Circulating Small Extracellular Vesicles Involved in Systemic Regulation Respond to RGC Degeneration in Glaucoma.

Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by progressive retinal ganglion cell (RGC) degeneration and vision loss. Since irreversible neurodegeneration occurs before diagnosable, early diagnosis and effective neuroprotection are critical for glaucoma management. Small extracellular vesicles (sEVs) are demonstrated to be potential novel biomarkers and therapeutics for a variety of diseases. In this study, it is found that intravitreal injection of circulating plasma-derived sEVs (PDEV) from glaucoma patients ameliorated retinal degeneration in chronic ocular hypertension (COH) mice. Moreover, it is found that PDEV-miR-29s are significantly upregulated in glaucoma patients and are associated with visual field defects in progressed glaucoma. Subsequently, in vivo and in vitro experiments are conducted to investigate the possible function of miR-29s in RGC pathophysiology. It is showed that the overexpression of miR-29b-3p effectively prevents RGC degeneration in COH mice and promotes the neuronal differentiation of human induced pluripotent stem cells (hiPSCs). Interestingly, engineered sEVs with sufficient miR-29b-3p delivery exhibit more effective RGC protection and neuronal differentiation efficiency. Thus, elevated PDEV-miR-29s may imply systemic regulation to prevent RGC degeneration in glaucoma patients. This study provides new insights into PDEV-based glaucoma diagnosis and therapeutic strategies for neurodegenerative diseases.

Total protein intake and subsequent risk of chronic kidney disease: the Circulatory Risk in Communities Study.

BACKGROUND: Whether dietary protein intake worsens renal function in the general population has been discussed but not yet determined. We aimed to examine the longitudinal association between dietary protein intake and risk of incident chronic kidney disease (CKD). METHODS: We conducted a 12-year follow-up study with 3,277 Japanese adults (1,150 men and 2,127 women) aged 40-74 years, initially free from CKD, who participated in cardiovascular risk surveys from two Japanese communities under the Circulatory Risk in Communities Study. The development of CKD was defined by the estimated glomerular filtration rate (eGFR) during the follow-up period. Protein intake was measured at baseline by using the brief-type self-administered diet history questionnaire. We estimated sex-, age-, community- and multivariate-adjusted hazard ratios (HR) for incident CKD were calculated using the Cox proportional hazards regression models according to quartiles of percentage of energy (%energy) from protein intake. RESULTS: During 26,422 person-years of follow-up, 300 participants developed CKD (137 men and 163 women). The sex-, age-, and community-adjusted HR (95% confidence interval, CI) for the highest (≥16.9%energy) versus lowest (≤13.4%energy) quartiles of total protein intake was 0.66 (0.48-0.90), p for trend = 0.007. The multivariable HR (95%CI) was 0.72 (0.52-0.99), p for trend = 0.016 after further adjustment for body mass index, smoking status, alcohol drinking status, diastolic blood pressure, antihypertensive medication use, diabetes mellitus, serum total cholesterol levels, cholesterol-lowering medication use, total energy intake, and baseline eGFR. The association did not vary by sex, age, and baseline eGFR. When examining animal and vegetable protein intake separately, the respective multivariable HRs (95%CIs) were 0.77 (0.56-1.08), p for trend = 0.036, and 1.24 (0.89-1.75), p for trend = 0.270. CONCLUSIONS: Higher protein intake, more specifically animal protein intake was associated with a lower risk of CKD.

Predictors of herpes zoster severity and immune responses according to pain trajectories: A community-based prospective cohort study.

