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Active cigarette smoking was intensively reported to increase the risk of aortic mortality while research on the association between smoking cessation and aortic mortality remains scarce. This study aimed to reconfirm the associations of exposure to cigarettes and smoking cessation associated with aortic mortality in a large Japanese population.In the Japan Collaborative Cohort (JACC) Study, 91,141 residents (57±10 years; men, 43%) who were free of stroke, coronary heart disease, and cancer were followed up from 1989-90 until 2009 during which 110 deaths from aortic dissection and 112 deaths from aneurysm were identified. Cox proportional hazard model was used to estimate multivariable hazard ratios (95%CI) for total and specific aortic mortality.Compared to never smoking, HRs for total aortic mortality were 2.39 (1.40-4.08) for ＜20, 3.57 (2.19-5.83)for 20-39, and 3.92 (2.37-6.48) for ≥ 40 pack-years exposure. Compared to current smoking, HRs for total aortic mortality were 0.42 (0.18-0.97) for 10-15 years, 0.27 (0.11-0.66) for ＞15 years of cessation, and 0.24 (0.13-0.44) for never smoking. Similar inverse dose-response pattern was observed between smoking cessation duration and risk of mortality from aortic aneurysm (p for trend=0.001), but the association with aortic dissection mortality did not reach statistical significance.Cigarette smoking was associated with an increased risk of aortic mortality while smoking cessation was so with a reduced risk among the Japanese population.

We aimed to examine the impact of overweight and obesity on mortality from nonrheumatic aortic valve disease.In the Japan Collaborative Cohort Study, we analyzed data of 98,378 participants aged 40-79 years, with no history of coronary heart disease, stroke, or cancer at baseline (1988-1990) and who completed a lifestyle questionnaire including height and body weight; they were followed for mortality until the end of 2009. The Cox proportional hazards model was used to calculate the multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) of nonrheumatic aortic valve disease mortality according to body mass index (BMI) after adjusting for potential confounding factors.During the median 19.2 years follow-up, 60 deaths from nonrheumatic aortic valve disease were reported. BMI was positively associated with the risk of mortality from nonrheumatic aortic valve disease; the multivariable HRs (95% CIs) were 0.90 (0.40-2.06) for persons with BMI ＜21 kg/mOverweight and obesity may be independent risk factors for nonrheumatic aortic valve disease mortality in Asian populations.

Aims Reports on the association between height and aortic disease have been modest, and there are only a few studies investigating the association between height and mortality from specific aortic disease types or by sex. Methods We conducted the Japan Collaborative Cohort Study, a prospective study of 99,067 Japanese (41,730 men and 57,337 women) aged 40-79 years old. Height was self-reported, and the participants were followed up from 1988-1989 to the end of 2009. Sex-specific hazard ratios (95% confidence intervals) of mortality from aortic disease type according to sex-specific quartiles of height were analyzed using the Cox proportional hazards model. Results During the median follow-up period of 19.1 years, the numbers of deaths due to aortic aneurysm, thoracic aortic aneurysm, abdominal aortic aneurysm, and aortic dissection were 87, 29, 48, and 56 among men and 35, 17, 15, and 65 among women, respectively. The sex-specific multivariate hazard ratios (95% confidence intervals) and p for trend for the highest versus lowest quartiles of height were 1.10 (0.66-1.83), p=0.58 among men and 1.54 (0.85-2.79), p=0.06 among women for total aortic disease; 1.85 (0.80-4.28), p=0.16 among men and 5.67 (0.90-35.77), p=0.08 among women for abdominal aortic aneurysm; and 1.13 (0.48-2.64), p=0.65 among men and 1.70 (0.82-3.50), p=0.04 among women for aortic dissection. The positive association was observed for both sexes, albeit more prominent among women. No association was found between height and mortality from thoracic aortic aneurysms. Conclusions As per our findings, we were able to determine that height was positively associated with mortality from abdominal aortic aneurysm in the Japanese population.

AIM Reports have shown that physical activity is inversely associated with heart failure risk, but evidence in Asian populations is lacking. We sought to examine the impacts of walking and sports participation on heart failure mortality among a Japanese population. METHODS We involved 36,223 Japanese men and 50,615 women (aged 40-79 years) who completed a self-administered questionnaire between 1988 and 1990. We divided participants into four categories of walking (＜0.5, 0.5, 0.6-1.0, and ≥ 1 h/day) and sports participation (＜1, 1-2, 3-4, and ≥ 5 h/week) and examined associations with activity and heart failure mortality through 2009. RESULTS We found inverse associations between physical activity and heart failure mortality. The multivariable hazard ratios (95% confidence intervals) for the highest category of walking time compared with the second-lowest category were 0.76 (0.59-0.99) in men and 0.78 (0.61-0.99) in women, while the ratios for the highest category of sports participation time compared with the second-lowest category were 0.62 (0.41-0.93) in men and 1.09 (0.73-1.65) in women. The lower hazard ratios in the highest categories of walking and sports participation time in men became no longer statistically significant after excluding heart failure deaths for the first 5, 10, and 15 years for walking time and 10 and 15 years for sports participation. However, in women, the low hazard ratios for the highest category ≥ 1.0 h/day of walking time did not change materially. CONCLUSIONS Physical activity was associated with a lower risk of mortality from heart failure in this Japanese community-based population. The attenuated and nonsignificant association of walking and sports participation with the risk in men after exclusion of first 5-15 years heart failure death was probably due to changes in physical activity and death certificate diagnosis during the follow-up and reverse causation. However, the persistent inverse association between walking and the risk in women suggests a beneficial preventive effect on heart failure.

