Search

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.

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.

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 ≥3 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.

Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

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.

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., (© 2023 European Academy of Neurology.)

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.

Aims: The 2021 European Society of Cardiology (ESC) guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, systemic coronary risk estimation 2 (SCORE2) and systemic coronary risk estimation 2 in older persons (SCORE2-OP), to predict CVD risk. We developed and validated an 'Add-on' to incorporate CKD measures into these algorithms, using a validated approach., Methods: In 3,054 840 participants from 34 datasets, we developed three Add-ons [eGFR only, eGFR + urinary albumin-to-creatinine ratio (ACR) (the primary Add-on), and eGFR + dipstick proteinuria] for SCORE2 and SCORE2-OP. We validated C-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997 719 participants from 34 different datasets., Results: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved C-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57 485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI [e.g. 0.100 (0.062-0.138) for SCORE2] compared to the qualitative approach in the ESC guideline., Conclusion: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD., Competing Interests: Conflict of interest: Ku.M. reports grants from NIDDK; grants and personal fees from Kyowa Kirin, personal fees from Akebia outside the submitted work. M.G. reports grants from NIH and National Kidney Foundation outside the submitted work. J.A. reports personal fees from AstraZeneca, Novartis, and Boerhinger Ingelheim outside the submitted work. A.R.C. reports personal fees from Novartis, Reata, and Amgen; grants from Novo Nordisk outside the submitted work. N.E. reports personal fees from Bayer and AG Leverkusen outside the submitted work. K.E. reports grants from Amgen, Astra Zenceca, Bayer, Evotec, and Vifor; personal fees from Akebia, Astra Zeneca, Bayer, Otsuka, and Retrophin outside the submitted work. S.K.J reports salary support from US Government and Department of Veterans Affairs during the conduct of the study. C.K. reports personal fees from Bayer, Abbott, Astra-Zeneca, Takeda, Tricida, Akebia, Cara Therapeutics, Vifor, Rockwell, CSL Behring, Reata, Boehringer Ingelheim, and GSK outside the submitted work. A.S.L. reports grants and contracts from NIH and NKF for studies in CKD and a contract from AstraZeneca for DSMB for clinical trials of dapagliflozin. Ka.M. reports grants from Ministry of Health, Labor, and Welfare, Japan. G.N.N reports personal fees from Renalytix, Daiichi Sankyo, Menarini Medical, Qiming Capital, and Variant Bio; other fees from Pensieve Health, Nexus I Connect outside the submitted work; patent KidneyIntelX pending to Renalytix. M.G.S. reports grants from NIH- NIA/NIDDK/NHLBI during the conduct of the study; personal fees from Cricket Health, Intercept Pharmaceuticals, Bayer Pharmaceuticals, AztraZeneca, Boeringer Ingelheim; grants from Bayer Pharmaceuticals outside the submitted work. M.D.S reports a honoraria from AstraZeneca outside the submitted work. N.S. is a current employee of GSK and employed at AMGA. M.W. reports personal fees from Amgen and Freeline outside the submitted work. J.C. reports grants from National Institute of Health and National Kidney Foundation, during the conduct of the study; personal fees from Healthy.io and SomaLogic outside the submitted work. No other potential conflicts of interest relevant to this article were reported. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Equol is an isoflavone (ISF)-derived metabolite by the gut microbiome in certain individuals termed equol-producers (EP). Equol might be the critical anti-atherogenic component of ISFs. In a population-based study of 979 Japanese men aged 40-79 without cardiovascular (CVD) or chronic kidney disease, we measured the urinary levels of equol and ISFs. Aortic calcification (AC) in the entire aorta was assessed by electron-beam or multi-detector-row computed tomography. Subjects with log10 (urinary equol to daidzein concentration) > - 1.5 were classified as EP. EP was further classified as person with low- and high-equol. We analyzed the association between equol-producing status and AC presence, defined as AC score > 0, by the logistic regressions. We found that EP (50% of the sample) had significantly lower odds of AC presence (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.39, 0.98) compared to non-EP. This association was independent of CVD risk factors. For the dose-response association, compared to non-EP, subjects with low and high levels of equol had ORs of 0.51 (95% CI 0.30, 0.84) and 0.67 (95% CI 0.39, 1.14) after adjusting for major CVD risk factors (p for trend = 0.06). ISFs concentrations were not significantly associated with AC presence (OR: 1.18, 95% CI: 0.82, 1.69). In conclusion, EP had a significantly lower burden of AC than non-EP, while ISFs were not associated with AC presence in Japanese men aged 40-79 years., (© 2022. The Author(s).)

