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To investigate the association between stage 1 hypertension, defined as systolic blood pressure (BP) of 130-139 mmHg or diastolic BP of 80-89 mmHg, in the first and second trimesters and the risk of adverse pregnancy outcomes.We analyzed 79,249 singleton pregnancies from a nationwide birth cohort study. BP in the first and second trimesters was classified into normal, elevated, stage1 hypertension, and stage 2 hypertension. We examined the risk of adverse pregnancy outcomes in each group using multivariable logistic regression analysis. We also investigated the influence of BP changes between the first and second trimesters on adverse pregnancy outcomes.Overall preterm birth (PTB 37 weeks), early PTB (34 weeks), and small for gestational age (SGA).Stage 1 hypertension in the first trimester was associated with increased risks of overall PTB (aOR, 1.23; 95 %CI, 1.08-1.39), early PTB (aOR, 1.38; 95 %CI, 1.07-1.79), and SGA (aOR, 1.19; 95 %CI, 1.04-1.36) compared to normal BP. These risks were more evident in the second trimester; overall PTB (aOR, 1.87; 95 %CI, 1.64-2.14), early PTB (aOR, 2.21; 95 %CI, 1.69-2.87), and SGA (aOR, 1.38; 95 %CI, 1.18-1.62). The risk of PTB was higher among women with an upward BP trajectory between the first and second trimesters.Stage 1 hypertension in the first and second trimesters was associated with increased risks of overall PTB, early PTB, and SGA. Monitoring the BP trajectory for stage 1 hypertension may be useful for identifying high-risk groups.

Background and purpose An effect of dietary carotenes on risk of cardiovascular disease (CVD) is uncertain. We aimed to investigate whether the association between dietary carotenes intake and risk of CVD mortality will persist after controlling for the intakes of potential cardioprotective dietary factors that correlate with dietary alpha- and/or beta-carotenes. Methods and results We followed up a total of 58,646 Japanese between 1988 and 1990 and 2009. We used a food frequency questionnaire (FFQ) to determine the dietary intakes of carotenes, and estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of CVD mortality in relation to carotene intake by the proportional hazard regression developed by David Cox. During 965,970 person-years of follow-up (median 19.3 years), we identified 3388 total CVD deaths. After adjusting for demographic and lifestyle factors, dietary intakes of alpha-carotene were significantly associated with the reduced risk of mortality from coronary heart disease (CHD); adjusted HR (95% CI) in the highest versus lowest quintiles of intake was 0.75 (0.58–0.96; P-trend = 0.02) and dietary intakes of beta-carotene were significantly associated with the reduced risk of mortality from CVD, CHD, and other CVD; adjusted HRs (95% CIs) were 0.88 (0.79–0.98; P-trend = 0.04), 0.78 (0.61–0.99; P-trend = 0.01), and 0.81 (0.67–0.98; P-trend = 0.04), respectively. However, after further adjusting for the dietary intakes of potassium, calcium, vitamins C, E, or K, these associations disappeared. Conclusions —Dietary alpha- and beta-carotene intakes were not associated with risk of CVD mortality after controlling for intakes of other potential cardioprotective nutrients.

Purpose To investigate whether and how unhealthy sleep habits (i.e., the frequency of difficulty falling or staying asleep, and the frequency of waking up tired) and the duration of sleep are related to the prevalence of dry eye disease (DED) in a general population. Methods This study included a total of 106,282 subjects aged 40–74 years who participated in a baseline survey of the Japan Public Health Center-based Prospective Study for the Next Generation. DED was defined as the presence of clinically diagnosed DED or severe symptoms. Multivariable-adjusted logistic regression models were used to assess the relationships of various components of sleep status with DED. Results Higher frequencies of having difficulty falling or staying asleep, and waking up tired were significantly related to increased DED in both sexes (Ptrend Conclusions Sleep deprivation and poor sleep quality were significantly related to DED in a Japanese population.

Background Despite the hypoglycemic and antioxidant effects of manganese, only one recent Chinese study has investigated the association between dietary manganese intake and type 2 diabetes. Methods We recruited 19,862 Japanese men and women in the Japan Collaborative Cohort Study. The participants completed a food frequency questionnaire at the baseline survey (1988 = 1990) and a diabetes history at both baseline and 5-year surveys. We calculated the odds ratios (95 % CIs) of the 5-year cumulative incidence of self-reported physician-diagnosed type 2 diabetes according to quartiles of dietary manganese intake. Results Within the 5-year period, we confirmed 530 new cases of type 2 diabetes (263 in men and 267 in women) with a 5-year cumulative incidence of 2.7 % (3.6 % in men and 2.1 % in women). Higher manganese intake was inversely associated with the women’s but not the men’s cumulative risk of type 2 diabetes over the 5-year period. In a full model adjusted for the participants’ characteristics, diabetes risk factors and a wide range of dietary variables, the multivariable odds ratios (95 %CIs) of type 2 diabetes across the increasing quartiles of manganese intake (Q1 to Q4) were 1.00, 0.97 (0.65, 1.43), 1.04 (0.67, 1.61) and 1.10 (0.64, 1.92), p-trend = 0.66 among men and 1.00, 0.74 (0.51, 1.06), 0.62 (0.41, 0.94) and 0.53 (0.31, 0.88), p-trend = 0.01 among women. The association was observed mainly for those with low iron intake in women, particularly premenopausal women. Conclusion Strong inverse associations between dietary manganese intake and risk of type 2 diabetes were observed in women but not men.

Purpose This population-based, cross-sectional study was performed to assess the influence of life-style modalities, including physical activity, sedentary behaviors, and visual display terminal (VDT) use, on the prevalence of dry eye disease (DED). Methods The study included a total of 102,582 participants aged 40–74 years, from the Japan Public Health Center-based Prospective Study for the Next Generation, a large nationwide prospective ongoing Japanese cohort study. Logistic regression analyses were used to investigate the relationship of total and leisure-time physical activity, duration of sedentary behaviors, and VDT use (hours/day) with DED. Results Among 47,346 men and 55,236 women, 25,234 (8315 males and 16,919 females) cases of DED were documented. Total physical activity was significantly related to decreased DED in both sexes; for the highest vs. lowest total physical activity quartiles, the multivariable-adjusted odds ratios (ORs) for DED were 0.90 (95% confidence interval [CI], 0.84–0.97; Ptrend Conclusions Physical inactivity, prolonged sedentary behaviors, and use of VDT were related to increased susceptibility to DED among middle-aged to older Japanese adults.