Aim We aimed to examine the impact of high-risk levels of cardiovascular risk factors on the incidence of cardiovascular disease (CVD) in overweight and non-overweight individuals without treatment for the risk factors. Methods A total of 8,051 individuals aged 40-74 years without a history of CVD and/or without treatment for hypertension, diabetes, hyperlipidemia, and kidney disease at baseline in 1995-2000 were followed up for a median of 14.1 years. We classified the participants into three risk categories (low-, intermediate-, and high-risk groups) on the basis of individual risk factors (blood pressure, serum glucose, low-density lipoprotein cholesterol [LDL-C], and urinary protein) according to the guidelines of Japanese clinical societies. The high-risk group (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg, fasting serum glucose ≥ 130 mg/dL or non-fasting serum glucose ≥ 180 mg/dL, LDL-C ≥ 180 mg/dL, proteinuria ≥ 2+) needed to refer to physicians or start treatment immediately. Overweight was defined as a body mass index of ≥ 25 kg/m2. Results Compared with those in the non-overweight low-risk group, the hazard ratios (HRs) (95% confidence intervals, population-attributable fractions [PAFs]) of CVD in the high-risk categories of blood pressure were 2.0 (1.4-2.9, 7.0%) in the non-overweight high-risk group and 2.9 (1.9-4.3, 6.8%) in the overweight high-risk group. The corresponding HRs (95% confidence intervals, PAFs) of serum glucose were 2.0 (1.2-3.4, 2.5%) and 2.2 (1.1-4.3, 1.5%) in the non-overweight and overweight high-risk groups, respectively. Such associations were not observed for the high-risk group of LDL-C and proteinuria. Conclusions The present long-term observational study implies that targeting persons with non-treated severe hypertension and diabetes is prioritized to prevent CVD regardless of overweight status.

Aim Seaweed contains soluble dietary fibers, potassium, and flavonoids and was recently reported to be inversely associated with the risk of coronary heart disease and mortality from stroke. However, epidemiological evidence on this issue has remained scarce. Methods At the baseline survey of four Japanese communities between 1984 and 2000, we enrolled 6,169 men and women aged 40-79 years who had no history of cardiovascular disease. We assessed their seaweed intake using the data from a 24 h dietary recall survey and categorized the intake into four groups (0, 1-5.5, 5.5-15, and ≥ 15 g/day). We used sex-specific Cox proportional hazards models to examine the association between seaweed intake and risk of cardiovascular disease (stroke, stroke subtypes, and coronary heart disease). Results During the 130,248 person-year follow-up, 523 cases of cardiovascular disease occurred: 369 cases of stroke and 154 cases of coronary heart disease. Seaweed intake levels were inversely associated with the risk of total stroke and cerebral infarction among men but not among women. Adjustment for cardiovascular risk factors did not change the associations: the hazard ratios (95% confidence intervals; P for trend) for the highest versus lowest categories of seaweed intake were 0.63 (0.42-0.94; 0.01) for total stroke and 0.59 (0.36-0.97; 0.03) for cerebral infarction. No associations were observed between seaweed intake and risks of intraparenchymal hemorrhage, subarachnoid hemorrhage, or coronary heart disease among men or women. Conclusions We found an inverse association between seaweed intake and risk of total stroke, especially that from cerebral infarction, among Japanese men.

Aims Patients with chronic kidney disease (CKD) have a higher burden of cardiovascular morbidity and mortality than the general population. Endothelial dysfunction has been suggested to play a role in both glomerular filtration rate loss and cardiovascular damage. Thus, the present study aimed to evaluate the relationship between endothelial dysfunction and the prevalence of CKD in the general Japanese population. Methods We conducted a cross-sectional study of 1042 men and women aged 30-81 years in two communities under the Circulatory Risk in Communities Study between 2013 and 2017. Endothelial function was evaluated by percent change of brachial artery flow-mediated dilation (%FMD) before and after the cuff inflation. Results Among the total 1042 participants, there were 62 cases of CKD (~6%). The multivariable odds ratios (ORs) (95% confidence intervals [CIs]) of CKD according to quartiles of %FMD were 2.02 (0.68-5.99), 3.56 (1.27-9.94), and 3.14 (1.10-8.93) for the third to lowest quartile compared with the highest %FMD quartile; p for trend=0.02. The respective multivariable ORs (95% CIs) of CKD in subjects without antihypertensive medication use (39 cases among 886 subjects) were 1.83 (0.46-7.33), 3.41 (0.92-12.61), and 4.60 (1.22-17.31); p for trend=0.01, and that for one-point decrement in %FMD was 1.16 (1.00-1.35); p for interaction with the status of antihypertensive medication use was 0.12. Conclusions Our cross-sectional study suggested the relationship between endothelial dysfunction and the higher prevalence of CKD in the general Japanese population.

Aim The fact that low concentrations of high-density lipoprotein cholesterol are associated with the risk of cardiovascular disease is well known, but high-density lipoprotein metabolism has not been fully understood. Apolipoprotein A2 (ApoA2) is the second-most dominant apolipoprotein of high-density lipoprotein. We tested the hypothesis that ApoA2 isoforms are inversely associated with myocardial infarction. Methods We measured the plasma levels of three ApoA2 isoforms (ApoA2-ATQ/ATQ, ApoA2-ATQ/AT, ApoA2-AT/AT) in nested case-control study samples of 1:2 from the Japan Public Health-Center-based Study (JPHC Study): 106 myocardial infarction incidence cases and 212 controls. Results ApoA2-AT/AT was inversely associated with risk of myocardial infarction, in a matched model (OR, 2.78; 95% CI, 1.26-6.09 for lowest compared with the highest quartile), but its association was attenuated after adjustment for smoking only (OR=2.13; 95% CI, 0.91-4.97) or drinking only (OR=2.07; 0.91-4.74), and the multivariable OR was 1.20 (95% CI, 0.41-3.57). Neither ApoA2-ATQ/ATQ nor ApoA2-ATQ/AT was associated with the risk of myocardial infarction. Conclusions Our nested case-control study did not show a significant association of ApoA2 isoforms with a risk of myocardial infarction.

