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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.

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.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.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.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.

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

Background: The association between overweight and chronic musculoskeletal pain may vary by anatomical site and be modified by hypertension status. This study examined the associations between overweight and low back and knee pains and their effect modification by hypertension status. Methods: We conducted a community-based cross-sectional study involving 2,845 adults (1,080 men and 1,765 women) aged 40–89 years. Chronic knee pain (CKP) and low back pain (CLBP) lasting more than 3 months were categorized into more or less severe pain. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between overweight and more or less severe CKP and CLBP were determined using logistic regression and stratified by hypertension status. Adjustment variables were age, sex, area, hypertension, smoking and drinking status, inactivity, job category, mental stress, depression, and overall CKP or CLBP. Results: Overall, 288 (10.1%) and 631 (22.2%) adults had more and less severe CKP, respectively, and 284 (10.0%) and 830 (29.2%) had more and less severe CLBP, respectively. Overweight was associated with overall CKP and more or less severe CKP, regardless of hypertension status. Overweight was not associated with overall CLBP; its association was more pronounced for more severe CLBP. The association between overweight and more severe CLBP was evident among non-hypertensives (multivariable OR 1.72; 95% CI, 1.09–2.71); however, that between overweight and less severe CLBP was not evident (multivariable OR 1.07; 95% CI, 0.73–1.56). Conclusions: As hypertension may attenuate the association between overweight and CLBP, we should consider hypertension status for proper management of CLBP among overweight individuals.

Aims Although aging is strongly associated with both heart failure and a decline in gait speed, a definition of slowness incorporating an age‐related decline has yet to be developed. We aimed to define an event‐driven cut‐off for the relative decline in gait speed against age‐adjusted reference values derived from the general population and evaluate its prognostic implications. Methods and results Standardized gait speed (SGS) was defined as the median gait speed stratified by age, sex, and height in 3777 elderly (age ≥ 65 years) individuals without a history of cardiovascular diseases (Tokyo Metropolitan Institute of Gerontology‐Longitudinal Interdisciplinary Study on Aging: general population cohort). The mortality event‐driven optimal cut‐off of the SGS ratio (actual gait speed divided by the respective SGS) was defined using FRAGILE‐HF cohort data and externally validated using Kitasato cohort data, comprising 1301 and 1247 hospitalized elderly patients with heart failure, respectively. Using FRAGILE‐HF data, the optimal SGS ratio cut‐off was determined as 0.527. In the Kitasato cohort, SGS ratio

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

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

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

The association between the urinary sodium (Na)/potassium (K) ratio and hypertension is well recognized. We investigated whether the urinary Na/K ratio might be associated with hypertension in community-dwelling older adults and whether the association was influenced by habitual dietary patterns. We enrolled a total of 684 older adults (mean age, 76.8 years) and conducted health examinations at Kusatsu, Japan, in 2021. The urinary Na/K ratio was found to be independently associated with systolic blood pressure (SBP) (p 0.0001), years of education (p = 0.0027), number of cohabitants (p = 0.0175), estimated glomerular filtrate rate (eGFR) (p = 0.0244), and Geriatric Depression Scale short-version (GDS15) score (p = 0.0366). In addition, an unsupervised hierarchical clustering analysis revealed a spectrum of habitual dietary patterns for higher and lower values of the urinary Na/K ratio. The decision tree indicated that the urinary Na/K ratio was associated with the history of milk consumption. A positive history of daily milk consumption predicted a mean urinary Na/K ratio of 2.8, and a negative history of daily milk consumption predicted a mean urinary Na/K ratio of 3.3. Furthermore, the frequency of fruit and vegetable consumption also predicted the urinary Na/K ratio. The relationship between the urinary Na/K ratio and hypertension was influenced by the frequency of consumption of milk, fruits, and vegetables in the subjects. This finding might be due to the influence of education and/or depression. The results suggested the importance of nutritional education in the development of hypertension.