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.

Previous studies have reported that the number of pregnancies and childbirths affected the risk of cardiovascular diseases (CVDs). However, the influence of reproductive history on hypertension and obesity, which are important risk factors for CVDs, is still unclear. Moreover, this association may vary depending on menopausal status. We evaluated the association of reproductive history with hypertension and obesity using a large cross-sectional dataset from the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). At the baseline survey, physical data, blood samples, and self-reported health questionnaires were collected. Participants with insufficient data were excluded, and 24,558 women from eight study regions were included in this study. Logistic regression analysis was conducted to evaluate the association of reproductive history with hypertension and obesity using multivariable-adjusted odds ratios. In premenopausal women, childbirth showed a generally protective effect on hypertension but not on obesity. In postmenopausal women, childbirth was positively associated with obesity and hypertension but not with hypertension after adjusting for BMI. In conclusion, reproductive history was associated with hypertension and obesity in a large Japanese population, and this association differed between premenopausal and postmenopausal women., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background: High levels of participation in leisure-time and household physical activity lower the risk of cardiovascular disease (CVD), although it is unclear whether the number of activity types is related to new-onset CVD. We aimed to evaluate the effect of the amount of leisure-time physical activity and the number of types of leisure-time physical activities on the risk of CVD incidence., Methods: From 2002 to 2003, 3,741 participants without any history of CVD participated in the Takashima Study. Data on the amount of leisure-time and household physical activity and the types of leisure-time and household physical activity were obtained from a self-administered questionnaire. Hazard ratios for CVD (acute myocardial infarction and stroke) incidence (follow-up data from 2002 to 2013), according to the participation level and number of activity types, were calculated using Cox proportional hazards models., Results: The mean age of the subjects was 58.7 ± 13.1 years. During the mean follow-up period of 8.0 ± 1.1 years, 92 participants developed CVD. An inverse dose-response relationship was noted between the amount of leisure-time and household physical activity and CVD events. After adjusting for baseline characteristics, lifestyle-related diseases, and the amount of physical activity other than leisure-time and household, the risk of CVD onset was compared by dividing the participants into two groups by the level of participation; the highest activity group had an adjusted hazard ratio (95% confidence interval) of 0.40 (0.20-0.82) compared to the lowest activity group. Compared to participants who engaged in 0-1 type of activity, participants who engaged in two or more types of activities had a multivariable-adjusted hazard ratio (95% confidence interval) of 0.31 (0.12-0.79)., Conclusion: Increasing the amount of leisure-time and household physical activity and promoting engagement in two or more types of such activities may reduce the rate of CVD incidence in the Japanese general population., (© 2022. The Author(s).)

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.

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 meta-analyses. 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.

Background/objectives: Individual eating habits may be influenced by genetic factors, in addition to environmental factors. Previous studies suggested that adherence to Japanese food patterns was associated with a decreased risk of all-cause and cardiovascular disease mortality. We conducted a genome-wide association study (GWAS) in a Japanese population to find genetic variations that affect adherence to a Japanese food pattern., Subjects/methods: We analyzed GWAS data using 14,079 participants from the Japan Multi-Institutional Collaborative Cohort study. We made a Japanese food score based on six food groups. Association of the imputed variants with the Japanese food score was performed by linear regression analysis with adjustments for age, sex, total energy intake, alcohol intake (g/day), and principal components 1-10 omitting variants in the major histocompatibility region., Results: We found one SNP in the 14q11.2 locus that was significantly associated with the Japanese food score with P values <5 × 10 -8 . Functional annotation revealed that the expression levels of two genes (BCL2L2, SLC22A17) were significantly inversely associated with this SNP. These genes are known to be related to olfaction and obesity., Conclusion: We found a new SNP that was associated with the Japanese food score in a Japanese population. This SNP is inversely associated with genes link to olfaction and obesity.

Aims: P-wave terminal force in lead V 1 (PTFV 1 ) 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 PTFV 1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV 1 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 PTFV 1 . Participants with PTFV 1 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, PTFV 1 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, PTFV 1 was independently related to high BNP concentration. PTFV 1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.