This study aimed to investigate whether the impact of body mass index (BMI) on the risk of cardiovascular disease (CVD) has changed among the 1960s, 1970s, 1980s, 1990s, and early 2000s in Japan.The study population consisted of residents in Japan aged 40-69 years who had no history of CVD. The baseline surveys have been conducted every year since 1963. We defined the first, second, third, fourth, and fifth cohorts as 1963-1969 (n=4,248), 1970-1979 (n=6,742), 1980-1989 (n=12,789), 1990-1999 (n=12,537), and 2000-2005 (n=9,140) respectively. The participants were followed up for a median of 15 years for each cohort to determine the incidence of CVD. We classified them into four categories (BMI ＜21.0, 21.0-＜23.0, 23.0-＜25.0, and ≥ 25.0 kg/mFrom 1963-1969 to 2000-2005, the prevalence of BMI ≥ 25.0 increased over time. Compared with BMI 23.0-＜25.0, the age-, sex- and community-adjusted hazard ratios (95% confidence interval [CIs]) of CVD for BMI ≥ 25.0 were 1.10 (0.77-1.57), 0.89 (0.68-1.18), 1.03 (0.85-1.26), 1.28 (1.04-1.58), and 1.36 (1.04-1.78)in the first, second, third, fourth, and fifth cohorts, respectively. The corresponding population attributable fractions were 2.0% (nonsignificant), -2.6% (nonsignificant), 0.9% (nonsignificant), 7.6%, and 10.9%. Further adjustment for systolic blood pressure and antihypertensive medication use in the fourth and fifth cohorts attenuated the associations, which may reflect that blood pressure may mediate the BMI-CVD association.The proportion of CVD attributable to overweight/obesity has increased during the periods between 1963-1969 and 2000-2005. The significant associations between overweight/obesity and risk of CVD after the 1990s were mediated by blood pressure levels.

The evidence for the impact of alcohol consumption on long-term mortality among myocardial infarction (MI) survivors was limited. We aimed to examine whether alcohol consumption was associated with cause-specific and all-cause mortality in men with or without a history of MI.A total of 32,004 men aged 40-79 years with no history of MI and 1,137 male MI survivors, free of stroke and cancer, were followed through the end of 2009. Alcohol consumption was assessed using self-administered questionnaires at baseline and five years.In MI survivors, consuming 23-45 g/day of alcohol was associated with a lower risk of coronary heart disease (CHD) mortality compared to never drinkers: the multivariable hazard ratio was 0.36 (95% confidence interval: 0.16-0.80). In non-MI men, a 10-26% lower risk was observed at ＜23 or 23-45 g/day with the U-shaped association for CHD, cardiovascular disease, other causes, and all causes (P-quadratic ＜0.001).Alcohol consumption of 23-45 g/day was associated with a lower CHD mortality in MI survivors as so in men without MI.

In this study, we aimed to evaluate the association between age at menarche and risk of cardiovascular disease mortality.In total, 54,937 women aged 40-79 years old between 1988 and 1990 without a history of cardiovascular disease were eligible for analysis and were followed through December 2009. We used the Cox proportional hazards models to examine the association between age at menarche and risk of cardiovascular disease.Compared with women with age at menarche of 15 years, the hazard ratios (95% confidence intervals) of stroke were 1.22 (0.85-1.75) for women with age at menarche of 9-12 years, 1.08 (0.85-1.36) for those of 13 years, 1.23 (1.02-1.47) for those of 14 years, 1.27 (1.07-1.50) for those of 16 years, 1.16 (0.95-1.41) for those of 17 years, and 1.39(1.16-1.68) for those of 18-20 years (P for trend=0.045). A similar pattern was observed for hemorrhagic stroke, ischemic stroke, and total cardiovascular disease. No such association was found for coronary heart disease. When stratified by age, for women aged 40-59 at baseline, the similar U-shaped association was observed. In contrast, for women aged 60-79 years at baseline, a significantly high hazard ratio was noted in the group of late age at menarche, but not in the group of early age at menarche.Both women with early and late age at menarche were determined to have higher risk of death from stroke and cardiovascular disease.

Epidemiological evidence is extremely limited about high-sensitivity cardiac troponin T (hs-cTnT) and future coronary heart disease (CHD) events for the general population in countries with low mortality from CHD. Therefore, we investigated the association between hs-cTnT levels and the risk of incident CHD using a nested case-control study in a large Japanese cohort study.The participants were residents of four Japanese communities in the Circulatory Risk in Communities Study (CIRCS). We obtained 120 cases (81 men and 39 women, aged 38-86 years at baseline) of first incident CHD and 240 controls matched by age, sex, communities, and blood sampling term. Serum hs-cTnT levels were measured using an electrochemiluminescence immunoassay with stored sera collected between 2001 and 2011. The median period between sampling at survey and CHD incidence was 2.0 (interquartile range, 0.9-3.7) years. After adjusting for conventional risk factors, the multivariable odds ratios (ORs) of CHD were calculated using conditional logistic regression analyses.hs-cTnT ranged from ≤ 3 (assay detection limit) to 155 ng/L. Compared with the lowest quartile of hs-cTnT, multivariable ORs (95% confidence intervals) of CHD for the second, third, and highest quartiles were 1.30 (0.57-2.95), 2.48 (1.09-5.64), and 3.01 (1.27-7.12), respectively. Similar associations were observed after adjusting for estimated glomerular filtration, or after excluding matched groups, including people with chronic kidney disease.Serum hs-cTnT could predict CHD in the Japanese general population. These findings implicate a benefit from monitoring hs-cTnT to predict CHD even among populations in countries with low mortality from CHD.