Background The minerals, vitamins, soluble dietary fibers, and flavonoids of seaweed are protective for preventing cardiovascular diseases. However, the association between seaweed intake and risk of cardiovascular disease has not been established. Objectives We examined the dietary intake of seaweed and its impact upon stroke and ischemic heart disease risk among a Japanese study population. Methods We surveyed 40,707 men and 45,406 women from 2 large cohorts (age range: 40-69 y). Seaweed intake was determined by FFQ at baseline (1990-1994). Incidences of stroke and ischemic heart disease were ascertained until the end of 2009 (Cohort I) or 2012 (Cohort II). Sex-specific cardiovascular disease HRs (95% CIs) were estimated using Cox proportional hazard models after stratification by area and adjustment for cardiovascular disease risk and dietary factors. Results During 1,493,232 person-years of follow-up, 4777 strokes (2863 ischemic stroke, 1361 intraparenchymal hemorrhages, and 531 subarachnoid hemorrhages) and 1204 ischemic heart disease cases were identified. Among men, significant multivariable HRs (95% CIs) for almost daily consumption compared with almost no consumption of seaweed were seen in ischemic heart disease [0.76 (0.58, 0.99); P-trend = 0.04] and total cardiovascular diseases [0.88 (0.78, 1.00); P-trend = 0.08]. Among women, such inverse associations were 0.56 (0.36, 0.85; P-trend = 0.006) for ischemic heart disease and 0.89 (0.76, 1.05; P-trend = 0.10) for total cardiovascular diseases. No significant associations were observed between seaweed intake and risk of total stroke or stroke types among either men or women. Conclusions Seaweed intake was inversely associated with risk of ischemic heart disease.

Several studies have shown that smoking is a significant risk factor for pneumonia, but it is uncertain to what extent smoking cessation reduces the risk. This study aimed to investigate whether and to what extent smoking cessation is associated with reduced risk of mortality from pneumonia in a Japanese, prospective, community-based cohort. We examined 94,972 individuals (mean age, 57 years; women, 57%) who provided valid responses to a lifestyle questionnaire including questions about smoking. We used years of smoking cessation at baseline to divide former smokers into 5 groups: 0-1 year, 2-4 years, 5-9 years, 10-14 years, and 15 years or more. The endpoint was the underlying cause of death from pneumonia. During the median 19-year follow-up of 94,972 study participants, 1806 died from pneumonia. Multivariable hazard ratios (95% confidence intervals) compared with the current smokers were 1.02 (0.72-1.45) for 0-1 year of smoking cessation at baseline, 0.92 (0.70-1.22) for 2-4 years, 0.95 (0.74-1.21) for 5-9 years, 0.71 (0.53-0.96) for 10-14 years, 0.63 (0.48-0.83) for 15 years or more, and 0.50 (0.36-0.70) for never-smokers. Although smoking increases the risk of pneumonia mortality, the present study showed that the risk of pneumonia mortality decreased with years of smoking cessation, eventually improving to levels similar to those of non-smokers for 10 years or more. Continued smoking cessation may be effective in preventing pneumonia deaths.

Summary Background & aims Many studies have suggested that fish intake is associated with protection from risk of atherosclerotic diseases; however, this association with aortic diseases has not been elucidated worldwide. We hypothesized that fish intake is inversely associated with mortality from aortic diseases (aortic dissection and aneurysm). Methods The study was conducted as a pooled analysis of original data from a maximum of 8 cohort studies, comprising a total of 366,048 community-based men and women who had no history of cardiovascular disease or cancer. In each cohort, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality from aortic dissection, aneurysm and total aortic disease according to the frequency of fish intake and estimated summary HRs derived from each study. Results Nonlinear inverse associations were found between fish intake and total aortic disease. Compared with persons who ate fish 1–2 times/week, persons who seldom ate fish had higher mortality from total aortic disease (multivariable-adjusted pooled HR = 1.93; 95% CI, 1.13–3.31). Higher mortality was not seen in those who ate fish 1–2 times/month. A similar pattern was observed for aortic dissection. Regarding aortic aneurysm, both persons who seldom ate fish and those who ate fish 1–2 times/month had higher mortality (HR = 1.99; 95% CI, 0.90–4.40 and HR = 1.86; 95% CI, 0.87–3.98, respectively). Conclusions Persons who seldom ate fish had higher mortality from aortic dissection, aneurysm, and total aortic diseases.

To investigate whether social support and social trust are associated with DED.Cross-sectional data from the Japan Public Health Center-Based Prospective Study for the Next Generation (JPHC-NEXT) were used. Subjects are 96,227 Japanese men and women aged 40 to 74. Data from respondents included information on DED, social support and social trust. DED was defined as the presence of clinically diagnosed DED or severe symptoms. Social support was measured by emotional support and tangible support. Social trust was measured by level of general trust in others. Multiple logistic regression analysis was conducted to assess the association of social determinants for DED.Individuals with high levels of social support and social trust were less likely to have severe symptoms of DED and clinically diagnosed DED (P for trend 0.001 in both cases). Those with the highest levels of social support and social trust were least likely to have DED (odds ratios [OR] = 0.64 [0.61-0.67], 95% confidence interval [CI] = 0.63 [0.60-0.67] for severe symptoms of DED; OR = 0.88 [0.83-0.93] and 0.85 [0.80-0.91] for clinically diagnosed DED).High levels of social support and social trust were associated with a lower prevalence of DED.

Background and aims Although a potential benefit of drinking green tea has been suggested to reduce the development of cardiovascular disease, no study has investigated the relationship between plasma tea catechin and risk of cardiovascular disease. Methods A prospective, nested case-control study was conducted to examine the association between plasma tea catechin and risk of stroke and coronary heart disease (CHD) in a cohort of 29,876 men and women aged 40–69 years without history of heart disease, stroke or cancer. Participants completed a survey and donated blood samples between 1990 and 1994, and were followed-up through 2008. A total of 1132 stroke cases and 209 CHD cases, matched 1:1 to controls (n = 1132) for stroke and 1:2 to controls (n = 418) for CHD, were included in the analysis. Results We found no significant association between plasma tea catechin and the incidence of stroke or CHD in either men or women. However, we found that high plasma levels of epigallocatechin gallate (EGCG) were associated with reduced risk of stroke in non-smoking men; the adjusted odds ratio (95% CI) for the highest vs. non-detectable levels was 0.53 (0.29–0.98). The respective OR in male smokers was 1.23 (0.75–2.16). A significant interaction by smoking status was found for the highest vs. non-detected plasma EGCG in relation to stroke (p-for-interaction: p = 0.09). Conclusions Plasma tea catechin was not associated with reduced risks of either stroke or CHD, while a protective effect of certain tea catechin on stroke risk is suggested for male non-smokers.