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 2 . 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.

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.

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.

Background: Results from observational studies regarding associations between fish (including shellfish) intake and cardiovascular disease risk factors, including blood pressure (BP) and BMI, are inconsistent., Objective: To investigate associations of fish consumption and associated urinary metabolites with BP and BMI in free-living populations., Methods: We used cross-sectional data from the International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP), including 4680 men and women (40-59 y) from Japan, China, the United Kingdom, and United States. Dietary intakes were assessed by four 24-h dietary recalls and BP from 8 measurements. Urinary metabolites (2 timed 24-h urinary samples) associated with fish intake acquired from NMR spectroscopy were identified. Linear models were used to estimate BP and BMI differences across categories of intake and per 2 SD higher intake of fish and its biomarkers., Results: No significant associations were observed between fish intake and BP. There was a direct association with fish intake and BMI in the Japanese population sample (P trend = 0.03; fully adjusted model). In Japan, trimethylamine-N-oxide (TMAO) and taurine, respectively, demonstrated area under the receiver operating characteristic curve (AUC) values of 0.81 and 0.78 in discriminating high against low fish intake, whereas homarine (a metabolite found in shellfish muscle) demonstrated an AUC of 0.80 for high/nonshellfish intake. Direct associations were observed between urinary TMAO and BMI for all regions except Japan (P < 0.0001) and in Western populations between TMAO and BP (diastolic blood pressure: mean difference 1.28; 95% CI: 0.55, 2.02 mmHg; P = 0.0006, systolic blood pressure: mean difference 1.67; 95% CI: 0.60, 2.73 mmHg; P = 0.002)., Conclusions: Urinary TMAO showed a stronger association with fish intake in the Japanese compared with the Western population sample. Urinary TMAO was directly associated with BP in the Western but not the Japanese population sample. Associations between fish intake and its biomarkers and downstream associations with BP/BMI appear to be context specific. INTERMAP is registered at www.clinicaltrials.gov as NCT00005271., (Copyright © The Author(s) 2019.)

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.

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; P trend  = 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; P trend  = 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.

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.

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., (Copyright © 2019 Elsevier Inc. 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.

Aims: Calcification in the coronary and aortic arteries has been linked to cardiovascular morbidity and mortality. The pathophysiological influence of aortic artery calcification (AAC) differs from that of coronary artery calcification (CAC). We aimed to compare the relationships between CAC and AAC and cardiovascular disease (CVD) risk factors., Methods: We examined a random sample of 1035 Japanese men aged 40-79 years. CAC and AAC were measured by computed tomography and scored according to the Agatston method. Using a logistic regression, we calculated the odds ratio (OR) as being in the highest quintile (Q5) of the calcification score compared to the lower quintiles (Q1-Q4) per 1 standard deviation higher CVD risk factor. Models were simultaneously adjusted for age, body mass index (BMI), systolic blood pressure, smoking (pack-year), alcohol intake, hemoglobin A1c, uric acid, estimated glomerular filtration rate (eGFR), serum lipids, and C-reactive protein. Differences in ORs were investigated using a generalized estimating equation. We performed a multiple linear regression using log-transformed CAC and AAC values as dependent variables., Results: CAC and AAC were independently associated with age (OR, 95% CI: 2.30 [1.77-2.98] for CAC and 3.48 [2.57-4.73] for AAC), p for difference ＜0.001), systolic blood pressure (1.29 [1.08-1.53] and 1.28 [1.07-1.54], p for difference=0.270), and smoking (1.22, [1.04-1.43] and 1.34 [1.13-1.58]) p for difference=0.071). Alcohol correlated with AAC only (1.17 [0.97-1.41] for CAC and 1.42 [1.16-1.73] for AAC, p for difference= 0.020)., Conclusions: CAC and AAC were associated with similar CVD risk factors. The strength of association slightly differed between CAC and AAC.

