dL) using 12 homogeneous assays and a BQ method simultaneously. Results: In total, 30.6% of non-diseased subjects and 46.0% of diseased subjects were in the postprandial state. The maximum inter- and intra-assay CVs were 1.8% and 1.5%, and 8 reagents had a CV of 1.0% or less. The mean bias ranged from -0.5% to 1.8% for non-diseased subjects and from -0.7% to 1.6% for diseased subjects. For non-diseased subjects, all but one reagent achieved the National Cholesterol Education Program (NCEP) total error requirement in more than 90% of samples. However, for diseased subjects, the number of reagents that met this requirement was low. With some reagents, LDL-C (H) was higher than LDL-C (BQ), especially in subjects with hypertriglyceridemia. While for other reagents, the difference between the two methods was not associated with hypertriglyceridemia except for type I (n = 2) and type III hyperlipidemia (n = 1). Postprandial sampling was not the main factor for discordant results. Conclusions: LDL-C (H) agrees with LDL-C (BQ) in non-diseased subjects, but exhibits positive bias for subjects with hypertriglyceridemia in diseased subjects for some reagents. © 2012 Elsevier Ireland Ltd.

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Relation between serum total cholesterol level and cardiovascular disease stratified by sex and age group: a pooled analysis of 65 594 individuals from 10 cohort studies in Japan.

Nagasawa SY, Okamura T, Iso H, Tamakoshi A, Yamada M, Watanabe M, Murakami Y, Miura K, Ueshima H, Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN) Research Group.

Journal of the American Heart Association 1 （ 5 ） e001974 2012年10月

研究論文（学術雑誌）, 共著, 査読有り

The relation between serum total cholesterol (TC) and cardiovascular disease in women and in the elderly is unclear, especially in Asian populations. We examined this relation in the largest-scale pooled analysis of the Japanese population, the Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN) study. A total of 65 594 participants who were 40 to 89 years of age and did not have a past history of cardiovascular disease were examined. Cox proportional-hazards models were used to estimate hazard ratios for death from total stroke, cerebral infarction, intracranial cerebral hemorrhage, or coronary heart disease. The mean follow-up period was 10.1 years, with the number of deaths from total stroke, cerebral infarction, cerebral hemorrhage, and coronary heart disease being 875, 457, 212, and 374, respectively. The participants were divided into 2 age groups: middle-aged (40 to 69 years; mean age 55 years) and elderly (70 to 89 years; mean age 75 years). In men, the multivariate-adjusted hazard ratios for coronary heart disease in the highest TC category (≥6.21 mmol/L) compared with the lowest category (<4.14 mmol/L) were 2.52 (95% confidence interval: 1.15-5.07) in middle-aged participants and 2.77 (1.09-7.03) in elderly participants. In women, the hazard ratios of the highest TC category (≥6.72 mmol/L) compared with the lowest category (<4.66 mmol/L) were 3.20 (1.44-7.09) in middle-aged participants and 1.02 (0.42-2.49) in elderly participants. TC levels were not associated with cerebral infarction in any age or sex group and were associated negatively with total stroke and cerebral hemorrhage. High serum TC levels are associated with coronary heart disease in middle-aged Japanese men and women, but evidence in elderly Japanese individuals is still limited.

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Blood cholesterol level and risk of stroke in community-based or worksite cohort studies

Tanaka Taichiro, Okamura Tomonori

Keio Journal of Medicine 61 （ 3 ） 79 - 88 2012年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0022-9717

Evidence of the causal relationship between hypercholesterolemia and coronary artery disease (CAD) has been established worldwide. However, little attention has been paid to the relationship between hypercholesterolemia and stroke, despite stroke being the most common cardiovascular disease in Japan. We therefore reviewed cohort studies that investigated this relationship in the Japanese population over the past 20 years, and compared their findings with clinical trials and cohort studies in Western countries. Fourteen cohort studies were carried out in Japan during this period. The number of subjects in the studies ranged from 1621 to 91,219 and the mean follow-up period ranged from 7.6 to 32 years. The majority of studies showed no association between hypercholesterolemia and total stroke. However, one report showed a positive association between low-density lipoprotein cholesterol and atherothrombotic cerebral infarction. The relationship between hypercholesterolemia and cerebral infarction may be modified by the proportion of atherothrombotic infarctions in the population surveyed. Randomized controlled trials on statins have shown a substantial reduction in cerebral infarction, and so the discrepancy between cohort studies and clinical trials requires further study. However, some studies have reported that subjects with low blood cholesterol are more susceptible to intracerebral hemorrhage. Two hypotheses have been proposed to explain this association between low cholesterol and intracerebral hemorrhage. First, low blood cholesterol may induce angionecrosis, possibly in combination with hypertension, and second, low blood cholesterol may reflect a poor nutritional status. Either way, further continuous research in various fields of medical science is required to clarify the overall effect of blood cholesterol on stroke in humans. © 2012 by The Keio Journal of Medicine.

Relationship between health-related quality of life and clustering of metabolic syndrome diagnostic components.

Katano S, Nakamura Y, Nakamura A, Suzukamo Y, Murakami Y, Tanaka T, Okayama A, Miura K, Okamura T, Fukuhara S, Ueshima H, HIPOP-OHP Research Group.

Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation 21 （ 7 ） 1165 - 1170 2012年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0962-9343

Purpose To examine the association of the number of metabolic syndrome diagnostic components (MetS-DC) with health-related quality of life (HR-QOL). Methods We examined the baseline data from 4,480 healthy workers in Japan (3,668 men and 812 women) aged 19-69 years. We assessed HR-QOL based on scores for five scales of the SF-36. We defined four components for MetS in this study as follows: (1) high blood pressure (BP); (2) dyslipidemia; (3) impaired glucose tolerance; and (4) overweight: a body mass index ≥25 kg/m ². Logistic regression analysis adjusted for lifestyle factors was used to examine the association of the number of MetS-DC with the HR-QOL sub-scales. Results Those who had 0-4 MetS-DC accounted for 2,287, 1,135, 722, 282, and 54 participants. The number of MetS-DC inversely contributed significantly to General Health (norm-based scoring >50) (odd ratios [OR] 0.59-0.82, P≪0.05) and positively associated with Mental Health (OR 1.37, P<0.05). Conclusion When adjusted for lifestyle factors, the number of MetS-DC was inversely associated with General Health and positively with Mental Health in men and women. © Springer Science+Business Media B.V. 2011.

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Blood pressure categories and long-term risk of cardiovascular disease according to age group in Japanese men and women.

Fujiyoshi A, Ohkubo T, Miura K, Murakami Y, Nagasawa SY, Okamura T, Ueshima H, Observational Cohorts in Japan (EPOCH-JAPAN) Research Group.

Hypertension research : official journal of the Japanese Society of Hypertension 35 （ 9 ） 947 - 953 2012年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0916-9636

Blood pressure (BP) categories defined by systolic BP (SBP) and diastolic BP (DBP) are commonly used. However, the BP category-specific risk of cardiovascular disease (CVD) has not been thoroughly investigated in different age groups. The aim of this study was to assess long-term CVD risk and its impact according to BP categories and age group. Pooling individual data from 10 cohorts, we studied 67 309 Japanese individuals (40-89 years old) who were free of CVD at baseline: we categorized them as belonging to three age groups: middle-aged (40-64 years), elderly (65-74 years) and very elderly (75-89 years). BP was classified according to the 2009 Japanese Society of Hypertension Guidelines. Cox models were used to estimate adjusted hazard ratios for CVD deaths. We observed 1944 CVD deaths over a mean follow-up of 10.2 years. In all age groups, the overall relationship between BP category and CVD risk was positive, with a greater strength observed for younger age groups. We observed a trend of increased risk from SBP/DBP130/85 mm Hg in the very elderly, and a significant increase from SBP/DBP120/80 mm Hg in the other age groups. The population attributable fractions (PAFs) of CVD death in reference to the SBP/DBP120/80 mm Hg category ranged from 23.4% in the very elderly to 60.3% in the middle-aged. We found an overall graded increase in CVD risk with higher BP category in the very elderly. The PAFs suggest that keeping BP levels low is an important strategy for primary CVD prevention, even in an elderly population. © 2012 The Japanese Society of Hypertension All rights reserved.

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Hypertension and life expectancy among Japanese: NIPPON DATA80.

Turin TC, Murakami Y, Miura K, Rumana N, Kita Y, Hayakawa T, Okamura T, Okayama A, Ueshima H, NIPPON DATA80/90 Research Group.

Hypertension research : official journal of the Japanese Society of Hypertension 35 （ 9 ） 954 - 958 2012年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0916-9636

Life expectancy (LE) is a measure that describes the health status of a population. The few published studies that have examined the impact of hypertension on LE were predominantly performed in Western populations. The effect of hypertension on LE has not been reported in an Asian population. Thus, we examined the impact of hypertension on LE in the Japanese population, which has the highest LE worldwide. The abridged life table method was applied to calculate the LEs of both normotensive and hypertensive men and women aged 40-85 years. Hypertensive participants were categorized as having either stage 1 or stage 2 hypertension. Age-specific mortality rates across different groups were estimated using the person-year method based on the follow-up data from a representative Japanese population in a national survey (NIPPON DATA80). The proportion of hypertensive patients in the baseline survey was 50.5% for men and 41.4% for women. The LE of 40-year-old men and women was 41.7 years and 48.7 years, respectively, in normotensive participants and 39.5 and 45.8 years, respectively, in hypertensive participants. The LE difference between normotensive and hypertensive participants was 2.2 years for men and 2.9 years for women. LE decreased with increasing stages of hypertension. Similar patterns of LE, with respect to blood pressure (BP) status, were observed in all index ages and for both genders. At the population level, hypertension leads to decreased LE and affects both genders similarly. Our findings highlight the importance of preventing high BP and the consequences of hypertension in Japanese population. © 2012 The Japanese Society of Hypertension All rights reserved.

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Diabetes and life expectancy among Japanese - NIPPON DATA80.

Turin TC, Murakami Y, Miura K, Rumana N, Kadota A, Ohkubo T, Okamura T, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Diabetes research and clinical practice 96 （ 2 ） e18 - 22 2012年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0168-8227

Life expectancy (LE) among the Japanese population with or without diabetes mellitus was estimated. LE in 40-year old men and women was 41.1 and 47.5. years in those without diabetes and 32.3 and 40.9. years in those with diabetes. The LE of 40-year old men and women with diabetes was 8.8 and 6.6. years shorter than in those without diabetes. Diabetes mellitus leads to a decrease in LE. The presence of impaired glucose tolerance also affected LE inversely. © 2012 Elsevier Ireland Ltd.

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Influence of smoking combined with another risk factor on the risk of mortality from coronary heart disease and stroke: pooled analysis of 10 Japanese cohort studies.

Nakamura K, Nakagawa H, Sakurai M, Murakami Y, Irie F, Fujiyoshi A, Okamura T, Miura K, Ueshima H, EPOCH-JAPAN Research Group.

Cerebrovascular diseases (Basel, Switzerland) 33 （ 5 ） 480 - 491 2012年05月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1015-9770

Background: In spite of the importance of a multifactorial approach to preventing cardiovascular disease in smokers, most information on the combined adverse effects of smoking and hypertension or high serum cholesterol on cardiovascular disease has been derived from Western populations, and coronary heart disease was often used as the only endpoint. Therefore, the present large-scale pooled analysis attempted to provide reliable information on the adverse effects of the coexistence of smoking and hypertension or high serum cholesterol on the risk of mortality from coronary heart disease and stroke in both, individuals and the entire population in Japan. Methods: A total of 27,385 male and 39,207 female participants aged 40-89 years were enrolled from 10 well-qualified Japanese cohort studies with a mean follow-up of 10.1 years. Hazard ratios and their corresponding 95% confidence intervals in smokers who had hypertension or high serum cholesterol were estimated for men and women separately using a Cox proportional hazards regression model that included age, body mass index, cohort and either serum total cholesterol or systolic blood pressure as covariates. Fractions of deaths attributable to the coexistence of these risk factors were also calculated. Results: The multivariate-adjusted hazard ratios in male and female current smokers with hypertension, compared with those with neither factor were 2.57 (95% confidence intervals, 1.51-4.38) and 6.14 (3.49-10.79) for coronary heart disease, and 3.28 (1.89-5.71) and 1.61 (0.81-3.18) for cerebral infarction, respectively. The fractions of deaths attributable to the coexistence of current smoking and hypertension in men and women were 24.6 and 9.6% for coronary heart disease and 28.1 and 2.0% for cerebral infarction, respectively. Smokers with high serum cholesterol were broadly comparable to hypertensive smokers only with respect to coronary mortality risk; the hazard ratios, compared with those with neither factor were 4.19 (2.33-7.53) for men and 3.90 (1.57-9.67) for women. The fraction of coronary deaths attributable to the coexistence of current smoking and high serum cholesterol was 6.3% in men and 2.2% in women. There was no interaction between smoking habit and blood pressure or serum total cholesterol for these two subtypes in both men and women. Conclusions: Particular attention should be given to smokers who have concomitant hypertension or high serum cholesterol for preventing deaths due to cardiovascular disease. From a public health perspective in Japan, priority should be given to hypertensive smokers, since this group makes a large contribution to the burden of both coronary and cerebral infarction deaths. Copyright © 2012 S. Karger AG, Basel.

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Prognostic values of clockwise and counterclockwise rotation for cardiovascular mortality in Japanese subjects: a 24-year follow-up of the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980-2004 (NIPPON DATA80).

Nakamura Y, Okamura T, Higashiyama A, Watanabe M, Kadota A, Ohkubo T, Miura K, Kasagi F, Kodama K, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Circulation 125 （ 10 ） 1226 - 1233 2012年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-7322

Background: Although clockwise rotation and counterclockwise rotation are distinct findings of the ECG, their prognostic significance is rarely studied. Methods and Results: We studied prognostic values of clockwise and counterclockwise rotation on total, cardiovascular disease (CVD), and subtype mortality using the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980-2004 (NIPPON DATA80) database with a 24-year follow-up. At baseline in 1980, data were collected on study participants aged ≥30 years from randomly selected areas in Japan. We followed 9067 participants (44% men; mean age, 51 years). During the 24-year follow-up, mortality was as follows: 2581 total, 887 CVD, 179 coronary heart disease, 173 heart failure, and 411 stroke. The multivariate-adjusted hazard ratio (HR) with the use of the Cox model including biochemical and other ECG variables revealed that clockwise rotation was significantly positively associated with heart failure in men and women combined (HR=1.79; 95% confidence interval [CI], 1.13-2.83; P=0.013), CVD in men and in men and women combined (HR=1.49; 95% CI, 1.12-1.98; P=0.007 in men; HR=1.28; 95% CI, 1.02-1.59; P=0.030 in combined), and total mortality in men and in men and women combined (HR=1.19; 95% CI, 1.00-1.49; P=0.0496inmen; HR=1.15; 95% CI, 1.00-1.32; P=0.045 in combined). Counterclockwise rotation was significantly inversely associated stroke in men and women combined (HR=0.77; 95% CI, 0.62-0.96; P=0.017), CVD in men and in men and women combined (HR=0.74; 95% CI, 0.59-0.94; P=0.011 in men; HR=0.81; 95% CI, 0.70-0.94; P=0.006 in combined), and total mortality in women (HR=0.87; 95% CI, 0.77-0.98; P=0.023). Conclusions: We found a significant positive association of clockwise rotation and a significant inverse association of counterclockwise rotation with CVD mortality in men and in men and women combined, independent of confounding factors including other ECG changes. © 2012 American Heart Association, Inc.

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Effects of public education by television on knowledge of early stroke symptoms among a Japanese population aged 40 to 74 years: a controlled study.

Miyamatsu N, Kimura K, Okamura T, Iguchi Y, Nakayama H, Toyota A, Watanabe M, Morimoto A, Morinaga M, Yamaguchi T

Stroke 43 （ 2 ） 545 - 549 2012年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0039-2499

Background and Purpose-: An educational campaign by mass media has been associated with great increases in the knowledge about early symptoms of stroke. However, few studies were conducted with a controlled community intervention study. Methods-: To clarify the effects of a 1-year television campaign for the whole population on improvement of knowledge about stroke symptoms in 2 cities, a campaign area and a control area in Japan were selected. Before and after the campaign, 1960 randomly selected residents aged 40 to 74 years answered a telephone survey regarding knowledge of early stroke symptoms. We calculated the percentage and 95% CIs of participants who correctly chose all 5 early symptoms of stroke in each area and in each year. Results-: Before the campaign, 53% of participants (95% CI, 50%-55%) in the campaign area and 46% (95% CI, 44%-49%) in the control area correctly chose 5 early symptoms. After the 1-year television campaign, knowledge was significantly improved only in the campaign area (campaign area, 63%; 95% CI, 60%-66%; control area, 51%; 95% CI, 48%-54%). After sex stratification, only women showed improved knowledge of early symptoms. The audience rate for the campaign television programs was found to be higher in women than in men. Conclusions-: A 1-year stroke educational television campaign effectively improved knowledge about early stroke symptoms among Japanese women aged 40 to 74 years. No impact was found among men in this age group. Future studies should examine the impact of this approach on stroke knowledge among younger individuals and whether there are any behavioral changes that contribute to earlier presentation for treatment. © 2011 American Heart Association, Inc.

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CDH13 gene coding T-cadherin influences variations in plasma adiponectin levels in the Japanese population.

Morisaki H, Yamanaka I, Iwai N, Miyamoto Y, Kokubo Y, Okamura T, Okayama A, Morisaki T

Human mutation 33 （ 2 ） 402 - 410 2012年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1059-7794

Adiponectin is most abundantly expressed in adipose tissue and well known to play an important role in metabolic regulation. Several studies have attempted to identify the genetic determinants of metabolic syndrome (MetS), though no study has revealed a cis- or transsingle nucleotide polymorphism (SNP) that affects plasma adiponectin levels, except the adiponectin structure gene and genes encoding adiponectin-regulatory proteins. We performed a genome-wide association study in regards to plasma adiponectin concentrations in 3,310 Japanese subjects. We identified the strongest statistically associated SNP (rs4783244) with adiponectin levels (P = 3.8 × 10 ^-19) in the first intron of CDH13 (T-cadherin) gene in a 30-kb haplotype block covering the promoter region to first intron. In addition, rs12051272 SNP genotypes in linkage disequilibrium with rs4783244 were found to be more significantly associated with adiponectin levels (P = 9.5×10 ^-20) and specifically with the levels of high-molecular weight (HMW) adiponectin, a subtype form associated with parameters related to glucose metabolism. Our results did show more significant association with adiponectin levels than rs12444338 (in CDH13) SNP genotypes reported recently. We suggest that the phenotype-affecting haplotype tagged by rs12051272 SNP would affect the plasma adiponectin levels and that we have to take the CDH13 genotype into account before considering the functional relevance of the adiponectin level. © 2011 Wiley Periodicals, Inc.

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[Effect of cardiovascular risk factors on individual and population medical expenditures: a 10-year cohort study of 4,535 National Health Insurance beneficiaries in Shiga].

Okamura T, Nakamura K, Hayakawa T, Kanda H, Miura K, Okayama A, Ueshima H

Nihon eiseigaku zasshi. Japanese journal of hygiene 67 （ 1 ） 38 - 43 2012年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-5082

A 10-year follow-up cohort study of 4,535 National Health Insurance beneficiaries aged 40 to 69 years in Shiga was performed as part of a research project conducted by the Health Promotion Research Committee of the Shiga National Health Insurance Organizations in 2002. The relationship between cardiovascular risk factors and medical expenditures during the 10-year study period has been examined in this cohort. For example, there was a positively graded correlation between blood pressure and individual total medical expenditures per month. The odds ratio for cumulative hospitalization and hazard ratio for all-cause mortality in severe hypertensives were also higher than those in normotensives. However, from the viewpoint of the entire population, the excess medical expenditures attributable to hypertension within the total medical expenditures were higher for mild-to-moderate hypertensives than for severe hypertensives. On the other hand, although individual medical expenditures per month were 1.7-fold higher for participants with 2 or 3 risk factors and obesity, which was broadly equivalent to metabolic syndrome, than for those without these factors, the excess medical expenditures determined by risk clustering within the total medical expenditures were higher in normal-weight people than in obese people because of the higher prevalence of normal weight. These findings suggest that high-risk individuals are a good target of a high-risk approach, such as intensive health guidance, from the viewpoint of medical expenditures. However, another approach for the majority with a low-to-moderate cardiovascular risk should be considered, because they account for a greater proportion of the excess medical expenditures. Another way to solve this problem may be a population approach with an effective method of providing information to citizens.

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Relation of dietary and lifestyle traits to difference in serum leptin of Japanese in Japan and Hawaii

Nakamura Y., Ueshima H., Okuda N., Miura K., Kita Y., Okamura T., Turin T. C., Okayama A., Rodriguez B., Curb J. D., Stamler J.

Nutrition, Metabolism and Cardiovascular Diseases 22 （ 1 ） 14 - 22 2012年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0939-4753

Background and Aims: Previously, we found significantly higher serum leptin in Japanese-Americans in Hawaii than Japanese in Japan. We investigated whether differences in dietary and other lifestyle factors explain higher serum leptin concentrations in Japanese living a Western lifestyle in Hawaii compared with Japanese in Japan. Methods and Results: Serum leptin and nutrient intakes were examined by standardized methods in men and women ages 40-59 years from two population samples, one Japanese-American in Hawaii (88 men, 94 women), the other Japanese in central Japan (123 men, 111 women). Multiple linear regression models were used to assess role of dietary and other lifestyle traits in accounting for serum leptin difference between Hawaii and Japan. Mean leptin was significantly higher in Hawaii than Japan (7.2 ± 6.8 vs 3.7 ± 2.3 ng/ml in men, P < 0.0001; 12.8 ± 6.6 vs 8.5 ± 5.0 in women <0.0001). In men, higher BMI in Hawaii explained over 90% of the difference in serum leptin; in women, only 47%. In multiple linear regression analyses in women, further adjustment for physical activity and dietary factors - alcohol, dietary fiber, iron - produced a further reduction in the coefficient for the difference, total reduction 70.7%; P-value for the Hawaii-Japan difference became 0.126. Conclusion: The significantly higher mean leptin concentration in Hawaii than Japan may be attributable largely to differences in BMI. Differences in nutrient intake in the two samples were associated with only modest relationship to the leptin difference. © 2010 Elsevier B.V.

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Multicenter study to determine the diagnosis criteria of heterozygous familial hypercholesterolemia in Japan.

Harada-Shiba M, Arai H, Okamura T, Yokote K, Oikawa S, Nohara A, Okada T, Ohta T, Bujo H, Watanabe M, Wakatsuki A, Yamashita S

Journal of atherosclerosis and thrombosis 19 （ 11 ） 1019 - 1026 2012年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: Heterozygous patients of familial hypercholesterolemia (FH) are known to have a high risk of coronary artery disease (CAD). Early diagnosis and prompt treatment are necessary to prevent their CAD. In this study we tried to amend the Japanese diagnostic criteria of FH for general practitioners by examining each component of the current criteria. Methods: A multicenter study was performed, which included 1356 dyslipidemic patients at 6 centers. Pretreatment demographic information including LDL-cholesterol (LDL-C), Achilles tendon thickness (ATT), family history of FH and premature CAD and the result of genetic analysis were analyzed. Results: Of 1356 patients, 419 were diagnosed with FH by criteria in 1988, which were used as a golden standard. We tried to define FH according to 3 conventional major items, i.e., 1) LDL-C, 2) ATT and/or cutaneous nodular xanthomas (CX), 3) family history of FH and/or family history of premature CAD. We then determined the cutoff of LDL-C using the new criteria. When we used 180 mg/dL as the cutoff of LDL-C, 94.3% of FH patients and 0.85% of non-FH satisfied 2 or more criteria. When we used 190 mg/dL, 92.1% of FH and 0.85% of non-FH satisfied 2 or more criteria; therefore, we chose 180 mg/dL for the cutoff of LDL-C in the new criteria and proposed that the diagnosis of definite FH can be made if 2 or more criteria are satisfied. Conclusions: We examined each component for the diagnosis of heterozygous FH in a multicenter study in Japan.

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Does high-sensitivity C-reactive protein or low-density lipoprotein cholesterol show a stronger relationship with the cardio-ankle vascular index in healthy community dwellers?: the KOBE study.

Higashiyama A, Wakabayashi I, Kubota Y, Adachi Y, Hayashibe A, Nishimura K, Sugiyama D, Kadota A, Imano H, Miyamatsu N, Miyamoto Y, Okamura T

Journal of atherosclerosis and thrombosis 19 （ 11 ） 1027 - 1034 2012年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: High-sensitivity C-reactive protein (hs-CRP) identifies individuals at risk for cardiovascular disease (CVD) without an increased level of low-density lipoprotein cholesterol (LDL-C). The present study was performed to compare hs-CRP and LDL-C in association with the cardio-ankle vascular index (CAVI) in Japanese community dwellers considered to be at low risk for atherosclerosis from their level of traditional CVD risk factors. Methods: A community-based study involving 386 healthy Japanese (261 men and 125 women) without a history of CVD and medications for hypertension, diabetes, and dyslipidemia was performed. Multiple adjustments were performed with linear regression models to estimate the association between CAVI and hs-CRP or LDL-C levels. The participants were divided into four groups on the basis of whether they were above or below the median hs-CRP and LDL-C values, and CAVI was compared among the four groups by analysis of covariance after adjusting for confounders. Results: In multiple linear regression models, hs-CRP showed a significant positive association with CAVI; however, no clear association was observed between CAVI and LDL-C. These results were similar in the analyses among the participants with LDL-C <140 mg/dL or hs-CRP <1.0 mg/L. CAVI was higher in the groups with high hs-CRP than in those with low hs-CRP, irrespective of LDL-C; however, CAVI was highest in the group with high LDL-C and high hs-CRP. Conclusions: The present study suggests that hs-CRP could be a better risk factor assessor for atherosclerosis than LDL-C in individuals considered to be at low risk for atherosclerosis assessed by their traditional CVD risk factors.

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Defining patients at extremely high risk for coronary artery disease in heterozygous familial hypercholesterolemia.

Sugisawa T, Okamura T, Makino H, Watanabe M, Kishimoto I, Miyamoto Y, Iwamoto N, Yamamoto A, Yokoyama S, Harada-Shiba M

Journal of atherosclerosis and thrombosis 19 （ 4 ） 369 - 375 2012年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: Heterozygous patients with familial hypercholesterolemia (FH) are known to be associated with a high risk of coronary artery disease (CAD), which is a major determinant of their clinical outcome. The prognosis of heterozygous FH patients substantially varies, being dependent on the level of their CAD risk, and their therapeutic regimen should be individualized. We assessed critical levels of LDLcholesterol (LDL-C) and Achilles tendon thickness (ATT) to identify heterozygous FH patients at "very high" risk for CAD. Methods: One hundred and nine heterozygous FH patients who had no history of CAD and had had their plasma lipid profile and ATT assessed before treatment were followed up until their first CAD event or 31 December 2010. Multivariable logistic regression models were used to analyze the correlation of LDL-C and/or ATT levels with the risk of developing CAD. Results: During the follow-up period, 21 of the 109 patients had a CAD event, diagnosed by coronary angiogram. Individuals in the highest tertile of LDL-C had a CAD risk 8.29-fold higher than those in the lowest tertile. Individuals in the highest tertile of the ATT group had a 7.82-fold higher CAD risk than those in the lowest tertile. Those who had either LDL-C ≥260 mg/dL or ATT ≥14.5 had a 23.94-fold higher CAD risk than those with LDL-C ≥260 mg/dL and ATT ≥14.5 mm. Conclusions: In heterozygous FH patients, LDL-C 260 mg/dL or higher and/or ATT 14.5 mm or thicker are useful markers for extracting patients at "very high" risk for CAD.

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Guidelines for the management of familial hypercholesterolemia.

Harada-Shiba M, Arai H, Oikawa S, Ohta T, Okada T, Okamura T, Nohara A, Bujo H, Yokote K, Wakatsuki A, Ishibashi S, Yamashita S

Journal of atherosclerosis and thrombosis 19 （ 12 ） 1043 - 1060 2012年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Familial hypercholesterolemia (FH) is a highly prevalent autosomal dominant hereditary disease, generally characterized by three major signs, hyper-low-density-lipoprotein (LDL) cholesterolemia, tendon/skin xanthomas and premature coronary artery disease (CAD). Because the risk of CAD is very high in these patients, they should be identified at an early stage of their lives and started on intensive treatment to control LDL-cholesterol. We here introduce a new guideline for the management of FH patients in Japan intending to achieve better control to prevent CAD. Diagnostic criteria for heterozygous FH are 2 or more of 1) LDL-cholesterol ≥180 mg/dL, 2) tendon/skin xanthoma(s), and 3) family history of FH or premature CAD within second degree relatives, for adults; and to have both 1) LDL-cholesterol ≥140 mg/dL and 2) family history of FH or premature CAD within second degree relatives, for children. For the treatment of adult heterozygous FH, intensive lipid control with statins and other drugs is necessary. Other risks of CAD, such as smoking, diabetes mellitus, hypertension etc., should also be controlled strictly. Atherosclerosis in coronary, carotid, or peripheral arteries, the aorta and aortic valve should be screened periodically. FH in children, pregnant women, and women who wish to bear a child should be referred to specialists. For homozygotes and severe heterozygotes resistant to drug therapies, LDL apheresis should be performed. The treatment cost of homozygous FH is authorized to be covered under the program of Research on Measures against Intractable Diseases by the Japanese Ministry of Health, Labour, and Welfare.

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Relation of dietary and lifestyle traits to difference in serum leptin of Japanese in Japan and Hawaii: the INTERLIPID study

Nakamura Y, Ueshima H, Okuda N, Miura K, Kita Y, Okamura T, Turin TC, OkayamaA, Rodriguez B, Curb JD, Stamler J; INTERLIPID Research Group

Nutr Metab Cardiovasc Dis 22 （ 1 ） 14-22 2012年

研究論文（学術雑誌）, 共著, 査読有り

生活習慣病の予防と医療費：10年間の追跡調査による健診所見と医療費の関連：滋賀国保コホート研究の知見から

岡村智教、中村幸志、早川岳人、神田秀幸、三浦克之、岡山明、上島弘嗣

日本衛生学雑誌 67 （ 1 ） 38-43 2012年

研究論文（学術雑誌）, 共著, 査読有り

循環器病の体質と予防戦略－日米比較研究・移民研究からの検証－

岡村智教

日本体質医学会雑誌 74 （ 1 ） 46-52 2012年

研究論文（学術雑誌）, 単著

前期高齢者におけるBMI別医療費と医療費高値群の特性．29,490人の大規模データを用いた検討．

鈴木（斎藤）智子、安村誠司、岡村智教、坂田清美、日高秀樹、三浦克之、岡山　明

日本公衆衛生雑誌 59 （ 7 ） 466-473 2012年

研究論文（学術雑誌）, 共著, 査読有り

Prognostic value of cardiac magnetic resonance imaging for idiopathic pulmonary arterial hypertension before initiating intravenous prostacyclin therapy.

Yamada Y, Okuda S, Kataoka M, Tanimoto A, Tamura Y, Abe T, Okamura T, Fukuda K, Satoh T, Kuribayashi S

Circulation journal : official journal of the Japanese Circulation Society 76 （ 7 ） 1737 - 1743 2012年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1346-9843

Background: Because few have reported the prognostic significance of cardiac magnetic resonance imaging (CMR) for idiopathic pulmonary arterial hypertension (IPAH), in this study we evaluated the value of CMR measurements as a prognostic predictor of IPAH before starting intravenous prostacyclin therapy. Methods and Results: A total of 121 consecutive CMR studies for evaluating right ventricular (RV) function were reviewed. Forty-one patients were diagnosed with IPAH and served as the study group. Factors, such as age, sex, New York Heart Association functional class (NYHAFC), 6-min walk test, plasma brain natriuretic peptide level, serum uric acid level and CMR measurements were analyzed as predictors of first hospitalization and death. The mean follow- up period was 1,350±769 days. Nine patients were hospitalized because of heart failure, and 4 patients died from cardiopulmonary causes. The univariate analyses suggested that the left ventricular (LV) mass index, the left and right ventricular end-diastolic volume indices (LVEDVI, RVEDVI), the LV and RV end-systolic volume indices (LVESVI, RVESVI) and NYHAFC predicted the risk for hospitalization and that RVEDVI, RVESVI and NYHAFC predicted mortality. The multivariate analyses suggested that RVEDVI and NYHAFC are independent predictors of both hospitalization and mortality. The effects of RVEDVI and NYHAFC on hospitalization were not substantially affected by the concomitant medication. Conclusions: In IPAH patients, the RVEDVI predicts both hospitalization for right heart failure and mortality before initiating intravenous prostacyclin therapy.

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Coronary artery calcification by computed tomography in epidemiologic research and cardiovascular disease prevention.

Sekikawa A, Curb JD, Edmundowicz D, Okamura T, Choo J, Fujiyoshi A, Masaki K, Miura K, Kuller LH, Shin C, Ueshima H

Journal of epidemiology 22 （ 3 ） 188 - 198 2012年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Both American and European guidelines recommend coronary artery calcification (CAC) as a tool for screening asymptomatic individuals at intermediate risk for coronary heart disease (CHD). These recommendations are based on epidemiologic studies mostly in the United States. We review (1) the use of CAC in primary prevention of CHD in the United States, (2) epidemiologic studies of CAC in asymptomatic adults outside of the United States, and (3) international epidemiologic studies of CAC. This review will not consider clinical studies of CAC among patients or symptomatic individuals. US studies have shown that CAC is a strong independent predictor of CHD in both sexes among middle-aged and old age groups, various ethnic groups, and individuals with and without diabetes and that CAC plays an important role in reclassifying individuals from intermediate to high risk. Studies in Europe support these conclusions. The Electron-Beam Tomography, Risk Factor Assessment Among Japanese and US Men in the Post-World-War-II birth cohort (ERA JUMP) Study is the first international study to compare subclinical atherosclerosis, including CAC among Japanese, Japanese Americans, Koreans, and whites. It showed that as compared with whites, Japanese had lower levels of atherosclerosis, whereas Japanese Americans had similar or higher levels. CAC is being increasingly used as a screening tool for asymptomatic individuals in Europe and the United States. CAC is a powerful research tool, because it enables us to describe differences in atherosclerotic burden across populations. Such research could identify factors responsible for differences among populations, which may improve CHD prevention. © 2012 by the Japan Epidemiological Association.

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Blood cholesterol level and risk of stroke in community-based or worksite cohort studies: a review of Japanese cohort studies in the past 20 years.

Tanaka T, Okamura T

The Keio journal of medicine 61 （ 3 ） 79 - 88 2012年

研究論文（学術雑誌）, ISSN 0022-9717

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Blood cholesterol level and risk of stroke in community-based or worksite cohort studies: a review of Japanese cohort studies in the past 20 years.

Tanaka T, Okamura T

The Keio journal of medicine 61 （ 3 ） 79 - 88 2012年

研究論文（学術雑誌）, ISSN 0022-9717

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Association of short sleep duration with impaired glucose tolerance or diabetes mellitus.

Katano S, Nakamura Y, Nakamura A, Murakami Y, Tanaka T, Takebayashi T, Okayama A, Miura K, Okamura T, Ueshima H, for HIPOP‐OHP Research Group.

Journal of diabetes investigation 2 （ 5 ） 366 - 372 2011年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2040-1116

Aims/Introduction: To examine the cross-sectional relationship between sleep duration and impaired glucose tolerance (IGT), including diabetes mellitus (DM), we analyzed a large-scale healthy workers database in Japan. Materials and Methods: We examined the baseline database of 4143 participants (3415 men and 728 women) aged 19-69years. Sleep duration of participants was categorized into four groups: <6, 6 to <7, 7 to <8 and ≥8h. The physical activity of each participant was classified according to the International Physical Activity Questionnaire (IPAQ). We defined IGT including DM (IGT/DM) in the present study according to previous studies as follows: fasting blood sugar level ≥110mg/dL, or if <8h after meals ≥140mg/dL, or on medication for diabetes mellitus, or those diagnosed as having DM. Logistic regression was applied to estimate the odds ratio (OR) to examine the relationship between IGT/DM, sleep duration and other related factors. Results: The number of participants with IGT/DM was 402 (9.7%). The factors that significantly associated with IGT/DM were age (OR 1.08, 95% confidence interval [CI] 1.07-1.10, P<0.001), high blood pressure (OR 1.94, CI 1.52-2.47, P<0.001), and <6h of sleep duration in comparison with 6 to <7h sleep (OR 2.32, CI 1.18-4.55, P=0.015). The associations of difficulty in sleep initiation, IPAQ classification, current smoking and alcohol intake with IGT/DM were not statistically significant. Conclusions: Our results showed that shorter sleep duration (<6h of sleep duration per night) was associated with a risk of IGT/DM independent of other lifestyle habits and metabolic risk factors. © 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd.

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血漿ホモシステイン高値、関連ビタミン群と動脈硬化性疾患の関連

久保田芳美、吉野佳織、岡村智教

総合臨床（永井書店） 60 （ 10 ） 2047-2052 2011年10月

研究論文（学術雑誌）, 共著

[Smoking is an important risk factor for cardiovascular disease in Japan].

Okamura T, Morimoto A

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 7 599 - 603 2011年09月

研究論文（学術雑誌）, 共著, ISSN 0047-1852

Differential association of docosahexaenoic and eicosapentaenoic acids with carotid intima-media thickness.

Sekikawa A, Kadowaki T, El-Saed A, Okamura T, Sutton-Tyrrell K, Nakamura Y, Evans RW, Mitsunami K, Edmundowicz D, Nishio Y, Nakata K, Kadota A, Otake T, Miura K, Choo J, Abbott RD, Kuller LH, Curb JD, Ueshima H, ERA JUMP Study group.

Stroke 42 （ 9 ） 2538 - 2543 2011年09月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0039-2499

Background and Purpose-Recent studies reported the differential effect of docosahexaenoic (DHA) and eicosapentaenoic acids (EPA). We examined the differential association of DHA and EPA with carotid intima-media thickness (IMT) in Japanese individuals in Japan and in U.S. white individuals and explored whether DHA or EPA contributes to the difference in IMT between the two groups. Methods-A population-based cross-sectional study in 608 Japanese and U.S. white men aged 40 to 49 was conducted to assess IMT, serum DHA, EPA, and other cardiovascular risk factors. Results-Japanese compared to U.S. whites had significantly lower IMT (mean±SD, 618±81 and 672±94 μm for Japanese and whites, respectively; P<0.001) and had >2-fold higher levels of DHA and EPA. DHA, but not EPA, had an inverse association with IMT in both Japanese and U.S. whites. The inverse association remained only in Japanese men after adjusting for risk and other factors. The significant difference in multivariable-adjusted IMT became nonsignificant after further adjusting for DHA (mean difference, 17 μm; 95% CI,-8 to 43; P=0.177) but not EPA. In this multivariable-adjusted model, DHA but not EPA was a significant predictor of IMT (P=-0.032 versus 0.863, respectively). Conclusions-These data suggest that DHA may have a more potent antiatherogenic effect than EPA, especially in levels observed in the Japanese, independent of risk factors. © 2011 American Heart Association. All rights reserved.

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High oolong tea consumption predicts future risk of diabetes among Japanese male workers

Hayashino Y., Fukuhara S., Okamura T., Tanaka T., Ueshima H.

Diabetic Medicine 28 （ 7 ） 805 - 810 2011年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0742-3071

Aims Acute administration of oolong tea decreases blood glucose levels. We investigated the association between long-term oolong tea intake and subsequent risk of developing diabetes among men of working age. Methods Data were analysed from a cohort of participants in the High-risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP), conducted in Japan from 1999 to 2004. Oolong tea intake at baseline and subsequent risk of diabetes was evaluated using a Cox proportional hazards model. Results Of 4975 male workers, a total of 201 cases of diabetes were reported over a median of 3.4years of follow-up. Mean age and BMI of all participants at baseline were 38.3years and 22.9kg/m ², respectively. Compared with those not consuming oolong tea, multivariable adjusted hazard ratios for developing diabetes were 1.00 (95%CI 0.67-1.49) for those who drank one cup of oolong tea per day and 1.64 (95%CI 1.11-2.40) for those drinking two or more cups per day. Fasting blood glucose increment per year was 0.11mmol/l (95%CI 0.09-0.12mmol/l), 0.12mmol/l (95%CI 0.09-0.15mmol/l) and 0.15mmol/l (95%CI 0.11-0.18mmol/l), respectively, for oolong tea consumption of 0, 1 and ≥2cups/day, with a significant linear trend (P<0.0001). Conclusions Long-term consumption of oolong tea may be a predictive factor for new onset diabetes. Further studies are necessary to elucidate the role of oolong tea in the risk of developing diabetes. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

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A revised definition of the metabolic syndrome predicts coronary artery disease and ischemic stroke after adjusting for low density lipoprotein cholesterol in a 13-year cohort study of Japanese: the Suita study.

Okamura T, Kokubo Y, Watanabe M, Higashiyama A, Ono Y, Nishimura K, Okayama A, Miyamoto Y

Atherosclerosis 217 （ 1 ） 201 - 206 2011年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Objective: Recently, several major organizations have proposed a unified definition for the metabolic syndrome (MetS), which should be evaluated in multiethnic groups. The effect of Mets on the incidence of cardiovascular disease needs to be assessed after adjusting for serum low density lipoprotein cholesterol (LDLC), a major risk factor for atherosclerotic diseases. This is especially needed to be evaluated in Asian populations with low incidence of coronary artery disease (CAD). Methods: We conducted a 13-year prospective study of 4939 Japanese living in an urban area. The MetS was defined using a unified classification that included cut-off points for waist circumference in Asians. The multivariable adjusted hazard ratios (HRs) of MetS for CAD and stroke were calculated using a Cox proportional model adjusted for other potential confounding factors with LDLC. Results and conclusion: During the follow-up period, there were 155 cases of CAD and 204 of stroke including 118 cerebral infarctions. In participants under 65 years old, the multivariable HRs of MetS for CAD were 1.21 (95% C.I., 0.64-2.28) in men and 4.44 (95% C.I., 1.73-11.4) in women; the HRs for ischemic stroke were 3.24 (95% C.I., 1.55-6.77) in men and 3.99 (95% C.I., 1.34-11.8) in women. In participants aged 65 years old and over, MetS only showed a significant association with CAD in men (HR 1.89, 95% C.I., 1.11-3.21). Serum LDLC was associated with increased risk of CAD in men irrespective of age group; however, it was not associated with CAD in women. There was no association between serum LDLC and ischemic stroke in any group stratified by sex and the age of 65. These results indicate that the new uniform MetS definition is useful for detecting high risk individuals, especially for middle-aged population. However, continuous screening for hypercholesterolemia is necessary to prevent CAD, especially in men, even in Asian countries such as Japan. © 2011 Elsevier Ireland Ltd.

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Prognostic value of ST-T abnormalities and left high R waves with cardiovascular mortality in Japanese (24-year follow-up of NIPPON DATA80).

Rumana N, Turin TC, Miura K, Nakamura Y, Kita Y, Hayakawa T, Choudhury SR, Kadota A, Nagasawa SY, Fujioshi A, Takashima N, Okamura T, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

The American journal of cardiology 107 （ 12 ） 1718 - 1724 2011年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0002-9149

Little is known about the prognostic value of ST-segment depression and/or T wave (ST-T abnormalities) with or without left high R waves on electrocardiogram recorded at rest for death from cardiovascular disease (CVD) in Asian populations. Japanese participants without a history of CVD and free of major electrocardiographic (ECG) abnormalities were followed for 24 years. Subjects were divided into 4 groups based on baseline ECG findings: isolated left high R waves, isolated ST-T abnormalities, ST-T abnormalities with left high R waves, and normal electrocardiogram. Cox proportional hazard model was used to estimate risk of CVD mortality in groups with ECG abnormalities compared to the normal group. Of 8,572 participants (44.4% men, mean age 49.5 years; 55.6% women, mean age 49.4 years), 1,142 had isolated left high R waves, 292 had isolated ST-T abnormalities, and 128 had ST-T abnormalities with left high R waves at baseline. Multivariable-adjusted hazard ratios of ST-T abnormalities with left high R waves for CVD mortality were 1.95 (95% confidence interval 1.25 to 3.04) in men and 2.68 (95% confidence interval 1.81 to 3.97) in women. Isolated ST-T abnormalities increased the risk for CVD death by 1.66 times (95% confidence interval 1.01 to 2.71) in men and 1.62 times (95% confidence interval 1.18 to 2.24) in women. Association of ECG abnormalities with CVD mortality was independent of age, body mass index, systolic blood pressure, serum cholesterol, blood glucose, smoking and drinking, and antihypertensive medication. In conclusion, ST-T abnormalities with or without left high R waves on electrocardiogram recorded at rest constitute an independent predictor of CVD mortality in Japanese men and women. © 2011 Elsevier Inc. All rights reserved.

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Serum 1,5-anhydro-d-glucitol levels predict first-ever cardiovascular disease

Watanabe M., Kokubo Y., Higashiyama A., Ono Y., Miyamoto Y., Okamura T.

Atherosclerosis 216 （ 2 ） 477 - 483 2011年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Objective: Serum 1,5-anhydro-d-glucitol (1,5-AG) is well-known to be a useful clinical marker of both short-term glycemic status and postprandial hyperglycemia. In addition, previous epidemiological studies have shown that an increased postload glucose level in an oral glucose tolerance test is a risk factor for cardiovascular diseases (CVD). However, no previous prospective study has reported the association between serum 1,5-AG levels and the risk of CVD. In this study, we examined whether serum 1,5-AG levels can predict the incidence of first-ever CVD. Methods: Our study was a population-based cohort study in an urban area of Japan. Study subjects comprised 2095 initially healthy Japanese (991 men and 1104 women, mean age: 58.5 years) with no history of coronary heart disease (CHD) or stroke. They were followed up for an average of 11.1 years, and 147 CVD events (64 CHD and 83 strokes) were observed. Results: The adjusted hazard ratios (HRs) of all CVD in men increased linearly (p= 0.004). The HR in the category with serum 1,5-AG levels of 14.0 μg/mL or less was 2.22 (95% confidence interval; 1.24-3.98) compared to the reference category (24.5 μg/mL or greater). Similar results were also shown with a sensitivity analysis in non-diabetic men. Conversely, no significant relationship between serum 1,5-AG levels and CVD risks was observed in women. Conclusions: Our results suggest that measurement of serum 1,5-AG levels is useful to detect individuals, especially men, at higher risk for CVD, regardless of the presence or absence of diabetes. © 2011 Elsevier Ireland Ltd.

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Association with serum gamma-glutamyltransferase levels and alcohol consumption on stroke and coronary artery disease: the Suita study.