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

Background: The frequency of laughter has been associated with cardiovascular disease and related biomarkers, but no previous studies have examined association between laughter and changes in blood pressure levels. We sought to identify temporal relationships between frequency of laughter in daily life and systolic and diastolic blood pressure changes in participants from 2010 through 2014. Methods: Participants were 554 men and 887 women aged 40–74 years who answered self-administered questionnaire quantifying frequency of laughter at baseline. We measured participant blood pressure levels twice using automated sphygmomanometers for each year from 2010 to 2014. The associations between laughter and changes in blood pressure over time were analyzed using linear mixed-effect models. Results: There was no significant difference in blood pressure according to frequency of laughter at baseline in either sex. Men with frequency of laughter 1 to 3 per month or almost never had significantly increased systolic and diastolic blood pressure levels over the 4-year period (time-dependent difference: 0.96 mm Hg (95% confidence interval [CI], −0.2 to 1.8; P = 0.05). Changes in blood pressure associated with infrequent laughter (ie, 1 to 3 per month or almost never) were evident in men without antihypertensive medication use over 4 years (0.94 mm Hg; 95% CI, −0.2 to 2.0; P = 0.09) and men who were current drinkers at baseline (1.29 mm Hg; 95% CI, −0.1 to 2.3; P = 0.04). No significant difference was found between frequency of laughter and systolic (0.23 mm Hg; 95% CI, −1.0 to 1.5; P = 0.72) and diastolic (−0.07 mm Hg; 95% CI, −0.8 to 0.7; P = 0.86) blood pressure changes in women. Conclusions: Infrequent laughter was associated with long-term blood pressure increment among middle-aged men.

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

The role of serum uric acid as a predictor of stroke among the general Japanese population remains controversial. We conducted a prospective cohort study of 5235 men and 8185 women aged 40-79 years at baseline between 1985 and 1994 in four Japanese communities, who were initially free from stroke, coronary heart disease, and medication for hyperuricemia or gout. Cox proportional hazards models were used to estimate sex-specific hazard ratios of stroke and its types in relation to serum uric acid level. During a median follow-up of 23.1 years, we recorded 1018 (488 men and 530 women) incident strokes, including 222 (99 and 123) intraparenchymal hemorrhages, 113 (33 and 80) subarachnoid hemorrhages and 667 (347 and 320) ischemic strokes. After adjustment for age, community and known cardiovascular risk factors, the multivariable hazard ratios (95% CIs) in the highest vs. lowest quintile of serum uric acid were 1.45 (1.07-1.96) for total stroke, 1.20 (0.65-2.20) for intraparenchymal hemorrhage, 1.46 (0.69-3.09) for subarachnoid hemorrhage and 1.61 (1.07-2.41) for ischemic stroke in women. The corresponding multivariable hazard ratios (95% CIs) in men were 1.02 (0.74-1.35), 0.83 (0.40-1.72), 1.19 (0.38-3.75) and 1.00 (0.70-1.41). Furthermore, those positive associations with risks of total and ischemic strokes in women were more evident in nonusers of antihypertensive medication than the users. In conclusion, elevated serum uric acid level is an independent predictor of total stroke in women but not in men. The positive association in women was mostly attributable to ischemic stroke and was more pronounced among nonusers of antihypertensive medication.

Background: Although an elevated systolic blood pressure (SBP) is associated with cognitive dysfunction, BP may decrease with advanced cognitive dysfunction; therefore, we attempted to identify the turning point in the relationship between cognitive function and SBP in elderly subjects. Methods: In pooled datasets of general populations and outpatient clinics (age>65 years), in which the risk of frailty or cognitive dysfunction was assessed (N = 4076), the relationship between SBP and the Mini Mental State Examination (MMSE) score was examined. Results: Mean age was 72.5 ± 6.2 years (male 45.1%), and SBP was 133.0 ± 19.5 mmHg. In an analysis of locally weighted scatter plot smoothing, the relationship between SBP and MMSE scores changed at an MMSE score of 24 points. In subjects with preserved cognitive function (MMSE ≥24 points), MMSE scores decreased with increases in SBP (B = −0.047 per 10 mmHg increase, P = 0.002) after adjustments for age, sex, body mass index, alcohol habit, smoking status, diabetes, a history of stroke, and the geriatric nutritional index; however, in subjects with reduced cognitive function (MMSE