To develop a risk chart or score that is based on recent data and applicable to the Japanese people, we need a large cohort study representative of the Japanese people without a need for long-term follow-up. The purpose of the present study was to develop a risk scoring system to estimate the 5- and 10-year absolute and cumulative incidence risk of stroke and acute myocardial infarction (AMI), composite outcome of stroke and AMI, and death from all cardiovascular disease (CVD). The cumulative incidence risk ratios were calculated using a multiple Poisson regression model and data from the Japan Arteriosclerosis Longitudinal Study, which included 67,969 men and women aged 40-89 years. An absolute risk scoring system for 5- and 10-year risk was developed. For blood pressure categories, the risk ratios for all outcomes increased from normal blood pressure (systolic blood pressure (SBP) 120-129 mmHg and diastolic blood pressure (DBP) 80-89 mmHg) to grade III hypertension (SBP ≥ 180 and/or DBP ≥ 110) based on the 2014 Guidelines for the Management of Hypertension compared to the reference optimal blood pressure (SBP < 120 and DBP < 80). Grade II (SBP 160-179 and/or DBP 100-109) and III hypertension treated with medication showed a lower risk compared to counterparts without medication. Other risk factors showed reasonable figures. The total of scores for each risk factor indicated the estimated absolute risk for stroke and AMI, the composite outcome of stroke and AMI, and all CVD. This scoring system may contribute to patient education and to the development of strategies for reducing CVD in the population.

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., (© 2019 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

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 three-day 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.

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.

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., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Aim: We investigated whether 2 types of personalized health guidance (repeated and single counseling) in the Japanese nationwide cardiovascular prevention system promoted smoking cessation among smokers., Methods: The study included 47,745 Japanese smokers aged 40 to 74 years classified into 2 personalized health guidance schemes. After a 1-year follow-up, we compared the rates of smoking cessation between individuals who had received counseling ("supported") and those who had not received counseling ("unsupported"). Using propensity score matching analysis, we estimated the average treatment effect (ATE) of each approach on smoking cessation after balancing out the characteristics between the supported and unsupported groups. The propensity score regression model included age, medical insurance type, weight gain since the age of 20 years, exercise, eating habits, alcohol intake, quality of sleep, readiness to modify lifestyle, willingness to receive support, and body mass index., Results: In the repeated counseling scheme, the age-adjusted rates of smoking cessation in the supported and unsupported groups were 8.8% and 6.3% for males, and 9.8% and 9.1% for females respectively. In the single counseling scheme, the corresponding rates were 8.4% and 7.3% for supported and unsupported males, and 11.0% and 11.7% for supported and unsupported females respectively. The ATE of repeated counseling was ＋2.64% (95% confidence interval: ＋1.51% to ＋3.77%) for males and ＋3.11% (－1.85% to ＋8.07%) for females. The ATE of single counseling was ＋0.61% (－1.17% to ＋2.38%) for males and －1.06% (－5.96% to ＋3.85%) for females., Conclusions: In the Japanese cardiovascular prevention system, repeated counseling may promote smoking cessation among male smokers.

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.

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.

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.

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.

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.

Atherosclerosis begins in early life and has a long latent period prior to onset of clinical disease. Measures of subclinical atherosclerosis, therefore, may have important implications for research and clinical practice of atherosclerotic cardiovascular disease (ASCVD). In this review, we focus on coronary artery calcium (CAC) and carotid artery intima-media thickness (cIMT) and plaque as many population-based studies have investigated these measures due to their non-invasive features and ease of administration. To date, a vast majority of studies have been conducted in the US and European countries, in which both CAC and cIMT/plaque have been shown to be associated with future risk of ASCVD, independent of conventional risk factors. Furthermore, these measures improve risk prediction when added to a global risk prediction model, such as the Framingham risk score. However, no clinical trial has assessed whether screening with CAC or cIMT/plaque will lead to improved clinical outcomes and healthcare costs. Interestingly, similar levels of CAC or cIMT/plaque among various regions and ethnic groups may in fact be associated with significantly different levels of absolute risk of ASCVD. Therefore, it remains to be determined whether measures of subclinical atherosclerosis improve risk prediction in non-US/European populations. Although CAC and cIMT/plaque are promising surrogates of ASCVD in research, we conclude that their use in clinical practice, especially as screening tools for primary prevention in asymptomatic adults, is premature due to many vagaries that remain to be clarified.

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., (Copyright © 2016. Production and hosting by Elsevier B.V.)

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 (R(2), 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 (R(2), 0.22, Chi-square value 0.749, p = 0.38) compared to women (R(2), 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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

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.

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/m(3) 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.

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.

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.