Aims: Reports on an association between body mass index and aortic disease, which remains controversial. This study investigated the association between body mass index and mortality from aortic disease. Methods: We conducted the Japan Collaborative Cohort Study, a prospective study of 103,972 Japanese men and women aged 40–79 years. Body mass index was calculated on the basis of self-reported height and weight, and the participants were followed up from 1988–89 through 2009. Sex-specific hazard ratios (95% confidence intervals) of mortality from aortic disease according to quintiles of body mass index were analyzed using the Cox proportional hazards model. Results: During the median 18.8 years of follow-up, we documented 139 deaths due to aortic aneurysm (including 51 thoracic and 74 abdominal aortic aneurysms) and 134 deaths due to aortic dissection. We observed positive associations of body mass index with mortality from aortic aneurysm among men: the multivariable hazard ratios (95% confidence intervals) for highest versus lowest quintiles of body mass index were 4.48 (2.10–9.58), P for trend < 0.0001 for aortic aneurysm; 6.52 (1.33–32.02), P = 0.005 for thoracic aortic aneurysm; 3.81 (1.39–10.49), P = 0.01 for abdominal aortic aneurysm; and 2.71 (1.59–4.62), P = 0.001 for total aortic disease. No association was found for aortic dissection. Among ever-smokers (men ≥ 90%) but not never-smokers (women ≥ 84%), an association between body mass index and aortic disease mortality was observed regardless of sex, which may explain the sex difference (P for sex-interaction = 0.046). Conclusions: We found a positive association between body mass index and mortality from aortic aneurysm among Japanese men and smokers.

Aim: The association between atrial fibrillation (AF) and risk of stroke mortality among men and women without traditional cerebrocardiovascular risk factors (TCVRFs) is unclear. This study aimed to determine whether AF was a risk factor for stroke and total cardiovascular disease mortality among individuals without TCVRFs. Methods: A total of 90,629 Japanese subjects from the Ibaraki Prefectural Health Study aged 40–79 years, with and without TCVRFs, were studied from 1993 to 2013. Hazard ratios (HRs) were calculated using the Cox proportional hazard regression model stratified by sex and the presence of TCVRFs. Covariates were age, systolic blood pressure, anti-hypertensive medication use, and serum total cholesterol levels. A standard 12-lead electrocardiogram at rest was used to screen AF. Cause-specific mortality was classified according to the International Classification of Disease code. Results: Compared with participants without AF, multivariable-adjusted hazard ratios (with 95% confidence intervals) for stroke mortality among participants without TCVRFs were 4.3 (1.1–17.8) and 15.0 (5.5–40.8) for men and women with AF, respectively. HRs for total cardiovascular disease mortality were 6.2 (2.8–14.2) for men and 10.7 (4.8–24.1) for women. For participants with TCVRFs, multivariable-adjusted HRs for stroke mortality were 3.1 (2.2–4.6) and 4.3 (2.6–7.3), whereas HRs for total cardiovascular disease mortality were 2.9 (2.2–3.8) and 3.5 (2.4–5.1) for men and women, respectively. Conclusions: AF was found to be an independent risk factor for stroke and total cardiovascular mortality even in individuals without other TCVRFs.

We investigated the optimal cut-off points of nonfasting and fasting triglycerides in Japanese individuals with lower average triglyceride levels than westerners.Residents aged 40-69 years without a history of ischemic heart disease or stroke were enrolled between 1980 and 1994 and followed. Serum triglyceride concentrations were measured from 10851 nonfasting (＜8 h after meal) and 4057 fasting (≥ 8 h) samples. As a prerequisite, we confirmed the shape of a receiver operating characteristic (ROC) curves, the area under ROC curves (AUC), and the integrated time-dependent AUC. We identified optimal cut-off points for incident ischemic heart disease based on C-statistic, Youden index, and Harrell's concordance statistic. We used dichotomized concentrations of triglycerides via the univariate logistic regression and Cox proportional hazards regression models. We also calculated multivariable hazard ratios and population attributable fractions to evaluate the optimal cut-off points.Nonfasting and fasting optimal cut-off points were 145 mg/dL and 110 mg/dL, with C-statistic of 0.594 and 0.626, Youden index of 0.187 and 0.252, and Harrell's concordance statistic of 0.590 and 0.630, respectively. The corresponding multivariable hazard ratios of ischemic heart disease were 1.43 (95%CI 1.09-1.88)and 1.69 (1.03-2.77), and the corresponding population attributable fractions were 16.1% (95%CI 3.3-27.2%) and 24.6 (-0.3-43.3).The optimal cut-off points of nonfasting and fasting triglycerides in the Japanese general population were 145 mg/dL and 110 mg/dL, respectively, lower than the current cut-off points recommended in the US and Europe.

Aim N-terminal pro-B-type natriuretic peptide (NT-proBNP), frequently used as a biochemical marker for detecting and monitoring heart failure, is also a risk marker for development of coronary heart disease and total stroke. However, studies that explore subtypes of ischemic stroke with regard to NT-proBNP are scarce. Here, we examined NT-proBNP and its impact upon subtypes of ischemic stroke (lacunar stroke, large-artery occlusive stroke and embolic stroke) among Japanese. Methods We measured NT-proBNP and categorized 4,393 participants of the Circulatory Risk in Communities Study into four groups (＜55, 55-124, 125-399, and ≥ 400 pg/ml). We used a multivariable Cox proportional hazards model to examine association with risks of stroke and subtypes. Results During 4.7 years of follow-up, we identified 50 strokes, including 35 ischemic (15 lacunar, 6 largeartery occlusive, 10 embolic strokes) and 14 hemorrhagic strokes. NT-proBNP was associated with stroke risk: the multivariable hazard ratio of total strokes was 7.29 (2.82-18.9) for the highest and 2.78 (1.25-6.16) for the second highest NT-proBNP groups compared with the lowest group. The respective hazard ratios for the highest NT-proBNP group were 9.37 (3.14-28.0) for ischemic stroke and 6.81 (1.11-41.7) for lacunar stroke. Further adjustment for atrial fibrillation did not attenuate these associations. The associations were similarly observed for large-artery occlusive and embolic strokes. Conclusion We found that even moderate serum levels of NT-proBNP were associated with the risk of total and ischemic strokes among Japanese whose NT-proBNP levels were relatively low compared with Westerners.