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

Background: Serum albumin and hemoglobin levels are independently associated with subsequent cognitive deterioration in older adults. This prospective study used repeated measures analysis to identify aging trajectories in serum albumin and hemoglobin levels and investigated if these trajectories were associated with incident disabling dementia among community-dwelling older Japanese. Methods: A total of 2,005 adults aged 65–90 years participated in annual geriatric health assessments during the period from June 2002 through July 2017; the total number of observations was 9,330. A review of a municipal database of the Japanese public long-term care insurance system identified 1,999 of 2,005 adults without dementia at baseline, 278 (13.9%) of whom developed disabling dementia during the follow-up period (June 2002 through December 2017). Results: We identified three trajectory patterns (high, moderate, and low) for serum albumin and hemoglobin levels for the age period 65 through 90 years. After controlling for potential confounders, participants with moderate and low trajectories for serum albumin level had hazard ratios of 1.27 (95% confidence interval 0.94–1.72) and 2.07 (1.37–3.11), respectively, for the development of incident disabling dementia, with the high trajectory group as reference. The respective hazard ratios for hemoglobin level were 1.31 (0.93–1.85) and 1.58 (1.04–2.40), respectively. Conclusion: Dementia risk was higher for individuals with low trajectories for serum albumin and hemoglobin levels. This finding highlights the importance of interventions that improve nutritional status and control relevant diseases in middle-aged and older adults with low serum albumin and hemoglobin levels.

Background Few prospective studies have explored the association between fatty acids (FA) and risk of CAD. Understanding of the role of each individual serum FA as a coronary risk or protective factor is still limited. The aim was to investigate which serum FA are associated with the incidence of CAD in Japanese subjects. Methods and Results: A prospective nested case-control study of 40-85-year-old Japanese subjects was undertaken using frozen serum samples collected from 12,840 participants who participated in cardiovascular risk surveys from 1984 to 1998 for 1 community and 1989-1997 for 2 other communities. Three control subjects per case were matched by sex, age, community, year of serum storage and fasting status. By 2005 we had identified 152 incident cases of CAD. Mean n-3-polyunsaturated and saturated FA did not differ between cases and controls, while mean n-6-polyunsaturated FA was higher in controls compared with cases. The multivariable OR of CAD for the highest vs. lowest quartiles of miristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), and linoleic acid (18:2) were 2.8 (95% CI: 1.5-5.2), 2.7 (95% CI: 1.4-5.5), 3.2 (95% CI: 1.7-6.1) and 0.4 (95% CI: 0.2-0.7), respectively. Conclusions High serum miristic acid, palmitic acid and palmitoleic acid have an adverse effect, and high serum linoleic acid had a protective effect, on the risk of CAD.

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.

Background Evidence on the associations of carotid intima‐media thickness and carotid plaque characteristics with stroke subtypes and coronary artery disease risks in Asians is limited. This study investigated these associations in the Japanese general population. Methods and Results Maximum intima‐media thicknesses of both the common carotid artery and internal carotid artery and carotid plaque characteristics were evaluated in 2943 Japanese subjects aged 40 to 75 years without history of cardiovascular disease. Subjects were followed up for a median of 15.1 years. Using a multivariate Cox proportional hazard model, we found that hazard ratios (HRs) and 95% CIs for the highest (≥1.07 mm) versus lowest (≤0.77 mm) quartiles of maximum intima‐media thicknesses of the common carotid artery were 1.97 (1.26–3.06) for total stroke, 1.52 (0.67–3.41) for hemorrhagic stroke, 2.45 (1.41–4.27) for ischemic stroke, 3.60 (1.64–7.91) for lacunar infarction, 1.53 (0.69–3.41) for nonlacunar cerebral infarction, 2.68 (1.24–5.76) for coronary artery disease, and 2.11 (1.44–3.12) for cardiovascular disease (similar results were found for maximum intima‐media thicknesses of the internal carotid artery). HRs(95% CIs) for heterogeneous plaque versus no plaque were 1.58 (1.09–2.30) for total stroke, 1.25 (0.58–2.70) for hemorrhagic stroke, 1.74 (1.13–2.67) for ischemic stroke, 1.84 (1.03–3.19) for lacunar infarction, 1.58 (0.80–3.11) for nonlacunar cerebral infarction, 2.11 (1.20–3.70) for coronary artery disease, and 1.71 (1.25–2.35) for cardiovascular disease. Conclusions Maximum intima‐media thicknesses of the common carotid artery, maximum intima‐media thicknesses of the internal carotid artery, and heterogeneous plaque were associated with the risks of stroke, lacunar infarction, coronary artery disease, and cardiovascular disease in Asians.