Higashiyama A, Wakabayashi I, Ono Y, Watanabe M, Kokubo Y, Okayama A, Miyamoto Y, Okamura T

Stroke 42 （ 6 ） 1764 - 1767 2011年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0039-2499

Background And Purpose- Light-to-moderate alcohol consumption is associated with reduced risk for cardiovascular disease, whereas high serum γ-glutamyltransferase (GGT) level is associated with cardiovascular disease. However, whether light-to-moderate alcohol drinking is still related to reduced risk of cardiovascular disease irrespective of GGT level is uncertain. Methods- We performed a 12.5-year cohort study of 2336 men (excluding exdrinkers) who were free from cardiovascular disease. They were classified into 4 groups according to alcohol consumption: never, and current light, moderate, or heavy drinker. The multivariate-adjusted hazard ratios of alcohol consumption for incidence of coronary artery disease, total stroke, and ischemic stroke compared with those of never drinkers were assessed with stratification by GGT median (32 IU/L). Results- In participants with GGT >32 IU/L, the hazard ratios of all current drinkers for total and ischemic stroke were higher than those of never drinkers. However, in all current drinkers with GGT ≤32 IU/L, the multivariate-adjusted hazard ratios for total and ischemic stroke were lower than in never drinkers. Conclusions- In men with above GGT median, alcohol drinking even with light-to-moderate consumption could be a risk factor for ischemic stroke. © 2011 American Heart Association, Inc.

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Association of intima-media thickening of carotid artery with genetic polymorphisms of the regulator of G-protein signaling 2 gene in patients with hypertension and in the general population.

Kamide K, Kokubo Y, Yang J, Takiuchi S, Horio T, Matsumoto S, Banno M, Matayoshi T, Yasuda H, Miwa Y, Yoshihara F, Nakamura S, Nakahama H, Iwashima Y, Oguro R, Ohishi M, Rakugi H, Okamura T, Miyata T, Kawano Y

Hypertension research : official journal of the Japanese Society of Hypertension 34 （ 6 ） 740 - 746 2011年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0916-9636

Regulator of G-protein signaling 2 (RGS2) is a key molecule in signal pathways of vasoactive peptides, such as angiotensin II and endothelin 1, and is believed to have an important role in the pathophysiology of atherosclerosis. We have previously reported that common polymorphisms of RGS2 are associated with hypertension in Japanese. In this study, we studied whether the three previously identified common polymorphisms of RGS2 (638AG, 1026TA and 1891-1892delTC) could be implicated in carotid atherosclerosis in Japanese patients with hypertension (459 men and 382 woman) and in a Japanese general population (814 men and 956 woman). We assessed two criteria for carotid atherosclerosis: maximal intima-media thickness (M-IMT) and mean-IMT. When subjects with atherosclerotic lesions were defined as having mean-IMT1.0 mm, multivariate logistic regression analysis performed after adjusting for confounding factors showed a significant association of the three common polymorphisms, 638AG (AA versus AGGG: odds ratio (OR), 1.55; 95% confidence interval (CI), 1.105-2.185; P0.0113 only for the general population), 1026TA (TT versus TAAA: OR, 1.42; 95% CI, 1.027-1.972; P0.034 for hypertensive subjects and OR, 1.56; 95% CI, 1.129-2.151; P0.0071 for the general population), and 1891-1892delTC (II versus IDDD: OR, 1.44; 95% CI, 1.043-2.008; P0.028 for hypertensive subjects, OR, 1.32; 95% CI 1.002-1.742; P0.048 for the total general population and OR 1.59; 95% CI 1.155-2.207; P0.0047 for the general population), with carotid atherosclerosis. When atherosclerosis was defined as M-IMT 1.0 mm, the values of M-IMT were also significantly different between the three genotypes in the three common polymorphisms. Taken together, these data suggest that genetic polymorphisms in RGS2 are associated with intima-media thickening of carotid artery in humans. © 2011 The Japanese Society of Hypertension All rights reserved.

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Corrigendum to 'Gamma-Glutamyltransferase and mortality risk from heart disease and stroke in Japanese men and women

Fujiyoshi Akira, Miura Katsuyuki, Hozawa Atsushi, Murakami Yoshitaka, Takashima Naoyuki, Okuda Nagako, Kadowaki Takashi, Kita Yoshikuni, Okamura Tomonori, Nakamura Yasuyuki, Hayakawa Takehito, Okayama Akira, Ueshima Hirotsugu

CVD Prevention and Control 6 （ 2 ） 63 2011年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1875-4570

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Fasting plasma insulin is associated with metabolic syndrome in farmers but not in nomads among the Mongolian population, China.

Kanda H, Wang P, Okamura T, Wuyun G, Wu H, Su X, Hayakawa T, Amamoto K, Ueshima H

Journal of atherosclerosis and thrombosis 18 （ 4 ） 291 - 297 2011年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

The World Health Organization (WHO) includes insulin resistance among its criteria for diagnosing metabolic syndrome (MetS); however, previous epidemiologic studies have limited their research to settled populations only. This study aims to clarify the relationship between plasma insulin and metabolic factors on a broader scale by studying data obtained from nomadic and settled Mongolian populations. A cross-sectional epidemiologic study of 200 nomads and 256 farmers was performed in Inner Mongolia, Republic of China. Plasma insulin levels and other metabolic factors, such as blood pressure, serum lipids and obesity, were measured. Participants were classified into 3 categories according to their plasma insulin levels. Cut-off values grouped into tertiles of fasting insulin for all participants were 6.73 nmol/L and 10.33 nmol/L. The mean number of metabolic risk factors, waist circumference, fasting plasma glucose and triglyceride were higher, and the mean HDL cholesterol was lower in the higher fasting insulin tertile among farmers after adjusting for age, gender, smoking, alcohol drinking and total cholesterol. However, no MetS factors were statistically related with fasting insulin tertile levels among nomads. In nomads, hyperinsulinemia may not be an indicator of MetS due to their specific life-style.

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Relationship of moderate metabolic risk factor clustering to cardiovascular disease mortality in non-lean Japanese: a 15-year follow-up of NIPPON DATA90.

Kadota A, Miura K, Okamura T, Hozawa A, Murakami Y, Fujiyoshi A, Takashima N, Hayakawa T, Kita Y, Okayama A, Nakamura Y, Ueshima H, NIPPON DATA90 Research Group.

Atherosclerosis 215 （ 1 ） 209 - 213 2011年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9150

Objective: The individual components of metabolic syndrome are defined as levels ranging from moderate to high level as to require medication. We investigated the impact of moderate metabolic risk factor clustering on cardiovascular disease (CVD) mortality. Methods: We followed up 6758 non-lean Japanese in randomly selected areas from all over the country who had no history of CVD for 15 years. The multivariate-adjusted hazards ratio (HR) and 95% confidence interval (CI) for CVD mortality according to the number of moderate metabolic risk factors (BMI≥25kg/m², 130/85mmHg≤systolic/diastolic BP<140/90mmHg, 140mg/dl≤casual blood glucose<200mg/dl, triglycerides≥150mg/dl and/or HDL cholesterol<40mg/dl [men], 50mg/dl [women]) were estimated using the Cox proportional hazards model. The population-attributable risk fraction of moderate metabolic risk factor clustering was also estimated. Results: During the follow-up, 282 participants died of CVD. CVD mortality tended to increase with the number of moderate metabolic risk factors. However, they were not statistically significant. The multivariate-adjusted HRs were 1.82 (95%CI: 0.89-3.73) for having any moderate metabolic risk factors and 2.87 (95%CI: 1.46-5.64) for having any medication-required metabolic risk factors, compared with participants without any moderate metabolic risk factors. The population-attributable risk fractions were 7.3% and 52.4% for any moderate and medication-required metabolic risk factors, respectively. Conclusions: We did not find the statistically significant increase of CVD mortality for moderate metabolic risk factor clustering. Its attribution was relatively small in this Japanese population. More efforts would be required to detect and control medication-required risk factors. © 2010 Elsevier Ireland Ltd.

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Population attributable numbers and fractions of deaths due to smoking: a pooled analysis of 180,000 Japanese.

Murakami Y, Miura K, Okamura T, Ueshima H, EPOCH-JAPAN Research Group.

Preventive medicine 52 （ 1 ） 60 - 65 2011年01月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0091-7435

Objective: Age- and sex-specific population attributable fraction (PAF) and premature deaths attributable to smoking were estimated from a pooled analysis of cohort studies in Japan. Methods: A pooled analysis of individual participant data from 13 well-qualified cohort studies throughout Japan (a total of 183,251 Japanese aged 40-89, 69,502 men and 113,749 women; the baseline years between 1987 and 1995 with average 10 years of follow-up) was performed. Poison regression model was used to estimate age- and sex-specific hazard ratios, and their PAFs of all-cause deaths and number of annual premature deaths attributable to smoking were estimated. Results: Overall PAF attributable to smoking was 24.6% in men and 6.0% in women. The estimated number of annual premature deaths due to smoking was 121,854 (men: 109,998; women: 11,856) in Japan. The age-specific PAF was largest in men aged 60-69 (47.7%) and in women aged 50-59 (12.2%). In the older group aged 70-79 and 80-89, PAF was 15.4% and 8.0% in men and 3.5% and 1.5% in women, respectively. Conclusions: Age-specific PAFs attributable to smoking in Japanese men are much larger than that reported from other Asian countries. © 2010 Elsevier Inc.

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Impairments in activities of daily living in older Japanese men in hawaii and Japan.

Abbott RD, Kadota A, Miura K, Hayakawa T, Kadowaki T, Okamura T, Okayama A, Masaki KH, Ueshima H

Journal of aging research 2011 324592 2011年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2090-2204

Introduction. Hypertension and cigarette smoking are dominant risk factors for cardiovascular disease in Japan while in westernized countries, broader effects encompass obesity, diabetes, and hypercholesterolemia. This paper examines whether different associations also appear important in the manifestation of activities of daily living (ADL) in older Japanese men in Hawaii and Japan. Methods. Measures of ADL (feeding, toileting, dressing, bathing, and walking around the house) were assessed from 1995 to 1999 in 1,893 men in Hawaii and 543 men in Japan. Concomitant risk factors were measured from 1990 to 1993. Results. In Hawaii, diabetes increased the odds of ≥1 ADL impairment nearly 1.5-fold (P=.020). A similar association was absent in Japan. In contrast, the odds of an ADL impairment in Japan was increased more than 5-fold in the presence of stroke (P<.001). The association in Hawaii was significantly weaker (P=.007). In both cohorts, past alcohol use was associated with a greater likelihood of ADL impairment. Conclusion. In this comparison of genetically similar samples, findings suggest that different strengths in risk factor associations with cardiovascular disease in Japan and westernized countries may also include different strengths in associations with impaired ADL. © 2011 Robert D. Abbott et al.

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Relationship between sleep duration and clustering of metabolic syndrome diagnostic components.

Katano S, Nakamura Y, Nakamura A, Murakami Y, Tanaka T, Takebayashi T, Okayama A, Miura K, Okamura T, Ueshima H, HIPOP-OHP Research Group.

Diabetes, metabolic syndrome and obesity : targets and therapy 4 119-125 - 25 2011年

研究論文（学術雑誌）, 共著, 査読有り

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NIPPON DATA80-リスク評価チャートの評価-.

渡邉至、岡村智教

The Lipid （メディカルレビュー社） 22 （ 1 ） 14-19 2011年

研究論文（学術雑誌）, 共著

禁煙専門医の立場から-リスクとしての喫煙、治療としての禁煙-.

岡村智教

治療（南山堂） 93 （ 4 ） 608-611 2011年

研究論文（学術雑誌）, 単著

粥状動脈硬化症の発症における脂質異常症の関与-疫学的側面から．

岡村智教

レジデント（医学出版） 4 （ 8 ） 6-16 2011年

研究論文（学術雑誌）, 単著

脳卒中予防のイノベーション-早期発見・早期受診・早期介入.

宮本恵宏、中山博文、岡村智教、豊田一則

Medicina （医学書院） 48 （ 7 ） 1254-1266 2011年

研究論文（学術雑誌）, 共著

脂質異常症と動脈硬化の疫学的エビデンスは？

田中太一郎、岡村智教

Heart View （メディカルビュー社） 15 （ 9 ） 915-920 2011年

研究論文（学術雑誌）, 共著

虚血性心疾患の最近の疫学的動向からみた実地診療のすすめかた.

田中太一郎、岡村智教

Medical Practice （文光堂） 28 （ 9 ） 1506-1512 2011年

研究論文（学術雑誌）, 共著

動脈硬化性疾患の絶対リスクの評価.

岡村智教、杉山大典

日本医師会雑誌 140 （ 6 ） 1208-1212 2011年

研究論文（学術雑誌）, 共著

ホモシステインの動脈硬化リスクについてのpros and cons.

岡村智教、久保田芳美、吉野佳織

循環器内科（科学評論社） 70 （ 2 ） 202-209 2011年

研究論文（学術雑誌）, 共著

心血管病の危険因子としての喫煙

岡村智教、森本明子

日本臨床（日本臨床社） 69 （増刊号7. 冠動脈疾患動脈（上巻）） 599-603 2011年

研究論文（学術雑誌）, 共著

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Okamura T in The International Consortium for Blood Pressure Genome-Wide Association Studies

Nature 478 103-109 2011年

研究論文（学術雑誌）, 共著, 査読有り

脂質異常症と動脈硬化性疾患（世界と日本の違い

岡村智教

臨床と研究（大道学館出版部） 88 （ 10 ） 1229-1234 2011年

研究論文（学術雑誌）, 単著

虚血性心疾患の一次予防：心臓を護るためになすべきこと.

中村幸志、岡村智教

Heart View（11月増刊号）（メジカルビュー社） 15 （ 12 ） 216-220. 2011年

研究論文（学術雑誌）, 共著

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

Okamura T in the International Consortium for Blood Pressure Genome-wide Association Studies (ICBP-GWAS)

Hum Mol Genet 20 （ 11 ） 2273-84 2011年

研究論文（学術雑誌）, 共著, 査読有り

Relationship between Dietary and Other Lifestyle Habits and Cardiometabolic Risk Factors in Men.

Katano S, Nakamura Y, Okuda N, Murakami Y, Chiba N, Yoshita K, Tanaka T, Tamaki J, Takebayashi T, Okayama A, Miura K, Okamura T, Ueshima H, HIPOP-OHP Research Group.

Diabetology & metabolic syndrome 3 （ 1 ） 30 2011年

研究論文（学術雑誌）, 共著, 査読有り

Background: Prevalence of men with cardiometabolic risk factors (CMRF) is increasing in Japan. Few studies have comprehensively examined the relation between lifestyles and CMRF. Methods. We examined the baseline data from 3,498 male workers ages 19 to 69 years who participated in the high-risk and population strategy for occupational health promotion (HIPOP-OHP) study at 12 large-scale companies throughout Japan. The physical activity of each participant was classified according to the International Physical Activity Questionnaire (IPAQ). Dietary intake was surveyed by a semi-quantitative Food Frequency Questionnaire. We defined four CMRF in this study as follows: 1) high blood pressure (BP): systolic BP 130 mmHg, or diastolic BP ≥85 mmHg, or the use of antihypertensive drugs; 2) dyslipidemia: high-density lipoprotein-cholesterol concentration < 40 mg/dl, or triglycerides concentration ≥150 mg/dl, or on medication for dyslipidemia; 3) impaired glucose tolerance: fasting blood sugar concentration ≥110 mg/dl; 4) obese: a body mass index ≥25 kg/m ². Results: Those who had 0 to 4 CMRF accounted for 1,597 (45.7%), 1,032 (29.5%), 587 (16.8%), 236 (6.7%), and 44 (1.3%) participants, respectively, in the Poisson distribution. Poisson regression analysis revealed that independent factors that contributed to the number of CMRF were age (b = 0.020, P < 0.01), IPAQ (b = -0.091, P < 0.01), alcohol intake (ml/day) (b = 0.001, P = 0.03), percentage of protein intake (b = 0.059, P = 0.01), and total energy intake (kcal)(b = 0.0001, P < 0.01). Furthermore, alcohol intake and its frequency had differential effects. Conclusions: Alcohol intake, percent protein and total energy intake were positively associated, whereas drinking frequency and IPAQ were inversely associated, with the number of CMRF. © 2011 Katano et al; licensee BioMed Central Ltd.

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Residual lifetime risk of cardiovascular diseases in Japan.

Turin TC, Rumana N, Okamura T

Journal of atherosclerosis and thrombosis 18 （ 6 ） 443 - 447 2011年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Risk assessment of cardiovascular diseases (CVD) is shifting from the relative risk to an absolute risk approach. The residual lifetime risk (LTR), which provides an absolute risk assessment, is an epidemiologic measure that expresses the probability of someone of a given age and sex developing a disease condition during their remaining lifespan. The LTR estimation is important because it could be more easily comprehended by clinicians and patients. The LTR for CVD was not estimated for the Japanese population until recently, when the LTR of stroke and acute myocardial infarction (AMI) was reported. The reported LTR of stroke and AMI for middle-aged adults is substantial. The observed probabilities illustrated that approximately 1 in 5 men and women of middle age will suffer from a stroke in their remaining lifetime. On the other hand, approximately 1 in 6 men and 1 in 9 women of middle age will suffer from AMI in their remaining lifetime. Aaginst the backdrop of the aging population and worsening risk factor scenario, these estimates re-emphasize that CVD is a public health burden that requires preventive interventions. These estimates provide a means to communicate the absolute risk of CVD to the lay population, policy makers, as well as health service providers in predicting the disease burden of CVD. This easily comprehended knowledge can be used as an important index to assist in public health education and planning.

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The combined impact of blood pressure category and glucose abnormality on the incidence of cardiovascular diseases in a Japanese urban cohort: the Suita Study.

Kokubo Y, Okamura T, Watanabe M, Higashiyama A, Ono Y, Miyamoto Y, Furukawa Y, Kamide K, Kawanishi K, Okayama A, Yoshimasa Y

Hypertension research : official journal of the Japanese Society of Hypertension 33 （ 12 ） 1238 - 1243 2010年12月

研究論文（学術雑誌）, ISSN 0916-9636

Few prospective studies have examined the combined impact of blood pressure (BP) categories and glucose abnormalities on the incidence of cardiovascular disease (CVD) in the general Asian population. This study aimed to examine the effect of the combined risks of these factors on the incidence of CVD in a general Japanese population. We studied 5321 Japanese individuals (aged 30-79 years), without CVD at baseline, who received follow-up for an average of 11.7 years. Serum fasting glucose categories were defined according to the 2003 American Diabetes Association recommendations. BP categories were defined by the 2009 Japanese Society of Hypertension Guidelines for the Management of Hypertension. The Cox proportional hazard ratios (HRs) for CVD according to the serum glucose and BP categories were calculated. In 62 036 person-years of follow-up, we documented 364 CVD events (198 stroke and 166 coronary heart disease (CHD)). Compared with normoglycemic subjects, the multivariable HRs (95% confidence intervals (CIs)) for CVD, CHD and stroke were 1.25 (1.00-1.58), 1.46 (1.04-2.04) and 1.11 (0.81-1.52), respectively, in individuals with impaired fasting glucose (IFG), whereas these values were 2.13 (1.50-3.03), 2.28 (1.34-3.88) and 2.08 (1.29-3.35), respectively, in individuals with diabetes mellitus (DM). Compared with normoglycemic and optimal blood pressure (BP) subjects, increased risks of CVD were observed in the normoglycemic subjects with high-normal BP or hypertension, the IFG subjects with normal or higher BP, and the DM subjects regardless of BP category (P-value for interaction0.046). In conclusion, the high-normal BP subjects in all glucose categories and the normal BP subjects with IFG showed increased risk of CVD in this Japanese population. Further investigation of larger cohorts of DM subjects should be conducted to better understand this phenomenon. © 2010 The Japanese Society of Hypertension All rights reserved.

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Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project.

Tabara Y, Kohara K, Kita Y, Hirawa N, Katsuya T, Ohkubo T, Hiura Y, Tajima A, Morisaki T, Miyata T, Nakayama T, Takashima N, Nakura J, Kawamoto R, Takahashi N, Hata A, Soma M, Imai Y, Kokubo Y, Okamura T, Tomoike H, Iwai N, Ogihara T, Inoue I, Tokunaga K, Johnson T, Caulfield M, Munroe P, Global Blood Pressure Genetics Consortium., Umemura S, Ueshima H, Miki T

Hypertension (Dallas, Tex. : 1979) 56 （ 5 ） 973 - 980 2010年11月

研究論文（学術雑誌）, ISSN 0194-911X

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10; allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. © 2010 American Heart Association, Inc.

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Lifetime risk of acute myocardial infarction in Japan.

Turin TC, Kokubo Y, Murakami Y, Higashiyama A, Rumana N, Watanabe M, Okamura T

Circulation. Cardiovascular quality and outcomes 3 （ 6 ） 701 - 703 2010年11月

研究論文（学術雑誌）, ISSN 1941-7713

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A genome-wide association study of hypertension-related phenotypes in a Japanese population.

Hiura Y, Tabara Y, Kokubo Y, Okamura T, Miki T, Tomoike H, Iwai N

Circulation journal : official journal of the Japanese Circulation Society 74 （ 11 ） 2353 - 2359 2010年11月

研究論文（学術雑誌）, ISSN 1346-9843

Background: Large-scale genome-wide association studies (GWAS) have been successful in identifying genes that contribute to common diseases and phenotypes. A GWAS of hypertension-related phenotypes in a Japanese population was conducted in the current study. Methods and Results: A total of 936 participants were recruited from the Suita Study and a GWAS with 538,732 single nucleotide polymorphisms (SNP) was performed. The phenotypes included were systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), waist-to-hip ratio (WHR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma brain natriuretic peptide (BNP) concentration and alcohol consumption (AC). The SNP exceeding the genome-wide significance level were subjected to subsequent association studies using samples available from the Suita Study and Nomura Study. There is no master gene in the Japanese population that profoundly affects SBP, DBP, BMI, WHR, PRA and PAC. AC was influenced by the functional polymorphism in ALDH2, which affected BP levels in men. The BNP concentration was influenced by a polymorphism in the 3' region of the gene encoding for BNP. However, this polymorphism did not influence blood pressure (BP). Six SNP were identified to be associated with hypertension in both the Suita and Nomura studies. Conclusions: Although several candidate SNP relevant to hypertension and those influencing AC and BNP were identified, our middle-sized GWAS indicated that there is no master gene in Japanese people that profoundly affects BP-related phenotypes.

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Comparison of low-density lipoprotein cholesterol concentrations measured by a direct homogeneous assay and by the Friedewald formula in a large community population.

Tanno K, Okamura T, Ohsawa M, Onoda T, Itai K, Sakata K, Nakamura M, Ogawa A, Kawamura K, Okayama A

Clinica chimica acta; international journal of clinical chemistry 411 （ 21-22 ） 1774 - 1780 2010年11月

研究論文（学術雑誌）, ISSN 0009-8981

Background: We compare the direct homogeneous low-density lipoprotein cholesterol (LDL-C) assay with the Friedewald formula (FF) for determination of LDL-C in a large community-dwelling population. Methods: A total of 21,194 apparently healthy subjects aged 40 to 79 years with triglyceride (TG) concentrations < 4.52 mmol/l were enrolled. LDL-C were directly measured by the enzymatic homogeneous assay (LDL-C (D)) and also estimated by the FF (LDL-C (F)). Paired t-test, Pearson's correlation coefficient and linear regression analysis were performed and the concordances of the National Cholesterol Education Program (NCEP) risk category were estimated. Results: Both in fasting (n. = 3270) and nonfasting samples (n. = 17,924), LDL-C (D) highly correlated with LDL-C (F): r= 0.971 and 0.955, respectively. Concordant results for NCEP categories were 84.8% for fasting samples and 80.1% for nonfasting samples. However, the bias between the 2 measurements increased in samples with TG concentrations > 1.69 mmol/l, especially in nonfasting samples. Conclusions: The results showing less variability of the direct LDL-C assay than that of the FF in nonfasting samples suggest that epidemiological studies can use LDL-C measured by the direct assay both in fasting and nonfasting samples. © 2010 Elsevier B.V.

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Association of carotid atherosclerosis with genetic polymorphisms of the klotho gene in patients with hypertension.

Oguro R, Kamide K, Kokubo Y, Shimaoka I, Congrains A, Horio T, Hanada H, Ohishi M, Katsuya T, Okamura T, Miyata T, Kawano Y, Rakugi H

Geriatrics & gerontology international 10 （ 4 ） 311 - 318 2010年10月

研究論文（学術雑誌）, ISSN 1444-1586

Aim: Previous studies suggest that klotho gene polymorphisms may be associated with atherosclerosis, but did not assess the relationship between klotho gene polymorphisms and atherosclerosis parameters such as carotid artery intima-media thickness (IMT). Here, we studied whether klotho single nucleotide polymorphisms (SNP) were associated with carotid atherosclerosis. Methods: All subjects were Japanese. Eight-hundred and fifty-three patients with hypertension (465 men and 388 women) in the outpatient clinic and 1783 subjects from the general population (821 men and 962 women) attending health check-ups were analyzed in the present study. We measured mean IMT of the common carotid artery to evaluate carotid atherosclerosis. Four single nucleotide polymorphisms (SNP) (rs7323281; intron1, rs5644481; exon4, rs3752472; exon3, rs650439; intron4) of klotho were selected as representative SNP in haplotype blocks. Results: Multivariate logistic regression analysis adjusted by confounding factors showed a significant association of rs650439 with carotid atherosclerosis in hypertensive patients (TT vs TA vs AA, P < 0.01; TT + TA vs AA, P < 0.01). By ancova considering confounding factors, rs650439 was also significantly associated with mean IMT (TT + TA vs AA, P = 0.04) in the hypertensive population. However, there was no significant association between klotho SNP and carotid IMT in the general population. Compared to the general population, the subject group with hypertensive patients clearly had more atherosclerosis risk factors. Conclusion: Only in hypertensive patients was klotho rs650439 strongly associated with mean IMT thickening of the common carotid artery. Therefore, klotho SNP (rs650439) may influence on the progression of carotid atherosclerosis in patients with hypertension. © 2010 Japan Geriatrics Society.

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[Drinking/smoking habits and knowledge regarding heavy drinking/ smoking as a risk factor of stroke among Japanese general population].

Morimoto A, Miyamatsu N, Okamura T, Nakayama H, Morinaga M, Toyota A, Suzuki K, Hata T, Yamaguchi T

Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 45 （ 5 ） 411 - 419 2010年10月

研究論文（学術雑誌）, ISSN 1341-8963

We examined the knowledge regarding heavy drinking and smoking as risk factors of stroke according to drinking/smoking habits among randomly selected Japanese general population. The Japan Stroke Association and co-researchers have performed a large-scale educational intervention to improve knowledge concerning stroke from 2006 to 2008. Prior to above-mentioned intervention, we conducted mail-surveillance on knowledge about stroke in 11,306 randomly selected residents aged 40 to 74. We assessed the relationship between drinking/smoking habits and knowledge regarding heavy drinking and smoking as risk factors by using the chi-square test and multiple logistic regression analysis adjusting for age, sex, area, employment, living situation, history of stroke and other stroke related diseases, history of liver disease, family history of stroke and drinking (non-drinker / ex-drinker / occasional drinker / habitual drinker) / smoking habits (non-smoker / ex-smoker / current smoker). Total 5,540 subjects (49.0%) participated in this study. Ex-smokers and current smokers had better knowledge regarding smoking as a risk factor of stroke than non-smokers (odds ratio and 95% confidence intervals: 1.89, 1.55-2.31, 1.76, 1.45-2.12, respectively). There was no difference between habitual drinkers and non-drinkers in their knowledge, whereas current smokers had greater knowledge regarding smoking than nonsmokers. Accordingly, it is suggested that it will be necessary for habitual drinkers to be enlightened regarding heavy drinking as a risk factor of stroke and for current smokers to be provided with information regarding not only these risks but also the specific strategies for invoking behavioral changes.

Genetic link between obesity and MMP14-dependent adipogenic collagen turnover.

Chun TH, Inoue M, Morisaki H, Yamanaka I, Miyamoto Y, Okamura T, Sato-Kusubata K, Weiss SJ

Diabetes 59 （ 10 ） 2484 - 2494 2010年10月

研究論文（学術雑誌）, ISSN 0012-1797

OBJECTIVE - In white adipose tissue, adipocytes and adipocyte precursor cells are enmeshed in a dense network of type I collagen fibrils. The fate of this pericellular collagenous web in diet-induced obesity, however, is unknown. This study seeks to identify the genetic underpinnings of proteolytic collagen turnover and their association with obesity progression in mice and humans. RESEARCH DESIGN AND METHODS - The hydrolysis and degradation of type I collagen at early stages of high-fat diet feeding was assessed in wild-type or MMP14 (MT1-MMP)-haploinsufficient mice using immunofluorescent staining and scanning electron microscopy. The impact of MMP14-dependent collagenolysis on adipose tissue function was interrogated by transcriptome profiling with cDNA microarrays. Genetic associations between MMP14 gene common variants and obesity or diabetes traits were examined in a Japanese cohort (n = 3,653). RESULTS - In adult mice, type I collagen fibers were cleaved rapidly in situ during a high-fat diet challenge. By contrast, in MMP14 haploinsufficient mice, animals placed on a high-fat diet were unable to remodel fat pad collagen architecture and display blunted weight gain. Moreover, transcriptional programs linking type I collagen turnover with adipogenesis or lipogenesis were disrupted by the associated decrease in collagen turnover. Consistent with a key role played by MMP14 in regulating high-fat diet-induced metabolic programs, human MMP14 gene polymorphisms located in proximity to the enzyme's catalytic domain were closely associated with human obesity and diabetes traits. CONCLUSIONS - Together, these findings demonstrate that the MMP14 gene, encoding the dominant pericellular collagenase operative in vivo, directs obesogenic collagen turnover and is linked to human obesity traits. © 2010 by the American Diabetes Association.

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Bundle branch block and other cardiovascular disease risk factors: US-Japan comparison.

Liu L, Okamura T, Kadowaki T, Murakami Y, Hozawa A, Kita Y, Takashima N, Okuda N, Okayama A, Ueshima H

International journal of cardiology 143 （ 3 ） 432 - 440 2010年09月

研究論文（学術雑誌）, ISSN 0167-5273

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Risk factors for heart failure and coronary heart disease mortality over 24-year follow-up period in Japan

Nakamura Yasuyuki, Turin Tanvir C., Rumana Nahid, Miura Katsuyuki, Kita Yoshikuni, Takashima Naoyuki, Fujiyoshi Akira, Hayakawa Takehito, Okamura Tomonori, Ueshima Hirotsugu

CVD Prevention and Control 5 （ 3 ） 97 - 103 2010年09月

ISSN 1875-4570

Background: Although prevention of heart failure (HF) is an urgent public health need with national and global implications, population-based studies are rare. Methods and results: We studied risk factors for HF and coronary heart disease (CHD) mortality using the NIPPON DATA80 database with a 24-year follow-up. At the baseline in 1980, data were collected on study participants aged 30 years and over from randomly selected areas in Japan. We followed 9300 participants (44% men, mean age 51). Over the 24-year follow-up, there were 189 deaths from HF (82 men and 107 women) and 188 (91 men and 97 women) from CHD. Cox analyses revealed common and specific risk factors for both mortalities. Common risk factors were: systolic blood pressure for male HF (hazard ratio: 1.28 per 1SD, P = 0.02) and for CHD in both (men: 1.20, P = 0.01; women: 1.27, P = 0.003), smoking for male CHD (1.31, P = 0.004) and for female HF (1.39, P = 0.01), blood sugar for HF and CHD in men (HF: 1.21 per 1SD, P = 0.009; CHD: 1.29, P < 0.0001); T wave abnormality in male HF (2.33, P = 0.003) and female CHD (1.84, P = 0.001). Specific risk factors were: serum creatinine for HF in both (men: 1.14 per 1SD, P < 0.0001, women: 1.09, P = 0.01); total cholesterol for CHD in men (1.38 per 1SD, P = 0.001), history of valvular heart disease (6.48, P = 0.002) or stroke (2.41, P = 0.048) in male HF, and history of angina in female CHD (3.59, P = 0.003). Conclusion: Common and specific measures need to be undertaken to prevent HF and CHD mortality. © 2010 Published by Elsevier Ltd. on behalf of World Heart Federation.

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Association of four genetic loci with uric acid levels and reduced renal function: the J-SHIPP Suita study.

Tabara Y, Kohara K, Kawamoto R, Hiura Y, Nishimura K, Morisaki T, Kokubo Y, Okamura T, Tomoike H, Iwai N, Miki T

American journal of nephrology 32 （ 3 ） 279 - 286 2010年09月

研究論文（学術雑誌）, ISSN 0250-8095

Background: Recent genome-wide association studies have identified several genetic variants as susceptibility loci for serum uric acid (UA) levels. We also identified a common nonsense mutation, W258X, responsible for renal hypouricemia. Here, we investigated clinical implications of these genetic variants by cross-sectional and longitudinal genetic epidemiological analysis. Methods: The study enrolled 5,165 Japanese subjects aged 64 ± 12 years from the general population. Clinical parameters were obtained from the personal health records, evaluated at medical checkups. Results: Serum UA levels were significantly different between the SLC22A12 rs11231825 (CC/CT/TT: 4.5 ± 1.6, 5.0 ± 1.4, 5.3 ± 1.4 mg/dl; p = 7.6 × 10 ^-20), SLC2A9 rs1014290 (TT/TG/GG: 4.9 ± 1.4, 5.1 ± 1.4, 5.3 ± 1.4 mg/dl; p = 3.1 × 10^-11) and ABCG2 rs2231142 (TT/TG/GG: 5.3 ± 1.5, 5.2 ± 1.4, 5.1 ± 1.4 mg/dl; p = 2.0 × 10^-5) genotypes. During 9.4 years of follow-up, 87 new cases of hyperuricemia were diagnosed. Multiple logistic regression analysis identified the accumulation of risk alleles as a significant determinant of future development of hyperuricemia (OR = 7.94; 95% CI: 1.97-53.6). In contrast, subjects with nonsense mutation predominantly showed lower UA levels (XX/XW/WW: 1.3 ± 1.7, 3.6 ± 1.0, 5.2 ± 1.4 mg/dl; p = 9.3 × 10^-82). However, these subjects showed significantly reduced renal function (β = -0.111; p < 0.001) independently of possible covariates. Conclusion: Accumulation of risk genotypes was an independent risk factor for future development of hyperuricemia. Genetically developed hypouricemia was an independent risk factor for decreased renal function. Copyright © 2010 S. Karger AG, Basel.

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Cigarette smoking in middle age and a long-term risk of impaired activities of daily living

Takashima Naoyuki, Miura Katsuyuki, Hozawa Atsushi, Okamura Tomonori, Hayakawa Takehito, Okuda Nagako, Kadowaki Takashi, Murakami Yoshitaka, Kita Yoshikuni, Nakamura Yasuyuki, Okayama Akira, Ueshima Hirotsugu, NIPPON DATA80 Research Group DATA80 Research Group

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 12 （ 9 ） 944 - 949 2010年09月

Few studies have reported the relationship between smoking in middle age and long-term risk of impaired activities of daily living (ADL). We analyzed 2,276 men and women aged 47-59 years at the baseline survey of NIPPON DATA80 in 1980. At the follow-up survey in 1999, ADL was surveyed among 1890 survivors. Multivariate-adjusted odds ratio (AOR) and 95% CI of impaired ADL or of composite outcome of either death or impaired ADL according to baseline smoking status were calculated by multiple logistic regression analyses. In 1999, 386 participants were dead, and 75 participants had impaired ADL. Compared with nonsmokers, AOR (95% CI) of impaired ADL was significantly higher in current smokers at baseline (odds ratio [OR] 2.11 [1.09-4.06]). Compared with nonsmokers, AOR of impaired ADL was higher as the number of cigarettes increased (OR 2.04 [1.02-4.06] for <20 cigarettes/day and OR 2.35 [0.94-5.88] for >20 cigarettes/day; p for trend = .04). AOR of composite outcome for current smoking was 1.83 (1.37-2.41). Smoking in middle age would increase future risks of impaired ADL. Smoking cessation may be important to prevent future impairment of ADL as well as death.

Cigarette smoking in middle age and a long-term risk of impaired activities of daily living: NIPPON DATA80.

Takashima N, Miura K, Hozawa A, Okamura T, Hayakawa T, Okuda N, Kadowaki T, Murakami Y, Kita Y, Nakamura Y, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 12 （ 9 ） 944 - 9 2010年09月

研究論文（学術雑誌）, ISSN 1462-2203

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Cigarette smoking in middle age and a long-term risk of impaired activities of daily living: NIPPON DATA80.

Takashima N, Miura K, Hozawa A, Okamura T, Hayakawa T, Okuda N, Kadowaki T, Murakami Y, Kita Y, Nakamura Y, Okayama A, Ueshima H, NIPPON DATA80 Research Group.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 12 （ 9 ） 944 - 9 2010年09月

研究論文（学術雑誌）, ISSN 1462-2203

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Relationship of the polyunsaturated to saturated fatty acid ratio to cardiovascular risk factors and metabolic syndrome in Japanese: the INTERLIPID study.

Guo Z, Miura K, Turin TC, Hozawa A, Okuda N, Okamura T, Saitoh S, Sakata K, Nakagawa H, Okayama A, Yoshita K, Kadowaki T, Choudhury SR, Nakamura Y, Rodriguez BL, Curb DJ, Elliott P, Stamler J, Ueshima H

Journal of atherosclerosis and thrombosis 17 （ 8 ） 777 - 84 2010年08月

研究論文（学術雑誌）, ISSN 1340-3478

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Relationship of the polyunsaturated to saturated fatty acid ratio to cardiovascular risk factors and metabolic syndrome in Japanese: the INTERLIPID study.

Journal of atherosclerosis and thrombosis 17 （ 8 ） 777 - 84 2010年08月

研究論文（学術雑誌）, ISSN 1340-3478

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Medical expenditures of men with hypertension and/or a smoking habit: a 10-year follow-up study of National Health Insurance in Shiga, Japan.

Nakamura K, Okamura T, Hayakawa T, Kanda H, Okayama A, Ueshima H, Health Promotion Research Committee of the Shiga National Health Insurance Organizations.

Hypertension research : official journal of the Japanese Society of Hypertension 33 （ 8 ） 802 - 807 2010年08月

研究論文（学術雑誌）, ISSN 0916-9636

Hypertension and smoking are major causes of disability and death, especially in the Asia-Pacific region, where there is a high prevalence of a combination of these two risk factors. We attempted to measure the medical expenditures of a Japanese male population with hypertension and/or a smoking habit over a 10-year period of follow-up. A cohort study was conducted that investigated the medical expenditures due to a smoking habit and/or hypertension during the decade of the 1990s using existing data on physical status and medical expenditures. The participants included 1708 community-dwelling Japanese men, aged 40-69 years, who were classified into the following four categories: neither smoking habit nor hypertension, smoking habit alone, hypertension alone or both smoking habit and hypertension. Hypertension was defined as a systolic blood pressure of 140 mm Hg, a diastolic blood pressure of 90 mm Hg or taking antihypertensive medications. In the study cohort, 24.9% had both a smoking habit and hypertension. During the 10-year follow-up period, participants with a smoking habit alone (18 444 Japanese yen per month), those with hypertension alone (21 252 yen per month) and those with both a smoking habit and hypertension (31 037 yen per month) had increased personal medical expenditures compared with those without a smoking habit and hypertension (17 418 yen per month). Similar differences were observed even after adjustment for other confounding factors (P<0.01). Japanese men with both a smoking habit and hypertension incurred higher medical expenditures compared with those without a smoking habit, hypertension or their combination. © 2010 The Japanese Society of Hypertension All rights reserved.

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Circulating levels of 8 cytokines and marine n-3 fatty acids and indices of obesity in Japanese, white, and Japanese American middle-aged men.

Sekikawa A, Kadowaki T, Curb JD, Evans RW, Maegawa H, Abbott RD, Sutton-Tyrrell K, Okamura T, Shin C, Edmundowicz D, Kadota A, Choo J, El-Saed A, Ueshima H, Kuller LH, ERA JUMP Study group.

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 30 （ 7 ） 541 - 548 2010年07月

研究論文（学術雑誌）, ISSN 1079-9907

This study examines the differences in circulating levels of cytokines among Japanese in Japan (JJ), Japanese Americans (JA), and whites and their associations with obesity and marine n-3 fatty acids (FA) in a cross-sectional population-based study of 297 men aged 40-49 (100 JJ, 99 whites, and 98 JA). Experimental studies show that cytokines are associated with obesity positively and marine n-3 FA inversely. Serum interleukin-1α (IL-1α), IL-1 receptor agonist (IL-1ra), IL-4, IL-8, IL-10, inducible protein-10 (IP-10), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and marine n-3 FA were determined. Body mass index (BMI), waist circumference, and computed tomography-measured visceral and subcutaneous adipose tissues were determined. The JJ had significantly lower levels of IL-1α, IL-4, IL-8, MCP-1, and TNF-α than whites and JA. Whites and JA had similar levels of IL-1α, IL-4, and IL-8 whereas whites had significantly higher levels of MCP-1 and TNF-α than JA. The JJ were least obese (BMI (kg/m²), mean-standard deviation) 23.6-2.8, 27.9-4.6, and 27.9-4.5 for JJ, whites, and JA, respectively. The JJ had marine n-3 FA about 100% higher than whites and JA (serum marine n-3 FA (%), median (interquartile range) 8.79 (7.41, 11.16), 3.47 (2.63, 4.83), and 4.44 (3.33, 6.01) for JJ, whites, and JA, respectively). Generally cytokines had weak and nonsignificant associations with indices of obesity and nonsignificant associations with marine n-3 FA. BMI had significant inverse associations with IL-1α, IL-4, and IL-8 in JA (P?<?0.05). Marine n-3 FA had marginally significant inverse associations with IL-8 in JJ (P?=?0.055) and TNF-α in whites (P?=?0.076). The JJ had lower levels of many cytokines than whites and JA. Generally cytokines had weak and nonsignificant associations with indices of obesity and marine n-3 FA. Further investigation is needed to determine why JJ had lower circulating levels of cytokines. © Mary Ann Liebert, Inc.

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Lifetime risk of stroke in Japan.

Turin TC, Kokubo Y, Murakami Y, Higashiyama A, Rumana N, Watanabe M, Okamura T

Stroke 41 （ 7 ） 1552 - 1554 2010年07月

研究論文（学術雑誌）, ISSN 0039-2499

Background and purpose: Lifetime risk (LTR) is an epidemiologic measure that expresses the probability of disease in the remaining lifetime for an index age. The LTR for stroke has not been reported for the Japanese population. Methods: We included all participants from the Suita Study who were cardiovascular disease-free at baseline. Age (in years) was used as the time scale. Age-specific stroke incidence and all-cause mortality were calculated with the person-year method, and we estimated the sex-and index age-specific LTRs of first-ever stroke and its subtypes, taking into account the competing risk of death. Results: We followed up 5498 participants from 1989 to 2005 for a total of 67 475 person-years. At age 55 years, the LTR for stroke, after accounting for competing risks of death, was 18.3% for men and 19.6% for women. The LTR for cerebral infarction was 14.6% for men and 15.5% for women, and the LTR for intracerebral hemorrhage was 2.4% for men and 1.4% for women at the index age of 55 years. The LTR for stroke remained similar across other index ages of 45, 55, and 65 years. Conclusions: The observed probabilities illustrate that 1 in 5 men and women of middle age will experience stroke in their remaining lifetime. This easy understandable information can be used as an important index to assist in public health education and planning. Copyright © 2010 American Heart Association. All rights reserved.

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Relationship among physical activity, smoking, drinking and clustering of the metabolic syndrome diagnostic components.

Katano S, Nakamura Y, Nakamura A, Murakami Y, Tanaka T, Nakagawa H, Takebayashi T, Yamato H, Okayama A, Miura K, Okamura T, Ueshima H, HIPOP-OHP Research Group.

Journal of atherosclerosis and thrombosis 17 （ 6 ） 644 - 650 2010年06月

研究論文（学術雑誌）, ISSN 1340-3478

Aim: To examine the relation between lifestyle and the number of metabolic syndrome (MetS) diagnostic components in a general population, and to find a means of preventing the development of MetS components. Methods: We examined baseline data from 3,365 participants (2,714 men and 651 women) aged 19 to 69 years who underwent a physical examination, lifestyle survey, and blood chemical examination. The physical activity of each participant was classified according to the International Physical Activity Questionnaire (IPAQ). We defined four components for MetS in this study as follows: 1) high BP: systolic BP ≥ 130 mmHg or diastolic BP ≥85 mmHg, or the use of antihypertensive drugs; 2) dyslipidemia: high-density lipoprotein-cholesterol concentration <40 mg/dL, triglycerides concentration ≥150 mg/dL, or on medication for dyslipidemia; 3) Impaired glucose tolerance: fasting blood sugar level ≥110 mg/d, or if less than 8 hours after meals ≥140 mg/dL), or on medication for diabetes mellitus; 4) obesity: body mass index ≥25 kg/m². Results: Those who had 0 to 4 MetS diagnostic components accounted for 1,726, 949, 484, 190, and 16 participants, respectively, in the Poisson distribution. Poisson regression analysis revealed that independent factors contributing to the number of MetS diagnostic components were being male (regression coefficient b = 0.600, p<0.01), age (b = 0.027, p<0.01), IPAQ class (b = -0.272, p = 0.03), and alcohol consumption (b = 0.020, p = 0.01). The contribution of current smoking was not statistically significant (b = -0.067, p = 0.76). Conclusion: Moderate physical activity was inversely associated with the number of MetS diagnostic components, whereas smoking was not associated.

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Serum n-6 fatty acids and lipoprotein subclasses in middle-aged men: the population-based cross-sectional ERA-JUMP study.

Choo J, Ueshima H, Curb JD, Shin C, Evans RW, El-Saed A, Kadowaki T, Okamura T, Nakata K, Otake T, Miura K, Abbott RD, Sutton-Tyrrell K, Edmundowicz D, Kuller LH, Sekikawa A, ERA-JUMP Study Group.

The American journal of clinical nutrition 91 （ 5 ） 1195 - 1203 2010年05月

研究論文（学術雑誌）, ISSN 0002-9165

Background: The associations of serum omega-6 (n-6) fatty acids with lipoprotein subclasses at the population level are uncertain. Objective: We aimed to examine associations between major n-6 fatty acids [ie, linoleic acid (LA, 18:2n-6) and arachidonic acid (AA, 20:4n-6)] and the lipoprotein subclasses VLDL, LDL, and HDL. Design: We conducted a cross-sectional study in 1098 participants using population-based data from US white, Japanese American, Japanese, and Korean men aged 40-49 y. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Multiple linear regression models as a function of each fatty acid were used after adjustment for age, population, body mass index, pack-years of smoking, alcohol consumption, diabetes, hypertension, and omega-3 (n-3) and trans fatty acids. Results: Serum LA was inversely associated with large VLDL (β = -0.62, P < 0.001), total LDL (β = -22.08, P < 0.001), and small LDL (β = -31.89, P < 0.001) particle concentrations and VLDL size (β = -0.72, P < 0.001). Serum LA was positively associated with large HDL particle concentration (β = 0.21, P < 0.001) and HDL size (β = 0.03, P < 0.001). The patterns of association of AA with large VLDL and large HDL particle concentrations were comparable with those of LA. Conclusions: At the population level, higher serum concentrations of LA were significantly associated with lower concentrations of total LDL particles. Higher serum concentrations of LA and AA were significantly associated with a lower concentration of large VLDL particles and a higher concentration of large HDL particles. These associations were consistent across the population groups. This trial was registered at clinicaltrials.gov as NCT00069797. © 2010 American Society for Nutrition.