Summary Background & aims The associations between dietary magnesium intake and stroke and coronary heart disease (CHD) incidences are inconsistent and not established in Asian. We aimed to determine the association between dietary magnesium intake and the risk of stroke and CHD in a Japanese population. Subjects/Methods We studied 85,293 Japanese subjects by questionnaire at baseline (age 45–74 years, without cardiovascular disease or cancer in 1995 and 1998 for Cohorts I and II, respectively). The participants were followed until the end of 2009 and 2010 in Cohorts I and II, respectively. Dietary magnesium intake was estimated from a self-administered 138-item food-frequency questionnaire. Results After 1,305,738 person-years of follow-up, 4110 strokes and 1283 cases of CHD were documented. The multivariable-adjusted hazard ratios (HRs, 95% confidence intervals, 95%CIs) of CHD for the fourth and fifth quintiles of dietary magnesium intake were 0.70 (0.50–0.99) and 0.66 (0.44–0.97) in men (P for trend = 0.036), respectively, and third quintile of dietary magnesium intake was 0.61 (0.39–0.96) in women (P for trend = 0.241), compared with the lowest quintile in men and women. We observed no decreased risks of incident stroke in men or women with higher dietary magnesium intakes. Conclusions Higher dietary magnesium intake was associated with a reduced risk of CHD in Japanese men.

Several studies have related cardiovascular disease (CVD) to serum concentrations of copper and zinc but not to their dietary intakes. We thought to examine the association between dietary intakes of copper and zinc with risk of mortality from CVD in a prospective study encompassing 58,646 healthy Japanese men and women aged 40-79 years. The intakes of copper and zinc were determined by a validated self-administered food frequency questionnaire, and their associations with risk of mortality from CVD were evaluated by Cox proportional hazard modelling. During 965, 970 person-years of follow-up between 1989-2009, we documented 3,388 CVD deaths [1,514 from stroke, 702 from coronary heart disease (CHD) and 1,172 from other CVD]. Copper intake was not associated with CHD mortality; however, the multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) for mortality from stroke, other CVD and total CVD in the highest versus the lowest quintiles of copper intake among men were 1.78 (1.16-2.77; P-trend=0.007), 1.61 (1.01-2.81; P-trend =0.03) and 1.63 (1.21-2.33; P-trend=0.001), respectively, and those among women were 1.49 (1.00-2.19; P-trend=0.04), 1.59 (1.09-2.55; P-trend =0.02) and 1.36 (1.06-1.69; P-trend=0.01), respectively. Higher intakes of zinc was inversely associated with mortality from CHD in men; 0.68 (0.58-1.03; P-trend=0.05) but not women; 1.13 (0.71- 1.49; P-trend=0.61). No associations were observed with other mortality endpoints. In conclusion, dietary copper intake was positively associated with mortality from CVD in both genders; whereas, higher dietary zinc intake was inversely associated with mortality from CHD in men but not women.

A finding between dietary pattern and cancer may provide visions beyond the assessment of individual foods or nutrients. We examined the influence of dietary pattern with colorectal cancer (CRC) among a Japanese population.A total of 93,062 subjects (43,591 men, 49,471 women) who participated in the Japan Public Health Center-based Prospective Study were followed from 1995-1998 to the end of 2012, during which 2482 cases of CRC (1514 men, 968 women) were newly identified. Dietary data was obtained from a validated food-frequency questionnaire between 1995 and 1998.Three dietary pattern was derived from principal components factor: prudent, westernized, and traditional pattern. After controlled for potential confounders, the prudent pattern showed a decreased association of CRC risk in men (HR for highest quintile vs lowest: 0.85; 95% CI: 0.72-1.00; P trend0.05), slightly more strongly with distal colon cancer (P trend0.05); but an increased risk of rectal cancer in women (P trend0.05). The westernized pattern showed a significant positive linear trend for colon (P trend0.05) and distal cancer (P trend0.05) in women. There was no apparent association of traditional Japanese dietary pattern on the overall or any specific sites risk of CRC.A prudent dietary pattern showed an inverse association with CRC risk in men, and a westernized pattern was related with a higher risk of colon and distal cancer in women.

Background: Randomized controlled studies have investigated the short-term effect of soy product intake on blood pressure (BP) in normotensive people. To our knowledge, no prospective studies exist on the effect of habitual intake of fermented soy products, separate from total soy products, on BP in the general population.Objective: We examined the association between the habitual intake of soy products, including fermented soy products, and the development of high BP during a 5-y period among participants in a population-based prospective cohort study in Japan.Methods: The study included normotensive participants aged 40-69 y at baseline (926 men and 3239 women) who completed 2 questionnaires and whose BP was measured at the baseline survey between 1993 and 1994 and the 5-y follow-up in the Japan Public Health Center-Based Prospective Study Cohort II. The intake of soy products was assessed with a food-frequency questionnaire. High BP was defined as systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥85 mm Hg, or antihypertensive medication use. ORs and 95% CIs of high BP by frequency of soy products (miso, natto, and tofu) consumption, intake of total and fermented soy products, and intake of isoflavones from total and fermented soy products were estimated with the use of multiple logistic regression analysis.Results: Multivariable-adjusted ORs of high BP for the highest compared with the lowest tertile of total and fermented soy product intake were 1.03 (95% CI: 0.84, 1.25; P-trend = 0.786) and 0.72 (95% CI: 0.56, 0.92; P-trend = 0.009), respectively. The frequency of nonfermented soy product (tofu) intake was not associated with the development of high BP (P-trend = 0.597).Conclusions: The intake of fermented soy products, but not total or nonfermented soy products, was inversely associated with developing high BP in men and women with normal BP.