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

Nutritional epidemiology shows that insufficient protein intake is related to senile dementia. The levels of protein intake in aged people are positively associated with memory function, and elderly people with high protein intake have a low risk of mild cognitive impairment. Although the beneficial roles of protein nutrition in maintaining brain function in aged people are well demonstrated, little is known about the mechanism by which dietary intake of protein affects memory and brain conditions. We fed aged mice a low protein diet (LPD) for 2 months, which caused behavioral abnormalities, and examined the nutritional effect of essential amino acid administration under LPD conditions. The passive avoidance test revealed that LPD mice demonstrated learning and memory impairment. Similarly, the LPD mice showed agitation and hyperactive behavior in the elevated plus maze test. Moreover, LPD mice exhibited decreased concentrations of gamma-aminobutyric acid (GABA), glutamate, glycine, dopamine, norepinephrine, serotonin and aspartate in the brain. Interestingly, oral administration of seven essential amino acids (EAAs; valine, leucine, isoleucine, lysine, phenylalanine, histidine, and tryptophan) to LPD mice, which can be a source of neurotransmitters, reversed those behavioral changes. The oral administration of EAAs restored the brain concentration of glutamate, which is involved in learning and memory ability and may be associated with the observed behavioral changes. Although the details of the link between decreased amino acid and neurotransmitter concentrations and behavioral abnormalities must be examined in future studies, these findings suggest the importance of dietary protein and essential amino acids for maintaining brain function.

Highlights • We examined links between medical claims and health check-up data for older adults. • Patients receiving pharmacotherapies were more likely to participate in health checkups. • Patients with intensive disease control were more likely to be aged ≥ 90 years. • Linking these databases can improve evaluations of diseases control in older adults., The Japanese government encourages older adults to participate in annual health checkups designed to detect lifestyle diseases such as hypertension, diabetes, and dyslipidemia. However, individuals who are already being treated for these diseases are unlikely to benefit from health checkup participation. This retrospective cohort study of older adults evaluated the associations of pharmacological treatments for these diseases with health checkup participation and identified the disease control factors among patients receiving treatments. Using medical claims data and health checkup data between September 2013 and August 2014 from 820,215 older adults aged ≥ 75 years residing in Tokyo, Japan, we examined the associations between pharmacological treatments and health checkup participation using binary logistic regression analysis. Next, patients receiving pharmacological treatments were categorized into intensive, moderate, or limited disease control based on their blood pressure, hemoglobin A1c levels, and lipid levels; multinomial logistic regression analyses were used to identify the disease control factors. The results showed that patients receiving pharmacological treatments were more likely (odds ratio: 1.374; P

Although evidence about skeletal muscle mass loss and type 2 diabetes risk has accumulated, little information is available on the combined effect of skeletal muscle mass and abdominal obesity on type 2 diabetes. We examined whether skeletal muscle mass and abdominal obesity were synergistically associated with the prevalence of type 2 diabetes.Skeletal muscle mass and waist circumference (WC) were measured in 1515 Japanese aged 40 to 69 years. Relative muscle mass was calculated as percentage of total skeletal muscle mass in body weight (SMM%). Type 2 diabetes was identified as fasting serum glucose ≥7.0 mmol/L (126 mg/dL), nonfasting serum glucose ≥11.1 mmol/L (200 mg/dL), glycosylated hemoglobin ≥ 6.5%, and/or diabetes medication use.The multivariable-adjusted odds ratio (OR) of prevalent diabetes from the lowest to the third quartile of SMM% compared to the highest quartile gradually increased in both sexes. The association between a high WC and prevalent diabetes was similar. The multivariable-adjusted OR (95% confidence intervals) for the prevalence of type 2 diabetes in the low skeletal muscle mass/high WC group was 3.19 (1.78-5.71) for men and 4.46 (2.09-9.51) for women compared with the high skeletal muscle mass/low WC group. The relative excess risk due to interaction was 2.2 (0.5-3.9) in men and 2.8 (0.2-5.3) in women for an excess burden of type 2 diabetes for low skeletal muscle mass and high WC.Low skeletal muscle mass and abdominal obesity were synergistically associated with presence of type 2 diabetes.背景: 虽然关于骨骼肌肉质量的下降与2型糖尿病风险的证据已有研究, 但关于骨骼肌质量和腹型肥胖对2型糖尿病的联合作用的信息很少。我们研究了骨骼肌质量和腹型肥胖是否与2型糖尿病的患病率协同相关。 方法: 测量1515名40-69岁日本人的骨骼肌质量和腰围。相对肌量以总骨骼肌质量占体重的百分比(SMM%)计算。2型糖尿病被定义为空腹血糖≥7.0 mmol/L(126 mg/dL), 非空腹血糖≥11.1mmol/L(200mg/dL), 糖化血红蛋白≥6 5%, 且或正在使用糖尿病药物。 结果: 相对肌量最低的四分之一与最高四分之一相比, 男性及女性糖尿病患病率的多变量调整优势比(OR)都有所升高。较高腰围和糖尿病发病率之间的联系也是相似的。与高骨骼肌质量/低腰围组相比, 低骨骼肌质量/高腰围组的2型糖尿病患病率多变量调整OR值于男性为3.19(1.78~5.71), 女性为4.46(2.09~9.51)。低骨骼肌质量与高腰围之间的交互作用导致了额外的糖尿病相对风险, 男性为2.2(0.5-3.9), 女性为2.8(0.2-5.3)。 结论: 低骨骼肌质量和腹型肥胖与2型糖尿病发病存在协同关系。.