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New diagnosis criteria for diabetes with hemoglobin A1c and risks of macro-vascular complications in an urban Japanese cohort: the Suita study.

Watanabe M, Kokubo Y, Higashiyama A, Ono Y, Okayama A, Okamura T

Diabetes research and clinical practice 88 （ 2 ） e20 - 3 2010年05月

研究論文（学術雑誌）, ISSN 0168-8227

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LOX index, a novel predictive biochemical marker for coronary heart disease and stroke.

Inoue N, Okamura T, Kokubo Y, Fujita Y, Sato Y, Nakanishi M, Yanagida K, Kakino A, Iwamoto S, Watanabe M, Ogura S, Otsui K, Matsuda H, Uchida K, Yoshimoto R, Sawamura T

Clinical chemistry 56 （ 4 ） 550 - 558 2010年04月

研究論文（学術雑誌）, ISSN 0009-9147

BACKGROUND: Lectin-like oxidized LDL receptor 1 (LOX-1) is implicated in atherothrombotic diseases. Activation of LOX-1 in humans can be evaluated by use of the LOX index, obtained by multiplying the circulating concentration of LOX-1 ligands containing apolipoprotein B (LAB) times that of the soluble form of LOX-1 (sLOX-1) [LOX index = LAB X sLOX-1]. This study aimed to establish the prognostic value of the LOX index for coronary heart disease (CHD) and stroke in a community-based cohort. METHODS: An 11-year cohort study of 2437 residents age 30-79 years was performed in an urban area located in Japan. Of these, we included in the analysis 1094 men and 1201 women without history of stroke and CHD. We measured LAB and sLOX-1 using ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody and with 2 monoclonal antibodies against LOX-1, respectively. RESULTS: During the follow-up period, there were 68 incident cases of CHD and 91 cases of stroke (with 60 ischemic strokes). Compared with the bottom quartile, the hazard ratio (HR) of the top quartile of LOX index was 1.74 (95% CI 0.92-3.30) for stroke and 2.09 (1.00-4.35) for CHD after adjusting for sex, age, body mass index, drinking, smoking, hypertension, diabetes, non-HDL cholesterol, and use of lipid-lowering agents. Compared with the bottom quartile of LOX index, the fully adjusted HRs for ischemic stroke were consistently high from the second to the top quartile: 3.39 (95% CI 1.34-8.53), 3.15 (1.22-8.13) and 3.23 (1.24-8.37), respectively. CONCLUSIONS: Higher LOX index values were associated with an increased risk of CHD. Low LOX index values may be protective against ischemic stroke. © 2009 American Association for Clinical Chemistry.

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The relationship between waist circumference and the risk of stroke and myocardial infarction in a Japanese urban cohort: the Suita study.

Furukawa Y, Kokubo Y, Okamura T, Watanabe M, Higashiyama A, Ono Y, Kawanishi K, Okayama A, Date C

Stroke 41 （ 3 ） 550 - 553 2010年03月

研究論文（学術雑誌）, ISSN 0039-2499

Background and Purpose:Body mass index is most commonly used as the obesity index. Recently, waist circumference (WC) has been shown to be associated with the risk of cardiovascular disease (CVD). However, no studies have observed an association between WC and CVD in Japan. We examined the relationships of WC and body mass index with CVD in a Japanese urban population. Methods-We studied 5474 Japanese individuals (aged 30 to 79 years without CVD at baseline) who completed a baseline survey and received follow-up through December 2005. WC was measured at the umbilical level of participants in the standing position to the nearest 1 cm. The Cox proportional hazard ratios for CVD according to the quartiles of WC were calculated after adjustment for age, smoking, and drinking status. Results-During a mean follow-up of 11.7 years, 207 strokes and 133 myocardial infarctions were documented. In women, compared with the lowest quartile (WC <70 cm), the hazard ratio (95% CIs) after adjusting for age, smoking, and drinking in the highest quartile (WC ≥84 cm) were 1.85 (1.03 to 3.31) for CVD and 2.64 (1.16 to 6.03) for stroke. However, no such relationships of WC with CVD or stroke risk were observed in men. After further adjustment of hypertension, diabetes, and hypercholesterolemia, all of the mentioned relationships were not statistically significant. No associations of body mass index with CVD or strokes were observed. Conclusions:s:WC may be a better predictor for CVD or stroke in Japanese women. © 2010 American Heart Association, Inc.

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Triglycerides and non-high-density lipoprotein cholesterol and the incidence of cardiovascular disease in an urban Japanese cohort: the Suita study.

Okamura T, Kokubo Y, Watanabe M, Higashiyama A, Ono Y, Miyamoto Y, Yoshimasa Y, Okayama A

Atherosclerosis 209 （ 1 ） 290 - 294 2010年03月

研究論文（学術雑誌）, ISSN 0021-9150

Objective: The impact of elevated triglycerides (TG) and non-high density lipoprotein cholesterol (non-HDLC) on the incidence of stroke and myocardial infarction (MI) has not been well evaluated in Asian populations such as in Japan, which have a lower incidence of myocardial infarction, but a higher risk of stroke than Western populations. Methods: The authors conducted an 11.7-year prospective study ending in 2005 of 5098 Japanese aged 30-79 living in an urban population, initially free of stroke or MI. The relationship between serum lipids and the risk for stroke and MI was determined by dividing the participants into four groups stratified by the combination of serum levels of TG and non-HDLC. The cut-off value was 1.7 mmol/L for TG and 4.9 mmol/L for non-HDLC. Results and conclusion: The total person-years were 59,774 (27,461 for men and 32,313 for women). During the follow-up period, there were 113 cases of MI and 180 of stoke (with 116 cerebral infarctions). Compared with the low TG/low non-HDLC group, the hazard ratio (95% confidence interval) for MI in the high TG/high non-HDLC group was 2.55 (1.53-4.24) after adjustment for other cardiovascular risk factors. The hazard ratio for cerebral infarction in the high TG alone group was 1.63 (1.03-2.56); however, the risk of cerebral infarction was not significantly increased in the other groups. High serum levels of TG and non-HDLC are both important targets for the prevention of cardiovascular disease in Japan. © 2009 Elsevier Ireland Ltd. All rights reserved.

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Association of the functional variant in the 3-hydroxy-3-methylglutaryl-coenzyme a reductase gene with low-density lipoprotein-cholesterol in Japanese.

Hiura Y, Tabara Y, Kokubo Y, Okamura T, Goto Y, Nonogi H, Miki T, Tomoike H, Iwai N

Circulation journal : official journal of the Japanese Circulation Society 74 （ 3 ） 518 - 522 2010年03月

研究論文（学術雑誌）, ISSN 1346-9843

Background: The association between single nucleotide polymorphisms (SNPs) at 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) and low-density lipoprotein-cholesterol (LDL-C) levels has been well replicated in genome-wide association studies (GWAS) of white populations. Recently, the common intronic SNP of HMGCR (rs3846662) has been reported to be a functional variant, influencing the alternative splicing of exon 13. The aim of this study was to examine the association between rs3846662 of HMGCR and the level of LDL-C in Japanese. Methods and Results: Significant differences in LDL-C levels were observed among the genotypes of rs3846662 (P=0.0002 (n=2,686) and P=0.004 (n=2,110)) for the Suita and Ehime samples, respectively. The G allele of rs3846662 was associated with higher LDL-C levels (ß, 3.56; P=4.91×10-5). Consistent with this observation, the risk G allele at rs3846662 was more prevalent in subjects with myocardial infarction (MI) (n=701) than in subjects without MI (n=3,118); 0.559 and 0.511 in MI cases and controls, respectively (nominal P=0.0038). The odds ratio adjusted for age, sex, diabetes, hypertension, and drinking and smoking habits was 1.15 (95% confidence interval 1.04-1.28; P=0.0075). Conclusions: The previously reported association of rs3846662 with LDL-C levels was replicated in the present Suita and Ehime samples. The LDL-associated SNP, rs3846662, appears to confer susceptibility to MI in Japanese.

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Relation of Gamma-glutamyltransferase and alcohol drinking with incident diabetes: the HIPOP-OHP study.

Hozawa A, Okamura T, Tanaka T, Miura K, Kikuchi Y, Kadowaki T, Yoshita K, Takebayashi T, Tamaki J, Minai J, Tada T, Chiba N, Okayama A, Ueshima H

Journal of atherosclerosis and thrombosis 17 （ 2 ） 195 - 202 2010年02月

研究論文（学術雑誌）, ISSN 1340-3478

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Relation of Gamma-glutamyltransferase and alcohol drinking with incident diabetes: the HIPOP-OHP study.

Hozawa A, Okamura T, Tanaka T, Miura K, Kikuchi Y, Kadowaki T, Yoshita K, Takebayashi T, Tamaki J, Minai J, Tada T, Chiba N, Okayama A, Ueshima H

Journal of atherosclerosis and thrombosis 17 （ 2 ） 195 - 202 2010年02月

研究論文（学術雑誌）, ISSN 1340-3478

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Changes in Weight, cardiovascular risk factors and estimated risk of coronary heart disease following smoking cessation in Japanese male workers: HIPOP-OHP study.

Tamura U, Tanaka T, Okamura T, Kadowaki T, Yamato H, Tanaka H, Nakamura M, Okayama A, Ueshima H, Yamagata Z, HIPOP-OHP research group.

Journal of atherosclerosis and thrombosis 17 （ 1 ） 12 - 20 2010年02月

研究論文（学術雑誌）, ISSN 1340-3478

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Relationship between 5-year decline in instrumental activity of daily living and accumulation of cardiovascular risk factors: NIPPON DATA90.

Hayakawa T, Okamura T, Okayama A, Kanda H, Watanabe M, Kita Y, Miura K, Ueshima H

Journal of atherosclerosis and thrombosis 17 （ 1 ） 64 - 72 2010年02月

研究論文（学術雑誌）, ISSN 1340-3478

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Changes in Weight, cardiovascular risk factors and estimated risk of coronary heart disease following smoking cessation in Japanese male workers: HIPOP-OHP study.

Tamura U, Tanaka T, Okamura T, Kadowaki T, Yamato H, Tanaka H, Nakamura M, Okayama A, Ueshima H, Yamagata Z, HIPOP-OHP research group.

Journal of atherosclerosis and thrombosis 17 （ 1 ） 12 - 20 2010年02月

研究論文（学術雑誌）, ISSN 1340-3478

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Relationship between 5-year decline in instrumental activity of daily living and accumulation of cardiovascular risk factors: NIPPON DATA90.

Hayakawa T, Okamura T, Okayama A, Kanda H, Watanabe M, Kita Y, Miura K, Ueshima H

Journal of atherosclerosis and thrombosis 17 （ 1 ） 64 - 72 2010年02月

研究論文（学術雑誌）, ISSN 1340-3478

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γ-Glutamyltransferase and mortality risk from heart disease and stroke in Japanese men and women

CVD Prevention and Control 5 （ 1 ） 27 - 34 2010年01月

ISSN 1875-4570

Background: Studies have shown that baseline serum γ- glutamyltransferase (GGT) is independently associated with cardiovascular disease (CVD) risk in men and women. However, less is known whether GGT is similarly associated with both stroke and heart disease (HD) risk in Asia. We examined an association between serum GGT and deaths from stroke and HD in Japanese men and women. Methods: From 1990 to 2005, we followed 7488 adults (3089 men) randomly selected from 300 districts throughout Japan, aged 30-95 with no history of coronary disease nor stroke at baseline. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) according to sex-specific GGT strata. Results: During the study period, observed deaths from HD and stroke were 165 (83 men), and 135 (66 men), respectively. After adjustment for confounding factors, HRs of HD death for 25th, 50th, 75th, and 90th GGT percentiles in reference to the lowest GGT stratum were 1.61, 2.28, 2.48, and 4.59 in women (P for trend = 0.001), and 0.90, 0.74, 1.42, and 1.56 in men (P for trend = 0.250). The corresponding HRs of total stroke death were 1.52, 0.95, 1.22, and 1.34 in women (P for trend = 0.785), and 0.75, 0.91, 1.26, and 1.02 in men (P for trend = 0.642). Results were similar when analysis was limited to never-drinkers. Conclusion: This cohort study of representative Japanese men and women suggested that baseline GGT independently predicts future HD mortality risk, especially in women, but not stroke mortality risk in Asian. © 2010 World Heart Federation. Published by Elsevier Ltd. All rights reserved.

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Relationship of the polyunsaturated to saturated fatty acid ratio to cardiovascular risk factors and metabolic syndrome in japanese

Guo Zhao, Miura Katsuyuki, Turin Tanvir Chowdhury, Hozawa Atsushi, Okuda Nagako, Okamura Tomonori, Saitoh Shigeyuki, Sakata Kiyomi, Nakagawa Hideaki, Okayama Akira, Yoshita Katsushi, Kadowaki Takashi, Choudhury Sohel R., Nakamura Yasuyuki, Rodriguez Beatriz L., Curb J. David, Elliott Paul, Stamler Jeremiah, Ueshima D. Hirotsugu

Journal of Atherosclerosis and Thrombosis 17 （ 8 ） 777 - 784 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: There have been few studies on the relationships of the dietary polyunsaturated to saturated fatty acid ratio (P/S) to cardiovascular risk factors and metabolic syndrome. We hypothesized that there would be favorable relationships. & Methods: Metabolic cardiovascular risk factors from dietary nutrient intake were investigated in 1,004 men and women aged 40-59 years from 4 population samples of Japanese. Multiple linear regression analysis was used to examine the relationship of the dietary P/S ratio to the following risk factors: hemoglobin A1c, blood pressure, serum triglycerides, LDL and total cholesterol, and HDL-cholesterol. Adjusted odds ratio of having metabolic syndrome was also calculated. & Results: The dietary P/S ratio was significantly and inversely related to serum total and LDL cholesterol with control for possible confounding variables. We did not find any significant relationship between the P/S ratio and single metabolic risk factors or the prevalence of metabolic syndrome. & Conclusions: Managing the P/S ratio is important to control serum LDL-cholesterol; however, increasing the P/S ratio may not improve metabolic risk factors. Other countermeasures, such as weight control, greater physical activity, and smoking cessation should be recommended to prevent and control metabolic syndrome.

一般市民の飲酒、喫煙習慣と脳卒中危険因子としての多量飲酒、喫煙の認識.

森本明子、宮松直美、岡村智教、中山博文、盛永美保、豊田章宏、鈴木一夫、畑隆志、山口武典.

日本アルコール・薬物医学会雑誌 45 （ 5 ） 411-419 2010年

研究論文（学術雑誌）, 共著, 査読有り

Comparison of the National Nutritional Survey in Japan estimated individual-based nutritional data and NIPPON DATA80 food frequency questionnaires.

Nakamura Y, Okuda N, Turin TC, Fujiyoshi A, Okamura T, Hayakawa T, Matsumura Y, Miura K, Ueshima H, NIPPON DATA80/90 Research Group.

Journal of epidemiology 20 （ SUPPL.3 ） S582 - 6 2010年

研究論文（学術雑誌）, ISSN 0917-5040

Background: The National Nutritional Survey in Japan (NNSJ) was initiated in 1946. Using the majority of the participants for NNSJ, the National Survey on Circulatory Disorders has been conducted every 10 year since 1960. We performed a comparative study of the NNSJ80 estimated individual-based nutritional data by comparing those with NIPPON DATA80 food frequency questionnaires (FFQ) data. Methods: A total of 10 546 community residents from 300 randomly selected districts participated in the both surveys in 1980. At baseline, history, physical, and blood biochemical measurement and a nutritional survey by FFQ were performed individually. From household-based NNSJ80 data, we estimated nutrient intakes of each household member by dividing household intake data proportionally using average intakes by sex and age groups calculated for NNSJ95. We re-categorized NNSJ80 estimated data to correspond to NIPPON DATA80 FFQ categories. Data were analyzed in men and women separately. Results: Cross tables showed fairly good agreement of the two categories. The majorities of participants situated on the diagonally aligned cells or the next to them. Weighted kappa ranged from 0.152 to 0.241. Spearman's rank correlation coefficients between the two categories ranged from 0.224 to 0.338, and those between NNSJ80 continuous data and NIPPON DATA80 categorical data ranged from 0.237 to 0.354. All these values have P < 0.001. Conclusions: These results may indicate that the present nutritional estimation method is applicable to, further studies. © 2010 by the Japan Epidemiological Association.

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Fatty acids intakes and serum lipid profiles: NIPPON DATA90 and the national nutrition monitoring.

Nakamura Y, Okuda N, Turin TC, Fujiyoshi A, Okamura T, Hayakawa T, Yoshita K, Miura K, Ueshima H, NIPPON DATA80/90 Research Group.

Journal of epidemiology 20 （ SUPPL.3 ） S544 - 8 2010年

研究論文（学術雑誌）, ISSN 0917-5040

Background: The National Nutritional Survey in Japan (NNSJ) was initiated in 1946. Using the majority of the participants for NNSJ, the National Survey on Circulatory Disorders (NSCD) has been conducted every 10 year since 1960. We compared fatty acids intakes obtained from NNSJ and serum lipid profiles from NSCD conducted in 1990. Methods: A total of 8344 community residents (4856 women and 3488 men, age ≥ 30) from 300 randomly selected districts participated in the both surveys in 1990. At baseline, history, physical, and blood biochemical measurement and a nutritional survey were performed. We estimated nutrient intakes of each household member by dividing household intake data proportionally using average intakes by sex and age groups calculated for NNSJ95. Results: Total fat, saturated fatty acids (SFA), poly-unsaturated fatty acids (PUFA), dietary cholesterol, and Keys dietary lipid factor (KEYS) were inversely associated with age in both men and women (all Ps < 0.001). In women, age and body mass index (BMI) adjusted serum total cholesterol (TC), high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol (LDLc) were positively associated with SFA, total fat intakes (%kcal), and with KEYS (P < 0.001). In men, age-BMI adjusted HDLc was not associated with SFA, total fat intakes, and with KEYS factors unlike in women. Other associations were similar to those in women. Conclusions: The total fatty acids, SFA intakes, and KEYS lipid factor obtained from NNSJ were significantly associated with serum total and LDL cholesterol from the National Survey on Circulatory Disorders conducted in 1990. © 2010 by the Japan Epidemiological Association.

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Population attributable fraction of smoking and metabolic syndrome on cardiovascular disease mortality in Japan: a 15-year follow up of NIPPON DATA90.

Takashima N, Miura K, Hozawa A, Kadota A, Okamura T, Nakamura Y, Hayakawa T, Okuda N, Fujiyoshi A, Nagasawa SY, Kadowaki T, Murakami Y, Kita Y, Okayama A, Ueshima H, NIPPON DATA 90 Research Group.

BMC public health 10 306 2010年

研究論文（学術雑誌）

Background. Smoking and metabolic syndrome are known to be related to cardiovascular diseases (CVD) risk. In Asian countries, prevalence of obesity has increased and smoking rate in men is still high. We investigated the attribution of the combination of smoking and metabolic syndrome (or obesity) to excess CVD deaths in Japan. Methods. A cohort of nationwide representative Japanese samples, a total of 6650 men and women aged 30-70 at baseline without history of CVD was followed for 15 years. Multivariate-adjusted hazard ratio for CVD death according to the combination of smoking status and metabolic syndrome (or obesity) was calculated using Cox proportional hazard model. Population attributable fraction (PAF) of CVD deaths was calculated using the hazard ratios. Results. During the follow-up period, 87 men and 61 women died due to CVD. The PAF component of CVD deaths in non-obese smokers was 36.8% in men and 11.3% in women, which were higher than those in obese smokers (9.1% in men and 5.2% in women). The PAF component of CVD deaths in smokers without metabolic syndrome was 40.9% in men and 11.9% in women, which were also higher than those in smokers with metabolic syndrome (7.1% in men and 3.9% in women). Conclusion. Our results indicated that a large proportion of excess CVD deaths was observed in smokers without metabolic syndrome or obesity, especially in men. These findings suggest that intervention targeting on smokers, irrespective of the presence of metabolic syndrome, is still important for the prevention of CVD in Asian countries. © 2010 Takashima et al; licensee BioMed Central Ltd.

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What psychosocial characteristics are associated with smoking cessation behavior and readiness to quit smoking among Japanese male ever-smokers with type 2 diabetes mellitus?

Morimoto A, Miyamatsu N, Okamura T, Hozawa A, Kadota A, Morinaga M, Ogita M, Kashiwagi A, Ueshima H

Journal of atherosclerosis and thrombosis 17 （ 4 ） 361 - 368 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: The relationship between psychosocial characteristics and smoking cessation behavior was examined among Japanese male ever-smokers with type 2 diabetes mellitus. Methods: The psychosocial characteristics and smoking cessation behavior of 441 male ever-smokers with type 2 diabetes mellitus were investigated. Personality was assessed using an egogram (five ego states: the Critical Parent, Nurturing Parent, Adult, Free Child, and Adapted Child) and each patient was classified into a high score or low score group based on the median. The current smokers were divided into 2 categories according to their readiness to quit smoking. Results: In multivariate analyses, the ever-smokers with a high Adult score had a lower risk of current smoking (OR=0.67, 95%CI=0.41-0.93), the ever-smokers with a high Free Child score were over 3 times more likely to currently smoke (OR=3.12, 95%CI=1.97-4.97), and the ever-smokers who had a low educational background had a higher risk of current smoking (OR=3.02, 95% CI=1.73-5.28). In addition, the current smokers with a high Adult score had a lower risk of being in the immotive and precontemplation stage (OR=0.55, 95%CI=0.24-0.96). The current smokers who had a low educational background had a higher risk of being in the immotive and precontemplation stage (OR=2.13, 95%CI=1.08-5.42). Conclusion: There is a need to develop a smoking cessation program for patients with high "Free Child" scores and a "low education level".

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Changes in weight, cardiovascular risk factors and estimated risk of coronary heart disease following smoking cessation in Japanese male workers

Tamura Unai, Tanaka Taichiro, Okamura Tomonori, Kadowaki Takashi, Yamato Hiroshi, Tanaka Hideo, Nakamura Masakazu, Okayama Akira, Ueshima Hirotsugu, Yamagata Zentaro

Journal of Atherosclerosis and Thrombosis 17 （ 1 ） 12 - 20 2010年

研究論文（学術雑誌）, 査読有り, ISSN 1340-3478

Aim: It is well established that people gain weight after smoking cessation; however, changes in cardiovascular risk factors and the estimated risk of coronary heart disease following smoking cessation have yet to be fully clarified. Methods: The participants were 1,995 Japanese male workers at 11 workplaces who participated continuously in the High-risk and Population Strategy for Occupational Health Promotion (HIPOPOHP) study. Participants with a smoking habit had cardiovascular risk factors measured at baseline and over a 4-yr period. Their estimated incidence risk of coronary heart disease was calculated by a formula based on a previous cohort study. Results: Successful abstainers who had stopped smoking for at least 6 months at the end of the follow-up period had weight gains of approximately 2 kg. These subjects had significant worsening of the following factors compared to continuing smokers: systolic and diastolic blood pressure, total cholesterol, triglyceride and fasting blood sugar levels. In contrast, HDL-cholesterol levels improved significantly. When the overall instantaneous incidence risk of coronary heart disease prior to smoking cessation was assumed to be 1.00, the estimated risk was 0.76 (95%CI: 0.68-0.85) in successful abstainers due mainly to smoking cessation, despite weight gain. Conclusion: Although smoking cessation leads to weight gain, the estimated risk of coronary heart disease was decreased markedly by smoking cessation.

Relationships between protein intake and renal function in a Japanese general population: NIPPON DATA90.

Higashiyama A, Watanabe M, Kokubo Y, Ono Y, Okayama A, Okamura T, NIPPON DATA80/90 Research Group.

Journal of epidemiology 20 （ SUPPL.3 ） S537 - 43 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: It has been considered that reducing protein intake is one of important measures to delay the progression of chronic kidney disease (CKD). However, the relationship between protein intake and renal function is still uncertain, especially in relatively healthy general population. Methods: 7404 individuals (3099 men and 4305 women) who participated in both National Survey on Circulatory Disorders and National Nutrition Survey in 1990 and were free from past history of renal diseases were included in the present study. We estimated sex-specific age- and multivariate-adjusted glomerular filtration rate (GFR) and odds ratios for the presence of CKD according to the quartiles of protein (total, animal, vegetable) intake per body weight (kg). Results: There were significant differences in each protein intake among the age groups in both men and women. Both participants with and without CKD took more protein intake than that of each recommended level. There were positive relationships between GFR and the quartiles of each protein intake in both sexes. The odds ratios for the presence of CKD were significantly decreased in the higher quartile of protein intake in women. Conclusions: The higher protein intake was associated with higher GFR in both sexes and low prevalence of CKD in women. However, further studies are needed to conclude the relationships between protein intake and renal function. © 2010 by the Japan Epidemiological Association.

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A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia.

Harada K, Miyamoto Y, Morisaki H, Ohta N, Yamanaka I, Kokubo Y, Makino H, Harada-Shiba M, Okayama A, Tomoike H, Okamura T, Saito Y, Yoshimasa Y, Morisaki T

Journal of atherosclerosis and thrombosis 17 （ 2 ） 131 - 140 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: The autosomal recessive hypercholesterolemia (ARH) gene is located on chromosome 1p35 and encodes a 308-amino acid protein containing a phosphotyrosine-binding domain. Several researchers have identified mutations of ARH that cause autosomal recessive hypercholesterolemia; however, it remains unknown whether this gene is involved in common hypercholesterolemia. Methods and Results: We searched for polymorphisms of the ARH gene by denaturing high-performance liquid chromatography and direct sequencing. We identified 18 single nucleotide polymorphisms of the gene, including 9 novel polymorphisms, and determined 2 haplotype blocks. No association was observed between common hypercholesterolemia and any polymorphisms or haplotypes of the ARH gene; however, we newly identified a rare Thr56Met missense mutation located in the phosphotyrosine-binding domain, which is the functional domain responsible for cholesterol metabolism. Among 1,800 Japanese individuals enrolled in the Suita study, only 4 were heterozygous for Thr56Met and all had hypercholesterolemia. The total cholesterol level and low-density lipoprotein cholesterol level of diabetic patients with the Thr56Met missense mutation was 276.3 ± 13.8 mg/dL and 185.3 ± 7.37 mg/dL, respectively. Conclusions: Because the Thr56Met missense mutation occurs in an orthologously conserved functional domain and all subjects with the mutation had hypercholesterolemia resembling familiar hypercholesterolemia, it may be a cause of familial hypercholesterolemia.

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Integration of data from NIPPON DATA80/90 and National Nutrition Survey in Japan: for cohort studies of representative Japanese on nutrition.

Okuda N, Miura K, Yoshita K, Matsumura Y, Okayama A, Nakamura Y, Okamura T, Saitoh S, Sakata K, Ojima T, Turin TC, Ueshima H, NIPPON DATA80/90 Research Group.

Journal of epidemiology 20 （ SUPPL.3 ） S506 - 14 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: Diet is one of the most important lifestyle factors that a affect healthy life expectancy through onset of various lifestyle-related diseases. Large-scale cohort studies with sufficient baseline nutritional information are scarce. NIPPON DATA80/90 is cohort study of representative Japanese population, and the cohorts also participated in the National Nutrition Survey in Japan (NNSJ) at the baseline. The corresponding datasets could be combined. Methods: Individual records of NIPPON DATA and NNSJ were compared and integrated. Intakes of nutrients and food groups for individual participants were calculated by distributing intakes in the each household in NNSJ, considering age and sex of the individuals. The results from an international cooperative epidemiological study (INTERMAP) were utilized to estimate intakes of 75 nutrients for NNSJ80 and 70 nutrients for NNSJ90. Nutrient intakes calculated utilizing INTERMAP data were compared with those in the NNSJ datasets. Results: NIPPON DATA80/90 datasets were enhanced with detailed baseline nutrient intake data (the numbers of participants combined were 10 422 and 8342 for NIPPON DATA80 and 90, respectively). The mean nutrient intakes calculated through utilizing INTEMRAP data and those calculated from the NNSJ datasets were similar, and the calculated values were strongly correlated with those calculated from NNSJ datasets (Pearson's correlation coefficients greater than 0.8 [P < 0.001]). Detailed nutrient intakes (eg, cholesterol, fatty acids, amino acids, and dietary fiber) were complemented. Conclusions: The nutrient intakes calculated from NNSJ datasets for the participants of NIPPON DATA are appropriate as the baseline nutrient intake data. The enhanced cohort datasets are suitable for investigations of baseline dietary habits and the consequent health status. © 2010 by the Japan Epidemiological Association.

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Relation of gamma-glutamyltransferase and alcohol drinking with incident diabetes

Hozawa Atsushi, Okamura Tomonori, Tanaka Taichiro, Miura Katsuyuki, Kikuchi Yuriko, Kadowaki Takashi, Yoshita Katsushi, Takebayashi Toru, Tamaki Junko, Minai Junko, Tada Takayo, Chiba Nagako, Okayama Akira, Ueshima Hirotsugu

Journal of Atherosclerosis and Thrombosis 17 （ 2 ） 195 - 202 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: Gamma-glutamyltransferase (GGT) is known to correlate well with alcohol consumption; however, the relation between GGT and diabetes and that between alcohol consumption and diabetes mellitus (DM) is inconsistent. Thus, several questions, such as whether light to moderate drinkers can be considered as low risk for diabetes incidence irrespective of their GGT level, is unresolved. In this study, we investigated the relation of GGT or alcohol drinking with DM incidence considering the body mass index (BMI) in healthy Japanese workers. Methods: We followed 3095 men who did not have DM at baseline for 4 years. Incident diabetes was defined as a fasting (non-fasting) plasma glucose level of ≥7.0 (11.1) mmol/L, or treatment of diabetes. Multiple adjusted hazard ratios (HR) were calculated using Cox proportional models. Results: Participants with higher GGT (GGT ≥27 IU/L) showed an increased risk of diabetes incidence even when their BMI level was low. Although a U-shaped relation between alcohol drinking and incident diabetes was observed, the risk to light to moderate drinkers (alcohol <23 g/day) was not low if they were either overweight (BMI ≥25 kg/m2) or had higher GGT (HR= 2.60, p= 0.08) or both overweight and higher GGT (HR= 3.16, p= 0.07) compared with never drinkers without higher GGT and overweight. Conclusions: Higher GGT was associated with a higher incidence of DM irrespective of drinking status or obesity. Although a U-shaped relation between alcohol drinking and incident diabetes was observed, the risk to light to moderate drinkers was not low if they were either overweight or had higher GGT.

Dyslipidemia and cardiovascular disease: a series of epidemiologic studies in Japanese populations.

Okamura T

Journal of epidemiology 20 （ 4 ） 259 - 265 2010年

研究論文（学術雑誌）, 単著, 査読有り, ISSN 0917-5040

Although the causal relationships of high serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) with coronary artery disease (CAD) are well established, there have been few community-based epidemiologic studies of these relations in Japan. Furthermore, even when analysis is restricted to ischemic stroke, the relationship between dyslipidemia and stroke is very weak. Accordingly, it is difficult to perform cohort studies of dyslipidemia and cardiovascular disease. A series of studies, such as the NIPPON DATA (National Integrated Project for Prospective Observation of Non-communicable Disease and Its Trends in the Aged) cohort study of a representative sample of Japanese, have greatly increased existing evidence. NIPPON DATA80 revealed a clear positive relationship between TC and CAD, and indicated that reverse causality between hypocholesterolemia and liver disease may increase all-cause mortality in hypocholesterolemic Japanese. NIPPON DATA90 showed that serum high-density lipoprotein cholesterol (HDL-C) was inversely associated with all-cause mortality, even when HDL-C was very high. NIPPON DATA80 revealed that low-normal levels of serum albumin and TC are associated with a decline in activity during old age, especially in women. The Suita study-a unique cohort study of urban residents-showed that LDL-C and non-HDL-C were equally accurate in predicting the incidence of myocardial infarction. Further research of this quality is needed to ascertain the public health burden of dyslipidemia in Japan. © 2010 by the Japan Epidemiological Association.

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Integration of data from NIPPON DATA80/90 and national nutrition survey in Japan

Okuda Nagako, Miura Katsuyuki, Yoshita Katsushi, Matsumura Yasuhiro, Okayama Akira, Nakamura Yasuyuki, Okamura Tomonori, Saitoh Shigeyuki, Sakata Kiyomi, Ojima Toshiyuki, Turin Tanvir Chowdhury, Ueshima Hirotsugu

Journal of Epidemiology 20 （ 4 ） 346 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

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Low blood cholesterol and intraparenchymal hemorrhage in cohort studies.

Okamura T

Journal of atherosclerosis and thrombosis 17 （ 3 ） 312 - 314 2010年

研究論文（学術雑誌）, 単著, 査読有り, ISSN 1340-3478

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Relationship between 5-year decline in instrumental activity of daily living and accumulation of cardiovascular risk factors

Hayakawa Takehito, Okamura Tomonori, Okayama Akira, Kanda Hideyuki, Watanabe Makoto, Kita Yoshikuni, Miura Katsuyuki, Ueshima Hirotsugu

Journal of Atherosclerosis and Thrombosis 17 （ 1 ） 64 - 72 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1340-3478

Aim: To clarify the relationship between the accumulation of cardiovascular risk factors and the 5-year decline in instrumental activity of daily living (IADL) among a cohort representative of the Japanese population aged 65 years and over. Methods: An IADL survey was performed by public health centers throughout Japan. Study subjects were elderly men and women living in districts under the jurisdiction of collaborating health centers. Subjects were invited to participate in the IADL survey assessed by the Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence twice in 1995 and in 2000; 1222 participants were eligible for the analysis. The relationship between the number of cardiovascular risk factors, such as hypertension, hypercholesterolemia, hypertriglycemia, low serum high-density lipoprotein cholesterol, diabetes, obesity and smoking, at baseline and the 5-year difference in IADL scores was examined by linear regression analysis and logistic regression analysis. Results: Decrease in IADL scores was larger in those with cardiovascular risk factors than in those without. The multivariable odds ratio (OR) for decreased IADL after adding one CVD risk factor was 1.16 (95% confidence interval (CI), 1.04-1.29) after adjusting for age, sex, alcohol consumption and TMIG score at baseline. Among participants who were regarded as physically independent with respect to basic ADL in the baseline survey, the odds ratio was also similar and significant. Conclusion: Preventive interventions directed against cardiovascular risk factors, especially against their accumulation, may contribute to maintaining IADL in the Japanese elderly.

Protein intakes and serum albumin levels in a Japanese general population: NIPPON DATA90.

Watanabe M, Higashiyama A, Kokubo Y, Ono Y, Okayama A, Okamura T, NIPPON DATA80/90 Research Group.

Journal of epidemiology 20 （ SUPPL.3 ） S531 - 6 2010年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0917-5040

Background: It is well-known that albumin is synthesized in the liver; serum albumin is a major component of serum proteins. However, it has not been well elucidated how dietary protein intakes are associated with serum albumin levels in general populations without extreme malnutrition. We cross-sectionally investigated in the representative Japanese the association between dietary protein intake and serum albumin levels. Methods: A total of 7715 subjects (3220 men and 4495 women, aged 30 years or more) with measurement of serum albumin who participated in both the National Survey on Circulatory Disorders in 1990 and the National Nutrition Survey in 1990 were analyzed in the present analysis. Multiple-adjustments were performed with linear regression models to estimate the association between serum albumin levels and animal or vegetable protein intake adjusting for age and body mass index. Results: The very weak positive association between animal protein and serum albumin levels was observed. On the other hand, there was no clear association observed between vegetable protein and serum albumin levels. Regardless of sex and models, age was inversely associated with serum albumin levels with statistically significance, and standardized coefficients of age were considerably larger in both sexes than other variables. Adjustment for body mass index hardly altered the coefficients of animal or vegetable protein intake, but adjustment for total cholesterol clearly attenuated the relationship between animal protein intake and serum albumin levels. Conclusions: Present analysis indicated the possibility that animal protein intake was related with serum albumin levels, while vegetable protein intake was not related. © 2010 by the Japan Epidemiological Association.

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Risk-prediction tools for cardiovascular disease based on Japanese cohort studies

Okamura Tomonori, Higashiyama Aya

Hypertension Research 32 （ 12 ） 1053 - 1054 2009年12月

ISSN 0916-9636

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Alcohol intake and 19-year mortality in diabetic men

Nakamura Yasuyuki, Ueshima Hirotsugu, Kadota Aya, Hozawa Atsushi, Okamura Tomonori, Kadowaki Sayaka, Kadowaki Takashi, Hayakawa Takehito, Kita Yoshikuni, Abbott Robert D., Okayama Akira

Alcohol 43 （ 8 ） 635 - 641 2009年12月

ISSN 0741-8329

Although moderate alcohol intake in diabetic Caucasians is associated with a reduction in coronary heart disease mortality, no study in Japanese with diabetes has examined the association between alcohol intake and mortality outcomes. We analyzed the relationship between alcohol intake and all-cause and cause-specific mortality using the database from NIPPON DATA80. At the baseline in 1980, data on history, lifestyle, and physical examinations were collected on study participants aged 30 years and older from randomly selected areas in Japan. After excluding participants with comorbidities, we followed 4,018 male participants (3,614 nondiabetics, 195 with impaired glucose tolerance and 209 diabetic) for 19 years. During the 19 years of follow-up, there were 990 deaths; 328 were from cardiovascular disease and 157 from all-heart diseases. With the never-drinking category serving as a reference, the Cox multivariate-adjusted hazard ratios for non-daily and daily drinkers for cardiovascular mortality were 0.43 (95% confidence intervals: 0.19-0.95) and 0.45 (0.25-0.80), respectively, and 0.33 (0.12-0.91) and 0.31 (0.15-0.67) for all-heart disease mortality in the combined impaired glucose tolerance and diabetic Japanese men. Alcohol drinking in men with glucose intolerance was associated with a significant reduction in cardiovascular and all-heart disease mortality as seen in the general population in Japan. © 2009 Elsevier Inc. All rights reserved.

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Relation of serum leptin to blood pressure of Japanese in Japan and Japanese-Americans in Hawaii

Nakamura Yasuyuki, Ueshima Hirotsugu, Okuda Nagako, Murakami Yoshitaka, Miura Katsuyuki, Kita Yoshikuni, Okamura Tomonori, Turin Tanvir C., Rodriguez Beatriz, Curb J. David, Stamler Jeremiah

Hypertension 54 （ 6 ） 1416 - 1422 2009年12月

ISSN 0194-911X

Data from animal studies clearly indicate an association between leptin and hypertension; results of human studies are less concordant. We investigated the role of leptin in obesity-related higher blood pressure (BP) in Japanese Americans living in Hawaii and Japanese in Japan. Serum leptin and BP were examined by standardized methods in men and women ages 40 to 59 years from 2 population samples, one Japanese American in Hawaii (88 men and 94 women) and the other Japanese in central Japan (123 men and 111 women). Multiple linear regression models were used to assess role of leptin in obesity-related higher BP. Across quartiles of leptin, there were significantly higher mean body mass index levels, systolic BP, and diastolic BP for both sexes and sites (P<0.01 to 0.02). In multivariate regression analyses using all of the data combined, relations of body mass index and leptin to systolic BP and diastolic BP remained significant with the interaction term (body mass index×log-leptin) in the models (P<0.01 to <0.05). These findings are consistent with the inference that leptin may be an independent mediator for obesity-related elevations in BP. © 2009 American Heart Association. All rights reserved.

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Dietary habits in middle age and future changes in activities of daily living - NIPPON DATA80-NIPPON DATA80 research group

Nakamura Yasuyuki, Hozawa Atsushi, Turin Tanvir Chowdhury, Takashima Naoyuki, Okamura Tomonori, Hayakawa Takehito, Kita Yoshikuni, Okayama Akira, Miura Katsuyuki, Ueshima Hirotsugu

Gerontology 55 （ 6 ） 707 - 713 2009年11月

ISSN 0304-324X

Background: Almost no studies have investigated the relationship between food intake measured at middle age and future disability. Objective: To examine the association of meat, fish and egg intake with risk of subsequent mortality and/or future decline in activities of daily living (ADL) among the elderly. Methods: The cohort consisted of 2,316 Japanese individuals aged 47-60 at the baseline who were randomly selected throughout Japan and followed up for 19 years from 1980. Results: Those who ate meat at least once every 2 days were younger, there were more men, daily drinkers, professional workers and urban residents compared to those who ate meat less than once every 2 days. Over 19 years of follow-up, 75 participants became dependent due to impaired ADL. A higher intake of meat was associated with a statistically significant decrease in impaired ADL occurrence (odds ratio = 0.61, 95% confidence intervals 0.38-0.99, p = 0.04). Fish and egg intake were not associated with any difference in impaired ADL occurrence. None of the 3 foods were associated with any changes in mortality. Conclusion: A higher intake of meat may prevent impaired ADL occurrence, although this was not associated with a lower mortality. Copyright © 2009 S. Karger AG, Basel.

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Cholesteryl Ester Transfer Protein, Coronary Calcium, and Intima-Media Thickness of the Carotid Artery in Middle-Age Japanese Men

Okamura Tomonori, Sekikawa Akira, Kadowaki Takashi, El-Saed Aiman, Abbott Robert D., Curb J. David, Edmundowicz Daniel, Nakamura Yasuyuki, Murata Kiyoshi, Kashiwagi Atsunori, Sutton-Tyrrell Kim, Evans Rhobert W., Zmuda Joseph M., Maegawa Hiroshi, Hozawa Atsushi, Mitsunami Ken Ichi, Nishio Yoshihiko, Miljkovic-Gacic Iva, Horie Minoru, Miyamatsu Naomi, Murakami Yoshitaka, Kuller Lewis H., Ueshima Hirotsugu

American Journal of Cardiology 104 （ 6 ） 818 - 822 2009年09月

ISSN 0002-9149

The relation between cholesteryl ester transfer protein (CETP) levels and atherosclerosis is controversial. We examined whether the serum CETP levels were associated with subclinical atherosclerosis, independent of its most common gene variant, in a sample of Japanese men. A population-based cross-sectional study of 250 Japanese men aged 40 to 49 years was conducted to assess the intima-media thickness of the carotid artery, coronary artery calcium, serum CETP levels, and the CETP D442G gene variant. Compared with the lowest CETP quartile, the multivariate adjusted odds ratio for coronary artery calcium was 0.77 (95% confidence interval 0.18 to 3.36), 0.96 (95% confidence interval 0.27 to 3.40), and 3.49 (95% confidence interval 1.05 to 11.6) with increasing CETP quartiles. The serum CETP quartiles were also positively associated with the intima-media thickness of the carotid artery (adjusted mean 602, 616, 615, and 646 μm for the lowest to top quartile, respectively). The findings remained unchanged after additional adjustment for the CETP D442G gene variant. No significant difference was found in the prevalence of coronary artery calcium or in the mean intima-media thickness of the carotid artery between participants with and without the CETP D442G gene variant. © 2009 Elsevier Inc. All rights reserved.

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Association between polymorphism of the AGTR1 and cardiovascular events in a Japanese general sample (The Shigaraki Study)

Tamaki Shinji, Nakamura Yasuyuki, Tabara Yasuharu, Okamura Tomonori, Kanda Hideyuki, Kita Yoshikuni, Kadowaki Takashi, Tsujita Yasuyuki, Chowdhury Turin Tanvir, Horie Minoru, Miki Tetsuro, Ueshima Hirotsugu

International Journal of Cardiology 136 （ 3 ） 354 - 355 2009年08月

ISSN 0167-5273

We examined whether the A1166C polymorphism of the angiotensin II type I receptor gene (AGTR1) affects cardiovascular event occurrence in a Japanese prospective cohort study. The 2212 participants who gave informed consent for genetic analysis were enrolled in this study (the Shigaraki Study). The average observation period was 1954 days. Cardiovascular events occurred in 37 individuals (1.7%). The independent factors which specified cardiovascular events were age (hazard ratio (HR) = 1.13; 95% confidence interval (CI): 1.10-1.16; p < 0.0001) and sex (HR = 2.18; 95%CI: 1.23-3.85; p = 0.007). However, the A1166C polymorphism of AGTR1 was not a predictive factor for cardiovascular events (HR = 1.11; 95%CI: 0.61-2.02; p = 0.731). © 2008 Elsevier Ireland Ltd. All rights reserved.

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Association study of 11β-hydroxysteroid dehydrogenase type 1 gene polymorphisms and metabolic syndrome in urban Japanese cohort

Miyamoto Yoshihiro, Morisaki Hiroko, Yamanaka Itaru, Kokubo Yoshihiro, Masuzaki Hiroaki, Okayama Akira, Tomoike Hitonobu, Nakao Kazuwa, Okamura Tomonori, Yoshimasa Yasunao, Morisaki Takayuki

Diabetes Research and Clinical Practice 85 （ 2 ） 132 - 138 2009年08月

ISSN 0168-8227

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), one of the isoforms of the 11β-hydroxysteroid dehydrogenase enzymes, acts as an oxo-reductase to reactivate cortisone to cortisol, plays a critical role in tissue-specific corticosteroid reactions, and is therefore a key molecule associated with the development of metabolic syndrome. We investigated whether variations in the 11β-HSD1 gene correlated with metabolic syndrome. We performed case-control study using a population-based urban Japanese cohort. Among 3005 urban residents, we examined 431 subjects diagnosed with metabolic syndrome according to the Japanese definition and 777 subjects with none of metabolic syndrome criteria as control. We genotyped three single nucleotide polymorphisms (SNPs) (+9410T>A, +17925C>T, +27447G>C) across the 11β-HSD1 gene in them and analyzed the associations of SNPs and haplotypes with metabolic syndrome. The +9410A allele showed a tendency to metabolic syndrome (OR = 1.5, 95%C.I., 1.0-2.2; P = 0.041 and Bonferroni corrected P = 0.123) without statistical significance. However, we could not find any significant association between metabolic syndrome and SNPs in the 11β-HSD1 gene. Our findings indicate that polymorphisms and haplotypes in the 11β-HSD1 gene are not significantly associated with metabolic syndrome in the Japanese population. © 2009 Elsevier Ireland Ltd. All rights reserved.