Aim A positive association between non-high-density lipoprotein cholesterol (non-HDL-C) and coronary heart disease (CHD) has been established; however, associations between non-HDL-C and stroke subtypes have not been determined. Methods We conducted a prospective study of 30,554 individuals aged 40-69 yrs with no history of cardiovascular disease (CVD) in Japan. Sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of stroke subtypes and CHD were estimated according to quintiles of non-HDL-C, using Cox proportional hazard models adjusted for other established risk factors. Results We identified 1,705 stroke and 296 CHD events over a median 15 yrs of follow-up. The fractional polynomials analysis revealed a U-shaped association between non-HDL-C and stroke risk in men. When analyzed for stroke subtypes, the data revealed an inverse relationship between non-HDL-C and intracerebral hemorrhage (ICH), primarily with lobar ICH, and a positive association between non-HDL-C and large-artery occlusive infarction in men [adjusted HR 0.55 (95% CI, 0.35-0.87) and 2.05 (95% CI, 1.07-3.93) for the highest and lowest quintile of non-HDL-C, respectively]. The lowest risk of ICH in women was observed in the fourth quintile, and the lowest risk of embolic infarction was observed in the third quintile. In contrast, non-HDL-C was positively associated with CHD in both sexes. Conclusions In Japanese men, lower non-HDL-C levels were associated with a decreased risk of large-artery occlusive infarction and an increased risk of ICH, particularly lobar ICH.

Aim Diabetes mellitus and hypertriglyceridemia may adversely interact with the development of ischemic cardiovascular disease, but epidemiological evidence on this issue is scarce. We hypothesized that the impact of hypertriglyceridemia on ischemic cardiovascular disease (ischemic heart disease and ischemic stroke) would differ according to the presence or absence of diabetes mellitus and tested our a priori hypothesis under a large population-based prospective study. Methods A total of 90,468 men and women aged 40-79 years in 1993 were enrolled in the Ibaraki Prefectural Health Study (IPHS), a community-based cohort study of Japanese. The participants' serum triglyceride levels (mostly nonfasting) were measured every 5 years, and the participants were followed up for mortality from ischemic cardiovascular disease through 2016. Hazard ratios (95% confidence intervals) were calculated according to 5-year updated triglyceride levels (＜100, 100-149, 150-199, 200-299, and ≥ 300 mg/dl). Results During 1,795,877 person-years, there were 3,323 deaths from ischemic cardiovascular diseases (1,968 ischemic heart diseases and 1,355 ischemic strokes). We found no association between triglyceride levels and the risk of mortality from ischemic cardiovascular disease after adjustment for known cardiovascular risk factors. However, when stratified by the presence or absence of diabetes mellitus, excess mortality from ischemic cardiovascular disease appeared among participants with diabetes mellitus with triglyceride levels of ≥ 300 mg/dl. Further adjustment for high-density lipoprotein-cholesterol attenuated the association toward being statistically nonsignificant. Conclusion The impact of high serum triglyceride levels on the risk of ischemic cardiovascular disease mortality was confined to participants with diabetes mellitus.

Aims: The frequency of breakfast intake has been reported to be inversely associated with the risk of cardiovascular events; however, it is uncertain what the impact of the energy and nutrient intakes from breakfast are. We assessed the association between these intakes from breakfast and the risk of stroke prospectively. Methods: In a baseline survey of four Japanese communities between 1981 and 1990, we enrolled 3 248 residents (1 662 men and 1 586 women) aged 40–59 years who were free from stroke and heart disease and who responded to the 24-hour dietary recall survey. We assessed the dietary intake at breakfast, lunch, dinner, and other times separately. Results: During the median 25-year follow-up, 230 individuals (147 men and 83 women) developed stroke. After adjustment for age, community, other dietary intakes, and lifestyle and physiological factors, the multivariable-adjusted hazard ratios (95% confidence intervals) of intracerebral hemorrhage for the highest versus lowest quartiles of energy intake from breakfast were 0.38 (0.15–0.99) in men and 1.36 (0.36–5.10) in women. For the major nutrients, a higher saturated or monounsaturated fat intake at breakfast was associated with a reduced risk of intracerebral hemorrhage in men, and remained statistically significant after further adjustment for intake of other major nutrients from breakfast. Conclusions: A higher intake of energy from breakfast, primarily saturated or monounsaturated fat, was associated with a reduced risk of intracerebral hemorrhage in Japanese men.

Aim This study aimed to investigate the associations of leukocyte count with the risks of stroke and coronary heart disease among the general Japanese population. Methods A total of 5,242 residents aged 40-69 years living in two Japanese communities underwent leukocyte count measurements between 1991 and 2000, and the data were updated using 5- or 10-year follow-ups or both. Participants who had histories of stroke, coronary heart disease, or high values of leukocyte count (＞130×102 cells/mm3) were excluded. Hazard ratios with 95% confidence intervals (CIs) were calculated according to quartiles of cumulative average leukocyte count. Results During follow-up of 21 years, 327 stroke and 130 coronary heart disease cases were determined. After adjustments for age, sex, community, and updated cardiovascular risk factors, the multivariable hazard ratio (95% CI) for the highest versus lowest quartile of leukocyte count was 1.50 (1.08-2.08) for ischemic stroke, 1.59 (1.00-2.51) for lacunar infarction, 1.42 (0.90-2.26) for non-lacunar infarction, 2.17 (1.33-3.55) for coronary heart disease, and 1.40 (1.11-1.76) for total cardiovascular disease. In smoking status-stratified analyses, the corresponding multivariable hazard ratio (95% CI) was 2.45 (1.11-5.38) for ischemic stroke, 2.73 (1.37-5.44) for coronary heart disease in current smokers, 2.42 (1.07-5.46), 1.55 (0.58-4.15) in former smokers, and 1.17 (0.75-1.82), 1.78 (0.83-3.82) in never smokers. Conclusion Leukocyte count was positively associated with the risks of ischemic stroke and coronary heart disease among the general Japanese population, especially in current smokers.

