Whether hyperuricemia (HU) independently predicts cardiovascular disease (CVD) remains debated, whereas chronic kidney disease (CKD) is a well-established risk factor. This study assessed the independent and mediated association of HU in CKD on long-term CVD mortality in a 30-year nationwide Japanese cohort. Data from NIPPON DATA90 participants aged ≥ 30 years enrolled in 1990 and followed for up to 30 years were used. HU was defined as serum uric acid ≥ 416.4 µmol/L, and CKD as an estimated glomerular filtration rate < 60 mL/min/1.73 m² or positive proteinuria. Four baseline categories were created (neither, HU-only, CKD-only, both conditions), and analyzed via Cox models to estimate hazard ratios (HR) for CVD mortality, adjusted for age, sex, hypertension, diabetes mellitus, dyslipidemia, BMI, and history of smoking/alcohol. Among 7,336 participants (58.5

Introduction: The American Heart Association’s new Life’s Essential-8 (LE8) metrics is considered a comprehensive framework for pursuing optimal cardiovascular health (CVH). However, its relationship with carotid atherosclerotic plaque is inadequately studied globally and not clarified in Asians. Hypothesis: We assessed the hypothesis that LE8 CVH is associated with carotid intima-media thickness (CIMT) and carotid plaque among Japanese men. Methods: We cross-sectionally analyzed data from 938 randomly selected asymptomatic men aged 40-79 years participating in the Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA), Kusatsu, Shiga, during 2006-2008. Utilizing diet, physical activity, nicotine exposure, sleep, body mass index, blood lipids, blood glucose, and blood pressure metrics, we quantified and categorized LE8 CVH (high, 80-100 points; moderate, 50-79 points; and low, 0-49 points) as the exposure. Ultrasonography-derived intima-media thickness (IMT) and plaque numbers were quantified from the right and left common carotid artery (CCA) to the internal carotid artery via the carotid bifurcation. The average of these segment-specific IMT values was calculated and defined as the mean CIMT. The prevalence of increased CIMT (mean IMT >1 mm), increased IMT in CCA (mean IMT in CCA >1 mm), and carotid plaque (plaque count ≥1), and the plaque burden (total count) were evaluated as the outcomes. Multivariable (adjusted for age and family history of cardiovascular disease) modified Poisson regression and negative binomial regression analyses were used. Results: Participants (mean [SD] age, 63.7 [10.0] years) had a prevalence of high, moderate, and low CVH of 16.7%, 77.6% and 5.6%, respectively. The prevalences of increased CIMT, increased IMT in CCA, and carotid plaque were 15.0%, 12.6%, and 77.5%, respectively. Compared to individuals with high CVH, those with moderate and low CVH had a higher risk (risk ratio [95% confidence interval]) of increased CIMT (2.06 [1.23-3.43] and 3.04 [1.53-6.05], respectively), increased IMT in CCA (2.01 [1.14-3.56] and 2.87 [1.28-6.46], respectively), and carotid plaque (1.09 [0.99-1.20] and 1.17 [1.01-1.36], respectively), and had a relative increase in the expected plaque counts (1.34 [1.14-1.59] and 1.65 [1.24-2.18], respectively). Conclusions: Lower LE8 CVH is associated with a higher risk of CIMT and carotid plaque in Japanese men. Healthy lifestyle practices may reduce the risk of subclinical carotid atherosclerosis.

Hypertension, encompassing white-coat hypertension (WCH), masked hypertension (MH), and sustained hypertension (SH), is an established risk factor for cardiovascular diseases (CVDs), including atherosclerosis. However, among the general population, findings on which target organ is affected by the different phenotypes of hypertension remain unclear. In this community-based observational study of Shiga Epidemiological Study of Subclinical Atherosclerosis, 740 Japanese men underwent brain magnetic resonance imaging to assess the presence of lacunar infarction, white-matter hyperintensities, microbleeds, and intracranial artery stenosis (ICAS) between 2012 and 2015. They also underwent office blood pressure (BP) measurements, home BP monitoring for at least five consecutive days, and coronary artery calcification (CAC) assessments between 2010 and 2014. The final analysis included 686 participants without a history of CVDs. Of the 686 participants, the mean age ( ± SD) was 68.0 ( ± 8.3) years, and 39.3% were taking antihypertensive medication. In multivariable-adjusted models, each of WCH, MH, and SH was significantly associated with a higher risk of microbleeds compared to normotension. However, the association of WCH with microbleeds was evident only among those on antihypertensive medication (adjusted odds ratio [OR] 6.75 [95% CI 1.83–24.86]) and absent in those not on such medication (adjusted OR 1.20 [95% CI 0.31–4.73]). SH was associated with lacunar infarction, ICAS, and CAC. Among Japanese men, WCH, MH, SH were associated with subclinical cerebrovascular diseases, whereas only SH was associated with CAC. Moreover, any elevated BP phenotype increased the risk of microbleeds. Our findings suggest that different hypertension phenotypes distinctly affect target organs, particularly the brain and heart.