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Higher liver fat content among Japanese in Japan compared with non-Hispanic whites in the United States

Azuma Koichiro, Kadowaki Takashi, Cetinel Cemal, Kadota Aya, El-Saed Aiman, Kadowaki Sayaka, Edmundowicz Daniel, Nishio Yoshihiko, Sutton-Tyrrell Kim, Okamura Tomonori, Evans Rhobert W., Takamiya Tomoko, Ueshima Hirotsugu, Curb J. David, Abbott Robert D., Kuller Lewis H., Kelley David E., Sekikawa Akira

Metabolism: Clinical and Experimental 58 （ 8 ） 1200 - 1207 2009年08月

ISSN 0026-0495

Among Asians, including Japanese, obesity is related to dyslipidemia and insulin resistance at a lower level of body mass index (BMI) compared with non-Hispanic whites (NHW). We hypothesize that this ethnic difference in the relationship between BMI and metabolic risks is partly associated with the ethnic difference in fat distribution, namely, liver fat as well as visceral adipose tissue. To compare liver fat content among Japanese vs NHW men, regional computed tomographic images were taken to measure liver computed tomographic density in population-based samples of 313 Japanese and 288 NHW men aged 40 to 49 years, along with the assessment of metabolic parameters. Liver fat content was higher in Japanese than NHW men (liver to spleen attenuation ratio [lower value means higher liver fat content]: 1.01 ± 0.16 vs 1.07 ± 0.15, respectively; P < .01), despite a lower mean BMI in Japanese men (BMI: 23.6 ± 2.9 vs 27.8 ± 4.2 kg/m², P < .01). Moreover, Japanese men had a greater disposition for fatty liver with a small increase in BMI than NHW (P < .01), whereas both groups had a similar relationship between visceral adipose tissue and BMI. In both groups, liver fat content correlated with triglycerides, homeostasis model assessment of insulin resistance, and C-reactive protein. Liver fat content is higher among Japanese than NHW; and this ethnic difference becomes more robust with a small increase in BMI, suggesting that fatty liver is a sensitive marker for the failure of the adipose tissue to expand to accommodate an increased energy influx, and is associated with similar metabolic risk in Japanese despite lower BMI compared with NHW men. © 2009 Elsevier Inc. All rights reserved.

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Relationship between blood pressure category and incidence of stroke and myocardial infarction in an Urban Japanese population with and without chronic kidney disease

Kokubo Yoshihiro, Nakamura Satoko, Okamura Tomonori, Yoshimasa Yasunao, Makino Hisashi, Watanabe Makoto, Higashiyama Aya, Kamide Kei, Kawanishi Katsuyuki, Okayama Akira, Kawano Yuhei

Stroke 40 （ 8 ） 2674 - 2679 2009年08月

ISSN 0039-2499

BACKGROUND AND PURPOSE-: Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for stroke and myocardial infarction (MI). Few studies, however, have examined the relationship between blood pressure (BP) category and these diseases in subjects with and without CKD. METHODS-: We studied 5494 Japanese individuals (ages 30 to 79, without stroke or MI at baseline) who completed a baseline survey and received follow-up through December 2005. The glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease study equation modified by the Japanese coefficient. CKD was defined as an estimated GFR <60 mL/min/1.73m. BP categories were defined by the European Society of Hypertension and European Society of Cardiology 2007 criteria. RESULTS-: In 64 395 person-years of follow-up, we documented 346 incidences of cardiovascular diseases (CVD; 213 strokes and 133 MI events). Compared with the GFR (≥90 mL/min/1.73m) group, the hazard ratios (95% confidential intervals) for stroke were 1.9 (1.3 to 3.0) in the GFR 50 to 59 mL/min/1.73m group and 2.2 (1.2 to 4.1) in the GFR <50 mL/min/1.73m group. Results for cerebral infarction were similar. Compared with the optimal BP subjects without CKD, the normal BP, high-normal BP, and hypertensive subjects without CKD showed increased risks of CVD and stroke; however the impact of each BP category on CVD (P for interaction: 0.04 in men, 0.49 in women) and stroke (0.03 in men, 0.90 in women) was more evident in men with CKD. CONCLUSIONS-: CKD may increase the association of BP and CVD in a Japanese urban population. © 2009 American Heart Association, Inc.

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Association of serum n-6 and n-3 polyunsaturated fatty acids with lipids in 3 populations of middle-aged men

Motoyama Kenneth R., Curb J. David, Kadowaki Takashi, El-Saed Aiman, Abbott Robert D., Okamura Tomonori, Evans Rhobert W., Nakamura Yasuyuki, Sutton-Tyrrell Kim, Rodriquez Beatriz L., Kadota Aya, Edmundowicz Daniel, Willcox Bradley J., Choo Jina, Katsumi Nakata, Otake Teruo, Kadowaki Sayaka, Kuller Lewis H., Ueshima Hirotusgu, Sekikawa Akira

American Journal of Clinical Nutrition 90 （ 1 ） 49 - 55 2009年07月

ISSN 0002-9165

Background: The association of serum polyunsaturated fatty acids (PUFAs) with lipids in different populations is not known. Objective: Our aim was to examine the association of serum n-6 (omega-6) or n-3 (omega-3) PUFAs with triglycerides or HDL-cholesterol concentrations in 261 white, 285 Japanese, and 212 Japanese American men aged 40-49 y. Design: We used a population-based cross-sectional study. Of the original sample (n = 926), those taking lipid-lowering medications or who had diabetes (n = 168) were excluded. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Multiple regression models as a function of tertile groups of each PUFA were used. Results: Serum n = 6 PUFAs were significantly inversely associated with triglycerides across populations after adjustment for age, body mass index, pack-years of smoking, and ethanol consumption [β = -0.39 (P < 0.001), -0.38 (P < 0.001), and -0.33 (P < 0.001) in whites, Japanese, and Japanese Americans, respectively]. Marine n-3 PUFAs were significantly inversely associated with triglycerides across populations [β = -0.15 (P < 0.001), -0.22 (P < 0.001), and -0.13 (P < 0.001) in whites, Japanese, and Japanese Americans, respectively]. n-6 PUFAs were significantly positively associated with HDL cholesterol in whites (β = 4.49, P < 0.001) and Japanese (β = 3.73, P < 0.01). Marine n-3 PUFAs were significantly positively associated with HDL cholesterol in Japanese (β = 2.15, P < 0.05), and eicosapentaenoic acid was significantly positively associated with HDL cholesterol in whites (β = 2.68, P < 0.01). Conclusion: Serum n-6 and n-3 PUFAs are inversely associated with triglycerides across populations. © 2009 American Society for Nutrition.

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Elevated serum creatine kinase predicts first-ever myocardial infarction

Watanabe Makoto, Okamura Tomonori, Kokubo Yoshihiro, Higashiyama Aya, Okayama Akira

International Journal of Epidemiology 38 （ 6 ） 1571 - 1579 2009年06月

ISSN 0300-5771

Background: In myocardial infarction (MI), it is well known that serum creatine kinase (s-CK) increases after onset, but it is unclear whether s-CK elevates before MI onset. The present analysis examined whether elevated s-CK levels predicted first-ever MI or stroke. Methods: This study was a population-based cohort study in a Japanese urban area. Study subjects were comprised of 5026 initially healthy Japanese (2370 men and 2656 women, mean age: 54.5 years) without a history of MI or stroke. They were followed-up for 11.8 years on average, and 103 MIs (definite: 45; probable: 58) and 168 strokes (definite: 126; probable: 42) were observed. There was no subject who developed MI just at baseline (the follow-up period among those with definite MI was, at earliest, 0.20 years). Results: The adjusted hazard ratio for definite MI was 4.18 (95% confidence interval 1.66-10.53) with s-CK levels of ≥200 IU/l, compared with the reference category (s-CK levels of ≤99 IU/l), whereas no relationship was observed between s-CK levels and the risk for stroke. With regard to definite MI, an interaction between s-CK levels and dyslipidaemia was observed. Among subjects with hypercholesterolaemia, the hazard ratio linearly elevated with increased s-CK levels. On the other hand, no linear elevation was observed among subjects without hypercholesterolaemia (P for interaction = 0.011). Conclusions: The present study suggested that screening for elevated s-CK levels in initially healthy Japanese subjects was useful to predict first-ever MI in the future, especially in subjects with dyslipidaemia. Published by Oxford University Press on behalf of the International Epidemiological Association. © The Author 2009.

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Identification of genetic markers associated with high-density lipoprotein-cholesterol by genome-wide screening in a Japanese population - The Suita study

Hiura Yumiko, Shen Chun Shen, Kokubo Yoshihiro, Okamura Tomonori, Morisaki Takayuki, Tomoike Hitonobu, Yoshida Teruhiko, Sakamoto Hiromi, Goto Yoichi, Nonogi Hiroshi, Iwai Naoharu

Circulation Journal 73 （ 6 ） 1119 - 1126 2009年06月

ISSN 1346-9843

Background: Recent genome-wide association studies (GWAS) have identified genes or loci affecting lipid levels. Given the difference in allele frequencies and linkage disequilibrium patterns across the populations, a GWAS was conducted using the Illumina 550K in a Japanese population (n=900) in search of population-specific genetic variations associated with high-density lipoprotein (HDL)-cholesterol. Methods and Results: Among the 368,274 single nucleotide polymorphisms (SNPs) with a minor allele frequency of at least 0.1, 43 SNPs exceeded the arbitrary threshold of -log₁₀P >4.0. The most significant SNP was rs3764261, located 5′upstream of CETP, exhibiting a -log₁₀P value of 6.17. Increasing the sample size by genotyping in the additional Suita sample (n=1,810) further improved the level of significance, with each additional copy of the minor allele being associated with an increase in HDL-cholesterol by 6.2 mg/dl (P=3.4×10^-12). Interestingly, the minor allele was more prevalent in cases with myocardial infarction than in controls (0.221 vs 0.196, nominal P=0.02). Conclusions: The association between genetic variants at CETP and HDL-cholesterol was replicated in our sample. None of the genetic variants exerted a greater influence on HDL levels than those at CETP. Associations for the top-ranked SNPs need to be tested for further replication in an independent sample.

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Low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol and the incidence of cardiovascular disease in an urban Japanese cohort study

Okamura Tomonori, Kokubo Yoshihiro, Watanabe Makoto, Higashiyama Aya, Miyamoto Yoshihiro, Yoshimasa Yasunao, Okayama Akira

Atherosclerosis 203 （ 2 ） 587 - 592 2009年04月

ISSN 0021-9150

Objective: Only a small number of population-based cohort studies have directly compared the predictive value of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDLC) for coronary artery disease in Asian populations, such as Japan. Methods: We performed an 11.9-year cohort study of 4694 men and women, aged 30-74 years, selected randomly from an urban general population in Japan. Baseline LDL-C levels were estimated using the Friedewald formula. The predictive values of LDL-C and non-HDLC for myocardial infarction (MI) and stroke were compared. Results and conclusion: During the follow-up period, there were 80 incident cases of MI and 139 of stoke, comprised of 23 intracerebral hemorrhages, 85 cerebral infarctions and 31 other types of stroke. The Hazard ratio (HR) for MI was highest in the top quintile of LDL-C (HR: 3.03, 95% CI, 1.32-6.96) when male and female data were combined. The HR for MI was also highest in the top quintile of non-HDLC (HR: 2.97, 95% CI, 1.26-6.97). Analysis of trends showed a significant positive relationship between MI incidence and serum LDL-C and non-HDLC levels (both P = 0.02). However, there was no relationship between the incidence of any subtype of stroke and either LDL-C or non-HDLC. The predictive value of LDL-C and non-HDLC for MI, assessed by calculating the differences in the -2 logarithm likelihood (-2 ln [L]) and area under the curve (AUC), were almost similar. © 2008 Elsevier Ireland Ltd. All rights reserved.

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Effects of habitual alcohol intake on ambulatory blood pressure, heart rate, and its variability among japanese men

Ohira Tetsuya, Tanigawa Takeshi, Tabata Minako, Imano Hironori, Kitamura Akihiko, Kiyama Masahiko, Sato Shinichi, Okamura Tomonori, Cui Renzhe, Koike Kazuko A., Shimamoto Takashi, Iso Hiroyasu

Hypertension 53 （ 1 ） 13 - 19 2009年01月

ISSN 0194-911X

We sought to examine effects of habitual alcohol intake on ambulatory blood pressure (BP), heart rate (HR), and HR variability among Japanese men. Subjects were 539 men aged 35 to 65 years from rural and urban communities. Ambulatory BP and HR were monitored with an automated, portable, noninvasive multibiomedical recorder. Power spectral analysis of the RR intervals on the ECG was performed every 5 minutes. Compared with nondrinkers, moderate drinkers (alcohol intake 23 to 45 g/d) and heavy drinkers (alcohol intake ≥46 g/d) showed higher age- and field-adjusted mean values of systolic and diastolic BPs during the morning and while awake, but there were no differences in BPs over 24-hour periods and while asleep among the alcohol intake categories. Alcohol intake was positively associated with mean values of sleep-morning differences and daytime variability in BPs, HRs while awake and asleep, and low frequency: high frequency ratio while asleep. The results were virtually unchanged after adjustment for body mass index, smoking, and diabetes mellitus. Compared with the nondrinkers, age- and field-adjusted odds ratios of the morning BP surge (excess elevation of BP in the morning: morning systolic BP minus sleep systolic BP ≥37 mm Hg) for light (alcohol intake 0 to 22 g/d), moderate, and heavy drinkers were 0.96 (95% CI: 0.34 to 2.78), 1.68 (95% CI: 0.64 to 4.38), and 2.73 (95% CI: 1.12 to 6.67), respectively. Habitual alcohol intake was associated with increased BP in the morning, HR while awake and asleep, and sympathetic activity while asleep, which may explain some of the mechanisms of the relationship between heavy alcohol intake and risk of cardiovascular diseases. © American Heart Association, Inc.

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Association of Asn221Ser mutation in tissue factor pathway inhibitor-β with plasma total tissue factor pathway inhibitor level

Ishikawa Junko, Okada Hiromi, Kato Hisao, Takeshita Satoshi, Honda Shigenori, Kawasaki Tomio, Suehisa Etsuji, Tsuji Hajime, Madoiwa Seiji, Sakata Yoichi, Kojima Tetsuhito, Murata Mitsuru, Ikeda Yasuo, Kokubo Yoshihiro, Okamura Tomonori, Tomoike Hitonobu, Miyata Toshiyuki

Blood Coagulation and Fibrinolysis 20 （ 1 ） 22 - 26 2009年01月

ISSN 0957-5235

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protease inhibitor that inhibits the tissue factor-initiated blood coagulation cascade reactions. Based on these anticoagulant functions of TFPI, we hypothesized that genetic variations in TFPI may alter the TFPI expression or impair the anticoagulant function and could predispose persons to deep vein thrombosis (DVT). This study was undertaken to examine whether the genetic polymorphisms in TFPI are associated with the plasma TFPI levels and risk for DVT. We sequenced the entire coding regions of TFPI in 175 Japanese DVT patients and identified 12 genetic variants, including one missense mutation, Asn221Ser. The missense mutation occurred at the site presumably attached to the glycosylphosphatidylinositol anchor in the TFPI-p form. The allele frequency of the mutant Ser-coding allele of the Asn221Ser mutation was 8% in the Japanese general population consisting of 1684 individuals. The Asn221Ser mutation was significantly associated with the total TFPI levels (Asn/Asn, n = 108, total TFPI = 56.57 ± 0.88 ng/ml (mean ± SD) vs. Asn/Ser + Ser/Ser, n = 16, total TFPI = 63.44 ±.28 ng/ml, P= 0.0058). The genotype was not associated with the free TFPI level. This Asn221Ser mutation was not associated with DVT. Thus, the Asn221Ser mutation occurring in the TFPI-p form was associated with the total TFPI level, but not a risk for DVT. The absence of the putative glycosylphosphatidylinositol anchor in TFPI-β under pathological conditions remains to be studied. Blood Coagul Fibrinolysis 20:22-26 © 2009 Wolters Kluwer Health Lippincott Williams & Wilkins.

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Risk of smoking and metabolic syndrome for incidence of cardiovascular disease - Comparison of relative contribution in urban Japanese population

Higashiyama Aya, Okamura Tomonori, Ono Yuu, Watanabe Makoto, Kokubo Yoshihiro, Okayama Akira

Circulation Journal 73 （ 12 ） 2258 - 2263 2009年

ISSN 1346-9843

Background: Risk factor clustering, the so-called metabolic syndrome (MetS), is an important risk factor for cardiovascular disease (CVD). Smoking is also an important CVD risk factor with still a high prevalence. However, few previous studies have compared the risk for CVD or the population-attributable fraction (PAF) of smoking, MetS, and both. Methods and Results: The present study was an 11.9-year cohort study of 1,822 men and 2,089 women, aged 40-74 years, selected randomly from an urban general population in Japan. MetS was defined according to the National Cholesterol Education Program on Adult Treatment Panel III (NCEP-ATPIII) guideline modified by the Asian criteria for waist circumference. The prevalence of smoking was 49.5% in men and 11.1% in women, and that of MetS was 19.8% and 23.5%, respectively. In men, the multivariate-adjusted hazard ratio for CVD incidence, compared with non-smoking participants without MetS, was 2.07 (1.26-3.40) in those who smoked, 2.09 (1.08-4.04) in those with MetS, and 3.56 (1.89-6.72) in those with both. In men the PAF for CVD incidence was 21.8% because of smoking, 7.5% because of MetS, and 11.9% because of both. Conclusions: Although countermeasures for MetS are important, smoking should continue to be considered an important public health problem and antismoking campaigns should be promoted, especially for men, to prevent CVD.

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High blood pressure in middle age is associated with a future decline in activities of daily living. NIPPON DATA80

Hozawa A., Okamura T., Murakami Y., Kadowaki T., Okuda N., Takashima N., Hayakawa T., Kita Y., Miura K., Nakamura Y., Okayama A., Ueshima H.

Journal of Human Hypertension 23 （ 8 ） 546 - 552 2009年

ISSN 0950-9240

Although several studies have reported on the relation between high blood pressure (BP) and impaired activities of daily living (ADL), only a few studies have reported on the relation of high BP in middle-aged subjects with future impaired ADL. Furthermore, no studies reported an excess impaired ADL due to non-normal BP. Using ADL 1999 data, we compared data from NIPPON DATA80 survivors without impaired ADL (N = 1816) with those with impaired ADL (N = 75) using baseline BP information collected in 1980. We analysed participants who were aged 47-59 years at baseline. Multiple adjusted logistic regression analyses were used to estimate the risk of impaired ADL, according to baseline BP categories using Joint National Committee 7 guidelines (normal BP, prehypertension, stage 1 hypertension (HT) and stage 2 HT). Subjects who used antihypertensive medications were classified as having stage 2 HT. We calculated excess impaired ADL due to non-normal BP. Compared with normal BP categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) of having impaired ADL was higher in subjects with prehypertension (OR = 1.50, 95% CI: 0.55-4.09), stage 1 HT (OR = 1.56, 95% CI: 0.56-4.32) and stage 2 HT (OR = 2.96, 95% CI: 1.09-8.05). Non-normal BP explained 45% (33.7/75) of impaired ADL. A positive relation of BP categories with the composite end point of mortality and impaired ADL was also observed. In conclusion, controlling BP in middle age may prevent deaths and future ADL decline.

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Prognostic value of Q wave for cardiovascular death in a 19-year prospective study of the Japanese general population

Higashiyama Aya, Hozawa Atsushi, Murakami Yoshitaka, Okamura Tomonori, Watanabe Makoto, Nakamura Yasuyuki, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu, Iimura Osamu, Omae Teruo, Ueda Kazuo, Horibe Hiroshi, Kodama Kazunori, Kasagi Fumiyoshi, Tanihara Shinichi, Saitoh Shigeyuki, Sakata Kiyomi, Nakamura Yosikazu, Kakuno Fumihiko, Takeuchi Toshihiro, Hasebe Mitsuru, Kusano Fumitsugu, Kawamoto Takahisa, Minowa Masumi, Kawaminami Katsuhiko, Choudhury Sohel R., Kiyohara Yutaka, Iida Minoru, Hashimoto Tsutomu, Terao Atsushi, Sawai Koryo, Shibata Shigeo

Journal of Atherosclerosis and Thrombosis 16 （ 1 ） 40 - 50 2009年

ISSN 1340-3478

Aim: Little is known about the prognostic value of q wave abnormality for cardiovascular disease (CVD) on a resting electrocardiogram (ECG) of the Japanese general population with an extremely low incidence of myocardial infarction. Methods: We followed 8,339 participants without a past and present history of CVD for 19 years. The multivariate-adjusted hazard ratio (HR) of q wave abnormality for CVD mortality was estimated by the Cox proportional hazards model. Results: The multivariate-adjusted HR of composite findings of moderate or severe q wave abnormality was 1.75 (95% confidence interval (CI): 0.97-3.17) for mortality due to CVD and 2.97 (95%CI: 1.43-6.16) due to heart diseases. The multivariate-adjusted HR of mild abnormality for mortality from heart diseases was 1.95 (95%CI: 1.00-3.81). The relationship between moderate or severe abnormalities and mortality from CVD was unchanged when participants with ST-T changes and high amplitude R waves were excluded and when participants were divided by the presence of major CVD risk factors such as hypertension. Q wave abnormality was not associated with the risk of stroke. Conclusion: Moderate or severe q wave abnormalities are prominent and important predictors of mortality due to CVD and heart disease in the Japanese general population without CVD history.

A Japanese diet and 19-year mortality

Nakamura Yasuyuki, Ueshima Hirotsugu, Okamura Tomonori, Kadowaki Takashi, Hayakawa Takehito, Kita Yoshikuni, Abbott Robert D., Okayama Akira

British Journal of Nutrition 101 （ 11 ） 1696 - 1705 2009年

ISSN 0007-1145

Few studies have examined the association between Japanese diet and mortality outcomes. We analysed the relationship between a healthy Japanese diet and all-cause and cause-specific mortality using the database from the National Integrated Project for Prospective Observation of Non-Communicable Diseases and its Trends in the Aged, 1980. At baseline in 1980, data were collected on study participants aged ≧30 years from randomly selected areas in Japan. We defined a measure of a healthy reduced-salt Japanese diet based on seven components from FFQ. The total score ranged from 0 to 7, with 0 being least healthy and 7 being most healthy. Participants were divided into approximate tertiles of dietary scores (0-2, 3 and 4-7 scores). After excluding participants with co-morbidities, we followed 9086 participants (44% men) for 19 years. There were 1823 all-cause and 654 cardiovascular deaths during the follow-up. With the dietary score group 0-2 serving as a reference, the Cox multivariate-adjusted hazard ratios for groups with scores 3 and 4-7 were 0.92 (95% CI 0.83, 1.04) and 0.78 (95% CI 0.70, 0.88) for all-cause mortality (trend P<0.0001), and 0.91 (95% CI 0.75, 1.10) and 0.80 (95% CI 0.66, 0.97) for cardiovascular mortality (trend P = 0.022). Adherence to a healthy reduced-salt Japanese diet was associated with an approximate 20% lower rate of all-cause and cardiovascular mortality.

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Effect of chronic kidney disease on individual and population medical expenditures in the Japanese population

Higashiyama Aya, Okamura Tomonori, Watanabe Makoto, Murakami Yoshitaka, Otsuki Hidemi, Adachi Noriko, Kaneko Chiaki, Uehara Emi, Okayama Akira, Ueshima Hirotsugu

Hypertension Research 32 （ 6 ） 450 - 454 2009年

ISSN 0916-9636

Chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease (CVD), and may also lead to an increase in medical expenditures. The effect of CKD on individual and population medical expenditures was examined in a Japanese cohort study. The participants included 4026 Japanese National Health Insurance beneficiaries aged 40-74 years living in one city, who had no history of major CVD. They were classified into three categories according to their glomerular filtration rate (GFR) at the baseline survey, and their total medical expenditures were followed-up for 3 years. The arithmetic and geometric means of the cumulative medical expenditures were calculated for each category. The geometric mean was also expressed after adjusting for several confounding factors using analysis of covariance. The CKD-related medical expenditures attributable to the participants with mild (60 ≤ GFR<90) or moderate (30 ≤ GFR<60) kidney dysfunction were compared with those of participants with normal (GFR < 90) kidney function. There was a negative correlation between the GFR category and the arithmetic and geometric means of personal medical expenditures (adjusted geometric mean: GFR < 90, 167879 yen; 60 ≤GFR <90, 210660 yen; and 30 ≤ GFR<60, 330050 yen). The CKD-related medical expenditures accounted for 11.5 and 6.5% of the total medical expenditures for the participants with mild and moderate kidney dysfunction, respectively. The prevention of mild CKD is very important for containing medical expenditures. Appropriate strategies, such as regular creatinine measurement, are needed for early detection of CKD.

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The taste of salt measured by a simple test and blood pressure in Japanese women and men

Michikawa Takehiro, Nishiwaki Yuji, Okamura Tomonor, Asakura Keiko, Nakano Makiko, Takebayashi Toru

Hypertension Research 32 （ 5 ） 399 - 403 2009年

ISSN 0916-9636

Salt intake is an important risk factor for hypertension. Because it has been reported that increased salt intake dulls the taste of salt, measuring the sense of taste might be a good way of identifying individuals who consume excessive salt. Using a recently developed simple salt taste test, we investigated the relationship between the taste of salt and blood pressure. The subjects in this cross-sectional study were 823 Japanese adults (479 women and 344 men) 40 years old or older. Following a taste test with salt-impregnated taste strips, the subjects were divided into two groups: normal (recognition threshold of salt at <1.0% concentration) and taste impaired (≥1.0%). We determined hypertension from the measured blood pressure. In women, the multi-adjusted odds ratio (95% CI) of hypertension in the impaired group was 2.47 (1.53-3.99) compared with the normal group, whereas no significant difference was observed between the two male groups. When we excluded subjects with moderate and severe hypertension, similar findings were observed. A sub-analysis of couples living alone showed a higher prevalence of hypertension among men whose wives were in the impairment group (58.8%) than in the normal group (36.7%, P=0.10). In conclusion, the taste of salt is associated with blood pressure in Japanese women, but not in men. Because most family meals in Japan are prepared by women, educating women about salt reduction may contribute to the prevention of hypertension, not only among women but also among their husbands and family members.

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Gender-specific associations of vision and hearing impairments with adverse health outcomes in older Japanese

Michikawa Takehiro, Nishiwaki Yuji, Kikuchi Yuriko, Nakano Makiko, Iwasawa Satoko, Asakura Keiko, Milojevic Ai, Mizutari Kunio, Saito Hideyuki, Ishida Susumu, Okamura Tomonori, Takebayashi Toru

BMC Geriatrics 9 （ 1 ） 2009年

ISSN 1471-2318

Background. Several epidemiological studies have shown that self-reported vision and hearing impairments are associated with adverse health outcomes (AHOs) in older populations; however, few studies have used objective sensory measurements or investigated the role of gender in this association. Therefore, we examined the association of vision and hearing impairments (as measured by objective methods) with AHOs (dependence in activities of daily living or death), and whether this association differed by gender. Methods. From 2005 to 2006, a total of 801 residents (337 men and 464 women) aged 65 years or older of Kurabuchi Town, Gunma, Japan, participated in a baseline examination that included vision and hearing assessments; they were followed up through September 2008. Vision impairment was defined as a corrected visual acuity of worse than 0.5 (logMAR = 0.3) in the better eye, and hearing impairment was defined as a failure to hear a 30 dB hearing level signal at 1 kHz in the better ear. Information on outcomes was obtained from the town hall and through face-to-face home visit interviews. We calculated the risk ratios (RRs) of AHOs for vision and hearing impairments according to gender. Results. During a mean follow-up period of 3 years, 34 men (10.1%) and 52 women (11.3%) had AHOs. In both genders, vision impairment was related to an elevated risk of AHOs (multi-adjusted RR for men and women together = 1.60, 95% CI = 1.05-2.44), with no statistically significant interaction between the genders. In contrast, a significant association between hearing impairment and AHOs (multi-adjusted RR = 3.10, 95% CI = 1.43-6.72) was found only in the men. Conclusion. In this older Japanese population, sensory impairments were clearly associated with AHOs, and the association appeared to vary according to gender. Gender-specific associations between sensory impairments and AHOs warrant further investigation. © 2009 Michikawa et al; licensee BioMed Central Ltd.

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Cardiovascular disease and risk factors in Asia

Ueshima Hirotsugu, Sekikawa Akira, Miura Katsuyuki, Turin Tanvir Chowdhury, Takashima Naoyuki, Kita Yoshikuni, Watanabe Makoto, Kadota Aya, Okuda Nagako, Kadowaki Takashi, Nakamura Yasuyuki, Okamura Tomonori

Circulation 118 （ 25 ） 2702 - 2709 2008年12月

ISSN 0009-7322

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Risk Factor Effects and Total Mortality in Older Japanese Men in Japan and Hawaii

Abbott Robert D., Ueshima Hirotsugu, Hozawa Atsushi, Okamura Tomonori, Kadowaki Takashi, Miura Katsuyuki, Okuda Nagako, Nakamura Yasuyuki, Okayama Akira, Kita Yoshikuni, Rodriguez Beatriz L., Yano Katsuhiko, Curb J. David

Annals of Epidemiology 18 （ 12 ） 913 - 918 2008年12月

ISSN 1047-2797

purpose: We sought to identify factors related to total mortality in older Japanese men in Japan and Hawaii. Methods: Baseline data were collected from 1980 to 1982 in 1379 men in Hawaii and 954 men in Japan. Ages ranged from 61 to 81 years, with mortality follow-up during a 19-year period. Results: Compared with Japan, men in Hawaii had a 2-fold excess of diabetes and a 4-fold excess of prevalent coronary heart disease (P < .001). Total cholesterol and body mass index were also greater in Hawaiian men (P < .001). In contrast, men in Japan had greater systolic blood pressure and were nearly 3 times more likely to smoke cigarettes (P < .001). Although each cohort had elements of a poor risk factor profile, there was a 1.4-fold excess in the risk of death in Japan (49.4 vs. 36.2/1,000 person-years, P < .001). Although mortality was similar after risk factor adjustment, only blood pressure and cigarette smoking accounted for the higher risk of death in Japan. Conclusions: Cigarette smoking and hypertension explain much of the excess mortality in Japan versus Hawaii. In this comparison of genetically similar cohorts, evidence further suggests that Japanese in Japan are equally susceptible to develop the same adverse risk factor conditions that exist in Hawaii. © 2008 Elsevier Inc. All rights reserved.

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Medical expenditure for diabetic patients

Nakamura K., Okamura T., Kanda H., Hayakawa T., Murakami Y., Okayama A., Ueshima H.

Public Health 122 （ 11 ） 1226 - 1228 2008年11月

ISSN 0033-3506

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Impact of high-normal blood pressure on the risk of cardiovascular disease in a Japanese urban cohort

Kokubo Yoshihiro, Kamide Kei, Okamura Tomonori, Watanabe Makoto, Higashiyama Aya, Kawanishi Katsuyuki, Okayama Akira, Kawano Yuhei

Hypertension 52 （ 4 ） 652 - 659 2008年10月

ISSN 0194-911X

Few prospective studies have examined the association between high-normal blood pressure and cardiovascular disease (CVD) in Asia. We examined the impact of high-normal blood pressure on the incidence of CVD in a general urban population cohort in Japan. We studied 5494 Japanese individuals (ages 30 to 79 years without CVD at baseline) after completing a baseline survey who received follow-up through December 2005. Blood pressure categories were defined on the basis of the ESH-ESC 2007 criteria. In 64 391 person-years of follow-up, we documented the incidence of 346 CVD events. The frequencies of high-normal blood pressure and hypertension Stage 1 and Stage ≥2 were 18.0%, 20.1%, and 10.1% for men and 15.9%, 15.6%, and 8.8% for women, respectively. Antihypertensive drug users were also classified into the baseline blood pressure categories. Compared with the optimal blood pressure group, the multivariable hazard ratios (95% confidence intervals) of CVD for normal and high-normal blood pressure and hypertension Stage 1 and Stage ≥2 were 2.04 (1.19 to 3.48), 2.46 (1.46 to 4.14), 2.62 (1.59 to 4.32), and 3.95 (2.37 to 6.58) in men and 1.12 (0.59 to 2.13), 1.54 (0.85 to 2.78), 1.35 (0.75 to 2.43), and 2.86 (1.60 to 5.12) in women, respectively. The risks of myocardial infarction and stroke for each blood pressure category were similar to those of CVD. Population-attributable fractions of high-normal blood pressure and hypertension for CVD were 12.2% and 35.3% in men and 7.1% and 23.4% in women, respectively. In conclusion, high-normal blood pressure is a risk factor for the incidence of stroke and myocardial infarction in a general urban population of Japanese men. © 2008 American Heart Association, Inc.

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Marine-Derived n-3 Fatty Acids and Atherosclerosis in Japanese, Japanese-American, and White Men. A Cross-Sectional Study

Sekikawa Akira, Curb J. David, Ueshima Hirotsugu, El-Saed Aiman, Kadowaki Takashi, Abbott Robert D., Evans Rhobert W., Rodriguez Beatriz L., Okamura Tomonori, Sutton-Tyrrell Kim, Nakamura Yasuyuki, Masaki Kamal, Edmundowicz Daniel, Kashiwagi Atsunori, Willcox Bradley J., Takamiya Tomoko, Mitsunami Ken ichi, Seto Todd B., Murata Kiyoshi, White Roger L., Kuller Lewis H.

Journal of the American College of Cardiology 52 （ 6 ） 417 - 424 2008年08月

ISSN 0735-1097

Objectives: We sought to examine whether marine-derived n-3 fatty acids are associated with less atherosclerosis in Japanese versus white populations in the U.S. Background: Marine-derived n-3 fatty acids at low levels are cardioprotective through their antiarrhythmic effect. Methods: A population-based cross-sectional study in 281 Japanese (defined as born and living in Japan), 306 white (defined as white men born and living in the U.S.), and 281 Japanese-American men (defined as Japanese men born and living in the U.S.) ages 40 to 49 years was conducted to assess intima-media thickness (IMT) of the carotid artery, coronary artery calcification (CAC), and serum fatty acids. Results: Japanese men had the lowest levels of atherosclerosis, whereas whites and Japanese Americans had similar levels. Japanese had 2-fold higher levels of marine-derived n-3 fatty acids than whites and Japanese Americans in the U.S. Japanese had significant and nonsignificant inverse associations of marine-derived n-3 fatty acids with IMT and CAC prevalence, respectively. The significant inverse association with IMT remained after adjusting for traditional cardiovascular risk factors. Neither whites nor Japanese Americans had such associations. Significant differences between Japanese and whites in multivariable-adjusted IMT (mean difference 39 μm, 95% confidence interval [CI]: 21 to 57μm, p < 0.001) and CAC prevalence (mean difference 10.7%, 95% CI: 2.9% to 18.4%, p = 0.007) became nonsignificant after we adjusted further for marine-derived n-3 fatty acids (22 μm, 95% CI: -1 to 46 μm, p = 0.065 and 5.0%, 95% CI: -5.3% to 15.4%, p = 0.341, respectively). Conclusions: Very high levels of marine-derived n-3 fatty acids have antiatherogenic properties that are independent of traditional cardiovascular risk factors and may contribute to lower the burden of atherosclerosis in Japanese, a lower burden that is unlikely the result of genetic factors. © 2008 American College of Cardiology Foundation.

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Relation of dietary and other lifestyle traits to difference in serum adiponectin concentration of Japanese in Japan and Hawaii

Nakamura Yasuyuki, Ueshima Hirotsugu, Okuda Nagako, Higashiyama Aya, Kita Yoshikuni, Kadowaki Takashi, Okamura Tomonori, Murakami Yoshitaka, Okayama Akira, Choudhury Sohel Reza, Rodriguez Beatriz, Curb J. David, Stamler Jeremiah

American Journal of Clinical Nutrition 88 （ 2 ） 424 - 430 2008年08月

ISSN 0002-9165

Background: In initial analyses, we found significant differences between serum adiponectin in Japanese living in Japan and Hawaii. Objective: We investigated whether differences in dietary and other lifestyle factors explain higher serum adiponectin concentrations in Japanese in Japan compared with Japanese emigrants living a Western lifestyle in Hawaii. Design: Serum adiponectin and nutrient intakes were examined by standardized methods in men and women aged 40-59 y from 2 population samples, one Japanese American in Hawaii (99 men, 104 women), the other Japanese in central Japan (124 men, 125 women). Multiple linear regression models were used to assess the role of dietary and other lifestyle traits in accounting for serum adiponectin difference between Hawaii and Japan. Results: Mean adiponectin was significantly higher in Japan than in Hawaii (10.5 ± 5.5 μg/mL compared with 6.7 ± 3.2 μg/mL in men, P = 0.002; 12.9 ± 5.9 μg/mL compared with 9.4 ± 4.2 in women, P < 0.0001). In men, the difference in body mass index (BMI; in kg/m²) in the 2 populations explained ≈90% of the difference in serum adiponectin; in women, only 29%. In multiple linear regression analyses in women further adjustment for physical activity and 4 nutrients (nonvegetable protein, n-3 polyunsaturated fatty acid, arachidonic acid, dietary cholesterol) produced a further reduction in the coefficient for the difference (total 56%); P value for the difference became 0.074. Conclusions: The significantly higher mean serum adiponectin concentration in Japan than in Hawaii may be attributable largely to differences in BMI. Differences in nutrient intake in the 2 samples were associated with only modest relation to the adiponectin difference. © 2008 American Society for Nutrition.

Marital status and cardiovascular risk factors among middle-aged Japanese male workers

Kamon Yuko, Okamura Tomonori, Tanaka Taichiro, Hozawa Atsushi, Yamagata Zentaro, Takebayashi Toru, Kusaka Yukinori, Urano Sumio, Nakagawa Hideaki, Kadowaki Takashi, Miyoshi Yuji, Yamato Hiroshi, Okayama Akira, Ueshima Hirotsugu

Journal of Occupational Health 50 （ 4 ） 348 - 356 2008年07月

ISSN 1341-9145

Marital status is related to cardiovascular disease (CVD) risk factors in Western countries. However, few studies have addressed the relationship between marital status and CVD risk factors in other populations. We investigated lifestyle and CVD risk factors relative to marital status among middle-aged Japanese men. We analyzed baseline data of 40-59-yr-old male workers who participated in the high-risk and population strategy for occupational health promotion (HIPOP-OHP) study. We compared lifestyle and CVD risk factors between men who were married (Group M; n=1,419, mean age 47.9 ±5.1 yr) and those who had never married (Group N; n=163, mean age 46.7 ±4.3 yr). Men in Group N were more likely to skip breakfast, work more shifts and exercise less. Current smoking rates, as well as average values of diastolic blood pressure (DBP), serum total cholesterol and fasting plasma glucose were also higher in Group N than in Group M. The proportion of participants with three or more CVD risk factors, namely smoking, hypertension, hypercholesterolemia and hyperglycemia was higher in Group N, than in Group M (12.9% vs. 5.0%, p<0.01). The difference between Groups M and N was more evident in the subgroup of living with others, than in the subgroup of living alone. Since men who have never married might be at higher risk for CVD, effort should be made to educate this population about decreasing lifestyle-related risk factors.

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Relationship between BMI and all-cause mortality in Japan

Hozawa Atsushi, Okamura Tomonori, Oki Izumi, Murakami Yoshitaka, Kadowaki Takashi, Nakamura Koshi, Miyamatsu Naomi, Hayakawa Takehito, Kita Yoshikuni, Nakamura Yosikazu, Nakamura Yasuyuki, Abbott Robert D., Okayama Akira, Ueshima Hirotsugu, Iimura Osamu, Omae Teruo, Ueda Kazuo, Yanagawa Hiroshi, Horibe Hiroshi, Kodama Kazunori, Kasagi Fumiyoshi, Tanihara Shinichi, Saito Shigeyuki, Sakata Kiyomi, Kakuno Fumihiko, Takeuchi Toshihiro, Hasebe Mitsuru, Kusano Fumitsugu, Kawamoto Takahisa, Minowa Masumi, Iida Minoru, Hashimoto Tsutomu, Tanaka Shigemichi, Terao Atsushi, Kawaminami Katsuhiko, Sawai Koryo, Shibata Shigeo

Obesity 16 （ 7 ） 1714 - 1717 2008年07月

ISSN 1930-7381

As body composition in Asian populations is largely different from Western populations, a healthy BMI could also differ between the two populations. Thus, further study is needed to determine whether a healthy BMI in Asians should be lower than Western populations, as recommended by the World Health Organization (WHO). We investigated the relationship between BMI and mortality in a sample of 8,924 Japanese men and women without stroke or heart disease. During 19 years of follow-up, 1,718 deaths were observed. We found a U-shaped relationship between BMI and fatal events. Risk of total mortality was highest in participants with BMI <18.5 kg/m² and lowest in participants with BMI 23.0-24.9 kg/m². These findings persisted even after excluding the first 5 years of follow-up with a focus on healthy participants who never smoked, were aged <70 years, and had total cholesterol (TC) levels ≥4.1 mmol/l (N = 3712). For both the full sample and healthy participants, all-cause mortality risk did not differ between BMI ranges 21.0-22.9 and 23.0-24.9 kg/m². Our findings do not support the recent WHO implications that BMIs <23.0 kg/m² is healthy for Asians. Therefore, further studies are needed to identify an optimal BMI range for Asia. © 2008 The Obesity Society.

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Erratum

Hayashino Y., Fukuhara S., Okamura T., Yamato H., Tanaka H., Tanaka T., Kadowaki T., Ueshima H.

Diabetes Care 31 （ 7 ） 1471 2008年07月

ISSN 0149-5992

Relation of blood pressure and all-cause mortality in 180 000 japanese participants pooled analysis of 13 cohort studies

Murakami Yoshitaka, Hozawa Atsushi, Okamura Tomonori, Ueshima Hirotsugu

Hypertension 51 （ 6 ） 1483 - 1491 2008年06月

ISSN 0194-911X

Hypertension is a leading cause of death because of cardiovascular disease and predominantly affects total mortality. To reduce avoidable deaths from hypertension, we need to collect blood pressure data and assess their impact on total mortality. To examine this issue, a meta-analysis of 13 cohort studies was conducted in Japan. Poisson regression was used for estimating all-cause mortality rates and ratios. In the model, blood pressure data were treated as continuous (10-mm Hg increase) and categorical (every 10 mm Hg) according to recommendations of the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Hypertension. Potential confounders included body mass index, smoking, drinking, and cohort. The impact of hypertension was measured by the population-attributable fraction. After excluding participants with cardiovascular disease history, 176 389 participants were examined in the analysis. Adjusted mortality rates became larger as the blood pressure increased, and these were more distinct in younger men and women. Hazard ratios also showed the same trends, and these trends were more apparent in younger men (hazard ratio [unit: 10-mm Hg increase] aged 40 to 49 years: systolic blood pressure 1.37 (range: 1.15 to 1.62); diastolic blood pressure 1.46 [range: 1.05 to 2.03]) than older ones (hazard ratio: aged 80 to 89 years: systolic blood pressure 1.09 [range: 1.05 to 1.13]and diastolic blood pressure 1.12 [range: 1.03 to 1.22]). Population-attributable fraction of hypertension was ≈20% when the normal category was used as a reference level and was 10% when we included the prehypertension group in the reference level. In conclusion, high blood pressure raised the risk of total mortality, and this trend was higher in the younger Japanese population. © 2008 American Heart Association, Inc.

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A prospective study of passive smoking and risk of diabetes in a cohort of workers

Hayashino Yasuaki, Fukuhara Shunichi, Okamura Tomonori, Yamato Hiroshi, Tanaka Hideo, Tanaka Taichiro, Kadowaki Takashi, Ueshima Hirotsugu

Diabetes Care 31 （ 4 ） 732 - 734 2008年04月

ISSN 0149-5992

OBJECTIVE - We investigated the impact of active smoking and exposure to passive smoke on the risk of developing diabetes. RESEARCH DESIGN AND METHODS - Data were analyzed from a cohort of participants in the High-Risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP) conducted in Japan from 1999 to 2004. Active and passive smoking status in the workplace was evaluated at baseline. RESULTS - Of 6,498 participants (20.9% women), a total of 229 diabetes cases were reported over a median 3.4 years of follow-up. In the workplace, compared with zero-exposure subjects, the multivariable-adjusted hazard ratios of developing diabetes were 1.81 (95% CI 1.06-3.08, P = 0.028) for present passive subjects and 1.99 (1.29-3.04, P = 0.002) for present active smokers. CONCLUSIONS - In this cohort, exposure to passive smoke in the workplace was associated with an increased risk of diabetes after adjustment for a large number of possible confounders. © 2008 by the American Diabetes Association.

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Relationship of elevated casual blood glucose level with coronary heart disease, cardiovascular disease and all-cause mortality in a representative sample of the Japanese population. NIPPON DATA80

Kadowaki S., Okamura T., Hozawa A., Kadowaki T., Kadota A., Murakami Y., Nakamura K., Saitoh S., Nakamura Y., Hayakawa T., Kita Y., Okayama A., Ueshima H.

Diabetologia 51 （ 4 ） 575 - 582 2008年04月

ISSN 0012-186X

Aims/hypothesis: High fasting blood glucose is one of the well-known risk factors for CHD. However, in certain settings, patients cannot always be expected to fast. For example, community screenings for cardiovascular disease (CVD) risk factors in Japan are performed under non-fasting conditions to achieve high participation rates. Thus, we examined a representative cohort of the Japanese population (n=9,444, follow-up period 17.3 years) to clarify whether high casual blood glucose (CBG) can predict CVD mortality. Methods: We defined CBG groups as follows: high CBG≥11.1 mmol/l or participants with a history of diabetes mellitus; borderline high, 7.77≤CBG<11.1 mmol/l; higher normal, 5.22≤CBG<7.77 mmol/l); and lower normal, CBG<5.22 mmol/l. The multivariate-adjusted hazard ratios (HRs) for CHD, CVD and all-cause mortality were calculated. Results: The crude CHD mortality rate was 0.84 per 1,000 person-years. Age- and sex-adjusted HRs for CHD mortality were high among participants with CBG levels ≥7.77 mmol/l, regardless of time since last meal. Multivariate-adjusted HRs (95% CI) of CHD mortality in high and borderline high CBG groups were 2.62 (1.46-4.67) and 2.43 (1.29-4.58), respectively. Similar results were observed for both CVD and all-cause mortality. Even within the normal blood glucose range, each 1 mmol/l increase in CBG was associated with a statistically significant increase in the HR for CVD mortality (1.12, 95% CI 1.02-1.22). Population-attributable fractions of the combined groups of high and borderline high CBG for CHD, CVD and all-cause mortality were 12.0, 4.9 and 3.5%, respectively. Conclusions/interpretation: Increases in CBG, even within the normal range, predict CVD mortality. © 2007 Springer-Verlag.

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Difference in Carotid Intima-Media Thickness Between Korean and Japanese Men

Choo Jina, Ueshima Hirotsugu, Jang Yangsoo, Sutton-Tyrrell Kim, El-Saed Aiman, Kadowaki Takashi, Takamiya Tomoko, Okamura Tomonori, Ueno Yoshiki, Nakamura Yasuyuki, Sekikawa Akira, Curb J. David, Kuller Lewis H., Shin Chol

Annals of Epidemiology 18 （ 4 ） 310 - 315 2008年04月

ISSN 1047-2797

Purpose: Koreans are recently at higher risk for coronary heart disease than are the Japanese. We aimed to evaluate levels of carotid intima-media thickness (IMT) and coronary risk factors in Korean and Japanese men in the post-World War II birth cohort. Methods: We conducted a population-based study of 352 randomly selected healthy men 40 to 49 years of age: 102 Koreans in Ansan City, Gyeonggi-do, Korea and 250 Japanese in Kusatsu City, Shiga, Japan. Imaging carotid IMT by ultrasonography and other procedures were standardized. Analyzing blood samples and reading carotid IMT were performed at the University of Pittsburgh. Results: Despite more favorable or similar features in coronary risk factors as compared to Japanese men, the Korean men had a higher crude IMT level than the Japanese men (mean ± standard error, 0.655 ± 0.008 mm vs 0.616 ± 0.005 mm, respectively, p < 0.0001). The difference in the levels of carotid IMT significantly remained after adjusting for metabolic and conventional risk factors (0.654 ± 0.008 mm vs. 0.616 ± 0.005 mm, respectively; p < 0.0001). Conclusions: Among men 40 to 49 years of age, Koreans had significantly higher levels of carotid IMT than the Japanese. Factors that underlie the different susceptibility to subclinical atherosclerosis need to be explored. © 2008 Elsevier Inc. All rights reserved.