Background:The effect of postprandial glucose on the risk of cardiovascular disease has been emphasized, but it is controversial whether nonfasting glucose is related to incident stroke and its types. Methods and Results:We investigated the associations of nonfasting glucose with incident stroke and its types among 7,198 participants aged 40–74 years from the Circulatory Risk in Communities Study, enrolled in 1995–2000. We estimated multivariable hazard ratios (HR) using Cox proportional hazard models. Over a median follow-up of 14.1 years, 291 cases of total stroke (ischemic strokes: 191 including 109 lacunar infarctions) were identified. Nonfasting glucose concentration was associated with greater risk of incident total stroke, ischemic stroke and lacunar infarction when modeled categorically (for prediabetic type: 7.8–11.0 mmol/L vs. normal type

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.

Comprehensive risk management for the prevention of cerebro- cardiovascular diseases in Japan

Background In Japan, a community-based screening program for cardiovascular disease (CVD) has been effective in preventing stroke and coronary artery disease (CAD). The present study aimed to clarify which risk factors assessed at the screening examinations affect the incidence of CVD and the magnitude of the association after the late 1990 s.Methods and Results:We conducted a 12.5-year prospective study of 10,612 Japanese residents aged 40-74 years between 1995 and 2000, initially free of CVD and who underwent the screening examinations. During the follow-up, 364 cases of stroke and 137 cases of CAD were identified. The population attributable fraction of stroke was the largest for hypertension (HT; 46%), while the relative risk of stroke was the highest for atrial fibrillation (multivariable hazard ratio, 4.9; 95% confidence interval, 2.9-8.3). The population attributable fraction of CAD was relatively large for HT, current smoking, and high non-high-density lipoprotein cholesterol (20-29%). A dose-response relationship was found between the incidence of these cardiovascular events and the number of comorbid hypertensive subclinical organ damage markers: funduscopic changes, ST-T changes on ECG at rest, proteinuria and low estimated glomerular filtration rate. Conclusions HT and hypertensive subclinical organ damage are significantly associated with incident stroke and CAD at the population level, suggesting that management of HT and assessment of subclinical organ damage in hypertensive subjects at a screening program are still beneficial for community-based CVD prevention.

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.

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

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

Objective The prognostic importance of changes in ischaemic ECG abnormalities over time (especially ST-T abnormalities) among Asians has not been fully investigated. We examined the associations between changes in ischaemic abnormalities upon serial ECG (improvement, persistence, deterioration) and cardiovascular disease (CVD) risk. Methods A prospective study cohort was conducted with 9374 men and women aged 40–69 years in four communities. Participants had multiple ECGs at study entry and during the next 10 years, and were followed up for a median period of 23.0 years. Total CVD (stroke and coronary heart disease) was ascertained under systematic surveillance. ECG abnormalities were defined by the Minnesota Code, ST depression (Code4), abnormal T wave (Code5) and categorised into nine groups (no–no, no–minor, no–major, minor–no, minor–minor, minor–major, major–no, major–minor, major–major) by comparison with the point of entrance and maximum change. Results We documented 1196 CVD events. Compared with no–no abnormality, no–minor, minor–major and major–major in Code4, HRs (95% CI) adjusted for cardiovascular risk factors were 1.19 (1.00–1.42), 1.57 (1.15–2.12) and 1.87 (1.42–2.47). Similar results were observed in Code5. Conclusions Changes in ischaemic ECG abnormalities from none to minor, and minor to major, as well as persistent major abnormalities, were associated with an increased risk of CVD.