Background and aims Limited evidence is available on the association between markers of arterial stiffness and the prevalence of atrial fibrillation among Asian populations. Therefore, we examined those associations in the Japanese population. Methods We conducted a cross-sectional population-based study of 4264 men and women aged 40–79 years. The augmentation index (AI), a marker of arterial stiffness, was calculated as the ratio of central pulse pressure/brachial pulse pressure, where the AI and central aortic pressure were measured by an automated tonometer: the HEM-9000AI device (Omron Healthcare co., Kyoto, Japan). Atrial fibrillation was estimated by the Minnesota codes using resting electrocardiograph (ECG). Results The prevalence of atrial fibrillation and total arrhythmia were higher with larger AI values. These associations did not change after adjustment for known cardiovascular risk factors. The multivariable odd ratios (95% confidence intervals) in the highest versus lowest tertiles of AI were 3.4 (1.4–8.6, p for trend = 0.008) for atrial fibrillation and 1.8 (1.2–2.7, p for trend = 0.004) for total arrhythmia. There was no association of central or brachial pulse pressure levels with the prevalence of atrial fibrillation or total arrhythmia. Conclusions AI values, but not brachial or central pulse pressures, were positively associated with the prevalence of atrial fibrillation and total arrhythmia, independent of cardiovascular risk factors.

Summary Background & aims It has been hypothesized that ω-3 polyunsaturated fatty acids have anti-atherosclerotic and neuronal protective functions and may benefit prevention of dementia, but the epidemiological evidence, especially for α-linolenic acid, is quite limited. The aim of this study was to examine whether serum ω-3 polyunsaturated fatty acids are associated with risk of dementia. Methods We performed an intracohort case–control study nested in a community-based cohort, the Circulatory Risk in Communities Study, involving 7586 Japanese individuals aged 40–74 years at the baseline period of 1984–1994. Omega-3 polyunsaturated fatty acid constituents (α-linolenic, eicosapentaenoic, and docosahexaenoic acids) in serum total lipid were measured in 315 cases of incident disabling dementia in the above-mentioned cohort between 1999 and 2004, and in 630 controls whose age, sex, area, and baseline year were matched with the cases. Results As we had postulated, serum α-linolenic acid was inversely associated with risk of disabling dementia: the multivariate odds ratios (95% confidence intervals) were 0.57 (0.39–0.85), 0.51 (0.34–0.76), and 0.61 (0.41–0.90) for persons with the second, third, and highest quartiles of serum α-linolenic acid, respectively, as compared with the lowest quartile ( P for trend = 0.01). Associations of other ω-3 fatty acids with disabling dementia were not statistically significant. Conclusions Serum α-linolenic acid was inversely associated with risk of disabling dementia. Although the causality needs to be confirmed by randomized control trials, we identified serum α-linolenic acid as a biomarker that predicts future dementia.

Background and aims Limited evidence has been available on the relationship between apoptosis and cardiovascular disease in population-based samples. We examined whether blood soluble Fas (sFas) are associated with mortality from cardiovascular diseases. Methods In a nested case-control study under a large prospective cohort, the Japan Collaborative Cohort (JACC) Study, where a total of 39,242 subjects, 40–79 years of age, provided serum samples and were followed up for 9 years, we measured sFas levels among cases and controls, matched for sex, age, area of residence and year of serum storage. Conditional logistic regression models were used to calculate odds ratio (95% CI) of mortality from stroke and stroke types, according to quartiles and 1-SD increment of sFas levels. Results During the follow-up (1988–1997), we identified 233 (121 in men and 112 in women) deaths from total stroke, comprising 49 (18 and 31) subarachnoid hemorrhages, 55 (27 and 28) intraparenchymal hemorrhages, 71 (44 and 27) ischemic strokes, and 97 (53 and 44) coronary heart diseases. After adjustment for cardiovascular risk factors, the multivariable odds ratio (95% CI) of subarachnoid hemorrhage associated with a 1-SD increment of sFas (1.3 ng/ml in both men and women) was 4.04 (1.07–15.3; p = 0.04). No association was found between blood sFas levels and risk of intraparenchymal hemorrhage, ischemic stroke or coronary heart disease. Conclusions Higher blood sFas levels were associated with higher mortality from subarachnoid hemorrhage, suggesting a potential role of apoptosis factors in the development or prognosis of subarachnoid hemorrhage.

Background and aims Chocolate consumption may have a beneficial effect on cardiovascular health, but evidence from prospective cohort studies is still limited. We aimed to examine the prospective associations between chocolate consumption and risk of stroke among men and women in a large population-based cohort. Methods A total of 38,182 men and 46,415 women aged 44–76 years, and free of cardiovascular disease, diabetes, and cancer at baseline in 1995 and 1998, were followed up until the end of 2009 and 2010, respectively. We obtained data on chocolate consumption for each participant using a self-administrated food frequency questionnaire that included 138 food and beverage items. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of stroke in relation to chocolate consumption. Results During a median follow-up of 12.9 years, we identified 3558 incident strokes cases (2146 cerebral infarctions and 1396 hemorrhagic strokes). After adjustment for age, body mass index, life styles, dietary intakes, and other risk factors, chocolate consumption was associated with a significant lower risk of stroke in women (HR = 0.84; 95% CI, 0.71–0.99). However, the association in men was not significant (HR = 0.94; 95% CI, 0.80–1.10). In addition, the association did not vary by stroke subtypes in either men or women. Conclusions Findings from this large Japanese cohort supported a significant inverse association between chocolate consumption and risk of developing stroke in women. However, residual confounding could not be excluded as an alternative explanation for our findings.

Background: The effect of lowering diastolic blood pressure (DBP) on the risk for ischemic cardiovascular disease (CVD) is usually only assessed with a single timepoint at baseline. This has led to a lack of explanation for the U- or J-shaped association between DBP and the risk for ischemic CVD among hypertensive patients. Methods: We studied a cohort of 7074 hypertensive patients (42.9% men) aged 35-79 years (mean age=56.5 years) at baseline in 1980-1989, with annually repeated blood pressure measurements. Time-dependent DBP trajectories were assessed by group-based trajectory analysis, adjusted by sex, age, and antihypertensive medication use. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) of ischemic CVD, composed of ischemic stroke and myocardial infarction, according to DBP trajectories were estimated by competing risk analysis. For references, we examined the same approaches mentioned above were used for systolic blood pressure. Findings: For 24.1 years, there were 799 incident cases of ischemic CVD. Eight DBP trajectories were identified. We found a U-shaped association between DBP trajectories and a risk for ischemic CVD. The HRs (95%CI) of ischemic CVD with reference to a moderately-stable trajectory were 2.0 (1.8-2.2) for a very-low-stable, 1.4 (1.3-1.6) for low-decreasing, 1.6 (1.3-1.5) for low-stable, 1.4 (1.3-1.5) for moderately-decreasing, 1.5 (1.4-1.7) for high-decreasing, 1.2 (1.1-1.4) for high-stable, and 1.4 (1.2-1.62) for very-high-stable. This U-shaped association was more pronounced in antihypertensive medication users than in non-users. No such association was observed for SBP trajectories. Interpretation: We found a U-shaped association between DBP trajectory and ischemic CVD in hypertensive patients in a time-dependent analysis, which cannot be detected by single timepoint analysis. Changes in DBP among hypertensive patients should be carefully documented for preventing ischemic CVD. Funding Statement: Ministry of Health, Labor and Welfare of Japan. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the ethics committees of Osaka University and Osaka Center for Cancer and Cardiovascular Disease Prevention, and was performed in accordance with the Declaration of Helsinki.