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Effect of a 4-year workplace-based physical activity intervention program on the blood lipid profiles of participating employees

Naito Mariko, Nakayama Takeo, Okamura Tomonori, Miura Katsuyuki, Yanagita Masahiko, Fujieda Yoshiharu, Kinoshita Fujihisa, Naito Yoshihiko, Nakagawa Hideaki, Tanaka Taichiro, Ueshima Hirotsugu

Atherosclerosis 197 （ 2 ） 784 - 790 2008年04月

ISSN 0021-9150

Individuals who are physically fit or engage in regular physical activity have a lower incidence of cardiovascular disease and risk of mortality. We conducted a large-scale controlled trial of interventions to decrease cardiovascular risk factors, during which we assessed the effect of a workplace-based intervention program, which was part of a population strategy for promoting long-term increases in physical activity, on the blood lipid profiles of participating employees. Data were collected from 2929 participants and this report presents the results of a survey conducted in five factories for the intervention group and five factories for the control group at baseline and year 5. The absolute/proportional changes in HDL-cholesterol were 2.7 mg/dL (4.8%) in the intervention group and -0.6 mg/dL (-1.0%) in the control group. The differences between the two groups in the change in serum levels of HDL-cholesterol were highly significant (p < 0.001) in each analysis of covariance, in which the number of cigarettes smoked was included or excluded. In the intervention group, the daily walking time increased significantly (p < 0.001) when compared between baseline and year 5, whereas no significant difference was observed in daily walking time in the control group over the identical period. Our results show that an intervention program promoting physical activity raises serum HDL-cholesterol levels of middle-aged employees. Increased awareness of the benefits of physical activity, using environmental rearrangement and health promotion campaigns, which especially target walking, may have contributed to a beneficial change in serum HDL-cholesterol levels in the participants. © 2007 Elsevier Ireland Ltd. All rights reserved.

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Lower levels of serum albumin and total cholesterol associated with decline in activities of daily living and excess mortality in a 12-year cohort study of elderly Japanese

Okamura Tomonori, Hayakawa Takehito, Hozawa Atsushi, Kadowaki Takashi, Murakami Yoshitaka, Kita Yoshikuni, Abbott Robert D., Okayama Akira, Ueshima Hirotsugu

Journal of the American Geriatrics Society 56 （ 3 ） 529 - 535 2008年03月

ISSN 0002-8614

OBJECTIVES: To examine the association between levels of serum albumin and total cholesterol (TC) and risk of subsequent mortality and future decline in activities of daily living (ADLs) in elderly people. DESIGN: Population-based cohort study. SETTING: National Integrated Project for Prospective Observation of Non-Communicable Disease and Its Trends in the Aged, 1980. PARTICIPANTS: One thousand eight hundred forty-four Japanese individuals aged 60 to 74 randomly selected throughout Japan and followed for 12.4 years. MEASUREMENTS: Decline in ADLs and mortality. RESULTS: After adjusting for other covariates, the multivariable odds ratios (ORs) of impaired ADLs were highest in the lowest albumin quartile (≤40 g/L) for women. The multivariable OR of having a composite outcome of death or impaired ADL for the lowest albumin quartile compared with the highest was 1.56 (95% confidence interval (CI)=1.94-2.57) for men and 3.06 (95% CI=1.89-4.95) for women. Serum albumin was significantly and inversely associated with a composite outcome of death or impaired ADLs in the group below the median of TC in both sexes (multivariable OR for 1-g/L increase in serum albumin=0.88 for men (95% CI=0.79-0.97) and 0.79 for women (95% CI=0.72-0.87)), which was not significantly associated in the group with TC at or above the median. CONCLUSION: In the Japanese general population, low-normal serum albumin and TC levels are associated with loss of activity during old age, especially for women. © 2007, Copyright the Authors.

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Intima-media thickness of the carotid artery and the distribution of lipoprotein subclasses in men aged 40 to 49 years between whites in the United States and the Japanese in Japan for the ERA JUMP study

Sekikawa Akira, Ueshima Hirotsugu, Sutton-Tyrrell Kim, Kadowaki Takashi, El-Saed Aiman, Okamura Tomonori, Takamiya Tomoko, Ueno Yoshiki, Evans Rhobert W., Nakamura Yasuyuki, Edmundowicz Daniel, Kashiwagi Atsunori, Maegawa Hiroshi, Kuller Lewis H.

Metabolism: Clinical and Experimental 57 （ 2 ） 177 - 182 2008年02月

ISSN 0026-0495

In men in the post-World War II birth cohort, that is, men aged 40 to 49 years, whites in the United States had significantly higher levels of intima-media thickness of the carotid arteries (IMT) than the Japanese in Japan (Electron-Beam Tomography and Risk Assessment Among Japanese and US Men in the Post World War II Birth Cohort [ERA JUMP] study). The difference remained after adjusting for traditional risk factors. Primary genetic effects are unlikely, given the degree to which IMT is increased in the Japanese who migrated to the United States. We investigated whether the differences in the distributions of lipoprotein subclasses explain the difference in IMT between the 2 populations. We examined population-based samples of 466 randomly selected men aged 40 to 49 years (215 whites from Allegheny County, Pennsylvania, and 241 Japanese from Kusatsu, Shiga, Japan). Lipoprotein subclasses were determined by nuclear magnetic resonance (NMR) spectroscopy. The whites had significantly higher levels of large very low-density lipoprotein particles and significantly lower levels of large high-density lipoprotein particles than the Japanese, whereas the 2 populations had similar levels of small low-density lipoprotein particles. The 2 populations had similar associations of IMT with NMR lipoproteins. Adjusting for NMR lipoproteins did not attenuate the significant difference in IMT between the 2 populations (0.671 ± 0.006 mm for the whites and 0.618 ± 0.006 mm for the Japanese, P = .01, mean ± SE). Differences in the distributions of NMR lipoproteins between the 2 populations did not explain the higher IMT in the whites. © 2008 Elsevier Inc. All rights reserved.

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Effects of the Y chromosome on cardiovascular risk factors in Japanese men

Hiura Yumiko, Fukushima Yasue, Kokubo Yoshihiro, Okamura Tomonori, Goto Yoichi, Nonogi Hiroshi, Takahashi Rie, Iwai Naoharu

Hypertension Research 31 （ 9 ） 1687 - 1694 2008年

ISSN 0916-9636

Excess cardiovascular risk in men compared with women has been suggested to be partly explained by effects of the Y chromosome. However, inconsistent results have been reported on the Y chromosome's genetic influence on blood pressure and lipid levels. The purpose of the present study was to settle the question whether genetic variants of the Y chromosome influence cardiovascular risk factors using a large epidemiological cohort, the Suita study. Possible influences of the Y chromosome polymorphisms (Y chromosome Alu insertion polymorphism [YAP], M175 and SRY+465) on cardiovascular risk factors were assessed in 974 Japanese men. The frequency of the YAP(+) allele in our study sample was 0.31. The prevalence of hypertension tended to be higher in YAP(+) than in YAP(-) men, and this tendency was found to be stronger among men aged 65 years or older. Men with the YAP(+) genotype had higher levels of high density lipoprotein (HDL) cholesterol compared with those with the YAP(-) genotype, even after adjustment for age, body mass index, and daily ethanol and cigarette consumption (57.0±14.6 mg/dL vs. 54.2±14.2 mg/dL, nominal p=0.011, adjusted p=0.0062). However, these observed nominal associations disappeared after adjusting for multiple testing (Bonferroni). No association was detected between the YAP genotype and myocardial infarction. Similarly, none of the associations with M175 and SRY+465 attained significance when multiple testing was taken into account. In conclusion, Y chromosome polymorphisms (YAP, M175 and SRY+465) do not appear to be associated with cardiovascular risk factors in Japanese men. Studies using much larger sample sizes and/or additional independent samples will be required for definitive conclusions.

Relationships between family histories of stroke and of hypertension and stroke mortality

Kadota Aya, Okamura Tomonori, Hozawa Atsushi, Kadowaki Takashi, Murakami Yoshitaka, Hayakawa Takehito, Kita Yoshikuni, Okayama Akira, Nakamura Yasuyuki, Ueshima Hirotsugu

Hypertension Research 31 （ 8 ） 1525 - 1531 2008年

ISSN 0916-9636

A family history of stroke seems to be related with increased risk of stroke although the relationship is not always significant. Increased risk of stroke is strongly associated with hypertension, which might be also associated with family history. However, investigations into the relationship between family history of hypertension and stroke mortality are scarce. We investigated whether a family history of stroke and that of hypertension evaluated using a simple questionnaire could predict stroke mortality in Japanese. We obtained parental histories of stroke and of hypertension from 8,037 randomly selected general Japanese without history of cardiovascular disease and followed them for 19 years. The multivariate adjusted hazard ratios (HRs) for total stroke mortality, intra-cerebral hemorrhage mortality and for cerebral infarction mortality according to family history were estimated using the Cox proportional hazards model. The prevalences of family histories of stroke and of hypertension were 20.6% and 31.1%, respectively. A family history of stroke was not related to total stroke mortality, intra-cerebral hemorrhage mortality or to cerebral infarction mortality. Meanwhile, a family history of hypertension was positively related to total stroke mortality among women aged less than 60 years and men aged 60 or more years (women: HR=3.41, 95% confidence interval [CI]: 1.49-7.81; men: HR=1.50, 95% CI: 1.00-2.24) even after adjustment for systolic blood pressure. In conclusion, a family history of stroke could not predict total stroke mortality. However, a family history of hypertension might predict an increased risk for total stroke.

Impact of metabolic syndrome components on the incidence of cardiovascular disease in a general urban Japanese population

Kokubo Yoshihiro, Okamura Tomonori, Yoshimasa Yasunao, Miyamoto Yoshihiro, Kawanishi Katsuyuki, Kotani Yasushi, Okayama Akira, Tomoike Hitonobu

Hypertension Research 31 （ 11 ） 2027 - 2035 2008年

ISSN 0916-9636

Abdominal obesity is a prerequisite for some definitions of metabolic syndrome (MetS). We investigated the impact of MetS defined by two different criteria, which either did or did not require abdominal obesity as a prerequisite, on cardiovascular disease (CVD) incidence in an urban Japanese cohort study. We studied 5,332 Japanese (aged 30-79 years, without CVD at baseline), who completed a baseline survey (September 1989 to March 1994) and were followed up through December 2005. MetS was defined by the NCEP-ATPIII (modified by Asian obesity criteria) and the Japanese criteria. After 61,846 person-years of follow-up, we documented 317 CVD incidences. The MetS frequencies of the Japanese and of the modified NCEP-ATPIII criteria were 17.7% and 25.1% for men and 5.0% and 14.3% for women, respectively. The multivariate hazard ratios (HRs; 95% confidence intervals [CI]) of CVD incidence for MetS by the modified NCEP-ATPIII criteria were 1.75 (1.27-2.41) in men and 1.90 (1.31-2.77) in women, and those for MetS by the Japanese criteria were 1.34 (0.96-1.87) in men and 2.20 (1.31-3.68) in women. The multivariate HRs of CVD incidence for MetS for the Japanese and for the modified NCEP-ATPIII criteria were 2.92 (1.54-5.55) and 1.94 (0.98-3.82) in men under 60 years old, respectively. The CVD incidence risks increased according to the number of MetS components. The risks were similar among participants with the same number of MetS components, regardless of abdominal obesity. In conclusion, the number of MetS components (modified NCEP-ATPIII criteria) may be more strongly associated with CVD incidence than the abdominal obesity essential criteria (the Japanese criteria) in a general urban Japanese population.

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Low-risk profile for cardiovascular disease and mortality in Japanese

Yamamoto Takako, Nakamura Yasuyuki, Hozawa Atsushi, Okamura Tomonori, Kadowaki Takashi, Hayakawa Takehito, Murakami Yoshitaka, Kita Yoshikuni, Okayama Akira, Abbott Robert D., Ueshima Hirotsugu

Circulation Journal 72 （ 4 ） 545 - 550 2008年

ISSN 1346-9843

Background: Some studies focusing on low-risk profiles for cardiovascular disease have been reported in Western countries. Yet, few reports have examined, with substantial longevity, the low-risk profile for cardiovascular disease in the Japanese population. This study examines whether having a favorable risk factor profile yields lower all-cause mortality and whether the proportion of those with a low-risk profile is larger in the Japanese population. Methods and Results: A total of 8,339 men and women aged 30-69 years without a history of cardiovascular diseases for 19 years, who had participated in the 1980 National Survey on Circulatory Disorders after being randomly selected from throughout Japan, were followed. Low risk was defined as having all of the following baseline characteristics: blood pressure (BP) <120/80 mmHg; no antihypertensive medication; serum cholesterol 160-240 mg/dl (4.14-6.22 mmol/L); no history of diabetes; and non-smoker. The long-term mortality of the low-risk group was compared with that of others using the Cox proportional hazard model. The prevalence of low risk was 9.4% of all participants. The multivariate-adjusted hazard ratios for low-risk individuals compared with others were as follows: 0.33 (95% confidence intervals (CI), 0.15-0.74) for cardiovascular disease and 0.63 (95% CI, 0.46-0.88) for all-cause mortality. The most attributable risk factor for all-cause mortality was high BP (≥120/80 mmHg). Conclusion Japanese individuals with favorable cardiovascular disease risk profiles had lower mortality from cardiovascular disease and all-causes than those without.

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The relationship between white blood cell count and risk of hypertension in populations with high prevalence of smoking

Okamura Tomonori, Watanabe Makoto

Hypertension Research 31 （ 7 ） 1279 - 1281 2008年

ISSN 0916-9636

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Association of lipoprotein-associated phospholipase A2 with coronary calcification among American and Japanese men

El-Saed Aiman, Sekikawa Akira, Zaky Riad Wahid, Kadowaki Takashi, Takamiya Tomoko, Okamura Tomonori, Edmundowicz Daniel, Kita Yoshikuni, Kuller Lewis H., Ueshima Hirotsugu

Journal of Epidemiology 17 （ 6 ） 179 - 185 2007年12月

ISSN 0917-5040

Background: We have previously reported that the prevalence of coronary artery calcification (CAC) was substantially lower among Japanese than American men despite a less favorable profile of many traditional risk factors in Japanese men. To determine whether lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are related to the difference in the prevalence of CAC between the two populations. Methods: A total of 200 men aged 40-49 years were examined: 100 residents in Allegheny County, Pennsylvania, United States, and 100 residents in Kusatsu City, Shiga, Japan. Coronary calcium score (CCS) was evaluated by electron-beam tomography, Lp-PLA2 levels, nuclear magnetic resonance (NMR) lipoprotein subclasses, and other factors were assessed in 2001-2002. Results: Lp-PLA2 levels were higher among American than Japanese men (Mean ± standard deviation 301.7 ± 82.6 versus 275.9 ± 104.7 ng/mL, respectively, p=0.06). Among all Japanese men and those with low density lipoprotein (LDL) cholesterol ≥130 mg/dL, there was an inverse association of the prevalence of CCS>0 with the tertile groups of Lp-PLA2 levels (p=0.08 and p=0.03, respectively). American men did not have any association between CCS>0 with the tertile groups of Lp-PLA2 (p=0.62). Although Lp-PLA2 among both populations correlated positively with LDL and total cholesterol, American and Japanese men had different correlations with NMR lipoprotein subclasses. Reported high odds ratio for CCS>0 among American compared to Japanese men was not reduced after adjusting for Lp-PLA2 levels. Conclusion: Lp-PLA2 may have different mechanisms of action among American and Japanese men. Lp-PLA2 levels can not explain the observed CAC differences between the two populations. Copyright © 2007 by the Japan Epidemiological Association.

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Erratum

Hayashino Y., Fukuhara S., Suzukamo Y., Okamura T., Tanaka T., Ueshima H.

Acta Diabetologica 44 （ 4 ） 241 2007年12月

ISSN 0940-5429

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Coronary artery calcification in Japanese men in Japan and Hawaii

Abbott Robert D., Ueshima Hirotsugu, Rodriguez Beatriz L., Kadowaki Takashi, Masaki Kamal H., Willcox Bradley J., Sekikawa Akira, Kuller Lewis H., Edmundowicz Daniel, Shin Chol, Kashiwagi Atsunori, Nakamura Yasuyuki, El-Saed Aiman, Okamura Tomonori, White Roger, Curb J. David

American Journal of Epidemiology 166 （ 11 ） 1280 - 1287 2007年12月

ISSN 0002-9262

Explanations for the low prevalence of atherosclerosis in Japan versus the United States are often confounded with genetic variation. To help remove such confounding, the authors compared coronary artery calcification (CAC), a marker of subclinical atherosclerosis, between Japanese men in Japan and Japanese men in Hawaii. Findings were based on risk factors and CAC measured from 2001 to 2005 in 311 men in Japan and 300 men in Hawaii. Men were aged 40-50 years and without cardiovascular disease. After age adjustment, there was a threefold excess in the odds of prevalent CAC scores of ≥10 in Hawaii versus Japan (relative odds = 3.2, 95% confidence interval: 2.1, 4.9). Whereas men in Hawaii had a generally poorer risk factor profile, men in Japan were four times more likely to smoke cigarettes (49.5% vs. 12.7%, p < 0.001). In spite of marked risk factor differences between the samples, none of the risk factors explained the low amounts of CAC in Japan. After risk factor adjustment, the relative odds of CAC scores of ≥10 in Hawaii versus Japan was 4.0 (95% confidence interval: 2.2, 7.4). Further studies are needed to identify factors that protect against atherosclerosis in Japanese men in Japan. © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

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Joint impact of smoking and hypertension on cardiovascular disease and all-cause mortality in Japan

Hozawa Atsushi, Okamura Tomonori, Murakami Yoshitaka, Kadowaki Takashi, Nakamura Koshi, Hayakawa Takehito, Kita Yoshikuni, Nakamura Yasuyuki, Abbott Robert D., Okayama Akira, Ueshima Hirotsugu

Hypertension Research 30 （ 12 ） 1169 - 1175 2007年12月

ISSN 0916-9636

Hypertension and smoking are major risk factors for death to cardiovascular disease (CVD). These attributions for CVD mortality should be higher in the countries where obesity-related conditions are uncommon. However, the joint effect of these risk factors on CVD and all-cause mortality have not been described. We followed a representative 8,912 Japanese men and women without a history of stroke and heart disease. Participants were categorized into 4 groups as follows: a group of individuals who neither smoked nor had hypertension (HT), a group of current smokers, a group with HT, and a group of current smokers with HT. We further calculated population-attributable fractions (PAF) of CVD and all-cause mortality based on relative hazards assessed by proportional hazard regression models. After 19 years of follow-up, we observed 313 and 291 CVID and 948 and 766 all-cause deaths for men and women, respectively. The PAF of CVD mortality due to smoking or HT were 35.1 % for men and 22.1 % for women. The PAF of CVID mortality was higher in participants <60 years of age (57.4% for men and 40.7% for women) vs. those who were older (26.3% for men and 18.1% for women). Aggressive aftempts to discourage smoking and to curb HT could yield large health benefits in Japan and throughout Asia, particularly for those aged <60 years. Efforts to warn about the adverse consequence of HT and smoking during adolescence and youth could yield the greatest health benefits, since positive behaviors adopted early are more easily continued into middle adulthood and later life.

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Is weak association between cigarette smoking and cardiovascular disease mortality observed in Japan explained by low total cholesterol? - NIPPON DATA80

Hozawa Atsushi, Okamura Tomonori, Kadowaki Takashi, Murakami Yoshitaka, Nakamura Koshi, Hayakawa Takehito, Kita Yoshikuni, Nakamura Yasuyuki, Okayama Akira, Ueshima Hirotsugu

International Journal of Epidemiology 36 （ 5 ） 1060 - 1067 2007年10月

ISSN 0300-5771

Background: An international comparison has indicated that the association between smoking and cardiovascular disease (CVD) differs according to total cholesterol (TC) levels. However, little has been published about the relationship between smoking and CVD mortality among populations with various cholesterol levels. Methods: We calculated the adjusted relative hazard (RH) of smoking for CVD mortality among 8912 Japanese individuals without a history of stroke or heart disease, who were separated according to TC levels of ≥5.40, 4.81-5.39, 4.26-4.80 and <4.25 mmol/l into groups Q4, Q3, Q2 and Q1, respectively. The P-values for multiple interactions between TC and smoking status for CVD mortality were calculated using TC as a continuous variable, dichotomized smoking status (never vs current), and by including cross-product terms in the regression models. Results: After 19 years of follow-up, 313 men and 291 women died of CVD. The RH of CVD mortality among men who currently smoked compared with those who never smoked was increased with higher TC (RH = 2.36 in Q4) and decreased in those with lower TC (RH = 0.85 in Q1) (interaction, P = 0.01). The profiles for coronary heart disease (CHD) mortality and ischaemic CVD (composite endpoint of CHD and ischaemic stroke) in men and for ischaemic CVD mortality in women were identical. The interaction might be explained by a biological mechanism and by frailty of those who have never smoked with lower TC. Conclusions: Counteractive measures should be implemented against smoking targeted towards Japanese with elevated TC levels. © The Author 2007; all rights reserved.

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The proportion of individuals with obesity-induced hypertension among total hypertensives in a general Japanese population

Nakamura Koshi, Okamura Tomonori, Hayakawa Takehito, Hozawa Atsushi, Kadowaki Takashi, Murakami Yoshitaka, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu

European Journal of Epidemiology 22 （ 10 ） 691 - 698 2007年10月

ISSN 0393-2990

The increased prevalence of obesity in Japan may contribute to the high prevalence of hypertension in Japan. In the present study, we calculated the odds ratio for hypertension in obesity (body mass index (BMI) ≥ 25.0 kg/m²) using data from independent nationwide surveys conducted in 1980 and 1990. We estimated the percentage of hypertensives whose condition was due to obesity among total hypertensives in the general Japanese population. In the 1980 survey, 18.8% of 4,623 male participants were obese and 50.4% were hypertensive, whereas 22.6% of 5,893 female participants were obese and 41.1% were hypertensive. For both sexes, obese participants had a higher odds ratio for hypertension than non-obese participants (BMI < 25.0 kg/m²), and there was a significant dose-response relationship between BMI and the odds ratio for hypertension. Among all hypertensives, the percentage whose hypertension was due to obesity in 1980 and 1990 was 11.4% (95% confidence interval (CI): 4.7-17.7%) and 15.3% (95% CI: 6.8-23.1%) for men and 19.3% (95% CI: 12.1-25.9%) and 22.3% (95% CI: 14.6-29.3%) for women, respectively. Approximately 80-90% of individuals with obesity-induced hypertension were in the 25.0 ≤ BMI < 30.0 kg/m² category for both sexes in each year. In conclusion, we found that obesity-induced hypertension as a proportion of total hypertension increased between 1980 and 1990 for both sexes. Obesity now is playing a more important role in the high prevalence of hypertension in Japan than it was before. © 2007 Springer Science+Business Media B.V.

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Medical costs of obese Japanese

Nakamura Koshi, Okamura Tomonori, Kanda Hideyuki, Hayakawa Takehito, Okayama Akira, Ueshima Hirotsugu, Yamashita Shigeo, Tominaga Yoshinori, Katsuyama Kazuaki, Kakuno Fumihiko, Kitanishi Machiko, Tobita Yukio, Okamura Kanehiro, Hatta Kiminobu, Okada Takao, Hatanaka Michiko

European Journal of Public Health 17 （ 5 ） 424 - 429 2007年10月

ISSN 1101-1262

Background: For the Japanese population, a body mass index (BMI) of 25.0-29.9 is classified as obesity and is a risk factor for cardiovascular disorders such as hypertension. Methods: A cohort study to clarify obesity costs for a Japanese population was conducted utilizing baseline BMI and medical costs over a 10-year follow-up period. The participants were 4502 community dwelling Japanese National Health Insurance (NHI) beneficiaries aged 40-69 years. According to their baseline BMI values (kg/m²), participants were classified into the following three categories: BMI < 18.5, 18.5 ≤ BMI < 25.0 and 25.0 ≤ BMI. Medical costs per person per month were compared among the three categories. Excess medical costs attributable to the 25.0 ≤ BMI category compared to the 18.5 ≤ BMI < 25.0 category were estimated. Results: Approximately 20% of the Japanese population studied had a BMI of 25.0 or over. A J-shaped relationship between BMI and personal total medical costs was observed. Personal total medical costs per month determined from the 10-year follow-up in each category were 189 Euros (BMI < 18.5), 134 Euros (18.5 ≤ BMI < 25.0) and 155 Euros (25.0 ≤ BMI). A J-shaped pattern was observed after adjusting for age, sex, smoking and drinking habits, and excluding early deceased participants. Furthermore, smoking habit did not modify the J-shaped pattern of total medical costs. The estimated excess medical costs for the 25.0 ≤ BMI category represented 3.1% of the total medical costs for the entire study population (634 105 Euros). Conclusion: The Japanese NHI beneficiaries with a BMI of 25.0 or over showed increased medical costs compared to those with a BMI of 18.5-24.9. © The Author 2007. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

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Awareness and treatment of hypertension and hypercholesterolemia in Japanese workers

Tanaka Taichiro, Okamura Tomonori, Yamagata Zentaro, Takebayashi Toru, Tamura Unai, Kusaka Yukinori, Urano Sumio, Miyoshi Yuji, Okayama Akira, Ueshima Hirotsugu, Sakata Kiyomi, Tsuji Keiko, Yoshita Katsushi, Kikuchi Yuriko, Nakagawa Hideaki, Miura Katsuyuki, Yamato Hiroshi, Chiba Nagako, Yanagita Masahiko, Kodama Kazunori, Kasagi Fumiyoshi, Nishi Nobuo, Saitoh Shigeyuki, Tanaka Hideo, Nakamura Masakazu, Naito Yoshihiko, Nakamura Yasuyuki, Watanabe Makoto, Nakamura Yoshikazu, Babazono Akira, Yamagata Zentaro, Urano Sumio, Kinoshita Fujihisa, Saitoh Isao, Tanihara Shinichi, Tamaki Junko, Tochikubo Osamu, Nakayama Takeo, Fukuhara Shunichi, Fujieda Yoshiharu, Naito Mariko, Mizushima Shunsaku, Miyoshi Yuji, Tada Takayo, Kadowaki Takashi, Yoshida Toshimi, Ide Mami

Hypertension Research 30 （ 10 ） 921 - 928 2007年10月

ISSN 0916-9636

The objective of this study was to clarify the awareness and treatment status of hypertension in Japanese workers, comparing with those of hypercholesterolemia. The subjects were 6,186 workers (age 19 to 69 years), who worked at 12 workplaces in Japan and who continuously participated in the High-risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) study at the baseline (1999 or 2000) and the subsequent year (2000 or 2001). No Intervention was performed during the study period. Blood pressure and total cholesterol level were measured at baseline. Awareness and treatment status were examined by a self-administered questionnaire in the following year. Untreated subjects were defined as those were not aware of hypertension (or hypercholesterolemia) or those not taking medication and not undergoing lifestyle modification. The percentages of subjects with hypertension defined as aware were 65.7% in men and 72.7% in women, respectively. The percentages of subjects with hypercholesterolemia defined as aware were 55.7% in men and 58.6% in women, respectively. In subjects 40 years and older, the awareness rate for hypertension was significantly higher than the awareness rate for hypercholesterolemia (75.0% vs. 59.2%, p<0.001). The percentage of untreated subjects with hypertension was significantly lower than the percentage of untreated subjects with hypercholesterolemia (41.0% vs. 57.1%, p<0.001). Although Japanese workers ≥40 years old have a higher awareness of and are more often treated for hypertension than for hypercholesterolernia, there are still many unaware and untreated individuals with either disease in all age groups. It is important to increase the awareness of risk factors in individuals with positive findings for these conditions.

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γ-Glutamyltransferase predicts cardiovascular death among Japanese women

Hozawa Atsushi, Okamura Tomonori, Kadowaki Takashi, Murakami Yoshitaka, Nakamura Koshi, Hayakawa Takehito, Kita Yoshikuni, Nakamura Yasuyuki, Okayama Akira, Ueshima Hirotsugu

Atherosclerosis 194 （ 2 ） 498 - 504 2007年10月

ISSN 0021-9150

The clinical importance of γ-glutamyltransferase (GGT) has recently been debated. Although some studies have suggested that the relationship between GGT and cardiovascular disease (CVD) mortality is independent of alcohol consumption, to our knowledge no studies have reported the relationship between GGT and CVD mortality in never-drinker subgroups. Since Japanese women are known to have a lower prevalence of alcohol consumption, we examined whether GGT predicts CVD mortality in never-drinkers. We followed 2724 Japanese men and 4122 Japanese women without prior CVD or liver dysfunction for 9.6 years and observed 83 and 82 CVD deaths, respectively. Current alcohol drinkers comprised 59% of men and 7% of women. Among women, the multiple adjusted hazard ratio (HR) for CVD mortality compared with the reference group (GGT: 1-12 U/L) was 2.88 (95% confidence interval (CI), 1.14-7.28) for the elevated group (GGT ≥ 50 U/L). This positive relationship was unchanged in the never-drinkers subgroup (HR for log-transformed continuous GGT, 1.62 (95% CI, 1.11-2.37)). No significant relationships were observed in men. GGT displays a strong positive association with CVD mortality among Japanese women, for whom the prevalence of ever-drinkers is very low. Exploring the significance and biological mechanisms of GGT might provide useful insights into CVD prevention. © 2006 Elsevier Ireland Ltd. All rights reserved.

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Response to letter by Walsh et al [14]

Hozawa Atsushi, Okamura Tomonori, Ueshima Hirotsugu

Stroke 38 （ 9 ） 2007年09月

ISSN 0039-2499

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Normal fasting plasma glucose levels and type 2 diabetes

Hayashino Y., Fukuhara S., Suzukamo Y., Okamura T., Tanaka T., Ueshima H.

Acta Diabetologica 44 （ 3 ） 164 - 166 2007年09月

ISSN 0940-5429

The objective of this study is to ascertain if higher normal fasting glucose levels are also an independent risk of developing diabetes in an Asian population, and we thus analysed data from a cohort of healthy Japanese workers. We used data from the non-randomised trial on health promotion intervention, High-risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) Study. Diabetes cases and those who had fasting blood glucose levels equal to or greater than 100 mg/dl at baseline were excluded, and the Cox proportional-hazards model was used for the analysis. During the four-year follow-up of 2212 participants, we found 37 diabetes cases. In the multivariable model, people with blood glucose levels in the 4th quartile had a higher risk of diabetes than those in the bottom quartile; the multivariable-adjusted odds ratio was 2.52. The risk of diabetes abruptly rose in persons with blood glucose levels higher than 94 mg/dl (fourth quartile). A significant linear trend was not observed in the 1st to 3rd quartiles (p=0.726). In conclusion, higher fasting glucose level was associated with the risk of diabetes, and we found a threshold in the association between fasting blood glucose levels and risk of diabetes in an Asian population. © 2007 Springer-Verlag.

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Fish consumption and early atherosclerosis in middle-aged men

Nakamura Yasuyuki, Ueno Yoshiki, Tamaki Shinji, Kadowaki Takashi, Okamura Tomonori, Kita Yoshikuni, Miyamatsu Naomi, Sekikawa Akira, Takamiya Tomoko, El-Saed Aiman, Sutton-Tyrrell Kim, Ueshima Hirotsugu

Metabolism: Clinical and Experimental 56 （ 8 ） 1060 - 1064 2007年08月

ISSN 0026-0495

To investigate the association between fish consumption and early atherosclerosis, we analyzed the relationship between fish consumption and average intima-media thickness (AveIMT) by carotid ultrasound in middle-aged Japanese men. Participants were 250 randomly selected, community-based Japanese men aged 40 to 49 years without a prior history of cardiovascular disease. AveIMT was calculated from the mean of 1-cm lengths of both the right and the left carotid arteries at 8 locations. A lifestyle survey was carried out using a self-administered questionnaire including the frequency of fish intake. There were 147 men in the fewer than 4 times per week fish consumption group and 103men in the 4 or more times per week group. The mean AveIMT was significantly higher in the low fish consumption group than in the high fish consumption group (0.623 ± 0.068 vs 0.605 ± 0.065 mm, P = .03). After adjustment for age, waist circumference, pack-years of smoking, alcohol consumption, diabetes, and lipid-lowering medications, the significant difference in the AveIMT between the 2 groups remained. However, after further adjustment for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and C-reactive protein in the model, the significant difference disappeared. Fish consumption may be protective against early atherosclerosis in middle-aged men, probably through its beneficial effects on inflammation. © 2007 Elsevier Inc. All rights reserved.

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The proportion of individuals with alcohol-induced hypertension among total hypertensives in a general japanese population

Nakamura Koshi, Okamura Tomonori, Hayakawa Takehito, Hozawa Atsushi, Kadowaki Takashi, Murakami Yoshitaka, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu, Iimura Osamu, Omae Teruo, Ueda Kazuo, Yanagawa Hiroshi, Horibe Hiroshi, Kodama Kazunori, Kasagi Fumiyoshi, Tanihara Shinichi, Saito Shigeyuki, Sakata Kiyomi, Nakamura Yosikazu, Kakuno Fumihiko, Takeuchi Toshihiro, Hasebe Mitsuru, Kusano Fumitsugu, Kawamoto Takahisa, Minowa Masumi, Iida Minoru, Hashimoto Tsutomu, Tanaka Shigemichi, Terao Atsushi, Kawaminami Katsuhiko, Sawai Koryo, Shibata Shigeo

Hypertension Research 30 （ 8 ） 663 - 668 2007年08月

ISSN 0916-9636

Japanese men consume more alcoholic beverages than men in many other developed countries. The high consumption rate of alcoholic beverages among Japanese men may contribute to the high prevalence of hypertension in Japan. In the present study, we calculated the odds ratio for hypertension in alcohol drinkers based on recent criteria using data from a nationwide survey conducted in Japan in 1990, and estimated, among total hypertensives in a general Japanese population, the percentage of hypertensives whose condition was due to alcohol consumption. Of 3,454 male participants, 64.8% were drinkers (1 gou/day, 28.9%; 2 gou/day, 20.1%; 3 gou/day or more, 8.7%; ex-drinkers, 7.0%) and 49.8% were hypertensive, whereas 7.6% of 4,808 female participants were drinkers (1 gou/day, 5.2%; 2 gou/day or more, 1.3%; ex-drinkers, 1.1%) and 43.1% were hypertensive (1 gou=23.0 g of alcohol). In both sexes, drinkers had a higher odds ratio for hypertension than never drinkers, and there was a significant dose-response relationship between the amount of alcohol consumed and the odds ratio for hypertension. Among all hypertensives, the percentage whose hypertension was due to alcohol consumption was 34.5% (95% confidence interval, 10.9%,51.9%) for men and 2.6% (0.8%,5.8%) for women. The corresponding proportion based on daily alcohol intake was 12.7% for 1 gou/day, 11.1 % for 2 gou/day, 5.8% for 3 gou/day or more, and 4.8% for ex-drinkers in men, and 1.8% for 1 gou/ day, 0.7% for 2 gou/day or more, and -0.1% for ex-drinkers in women. In conclusion, we found that a large percentage of the hypertensives in a general Japanese male population had alcohol-induced hypertension.

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Reduced HDL-cholesterol levels associated with smoking

Okamura Tomonori, Higashiyama Aya, Miyamatsu Naomi

Nippon rinsho. Japanese journal of clinical medicine 65 Suppl 7 663 - 666 2007年07月

ISSN 0047-1852

Serum ghrelin levels are higher in Caucasian men than Japanese men aged 40-49 years

Matsunaga-Irie S., Ueshima H., Zaky W. R., Kadowaki T., Evans R. W., Okamura T., Takamiya T., Kita Y., Kuller L. H., Sekikawa Akira

Diabetes, Obesity and Metabolism 9 （ 4 ） 591 - 593 2007年07月

ISSN 1462-8902

Background: Ghrelin, a 28-amino-acid gastric peptide hormone, has an appetite-stimulating effect and controls the energy balance. Serum ghrelin levels inversely correlate with body mass index. Recently, several papers reported the ethnic difference in the ghrelin levels. To our knowledge, however, no studies have compared the serum ghrelin levels between Caucasians in the USA and the Japanese in Japan. Methods: We conducted a cross-sectional study of 189 men 40-49 years of age (91 US Caucasians in the U.S. and 98 Japanese in Japan) to examine serum ghrelin levels and metabolic and other factors. Results: Serum ghrelin levels correlated with waist circumferences and lipid profiles among Caucasian Americans and the Japanese. Serum ghrelin levels were significantly higher among Caucasian Americans than among the Japanese (904.5 (632.0, 1132.0) pg/mL, 508.0 (399.0, 1378.3) pg/mL (median and 95% confidence interval), respectively, P < 0.01), although Caucasian Americans were much more obese (BMI: 26.9 ± 3.3 kg/m² versus 23.3 ± 3.1 kg/m² respectively, P < 0.01). The ethnic difference remained after adjusting for metabolic factors, smoking status, and other factors (P < 0.01). Conclusions: We have shown in our population-based study that serum ghrelin levels among men aged 40-49 are significantly higher in Caucasian Americans than in the Japanese in Japan. Reasons for the ethnic difference in the ghrelin levels are largely unknown and warrant further investigation. © 2006 Blackwell Publishing Ltd.

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Lifestyle and work predictors of fatigue in Japanese manufacturing workers

Yamazaki Shin, Fukuhara Shunichi, Suzukamo Yoshimi, Morita Satoshi, Okamura Tomonori, Tanaka Taichiro, Ueshima Hirotsugu

Occupational Medicine 57 （ 4 ） 262 - 269 2007年06月

ISSN 0962-7480

Background: Fatigue is one of the most common symptoms encountered in medical practice. However, little is known about the causal relationship between change in lifestyle and fatigue. Aim: To help prevent fatigue-related disorders, we investigated the association between changes in lifestyle and fatigue among employees. Methods: We studied data sets from the High-risk and Population Strategy for Occupational Health Promotion study for employees at 10 workplaces in Japan. The baseline survey was done in 1999 and the follow-up survey in 2003 via a questionnaire which examined lifestyle and fatigue variables using the vitality domain scale of the SF-36 Health Survey. The lifestyle factors focused on were diet, smoking and alcohol habits and working conditions. Four-year changes in lifestyle that predicted the vitality domain score in the follow-up survey were examined by analysis of covariance. Results: Of the 6284 participants in the baseline survey, 4507 replied to the follow-up survey, of whom 3498, with a mean age of 37 (SD 18) years, returned valid responses. A low vitality score at follow-up was predicted by a change in lifestyle factors such as an increase in overtime work, change to non-sedentary work and increased frequency of eating between meals (P < 0.01, P < 0.01 and P = 0.02, respectively). Conclusion: Fatigue in salaried workers as measured by the vitality domain of the SF-36 is predicted by an increase in overtime work, change to non-sedentary work and an increase in the frequency of eating between meals. © The Author 2007. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved.

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Does self-reported history of hypertension predict cardiovascular death? Comparison with blood pressure measurement in a 19-year prospective study

Higashiyama Aya, Murakami Yoshitaka, Hozawa Atsushi, Okamura Tomonori, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu

Journal of Hypertension 25 （ 5 ） 959 - 964 2007年05月

ISSN 0263-6352

OBJECTIVES: Hypertension as assessed by blood pressure (BP) measurement is one of the most important risk factors for cardiovascular diseases (CVD). Self-reported history of hypertension (self-reported HT) is an easy way to obtain information on BP and is known to have a certain sensitivity and high specificity for hypertension confirmed by BP measurement (confirmative HT). Thus, it might predict CVD mortality, but few studies have reported on this relationship. METHODS: We followed 6427 participants aged 30-59 years without a history of CVD for 19 years. The multivariate-adjusted hazard ratio (HR) of CVD mortality was estimated by the Cox proportional hazard model. RESULTS: The sensitivity and specificity of self-reported HT for confirmative HT were 52-65% and 95%, respectively. The multivariate-adjusted HR of self-reported HT for CVD death was 2.49 [95% confidence interval (CI) = 1.72-3.61]. Compared to participants with neither self-reported HT nor confirmative HT, those with confirmative HT showed a consistently higher HR for CVD mortality. Self-reported HT without confirmative HT was also significantly related to CVD mortality (HR = 2.10, 95% CI = 1.04-4.26). These tendencies were unchanged when we further adjusted for systolic BP (SBP) level. The age-adjusted mortality rate of individuals with self-reported HT corresponded to the age-adjusted mortality rate of individuals whose SBP was 160-179 mmHg. CONCLUSION: Self-reported HT could screen one-half of the participants for confirmative HT and was significantly associated with CVD mortality. These results indicate that self-reported HT can be a useful tool to screen for individuals with high BP if it is difficult to perform BP measurements continuously among all members of a community. © 2007 Lippincott Williams & Wilkins, Inc.

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Relationship between metabolic risk factor clustering and cardiovascular mortality stratified by high blood glucose and obesity

Kadota Aya, Hozawa Atsushi, Okamura Tomonori, Kadowak Takashi, Nakmaura Koshi, Murakami Yoshitaka, Hayakawa Takehito, Kita Yoshikuni, Okayama Akira, Nakamura Yasuyuki, Kashiwagi Atsunori, Ueshima Hirotsugu

Diabetes Care 30 （ 6 ） 1533 - 1538 2007年05月

ISSN 0149-5992

OBJECTIVE - Metabolic syndrome is diagnosed according to several criteria. Of these, some require glucose intolerance and others require obesity for the diagnosis. We investigated the relationship between metabolic risk factor clustering and cardiovascular disease (CVD) mortality stratified by high blood glucose or obesity. RESEARCH DESIGN AND METHODS - We followed 7,219 Japanese men and women without a history of CVD for 9.6 years. We defined high blood pressure, high blood glucose, high triglycerides, low HDL cholesterol, and obesity as metabolic factors. The multivariate adjusted hazard ratio (HR) for CVD mortality according to the number of clustering metabolic factors was calculated using the Cox proportional hazards model. RESULTS - During follow-up, 173 participants died of CVD. The numbers of metabolic risk factors and CVD mortality were positively correlated (P_trend = 0.07). The HR was obviously higher among participants with than among those without high blood glucose and clustering of ≥2 other metabolic risk factors (HR 3.67 [95% CI 1.49-9.03]). However, the risk increase was only modest in participants without high blood glucose even if they had ≥2 other metabolic risk factors (1.99 [0.93-4.28]). Conversely, metabolic risk factor clustering was related to CVD mortality irrespective of obesity. CONCLUSIONS - Our findings suggest that glucose tolerance plays an important role in CVD mortality. Because the prevalence of nonobese participants with several metabolic risk factors was quite high and their CVD risk was high, excluding them from the diagnosis of metabolic syndrome because of the absence of obesity might overlook their risk. © 2007 by the American Diabetes Association.

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Life expectancy among Japanese of different smoking status in Japan

Murakami Yoshitaka, Ueshima Hirotsugu, Okamura Tomonori, Kadowaki Takashi, Hozawa Atsushi, Kita Yoshikuni, Hayakawa Takehito, Okayama Akira

Journal of Epidemiology 17 （ 2 ） 31 - 37 2007年04月

ISSN 0917-5040

Background: The life expectancy is an important measure for describing health status among population. Several studies from the United States and Europe showed the harm of smoking by describing the life expectancies with different smoking status. No such study is examined in Japan, the country with the world's highest life expectancy irrespective of high smoking rate among men. Methods: The abridged life table method was applied to calculate the life expectancies of men and women among different smoking status from age 40 until age 85. Age-specific mortality rates stratified by different smoking status were obtained from follow-up data from random sample in Japanese population (NIPPON DATA80). Results: Proportion of current smokers was 62.9% in men and 8.8% in women at the baseline survey in 1980. The life expectancies of 40-year-old never smokers, ex-smokers and current smokers were 42.1, 40.4, and 38.6 years in men and 45.6, 45.9, and 43.4 years in women. The life expectancy of 40-year-old men who smoked less than one pack per day was 39.0 and was longer than that of those who smoked one or two packs (38.8) and more than two packs (38.1). Conclusion: Life expectancy decreased gradually as the grade of smoking increased in the Japanese population. Copyright © 2007 by Japan Epidemiological Association.

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Both angiotensinogen M235T and α-adducin G460W polymorphisms are associated with hypertension in the Japanese population

Nakamura Y., Tabara Y., Miki T., Tamaki S., Kita Y., Okamura T., Ueshima H.

Journal of Human Hypertension 21 （ 3 ） 253 - 255 2007年03月

ISSN 0950-9240

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Medical costs of individuals with proteinuria

Nakamura Koshi, Okamura Tomonori, Kanda Hideyuki, Hayakawa Takehito, Okayama Akira, Ueshima Hirotsugu

Public Health 121 （ 3 ） 174 - 176 2007年03月

ISSN 0033-3506

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The association between high-density lipoprotein cholesterol level and cholesteryl ester transfer protein TaqIB gene polymorphism is influenced by alcohol drinking in a population-based sample

Tsujita Yasuyuki, Nakamura Yasuyuki, Zhang Qishan, Tamaki Shinji, Nozaki Akihiko, Amamoto Kenji, Kadowaki Takashi, Kita Yoshikuni, Okamura Tomonori, Horie Minoru, Ueshima Hirotsugu

Atherosclerosis 191 （ 1 ） 199 - 205 2007年03月

ISSN 0021-9150

Cholesteryl ester transfer protein (CETP) is a key enzyme in high-density lipoprotein (HDL) cholesterol metabolism. We studied the association between CETP TaqIB polymorphism and the HDL cholesterol levels considering environmental factors in a population-based sample consisting of 1729 participants who did not use lipid-lowering agents (659 men and 1070 women). The CETP TaqIB genotypes were determined by PCR-RFLP analysis. The serum HDL cholesterol levels of female participants with the B2B2 genotype were significantly higher than those with other genotypes (p < 0.001). Multiple regression analysis with covariates such as age, waist to hip (W/H) ratio, alcohol drinking, current smoking, non-HDL cholesterol, and logarithm of triglyceride revealed that the CETP TaqIB genotype was an independent determinant of HDL cholesterol levels in men (p = 0.049) and women (p < 0.001). Subgroup analysis revealed that an interaction was observed between the CETP TaqIB polymorphism and alcohol consumption in the regulation of HDL cholesterol levels in men (p = 0.049) and women (p = 0.022). No interactions were observed between the CETP TaqIB polymorphism and current smoking status, body mass index, or W/H ratio in the regulation of HDL cholesterol levels. The association between the CETP TaqIB polymorphism and HDL cholesterol levels was more evident in alcohol consumers than in non-drinkers. © 2006 Elsevier Ireland Ltd. All rights reserved.