Aim This study aimed to investigate the association between the serum high-sensitivity C-reactive protein (hs-CRP) levels and incident atrial fibrillation risk in the general Japanese population, who have lower hs-CRP levels than the Western population, and assess whether the association is modified by sex, overweight, hypertension, and smoking status. Methods We conducted a prospective study in 6517 Japanese men and women aged 40-79 years without atrial fibrillation at baseline and enrolled in the Circulatory Risk in Communities Study (2002-2008). The hs-CRP levels were measured using the latex particle-enhanced immunonephelometric assay. Atrial fibrillation was identified using standard 12-lead electrocardiograms and information on physician-diagnosed atrial fibrillation history from the follow-up surveys. We used a Cox proportional hazard regression stratified by community. Results During a median follow-up of 11 years, 127 new cases of atrial fibrillation (74 and 53 cases among men and women, respectively) were found. Compared to the lowest quintile of hs-CRP levels, the multivariable hazard ratios (95% confidence intervals) were 2.54 (1.17-5.50), 2.28 (1.06-4.93), 2.92 (1.37-6.23), and 2.77 (1.30-5.91) for the second, third, fourth, and fifth (highest) quintiles, respectively. There was no significant effect modification by sex, overweight, hypertension, and smoking status (P for interaction ＞0.05). Conclusions Elevated hs-CRP levels were significantly associated with increased risk of atrial fibrillation in the Japanese population. The association of hs-CRP levels with incident atrial fibrillation did not vary according to sex, overweight, hypertension status, or smoking status.

Aim: Seaweed is a popular traditional foodstuff in Asian countries. To our knowledge, few studies have examined the association of seaweed intake with mortality from cardiovascular disease. We examined the association of frequency of seaweed intake with total and specific cardiovascular disease mortality. Methods: We examined the association of seaweed intake with mortality from cardiovascular disease among 40,234 men and 55,981 women who participated in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. Sex-specific hazard ratios for mortality from cardiovascular disease (stroke, stroke subtypes, and coronary heart disease) according to the frequency of seaweed intake were calculated stratified by study area and adjusted for potential cardiovascular risk factors and dietary factors. Results: During the 1,580,996 person-year follow-up, 6,525 cardiovascular deaths occurred, of which 2,820 were due to stroke, and 1,378, to coronary heart disease. Among men, the multivariable analysis showed that participants who ate seaweed almost every day compared with those who never ate seaweed had hazard ratios (95% confidence interval; P for trend) of 0.79 (0.62–1.01; 0.72) for total cardiovascular disease, 0.70 (0.49–0.99; 0.47) for total stroke, 0.69 (0.41–1.16; 0.11) for cerebral infarction. Among women, the multivariable-adjusted hazard ratios were 0.72 (0.55–0.95; 0.001) for total cardiovascular disease, 0.70 (0.46–1.06; 0.01) for total stroke, and 0.49 (0.27–0.90; 0.22) for cerebral infarction. No associations were observed between seaweed intake and risk of intraparenchymal hemorrhage and coronary heart disease among either men or women. Conclusions: We found an inverse association between seaweed intake and cardiovascular mortality among Japanese men and women, especially that from cerebral infarction.

Aim: To investigate the association of retinal vascular changes with a risk of dementia in longitudinal population-based study., Methods: We performed a nested case-control study of 3,718 persons, aged 40–89 years, enrolled between 1983 and 2004. Retinal vascular changes were observed in 351 cases with disabling dementia (average period before the onset, 11.2 years) and in 702 controls matched for sex, age, and baseline year. Incidence of disabling dementia was defined as individuals who received cares for disabilities including dementia-related symptoms and/or behavioral disturbance. Conditional logistic regression analysis was used to calculate odds ratio (OR) and multivariable adjusted OR (Models 1 and 2) for incidence of dis- abling dementia according to each retinal vascular change. Regarding confounding variables, Model 1 included overweight status, hypertension, hyperglycemia, dyslipidemia, and smoking status, whereas Model 2 also included incidence of stroke prior to disabling dementia for further analysis., Results: The proportion of cases (controls) with retinal vascular changes was 23.1 (15.7)% for general-ized arteriolar narrowing, 7.7 (7.5)% for focal arter iolar narrowing, 15.7 (11.8)% for arteriovenous nick-ing, 10.5 (9.3)% for increased arteriolar wall reflex, and 11.4 (9.8)% for any other retinopathy. General-ized arteriolar narrowing was associated with an in creased risk of disabling dementia: crude OR, 1.66 (95% confidence interval, 1.19 –2.31); Model 1: OR, 1.58 (1.12–2.23); Model 2: OR, 1.48 (1.04–2.10). The number of retinal abnormalities was associated in a dose–response manner with the risk., Conclusion: Generalized arteriolar narrowing and total number of retinal abnormalities may be use-ful markers for identifying persons at higher risks of disabling dementia.

Aim Data for long-term trends in blood pressures, body mass index (BMI), and their relations are needed to set future intervention priorities for prevention of cardiovascular disease. The objective of this study was to investigate these trends revealed by repeated cross-sectional surveys conducted from 1963 to 2013 in a Japanese community. Methods Men and women aged 40-79 years who participated in annual cardiovascular checkups were enrolled, and the number of participants ranged between 1,776 and 2,366 with consistently high participation rates for both sexes aged 60-69 years. Sex- and age-specific mean systolic and diastolic blood pressures were calculated using mixed effects modeling for repeated measurement, and the prevalence of hypertension with and without obesity (BMI ≥ 25 kg/m2) were also calculated. Results Sex- and age-specific mean systolic and diastolic blood pressures declined irrespective of antihypertensive medication use in both men and women from 1963-1966 to 2009-2013, while mean BMI increased among men of all ages and women of ages 60-69 and 70-79 years. For both sexes aged 60-69 years, the prevalence of hypertension with obesity increased, but the prevalence of hypertension without obesity was still higher that with obesity. Conclusions Despite the transition to increased BMI levels, targeting non to obese hypertension remains important in addition to targeting obese hypertension for cardiovascular disease prevention.