Objective We aimed to investigate associations between cardiovascular reactivity to acute stress and sickness absence among Japanese male and female workers, in a prospective study. Methods Among healthy employed Japanese workers who underwent mental health checks between 2006 and 2009, data of 111 participants were analyzed. Changes in blood pressure, pulse rate, peripheral blood flow (PBF), and heart rate variability (HRV) (high frequency [HF] and low frequency [LF]) were calculated using differences between the two tasks, mirror drawing stress [MDS] and a maze task, and the postperiod value. Sickness absence through March 2010 was followed up by mail survey (average follow‐up 2.3 years). Logistic regression analysis was used, adjusting for lifestyle factors. Results Among 12 participants who took sickness absences, eight were owing to mental problems. Changes in the LF during the MDS and maze tasks and LF‐to‐HF ratio during the MDS task were positively associated with all sickness absences (odds ratio [OR], 95% confidence interval [CI]: 2.09, 1.03–4.22; 2.04, 1.09–3.82; and 3.10, 1.46–6.58, respectively). Changes in PBF during the MDS task were also associated with increased risk of sickness absence (OR, 95% CI: 2.53, 1.10–5.81). Conclusion Cardiovascular reactivity to acute stress should be considered at workers' health checks., Changes in the LF during the MDS and maze tasks and LF‐to‐HF ratio during the MDS task were positively associated with all sickness absences. Changes in PBF during the MDS task were also associated with increased risk of sickness absence.

OBJECTIVES: Increase of elderly people, dementia and cognitive decline has been already one of the social problems all over the world. There are a lot of risk factors including dietary composition. Several studies have reported the importance of protein for maintaining brain functions in the elderly, but the details are not well understood. To clarify the relationship between protein intake and brain function in the elderly, we evaluated the effect of low protein diet on cognitive function and psychiatric symptoms in aged mice. METHODS: Male mice at 60 weeks of age were fed a control diet (NPD; casein 20%) or a low protein diet (LPD; casein 5%). To evaluate neurobehavioral abnormality, we performed the elevated plus maze task (Day 64) and Passive avoidance task (conditioning: Day 66, evaluation: Day 67). Cerebral cortex tissues and plasma were measured for free amino acid concentration by LC-MSMS method, and monoamine concentration in cerebral cortex was measured by HPLC method. RESULTS: In the Passive avoidance task, LPD group decreased the time to keep staying in the light box and the rate of individuals entering the dark box during the test period. In the elevated plus maze task, LPD group significantly increased in the number of entry and staying times in open arm. In addition, total travel distance was significantly increased. Moreover, LPD decreased the concentration of not only amino acid in plasma and cerebral cortex but also neurotransmitter such as Glutamate, GABA, Aspartate, Glycine, Dopamine, Norepinephrine, Serotonin. CONCLUSIONS: We found that long-term intake of low-protein diet occurred memory loss and anxiety like behavior in elderly mice. Intracerebral neurotransmitters are mainly synthesized from amino acids, which is transferred from blood, within the brain. Therefore, behavioral change observed in LPD group might be induced by the decrease of neurotransmitters in the brain. FUNDING SOURCES: Ajinomoto Co., Inc.

No study has reported trajectories of kidney function in later life. This long-term prospective study attempted to classify trajectories of estimated glomerular filtration rate (eGFR) and identify factors associated with these trajectories. We collected data from annual geriatric health checkups conducted during 2002–2017 in Kusatsu Town, Gunma Prefecture, Japan. The participants were 1990 adults aged 65–90 years (mean [SD] age, 71.0 [5.7] years; 57.0% women), and the total number of observations was 9291. Data were analyzed with a group-based semiparametric mixture model and age-adjusted univariable cumulative logit models. Trajectory of kidney function, as determined by eGFR, was classified as low, middle, and high (4.8%, 38.9%, and 56.3% of men, respectively, and 5.2%, 31.5%, and 63.3% of women). Among men and women in the low trajectory group, chronic kidney disease (CKD) stage worsened from stage G3a (51.8 ml/min/1.73 m2 in men and 53.6 in women) at age 65 years to stage G4 (28.0 ml/min/1.73 m2 in men and 28.5 in women) by age 85 years. A history of hypertension (men and women) and heart disease (men) were more likely in the low trajectory group than in the middle and high trajectory groups. About 5% of community-dwelling older adults had an eGFR

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.