BACKGROUND:Circulating n-3 polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), have been linked to brain structural integrity. However, much of the existing evidence stems from Western populations with relatively low n-3 PUFA exposure. Data from Japan-where fish consumption and n-3 PUFAs concentrations are substantially higher-remain scarce, and few studies have contrasted the differential associations of DHA and eicosapentaenoic acid (EPA) with brain structure. OBJECTIVES:The aim of our study was to examine the association between circulating EPA, DHA, and EPA + DHA concentrations and brain volume in older Japanese women. METHODS:This cross-sectional study included 527 community-dwelling women aged 60 to 85 y residing in Kusatsu City, Shiga, Japan. Serum concentrations of EPA and DHA were measured using gas chromatography, and their combined concentration (EPA + DHA) was calculated. Brain volume (total brain, gray matter, white matter, and hippocampal volume) was assessed using 1.5-Tesla magnetic resonance imaging. Analysis of covariance was performed to compare the adjusted mean values for brain volume according to the quartile of EPA, DHA, and EPA + DHA concentrations. Covariates included age, total intracranial volume, body mass index, years of education, smoking and drinking status, step count, diabetes, hypertension, and statin use. RESULTS:Participants' mean age was 74.2 y. Serum concentrations of DHA were significantly and positively associated with gray matter volume (P for trend = 0.036), whereas EPA concentrations were not. Notably, serum concentrations of EPA + DHA exhibited a positive trend with gray matter volume (P for trend = 0.085). No significant associations were found between EPA, DHA, or EPA + DHA concentrations and white matter volume, total brain volume, or hippocampal volume. CONCLUSIONS:DHA exhibits a stronger positive association with gray matter volume than EPA, for which associations are limited, supporting the importance of DHA-rich diets for healthy brain aging.

Introduction Most studies have examined ‘perceived harm of heated tobacco products (HTPs)’ relative to combustible cigarettes (CCs). However, there is a lack of understanding regarding whether the public perceives HTPs as harmful in an absolute sense and whether this perception varies according to smoking status. Therefore, we examined the perceived absolute harm of HTPs (not relative to CCs) across different smoking statuses.Methods We surveyed 8229 respondents (3292 females) online in Japan in 2020. Analyses were stratified by sex because of corresponding differences in smoking rates in Japan. Logistic regression was performed to calculate the ORs, adjusted for potential confounders, including age and education, of agreeing with the statements ‘HTP does little harm to self’ and ‘HTP does no harm to others’ among current smokers (CC-only, HTP-only and dual users) in reference to current non-smokers.Results Current male smokers, particularly HTP users, were more likely to agree with ‘little harm to self’ than current non-smokers: ORs (95% CI, 1.64 (1.27 to 2.12), 3.08 (2.25 to 4.20) and 4.78 (3.82 to 5.97) in CC-only, HTP-only and dual users, respectively. The corresponding ORs of agreeing with ‘no harm to others’ in male smokers were 1.95 (1.58 to 2.42), 5.40 (4.15 to 7.01) and 4.78 (3.90 to 5.85). The results for females were qualitatively similar to those of males.Conclusions Regardless of sexes, current smokers, particularly HTP users, tended to perceive HTP to do little harm to themselves and no harm to others in an absolute sense than current non-smokers. Providing accurate and up-to-date health information regarding HTP is crucial in minimising potential health risks to both smokers and non-smokers.