Aim: Patients with peripheral artery disease (PAD) are at a high risk of cardiovascular disease (CVD) among Western populations. However, evidence for an elevated risk in Asian populations is limited.Methods: This prospective cohort study examined 939 Japanese men 60-74 years of age at the time of the baseline survey. A total of 115 cases of CVD were detected during a median 9.3 years of follow-up, and the ankle brachial blood pressure index (ABI) functioned as a surrogate measurement of PAD.Results: The age-adjusted risks of coronary heart disease, ischemic stroke and ischemic CVD (coronary heart disease and ischemic stroke) were higher among men in the lowest ABI tertile compared with that observed in the men in the highest tertile (＜1.08 vs. ＞1.17). These associations did not change substantially after adjusting for cardiovascular risk factors. The respective multivariable hazard ratios (HRs, 95% CI) for the three conditions were as follows: 2.48 (1.08-5.71), p for trend=0.03; 1.95 (0.94-4.02), p for trend=0.04; and 2.16 (1.25-3.72), p for trend=0.004. These results did not vary based on a comparison of the three ABI categories: ≤0.90, 0.91-1.10 and ＞1.10. The multivariable HRs (95% CI) for an ABI ≤0.90 versus ＞1.10 were as follows: 2.04 (0.67-6.20), p for trend=0.14 for coronary heart disease; 3.39 (1.10-10.5), p for trend=0.006 for ischemic stroke; and 2.61 (1.19-5.76), p for trend=0.003 for ischemic CVD. There were no associations between the ABI and the risk of hemorrhagic stroke.Conclusions: A low ABI is associated with the risk of coronary heart disease, ischemic stroke and ischemic CVD in elderly Japanese men.

Aim: Previous studies have reported that moderate alcohol consumption is protective against cardiovascular disease, but heavy alcohol consumption increases its risk. Endothelial dysfunction is hypothesized to contribute to the development of atherosclerosis and cardiovascular disease. However, few population-based studies have examined a potential effect of alcohol consumption on endothelial function. Methods: This study included 404 men aged 30–79 years who were recruited from residents in 2 communities under the Circulatory Risk in Communities Study in 2013 and 2014. We asked the individuals about the frequency and volume of alcohol beverages and converted the data into grams of ethanol per day. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD) measurements during reactive hyperemia. We performed cross-sectional analysis of alcohol consumption and %FMD by logistic regression analysis, adjusting for age, baseline brachial artery diameter, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, HbA1c, smoking, antihypertensive medication use, and community. Results: Individuals who drank ≥ 46 g/day ethanol had a lower age-adjusted mean %FMD than non-drinkers (p

Aim: The aim of this study was to identify the threshold level for non-high-density lipoprotein cholesterol (non-HDL-cholesterol) to raise the risk of coronary heart disease (CHD) incidence in a Japanese general population.Methods: A total of 8,132 men and women, aged 40 to 69 years with no history of stroke or CHD, completed the baseline risk factor surveys between 1975 and 1987. Systematic surveillance of cardiovascular disease incidence was performed through 2003 (the median follow-up period was 21.9 years), and 155 incidents of CHD were identified.Results: We found a statistically significant association between non-HDL-cholesterol levels and the risk of CHD with a threshold around 140 mg/dL. After adjustment for potential confounding factors, this association did not change materially. The multivariable hazard ratio of CHD compared with that for levels of < 100 mg/dL was 2.49 (95% confidence interval: 1.35 to 4.61) for 140-159 mg/dL and 3.13 (1.58-6.21) for ≥ 180 mg/dL. Setting the cut-off point at ≥ 140 mg/dL non-HDL-cholesterol resulted in the greatest improvement of integrated discrimination.Conclusions: Higher concentrations of non-HDL-cholesterol are associated with an increased risk of CHD with a threshold around 140 mg/dL, suggesting that the optimal cut-off point for healthy per-sons to prevent increasing the risk of CHD might be around 140 mg/dL non-HDL-cholesterol.

Aim: We investigated whether nocturnal intermittent hypoxia, a surrogate marker for obstructive sleep apnea, is associated with metabolic syndrome and its components among Japanese.Methods: We examined 1,710 male and 2,896 female community-dwelling Japanese aged 40 to 69, who participated in annual cardiovascular examinations and investigations of sleep. Nocturnal intermittent hypoxia was estimated based on a 3% oxygen desaturation index measured with pulse-oximetry during sleep. No, mild and moderate-to-severe nocturnal intermittent hypoxia were defined by

Aim: To examine whether plasma levels of coagulation factors II, V, IX, X, XI, and XII, plasminogen, and α-2 antiplasmin are associated with coronary heart disease (CHD) in a prospective case-cohort study.Methods: This case-cohort sample consisted of 368 African-Americans or whites with incident CHD that occurred between 1990-92 and 1998, from the Atherosclerosis Risk in Communities (ARIC) study, and a cohort random sample of n=412. Hemostatic factors were measured in the case-cohort sample using plasma stored at -70°C since 1990-92.Results: After adjustments for age, sex and race, coagulation factors IX and XI, and α-2 antiplasmin were associated positively with risk of CHD: The hazard ratio [95% confidence interval] for the highest vs lowest quartiles was 1.52 [1.01-2.27] for factor IX; 2.26 [1.47-3.48] for factor XI; and 1.64 [1.05-2.57] for α-2 antiplasmin. However, as these hemostatic factors were correlated with classical risk factors, their association with CHD was attenuated and no longer statistically significant after multivariable adjustments. No association was observed between CHD and factor II, V, X, or XII, or plasminogen.Conclusions: Positive associations of factors IX and XI, and α-2 antiplasmin with incident CHD were not strong and accounted for by classical coronary risk factors.