Objective : To examine whether coenzyme Q10, a potent antioxidant, is associated with risk of dementia, which has not yet been elucidated. Approach and results : We performed a case–control study nested in a community-based cohort of approximately 6000 Japanese aged 40–69 years at baseline (1984–1994). Serum coenzyme Q10 was measured in 65 incident cases of disabling dementia with dementia-related behavioral disturbance or cognitive impairment incident between 1999 and 2004, and in 130 age-, sex- and baseline year-matched controls. Serum coenzyme Q10 was inversely associated with dementia: the multivariate odds ratios (95% confidence intervals) were 0.68 (0.26–1.78), 0.92 (0.33–2.56), and 0.23 (0.06–0.86) for individuals with the second, third, and highest quartiles of coenzyme Q10, respectively, as compared with the lowest quartile ( P for trend = 0.05). A similar association was found for the coenzyme Q10/total cholesterol ratio: the respective ORs were 0.67 (0.25–1.78), 0.73 (0.28–1.92), and 0.21 (0.05–0.90) ( P for trend = 0.04). Conclusions : Serum coenzyme Q10 levels were inversely associated with risk of disabling dementia.

Objective Studies have shown that elevated high-sensitivity C-reactive protein (hs-CRP) predicts stroke, which is a risk factor for dementia. It remains, however, unclear whether hs-CRP increases risk of dementia. Methods A prospective nested case–control study of Japanese 40–69 years of age was conducted using frozen serum samples collected from approximately 7531men and women who participated in cardiovascular risk surveys from 1984 to 1994 in one community and 1989–1995 in another community under the Circulatory Risk in Communities Study (CIRCS). Two control subjects per case were matched by sex, age, community, and year of serum storage. The hs-CRP was measured using a latex particle-enhanced immunonephelometric assay. Results Between 1999 and 2013, we identified 275 disabling dementia cases (96 cases with history of stroke and 179 without it). There was a positive association between hs-CRP levels and risk of dementia with history of stroke. No significant association was observed between hs-CRP levels and risk of dementia without history of stroke. After adjustment for hypertension, diabetes and other confounding variables, the positive association remained statistically significant. The multivariable odds ratios associated with 1-SD increment of log hs-CRP were 1.02 (0.87–1.20) for total dementia, 1.35 (1.02–1.79) for dementia with history of stroke, and 0.89 (0.72–1.10) for dementia without history of stroke. Conclusion Elevated hs-CRP levels were associated with increased risk of disabling dementia in individuals with history of stroke but not in those without it.

Several studies have reported that height and risk of stroke are inversely associated based on the hypothesis that height is a marker of childhood physical condition. However, a limited number of studies have taken account of the effect of current physical condition on the relationship between height and risk of stroke.We conducted a prospective cohort study of 12,222 40- to 69-year-old Japanese patients under systematic surveillance for stroke incidence. Because body mass index (BMI) is regarded as a surrogate marker of current physical condition for cardiovascular risk, we performed a stratified analysis of this risk based on BMI.During the median 17-year follow-up, there were 565 incident strokes (326 ischemic and 186 hemorrhagic strokes) showing an inverse association between height and risk of stroke independent of classical cardiovascular risk factors. Compared with the lowest height group (159 cm for men and148 cm for women) as reference, the multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the highest height group (166 cm for men and154 cm for women) were 0.70 (95% CI 0.49-1.00; P = .043) for men and 0.44 (95% CI 0.27-0.70; P.001) for women. When the analysis was restricted to those with BMI23 kg/m(2), the associations were stronger for both hemorrhagic and ischemic stroke.Height was found to be inversely associated with risk of stroke for middle-aged Japanese men and women, especially with lower BMIs. Our findings suggest that childhood social and physical conditions may contribute to the development of stroke in adulthood because height is a surrogate marker of these conditions.

Objective The association of adiponectin levels with cardiovascular disease (CVD) may vary by age and health condition. It is unknown whether adiponectin predicts CVD events among individuals with high blood glucose levels. Methods We conducted a nested case–control study among 15,566 men and women aged 40–85 years from four communities, who were free of CVD at baseline. During 192,181 person-years of follow-up, 117 individuals subsequently developed coronary heart disease or ischemic stroke and had high plasma glucose concentrations (fasting/nonfasting ≥ 5.6/7.2 mmol/L or treated) at baseline. Controls were randomly selected at a 2:1 ratio and matched for sex, age, blood glucose, year of survey, fasting conditions, and community ( n = 234). Baseline total and high molecular weight (HMW) adiponectin and their ratio were examined for total subjects and the association with CVD was compared between ages of 40–69 and 70–85 years. Results After adjustment for matched variables and traditional risk factors, total and HMW adiponectin and their ratio were not associated with overall risk of CVD. However, significant interactions of the associations between the age groups were found. The highest quartile for HMW adiponectin and HMW/total adiponectin ratio decreased risk of CVD compared with the lowest quartile among middle-aged individuals (multivariable-adjusted odds ratio = 0.33 [95%CI, 0.13–0.83] and 0.47 [0.22–0.98], respectively), while this association was not seen among the elderly. Conclusions High HMW adiponectin levels may decrease the risk of CVD in middle-aged adults with high blood glucose.

Background Soft drink intake has been associated with obesity and diabetes, but its relation with risk of cardiovascular disease (CVD) is limited. Objective We examined the association between soft drink intake and risk of CVD in a Japanese population. Design This was a prospective study in 39,786 Japanese men and women aged 40-59 y in which soft drink intake was determined by using a self-administered food-frequency questionnaire. Follow-up was from 1990 to 2008. HRs and 95% CIs of incidence were calculated according to categories of soft drink intake. Results During 18 y of follow-up, we ascertained 453 incident cases of ischemic heart disease (IHD) and 1922 cases of stroke, including 859 hemorrhagic and 1047 ischemic strokes. Soft drink intake was positively associated with risk of total stroke and more specifically ischemic stroke for women; the multivariable HR (95% CI) in the highest soft drink intake (almost every day) category compared with the lowest intake (never or rarely) category was 1.21 (0.88, 1.68; P-trend = 0.02) for total stroke and 1.83 (1.22, 2.75; P-trend = 0.001) for ischemic stroke. That association did not change significantly after the exclusion of early incident cases within 3-9 y from baseline. A nonsignificant inverse trend for risks of total and ischemic strokes was shown for men, and it was weakened after the exclusion of early incident cases or after the exclusion of participants with baseline comorbidities. Soft drink intake was not associated with risk of IHD or hemorrhagic stroke for either sex. Conclusion Soft drink intake is associated with higher risk of ischemic stroke for women.