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Less subclinical atherosclerosis in Japanese men in Japan than in white men in the United States in the post-world war II birth cohort

Sekikawa Akira, Ueshima Hirotsugu, Kadowaki Takashi, El-Saed Aiman, Okamura Tomonori, Takamiya Tomoko, Kashiwagi Atsunori, Edmundowicz Daniel, Murata Kiyoshi, Sutton-Tyrrell Kim, Maegawa Hiroshi, Evans Rhobert W., Kita Yoshikuni, Kuller Lewis H.

American Journal of Epidemiology 165 （ 6 ） 617 - 624 2007年03月

ISSN 0002-9262

Coronary heart disease incidence and mortality remain very low in Japan despite major dietary changes and increases in risk factors that should have resulted in a substantial increase in coronary heart disease rates (Japanese paradox). Primary genetic effects are unlikely, given the substantial increase in coronary heart disease in Japanese migrating to the United States. For men aged 40-49 years, levels of total cholesterol and blood pressure have been similar in Japan and the United States throughout their lifetimes. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery calcification, and intima-media thickness of the carotid artery in men aged 40-49 years are similar in Japan and the United States. They conducted a population-based study of 493 randomly selected men: 250 in Kusatsu City, Shiga, Japan, and 243 White men in Allegheny County, Pennsylvania, in 2002-2005. Compared with the Whites, the Japanese had a less favorable profile regarding many risk factors. The prevalence ratio for the presence of a coronary calcium score of ≥10 for the Japanese compared with the Whites was 0.52 (95% confidence interval: 0.35, 0.76). Mean intima-media thickness was significantly lower in the Japanese (0.616 mm (standard error, 0.005) vs. 0.672 (standard error, 0.005) mm, p < 0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations. Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved.

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Hypertension and medical expenses

Nakamura Koshi, Okamura Tomonori, Ueshima Hirotsugu

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 96 （ 1 ） 101 - 105 2007年01月

ISSN 0021-5384

Relation of adult height with stroke mortality in Japan NIPPON DATA80

Hozawa Atsushi, Murakami Yoshitaka, Okamura Tomonori, Kadowaki Takashi, Nakamura Koshi, Hayakawa Takehito, Kita Yoshikuni, Nakamura Yasuyuki, Okayama Akira, Ueshima Hirotsugu, Okamura T., Kadowaki T., Hayakawa T., Kita Y., Okayama A., Ueshima H.

Stroke 38 （ 1 ） 22 - 26 2007年01月

ISSN 0039-2499

BACKGROUND AND PURPOSE - The age-adjusted stroke mortality rate in Japan was the highest in the world from 1950 to the 1970s, but it started to dramatically decrease after 1965. In addition to improved management of high blood pressure, the increase in average height might also contribute to this reduction. The present study investigates whether height is an independent risk for stroke mortality in Japan. METHODS - Among participants of the National Survey on Cardiovascular Diseases in 1980 who were randomly selected from the Japanese population, we followed up 3969 and 4955 Japanese men and women without prior cardiovascular disease for a maximum of 19 years and observed 158 and 132 stroke deaths. RESULTS - Height was inversely correlated with age and with crude stroke mortality. The relationship was attenuated in men when we adjusted for age or other possible confounders (multivariate adjusted relative hazards of a 5-cm increase of height for stroke mortality: 0.92, 95% CI: 0.79 to 1.08). For women, the inverse relationship (relative hazard: 0.77: 95% CI: 0.64 to 0.91) remained after multivariate adjustment. These relationships persisted when we stratified participants by age. CONCLUSIONS - Height is inversely related to stroke mortality and the relationship is statistically significant among Japanese women. © 2007 American Heart Association, Inc.

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The relationship between serum total cholesterol and all-cause or cause-specific mortality in a 17.3-year study of a Japanese cohort

Okamura Tomonori, Tanaka Hideo, Miyamatsu Naomi, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Nakamura Yasuyuki, Okayama Akira, Ueshima Hirotsugu

Atherosclerosis 190 （ 1 ） 216 - 223 2007年01月

ISSN 0021-9150

No study has shown a positive relationship between hypercholesterolemia and all-cause mortality in the Japanese population. Therefore, a cohort study of 17.3 years' duration was conducted on 9216 participants aged 30 years or older, selected randomly from throughout Japan. In both the lowest (<4.14 mmol/L, 160 mg/dl) and highest (≥6.71 mmol/L, 260 mg/dl) total cholesterol (TC) groups, there was a positive association between TC and risk of all-cause mortality (hazard ratio (HR) 1.19; 95% confidence interval (CI), 1.03-1.37 and 1.36 (95% CI, 1.05-1.77), respectively). The lowest TC group had an increased risk of liver disease (HR 3.03; 95% CI, 1.70-5.43), whereas the highest TC group had an increased risk of coronary heart disease (HR 3.81; 95% CI, 1.70-5.43). After exclusion of deaths due to liver disease during the entire follow-up period and all-cause deaths within the first 5 years of follow-up, the increased HR in the lowest TC group disappeared (HR 1.05; 95% CI, 0.89-1.24). Although the cut-off point seemed to be higher than that for Western populations, hypercholesterolemia was shown to be positively associated with all-cause mortality in Japan. © 2006 Elsevier Ireland Ltd. All rights reserved.

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Associations of obesity measures with metabolic risk factors in a community-based population in Japan

Nakamura Yasuyuki, Turin Tanvir C., Kita Yoshikuni, Tamaki Shinji, Tsujita Yasuyuki, Kadowaki Takashi, Murakami Yoshitaka, Okamura Tomonori, Ueshima Hirotsugu

Circulation Journal 71 （ 5 ） 776 - 781 2007年

ISSN 1346-9843

Background: The association of obesity measures (ie, body mass index (BMI), waist circumference (WC) and waist-to hip ratio (WHR)) with metabolic risk factors in community-based populations has not been well studied. Methods and Results: In the present study 759 men and 1,255 women aged between 30 and 79 years, without histories of stroke or coronary heart diseases, were dichotomized at the medians of BMI-WHR, WC-WHR and BMI-WC. The accumulation of 4 metabolic risk factors (risk _ sum) were examined: high blood pressure (≥130/85 mmHg or on antihypertensive therapy); high triglycerides (≥170 mg/dl); low high-density lipoprotein-cholesterol (<40 mg/dl); and impaired glucose tolerance (hemoglobin A1c ≥5.6% or on antidiabetic therapy). BMI and WC correlated well in both men (r=0.871) and women (r=0.874). All 3 obesity measures related with the metabolic risk factors. The area under the receiver-operating characteristic curve for BMI, WC and WHR to predict the risk sum ≥2 for men was 0.683, 0.709, and 0.700, respectively, and 0.715, 0.739, and 0.746, respectively, for women. Conclusions: BMI may be used instead of WC if the latter is not available. When WC is measured, hip circumference also should be measured because the WHR may be the most valuable measure of obesity.

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Mortality risk attributable to atrial fibrillation in middle-aged and elderly people in the Japanese general population - Nineteen-year follow-up in NIPPON DATA80

Ohsawa Masaki, Okayama Akira, Okamura Tomonori, Itai Kazuyoshi, Nakamura Motoyuki, Tanno Kozo, Kato Karen, Yaegashi Yumi, Onoda Toshiyuki, Sakata Kiyomi, Ueshima Hirotsugu

Circulation Journal 71 （ 6 ） 814 - 819 2007年

ISSN 1346-9843

Background: The extent to which atrial fibrillation (AF) contributes to mortality in the Japanese general population has not been clarified. Methods and Results: A randomly sampled general population from all over Japan (4,154 men, 5,329 women; age ≥30 years) was enrolled. Single electrocardiogram recordings were taken in the baseline survey. Stroke death, cardiovascular deaths and all-cause deaths during the subsequent 19 years were analyzed by the presence of AF at baseline. Cox's regression analysis was carried out to estimate the hazard ratios (HRs) of each cause of death attributable to AF after adjusting for other risk factors. Prevalence of AF was 0.64% in the study. The observed person-years were 162,980 among persons without AF and 699 among persons with AF. There were 1,919 deaths. Multivariate adjusted HRs for stroke death, cardiovascular death and all-cause death were 2.69, 2.76 and 1.88, respectively (p<0.05). These HRs were 14.7, 9.63 and 4.00 among persons aged 64 years or younger (p<0.05). Conclusion: AF affects stroke mortality, cardiovascular mortality and all-cause mortality in the Japanese general population. Careful attention should be paid to persons with AF in order to prevent future cardiovascular events.

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Discussion

Crabb David W., Yin Shih Jiun, Apte Minoti V., Emery Peter, Preedy Victor R., Peter Eriksson C. J., Salaspuro Mikko, Quertemont Etienne, Deitrich Richard A., Okamura Tomonori

63 - 68 2007年

Effect of combined cardiovascular risk factors on individual and population medical expenditures - A 10-year cohort study of National Health Insurance in a Japanese population

Okamura Tomonori, Nakamura Koshi, Kanda Hideyuki, Hayakawa Takehito, Hozawa Atsushi, Murakami Yoshitaka, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu

Circulation Journal 71 （ 6 ） 807 - 813 2007年

ISSN 1346-9843

Background: Although obesity is required for some criteria defining metabolic syndrome, clustering of other risk factors also indicates an increased risk of cardiovascular disease. Whether the relationship between cardiovascular risk factor clustering and medical expenditures differs with body mass index (BMI) requires investigation, especially in a population with a low prevalence of obesity such as that in Japan. Methods and Results: A 10-year cohort study of 4,478 Japanese National Health Insurance beneficiaries aged 40-69 years in a community between 1990 and 2001 was carried out in the present study. The clustering of cardiovascular risk factors showed a positive and graded relationship to personal medical expenditures in participants who are overweight (BMI ≥25.0) and normal weight (BMI <25.0). The individual medical expenditures per month were 1.7-fold higher for participants with 2 or 3 risk factors and overweight than for those without these factors (26,782 vs 15,377 Japanese yen). Differences in the geometric means were similarly significant after adjustment for other confounding factors. However, the excess medical expenditures by risk clustering of normal weight categories within the total medical expenditures were higher than those of overweight categories because more participants were of normal weight. Conclusions: Cardiovascular risk factor clustering and being overweight can be a useful predictor of medical expenditures in a Japanese population.

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Cardiovascular risk clustering with obesity

Okamura Tomonori

Circulation Journal 71 （ 10 ） 1667 2007年

ISSN 1346-9843

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Discussion

Seitz Helmut K., Deitrich Richard A., Peter Eriksson C. J., Apte Minoti V., Preedy Victor R., Morris John B., Albano Emanuele, Worrall Simon, Emery Peter, Ren Jun, Crabb David W., Salaspuro Mikko, Quertemont Etienne, Thornalley Paul J., Rao Radhakrishna K., Aranda Agustin, Okamura Tomonori, Shukla Shivendra D., Niemelä Onni, Jamal Mostofa

40 - 51 2007年

Discussion

Preedy Victor R., Peter Eriksson C. J., Morris John B., Salaspuro Mikko, Emery Peter, Thornalley Paul J., Seitz Helmut K., Rao Radhakrishna K., Worrall Simon, Apte Minoti V., Okamura Tomonori, Yin Shih Jiun

256 - 260 2007年

White blood cell count and risk of all-cause and cardiovascular mortality in nationwide sample of Japanese - Results from the NIPPON DATA90

Tamakoshi Koji, Toyoshima Hideaki, Yatsuya Hiroshi, Matsushita Kunihiro, Okamura Tomonori, Hayakawa Takehito, Okayama Akira, Ueshima Hirotsugu

Circulation Journal 71 （ 4 ） 479 - 485 2007年

ISSN 1346-9843

Background: The association of white blood cell (WBC) count with all-cause and cardiovascular disease (CVD) mortality were examined in the National Integrated Project for Prospective Observation of Non-communicable Disease and Its Trends in the Aged (NIPPON DATA) 90. Methods and Results: A total of 6,756 Japanese residents (2,773 men and 3,983 women) throughout Japan without a history of CVD were followed for 9.6 years. A Cox proportional hazards regression model was used to estimate the relative risk (RR) and 95% confidence interval (CI). We documented 576 deaths with 161 deaths from CVD. Overall, after adjusting for several confounders including age, sex, body mass index at baseline, smoking status, alcohol consumption, regular exercise, diastlic blood pressure, total cholesterol, high-density lipoprotein-cholesterol and hemoglobin A1c, a graded association between WBC count and higher risk of allcause mortality was observed (WBC of 9,000-10,000 cells/mm³ vs WBC of 4,000-4,900: RR =1.61, 95% CI: 1.07-2.40, p for trend=0.02). Elevated WBC count was almost significantly associated with high risk of CVD mortality (WBC of 9,000-10,000 vs WBC of 4,000-4,900: RR=1.79, 95% CI: 0.97-3.71). These associations strengthened among women. Stratified by smoking status, never-smokers with WBC counts of 9,000-10,000 had a 3.2 fold elevated risk for CVD death compared with those with WBC counts of 4,000-4,900. Conclusions: The WBC count may have potential as a predictor for all-cause mortality, particularly CVD mortality.

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Relation between sleep quality and quantity, quality of life, and risk of developing diabetes in healthy workers in Japan

Hayashino Yasuaki, Fukuhara Shunichi, Suzukamo Yoshimi, Okamura Tomonori, Tanaka Taichiro, Ueshima Hirotsugu

BMC Public Health 7 2007年

Background. The effect of sleep on the risk of developing diabetes has not been explored in an Asian population. The objective of this study is to investigate the effect of self-reported sleep duration and sleep quality on the risk of developing diabetes in a prospective cohort in Japan. Methods. Data were analyzed from the cohort of participants in a High-risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP), conducted in Japan from the year 1999 until 2004. A Cox proportional hazard model was used to evaluate the association between sleep duration or sleep quality and the risk of diabetes. Results. Of 6509 participants (26.1% of women, 19-69 years of age), a total of 230 type 2 diabetes cases were reported over a median 4.2 years of follow-up. For participants who often experienced difficulty in initiating sleep, the multivariate-adjusted hazard ratios for diabetes were 1.42 (95%CI, 1.05-1.91) in participants with a medium frequency of difficulty initiating sleep, and 1.61 (95%CI, 1.00-2.58) for those with a high frequency, with a statistically significant linear trend. Significant association was not observed in the association between difficulty of maintaining sleep or duration of sleep, and risk of diabetes. Conclusion. Medium and high frequencies of difficulty initiating sleep, but not difficulty in maintaining sleep or in sleep duration, are associated with higher risks of diabetes in relatively healthy Asian workers, even after adjusting for a large number of possible further factors. © 2007 Hayashino et al; licensee BioMed Central Ltd.

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Higher levels of adiponectin in American than in Japanese men despite obesity

Kadowaki Takashi, Sekikawa Akira, Okamura Tomonori, Takamiya Tomoko, Kashiwagi Atsunori, Zaky Wahid R., Maegawa Hiroshi, El-Saed Aiman, Nakamura Yasuyuki, Evans Rhobert W., Edmundowicz Daniel, Kita Yoshikuni, Kuller Lewis H., Ueshima Hirotsugu

Metabolism: Clinical and Experimental 55 （ 12 ） 1561 - 1563 2006年12月

ISSN 0026-0495

Levels of adiponectin are inversely associated with obesity levels. We examined the levels of adiponectin in American (n = 98) and Japanese (n = 92) men aged 40 to 49 years. Contrary to our expectations, the American men had higher levels of adiponectin than the Japanese men (13.3 ± 5.8 vs 7.3 ± 4.2 (μg/mL) despite higher levels of obesity. Smaller areas of visceral adipose tissue in American than in Japanese men may have resulted in the higher levels of adiponectin. © 2006 Elsevier Inc. All rights reserved.

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Relationship between metabolic syndrome and Trp64Arg polymorphism of the β3-adrenergic receptor gene in a general sample

Tamaki Shinji, Nakamura Yasuyuki, Tabara Yasuharu, Okamura Tomonori, Kita Yoshikuni, Kadowaki Takashi, Tsujita Yasuyuki, Horie Minoru, Miki Tetsuro, Ueshima Hirotsugu

Hypertension Research 29 （ 11 ） 891 - 896 2006年11月

ISSN 0916-9636

It has been reported that the β3-adrenergic receptor gene (ADRB3) is associated with abnormal metabolic risk factors. Therefore, we examined whether the Trp64Arg polymorphism of ADRB3 affects the occurrence of metabolic syndrome (MS). The participants were 2,395 subjects who underwent a medical examination in Shigaraki in Shiga, Japan. Among them, 1,416 subjects who gave informed consent for genetic analysis and were not receiving treatment for hypertension, diabetes, or hyperlipidemia were enrolled in this study. MS was diagnosed in 86 (16.0%) of 537 men, and 8 (0.9%) of 879 women. There was no significant relationship between ADRB3 polymorphism and the frequency of MS. Multiple logistic regression analysis including smoking, sex, and age as confounding factors showed no interaction between MS and ADRB3 polymorphism (odds ratio: 0.94; 95% confidence interval: 0.59-1.49; p=0.78). Subjects were also analyzed according to differences in the number of abnormal metabolic risk factors. However, there was no significant relationship between ADRB3 polymorphism and the number of such factors. In conclusion, in a general sample, the frequency of MS as 16.0% in men, and 0.9% in women. There was no relationship between ADRB3 polymorphism and MS.

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Medical costs of patients with hypertension and/or diabetes

Nakamura Koshi, Okamura Tomonori, Kanda Hideyuki, Hayakawa Takehito, Okayama Akira, Ueshima Hirotsugu

Journal of Hypertension 24 （ 11 ） 2305 - 2309 2006年11月

ISSN 0263-6352

BACKGROUND AND METHODS: A cohort study investigating medical costs associated with the combination of hypertension and diabetes was conducted. The participants included 4535 community-dwelling Japanese individuals, aged 40-69 years, who were classified into the following four categories: 'Neither hypertension nor diabetes', 'Hypertension alone', 'Diabetes alone' or 'Both hypertension and diabetes'. Medical costs per person per month were compared among the four categories. RESULTS AND CONCLUSION: Of the study population, 1.3% had both hypertension and diabetes. During the 10-year follow-up period, participants with both hypertension and diabetes incurred higher medical costs, as compared with those without hypertension, diabetes or their combination, even after adjustment for other confounding factors. © 2006 Lippincott Williams & Wilkins, Inc.

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Body mass index and risk of stroke mortality among a random sample of Japanese adults

Oki Izumi, Nakamura Yosikazu, Okamura Tomonori, Okayama Akira, Hayakawa Takehito, Kita Yoshikuni, Ueshima Hirotsugu, Iimura Osamu, Omae Teruo, Ueda Kazuo, Yanagawa Hiroshi, Horibe Hiroshi, Kodama Kazunori, Kasagi Fumlyoshi, Tanihara Shinichi, Saito Shigeyuki, Sakata Kiyomi, Kakuno Fumihiko, Takeuchi Toshihiro, Hasebe Mitsuru, Kusano Fumitsugu, Kawamoto Takahisa, Minowa Masumi, Kawaminami Katsuhiko, Choudhury Sohel R., Kiyohara Yutaka, Iida Minoru, Hashimoto Tsutomu, Terao Atsushi, Sawai Koryo, Shibata Shigeo

Cerebrovascular Diseases 22 （ 5-6 ） 409 - 415 2006年10月

ISSN 1015-9770

Background: The relationship between body mass index (BMI) and stroke mortality remains unclear. The aim of the present study was to elucidate the relationship between BMI and stroke death in a representative cohort of Japanese men and women. Methods: We analyzed a database of 9,526 men and women aged 30 years and older who were randomly selected throughout Japan in 1980. These individuals had no history of stroke and were followed for 19 years. Hazard ratios (HR) and their 95% confidence intervals (CI) of deaths due to total stroke, cerebral infarction, and intracerebral hemorrhage were examined using Cox's proportional hazards regression models of BMI levels. Results: A U-shaped association between BMI and cerebral infarction mortality was observed. Participants with the highest BMI category (BMI ≥ 30.0) showed a significantly highest HR for cerebral infarction (HR 2.46, 95% CI 1.01-5.99). The excess risk at the lower extreme of the BMI was confined to men. These associations did not change after excluding deaths occurring in the first 2 years of follow-up. Conclusions: In the Japanese general population, a U-shaped association between BMI and cerebral infarction mortality was found and the excess risk at the lower extreme of the BMI was confined to men. Copyright © 2006 S. Karger AG.

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Erratum

Nakamura Koshi, Okamura Tomonori, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu

Hypertension Research 29 （ 10 ） 833 2006年10月

ISSN 0916-9636

Continuation of smoking cessation and following weight change after intervention in a healthy population with high smoking prevalence

Kadowaki Takashi, Watanabe Makoto, Okayama Akira, Hishida Kayoko, Okamura Tomonori, Miyamatsu Naomi, Hayakawa Takehito, Kita Yoshikuni, Ueshima Hirotsugu

Journal of Occupational Health 48 （ 5 ） 402 - 406 2006年09月

ISSN 1341-9145

Smoking prevalence among males is conspicuously high in Asian countries including Japan. There are few prospective intervention studies on the duration of smoking cessation within regions with a high prevalence of smokers, such as Asia. We investigated the extent to which subjects continued abstaining from smoking after receiving smoking cessation support provided for all smokers in an occupational setting, regardless of their willingness to quit smoking. The subjects were 251 male workers who were smokers and had received a smoking cessation intervention in 1997 in an occupational setting. Smoking cessation rates and body mass index (BMI) at 10, 18, 30, 42, 54, and 66 months after the initial intervention were confirmed during annual health check-ups. Those who quit smoking following the intervention and continuously abstained from smoking throughout the study period were separately examined for BMI. After five years, 10.6% of the smokers continued smoking cessation. Of the abstainers who quit following the intervention, the abstinence rate decreased in the first and second year, but it stabilized at approximately 45% after the third year. High nicotine dependence and a selfreported lack of willingness to quit smoking did not lower long-term abstinence rates. Abstainers initially gained 1.55 BMI on average, but decreased the weight gain to 0.96 BMI over six years. Introducing smoking cessation support without nicotine replacement therapy is an effective long-term strategy in a healthy population with a high smoking prevalence. Abstainers maintain their smoking cessation if they refrain from smoking for three years.

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Alcohol Consumption and Coronary Artery Calcium in Middle-Aged Japanese Men

Okamura Tomonori, Kadowaki Takashi, Sekikawa Akira, Murata Kiyoshi, Miyamatsu Naomi, Nakamura Yasuyuki, El-Saed Aiman, Kashiwagi Atsunori, Maegawa Hiroshi, Nishio Yoshihiko, Takamiya Tomoko, Kanda Hideyuki, Mitsunami Kenichi, Kita Yoshikuni, Edmundowicz Daniel, Tamaki Shinji, Tsujita Yasuyuki, Kuller Lewis H., Ueshima Hirotsugu

American Journal of Cardiology 98 （ 2 ） 141 - 144 2006年07月

ISSN 0002-9149

Epidemiologic studies have investigated the relation between alcohol intake and coronary calcification, with controversial results. Furthermore, the influence of heavy drinking has not been well elucidated. In the present study, a random sample of community-based Japanese men aged 40 to 49 years without a history of cardiovascular disease (n = 245) were examined for coronary artery calcium (CAC) determined by electron-beam computed tomography and drinking status. There was a J-shaped association between alcohol intake and CAC. There was an increase of CAC in heavy drinkers (≥46 g/day), and participants who were drinking ≥69 g/day showed a significant increase in CAC compared with never drinkers after adjusting for other cardiovascular risk factors. © 2006 Elsevier Inc. All rights reserved.

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Japanese men have larger areas of visceral adipose tissue than Caucasian men in the same levels of waist circumference in a population-based study

Kadowaki T., Sekikawa A., Murata K., Maegawa H., Takamiya T., Okamura T., El-Saed A., Miyamatsu N., Edmundowicz D., Kita Y., Sutton-Tyrrell K., Kuller L. H., Ueshima H.

International Journal of Obesity 30 （ 7 ） 1163 - 1165 2006年07月

ISSN 0307-0565

Visceral adipose tissue (VAT) is an independent risk factor for metabolic and cardiovascular disorders. There has been no study that demonstrated different abdominal fat distribution between Asian and Caucasian men. As the Japanese are less obese but more susceptible to metabolic disorders than Caucasians, they may have larger VAT than Caucasians at similar levels of obesity. We compared the abdominal fat distribution of the Japanese (n=239) and Caucasian-American (n=177) men aged 40-49 years in groups stratified by waist circumference in a population-based sample. We obtained computed tomography images and determined areas of VAT and subcutaneous adipose tissue (SAT). We calculated VAT to SAT ratio (VSR). The Japanese men had a larger VAT and VSR in each stratum, despite substantially less obesity overall. In multiethnic studies, difference in abdominal fat distribution should be considered in exploring factors related to obesity. © 2006 Nature Publishing Group All rights reserved.

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Smoking scenes in popular Japanese serial television dramas

Kanda Hideyuki, Okamura Tomonori, Turin Tanvir Chowdhury, Hayakawa Takehito, Kadowaki Takashi, Ueshima Hirotsugu

Health Promotion International 21 （ 2 ） 98 - 103 2006年06月

ISSN 0957-4824

Japanese serial television dramas are becoming very popular overseas, particularly in other Asian countries. Exposure to smoking scenes in movies and television dramas has been known to trigger initiation of habitual smoking in young people. Smoking scenes in Japanese dramas may affect the smoking behavior of many young Asians. We examined smoking scenes and smoking-related items in serial television dramas targeting young audiences in Japan during the same season in two consecutive years. Fourteen television dramas targeting the young audience broadcast between July and September in 2001 and 2002 were analyzed. A total of 136 h 42 min of television programs were divided into unit scenes of 3 min (a total of 2734 unit scenes). All the unit scenes were reviewed for smoking scenes and smoking-related items. Of the 2734 3-min unit scenes, 205 (7.5%) were actual smoking scenes and 387 (14.2%) depicted smoking environments with the presence of smoking-related items, such as ashtrays. In 185 unit scenes (90.2% of total smoking scenes), actors were shown smoking. Actresses were less frequently shown smoking (9.8% of total smoking scenes). Smoking characters in dramas were in the 20-49 age group in 193 unit scenes (94.1% of total smoking scenes). In 96 unit scenes (46.8% of total smoking scenes), at least one non-smoker was present in the smoking scenes. The smoking locations were mainly indoors, including offices, restaurants and homes (122 unit scenes, 59.6%). The most common smoking-related items shown were ashtrays (in 45.5% of smoking-item-related scenes) and cigarettes (in 30.2% of smoking-item-related scenes). Only 3 unit scenes (0.1 % of all scenes) promoted smoking prohibition. This was a descriptive study to examine the nature of smoking scenes observed in Japanese television dramas from a public health perspective. © The Author (2006). Published by Oxford University Press. All rights reserved.

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Effectiveness of a low-intensity intra-worksite intervention on smoking cessation in Japanese employees

Tanaka Hideo, Yamato Hiroshi, Tanaka Taichiro, Kadowaki Takashi, Okamura Tomonori, Nakamura Masakazu, Okayama Akira, Ueshima Hirotsugu

Journal of Occupational Health 48 （ 3 ） 175 - 182 2006年05月

ISSN 1341-9145

To test the effectiveness of a low-intensity intervention program for smoking cessation targeting the worksite environment in employees who had a low readiness to quit, we conducted an intervention trial at six intervention and six control worksites in Japan. A total of 2,307 smokers at baseline who remained at their worksite throughout the three-year study period were analyzed (1,017 in intervention and 1,290 in control groups). The multi-component program at the worksites consisted of (1) presenting information on the harms of tobacco smoking and the benefits of cessation by posters, websites, and newsletters; (2) smoking cessation campaigns for smokers; (3) advice on designation of smoking areas; and (4) periodic site-visits of the designated smoking areas by an expert researcher. At baseline, the intervention and control groups each had high prevalence of immotive or precontemplation, that reflected low readiness to quit (71.5% and 73.2%, respectively). The smoking cessation rate, as not having smoked for the preceding six months or longer, assessed at 36 months after the baseline survey by a self-administered questionnaire was significantly higher in the intervention group than the control group (12.1%, vs. 9.4%, p=0.021). The intervention program still had a significant effect on the smoking cessation rate after multiple logistic regression analysis adjusted for sex, age, type of occupation, age of starting smoking, quit attempts in the past, number of cigarettes per day, and readiness to quit (odds ratio: 1.38, 95% confidence interval: 1.05-1.81, p=0.02). The cost per additional quitter due to the intervention was calculated to be ¥ 70,080. These findings indicate that this program is effective and can be implemented in similar workplaces where the prevalence of smoking is high and smokers' readiness to cease smoking is low.

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The determinants of plasma plasminogen activator inhibitor-1 levels differ for American and Japanese men aged 40-49

Takamiya Tomoko, Kadowaki Takashi, Zaky Wahid R., Ueshima Hirotsugu, Evans Rhobert W., Okamura Tomonori, Kashiwagi Atsunori, Nakamura Yasuyuki, Kita Yoshiyuki, Tracy Russell P., Kuller Lewis H., Sekikawa Akira

Diabetes Research and Clinical Practice 72 （ 2 ） 176 - 182 2006年05月

ISSN 0168-8227

Background: Elevated plasma plasminogen activator inhibitor-1 (PAI-1) levels were associated with higher incidence of type II diabetes. Elucidating the determinants of PAI-1 in various ethnicities may help to understand the susceptibility to developing diabetes. The aim of our study was to compare PAI-1 levels between Americans and the Japanese in the post-war generation and to elucidate the determinants of the PAI-1 levels. Methods: We conducted a cross-sectional study on a total of 198 men aged 40-49 in the US (Body mass index (BMI): 27.0 ± 3.3 kg/m²) and Japan (BMI: 23.3 ± 3.1 kg/m²). Examination included physique measurement (BMI and waist girth), blood analysis (lipid profiles, glucose, insulin, C-reactive protein, and PAI-1), and life-style assessment by self-administered questionnaires. Results: PAI-1 levels were significantly lower in American than in Japanese men, even after adjustment for age, waist girth, cigarette smoking, habitual alcohol drinking, and other factors. In the Americans, waist girth, insulin, and cigarette smoking were significantly associated with PAI-1 levels, while waist girth and triglycerides were significantly associated with PAI-1 levels in the Japanese. Conclusions: PAI-1 levels were significantly lower in American than in Japanese men and the determinants of PAI-1 levels differ for American and Japanese men aged 40-49. © 2005 Elsevier Ireland Ltd. All rights reserved.

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Electrocardiogram screening for left high R-wave predicts cardiovascular death in a Japanese community-based population

Nakamura Koshi, Okamura Tomonori, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu, Iimura Osamu, Omae Teruo, Ueda Kazuo, Yanagawa Hiroshi, Horibe Hiroshi, Kodama Kazunori, Kasagi Fumiyoshi, Tanihara Shinichi, Saito Shigeyuki, Sakata Kiyomi, Nakamura Yoshikazu, Kakuno Fumihiko, Takeuchi Toshihiro, Hasebe Mitsuru, Kusuno Fumitsugu, Kawamoto Takahisa, Minowa Masumi, Iida Minoru, Hashimoto Tsutomu, Tanaka Shigemichi, Terao Atsushi, Kawaminami Katsuhiko, Sawai Koryo, Shibata Shigeo

Hypertension Research 29 （ 5 ） 353 - 360 2006年05月

ISSN 0916-9636

Little is known about the efficacy of left ventricular hypertrophy diagnosed by electrocardiography for predicting cardiovascular disease in a general Japanese population. In a large cohort of participants selected randomly from the overall Japanese population, we attempted to evaluate the usefulness of a high amplitude R-wave (left high R-wave) on the electrocardiogram for predicting cardiovascular death. A total of 6,688 Japanese (mean age, 50.7 years old; 57% women) free of previous cardiovascular disease and use of antihypertensive agents at baseline were followed for 10 years, from 1990 to 2000. Left high R-wave on the electrocardiogram (the Minnesota Code, 3-1 or 3-3) was found in 9.4% of the 6,688 participants, in 14.6% of the 2,413 hypertensives and in 4.1% of the 4,275 normotensives. During the follow-up period, 128 participants died due to cardiovascular disease. After adjustment for systolic blood pressure and other risk factors, left high R-wave conferred an increased risk of cardiovascular death; the hazard ratio among all the participants was 1.88 (95% confidence interval, 1.22-2.89; p<0.01), that among hypertensives was 1.97 (1.20-3.24; p=0.01), and that among normotensives was 1.66 (0.69-3.98; p=0.26). The population attributable risk percent of left high R-wave for cardiovascular death was 7.6% among all participants, 12.4% among hypertensives and 4.1% among normotensives. Left high R-wave on electrocardiogram, irrespective of the level of systolic blood pressure, was a predictive marker for cardiovascular death among community-dwelling Japanese.

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Age-specific effects of systolic and diastolic blood pressures on mortality due to cardiovascular diseases among Japanese men (NIPPON DATA80*)

Okayama Akira, Kadowaki Takashi, Okamura Tomonori, Hayakawa Takehito, Ueshima Hirotsugu

Journal of Hypertension 24 （ 3 ） 459 - 462 2006年03月

ISSN 0263-6352

Objective: To clarify the relationship between mortality due to cardiovascular diseases (CVD) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in young and elderly Japanese men in the absence of antihypertensive treatments. Design: A 19-year cohort study using the 1980 National Survey of Cardiovascular Diseases and the identification of the underlying causes of death using national vital statistics data. Methods: In 1999, a 19-year follow-up study was conducted among participants randomly selected from the Japanese population for the 1980 National Survey of Cardiovascular Diseases. Among the male participants that were not receiving antihypertensive treatment, information was obtained for about 91.3% of the subjects (n = 3779). Age-adjusted mortality rates using the person-year method were calculated to compare the relationships of SBP and DBP levels with CVD mortality for different age groups (aged 30-64, 65-74, and 75 years or more). Results: The total number of observed person-years was 64 598 and the number of CVD-related deaths after 19 years was 253. Both SBP and DBP levels were significantly and linearly related to CVD mortality in the age groups 30-64 years (P < 0.001 and P = 0.01, respectively) and 65-74 years (P < 0.001 and P = 0.03, respectively). In the group of participants that were at least 75 years old, however, no significant increase in the relative risk of CVD was observed with increasing DBP levels (P = 0.156), whereas the relative risk of CVD increased significantly with increasing SBP levels (P = 0.038). Multivariate analysis adjusting for major risk factors confirmed these relationships. Standardized hazard ratios (95% confidence intervals) of SBP were 1.53 (1.19-1.96) for 30-64 year olds, 1.70 (1.31-2.20) for 64-74 year olds, and 1.23 (1.03-1.47) for participants 75 years old or more, whereas those of DBP were 1.52 (1.12-2.06), 1.60 (1.21-2.10), and 1.10 (0.94-1.28), respectively. Conclusions: These data show that elevated SBP is an independent risk factor for CVD mortality for Japanese men of all ages, whereas elevated DBP is not an independent risk factor for CVD mortality for elderly men. © 2006 Lippincott Williams & Wilkins.

Are comprehensive environmental changes as effective as health education for smoking cessation?

Kadowaki Takashi, Kanda H., Watanabe M., Okayama A., Miyamatsu N., Okamura T., Hayakawa T., Hishida K., Kita Y., Ueshima H.

Tobacco Control 15 （ 1 ） 26 - 29 2006年02月

ISSN 0964-4563

Objectives: To compare the effectiveness of health education on smoking cessation for all smokers regardless of their willingness to quit smoking and cumulative environmental changes including designation of smoking places, legislation, and price rise. Design: Comparison of smoking cessation rates over two time periods: the period of health education on smoking cessation (1997-1999), and the period of cumulative environmental changes (2002-2004). Setting: An occupational setting in a radiator manufacturing factory in Japan. Subjects: All habitual male smokers who remained in the worksite through the pertinent time period (n = 202 in the period of health education and n = 170 in the period of environmental changes). Main outcome measurements: Smoking cessation rates at the end of each time period. Results: The smoking cessation rates over the periods of health education and environmental changes were 8.9% and 7.1%, respectively. There was no difference between these two proportions in χ² test (p = 0.513). The age adjustment did not significantly alter the cessation rate. Conclusions: Cumulative environmental changes are fairly effective in promoting smoking cessation, and may yield similar smoking cessation rates as a health education intervention reaching all smokers regardless of their willingness to quit smoking.

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The inverse relationship between serum high-density lipoprotein cholesterol level and all-cause mortality in a 9.6-year follow-up study in the Japanese general population

Okamura Tomonori, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu

Atherosclerosis 184 （ 1 ） 143 - 150 2006年01月

ISSN 0021-9150

In populations with higher high-density lipoprotein cholesterol (HDL-C) levels and lower coronary mortality than Western populations, such as in Japan, the beneficial effect of HDL-C on all-cause mortality may be different. Furthermore, prior studies have not focused on very high level of HDL-C. A total of 7175 community Japanese residents without a past history of cardiovascular disease in 300 randomly selected districts were followed for 9.6 years. During follow-up, there were 636 deaths. The multivariate adjusted hazard ratio (HR) of HDL-C for all-cause or cause-specific mortality was calculated using a Cox proportional hazard model adjusted for other cardiovascular risk factors. The all-cause mortality suggested an inverse, graded relation with HDL-C categories; HR for the very high HDL-C category (≥1.82 mmol/L), compared with the reference group (1.04-1.55 mmol/L), was 0.73 (95% confidence interval, C.I., 0.50-1.06) for men, 0.63 (95% C.I., 0.41-0.94) for women and 0.70 (95% C.I., 0.53-0.93) when men and women were combined. Serum HDL-C as a continuous variable showed a significant inverse association with all-cause mortality. The cardiovascular mortality indicated a non-significant but inverse graded relation with HDL-C categories. As in the many Western populations, serum HDL-C levels were inversely associated with all-cause mortality in the Japanese general population. © 2005 Elsevier Ireland Ltd. All rights reserved.

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Chronic kidney disease is a risk factor for cardiovascular death in a community-based population in Japan - NIPPON DATA90

Nakamura Koshi, Okamura Tomonori, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Ohnishi Hirofumi, Saitoh Shigeyuki, Sakata Kiyomi, Okayama Akira, Ueshima Hirotsugu

Circulation Journal 70 （ 8 ） 954 - 959 2006年

ISSN 1346-9843

Background: Chronic kidney disease (CKD) has been identified as a risk factor for cardiovascular disease (CVD). Methods and Results: The risk of cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. Participants (mean age, 52.4 years) free of previous CVD were followed up for 10 years. Glomerular filtration rate (GFR) was estimated using the abbreviated equation developed at the Cleveland Clinic laboratory for the Modification of Diet in Renal Disease study. Of the 7,316 participants, 6.7% had CKD with a GFR <60 at baseline. Even after adjustment for other risk factors, the presence of CKD conferred an increased risk of cardiovascular death with a hazard ratio of 1.20 (95% confidence interval, 0.82-1.76). Furthermore, a negative, graded correlation between GFR and risk of cardiovascular death was observed: 1.09 (0.72-1.64) for a 60≤ GFR <90, 1.15 (0.67-1.99) for a 45≤ GFR <60, 1.23 (0.49-3.09) for a 30≤ GFR <45, 5.52 (1.62-18.75) for a 15≤ GFR <30, 9.12 (2.12-39.29) for a GFR <15, as compared with normal kidney function (GFR ≥90). The proportion of excess cardiovascular death due to CKD was 1.3%. Conclusion: CKD was an independent risk factor for cardiovascular death in a community-dwelling Japanese population.

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Gender and age effects on ventricular repolarization abnormality in Japanese general carriers of a G643S common single nucleotide polymorphism for the KCNQ1 gene

Ozawa Tomoya, Ito Makoto, Tamaki Shinji, Yao Takenori, Ashihara Takashi, Kita Yoshikuni, Okamura Tomonori, Ueshima Hirotsugu, Horie Minoru

Circulation Journal 70 （ 6 ） 645 - 650 2006年

ISSN 1346-9843

Background: The KCNQ1 single nucleotide polymorphism (SNP), G643S, is known to be associated with secondary long QT syndrome (LQTS) and to cause a mild reduction in KCNQ1 current. However, the precise incidence and its association with QT intervals remain unknown in the greater cohort of the population in Japan. Methods and Results: The genotype was screened at codon 643 of KCNQ1 in 992 residents of a farming community. Eighty-eight individuals (female/male=52/36, 8.9%) were found to have a heterozygous G643S SNP. Matching both gender and age, we randomly selected 243 control (G643G) cases and compared the electrocardiogram parameters in both groups; QT, QTf (QT corrected by Fridericia's formula) intervals, the peak and the end of the T wave (Tpe) interval, and the Tpe/QT ratio. The latter 2 reflect the transmural dispersion of ventricular repolarization (TDR). In G643S carriers, both Tpe and Tpe/QT were significantly longer than in noncarriers, without significant QT prolongation. Both genders showed a tendency for an increase in QTf with aging. In females, both Tpe and Tpe/QT showed a similar significant increase with age, which was not observed in males. Conclusions: In elderly females, G643S might be an independent risk factor for secondary LQTS by causing a greater TDR.

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Combined cardiovascular risk factors and outcome - NIPPON DATA80, 1980-1994

Nakamura Yasuyuki, Yamamoto Takako, Okamura Tomonori, Kadowaki Takashi, Hayakawa Takehito, Kita Yoshikuni, Saitoh Shigeyuki, Okayama Akira, Ueshima Hirotsugu

Circulation Journal 70 （ 8 ） 960 - 964 2006年

ISSN 1346-9843

Background: To examine the prognostic significance of the high-risk group with combined cardiovascular risk factors in the Japanese, we analyzed the relationship between the high-risk group with combined risks and coronary heart disease (CHD) and stroke mortality using the NIPPON DATA80 database. Methods and Results: At baseline in 1980, those of age ≥30 years were randomly selected and 4,144 men and 5,318 women without CHD and/or stroke at baseline were followed for 14 years. The cutoff values for risk components obtained heuristically by Cox analysis were hypertension (systolic ≥130, or diastolic ≥85 mmHg, or on antihypertensive drugs), hypercholesterolemia (total cholesterol ≥200 mg/dl), hyperglycemia (≥130 mg/dl, or self-reported diabetes) and obesity (body mass index ≥27 kg/m²). Subjects were divided into 3 groups (0, 1-2 and 3-4 risks). Compared with those men in the risk 0 group, the hazard ratios in men in the risk 3-4 for CHD mortality was 8.04 (95% confidence interval: 1.03-62.6), and the stroke mortality was 5.06 (1.53-16.7). In women, no statistically significant difference was found due to a lesser number of events. Conclusion: The high-risk group with combined risk factors is important risk for Japanese men.

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The value of combining serum alanine aminotransferase levels and body mass index to predict mortality and medical costs

Journal of Epidemiology 16 （ 1 ） 15 - 20 2005年12月

ISSN 0917-5040

Background: Evidence suggests that the predictive value of serum alanine aminotransferase (ALT) levels for prognosis, measured by indices such as all-cause mortality and medical costs, may be modified by body mass index (BMI). However, the relationship between serum ALT and BMI has not been satisfactorily elucidated. Methods: Four thousand, five hundred and twenty-four community dwelling Japanese National Health Insurance beneficiaries, 40-69 years old, were classified into five categories according to their serum ALT levels (IU/L) (ALT<20, 20≤ALT<30, 30≤ALT<40, 40≤ALT<50 and 50≤ALT) and followed for 10 years. Hazard ratios for all-cause mortality, with reference to the lowest serum ALT category, and medical costs per person were evaluated for each serum ALT category after analyzing interactions between serum ALT levels and BMI for all-cause mortality and for medical costs. Results: A significant interaction between serum ALT levels and BMI was observed. In participants below the median BMI, positive, graded relationships were identified between serum ALT levels and all-cause mortality as well as between serum ALT levels and personal medical costs. The multivariate-adjusted hazard ratio in the "50≤ALT" category showed an approximately 8-fold increase. However, in the participants at or above the median BMI, no significant relationships between serum ALT levels and all-cause mortality or personal medical costs were identified. Conclusions: In these Japanese participants, the predictive value of serum ALT levels for prognosis was more evident if BMI was taken into account. A combination of high serum ALT levels and below median BMI was associated with excess mortality and medical cost. Copyright © 2006 by the Japan Epidemiological Association.

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Impact of hypertension on medical economics

Nakamura Koshi, Okamura Tomonori, Kanda Hideyuki, Hayakawa Takehito, Kadowaki Takashi, Okayama Akira, Ueshima Hirotsugu, Yamashita Shigeo, Tominaga Yoshinori, Katsuyama Kazuaki, Kakuno Fumihiko, Kitanishi Machiko, Tobita Yukio, Okamura Kanehiro, Hatta Kiminobu, Okada Takao, Hatanaka Michiko

Hypertension Research 28 （ 11 ） 859 - 864 2005年11月

ISSN 0916-9636

Hypertension and related cardiovascular diseases may lead to an increase in medical costs for patients. We attempted to clarify the relationship between hypertension and long-term medical costs by a cohort study utilizing existing data as well as baseline blood pressures and medical costs over a 10-year period. The participants included 4,191 Japanese National Health Insurance beneficiaries aged 40-69 years, living in one area, who were not taking anti-hypertensive medication and did not have a history of major cardiovascular disease. They were classified into four categories according to their blood pressure. We evaluated the mean medical costs per month, cumulative hospitalization, and all-cause mortality for each blood pressure category. Hypertension-related medical costs attributable to hypertensive individuals, as compared to normotensive individuals, were estimated. There was a positively graded correlation between blood pressure and personal total medical costs, especially for men. The odds ratio for cumulative hospitalization and hazard ratio for all-cause mortality in severe hypertensive men were also higher than those in normotensive men. However, the hypertension-related medical costs for mild to moderate hypertensives were higher than those for severe hypertensives. The hypertension-related medical costs for all hypertensives accounted for 23.7% of the total, medical costs for the Japanese population. In conclusion, high blood pressure was a useful predictor for excess medical costs; moreover, concomitant hypertension, regardless of the grade, increased the medical costs of Japanese National Health Insurance beneficiaries.

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A cross-sectional study of alcohol drinking and health-related quality of life among male workers in Japan

Saito Isao, Okamura Tomonori, Fukuhara Shunichi, Tanaka Taichiro, Suzukamo Yoshimi, Okayama Akira, Ueshima Hirotsugu

Journal of Occupational Health 47 （ 6 ） 496 - 503 2005年11月

ISSN 1341-9145

Background: Although light and moderate alcohol drinkers are likely to have better subjective health, the sub-scales for subjective health have not been well documented. Methods: We studied 4,521 male workers aged 25 yr and older with no history of cancer or cardiovascular disease, in 12 occupational groups in Japan. Data were from the High-risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP). Drinking status was classified according to daily alcohol intake or frequency of drinking. We assessed the health-related quality of life (HRQOL) based on scores for five scales of the SF-36. Results: Decreased odds ratios of sub-optimal HRQOL conditions, defined as less than the median SF-36 scores, for Role-Physical and General Health were found among persons who consumed 1.0 to 22.9 g/d of alcohol. Odds ratios for sub-optimal Vitality conditions were lowered according to increased levels of alcohol intake. Role-Emotional scores were not associated with alcohol drinking. People who drank 5 to 6 d/wk had higher levels of Role-Physical and Vitality, and those who drank 1 to 2 d/wk had better Vitality and Mental Health scores than non-drinkers. When adjusted for age, marital status, working hours, physical activity at work, self-reported job stress, smoking, regular exercise, hypertension, hyperlipidemia, and diabetes, the associations were almost unchanged except for General Health. Conclusions: Associations of drinking patterns with subjective health varied in five sub-scales of the SF-36. Overall, alcohol drinkers rated their health as good in comparison with non-drinkers.