Background Although frailty and cognitive impairment are critical risk factors for disability and mortality in the general population of older inhabitants, the prevalence and incidence of these factors in individuals treated in the specialty outpatient clinics are unknown. Methods We recently established a frailty clinic for comprehensive assessments of conditions such as frailty, sarcopenia, and cognition, and planned 3-year prospective observational study to identify the risk factors for progression of these aging-related statuses. To date, we recruited 323 patients who revealed symptoms suggestive of frailty mainly from a specialty outpatient clinic of cardiology and diabetes. Frailty status was diagnosed by the modified Cardiovascular Health Study (mCHS) criteria and some other scales. Cognitive function was assessed by Mini-Mental State Examination (MMSE), Japanese version of the Montreal Cognitive Assessment (MoCA-J), and some other modalities. Sarcopenia was defined by the criteria of the Asian Working Group for Sarcopenia (AWGS). In this report, we outlined our frailty clinic and analyzed the background characteristics of the subjects. Results Most patients reported hypertension (78%), diabetes mellitus (57%), or dyslipidemia (63%), and cardiovascular disease and probable heart failure also had a higher prevalence. The prevalence of frailty diagnosed according to the mCHS criteria, cognitive impairment defined by MMSE (≤27) and MoCA-J (≤25), and of AWGS-defined sarcopenia were 24, 41, and 84, and 31%, respectively. The prevalence of frailty and cognitive impairment increased with aging, whereas the increase in sarcopenia prevalence plateaued after the age of 80 years. No significant differences were observed in the prevalence of frailty, cognitive impairment, and sarcopenia between the groups with and without diabetes mellitus, hypertension, or dyslipidemia with a few exceptions, presumably due to the high-risk subjects who had multiple cardiovascular comorbidities. A majority of the frail and sarcopenic patients revealed cognitive impairment, whereas the frequency of suspected dementia among these patients were both approximately 20%. Conclusions We found a high prevalence of frailty, cognitive impairment, and sarcopenia in patients with cardiometabolic disease in our frailty clinic. Comprehensive assessment of the high-risk patients could be useful to identify the risk factors for progression of frailty and cognitive decline.

Cardiovascular stress reactivity is a predictor of atherosclerosis and cardiac events. Dehydroepiandrosterone (DHEA) protects against cardiovascular diseases, but results among previous studies have been inconsistent. We investigated the association between dehydroepiandrosterone-sulfate (DHEA-s) and cardiovascular stress reactivity in Japanese women and men. Among 979 healthy Japanese subjects (641 women and 338 men), serum levels of DHEA-s, systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate, heart rate variability, and peripheral blood flow were measured under rest and two types of task. Mean differences in measured variables during tasks and a post-task period were calculated as changes in stress reactivity. Variables of stress reactivity were adjusted for multiple potential confounding factors. In women, DHEA-s levels showed positive associations with changes in SBP and DBP (standardized beta=0.12, p=0.020; 0.17, 0.002, respectively). Stratification by menopausal status and other lifestyle factors (e.g., smoking status, alcohol consumption) were conducted. Significant positive associations remained in pre-menopausal (standardized beta=0.13, p=0.037; 0.18, 0.005), non-smoking (0.12, 0.010; 0.18

Background The aim of this study was to examine whether the burden of diabetes on cardiovascular disease (CVD) in Japan has increased in recent years.Methods and Results:Three cohorts were established, consisting of Japanese residents aged 40-69 years, in 1992-1995 (n=8,744), 1996-1999 (n=7,996), and 2000-2003 (n=7,273). All participants had follow-up for a median of 10 years. Diabetes was defined according to the following criteria: (1) fasting serum glucose ≥7.0 mmol/L; (2) non-fasting serum glucose ≥11.1 mmol/L; or (3) anti-diabetic treatment at baseline. During follow-up, the number of CVD incidents was 277 in the first, 214 in the second, and 190 in the third cohorts. The prevalence of diabetes increased slightly over time. Adjusting for traditional cardiovascular risk factors, multivariable HR (95% CI) for diabetes as a cardiovascular risk factor were 1.40 (0.91-2.14) in the first, 1.93 (1.25-3.00) in the second, and 2.59 (1.77-3.81) in the third cohorts. The population attributable fraction of CVD due to diabetes was 2.8%, 5.6%, and 12.4%, respectively. Conclusions This is the first study in middle-aged Japanese people to clarify an increased burden of CVD due to diabetes since the early 1990 s. Further efforts are needed to prevent and control diabetes through lifestyle modification and treatment. (Circ J 2016; 80: 2343-2348).