Objective To investigate an effect of smoking cessation on chronic obstructive pulmonary disease (COPD) mortality in Asians. Methods The data was obtained from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). A total of 41465 Japanese men and 52662 Japanese women aged 40–79 years who had no history of COPD, asthma, other chronic lung diseases, cardiovascular disease or cancer were followed between 1988 and 2008. Results During median 18-year of follow-up, there were 285 (251 men and 34 women) documented deaths from COPD. Multivariable-adjusted hazard ratios with 95% confidence intervals of COPD death were 4.46 (2.72–7.29) and 9.26 (4.19–20.5), respectively for current male and female smokers when compared to never smokers. Compared with current smokers, the multivariable HRs for 5–9 years and 10 years or more smoking cessation prior to baseline were 0.44 (0.22–0.87) and 0.36 (0.22–0.58) in men, respectively while the HR for never smokers was 0.30 (0.16–0.57). There were an insufficient number of COPD deaths in women to clarify this association. Conclusion Smoking cessation for ten years or more prior to enrollment reverses the excess risk of COPD mortality to a level similar to that observed among never smokers in men.

Objective The objective was to determine whether non-fasting glucose concentration is a predictor for incident coronary heart disease. Methods We investigated a cohort data of 9,900 40- to 69-year-old residents in four Japanese communities for 1975–1986 baseline surveys of the Circulatory Risk in Communities Study (CIRCS). Non-fasting blood glucose concentrations were available for 7,332 participants. Diabetic type was defined as a glucose level of ≥ 11.1 mmol/L and/or the use of medication for diabetes mellitus. Results A total of 170 coronary heart disease including 113 myocardial infarctions occurred in non-fasting participants within the median 22-year follow-up period. Multivariable hazard ratios (HRs) of incident coronary heart disease for the participants with diabetic type compared with the normal type were 1.98 (0.84–4.68) for men, 3.39 (1.47–7.81) for women, and 2.47 (1.37–4.46) for total subjects. Corresponding HRs for myocardial infarction were 2.14 (0.83–5.55), 5.70 (2.21–14.67) and 3.17 (1.65–6.10), respectively. Multivariable HRs of incident coronary heart disease per one standard deviation of serum glucose levels were 1.17 (1.02–1.36), 1.19 (1.03–1.38), and 1.19 (1.08–1.32), respectively. The corresponding HRs for myocardial infarction were 1.18 (1.00–1.38), 1.27 (1.07–1.49) and 1.23 (1.10–1.37). Conclusion Non-fasting glucose concentration, either as diagnosis of diabetic type or as continuous variable, proved to be an independent predictor for incident coronary heart disease in middle-aged general population.

To determine whether the 9p21 SNP association with coronary heart disease is modified by other classical or novel risk markers.The 9p21 SNP (rs10757274) and multiple risk markers were measured in the Atherosclerosis Risk in Communities Study, and incident coronary disease events were ascertained. Effect modification (interaction) of the 9p21 SNP with risk markers was tested in Cox proportional hazard regression models.The incidence rates of coronary heart disease per 1000 person-years were 14.4, 17.0, and 18.7 for AA, AG, and GG genotypes, yielding hazard ratios of 1.0, 1.20 (95% CI = 1.07-1.36), and 1.34 (95% CI = 1.16-1.53). There was no meaningful evidence of an interaction (all p-interaction0.04) between 9p21 SNP and any of 14 other risk markers for coronary heart disease. These included novel markers not previously explored for 9p21 interaction (e.g., cardiac troponin T and N-terminal pro-brain natriuretic peptide).Our study extends evidence that the 9p21 SNP association with coronary heart disease is not modified by classical or novel risk markers. Our findings therefore rule out additional plausible pathways by which 9p21 might have increased coronary heart disease risk.

Objective Limited evidence has been available on the relationships of cellular growth factors with cardiovascular disease in population-based samples. Methods We conducted a nested case–control study under a large prospective cohort study (JACC study) where a total of 39,242 subjects aged 40–79 years provided serum sample. We measured cellular growth factors [insulin-like growth factors I, II and binding protein-3 (IGF-I, IGF-II and IGFBP-3) and transforming growth factor (TGF-β1)] among cases and controls, matched for sex, age, area of residence and year of serum storage. Results and conclusions During the follow-up for 9 years, there were 233 deaths from total stroke (49 subarachnoid hemorrhages, 55 intraparenchymal hemorrhages, 71 ischemic strokes), and 97 deaths from coronary heart disease. The multivariable odds ratio (95%CI) of intraparenchymal hemorrhage associated with a 1-SD increment of IGF-I (men:4 8 ng/ml, women: 61 ng/ml) was 0.31 (0.14–0.71). That of ischemic stroke associated with a 1-SD increment of TGF-β1 (men: 8.0 ng/ml, women: 10.9 ng/ml) was 0.58 (0.34–0.98). Serum IGF-II and IGFBP-3 were not associated with mortality from any outcomes. In conclusion, IGF-I was inversely associated with mortality from intraparenchymal hemorrhage while TGF-β1 was so with ischemic stroke, suggesting potential roles of cellular proliferation in the development or prognosis of stroke.