The authors aimed to identify determinants of the clinical course of herpes zoster and immunological responses, focusing on pain trajectories. This prospective community-based cohort study involved the analysis of responses to a valid pain survey provided by 375 patients diagnosed with herpes zoster based on clinical symptoms and virus identification by polymerase chain reaction. The authors analyzed most patients for humoral/cell-mediated immune response against varicella-zoster virus at the onset and 3 months post-onset. Six months post-initial visit, patients self-reported pain on a scale of 0 (no pain) to 5 (extremely strong pain) at up to 18 time points. Moreover, the pain trajectories were traced using group-based trajectory modeling. Subsequently, the authors used analysis of covariance to explore predictors and the humoral/cell-mediated immune response according to the pain trajectories. In addition, humoral/cell-mediated immune responses were assessed among each trajectory using paired t tests. Amon the five identified trajectories, two were isolated that particularly developed postherpetic neuralgia, with or without severe acute pain. Cancer therapy and corticosteroid use before herpes zoster onset specifically predicted postherpetic neuralgia without severe acute pain. In contrast, prescription of nonsteroidal anti-inflammatory drugs was uniquely associated with postherpetic neuralgia accompanied by severe acute pain. The aforementioned trajectories with postherpetic neuralgia showed increased antibodies and decreased cell-mediated immunity compared with those without postherpetic neuralgia. The authors could successfully distinguish between postherpetic neuralgia trajectories with and without severe acute pain. The identified key predictors and immunological responses against varicella-herpes zoster contribute further evidence to our understanding of the clinical features of herpes zoster and postherpetic neuralgia.

Trends in stroke, cardiovascular disease, and medical expenditure under a community-based long-term stroke prevention program.

BACKGROUND: Evidence on the effects of preventive measures for noncommunicable disease is urgently needed for low-income and middle-income countries suffering from stroke epidemics along with population aging. OBJECTIVES: We sought to examine the impact of a community-based stroke prevention program on incidences of stroke and ischemic heart disease, mortality from cardiovascular disease, and medical expenditure. METHODS: Trends in the incidences of stroke and ischemic heart disease were documented in a Japanese rural community, Kyowa, from 1981 through 2015. Trends in mortality from cardiovascular disease and in medical expenditures were compared between Kyowa and its surrounding municipalities from 1981 through 2004. RESULTS: In Kyowa, the age-and-sex-adjusted incidences of stroke and of ischemic heart disease decreased by half (from 4.1 to 1.9 and from 1.5 to 0.7 per year/1000 persons, respectively) over the past 35 years. A similar decreasing trend was observed for the age-and-sex-adjusted mortality from cardiovascular disease, and this decreasing trend occurred earlier than that in the surrounding municipalities. The medical expenditures for cardiovascular disease became lower in Kyowa than in the surrounding municipalities over time. CONCLUSION: Our study's findings suggest that a community-based stroke prevention program augmented the decline in the incidences of stroke and ischemic heart disease, mortality from cardiovascular disease, and attenuated the increase in medical expenditures for cardiovascular disease.

Body Mass Index and Mortality from Nonrheumatic Aortic Valve Disease among Japanese Men and Women.

AIM: We aimed to examine the impact of overweight and obesity on mortality from nonrheumatic aortic valve disease. METHODS: 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. RESULTS: 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/m2, 1.71 (0.81-3.58) for BMI 23-24.9 kg/m2, 1.65 (0.69-3.94) for BMI 25-26.9 kg/m2, and 2.83 (1.20-6.65) for BMI ≥ 27 kg/m2 (p for trend=0.006), compared with persons with BMI 21-22.9 kg/m2. Similar associations were observed between men and women (p for interaction=0.56). Excluding those who died during the first ten years of follow-up or a competing risk analysis with other causes of death as competing risk events did not change the association materially. CONCLUSIONS: Overweight and obesity may be independent risk factors for nonrheumatic aortic valve disease mortality in Asian populations.

Alcohol Consumption and Long-Term Mortality in Men with or without a History of Myocardial Infarction.

AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Alcohol consumption of 23-45 g/day was associated with a lower CHD mortality in MI survivors as so in men without MI.

Relationships between Age at Menarche and Risk of Cardiovascular Disease Mortality among Japanese Women: The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) Study.

AIM: In this study, we aimed to evaluate the association between age at menarche and risk of cardiovascular disease mortality. METHODS: 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. RESULTS: 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. CONCLUSIONS: Both women with early and late age at menarche were determined to have higher risk of death from stroke and cardiovascular disease.