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Combined analysis of polymorphisms in angiotensinogen and adducin genes and their effects on hypertension in a Japanese sample

Tamaki Shinji, Nakamura Yasuyuki, Tabara Yasuharu, Okamura Tomonori, Kita Yoshikuni, Kodawaki Takashi, Tsujita Yasuyuki, Horie Minoru, Miki Tetsuro, Ueshima Hirotsugu

Hypertension Research 28 （ 8 ） 645 - 650 2005年08月

ISSN 0916-9636

We examined the interactions between lifestyle and polymorphisms of salt-sensitive genes and their effects on hypertension in a general Japanese sample (The Shigaraki Study). The study group consisted of 2,902 subjects who underwent a medical examination in 1999 in Shigaraki, a suburban area in Shiga. Among 1,647 subjects not receiving antihypertensive medication, in a combined analysis of angiotensinogen (AGT) and adducin (ADD1) polymorphisms, double homozygosity of 235Trp or 460Trp was not found to be associated with hypertension. A multiple logistic regression analysis showed that age (odds ratio [OR]: 1.07, 95% confidence interval [95% CI]: 1.06-1.08), body mass index (BMI) (OR: 1.18, 95% CI: 1.13-1.23), alcohol consumption (OR: 1.39, 95% CI: 1.16-1.66), family history of hypertension (OR: 1.57, 95% CI: 1.18-2.07), and combined AGT M235T Thr/Thr and ADD1 Trp/Trp polymorphisms (OR: 1.37, 95% CI: 1.03-1.82) were associated with hypertension. However, there was no interaction between eating salty food and combined AGT and ADD1 polymorphisms. Furthermore, eating salty food was not associated with hypertension in a multivariate analysis. Therefore, a combination of the AGT and ADD1 polymorphisms appears to be associated with hypertension. However, a simple questionnaire regarding salt intake was not sufficient to confirm the relationship between salt intake and hypertension and/or salt-sensitive genes.

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The influence of alcohol drinking on medical care expenditures among National Health Insurance beneficiaries

Kanda Hideyuki, Nakamura Koshi, Hayakawa Takehito, Okamura Tomonori, Ueshima Hirotsugu

Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 40 （ 3 ） 171 - 180 2005年06月

ISSN 1341-8963

Heavy alcohol drinking is an important risk factor for some lifestyle-related diseases. However, the relationship between drinking habits and medical care expenditures has not been elucidated in a Japanese general population. We examined this relationship in a 9-year cohort study. Study participants were 2039 National Health Insurance beneficiaries aged 40-69 years living in a rural Japanese community. The baseline survey, with medical check-up, was performed in 1989 or 1990 and the subjects' drinking habits were estimated by questionnaire. Medical care use and costs were monitored by linkage with the National Health Insurance claim history files at baseline survey through the end of March 2000. Men who were daily heavy drinkers (ethanol intake > or =69 g per day) had significantly higher medical costs compared to participants who drank less, within 5 years after baseline. This difference was 2000 yen per month after adjusting for age, body mass index, smoking, systolic blood pressure, glycosuria, serum total cholesterol and alanine aminotransferase. Daily heavy male drinkers also had a higher hazard ratio for total mortality compared to occasional drinkers, by the Cox proportional hazard model (hazard ratio: 1.81), although it did not reach statistical significance (P = 0.153). In women, medical costs were almost the same for occasional and daily drinkers. Total medical costs among Japanese men aged 20 years and over may be decreased by about 8400 billon yen per year if we assume a 20% decrease in daily heavy drinkers. To reduce national medical costs, it is important to promote a program for heavy drinkers, as described in the "Health Japan 21" initiative, the Japanese national health promotion guidelines for the first 10 years of the 21st century.

Different effects of blood pressure on mortality from stroke subtypes depending on BMI levels

Miyamatsu N., Kadowaki T., Okamura Tomonori, Hayakawa T., Kita Yoshikuni, Okayama Akira, Nakamura Yosikazu, Oki I., Ueshima Hirotsugu, Iimura Osamu, Omae Teruo, Ueda Kazuo, Yanagawa Hiroshi, Kodama Kazunori, Kasagi Fumiyoshi, Saito Shigeyuki, Sakata Kiyomi, Hayakawa Takehito, Tanihara Shinichi, Horibe Hiroshi, Minowa Masumi, Takeuchi Toshihiro, Hasebe Mitsuru, Kusano Fumitsugu

Journal of Human Hypertension 19 （ 4 ） 285 - 291 2005年04月

ISSN 0950-9240

To evaluate the relationship between blood pressure and cerebrovascular death depending on body mass index (BMI) levels, we analysed a database of 9338 subjects from the National Integrated Project for Prospective Observation of Non-communicable Disease and its Trends in the Aged, which was originally conducted a baseline survey in 1980 and followed up in 1999. Relative risk (RR) and a 95% confidence interval (CI) of death from total stroke, cerebral infarction, and intracerebral haemorrhage after adjusting for age, sex, serum cholesterol, albumin, glucose, the use of anti-hypertensive agents, a past history of diabetes, BMI, smoking, and drinking were estimated with the Cox-proportional hazard model in the BMI tertile groups of a representative Japanese population. Cutoff points of BMI tertiles are 21.2 and 23.8 kg/m². The results indicated that a 10 mmHg systolic blood pressure (SBP) increase was associated with mortality from intracerebral haemorrhage at low and middle BMI groups (RR= 1.38 and 1.23; 95% CI=1.17-1.62 and 1.03-1.47, respectively). SBP was positively associated with mortality from cerebral infarction in middle and high BMI groups (RR=1.19 and 1.21; 95% CI=1.06-1.33 and 1.06-1.38, respectively). The effects of diastolic blood pressure on intracerebral haemorrhage and infarction had the same tendency as those of SBP. These results suggested that the causal effect of blood pressure on stroke subtypes might be modified by BMI. © 2005 Nature Publishing Group All rights reserved.

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Association between fish consumption and all-cause and cause-specific mortality in Japan

Nakamura Yasuyuki, Ueshima Hirotsugu, Okamura Tomonori, Kadowaki Takashi, Hayakawa Takehito, Kita Yoshikuni, Tamaki Shinji, Okayama Akira

American Journal of Medicine 118 （ 3 ） 239 - 245 2005年03月

ISSN 0002-9343

PURPOSE: Although high consumption of fish may be one of the contributing factors for Japanese longevity, no epidemiological study using Japanese data has tested this hypothesis. SUBJECTS AND METHODS: The relationship between fish consumption and all-cause as well as cause-specific mortality was analyzed using the database of NIPPON DATA80. At baseline in 1980, history, physical, and blood biochemical measurement and a nutritional survey by the food-frequency method were performed in randomly selected community-based subjects aged 30 years and over in Japan. After exclusion of subjects with significant comorbidities at baseline, we followed 3 945 men and 4 934 women for 19 years. Men and women were analyzed comprehensively. Age- and sex-adjusted and multivariate adjusted relative risk for all-cause or cause-specific mortality was calculated using a Cox proportional hazards model with delayed entry. RESULTS: During 19 years of followup, there were 1 745 deaths. Subjects were divided into 5 groups according to fish consumption frequency. The multivariate Cox analyses showed that relative risks for subjects who ate fish more than twice daily compared with those of subjects who ate 1 to 2 times weekly were 0.99 (95% confidence intervals: 0.77-1.27) for all-cause, 1.26 (0.70-2.29) for stroke, 0.92 (0.20-4.23) for cerebral hemorrhage, 1.09 (0.48-2.43) for cerebral infarction, and 0.91 (0.35-2.35) for coronary heart disease mortality. CONCLUSION: Our results did not provide evidence in support of the fish hypothesis, perhaps because the majority of the Japanese subjects in the study ate fish more than the threshold level shown to be beneficial in the previous studies. © 2005 Elsevier Inc. All rights reserved.

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What factors are associated with high plasma B-type natriuretic peptide levels in a general Japanese population?

Kanda H., Kita Y., Okamura T., Kadowaki T., Yoshida Y., Nakamura Y., Ueshima H.

Journal of Human Hypertension 19 （ 2 ） 165 - 172 2005年02月

ISSN 0950-9240

There are few community-based epidemiologic studies that have dealt with risk factors for heart failure in non-Western populations. It has been reported that the measurement of plasma B-type natriuretic peptide (BNP) is useful for detecting patients with asymptomatic heart failure. To clarify the determinants of high plasma BNP level, the association of BNP with cardiovascular risk factors in community dwelling residents was examined. The plasma BNP levels were measured in 686 residents aged 35-69 years who received annual health check-up. The relationship of BNP to blood pressure, blood haemoglobin, serum cholesterol (total and high-density lipoprotein cholesterol), plasma glucose, electrocardiographic (ECG) findings, urinary salt excretion, and lifestyle factors (smoking and alcohol consumption) were cross-sectionally analysed. The plasma BNP geometric mean was 13.7 pg/ml. Both linear and logistic regression analyses indicated that the plasma BNP levels were positively associated with age, urinary salt excretion, higher blood pressure, high R-wave voltage in the 12-lead ECG (Minnesota Code 3-1 or 3-3), and female gender. Plasma BNP levels were inversely associated with blood haemoglobin levels. Gender-specific analysis showed similar results. However, plasma BNP did not correlate with other cardiovascular risk factors such as serum lipids. © 2005 Nature Publishing Group All rights reserved.

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Much lower prevalence of coronary calcium detected by electron-beam computed tomography among men aged 40-49 in Japan than in the US, despite a less favorable profile of major risk factors

Sekikawa Akira, Ueshima Hirotsugu, Zaky Wahid Riad, Kadowaki Takashi, Edmundowicz Daniel, Okamura Tomonori, Sutton-Tyrrell Kim, Nakamura Yasuyuki, Egawa Katsuya, Kanda Hideyuki, Kashigawa Atsunori, Kita Yoshiyuki, Maegawa Hiroshi, Mitsunami Kenichi, Murata Kiyoshi, Nishio Yoshihiko, Tamaki Shinji, Ueno Yoshiki, Kuller Lewis H.

International Journal of Epidemiology 34 （ 1 ） 173 - 179 2005年02月

ISSN 0300-5771

Background: Since World War II (WWII), exposures to westernized lifestyle have occurred in many non-Western countries, including Japan. National surveys showed that risk factor profiles for atherosclerosis around 1990 were similar in men in the post WWII birth cohorts in the US and Japan. We compared the degree of coronary calcium and other factors in men in the post WWII birth cohort: men aged 40-49 in the US and Japan. Methods: We conducted a cross-sectional study examining randomly selected 100 men from Kusatsu, Japan, and 100 men from Allegheny County, US. Coronary calcium was assessed using electron-beam computed tomography. Results: Systolic blood pressure, total cholesterol, low density lipoprotein (LDL)-cholesterol, and smoking rates were higher among the Japanese (122.6 ± 14.1 versus 113.7 ± 9.6 mmHg, P < 0.01; 5.72 ± 0.90 versus 4.99 ± 0.81 mmol/l (220.9 ± 34.6 versus 192.8 ± 31.3 mg/dl), P < 0.01; 3.52 ± 1.01 versus 3.10 ± 0.78 mmol/l (136.0 ± 39.0 versus 119.7 ± 30.0 mg/dl), P < 0.01; and 48 versus 15%, P < 0.01, respectively). Triglycerides and fibrinogen were similar. High density lipoprotein (HDL)-cholesterol was higher among the Japanese. Body mass index, fasting insulin, and C-reactive protein were higher among the Americans. Prevalence of coronary artery calcium score >0 was strikingly lower among the Japanese than the Americans (13% versus 47%, P < 0.01). Conclusions: Much lower prevalence of coronary calcium despite a less favourable profile of many major independent risk factors in the Japanese might imply that there are strong protective factors against atherosclerosis in the Japanese. Further investigation is of critical importance. © International Epidemiological Association 2004; all rights reserved.

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Proteinuria is a prognostic marker for cardiovascular mortality

Tanihara Shinichi, Hayakawa Takehito, Oki Izumi, Nakamura Yosikazu, Sakata Kiyomi, Okayama Akira, Fujita Yasuyuki, Ueshima Hirotsugu, Iimura Osamu, Omae Teruo, Ueda Kazuo, Yanagawa Hiroshi, Kodama Kazunori, Kasagi Fumiyoshi, Okamura Tomonori, Kita Yoshikuni, Saito Shigeyuki, Sakata Kiyomi, Tanihara Shinichi, Horibe Hiroshi, Minowa Masumi, Takeuchi Toshihiro, Hasebe Mitsuru, Kusano Fumitsugu, Kawaminami Katsuhiko, Choudhury Sohel R., Kiyohara Yutaka, Iida Minoru, Hashimoto Tsutomu, Terao Atsushi, Sawai Koryo, Shibata Shigeo

Journal of Epidemiology 15 （ 4 ） 146 - 153 2005年

ISSN 0917-5040

Background: Proteinuria has been considered to be a prognostic marker for persons with diabetes mellitus, but only a limited number of studies about the relationship between proteinuria and mortality among general population has been available. Methods: The subjects were 10,897 individuals who participated in the National Cardiovascular Survey conducted in 1980 and who were aged 30 years or older living in 300 districts that had been randomly selected throughout Japan. The vital records were confirmed in 1999 and 7,203 subjects (3,180 males and 4,023 females) without a history of hypertension, stroke, heart disease, renal disease, or diabetes mellitus at the start of the study were investigated. Results: There were 126,825 person-years of follow-up. During the observed period of time, 371 died of cardiovascular causes, including 171 stroke deaths and 74 coronary deaths. The risk of proteinuria for cardiovascular mortality was greater than unity for those with a normal serum creatinine level, after adjusting for age and other cardiovascular disease risk factors. Conclusions: When contrasted with other cardiovascular disease risk factors, urinary protein is an independent risk factor for cardiovascular death among the Japanese population. Copyright © 2005 by the Japan Epidemiological Association.

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A combination of serum low albumin and above-average cholesterol level was associated with excess mortality

Okamura Tomonori, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Elliott Paul, Ueshima Hirotsugu

Journal of Clinical Epidemiology 57 （ 11 ） 1188 - 1195 2004年11月

ISSN 0895-4356

There is no population-based prospective study concerning the relation between serum albumin and mortality in a non-Western population, and few previous studies included the subgroup analysis stratified by serum cholesterol level. A 13.7-year cohort study was conducted on 6,957 males and females aged 30-59 years from 300 randomly selected areas throughout Japan, who participated in the National Survey on Circulatory Disorders in 1980. In the group with median and above of total cholesterol, one standard deviation (SD) increment of serum albumin (2.6 g/L for males and 2.4 g/L for females) was inversely associated with all-cause mortality for both males and females (relative risk RR = 0.68 and 0.81; 95% confidence interval CI = 0.53-0.87 and 0.68-0.98), and with cancer mortality for females (RR = 0.74; 95% CI = 0.57-0.96); and the lowest category of serum albumin (≤43 g/L) showed the highest cardiovascular mortality for males (RR = 5.04; 95% CI = 1.04-24.5) among the three albumin categories. These relationships were not evident in the group with total cholesterol level below median. A combination of a low albumin level and above average cholesterol level, even both within the clinical normal range, is associated with excess mortality in the Japanese general population. © 2004 Elsevier Inc. All rights reserved.

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Applicability of the stages of change model for analyzing fruit and vegetable intake in relation to urinary potassium excretion

Tamaki Junko, Yoshita Katsushi, Kikuchi Yuriko, Takebayashi Toru, Chiba Nagako, Okamura Tomonori, Tanaka Taichiro, Kasagi Fumiyoshi, Minai Junko, Ueshima Hirotsugu

Hypertension Research 27 （ 11 ） 843 - 850 2004年11月

ISSN 0916-9636

The Stages of Change model evaluates and conceptualizes attempts to alter particular behavior patterns. To investigate the validity of this model for assessing fruit and vegetable intake, we examined the association between the stage of change in fruit and vegetable intake and urinary potassium excretion. The data were from baseline surveys taken in 1999 and 2000 from the High-Risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) study in Japan. This was a non-randomized control trial at 12 worksites in Japan and aimed to decrease cardiovascular risk factors. Cross-sectional analysis was performed using data from 6,774 participants (5,364 men and 1,410 women). We used three categories of the model: precontemplation or contemplation (P/C), indicating no commitment to change; preparation (P), indicating readiness to change behavior but not actually doing so; and action or maintenance (A/M), indicating an actual change in behavior. Urinary potassium excretion was estimated from the potassium and creatinine concentrations in spot urine samples. Multivariate analysis indicated that urinary potassium excretion in the A/M stage was 1.65 mmol/day more than in the P stage, and 1.44 mmol/day more than in the P/C stage for men (p<0.05, respectively). For women, urinary potassium excretion in the A/M stage was 1.26 mmol/day more than in the P/C stage (p< 0.05) and 1.04 mmol/day more than in the P stage, although the latter result lacked statistical significance (p=0.08). This study supports the potential value of the Stages of Change model for increasing fruit and vegetable intake in the design of dietary intervention programs.

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Cigarette smoking as a risk factor for stroke death in Japan NIPPON DATA80

Ueshima Hirotsugu, Choudhury Sohel Reza, Okayama Akira, Hayakawa Takehito, Kita Yoshikuni, Kadowaki Takashi, Okamura Tomonori, Minowa Masumi, Iimura Osamu

Stroke 35 （ 8 ） 1836 - 1841 2004年08月

ISSN 0039-2499

Background and Purpose - Some previous Japanese cohort studies failed to show an association between smoking and stroke risk. Because such an association has been noted in other populations, this issue should be re-examined in a recent representative Japanese cohort with a higher total cholesterol level. Methods - A total of 9638 men and women aged 30 years and older without a history of cardiovascular disease (CVD) at baseline in 1980 were followed-up for 14 years. Results - We observed 203 stroke deaths (107 cerebral infarctions, 45 cerebral hemorrhages, and 51 others), 191 heart disease deaths, and 413 CVD deaths. The average serum total cholesterol level was ≈4.91 mmol/L. Cox proportional hazard ratios were calculated adjusting for age, systolic blood pressure, and other conventional risk factors. The hazard ratios for men who smoked 1 to 20 cigarettes/day for all strokes, cerebral infarction, and cerebral hemorrhage were 1.60 (95% CI, 0.91 to 2.79), 2.97 (CI, 1.27 to 6.98), and 0.42 (CI, 0.16 to 1.09), respectively, and for those who smoked ≥21 cigarettes/day, they were 2.17 (CI, 1.09 to 4.30), 3.26 (CI, 1.11 to 9.56), and 0.68 (CI, 0.20 to 2.33), respectively. For women who smoked ≥21 cigarettes/day, the hazard ratio for all strokes was 3.91 (CI, 1.18 to 12.90). For CVD, all heart disease, and ischemic heart disease, the hazard risks of smoking were significant (1.49 to 4.25) for men but not significant for women. Conclusions - Smoking in a cohort with moderate serum total cholesterol level was a potent risk factor for stroke, especially cerebral infarction, for both men and women, and for CVD and ischemic heart disease for men.

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Methodological issues for a large-scale intervention trial of lifestyle modification

Okamura Tomonori, Tanaka Taichiro, Takebayashi Toru, Nakagawa Hideaki, Yamato Hiroshi, Yoshita Katsushi, Kadowaki Takashi, Okayama Akira, Ueshima Hirotsugu

Environmental Health and Preventive Medicine 9 （ 4 ） 137 - 143 2004年07月

ISSN 1342-078X

Objective: To clarify the methodological issues for the High-risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP study), which is a 4-year non-randomized control trial, an interim assessment of male participants was performed 3 years after the baseline survey. Methods: We had approximately 2,500 and 4,000 participants in the intervention and control groups, respectively. The population measures and prevalence of risk factors at each year, and between the baseline and 4th examinations were compared between the two groups. The personal trends of returning participants who were in the study at the 1st and 4th examinations were also evaluated. Results: During the 3 years, an increase in serum HDL cholesterol (2.7 mg/dl), and a reduction in the prevalence of hypertriglycemia detected with fasting blood samples (3.6%) and current smokers (5.4%) were observed in the intervention group. The mean HDL cholesterol level was significantly higher in the intervention group than in the control group at the 4th examination, reversed from the baseline survey. The serum non-HDL cholesterol level was significantly increased only in the control group. There was also a significant increase in the prevalence of hypertriglycemia and high plasma glucose detected with fasting blood samples in the control group. The return participation rate after 3 years was 72.2% for the intervention group and 74.9% for the control group. The above-mentioned changes for risk factors were mainly due to returning participants at each examination. Conclusion: These interventional methods may be effective in improving overall cardiovascular risk factors in the population. However, the low return participation rate will dilute the effect of the intervention.

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Egg consumption, serum cholesterol, and cause-specific and all-cause mortality

Nakamura Yasuyuki, Okamura Tomonori, Tamaki Shinji, Kadowaki Takashi, Hayakawa Takehito, Kita Yoshikuni, Okayama Akira, Ueshima Hirotsugu

American Journal of Clinical Nutrition 80 （ 1 ） 58 - 63 2004年07月

ISSN 0002-9165

Background: Because egg yolk has a high cholesterol concentration, limited egg consumption is often suggested to help prevent ischemic heart disease (IHD). Objective: We epidemiologically examined the validity of this recommendation. Design: We analyzed the relations of egg consumption to serum cholesterol and cause-specific and all-cause mortality by using the NIPPON DATA80 (National Integrated Project for Prospective Observation of Non-communicable Disease And its Trends in the Aged, 1980) database. At the baseline examination in 1980, a nutritional survey was performed by using the food-frequency method in Japanese subjects aged ≥30 y. We followed 5186 women and 4077 men for 14 y. Results: The subjects were categorized into 5 egg consumption groups on the basis of their responses to a questionnaire (≥2/d, 1/d, 1/2 d, 1-2/wk, and seldom). There were 69, 1396, 1667, 1742, and 315 women in each of the 5 groups, respectively. Age-adjusted total cholesterol (5.21, 5.04, 4.95, 4.91, and 4.92 mmol/L in the 5 egg consumption categories, respectively) was related to egg consumption (P < 0.0001, analysis of covariance). In women, unadjusted IHD mortality and all-cause mortality differed significantly between the groups [IHD mortality: 1.1, 0.5, 0.4, 0.5, and 2.0 per 1000 person-years, respectively (P = 0.008, chi-square test); all-cause mortality: 14.8, 8.0, 7.5, 7.5, and 14.5 per 1000 person-years, respectively (P < 0.0001, chi-square test)]. In men, egg consumption was not related to age-adjusted total cholesterol. Cox analysis found that, in women, all-cause mortality in the 1-2-eggs/wk group was significantly lower than that in the 1-egg/d group, whereas no such relations were noted in men. Conclusion: Limiting egg consumption may have some health benefits, at least in women in geographic areas where egg consumption makes a relatively large contribution to total dietary cholesterol intake. © 2004 American Society for Clinical Nutrition.

The evaluation of materials to provide health-related information as a population strategy in the worksite

Yoshita Katsushi, Tanaka Taichiro, Kikuchi Yuriko, Takebayashi Toru, Chiba Nagako, Tamaki Junko, Miura Katsuyuki, Kadowaki Takashi, Okamura Tomonori, Ueshima Hirotsugu

Environmental Health and Preventive Medicine 9 （ 4 ） 144 - 151 2004年07月

ISSN 1342-078X

Objective: To examine the effectiveness of newly developed materials for providing health-related information to the worksite population, we compared the amount of attention that employees paid to the materials. Methods: Study subjects were 2,361 employees in six companies partcipating in an intervention program between 2002 and 2003. Three kinds of media were used as tools for providing health information: [1] Point Of Purchase advertising menus (POP menus) were placed on all tables in company restaurants, [2] posters were put on walls and [3] leaflets were distributed at health-related events. One year or more after the introduction of these media, we compared the amount of attention paid to each type of medium. Results: Amongst the three types of media, the POP menu drew the most attention, although results were not consistent in all gender and company groups. Every piece of information provided by the POP menus was "always" or "almost always " read by 41% of the men and 51% of the women surveyed. The corresponding rate for posters was 30% in men and 32% in women. For leaflets, only 16% of men and 22% of women read almost all of the leaflets. More attention was paid to the POP menu when the sample was women, older, and ate at the company restaurant at least three times a week. Conclusion: The POP menu may provide health-related information to a broader range of people than posters and leaflets, therefore, it is an effective material for population strategy.

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Effectiveness of annual interventions for smoking cessation in an occupational setting in Japan

Kadowaki Takashi, Okamura Tomonori, Funakoshi Tsutae, Okayama Akira, Kanda Hideyuki, Miyamatsu Naomi, Kita Yoshikuni, Ueshima Hirotsugu

Environmental Health and Preventive Medicine 9 （ 4 ） 161 - 164 2004年07月

ISSN 1342-078X

Objective: To examine the effectiveness of a small-scale smoking cessation intervention program conducted annually for ten years in an occupational setting in Japan. Methods: We conducted an annual intervention program promoting smoking cessation in male smokers from 1993 to 2002 in an occupational setting in Hyogo, Japan. Trends in smoking prevalence in this worksite were compared with a control group from two similar worksites of the same company. The intervention program was carried out by medical students (the fourth year of a six-year course) who received training on the protocol prior to the intervention. This protocol consisted of one initial group session, followed by periodical correspondence for two months. Successful cessation of smoking was determined by self-declaration of abstinence for longer than four weeks after intervention, confirmed by an expiratory carbon monoxide concentration of less than nine ppm. Smoking prevalence was determined by a self-administered questionnaire provided at the annual health checkup. Results: The proportion of smokers who participated in the program was 3.47% on average. Abstinence rates following each intervention ranged from 13.3% to 60.0%, with the prevalence of male smokers at the intervention worksite decreasing from 56.2% in 1993 to 47.0% in 2002. In contrast, the smoking prevalence of the control worksites remained largely unchanged, being 60.2% in 1995 and 57.6% in 2002. At the end of the study, the intervention worksite had a significantly lower prevalence of smokers in either the crude or age-adjusted rate. Conclusion: A small-scale but repeated smoking cessation intervention program at a worksite can reduce smoking prevalence more efficiently than the natural trend.

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The high-risk and population strategy for occupational health promotion (HIPOP-OHP) study

Okamura T., Tanaka T., Babazono Akira, Yoshita Katsushi, Chiba Nagako, Takebayashi Toru, Nakagawa Hideaki, Yamato Hiroshi, Miura Katsuyuki, Tamaki J., Kadowaki T., Okayama Akira, Ueshima Hirotsugu, Nishi Nobuo, Tsuji Keiko, Kikuchi Yuriko, Yanagita Masahiko, Kodama Kazunori, Kasagi Fumiyoshi, Kusaka Yukinori, Saitoh Shigeyuki, Sakata Kiyomi, Tanaka Hideo, Nakamura Masakazu, Naito Yoshihiko, Nakamura Yasuyuki, Watanabe Makoto, Nakamura Yoshikazu, Tamura Unai, Minai Junko, Yamagata Zentaro, Urano Sumio, Kinoshita Fujihisa, Saitoh Isao, Tanihara Shinichi, Tamaki Junko, Tochikubo Osamu

Journal of Human Hypertension 18 （ 7 ） 475 - 485 2004年07月

ISSN 0950-9240

In order to establish the methodology of a population strategy for improving cardiovascular risk factors, we have planned the High-risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP study). This study is a nonrandomized control trial in approximately 6500 participants in six intervention and six control companies. Our population strategy is based on three factors, nutrition, physical activity, and smoking. For each factor, a researcher's working team was organized and has been supporting the intervention. A standardized method to obtain comparable data has also been established. In the baseline survey, urinary sodium excretion in male subjects was higher, and urinary potassium excretion was lower in both genders in the intervention group compared to the control group. The prevalence of hypertension for both genders was also higher in the intervention group. Male subjects in the intervention group had higher serum total cholesterol than controls, while high-density lipoprotein cholesterol was lower in both genders in the intervention group compared to the control group. These differences were reflected by our finding that the predicted relative risk of coronary heart disease for male subjects was significantly higher in the intervention group (relative risk, RR: 1.17; 95% confidence interval, 95% CI.: 1.09, 1.25) and significantly lower in the control group (RR: 0.93; 95% CI.: 0.89, 0.98) compared to a model Japanese population. Similar results were observed in the female subjects. Taken together, these findings indicate that it is possible to compare trends of predicted relative risk for coronary heart disease between two groups. © 2004 Nature Publishing Group All rights reserved.

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Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese

Iso Hiroyasu, Moriyama Yuri, Sato Shinichi, Kitamura Akihiko, Tanigawa Takeshi, Yamagishi Kazumasa, Imano Hironori, Ohira Tetsuya, Okamura Tomonori, Naito Yoshihiko, Shimamoto Takashi

Circulation 109 （ 22 ） 2766 - 2772 2004年06月

ISSN 0009-7322

Background - To date, no prospective studies have examined the association between serum homocysteine levels and the risk of stroke and stroke subtypes in Asian populations. Methods and Results - A prospective, nested, case-control study of Japanese subjects 40 to 85 years of age was conducted by using frozen serum samples from 11 846 participants in cardiovascular risk surveys collected from 1984 to 1995 for one community and 1989 to 1995 for the other two communities. By the end of 2000, we identified 150 incident strokes, the subtypes of which were confirmed by imaging studies. Three control subjects per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Serum total homocysteine levels were measured by high-performance liquid chromatography. Compared with control subjects, total (n=150), hemorrhagic (n=52), and ischemic (n=98) strokes had higher geometric mean values of total homocysteine and higher proportions of homocysteine ≥11.0 μmol/L. The multivariate odds ratios (95% CI) for highest (≥11.0 μmol/L) versus lowest quartiles (<7.0 μmol/L) of homocysteine after adjustment for body mass index, smoking, alcohol intake, hypertension, serum total cholesterol, and other cardiovascular risk factors were 2.99 (1.51 to 5.93) for total stroke, 3.89 (1.60 to 9.46) for ischemic stroke, 3.36 (1.27 to 8.90) for lacunar infarction, and 1.63 (0.44 to 6.00) for hemorrhagic stroke. The respective multivariate odds ratios associated with a 5-μmol/L increase in homocysteine were 1.40 (1.09 to 1.80), 1.52 (1.07 to 2.14), 1.48 (1.01 to 2.18), and 1.10 (0.76 to 1.59). The excess risk of total and ischemic strokes did not vary significantly according to sex, age, smoking status, or hypertensive status. Conclusions - High total homocysteine concentrations were associated with the increased risk of total stroke, more specifically ischemic stroke and lacunar infarction, among Japanese men and women.

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Resting heart rate and cause-specific death in a 16.5-year cohort study of the Japanese general population

Okamura Tomonori, Hayakawa Takehito, Kadowaki Takashi, Kita Yoshikuni, Okayama Akira, Elliott Paul, Ueshima Hirotsugu

American Heart Journal 147 （ 6 ） 1024 - 1032 2004年06月

ISSN 0002-8703

Background Several prospective studies have reported resting heart rate (HR) to be a risk factor for certain cause-specific death, together with sex- or age-specific differences in the effects of HR on death. However, there have been few prospective data from non-Western populations. Methods Cohort study, over 16.5 years to date of death or end of follow-up (November 15, 1998) involving 8800 men and women ≥30 years of age randomly selected throughout Japan, who participated in the National Survey on Circulatory Disorders in 1980. Resting HR was determined from 3 consecutive intervals between R waves on the 12-lead electrocardiogram. Results For middle-aged men (30 to 59 years of age), in the highest quartile of HR, there was a significant positive association with cardiovascular (RR, 2.55; 95% CI, 1.22 to 5.31) and all-cause death (RR, 1.45; 95% CI, 1.06 to 2.00). For middle-aged women, in the highest quartile, there was a significant positive association with noncancer, noncardiovascular (RR, 2.41; 95% CI, 1.04 to 5.59), and all-cause death (RR, 1.94; 95% CI, 1.26 to 3.01). Resting HR also showed a significant positive association with cardiac events but not to stroke. These relations were not evident for elderly subjects (≥60 years of age). Results were not affected when deaths within the first 5 years of follow-up were excluded, except for noncancer, noncardiovascular death. Conclusions High resting HR is an independent predictor of long-term death in the Japanese general population.

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Stages of change for salt intake and urinary salt excretion

Tamaki Junko, Kikuchi Yuriko, Yoshita Katsushi, Takebayashi Toru, Chiba Nagako, Tanaka Taichiro, Okamura Tomonori, Kasagi Fumiyoshi, Minai Junko, Ueshima Hirotsugu

Hypertension Research 27 （ 3 ） 157 - 166 2004年03月

ISSN 0916-9636

We investigate the relationship of urinary salt excretion to the stage of change to decrease salt intake in the Japanese diet. The data reported here were obtained from a baseline survey of the High-Risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) study that was conducted as a non-randomized control trial at 12 worksites in Japan. A total of 6,816 subjects (5,410 male, 1,406 female) were used in 1999 and 2000 for the analysis. We used three categories of stage of change: precontemplation or contemplation (P/C), preparation (P), and action or maintenance (A/M). Urinary salt excretion was estimated from the sodium and creatinine concentrations in spot urine samples. Multivariate analysis indicated that urinary salt excretion among males was 0.3 g/day greater in the P/C stage than in the A/M stage (p<0.05). For non-obese females, urinary salt excretion in the P/C stage was 0.6 g/day greater than in the A/M stage (p<0.05). Multivariate analysis showed that diastolic blood pressure in males not taking antihypertensive agents was 1.3 mmHg lower in the P/C stage than in the A/M stage (p<0.05). A similar but statistically insignificant tendency was observed among non-obese females. A significant association was demonstrated between stage of change for dietary salt intake and urinary salt excretion for both males and non-obese females. There may be a potential application of the stage of change model for reducing dietary salt intake in a health promotion program.

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Non-invasive measurement of brachial-ankle pulse wave velocity is associated with serum C-reactive protein but not with α-tocopherol in Japanese middle-aged male workers

Okamura Tomonori, Moriyama Yuri, Kadowaki Takashi, Kanda Hideyuki, Ueshima Hirotsugu

Hypertension Research 27 （ 3 ） 173 - 180 2004年03月

ISSN 0916-9636

Pulse wave velocity (PWV) is an indicator of arterial stiffness, especially in the aorta, and a marker for vascular damage. We examined the association of brachial-ankle PWV (baPWV) with serum α-tocopherol and C-reactive protein (CRP) levels in addition to the traditional risk factors. Study subjects were 178 Japanese male workers aged 50-59 without past histories of cardiovascular diseases. The relation of baPWV with serum α-tocopherol and CRP levels was cross-sectionally analyzed after adjusting for other cardiovascular risk factors. The arithmetic mean of serum α-tocopherol was 38.9 μmol/l, and the geometric mean of serum CRP was 0.47 mg/l. Multiple linear regression analysis indicated that serum CRP levels were associated with an elevation of baPWV, in addition to age, systolic blood pressure and heart rate. However, serum α-tocopherol, serum lipids (triglyceride, low and high density lipoprotein cholesterol), fasting plasma glucose, body mass index, smoking and alcohol drinking did not significantly correlate to baPWV. Multivariate-adjusted means of baPWV according to serum CRP quartile were 1,431, 1,436, 1,507 and 1,508 cm/s (p=0.033). The serum CRP level might be an important marker for arterial stiffness in Japanese middle-aged males. However, no relation was observed between α-tocopherol and baPWV.

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Specific alcoholic beverage and blood pressure in a middle-aged Japanese population

Okamura T., Tanaka T., Yoshita K., Chiba N., Takebayashi T., Kikuchi Y., Tamaki J., Tamura U., Minai J., Kadowaki T., Miura K., Nakagawa H., Tanihara S., Okayama A., Ueshima H.

Journal of Human Hypertension 18 （ 1 ） 9 - 16 2004年01月

ISSN 0950-9240

The purpose of this study was to clarify the effects of popular Japanese alcoholic beverages on blood pressure. We performed a cross-sectional study on 4335 Japanese male workers using baseline data from an intervention study. We defined six groups according to the type of alcoholic beverage that provided two-thirds of the subject's total alcohol consumption: beer, sake (rice wine), shochu (traditional Japanese spirits), whiskey, wine and others. The partial regression coefficients of daily alcohol intake (1 drink = 11.5 g of ethanol) to systolic blood pressure (SBP) and diastolic blood pressure (DBF) were 0.87(P < 0.001, standard error (s.e.) = 0.09) and 0.77(P < 0.001, s.e. = 0.06), respectively. A comparison among the types of alcoholic beverages mainly consumed revealed significant differences in SBP and DBP. Both SBP and DBP were highest in the shochu group. However, an analysis of covariance adjusting for total alcohol consumption resulted in the disappearance of these differences. Although after adjustment for total alcohol consumption, the shochu group exhibited a significant positive association with 'high-normal blood pressure or greater' (odds ratio 1.43, 95% confidence interval 1.06-1.95) compared with the beer group, this significant relation disappeared after adjusting for the body mass index (BMI), urinary sodium and potassium excretion. The pressor effect, per se, of popular Japanese alcoholic beverages on blood pressure may not be different among the types of alcoholic beverages after adjusting for other lifestyle factors.

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Weight-control intervention in overweight subjects at high risk of cardiovascular disease

Okuda Nagako, Okamura Tomonori, Kadowaki Takashi, Tanaka Taichiro, Ueshima Hirotsugu

[Nippon kōshū eisei zasshi] Japanese journal of public health 51 （ 7 ） 552 - 560 2004年

ISSN 0546-1766

OBJECTIVE: To evaluate the effectiveness of a weight-control intervention for overweight subjects at high risk of cardiovascular disease (CVD) at a worksite conducted by medical students as a public health practical training program. METHODS: A total of 45 men and women who were obese (BMI > or = 24.0 kg/m2) and found to be hypertensive (SBP > or = 140 mmHg or DBP > or = 90 mmHg) or suffering from hypercholesterolemia (total serum cholesterol > or = 220 mg/dl) in an annual health check up in November 2001 were invited to participate in a weight-control intervention program. Eight individuals agreed (intervention group) and other sixteen control subjects whose sex and age (+/- 3 years) were matched to the intervention subjects were selected. The duration of the program was three months (from July to October 2002) and a 2 kg weight reduction in that period was set as the goal. The baseline survey consisted of a dietary questionnaire and a health quiz. Subjects had two counseling sessions and received four personal letters in the three months. A semi-quantitative food frequent questionnaire, a photograph method (Diet Agent Service, Matsushita Electric Works, Ltd.) and three day food records were conducted for dietary surveys. Changes in bodyweight, BMI, blood pressure, and serum total cholesterol concentration from November 2001 to November 2002 were compared between the intervention and control groups. Food group intakes and nutrient intakes were compared between weight reduction achievers and non-achievers. RESULTS: Mean bodyweight changes from November 2001 to November 2002 were -2.3 kg (SD 3.3 kg) for the intervention group and +0.3 kg (SD 1.5 kg) for the control group, the difference being significant (p = 0.013). For the intervention group mean bodyweight change from July to October 2002 was -1.5 kg (SD 2.4 kg). For total serum cholesterol, the mean changes were -32.1 mg/dl vs. +0.5 mg/dl (p = 0.005), for SBP -9.5 mmHg vs. +4.7 mmHg (p = 0.083) and for DBP -2.8 mmHg vs. +1.4 mmHg (p = 0.438). These were thought to be consequences of weight-control intervention. From dietary surveys, weight reduction achievers increased fish intake and decreased fats, snacks and sweets. Those who answered the health quiz more correctly demonstrated more reduction of bodyweight. CONCLUSIONS: Effectiveness of a weight-control intervention for reduction of CVD risk factors was found in the present public health practical training program for medical students. Dietary advice based on various dietary surveys was indicated to be effective in the weight-control program. A population strategy to distribute health information appeared necessary for effective health education programs for high-risk subjects.

Haplotype analyses of cholesteryl ester transfer protein gene promoter

Lu Hong, Inazu Akihiro, Moriyama Yuri, Higashikata Toshinori, Kawashiri Masa Aki, Yu Wenxin, Huang Zhiping, Okamura Tomonori, Mabuchi Hiroshi

Journal of Molecular Medicine 81 （ 4 ） 246 - 255 2003年04月

ISSN 0946-2716

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans, However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the [gaaa]_n repeat ("S" denotes [gaaa]_n=329 bp and longer, "L" denotes >329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, [gaaa]_n, -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0±0.6 μg/ml) and higher HDL cholesterol levels (55.1±12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the [gaaa]_n repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the [gaaa]_n repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.

A "natural experiment" in cardiovascular epidemiology in the early 21st century

Sekikawa Akira, Horiuchi B. Y., Edmundowicz D., Ueshima H., Curb J. D., Sutton-Tyrrell K., Okamura T., Kadowaki T., Kashiwagi A., Mitsunami K., Murata K., Nakamura Y., Rodriguez B. L., Kuller L. H.

Heart 89 （ 3 ） 255 - 257 2003年03月

ISSN 1355-6037

What cause of mortality can we predict by cholesterol screening in the Japanese general population?

Okamura Tomonori, Kadowaki T., Hayakawa T., Kita Y., Okayama A., Ueshima H.

Journal of Internal Medicine 253 （ 2 ） 169 - 180 2003年02月

ISSN 0954-6820

Objective. In a population with a markedly lower coronary mortality such as in Japan, the benefit of cholesterol screening may be different from Western populations. We attempted to assess the importance of cholesterol screening in Japan. Design. A 13.2-year cohort study for cause-specific mortality. Setting. Three hundred randomly selected districts throughout Japan in which the National Survey on Circulatory Disorders 1980 was performed. Subjects. A total of 9216 community dwelling persons aged 30 years and over, with standardized serum cholesterol measurement and without a past history of cardiovascular disease. Results. There were 1206 deaths, which included 462 deaths due to cardiovascular disease with 79 coronary heart diseases. Hypercholesterolemia (>6.21 mmol L^-1) showed a significant positive relation to coronary mortality (relative risk; 2.93, 95% confidence interval: 1.52-5.63) but not to stroke. Although hypocholesterolemia (<4.14 mmol L^-1) was significantly associated with an increased risk of liver cancer, noncardiovascular, noncancer disease and all-cause mortality, these associations, except for liver cancer, disappeared after excluding deaths in the first 5 years of the follow-up. The multivariate adjusted attributable risk of hypercholesterolaemia for coronary disease was 0.98 per 1000 person-years, which was three-fold higher than that of hypocholesterolemia for liver cancer: 0.32 per 1000 person-years. The attributable risk percentage of hypercholesterolaemia was 66% for coronary heart disease. Conclusion. Similar to Western populations, it is recommended to provide screening for hypercholesterolaemia in Japan, especially for males, although its attributable risk for coronary disease might be small.

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Electron-beam computed tomography for identification of high-risk persons in primary prevention of coronary heart disease in the United States and its implication for Japan

Sekikawa Akira, Okamura Tomonori, Kadowaki Takashi, Mitsunami Kenichi, Murata Kiyoshi, Kashiwagi Atsunori, Nakamura Yasuyuki, Kanda Hideyuki, Edmundowicz Daniel, Sutton-Tyrrell Kim, Curb J. David, Kuller Lewis H., Ueshima Hirotsugu

[Nippon kōshū eisei zasshi] Japanese journal of public health 50 （ 3 ） 183 - 193 2003年

ISSN 0546-1766

Coronary heart disease (CHD) is the leading cause of death in the United States (US). Approximately half of deaths from (CHD) occur out of hospital, most being sudden. The majority of sudden cardiac deaths occur in asymptomatic subjects. Recent lipid-lowering trials in asymptomatic subjects have demonstrated the potential for risk reduction for CHD events by primary prevention. It is, however, generally acknowledged that risk will be underestimated in asymptomatic subjects who fall into the category of intermediate risk by the traditional risk factors. Non-invasive measurements of subclinical atherosclerosis, which is the end result of risk-factor exposure, have the possibility of improving the risk stratification of asymptomatic subjects in intermediate-risk. Electron-beam computed tomography (EBCT) is a non-invasive and highly sensitive means to detect calcification within coronary arterial wall. Coronary artery calcification (CAC) is a recognized marker of atherosclerosis. Atherosclerotic burden of coronary arteries correlates strongly with the amount of CAC measured by EBCT. Studies examining the predictive value of CAC among asymptomatic subjects consistently reported that CAC is a risk for CHD. Two studies reported that unadjusted odds ratios of CAC for CHD were over 20. Incremental value of EBCT over the traditional risk assessment models, however, has not been established. Although CHD mortality in Japan remains uniquely low in industrialized countries, among men aged 30-49, risk factor profiles for CHD are similar between men in the US and Japan, except higher prevalence of cigarette smoking in Japan and higher prevalence of obesity in the US. It is reported that the declining trend in CHD mortality in Japan has recently slowed down in metropolitan areas, especially in men aged 30-49, and that the incidence has increased in middle-aged workers in a metropolitan area. A mortality validation study reported that the differences in CHD mortality between the US and Japan were not as large as suggested by vital statistics. It is, therefore, important to evaluate subclinical atherosclerosis measured by EBCT in men in recent birth cohorts in Japan and compare it to that in men in the US in order to predict future trend in CHD in Japan.

Smoking scenes in Japanese television dramas

Kanda Hideyuki, Okamura Tomonori, Kadowaki Takashi, Hayakawa Takehito, Kita Yoshikuni, Ueshima Hirotsugu

[Nippon kōshū eisei zasshi] Japanese journal of public health 50 （ 1 ） 62 - 70 2003年

ISSN 0546-1766

BACKGROUND: Exposure to smoking scenes in movies and TV dramas has been known to be a trigger for young people starting habitual smoking, but it has not been clarified to what extent youth is routinely exposed to smoking scenes in television programs in Japan. OBJECTIVE: To clarify the status quo of smoking scenes and smoking-related items in serial TV dramas targeting young audience in Japan. METHOD: Seven TV dramas targeting a young audience broadcast between July and September, 2001 were analyzed. A total of 63 hours of TV programs were divided into units of three minutes (a total of 1,264 units). All the units were reviewed for smoking scenes, description of social contexts related to smoking behavior, existence of smoking and smoking-related items. FINDINGS: Among the 1,264 three-minute units, 129 (10.2%) contained smoking behavior, and 258 (20.4%) depicted smoking environment with presence of smoking-related items. Smokers were male actors (126 units, 97.7%), aged 20-40 years (118 units, 91.5%), leading actors (72 units, 55.8%), and were smoking alone (80 units, 62.0%). Smoking places mainly took place in indoor settings (56 units, 43.4%). Ashtrays were the most frequently observed smoking-related items (8.1% of the total units). The smoking scenes with actions other than smoking itself accounted for 70 units (54.3% of the smoking scenes). As for the actions other than smoking, working (28 units, 21.7%) and eating (17 units, 13.2%) were commonly observed. Regarding smoking scenes without any other actions, 32 units (24.8%) were observed in the beginning or ending telops, and 27 units (20.9%) showed a person smoking without doing anything else. There were only 3 units (0.2%) which were against smoking behavior. Approximately 30% of the Japanese serial television drama scenes featured tobacco use in story plots. As the general features of the smoking scenes, most of them do not necessarily require smoking in the story. Furthermore, there was little consideration about separation of designated smoking areas.