Summary Background The associations between alcohol consumption and sleep-disordered breathing in women are uncertain. Methods We conducted a cross-sectional study of 3113 women aged 30–69 years. The 3% oxygen desaturation index (3%ODI), based on overnight pulse oximetry findings, was selected as an indicator of sleep-disordered breathing. Results 3%ODI frequencies of ≥5 were higher for drinking women with ethanol intakes of ≥23.0 g/d than for never drinkers: the respective multivariable odds ratios and 95% confidence intervals was 1.8(1.0–3.4). The corresponding odds ratio was 3.0(1.6–5.8) for habitual snoring. The associations of ethanol intakes of ≥23.0 g/d with 3%ODI ≥ 5 was more evident among women with BMI

Rice is a staple food in Japan and provides 43% of carbohydrate and 29% of energy intake in the Japanese population. In a prospective study encompassing 83,752 Japanese men and women aged 40-79 y, rice intake was determined by self-administered FFQ. Median follow-up time was 14.1 y from 1988-1990 to the end of 2003, and HR and 95% CI of mortality were calculated according to quintiles of energy-adjusted rice intake. A total of 3514 cardiovascular deaths [1640 strokes, 707 coronary heart disease (CHD), and 560 heart failure] were documented. There was a gender difference on the effect of rice intake on the risk of cardiovascular disease (CVD). Overall, rice intake was inversely associated with CHD, heart failure, and total CVD in men but not in women. Rice intake was not associated with risk of stroke in either gender. The multivariable HR (95% CI) for the extreme quintiles of rice intake in men were 0.70 [(0.49-0.99); P-trend = 0.02] for CHD, 0.70 [(0.46-1.05); P-trend = 0.05] for heart failure, and 0.82 [(0.70-0.97); P-trend = 0.006] for total CVD. For women, rice was not associated with reduced risk of mortality from CVD after adjusting for lifestyle and dietary variables. In conclusion, the consumption of steamed rice was associated with reduced risk of mortality from CVD in Japanese men but not women. This finding necessitates further investigations on the mechanisms leading to this gender difference.

Background: Prospective epidemiologic studies have generated mixed results regarding the association between saturated fatty acid (SFA) intake and risk of ischemic heart disease (IHD) and stroke. These associations have not been extensively studied in Asians. Objective: The aim of this study was to test the hypothesis that SFA intake is associated with the risk of cardiovascular disease mortality in Japanese whose average SFA intake is low. Design: The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study) comprised 58,453 Japanese men and women who completed a food-frequency questionnaire. Participants were aged 40–79 y at baseline (1988–1990) and were followed up for 14.1 y. Associations of energy-adjusted SFA intake with mortality from stroke (intraparenchymal and subarachnoid hemorrhages and ischemic stroke) and heart diseases (IHD, cardiac arrest, and heart failure) were examined after adjustment for age, sex, and cardiovascular disease risk and dietary factors. Results: We observed inverse associations of SFA intake with mortality from total stroke [n = 976; multivariable hazard ratio (95% CI) for highest compared with lowest quintiles: 0.69 (0.53, 0.89); P for trend = 0.004], intraparenchymal hemorrhage [n = 224; 0.48 (0.27, 0.85); P for trend = 0.03], and ischemic stroke [n = 321; 0.58 (0.37, 0.90); P for trend = 0.01]. No multivariable-adjusted associations were observed between SFA and mortality from subarachnoid hemorrhage [n = 153; 0.91 (0.46, 1.80); P for trend = 0.47] and heart disease [n = 836; 0.89 (0.68, 1.15); P for trend = 0.59]. Conclusion: SFA intake was inversely associated with mortality from total stroke, including intraparenchymal hemorrhage and ischemic stroke subtypes, in this Japanese cohort. Am J Clin Nutr 2010;92:759–65.

To examine the association between concentrations of serum vitamin C, a contributive factor to prevention of cardiovascular disease and levels of hs-CRP, a risk factor for cardiovascular disease, in population-based samples of middle-aged men and women.A cross-sectional study.The subjects were 778 men and 1404 women, aged 40-69 years, who participated in a cardiovascular risk survey in Kyowa, Ibaraki prefecture in 2002 as part of the Circulatory Risk in Communities Study (CIRCS). Inverse associations between serum vitamin C concentrations and hs-CRP levels were established for both men and women. Multivariable-adjusted mean values of hs-CRP for the lowest to highest quintiles of vitamin C levels were 0.75, 0.65, 0.61, 0.61 and 0.47 mg/L (P for trend0.001) for men, and 0.56, 0.51, 0.49, 0.41 and 0.41 mg/L (P for trend0.001) for women. The inverse association between vitamin C and hs-CRP was stronger for non-smoking men and women, non-overweight women and postmenopausal women.Serum vitamin C concentrations were found to be inversely associated with hs-CRP levels in both men and women, primarily among non-smokers, non-overweight women and postmenopausal women. The respective roles of serum vitamin C and hs-CRP levels in the development of cardiovascular disease thus warrant further investigation.

Summary. Background: Protein C is an important plasma natural anticoagulant. Although protein C deficiency increases risk of venous thrombosis, it remains uncertain whether low protein C increases risk of atherothrombosis. Objective: To examine whether low protein C may be a risk factor for ischemic stroke or coronary events in a prospective population-based study. Patients/Methods: The Atherosclerosis Risk in Communities Study assessed protein C antigen by ELISA at baseline in 1987–89 and followed participants (n = 13 879) for incident ischemic stroke or coronary events through 2005. Results: Over a median of 16.9 years of follow-up, 613 ischemic strokes and 1257 coronary heart disease events occurred. Protein C was inversely associated with incidence of ischemic stroke. Adjusted for multiple risk factors, the rate ratios (95% CIs) from highest to lowest quintiles were 1.0, 1.16 (0.90–1.50), 1.22 (0.94–1.58), 1.18 (0.90–1.55) and 1.52 (1.17–1.98). This inverse association was stronger for non-lacunar and cardioembolic stroke than for lacunar stroke. In contrast, there was a positive association between protein C and coronary heart disease in incompletely adjusted models, but no association after adjustment for plasma lipids. Conclusions: In this cohort study, low protein C was a risk factor for incident ischemic stroke but not coronary heart disease. Levels of protein C associated with stroke risk were not restricted to the traditional ‘deficient’ range for protein C (

Objective We sought to clarify the validity of self-reported stroke and myocardial infarction (MI) among Japanese population, because information on the validity, particularly on the sensitivity, of self-reported cardiovascular disease is limited and may differ among countries. Study Design and Setting Using the 10-year follow-up questionnaire and a stroke and MI registry in the Japan Public Health Center–based prospective Study (JPHC Study) cohort ( n = 91,186), we calculated sensitivity and positive predictive values of self-reported stroke and MI incidence over 10 years. Results Sensitivity of self-reported incident stroke was 73%, and that for MI was 82%. Positive predictive values were 57% for stroke and 43% for MI. The supplemental inclusion of self-reported angina pectoris increased the sensitivity of MI to 89%, but attenuated the positive predictive value to 18%. Sensitivity of self-reported stroke was highest for subarachnoid hemorrhage (88%), but did not differ greatly among other stroke subtypes, affected sites or size. Conclusion Self-reported stroke and MI seem sensitive enough to use for exclusion of stroke and MI at baseline in Japanese cohort studies. However, self-report has too many false positives to be used as the only criterion for incident stroke and MI.