Smoking Cessation and Mortality from Aortic Dissection and Aneurysm: Findings from the Japan Collaborative Cohort (JACC) Study.

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Cigarette smoking was associated with an increased risk of aortic mortality while smoking cessation was so with a reduced risk among the Japanese population.

Trends for the Association between Body Mass Index and Risk of Cardiovascular Disease among the Japanese Population: The Circulatory Risk in Communities Study (CIRCS).

AIM: 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. METHODS: 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/m2). RESULTS: From 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. CONCLUSION: 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.

Breakfast Type and Cardiovascular Mortality: The Japan Collaborative Cohort Study.

AIM: Little is known regarding the association between breakfast type and cardiovascular mortality. We examined the associations between breakfast type and risks of mortality from stroke, coronary heart disease (CHD), and total cardiovascular disease (CVD). METHODS: A total of 85,319 males and females aged 40 to 79 years who were free from CVD and cancers at baseline were involved in this study. The participants were divided into five groups according to their self-reported breakfast types: Japanese breakfast, Western breakfast, mixed Japanese-Western breakfast, other breakfast, and skipping breakfast groups. All hazard ratios (HRs) were estimated using Cox proportional hazards regression models after adjusting for the potential confounding factors. RESULTS: During the median 19-year follow-up, we identified CVD deaths of 5,870 subjects. Compared to the Japanese breakfast, the multivariable HRs (95% CIs) of total CVD were 0.64 (0.52-0.79) for mixed Japanese-Western breakfast, 0.90 (0.77-1.04) for Western breakfast, 1.24 (0.95-1.61) for other breakfast, and 1.31 (1.00-1.71) for skipping breakfast. The corresponding HRs (95% CIs) of total stroke were 0.67 (0.49-0.91), 0.83 (0.66-1.05), 1.15 (0.76-1.74), and 1.25 (0.82-1.92), and those of CHD were 0.73 (0.48-1.12), 1.08 (0.81-1.44), 1.09 (0.60-1.98), and 1.77 (1.11-2.83). CONCLUSION: Compared to Japanese breakfast, mixed Japanese-Western breakfast may have a protective role in cardiovascular mortality whereas skipping breakfast may harm cardiovascular health.

Trends in the incidence of stroke and its subtypes from 1963 to 2018 in Japanese urban and rural communities: The Circulatory Risk in Communities Study (CIRCS).

BACKGROUND: Few studies have provided observational data on long-term trends in the incidence of stroke and its subtypes, and shown the urban-rural disparities of stroke incidence in Japan. METHODS: A multiple-source, community-based stroke surveillance was performed since 1963/1964 to determine all first-ever stroke cases among Japanese residents aged ⩾40 years living in the Minami-Takayasu district in Yao city, an urban community, and Ikawa town, a rural community. Sex-specific, age-standardized incidence per 1000/year with 95% confidence intervals was calculated during seven periods of 1963/1964-1971 (urban population (% men): 3242 (47.3%); rural population (% men): 2311 (46.0%)), 1972-1979, 1980-1987, 1988-1995, 1996-2003, 2004-2011, and 2012-2018 (13,307 (46.7%); 3586 (44.8%)). RESULTS: The age-standardized incidence of all strokes in the Japanese urban community decreased from 6.60 to 1.15 per 1000/year for men and 3.28 to 0.59 for women. In the rural community, the corresponding incidence decreased from 11.51 to 1.98 for men and 6.46 to 1.31 for women. Similar reductions were observed in the incidence of intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke, and lacunar stroke. In the period of 2012-2018, the incidence ratios (95% confidence intervals) of all strokes for the rural compared to the urban community were 1.72 (1.08-2.75) for men and 2.23 (1.23-4.03) for women. CONCLUSION: The stroke incidence continued to decline in both urban and rural Japanese communities with the regional disparities over the past half century, whereas it remained higher than that in many Western countries.