Determinants of platelet aggregation in 50-70-year-old men from three Japanese communities

Imano Hironori, Iso Hiroyasu, Sato Shinichi, Kitamura Akihiko, Okamura Tomonori, Tanigawa Takeshi, Ohira Tetsuya, Kudo Minako, Naito Yoshihiko, Iida Minoru, Shimamoto Takashi

Atherosclerosis 165 （ 2 ） 327 - 334 2002年12月

ISSN 0021-9150

To investigate the association of lifestyle and constitutional variables with platelet aggregation, we examined the platelet aggregation, serum fatty acid composition, alcohol intake, smoking, and dietary intake of seafood and soybean estimated by a 1-week dietary record in 448 males aged 50-70 in three rural Japanese communities: Ikawa, Akita prefecture (northeast coast), Noichi, Kochi prefecture (southwest coast), and Kyowa, Ibaraki prefecture (central inland). Platelet aggregatory threshold index (PATI) was used to determine the minimum concentration of adenosine 5′-diphosphate (ADP) that caused a non-reversible aggregation of platelets. Intake of seafood and n3-polyunsaturated fatty acid and ingestion of ethanol were higher in the northeast coastal community than in the other two communities. Mean platelet and white blood cell counts were lower in northeast coastal community than in the other two communities. The geometric mean PATI was higher (i.e. platelet aggregation was lower) in the northeast coastal community than the other two communities. Within the entire sample, platelet aggregation correlated inversely with serum level of n3-polyunsaturated fatty acids and γ-glutamyl transpeptidase, an index of alcohol consumption, and positively with platelet and white blood cell counts. Platelet aggregation tended to correlate positively with serum arachidonic acid. There was no correlation between smoking and platelet aggregation. Our results suggest that seafood intake and moderate alcohol consumption reduce platelet aggregation. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

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Epidemiologic study of the association of low-Km mitochondrial acetaldehyde dehydrogenase genotypes with blood pressure level and the prevalence of hypertension in a general population

Amamoto Kenji, Okamura Tomonori, Tamaki Shinji, Kita Yoshikuni, Tsujita Yasuyuki, Kadowaki Takashi, Nakamura Yasuyuki, Ueshima Hirotsugu

Hypertension Research 25 （ 6 ） 857 - 864 2002年11月

ISSN 0916-9636

In Japanese and other Asians, the prevalence of genetically decreased mitochondrial aldehyde dehydrogenase (ALDH2) activity is higher than in Caucasians. The aim of this study was to elucidate the relation between ALDH2 genotypes and blood pressure levels or hypertension in Japanese. After obtaining informed consent for genetic analysis from 917 men and 1,478 women who lived in a mountainous farming region near Kyoto and who were free from cardiovascular disease and liver dysfunction, the authors identified the ALDH2 genotype in all subjects. Differences in blood pressure level among genotypes were then compared by analysis of covariance, and the relation between genotypes and hypertension was also analyzed by logistic regression analysis. The frequencies of genotypes *1/*1, *1/*2, and *2/*2 were 44.7%, 46.9% and 8.4% in men, and 50.1%, 43.2% and 6.8% in women, respectively. In men, systolic and diastolic blood pressures tended to decrease in the order of *1/*1>*1/*2>*2/*2. However, adjustment for confounding factors including alcohol consumption resulted in the disappearance of significance. Logistic regression analysis adjusted for the same confounding factors for men showed that the odds ratios (OR) of being hypertensive in the *2 allele to not having *2 allele were 0.67 (95% confidence interval (CI): 0.47-0.96). However, in the subgroup analyses, this relation was not observed in the group having a below-median level of alcohol consumption (OR=0.92; 95% CI: 0.53-1.62) or in the group not taking antihypertensive agents (OR=0.77; 95% CI: 0.52-1.15). Furthermore, we did not observe any relation between the ALDH2/*2 allele and hypertension in women (OR=1.07; 95% CI: 0.80-1.42). The results suggest that there may be no causal relation between hypertension and the ALDH2 genotype per se, after excluding for some confounding factors, especially for alcohol drinking.

Polymorphism of the angiotensin converting enzyme gene and blood pressure in a Japanee general population (the Shigaraki study)

Tamaki Shinji, Nakamura Yasuyuki, Tsujita Yasuyuki, Nozaki Akihiko, Amamoto Kenji, Kadowaki Takashi, Kita Yoshikuni, Okamura Tomonori, Iwai Naoharu, Kinoshita Masahiko, Ueshima Hirotsugu

Hypertension Research 25 （ 6 ） 843 - 848 2002年11月

ISSN 0916-9636

Recent studies have described a linkage between angiotensin converting enzyme (ACE) gene polymorphism and hypertension in a large number of hypertensive sibs. Moreover, among Japanese, the DD genotype of the ACE gene has been reported to be a genetically predisposing factor for hypertension in a large general population. However, there is some controversy regarding the association between the ACE insertion/deletion (I/D) polymorphism and systemic hypertension. Therefore, we examined the influence of the ACE I/D polymorphism in a random Japanese population. The participants were 2,892 subjects (1,110 males: mean age, 58.4±15.5; 1,782 females: mean age, 56.2±15.7) who underwent medical examinations in 1999 in Shigaraki, a suburban town located in an urban area in Shiga prefecture. Among them, 2,395 subjects (917 males: mean age, 58.0±15.7; 1478 females: mean age, 56.3±15.6) who gave their informed consent for genetic analysis were enrolled in the present study. Every year since 1991, we have repeatedly performed medical examinations in Shigaraki. ACE genotypes were determined by polymerase chain reaction (PCR) methods. Logistic analysis revealed that age (p<0.001; odds ratio=1.091), body mass index (BMI) (p<0.001; odds ratio=1.211), and family history of hypertension (p<0.001; odds ratio=0.371) were associated with hypertension (systolic blood pressure greater than 140 mmHg and diastolic greater than 90 mmHg). There was no association between ACE polymorphism and blood pressure. There were also no significant differences in blood pressure among males or females across the three genotypes. Moreover, in an analysis of 1,484 subjects (549 males: mean age, 62.8±12.1; 935 females: mean age, 61.2±12.6) who were followed-up since 1991, there was no association between ACE polymorphism and changes in blood pressure (p=0.3905). We conclude that ACE polymorphism does not appear to have any significant association with blood pressure, changes in blood pressure or sex in Japanese subjects, who have a more homogeneous genetic background than any other group reported to date.

Effects of serum B vitamins on elevated plasma homocysteine levels associated with the mutation of methylenetetrahydrofolate reductase gene in Japanese

Moriyama Yuri, Okamura Tomonori, Kajinami Kouji, Iso Hiroyasu, Inazu Akihiro, Kawashiri Masaaki, Mizuno Mihoko, Takeda Yoshiko, Sakamoto Yasuki, Kimura Humio, Suzuki Hideyoshi, Mabuchi Hiroshi

Atherosclerosis 164 （ 2 ） 321 - 328 2002年10月

ISSN 0021-9150

High plasma homocysteine, a risk factor for atherosclerosis, is frequently caused by a common mutation in the gene for the enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR), C677T (alanine to valine substitution) or low intake of B vitamins that affect the remethylation or transsulfuration pathways in homocysteine metabolism. However, the interaction of the C677T mutation and B vitamins other than folate has not been well elucidated. We conducted a cross-sectional survey of 324 men and 641 women who participated in a 1996 health examination under a hypothesis that high nutritional status of folate, vitamin B12 and vitamin B6 expressed as high serum levels, may compensate for the hyperhomocysteinemia associated with homozygosity for the C677T mutation, but not for having the mutation per se. Age-adjusted plasma homocysteine levels were higher for both men and women with the homozygous genotype for the mutation than those who were heterozygous or had no mutation. Elevated homocysteine levels in homozygous genotype was attenuated among persons with higher serum levels of vitamin B12 and folate, but not vitamin B6, and among persons with the combination of lower folate and higher vitamin B12 and of higher folate and higher vitamin B12, split by the median. These findings suggest that elevated homocysteine levels among Japanese with the homozygous genotype for the MTHFR gene mutation can be modified efficiently by dietary supplement of vitamin B12 as well as folate. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

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What unfavorable factors are associated with low serum total cholesterol in a Japanese population?

Mao Xu, Okamura Tomonori, Choudhury Sohel R., Kita Yoshikuni, Kadowaki Takashi, Okayama Akira, Niki Isao, Ueshima Hirotsugu

Journal of Epidemiology 12 （ 3 ） 271 - 279 2002年05月

ISSN 0917-5040

An inverse association between blood cholesterol level and excess mortality in low cholesterol level subjects has been reported, but there has been no reasonable explanation widely accepted. To evaluate the associations between unfavorable factors and low blood cholesterol in non-Western populations, we performed a cross-sectional study in a rural Japanese population. A self-administered questionnaire concerning health characteristics and a nutritional survey, using a continuous 48-hour dietary record, was conducted on 461 males and 571 females aged 20-79 years old. The serum total cholesterol (TC) of less than 160 mg/dl was defined as low cholesterol, which accounted for 18% of the subjects. The multivariate odds ratio of having low cholesterol adjusted for age and selected variables were 0.70 (95% Cl: 0.52-0.94) for 1SD increment of Key's lipid factor, 0.71 (0.51-0.97) for 1SD increment of vitamin A intake, 2.23 (1.01-4.91) for heavy drinking, 2.80 (1.21-6.46) for being underweight and 2.59 (1.01-6.61) for blood transfusion in males, and 1.04 (1.00-1.08) for 10 cigarette-year increase in smoking in females. Even when further adjusted for body mass index, these associations were still significant except for those who were underweight and had undergone blood transfusion in males. These findings may partly explain the excess mortality of the Japanese males with low serum TC.

A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen

Tanaka Taichiro, Okamura T., Miura K., Kadowaki T., Ueshima H., Nakagawa H., Hashimoto T.

Journal of Human Hypertension 16 （ 2 ） 97 - 103 2002年

ISSN 0950-9240

In order to estimate the salt and potassium intake in a population and to compare their annual trends, we developed a simple method to estimate population mean levels of 24-h urinary sodium (24HUNaV) and potassium (24HUKV) excretion from spot urine specimens collected at any time. Using 591 Japanese data items from the INTERSALT study as a gold standard, we developed formulas to estimate 24-h urinary creatinine (24HUCrV), 24HUNaV and 24HUKV using both spot and 24-h urine collection samples. To examine the accuracy of the formulas, we applied these equations to 513 external manual workers. The obtained formulas were as follows: (1) PRCr (mg/day) = -2.04 × age + 14.89 × weight (kg) + 16.14 × height (cm) - 2244.45; (2) estimated 24HUNaV (mEq/day) = 21.98 × XNa^0.392; (3) estimated 24HUKV (mEq/day) = 7.59 × XK^0.431; where PRCr = predicted value of 24HUCr, SUNa = Na concentration in the spot voiding urine, SUK = K concentration in the spot voiding urine, SUCr = creatinine concentration in the spot voiding urine, XNa (or XK) = SUNa (or SUK)/SUCr × PRCr. In the external group, there was a significant but small difference between the estimated and measured values in sodium (24.0 mmol/day) and potassium (3.8 mmol/day) excretion. In every quintile divided by the estimated 24HUNaV or 24HUKV, the measured values were parallel to the estimated values. In conclusion, although this method is not suitable for estimating individual Na and K excretion, these formulas are considered useful for estimating population mean levels of 24-h Na and K excretion, and are available for comparing different populations, as well as indicating annual trends of a particular population.

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Linoleic acid, other fatty acids, and the risk of stroke

Iso Hiroyasu, Sato Shinichi, Umemura Utako, Kudo Minako, Koike Kazuko, Kitamura Akihiko, Imano Hironori, Okamura Tomonori, Naito Yoshihiko, Shimamoto Takashi

Stroke 33 （ 8 ） 2086 - 2093 2002年

ISSN 0039-2499

Background and Purpose - The role of serum fatty acids as a risk factor for stroke and stroke subtypes is largely unknown. Methods -A prospective nested case-control study of Japanese 40 to 85 years of age was conducted through the use of frozen serum samples from 7450 participants in cardiovascular risk surveys collected from 1984 to 1989 for 1 community and 1989 to 1992 for the other 2 communities. By the end of 1998, we identified 197 incident strokes whose subtypes were confirmed by imaging studies. Three controls per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Results - Compared with controls, total (n=197), hemorrhagic (n=75), and ischemic (n=122) strokes had similar proportions of n3 polyunsaturated fatty acids, lower proportions of linoleic and arachidonic acids, and higher proportions of saturated and monosaturated acids, determined by gas chromatography. The multivariate odds ratios associated with a 1-SD increase in linoleic acid (5%) after adjustment for hypertension, diabetes, serum total cholesterol, and other cardiovascular risk factors were 0.72 [95% confidence interval (CI), 0.59 to 0.89] for total stroke, 0.66 (95% CI, 0.49 to 0.88) for ischemic stroke, 0.63 (95% CI, 0.46 to 0.88) for lacunar infarction, and 0.81 (95% CI, 0.59 to 1.12) for hemorrhagic stroke. The respective odds ratios for saturated fatty acids (4%) were 1.13 (95% CI, 1.05 to 1.65), 1.35 (95% CI, 1.01 to 1.79), 1.44 (95% CI, 1.03 to 2.01), and 1.21 (95% CI, 0.82 to 1.80). Further adjustment for other fatty acids attenuated these relations, but the relation between linoleic acid and risk of ischemic stroke remained statistically significant. Conclusions - A higher intake of linoleic acid may protect against ischemic stroke, possibly through potential mechanisms of decreased blood pressure, reduced platelet aggregation, and enhanced deformability of erythrocyte cells.

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Genetic variation in aldehyde dehydrogenase 2 and the effect of alcohol consumption on cholesterol levels

Nakamura Yasuyuki, Amamoto Kenji, Tamaki Shinji, Okamura Tomonori, Tsujita Yasuyuki, Ueno Yoshiki, Kita Yoshikuni, Kinoshita Masahiko, Ueshima Hirotsugu

Atherosclerosis 164 （ 1 ） 171 - 177 2002年

ISSN 0021-9150

Moderate drinkers with a defective alcohol dehydrogenase type 3 (ADH3) genotype have higher high-density lipoprotein (HDL) levels and a decreased risk of coronary artery disease (CAD). We examined the interaction between the aldehyde dehydrogenase type 2 (ALDH2), alcohol intake, and HDL levels in 826 men and 1295 women in a rural town in Japan. The ALDH2 genotype of each subject was determined by polymerase chain reaction (PCR) analysis. HDL was adjusted for the alcohol intake, age, body mass index, smoking status, total cholesterol, triglycerides and HbA1c levels. None of the subjects had a history or ECG suggestive of CAD. The proportions of ALDH2, *1/*1, *1/*2, and *2/*2 (defective homozygote) were 45.8, 46.0, and 8.2%, respectively, for men. Drinking more than two drinks daily was associated with lower HDL levels in men with the defective genotypes compared with men with a normal genotype (55.6±0.9 vs. 51.2±0.9 mg/dl, mean±S.E., P<0.0001). Also, drinking more than 0.5 drinks daily was not associated with beneficial effects on HDL levels in women with defective ALDH2 genotypes. Conclusions: Alcohol intake did not have beneficial effects on HDL levels in the defective ALDH2 genotype and may not protect against CAD in subjects with defective ALDH2 genotypes. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

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Estimated relative and absolute risk for cardiovascular disease according to alcohol consumption increase in Japanese general population

Okamura T., Hayakawa T., Kadowaki T., Amamoto K., Kita Y., Okayama A., Ueshima H.

Nihon Arukoru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 36 （ 6 ） 586 - 595 2001年12月

ISSN 1341-8963

To calculate the estimated relative and absolute risks for cardiovascular diseases according to alcohol consumption increase, we performed a cross-sectional study of men aged 40-79 years using the data from the National Survey of Circulatory Disorders 1990 in Japan. First, we investigated the association between alcohol intake and two types of biochemical variables: serum lipids and blood pressure, by using analysis of variance. Then, concerning the subjects aged 40-59 years, linear regression analyses between alcohol intake and these biochemical markers were done to calculate regression coefficients adjusted for confounding factors. Finally, we substituted these regression coefficients for previously reported regression coefficients in Cox proportional hazard models to calculate relative and absolute risks for coronary heart disease and stroke. Alcohol intake positively correlated to systolic and diastolic blood pressure (SBP and DBP) and high-density lipoprotein cholesterol (HDLC). However, there was no relation between alcohol intake and serum total cholesterol. Linear regression coefficients of SBP, DBP and HDLC were 2.25, 1.43, 2.70, respectively. We used two proportional hazard regression formulas of Japanese population: one for coronary disease (Circulation 89, 2533-39) and the other for stroke (NIPPON DATA80, a 14-year cohort study of randomly selected Japanese). The estimated relative risks of coronary heart disease and stroke were 0.89 and 1.06 for 1 "go" (23 g of ethanol) increment of alcohol intake. The results indicate that the mortality rates shift from 0.44 to 0.39 per 1,000 person-years for coronary heart disease and from 0.76 to 0.81 per 1,000 person-years for stroke in the representative Japanese population aged 40-59 years. The absolute risk of cardiovascular disease may be unchanged if we assume 23 g increment of ethanol intake in Japan because the risk reduction in coronary heart disease was nearly equal to the risk increment in stroke.

Serum triglycerides and risk of coronary heart disease among Japanese men and women

Iso Hiroyasu, Naito Yoshihiko, Sato Shinichi, Kitamura Akihiko, Okamura Tomonori, Sankai Tomoko, Shimamoto Takashi, Iida Minoru, Komachi Yoshio

American Journal of Epidemiology 153 （ 5 ） 490 - 499 2001年03月

ISSN 0002-9262

To examine the relation of triglycerides with coronary heart disease among populations with low mean total cholesterol, the authors conducted a 15.5-year prospective study ending in 1997 of 11,068 Japanese aged 40-69 years (4,452 men and 6,616 women with mean total cholesterol = 4.73 mmol/liter and 5.03 mmol/liter, respectively), initially free of coronary heart disease or stroke. There were 236 coronary heart disease events comprising 133 myocardial infarctions, 68 angina pectoris events, and 44 sudden cardiac deaths. The coronary heart disease incidence was greater in a dose-response manner across increasing quartiles of nonfasting triglycerides for both sexes. The multivariate relative risk of coronary heart disease adjusting for coronary risk factors and time since last meal associated with a 1-mmol/liter increase in triglycerides was 1.29 (95% confidence interval (Cl): 1.09, 1.53; p = 0.004) for men and 1.42 (95% Cl: 1.15, 1.75; p = 0.001) for women. The trend was similar for myocardial infarction, angina pectoris, and sudden cardiac death. The relation of triglycerides with coronary heart disease was not influenced materially by total cholesterol levels or, in a subsample analysis (51% of total sample), by high density lipoprotein cholesterol levels. Nonfasting serum triglycerides predict the incidence of coronary heart disease among Japanese men and women who possess low mean values of total cholesterol. Further adjustment for high density lipoprotein cholesterol suggests an independent role of triglycerides on the coronary heart disease risk.

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Lipid disorder and atherosclerosis caused by smoking

Kadowaki T., Okamura T., Ueshima H.

Nippon rinsho. Japanese journal of clinical medicine 59 Suppl 3 214 - 219 2001年

ISSN 0047-1852

A changing pattern of food frequency according to aging. A study in a rural cohort with 14-year follow-up

Iino M., Moriwake S., Okamura T., Sato S., Murayama M., Suzuki R., Terao A., Ishikawa Y., Kitamura A., Naito Y., Imano H., Nagano E., Nakagawa Y., Iida M.

[Nippon kōshū eisei zasshi] Japanese journal of public health 48 （ 1 ） 38 - 46 2001年

ISSN 0546-1766

Plasma fibrinogen and coronary heart disease in urban japanese

Sato Shinichi, Nakamura Masakazu, Iida Minoru, Naito Yoshihiko, Kitamura Akihiko, Okamura Tomonori, Nakagawa Yuko, Imano Hironori, Kiyama Masahiko, Iso Hiroyasu, Shimamoto Takashi, Komachi Yoshio

American Journal of Epidemiology 152 （ 5 ） 420 - 423 2000年09月

ISSN 0002-9262

There is little information on the relation of plasma fibrinogen concentration to the risk of coronary heart disease in Asians, including Japanese, whose plasma fibrinogen concentration has been reported to be low by Western standards. The authors conducted a prospective study with 4.8 years of follow-up of 11,977 men and women aged 21-89 years (mean value of fibrinogen = 267 mg/dl) living or working in Osaka, Japan, in 1990-1996 to examine the relation of plasma fibrinogen with the incidence of coronary heart disease (myocardial infarction and angina pectoris). Mean fibrinogen concentration was 293.6 mg/dl for men who developed coronary heart disease (n = 35) compared with 261.6 mg/dl for men free of coronary heart disease (n = 8,094; difference, p < 0.01), and 355.2 mg/dl for women who developed coronary heart disease (n = 6) compared with 276.8 mg/dl for women free of coronary heart disease (n = 3,842; difference, p < 0.01). With a Cox proportional hazards model to adjust for cardiovascular risk factors, the relative risk for the highest fibrinogen quartile (≥295 mg/dl) compared with the lowest (<228 mg/dl) was 4.8 (95% confidence interval: 1.4, 16.8, p = 0.01) for coronary heart disease, and 3.8 (95% confidence interval: 1.1, 13.4, p = 0.04) for myocardial infarction. Plasma fibrinogen is useful to predict the risk of coronary heart disease among urban Japanese, whose mean plasma fibrinogen is relatively low.

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Prospective study on alcohol intake and risk of subarachnoid hemorrhage among Japanese men and women

Sankai Tomoko, Iso Hiroyasu, Shimamoto Takashi, Kitamura Akihiko, Naito Yoshihiko, Sato Shinichi, Okamura Tomonori, Imano Hironori, Iida Minoru, Komachi Yoshio

Alcoholism: Clinical and Experimental Research 24 （ 3 ） 386 - 389 2000年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0145-6008

Background: Few prospective data are available to evaluate potential risk factors of subarachnoid hemorrhage among the Japanese, although several prospective studies conducted in the United States and in Europe have shown a positive relationship between alcohol intake and the risk of subarachnoid hemorrhage. Methods: A 9.4 year follow-up study was conducted on 12,372 men and women age 40 to 69 years who had no history of stroke, in six communities in Japan. The incident cases of subarachnoid hemorrhage were confirmed with computed tomography findings and/or clinical findings. Alcohol intake and other cerebrovascular risk factors were measured at the baseline examination. A Cox proportional hazard analysis was used to estimate the relative risks and 95% confidence intervals of the incidence of subarachnoid hemorrhage. Results: During the follow-up assessment, 71 cases of subarachnoid hemorrhages occurred. For men, heavy drinking appeared to be an independent risk factor for subarachnoid hemorrhage; multivariate-adjusted relative risk was 4.3 (95% confidence interval [CI]: 1.1-16.8;p = 0.04). Among women, no excess risk was found for heavy drinking, probably due to the small number of heavy drinkers (n = 15). The combination of heavy drinking with smoking or hypertension increased the risk of subarachnoid hemorrhage substantially for men; the multivariate-adjusted relative risk was 6.0 (95% CI: 1.8-20.1;p = 0.004) for heavy drinking smokers and 13.0 (95% CI: 3.9-43.9; p < 0.001) for heavy drinking hypertensives. Conclusions: A reduction in alcohol intake, smoking cessation, and control of hypertension are important in preventing subarachnoid hemorrhage among Japanese men.

Validity and reliability of the japanese version of the selected anger expression scale and age, sex, occupation and regional differences in anger expression among Japanese

Ohira Tetsuya, Iso Hiroyasu, Tanigawa Takeshi, Sankai Tomoko, Imano Hironori, Okamura Tomonori, Kiyama Masahiko, Kitamura Akihiko, Nakagawa Yuko, Sato Shinichi, Naito Yoshihiko, Lida Minoru, Shimamoto Takashi

Journal of Epidemiology 10 （ 2 ） 118 - 123 2000年

ISSN 0917-5040

To examine the reliability and construct validity of the Japanese version of the Anger Expression Scale among four Japanese communities, and to examine distributions of anger expression scores according to sex, age, occupation, and community, we performed a crosssectional study among 1,802 men and 3,229 women aged 20-70 in four geographic populations in 1995-97. We handed a self-administered questionnaire, which was selected from the Spielberger Anger Expression Scale, to the participants in the risk factor surveys and measured anger-in and anger-out as the anger expression scale. These scales had high internal consistency (Cronbach's alpha coefficient was 0.97-0.98 for anger-out and 0.77-0.86 for angerin) and were of almost the same structure as the original. The Pearson correlation coefficients for the anger expression scale examined in 1995 and 1996 were 0.69 for anger-out and 0.57 for anger-in (both p<0.001). The mean scores of both anger-out and anger-in were inversely associated with age. The mean anger-out score was higher for men than for women (p<0.001), whereas the mean anger-in score did not vary significantly between the sexes. Furthermore, the mean scores of anger-out and anger-in varied among populations and occupational groups. The present study suggests that the Japanese version of the selected Anger Expression Scale is an acceptable scale for evaluatinq anger expression among Japanese.

質問紙調査による基本健康診査の受診に関連する要因の検討－社会的ネットワーク得点を含めた分析．

Okamura T., Suzuki R., Nakagawa Y., Terao A., Sato S., Kitamura A., Naito Y., Imano H., Tamura Y., Iida M., Komachi Y.

[Nippon kōshū eisei zasshi] Japanese journal of public health 46 （ 8 ） 616 - 623 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0546-1766

Since 1969, community-based stroke prevention programs have been conducted in N town, Kochi prefecture. To clarify factors related to participation in medical checkups including social networks, a cross-sectional questionnaire survey was performed on 6,704 residents aged 40 and over in N town in 1996. 1. Location of the workplace, types of medical insurance and interest in health were significantly associated with participation in medical checkups. 2. Participation in medical examinations provided at the workplace was significantly, inversely related with participation rates in community checkups in the group aged 40 to 59 years. 3. Low independence level in daily activities was inversely associated with participation rates for medical checkups in groups aged 60 years and older. 4. Visiting medical facilities was inversely associated with the participation rate for medical checkups in female groups. 5. The group with the highest social networks score (5 points) had the highest participation rate for medical checkups. After adjusting for other participation related factors, social networks scores had a significantly positive association with the participation rate for medical checkups provided by the Health Services for the Elderly Act.

Plasma level of homocysteine is correlated to extracranial carotid- artery atherosclerosis in non-hypertensive Japanese

Okamura Tomonori, Kitamura Akihiko, Moriyama Yuri, Imano Hironori, Sato Shinichi, Terao Atushi, Naito Yoshihiko, Nakagawa Yuko, Kiyama Masahiko, Tamura Yoshitaka, Iida Minoru, Suzuki Hideyoshi, Komachi Yoshio

Journal of Cardiovascular Risk 6 （ 6 ） 371 - 377 1999年

研究論文（学術雑誌）, 共著, ISSN 1350-6277

Background: Results of some epidemiologic studies in Western countries have clarified that hyperhomocysteinemia is a plausible risk factor for atherosclerotic vascular disease, but its role in Japanese communities is not known. Design: A community-based cross-sectional design. Methods: We performed a cross-sectional study of 474 elderly men aged 60-74 years in two Japanese rural communities (Noichi in southwestern Japan and Ikawa in northeastern Japan). We examined the association between plasma concentrations of homocysteine and the maximum intima-media thickness (assessed by ultrasonography). Results: The prevalence of thickening was 10.7% for the lowest fertile of homocysteine level and 21.1% for the highest fertile. For the subjects without hypertension, the odds ratio for having carotid intima-media thickening was 5.8; it was significantly higher for the highest fertile of homocysteine level than it was for the lowest after adjusting for age, hypercholesterolemia, hypoalphalipoproteinemia, diabetes, and smoking by using a multiple logistic regression model. However, its correlation was not evident for those with hypertension. Conclusions: High levels of plasma homocysteine are correlated to extracranial carotid artery atherosclerosis in elderly men without hypertension in Japanese rural communities.

Cohort study on risk factors for subarachnoid hemorrhage among Japanese men and women

Sankai Tomoko, Iso Hiroyasu, Shimamoto Takashi, Kitamura Akihiko, Naito Yoshihiko, Sato Shinichi, Okamura Tomonori, Imano Hironori, Iida Minoru, Komachi Yoshio

Japanese Journal of Hygiene 53 （ 4 ） 587 - 595 1999年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-5082

Purpose: To examine the risk factors for subarachnoid hemorrhage, for few prospective data have been available on risk factors of subarachnoid hemorrhage among Japanese. Methods: A 9.4-year cohort study was conducted on 12,372 men and women, aged 40-69 years, free of history of stroke in six communities in Japan. Results: During the follow-up, seventy-one incidents of subarachnoid hemorrhage occurred. After adjusting for age, serum total cholesterol, body mass index, history of diabetes mellitus, blood pressure category and drinking category, current smokers had a significantly increased risk of subarachnoid hemorrhage compared with 'never-smokers': multivariate relative risk (RR) [95% confidence interval (95%CI)] = 3.1(1.4-6.9) for women, 1.5(0.4-5.3) for men and 2.7(1.3-5.5) for men and women. Hypertensives had a significantly increased risk of subarachnoid hemorrhage compared with normotensives: multivariate RR(95%CI) = 3.1(1.6-6.0) for women, 4.3(1.5- 12.0) for men and 3.4(2.0-5.9) for men and women. For men, heavy drinkers (>=69 g per day ethanol), had a significantly increased risk of subarachnoid hemorrhage compared with 'never-drinkers': multivariate RR(95%CI) = 4.3(1.1- 16.8). For women, the relationship between heavy drinking and risk was not examined due to the small number of heavy drinkers (n=13). Multivariate RR(95%CI) for men who smoked currently and drank heavily compared with men who did not smoke currently nor drink heavily was 6.0(1.8-20.1). Multivariate RR(95%CI) for hypertensive men who drank heavily compared with normotensive or borderline hypertensive men who did not drink heavily was 13.0(3.9-43.9). Multivariate RR(95%CI) for hypertensive men and women who smoked currently compared with normotensive or borderline hypertensive men and women who did not smoke currently was 6.1(1.3-28.7) for men and 6.3(1.4-28.0) for women. Furthermore, the combination of smoking, hypertension and heavy drinking raised the risk of subarachnoid hemorrhage substantially: multivariate RR(95%CI) = 17.5(3.4-90.2). Conclusion: Smoking and hypertension appeared to increase the risk of subarachnoid hemorrhage. For men, although the association of smoking with the risk of subarachnoid hemorrhage was weak compared with women, the combination of smoking, hypertension and heavy drinking increased the risk substantially. For women, smoking appeared to be an independent risk of subarachnoid hemorrhage, and the combination of smoking and hypertension increased the risk in additive fashion.

都市部における脳卒中患者の退院時登録と地域ケアへの展開－退院時の生存状況・後遺症・日常生活動作能力等に関する調査研究．

Kitamura A., Iida M., Nakagawa Y., Kiyama M., Sato S., Okamura T., Naito Y., Imano H., Yamane N., Ootsuka J., Yamamoto R., Matsumura K., Kijima H., Komachi Y.

[Nippon kōshū eisei zasshi] Japanese journal of public health 45 （ 8 ） 740 - 748 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0546-1766

The purpose of this study was to obtain the overall characteristics and outcome in stroke patients in an urban area of Japan, in order to develop some strategies for a community-based care system for improvement of the prognosis and activities of daily life in stroke patients. The present study, based on 4 hospitals in Yao city in Osaka, showed results as follows: 1) The number of stroke patients discharged from 4 hospitals during a recent one year period was 377 (216 men and 161 women). 2) The proportion of patients who died was 27%. Of the living patients, the proportions of patients who had motor paralysis or speech disturbance at discharge were 54% and 27%, respectively. 3) The proportion of patients who were to return to their home was 77% for all living patients. The proportion of patients who were not able to walk by themselves, or needed assistance in at least one of the activities of daily life was 31% and 28%, respectively, for all living patients who were to return to their home. This study showed that stroke registry from major hospitals in an urban area is useful for obtaining the overall characteristics of stroke patients in the area and promote community-wide programs in the prevention and home care of stroke.

地域住民における血小板凝集能と身体・生活要因との関連．

Imano H., Iso H., Tanigawa T., Sankai T., Ohira T., Kudo M., Shimamoto T., Sato S., Okamura T., Iida M.

[Nippon kōshū eisei zasshi] Japanese journal of public health 45 （ 6 ） 536 - 551 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0546-1766

To investigate the contribution of the platelet aggregation in the development of cardiovascular diseases, we examined the relation of constitutional and lifestyle variables with platelet aggregation for a total of 306 males aged 50 to 70 in Ikawa town, Akita prefecture (n = 163) and Noichi town, Kochi prefecture (n = 143). The examination of platelet aggregation was completed within 3 hours of obtaining blood samples. We used ADP (Adenosine 5'-diphosphate) as an agonist and obtained PATI (the platelet aggregatory threshold index) by nephelometry. Platelet count, mean platelet volume, white blood cell count, serum fatty acid compositions were also examined and dietary intake of fish, seafood and soy bean foods were inquired using one-week dietary records. PATI indicated a logarithmic normal distribution in both Ikawa and Noichi. The mean of logarithmic transformed PATI (log PATI) was higher in Ikawa than in Noichi. Thus platelet aggregation was lower in Ikawa than in Noichi. According to multiple regression analysis, age, platelet count in platelet rich plasma, mean platelet volume in platelet rich plasma, and white blood cell count were inversely associated with log PATI. Serum arachidonic acid composition tended to be inversely related with log PATI. Serum n3-polyunsaturated fatty acid composition was positively related with log PATI, and log gamma-GTP tended to be positively associated with log PATI. Soy protein intake and cigarette smoking showed no consistent associations with log PATI. This cross-sectional study suggests that serum n3-polyunsaturated fatty acid, and gamma-GTP, as an index of alcohol intake, reduce platelet aggregation while age, white blood cell count, platelet count, mean platelet volume, and serum arachidonic acid raise platelet aggregation.

A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency

Moriyama Yuri, Okamura Tomonori, Inazu Akihiro, Doi Mitsunori, Iso Hiroyasu, Mouri Yoshitaka, Ishikawa Yoshinori, Suzuki Hideyoshi, Iida Minoru, Koizumi Junji, Mabuchi Hiroshi, Komachi Yoshio

Preventive Medicine 27 （ 5 I ） 659 - 667 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0091-7435

Background. Use of genetic analysis may improve the predictive value of risk factors for disease. A high plasma level of high-density lipoprotein (HDL) cholesterol is a strong negative risk factor for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) deficiency causes increased levels of HDL cholesterol. However, recent studies suggest that CETP deficiency is a risk factor for CHD despite elevated HDL cholesterol levels. Methods. Plasma lipid levels, CHD prevalence, resting electrocardiograms, and common CETP gene mutations were analyzed cross-sectionally in a population of 19,044 male and 29,487 female Japanese subjects (ages 45-79 years). Results. High HDL cholesterol levels (serum HDL cholesterol ≤80 mg/dl, ≤95th percentile) were found in 6 and 5% of Japanese men and women, respectively. In the group with HDL cholesterol ≤80 mg/dl, common CETP gene mutations were identified in 23-24% of men and 31-49% of women. The prevalence of CHD in the group with high HDL cholesterol (≤80 mg/dl) was low among both men (1.0%) and women (1.3%). There was no difference in CHD prevalence between hyper- HDL-cholesterolemic subjects with and without CETP mutations. Conclusions. Subjects with very high HDL levels (HDL cholesterol ≤80 mg/dl) as well as mild-to-moderate HDL elevations (60-79 mg/dl) appear to be protected against CHD, whether or not they have CETP deficiency, a genetic cause of elevated HDL.

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Alcohol intake and premature coronary heart disease in urban Japanese men

Kitamura Akihiko, Iso Hiroyasu, Sankai Tomoko, Naito Yoshihiko, Sato Shinichi, Kiyama Masahiko, Okamura Tomonori, Nakagawa Yuko, Iida Minoru, Shimamoto Takashi, Komachi Yoshio

American Journal of Epidemiology 147 （ 1 ） 59 - 65 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0002-9262

To examine the relation between alcohol intake and the incidence of coronary heart disease among Japanese, the authors analyzed data from a prospective study of 8,476 Japanese male employees, who were 40-59 years old at baseline (between 1975 and 1984) and worked for 13 urban companies in Osaka, Japan. These men were followed until the end of 1993, on average, an 8.8-year follow-up. Eighty-three coronary heart disease events (54 myocardial infarction, 32 angina pectoris) occurred during the employment period under study. Compared with the risk of coronary heart disease for never drinkers, the age-adjusted relative risk for those with an increased ethanol intake was lower, but the risk did not appear to be reduced further with the intake of ≤69 g of ethanol per day. The multivariate relative risk adjusted for age, serum total cholesterol, cigarette smoking, body mass index, left ventricular hypertrophy, and a history of diabetes mellitus was 0.83 (95% confidence interval (CI) 0.24-2.86) in exdrinkers, 0.69 (95% CI 0.37-1.29) in drinkers of 1-22 g/day of ethanol, 0.55 (95% CI 0.29-1.05) in drinkers of 23-45 g/day, 0.41 (95% CI 0.19-0.88) in drinkers of 46-68 g/day, and 0.59 (95% CI 0.23- 1.51) in drinkers of ≤69 g/day. The inverse association with alcohol intake was similar between myocardial infarction and angina pectoris. Alcohol intake seemed to prevent the premature incidence of coronary heart disease among urban Japanese middle-aged men.

脳卒中の生命予後、機能予後に関する疫学的研究－CT所見を中心とした分類を用いた検討．

Sankai T., Iso H., Imano H., Ohira T., Tanigawa T., Shimamoto T., Kitamura A., Sato S., Naito Y., Kiyama M., Okamura T., Nakagawa Y., Iida M., Komachi Y.

[Nippon kōshū eisei zasshi] Japanese journal of public health 45 （ 6 ） 552 - 563 1998年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0546-1766

PURPOSE: We conducted an epidemiological study of survival and disability in stroke in three Japanese communities to seek community strategies for improvement in survival and disability. METHODS: A total of 297 first-ever strokes were identified between 1988 and 1992 in three rural communities (total population = 47,000) located in Akita and Ibaraki. We analyzed survival rates and activity of daily living by sex, age-group and stroke subtypes. Successful review of computed tomography (CT) for 84 percent of the strokes (249 out of 297) was possible and the data were used for subtype analyses. RESULTS: For all strokes (n = 297) survival rates were 85% for 30 day, 70% for one year, 62% for three year. The rates tended to be lower in women than in men. The rates were lowest in ages less than 60 at thirty day, and in ages 80 and older at the end of the first and third year. Intracerebral hemorrhage with ventricular rupture, subarachnoid hemorrhage and cortical cerebral infarction had lower survival rates than intracerebral hemorrhage without ventricular rupture and lacunar infarction. Based on Cox's proportional hazard model, risk ratio for death was 2.07 in ages 70-79, and 3.80 in ages 80 and older compared with ages 60-69. The risk ratio was 3.46 for intracerebral hemorrhage with ventricular rupture, 3.38 for subarachnoid hemorrhage and 2.46 for cortical cerebral infarction compared with lacunar infarction. The proportion of stroke survivors who need assistance from others in the first and third years tended to be higher in women than in men. The proportion was higher in older patients than in the younger, and higher for intracerebral hemorrhage with ventricular rupture and cortical cerebral infarction than in other subtypes of stroke. From logistic regression analysis, the odds ratio for disability in the first year was 6.55 for ages 80 and older compared with ages 60-69. The odds ratio was 5.61 for intracerebral hemorrhage with ventricular rupture, 4.53 for cortical cerebral infarction compared with lacunar infarction. In the third year the odds ratio was significant for ages 70-79, and decreased for intracerebral hemorrhage with ventricular rupture (odds ratio = 2.98), and increased for cortical cerebral infarction (odds ratio = 6.06). CONCLUSIONS: Survival and disability in stroke depended on age and stroke subtypes. Even after age adjustment, stroke subtypes with large cerebral involvement had worse prognosis than stroke subtypes. Community-based hypertension control programs are important to prevent any subtypes of stroke. Stroke subtypes as well as age should be taken into account to develop effective care and medical treatments for strokes.

地域，職域におけるアルコール摂取と身体所見の関連についての疫学的検討．

Kitamura A., Iso H., Sato S., Iida M., Naito Y., Kiyama M., Okamura T., Nakagawa Y., Shimamoto T., Sankai T., Imano H., Komachi Y.

[Nippon kōshū eisei zasshi] Japanese journal of public health 43 （ 2 ） 86 - 101 1996年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0546-1766

To investigate associations of alcohol intake to constitutional and biochemical variables, cross-sectional studies of men aged 40-59 years from six geographical and occupational populations with varied lifestyles were conducted in the 1990's. Systolic and diastolic blood pressures, glutamic oxaloacetic transaminase, gamma glutamyl transpeptidase, HDL-cholesterol, and uric acid were linearly associated with alcohol intake in all six populations. Drinkers of 2+ drinks (46 g ethanol or more) per day showed higher levels of triglyceride, glutamic pyruvic transaminase than never-drinkers. In two urban occupational populations, men who mainly drank beer had higher uric acid levels; men mainly drinking sake had higher blood pressures and lower serum total cholesterol; men mainly drinking whiskey had higher obesity indices. These differences in constitutional and biochemical variables related to type of alcoholic beverage consumed may be due to differences in lifestyles such as diet and physical activity.

老人保健事業における機能訓練事業参加者の実態と日常生活自立度に関する研究．

Okamura T., Nakagawa Y., Ishikawa Y., Kitamura A., Kiyama M., Sato S., Naito Y., Iida M., Iso H., Shimamoto T.

[Nippon kōshū eisei zasshi] Japanese journal of public health 42 （ 10 ） 878 - 887 1995年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0546-1766

To clarify characteristics of participants in community-based rehabilitation programs provided by local municipalities (cities, towns, and villages) and effect of the program on their levels of independence in activities of daily living (ADL), a cross-sectional study was performed on 422 participants in 49 municipalities in Kochi Prefecture. 1. Mean age of participants was 68.3 +/- 9.0, and 77.7% of them were stroke patients. 2. The mean interval between disease onset and program participation was 40.4 months, and the mean duration of program participation was 54.5 months. 3. At the start of rehabilitation programs and at the time of the investigation (December 1993), about 90% of the participants had good levels of independence in ADL (Rank A and over according to the standard of the Ministry of Health and Welfare). 4. The frequency of rehabilitation programs and the presence of occupational therapists were positively associated with the improvement of levels of independence in ADL. In particular, the frequency of rehabilitation programs was associated with improvement of quality of life in self-supporting participants (Rank J2), and the presence of occupational therapists was associated with the improvement of ADL in semi-bed-ridden participants (Rank A). 5. After adjusting for age and sex, using multiple logistic regression analysis, type of diseases (non-stroke), hospital rehabilitation immediately after onset, higher levels of independence in ADL at the start of rehabilitation programs, and higher frequency of rehabilitation programs were significantly associated with improvements in levels of independence in ADL. Shorter interval between disease onset and program participation, and the presence of occupational therapists were also associated with improvements in levels of independence in ADL, although the relation did not reach statistical significance.

入院受療率に関連する家族要因－高知県と島根県の比較と高知県N町における検討．

Okamura T., Iida M., Tanigaki M., Doi M., Iso H., Shimamoto T., Komachi Y.

[Nippon koshu eisei zasshi] Japanese journal of public health 41 （ 4 ） 352 - 361 1994年04月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0546-1766

Kochi Prefecture had a higher admission rate for patients with cardiovascular disease, particularly for stroke, than Shimane Prefecture which has a similar socio-economic level. Kochi Prefecture had a smaller average number of persons in a household, a lower proportion of three generation households, and a lower proportion of households with six persons or more than Shimane Prefecture. The decline in number of persons in a household was greater in Kochi Prefecture than in Shimane Prefecture from 1960 to 1985, especially between 1970 and 1975. The association between family make-up and hospital discharge one year after stroke was examined in a rural community in Kochi Prefecture. Two hundred forty nine patients aged 40 years and older who were admitted immediately after stroke events were registered between 1969 and 1988, and they were followed for one year. According to family make-up, the subjects were divided into four groups: 1) persons who lived with spouse and daughter-in-law, 2) persons who lived with spouse, 3) persons who lived with daughter-in-law, 4) persons who lived without spouse and daughter-in-law. Although mean age and the proportion of serious cases were not different between group 1 and group 4, the proportion of admitted patients of group 1 was significantly lower than that of group 4. About 60% of group 1 had households with six persons or more. Group 2 had the lowest proportion of admitted patients, but this group was significantly younger than other groups. Within group 3, the proportion of admitted patients was higher in households in which the daughter-in-law had a job than in households in which she did not. These results suggest that the high admission rate in Kochi Prefecture is attributable to households which are short of personnel for home care.

長期的な予防対策を実施した地域における脳卒中発生状況と予後の推移に関する研究

Okamura T.

[Nippon koshu eisei zasshi] Japanese journal of public health 41 （ 1 ） 56 - 66 1994年01月

研究論文（学術雑誌）, 単著, 査読有り, ISSN 0546-1766

Trends for stroke incidence and prognosis were investigated in a southwest rural town in Japan, where a community-based stroke prevention program has been conducted since 1969. Four hundred forty-nine stroke patients aged 40 years and older were registered from 1969 to 1988. From among these, 405 (90%) were followed for 3 years to examine prognosis. 1. Age-adjusted stroke incidence in each 5 year interval decreased from 1969 to 1988 with stroke incidence decreasing in almost all age groups 40 years and older for both men and women. A small increase in incidence was observed for women aged 70 years and older between 1979-1983 and 1984-1988. 2. While there was a 46% increase in the population aged 40 years and older, the number of stroke patients decreased between 1969-1973 and 1984-1988. 3. Mortality rates between one week and three years after a stroke have shown a decrease from 1969-1978 to 1979-1988. The proportion of those not requiring nursing care between one week years after stroke has increased. The proportion of all patients requiring nursing care however did not change. 4. After adjusting for age, sex, type of stroke, and loss of consciousness, the blood pressure level within 5 years prior to the stroke was positively associated with death between one week and three years after the event, and was negatively associated with the proportion of those not requiring nursing care. 5. Despite a 31% increase in the census population of all ages between 1969-1978 and 1979-1988, the number of those requiring nursing care has increased only 6% at one year after stroke. If the population had remained constant, the number of those requiring nursing care would have decreased by 10% at one year after the event. These results suggest that a long-term community-based stroke prevention program can decrease both the number of those requiring nursing care and mortality after stroke, as well as stroke incidence and the number of stroke patients.

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