Background Some previous prospective studies showed that dietary intake of ω3 polyunsaturated fatty acids was associated with lower risk of heart failure (HF), but no study has examined the association between plasma fatty acids and HF. Methods We included 3,592 white participants from the Minneapolis field center of the Atherosclerosis Risk in Communities (ARIC) Study, aged 45 to 64 at baseline (1987-1989), initially free of coronary heart disease, stroke, and HF and who had cholesterol ester and phospholipid plasma fatty acids measured. Participants were followed through 2003, and incident HF was defined by a hospital discharge or death including a HF International Classification of Diseases code. Results During the 14.3-year follow-up, we identified 197 cases of HF (110 for men and 87 for women). After adjustment for age and other confounders, higher saturated fatty acids, especially myristic (14:0) acid, were associated positively with incident HF in both men and women. Higher arachidonic (20:3,ω6) and long-chain ω3 polyunsaturated fatty acids, especially docosahexaenoic (22:6,ω3) acid, were associated inversely with HF in women but not in men. Neither plasma α-linolenic nor eicosapentaenoic acid was associated with incident HF. Conclusions In both men and women, greater levels of saturated fatty acids may increase risk of HF. In women, arachidonic acid and long-chain ω3 polyunsaturated fatty acids may decrease risk of HF.

Fish, ω-3 Polyunsaturated Fatty Acids, and Mortality From Cardiovascular Diseases in a Nationwide Community-Based Cohort of Japanese: The JACC (Japan Collaborative Cohort Study for Evaluation of Ca...

A continuous decline in mortality and morbidity from coronary heart disease (CHD) has been documented in the U.S. ([1–4][1]). This decline is accompanied by a reduction in serum total cholesterol levels, which has been attributed to improvements in medical care and community-based prevention

To examine the relationship between metabolic syndrome and endothelial dysfunction, we investigated cross-sectionally the correlation between metabolic risk factors and urinary excretion of cyclic guanosine 3',5'-monophosphate (cGMP), a second messenger of nitric oxide (NO), in 1541 Japanese men and women aged 40-79 years. The 24-h urinary excretion of cGMP was measured using a (125)I-labeled cGMP radioimmunoassay and was adjusted for urinary creatinine excretion (nmol/mmol creatinine). The components of metabolic syndrome were defined based on the following criteria: body mass index (BMI)or =25.0 kg/m(2), fasting plasma glucoseor =6.11 mmol/l or non-fasting plasma glucose levelor =11.1 mmol/l, systolic blood pressureor =130 mm Hg or diastolic blood pressureor =85 mm Hg, high-density lipoprotein (HDL)-cholesterol1.03 mmol/l for men and1.29 mmol/l for women, and triglycerideor =1.69 mmol/l. The number of components of metabolic syndrome correlated inversely with urinary cGMP excretion; means of cGMP excretion for the whole group adjusted for age, sex, and cardiovascular risk factors were 53.6, 48.6, 47.9, 44.4 and 42.3 nmol/mmol for 0, 1, 2, 3, and 4-5 components of metabolic syndrome, respectively (p=0.002). Our data suggest that a reduction of NO bioactivity concur with clustered features of the metabolic syndrome.

Peripheral artery disease correlates with preclinical carotid atherosclerosis in Western populations. However, little is known about this correlation in Asian populations. In a cross-sectional population-based study, we examined the correlation between peripheral arterial disease and carotid intima-media thickness (IMT) among 726 Japanese men aged 60-79 years. None of them had a history of clinical peripheral arterial disease. The ankle-to-arm systolic blood pressure index (AAI) was used as a surrogate estimate of peripheral arterial disease. Compared to men with AAIor =0.90, those with AAI0.90 were 1-4 years older, and had lower mean body mass index and higher prevalence of current smokers. The mean AAI correlated inversely and linearly with maximum IMT in the common and internal carotid arteries (CCA and ICA), and men with AAI0.90 had higher prevalence of maximum ICA IMTor =1.5mm than did those with AAIor =0.90. The multivariate odds ratio (95% confidence interval) of maximum ICA IMTor =1.5mm was 2.9 (1.0-8.4), while that of maximum CCA IMTor =1.1mm was 1.4 (0.5-3.8) for men with AAI0.90 versusor =1.30. The sensitivity was 65% and the specificity was 98% for low AAI to detect ICA IMTor =1.5mm. Low AAI is a strong correlate for internal carotid atherosclerosis and the AAI measurement may be of use to screen for preclinical peripheral atherosclerosis among Japanese elderly men.

Dysfunction of the nitric oxide (NO) system is potentially involved in the development of hypertension, but only limited data are currently available from experimental or clinical studies. We investigated cross-sectionally the relation between urinary excretion of cyclic guanosine 3',5'-monophosphate (cyclic GMP), a second messenger of NO, and hypertension in a general population sample of Japanese men and women. The samples comprised 1541 subjects (788 men and 753 women) aged 40-79 years who participated in cardiovascular risk surveys between 1997 and 2002 and underwent a 24h urine collection. Urinary excretion of cyclic GMP was measured using a 125I-labeled cyclic GMP radioimmunoassay, and was adjusted for urinary creatinine excretion (nmol/mmol creatinine). Urinary cyclic GMP excretion was 66.0+/-62.0nmol/mmol creatinine (mean+/-S.D.). Compared with normal blood pressure individuals, the multivariate-adjusted mean value of urinary cyclic GMP excretion was significantly higher in people with moderate hypertension, but not higher in severe hypertension. Among subjects with hypertensive end-organ damage, we observed reduced urinary cyclic GMP excretion in severe hypertension and no increased excretion in moderate hypertension, compared with normal blood pressure. Although we had the limited number of subjects with severe hypertension (n=15), our data suggest that NO bioactivity may be increase in the early stage of hypertension but decreased in severe hypertension with end-organ damage.

To examine the relation of triglycerides with ischemic heart disease (IHD) among populations with low mean total cholesterol, we conducted a 16-year prospective study of 11,068 Japanese aged 40–69 (4452 men and 6616 women with mean total cholesterol=4.73 and 5.03 mmol/l, respectively), initially free of IHD or stroke. We documented 236 IHD events comprising 133 myocardial infarctions, 68 angina pectoris and 44 sudden cardiac deaths. Median values of serum triglycerides were higher among IHD incident cases than among controls in each of subgroups of time since last meal