Changes in cardiovascular disease risk factors during menopausal transition in Japanese women: the Circulatory Risk in Communities Study (CIRCS).

OBJECTIVE: We aimed to longitudinally clarify the changes in cardiovascular disease risk factors associated with menopause in Japanese women in the 2000s. METHODS: Of the 4,596 women who underwent health examinations between 2007 and 2012 in three communities of the Circulatory Risk in Communities Study, 263 women who reported going through menopause during that period were included in the study. We randomly selected 1,665 men as control subjects who participated in a health examination at least once between 2001 and 2009 and at least once between 2010 and 2018 by 1:1 pair-matching for age, community, and examination year. The health examination data from 3 to 6 years before (2001-2009) and after menopause age (2010-2018) were compared in terms of body mass index, systolic and diastolic blood pressure levels, serum total cholesterol, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, triglycerides, uric acid, hemoglobin A 1c , hemoglobin, aspartate aminotransferase, alanine aminotransferase, and current smoker status. RESULTS: Compared with the men, the women showed a greater increase in serum total cholesterol (+16.7 vs -3.1 mg/dL, P < 0.001), non-high-density lipoprotein cholesterol (+15.9 vs -6.3 mg/dL, P < 0.001), fasting triglycerides (+1.2 vs +1.0 mg/dL, P = 0.027), triglycerides regardless of fasting status (+1.2 vs -0.9 mg/dL, P < 0.001), uric acid (+0.5 vs +0.2 mg/dL, P = 0.008), hemoglobin (+0.9 vs -0.3 g/dL, P < 0.001), aspartate aminotransferase (+2.9 vs -2.7 IU/L, P < 0.001), and alanine aminotransferase (+2.9 vs -2.6 IU/L, P < 0.001). No differences were found in the changes in body mass index, systolic and diastolic blood pressures, and hemoglobin A 1c between the women and the matched men. CONCLUSIONS: Menopause may be a crucial factor related to changes in serum total cholesterol, non-high-density lipoprotein cholesterol, triglycerides, uric acid, hemoglobin, and liver enzymes.

The Associations between Evacuation Status and Lifestyle-Related Diseases in Fukushima after the Great East Japan Earthquake: The Fukushima Health Management Survey.

BACKGROUND: This study aimed to investigate the association between evacuation status and lifestyle-related disease risks among Fukushima residents following the Great East Japan earthquake. METHODS: Fukushima health management survey respondents were classified into non-evacuees, returnees, evacuees in lifted areas, and evacuees in banned areas. During a seven-year follow-up, 22,234 men and 31,158 women were included. Those with a history of diabetes, hypertension, or dyslipidemia at baseline were excluded. The odds ratios of risk factors (ORs) and 95% confidence intervals (CIs) for diabetes, hypertension, and dyslipidemia were calculated using a logistic regression model. Spatial autocorrelation of the prevalence of these diseases in the Fukushima area in 2017, was calculated to detect the disease prevalence status. RESULTS: The risks of diabetes, hypertension, and dyslipidemia were higher in evacuees in banned areas than in non-evacuees; the multivariable ORs were 1.32 (95% CI: 1.19-1.46), 1.15 (1.06-1.25), and 1.20 (1.11-1.30) for diabetes, hypertension, and dyslipidemia, respectively. Returnees and evacuees in lifted areas had no increased risk of diseases. The area analyzed had a non-uniform spatial distribution of diabetes, hypertension, and hyperlipidemia, with clusters around Fukushima and Koriyama. CONCLUSION: Our findings imply the need for continuous support for evacuees in banned areas.

Retinal microvascular abnormalities and risks of incident stroke and its subtypes: The Circulatory Risk in Communities Study.