ObjectiveTo assess the association between low serum creatinine levels and an increased risk of type 2 diabetes mellitus and dysglycemia.Research design and methodsWe conducted a retrospective cohort study of 3313 Japanese male workers aged 30–55 years, who underwent annual health check-ups during 2001–2008 and showed no type 2 diabetes mellitus, and underwent follow-up examinations until March 2013. Dysglycemia was defined as a fasting plasma glucose concentration of≥110 mg/dL (6.1 mmol/L), or a non-fasting plasma glucose concentration of≥140 mg/dL (7.8 mmol/L). A Cox proportional model was used to calculate HRs and 95% CIs for developing type 2 diabetes mellitus or dysglycemia.ResultsDuring the median 6.7-year follow-up, there were 207 cases of incident type 2 diabetes mellitus and 596 cases of incident dysglycemia, including 115 cases of type 2 diabetes mellitus among the subjects with normal glucose concentrations at baseline. After adjustment for age, body mass index and known diabetes risk factors, the multivariable HR of type 2 diabetes mellitus for the lowest category of serum creatinine (ConclusionsLow serum creatinine levels were associated with an increased risk of type 2 diabetes mellitus and dysglycemia.

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 To investigate the hypothesis that postmenopausal women demonstrate greater cardiovascular stress reactivity during mental stress tasks than do both premenopausal women and men. METHODS The study included 979 Japanese participants (338 men and 641 women [238 postmenopausal]) aged 16 to 82 years. Blood pressure, heart rate, heart rate variability, and peripheral blood flow were measured at rest and during a mirror drawing stress task and a maze task. Differences between measured variables during tasks and at rest were calculated and considered to represent reactivity to stress. Analyses were adjusted for age and other potential confounding factors. RESULTS After adjusting for multiple factors, significant group effects were found for systolic blood pressure (SBP), diastolic blood pressure, heart rate, low-frequency (LF), LF/high-frequency, and peripheral blood flow (effect size: partial η = 0.015, 0.011, 0.013, 0.013, 0.008, and 0.009, respectively). Postmenopausal women were more reactive than men to stress for SBP (15.4 ± 0.8 versus 11.7 ± 0.6 mm Hg), diastolic blood pressure (10.4 ± 0.6 versus 8.0 ± 0.5 mm Hg), heart rate (2.7 ± 0.5 versus 0.7 ± 0.4 beats/min), LF (23.0 ± 5.2 versus 3.2 ± 3.8 ms/Hz), and peripheral blood flow (-39.0 ± 3.8 versus -25.9 ± 2.8 Laser Doppler Perfusion Units) and more reactive than premenopausal women (p < .050) for SBP (15.4 ± 0.8 versus. 12.4 ± 0.5 mm Hg) and LF/high-frequency (1.7 ± 0.1 versus 1.3 ± 0.1). CONCLUSIONS Postmenopausal Japanese women evidenced greater cardiovascular stress reactivity during mental stress tasks than did Japanese men or premenopausal women. Cardiovascular hyperreactivity could play a role in the higher risks of cardiovascular diseases in postmenopausal women.

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.

Digestion and the absorption of food and nutrients have been considered the only functions of the gastrointestinal (GI) tract. However, recent studies suggest that taste cells in the oral cavity and taste-like cells in the GI tract share many common characteristics (taste receptors and transduction signaling). Over the last two decades, it has been revealed that the GI tract is a chemosensory organ that transfers nutrient information via GI hormone secretion (glucagon-like peptide-1, Peptide YY, oxyntomodulin, glucose-dependent insulinotropic polypeptide and others) and the activation of abdominal vagus afferents. In addition, the information relayed via the abdominal vagus nerve plays an important role in autonomic reflexes. This information, both humoral and neural, contributes to the maintenance of homeostasis (digestion, absorption, metabolism and food intake) in the body. In this review, we provide a brief overview of the following: GI chemosensory molecules, their distribution, the effect of nutrients on GI hormone secretion and the activation of vagus afferent nerves. We also focus on the possibility of clinical applications that control abdominal vagus activity.

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.

Item does not contain fulltext Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure >/=140 mm Hg and a diastolic blood pressure >/= 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.