Aim: E-selectin and C-reactive protein have been linked with carotid atherosclerosis; however, the findings on this association have been inconsistent.Methods and Results: We conducted a cross-sectional study to examine the associations of soluble E-selectin (sE-selectin) and high-sensitivity-CRP (hs-CRP) levels with carotid intima-media thickness (IMT) in 505 Japanese men aged 6074 years. Maximum IMT of common (CCA) and internal carotid arteries (ICA) was positively associated with sE-selectin levels after adjustment for age, hs-CRP and other cardiovascular risk factors: means of maximum CCA IMT were 1.12, 1.21 and 1.27 mm for the lowest to highest tertiles of sE-selectin, respectively, p=0.04, and those of ICA IMT were 1.73, 2.09 and 2.09 mm, respectively, p=0.009. Maximum IMT of CCA tended to be positively associated hs-CRP levels after adjustment for age, sE-selectin and other cardiovascular risk factors: means of maximum CCA IMT were 1.10, 1.25, and 1.26 mm, for the lowest to highest tertiles of hs-CRP, respectively, p=0.06. Compared with subjects with the lowest tertiles of sE-selectin and hs-CRP, those with the highest tertiles had a higher prevalence of heterogeneous plaque: multivariable odds ratios were 2.2 (1.03.7), p=0.002 and 1.6 (1.02.7), p=0.046, respectively.Conclusions: Serum levels of sE-selectin and hs-CRP could be biomarkers for atherosclerosis in general populations.

AIM Aging and postmenopausal women are associated with increased risks of cardiovascular disease; however, epidemiological evidence concerning the relationship of aging and the menopause with vascular biological activity is limited. METHODS We investigated the relationship of aging and the menopause with urinary excretion of cyclic guanosine 3',5' monophosphate (cGMP) in 1,541 Japanese men and women aged 40 to 79 years. The 24-hour urinary excretion of cGMP was measured with a (125)I-labeled cGMP radioimmunoassay and was adjusted for urinary creatinine excretion (nmol/mmol creatinine). RESULTS Aging was positively associated with urinary excretion of cGMP for both sexes. Postmenopausal women excreted significantly less urinary cGMP than premenopausal women after adjustment for age and other cardiovascular risk factors: 48.3+/-0.04 nmol/mmol vs. 61.5+/-0.07 nmol/mmol, p=0.006. CONCLUSIONS Our data suggest that cGMP-related vasodilatation is impaired in postmenopausal women.

The evidence for the impact of saturated fat intake on cardiovascular disease remains inconsistent. One reason for this inconsistency may be the large difference in the distribution of saturated fat intake between the East and West. In this review, we focus on the published literature on this topic among Japanese population. Three studies have examined the link between saturated fat intake and intraparenchymal hemorrhage, consistently showing an inverse association. However, the association for ischemic stroke is less clear, although it is generally inverse. As for myocardial infarction, the findings in Japanese studies are inconsistent, as are those of Western studies. The JPHC study, however, found a positive association, the first report in Asia. Taken together with the results of the JPHC and Western studies, a saturated fat intake of around 20 g/day (approximately 10% of total energy) may be optimal, which corresponds to 200 g of milk a day and 150 g of meat every other day.

To examine the impact of C-reactive protein on the risks of stroke and its subtypes, particularly among Asian populations in which median C-reactive protein levels are typically lower than in Western populations.A prospective, nested case-control study was conducted to examine the associations between high sensitivity-CRP (hs-CRP) and risks of cardiovascular disease within a cohort of 29,876 men and women aged 40-69 years, with no history of stroke, ischemic heart disease or cancer, who submitted blood samples between 1990 and 1993. Systematic cardiovascular surveillance was performed throughout 2007. One control for each stroke and two controls for each ischemic heart disease were matched for sex, age, date of blood drawing, time since last meal and study location.We documented 1,132 incident strokes (638 ischemic and 494 hemorrhagic strokes) and 209 ischemic heart diseases (168 myocardial infarctions and 41 sudden cardiac deaths), and observed a linear association between hs-CRP levels and risks of ischemic stroke and ischemic heart disease, more specifically myocardial infarction. The multivariable odds ratios associated with 1-SD increment of logarithmically transformed hs-CRP were 1.13 (0.99-1.29),p= 0.07 for ischemic stroke, 1.16 (0.96-1.41),p= 0.13 for lacunar infarction, 1.41 (0.98-2.01),p= 0.06 for embolic infarction, and 1.28 (1.03-1.59),p= 0.03 for myocardial infarction. The predictive value of hs-CRP for ischemic stroke was reduced primarily after adjustment for hypertensive status and body mass index. No association was found between hs-CRP levels and the risk of hemorrhagic or total stroke.High serum hs-CRP levels were associated with the risk of myocardial infarction and more weakly with the risk of ischemic stroke among middle-aged Japanese men and women.

Aim To examine the impact of C-reactive protein on the risks of stroke and its subtypes, particularly among Asian populations in which median C-reactive protein levels are typically lower than in Western populations. Methods A prospective, nested case-control study was conducted to examine the associations between high sensitivity-CRP (hs-CRP) and risks of cardiovascular disease within a cohort of 29,876 men and women aged 40-69 years, with no history of stroke, ischemic heart disease or cancer, who submitted blood samples between 1990 and 1993. Systematic cardiovascular surveillance was performed throughout 2007. One control for each stroke and two controls for each ischemic heart disease were matched for sex, age, date of blood drawing, time since last meal and study location. Results We documented 1,132 incident strokes (638 ischemic and 494 hemorrhagic strokes) and 209 ischemic heart diseases (168 myocardial infarctions and 41 sudden cardiac deaths), and observed a linear association between hs-CRP levels and risks of ischemic stroke and ischemic heart disease, more specifically myocardial infarction. The multivariable odds ratios associated with 1-SD increment of logarithmically transformed hs-CRP were 1.13 (0.99-1.29),p= 0.07 for ischemic stroke, 1.16 (0.96-1.41),p= 0.13 for lacunar infarction, 1.41 (0.98-2.01),p= 0.06 for embolic infarction, and 1.28 (1.03-1.59),p= 0.03 for myocardial infarction. The predictive value of hs-CRP for ischemic stroke was reduced primarily after adjustment for hypertensive status and body mass index. No association was found between hs-CRP levels and the risk of hemorrhagic or total stroke. Conclusions High serum hs-CRP levels were associated with the risk of myocardial infarction and more weakly with the risk of ischemic stroke among middle-aged Japanese men and women.