BACKGROUND: This study aimed to investigate the association between retinal microvascular abnormalities and the risk of incident stroke and its subtypes in the general Japanese population. METHODS: A total of 12 965 residents aged 40-74 years without a history of stroke and/or coronary heart disease underwent retinal photography during the annual health checkups of four Japanese communities between 1990 and 1999. Retinal microvascular abnormalities, such as the presence or absence of generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar light reflex, and retinal hemorrhages were graded using standard protocols. RESULTS: During a median follow-up of 20 years, 817 patients were diagnosed with incident stroke. Retinal microvascular abnormalities were positively associated with the risk of total stroke; after adjustment for age, sex, community, SBP, antihypertensive medication use, and other cardiovascular risk factors, the multivariable hazard ratio [95% confidence interval (CI)] was 1.68 (1.42-1.98), 1.67 (1.34-2.07), 1.41 (1.17-1.72), 1.54 (1.26-1.87), and 1.57 (1.19-2.07) for generalized arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar light reflex, and retinal hemorrhages, respectively. Similar positive associations were observed for the risk of stroke subtypes, except for subarachnoid hemorrhage, for which no association was observed. Furthermore, the positive associations were similar in participants with and without hypertension. CONCLUSION: Retinal microvascular abnormalities were positively associated with the risk of incident stroke in the general Japanese population. Routine retinal photography could provide positive clinical insights into stroke risk stratification independent of blood pressure, antihypertensive medication use, and other risk factors.

Association between Dietary Manganese Intake and Mortality from Cardiovascular Disease in Japanese Population: The Japan Collaborative Cohort Study.

AIM: Manganese (Mn) is an essential element in the human body, and it has a significant impact on cardiovascular risk factors such as diabetes, blood pressure, and cholesterol levels. However, no research has been conducted on the association between Mn and cardiovascular disease (CVD), to the best of our knowledge. This study thus examined the association between dietary Mn intake and CVD mortality in the general Japanese population. METHODS: The CVD mortality among 58,782 participants from the Japan Collaborative Cohort Study (JACC) aged 40-79 years was determined during a median follow-up period of 16.5 years. The Mn intake was estimated using a food frequency questionnaire at the baseline (1989-1990), and multivariate-adjusted hazard ratios (HRs) for mortality were computed according to quintiles of energy-adjusted Mn intake. RESULTS: During the follow-up period, a total of 3408 CVD deaths were recorded. Participants in the highest quintile of Mn intake had a lower risk of mortality from total stroke (HR:95% CI, 0.76: 0.64-0.90), ischemic stroke (HR: 0.77, 0.61-0.97), ischemic heart disease (HR: 0.76, 0.58-0.98), and total CVD (HR: 0.86, 0.76-0.96) compared with those in the lowest quintile. The reduced risk of mortality from intraparenchymal hemorrhage with high Mn intake was observed among women (HR: 0.60, 0.37-0.96) but not men (HR: 0.93, 0.59-1.47). The observed associations were more robust in postmenopausal than in premenopausal women. CONCLUSIONS: Our study is the first to show the prospective association between dietary Mn intake and reduced risk of mortality from CVD in the Japanese population.

Association between Serum Uric Acid and Impaired Endothelial Function: The Circulatory Risk in Communities Study.

AIMS: Higher serum uric acid (UA) may impair endothelial function. However, population-based evidence examining the association between serum UA levels and endothelial function remains to be limited. Thus, in this study, we aimed to investigate this in the general population. METHODS: In this cross-sectional study, 1000 participants (496 males and 504 females), aged 30-79 years, free from a history of gout, have undergone both serum UA and brachial artery flow-mediated dilation (FMD) measurements. Participants were divided into four groups based on serum UA quartiles. Logistic regression models were used to calculate odds ratios (ORs) for low FMD according to the serum UA levels. RESULTS: In total, 203 participants (138 males and 65 females) with %FMD ≤ 5.0% were identified to have endothelial dysfunction. The multivariable OR of low FMD for highest quartiles vs. lowest quartiles was 2.39 (95% confidence interval [CI]: 1.32-4.34), while OR per 1-standard deviation (SD) increment was 1.28 (95% CI: 1.04-1.56). The positive association was noted to be more evident in females (OR per 1-SD increment: 1.46; 95% CI: 1.08-1.96) than in males and confined to individuals not using antihypertensive medications. The ORs per 1-SD increment were 1.01 (95% CI: 0.68-1.50) among individuals using antihypertensive medications and 1.43 (95% CI: 1.12-1.81) among individuals not using antihypertensive medications. CONCLUSION: Higher serum UA was positively associated with the prevalence of endothelial dysfunction in samples of the general Japanese population and that positive association was confined to individuals not using antihypertensive medications.

Impact of Major Cardiovascular Risk Factors on the Incidence of Cardiovascular Disease among Overweight and Non-Overweight Individuals: The Circulatory Risk in Communities Study (CIRCS).

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.

Leukocyte Count and Risks of Stroke and Coronary Heart Disease: The Circulatory Risk in Communities Study (CIRCS).

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.

Smoking cessation, weight gain and risk of cardiovascular disease.

OBJECTIVE: To examine whether the relationship between smoking cessation and risk of cardiovascular disease (CVD) was modified by weight gain. METHODS: A total of 69 910 participants (29 650 men and 46 260 women) aged 45-74 years were grouped into six groups by smoking status in the first and 5-year surveys: sustained smokers, recent quitters according to postcessation weight gain (no weight gain, 0.1-5.0 kg, >5.0 kg), long-term quitters and never smokers. Quitting smoking within and longer than 5 years were defined as recent and long-term quitters, respectively. We used Cox proportional hazard models to estimate the HR for incident CVD, coronary heart disease (CHD) and stroke. RESULTS: We identified 4023 CVDs (889 CHDs and 3217 strokes) during a median of 14.8 years of follow-up. Compared with sustained smokers, the multivariable HR (95% CI) for CVD was 0.66 (0.52 to 0.83) for recent quitters without weight gain, 0.71 (0.55 to 0.90) for recent quitters with weight gain of 0.1-5.0 kg, 0.70 (0.44 to 1.10) for recent quitters with weight gain of >5.0 kg, 0.56 (0.49 to 0.64) for long-term quitters, and 0.60 (0.55 to 0.66) for never smokers. The analysis restricted to men showed a similar association. Prespecified analysis by age suggested that recent quitters overall had a lower HR for CVD among those aged <60 years vs ≥60 years. Similar patterns of association were observed in CHD and stroke. CONCLUSIONS: Postcessation weight gain did not attenuate the protective association between smoking cessation and risk of CVD.

Non-alcoholic beverages intake and risk of CVD among Japanese men and women: the Japan Public Health Center study.

The association between the intake of non-alcoholic beverages and CVD in Asians is uncertain. The intake of non-alcoholic beverages was estimated in 77 407 participants of the Japan Public Health Centre-based cohort study aged 45-74 years. The Cox regression calculated the hazard ratios (HR) and 95 % CI for incident CVD according to sex-specific quintiles of intake of non-alcoholic beverages. A total of 4578 incident CVD (3751 strokes and 827 CHD) were diagnosed during a 13·6-year median follow-up. The risks of stroke and total CVD were lower for the highest v. lowest intake quintiles of non-alcoholic beverages in men and women: the multivariable HRs (95 % CIs) were 0·82 (0·71, 0·93, Ptrend = 0·005) and 0·86 (0·76, 0·97, Ptrend = 0·02), respectively, in men and were 0·73 (0·63, 0·86, Ptrend = 0·003) and 0·75 (0·65, 0·87, Ptrend = 0·005), respectively, in women. The reduced risk was evident for both ischaemic and haemorrhagic strokes and was mainly attributable to green tea consumption. The intake of non-alcoholic beverages from coffee and other beverages was not associated with the risk of CVD in both men and women. Also, there was no association between the intake of non-alcoholic beverages and the risk of CHD in either sex. In conclusion, the risks of stroke and total CVD were lower with a higher intake of non-alcoholic beverages in Japanese men and women.