Background and aims:The American Heart Association's Life's Essential-8 (LE8) cardiovascular health (CVH) metrics is considered a comprehensive framework for optimal cardiovascular wellbeing. However, its relationship with the progression of subclinical atherosclerosis, like coronary artery calcification (CAC), is not clarified. We investigated the associations of LE8 CVH metrics with the prevalence and progression of CAC in Japanese men. Methods:We analyzed data from 760 asymptomatic men participating in the Shiga Epidemiological Study of Subclinical Atherosclerosis. We assessed baseline (2006-2008) LE8 CVH (low, 0-49 points; moderate, 50-79 points; high, 80-100 points) using its eight components (diet, physical activity assessed by step count, smoking, sleep, body mass index, blood lipids, blood glucose, blood pressure). We quantified CAC at baseline and follow-up of 5 years employing Agatston's method and defined its baseline prevalence (CAC >0) and progression (employing Berry's criteria). Modified Poisson regression analyses were used to estimate risk ratio (RR) and 95 % confidence interval (CI), adjusted for age and family history of cardiovascular disease. Results:Participants (mean [SD] age, 63.8 [9.4] years) had 63.2 % and 44.9 % prevalence of CAC at baseline and CAC progression at follow-up, respectively. Individuals with moderate and low CVH at baseline had a higher risk of prevalent CAC (RR [95 % CI], 1.42 [1.18-1.71] and 2.07 [1.67-2.57], respectively) at baseline, compared to those with high CVH. Those with moderate and low CVH at baseline had a higher risk of CAC progression (RR [95 % CI], 1.52 [1.17-1.97] and 1.99 [1.42-2.81], respectively), compared to high CVH individuals. Conclusions:A lower LE8 CVH is significantly associated with a higher risk of prevalence and progression of CAC in general Japanese men.

Decreased bone mineral density (BMD) is associated with atherosclerosis in postmenopausal women and older men. Limited research has explored this relationship in middle-aged men. Aortic calcification (AC) is a novel biomarker for aortic atherosclerosis. This study aimed to examine whether baseline BMD is associated with the progression of AC in an international multi-ethnic cohort of middle-aged men participating in the ERA-JUMP Study (The Electron-Beam Tomography Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort). We hypothesized that higher BMD at baseline would be associated with less progression of AC. This analysis included participants who completed two visits an average of 5.69 years apart. Participants (mean age: 45.3 + 2.9) were recruited from population-based samples in the United States (Pennsylvania and Hawaii) and Japan (Shiga). All participants were free of clinical cardiovascular disease at baseline. BMD was measured via electron-beam tomography images of the T12 to L4 vertebrae. AC was evaluated from the aortic arch to the iliac bifurcation with computed tomography and scored via the Agatston Scoring Method. Incidence of AC was defined as an AC score <100 at baseline and ≥ 100 at follow-up. Linear regression was employed to assess the association between baseline BMD and changes in AC (Visit 2 – Visit 1). Model 1 adjusted for follow-up time, age, and race/ethnicity. Model 2 was further adjusted for cardiovascular risk factors: hypertension, diabetes, LDL-C, HDL-C, and lipid medication. Model 3 additionally adjusted for BMI and smoking status. Logistic regression, with the same models, was used to assess the association between baseline BMD and incident AC at Visit 2. At baseline, the average BMD was 173.1 HU (+ 37.1), and the median AC score was 3.0. The median change in AC score was 39.76 (IQR: 0- 220.3). There were 159 incident cases of AC in the cohort. Baseline BMD was inversely associated with the change in AC in Models 1, 2 (p<0.05) and Model 3 (p<0.1). Similarly, baseline BMD was inversely associated with incident AC in Models 1, 2 (p<0.05), and Model 3 (p=0.10). Our findings suggest that skeletal and cardiovascular health may be linked in middle-aged healthy men. Higher baseline BMD appears to be associated with reduced progression and lower incidence of AC. These results underscore the need for further longitudinal studies to confirm this relationship and explore its clinical implications.

AIMS:Continued low mortality from coronary heart disease in Japan, despite deleterious changes in traditional risk factors, remains unexplained. Since aortic calcification (AC) was an early predictor of cardiovascular mortality, we compared the progression and incidence of AC between Japanese in Japan, white Americans, and third-generation Japanese Americans in the ERA JUMP cohort. We examined whether higher blood levels of marine-derived n-3 fatty acids (FAs) in Japanese than in Americans accounted for the difference. METHODS AND RESULTS:Men (n = 700) aged 40-49 years (252 Japanese in Japan, 238 white, and 210 Japanese Americans) were examined at baseline and 4-7 years later. AC was evaluated from the aortic arch to the iliac bifurcation with computed tomography and quantified by the Agatston method. Robust linear regression and linear mixed models were used to compare the progression of AC. Multivariable logistic regression models were fitted to compare the incidence of AC (AC ≥ 50 at follow-up) among those with baseline AC < 50. Japanese in Japan had a significantly slower progression of AC than white and Japanese Americans after adjusting for age, baseline AC, follow-up time, and traditional risk factors. White Americans had a significantly higher incidence of AC than Japanese in Japan [OR = 4.61 (95% CI, 1.27-16.82)]. Additional adjustment for blood levels of n-3 FAs accounted for the difference in AC incidence but not progression. CONCLUSION:Japanese in Japan had a significantly slower progression and lower incidence of AC than white Americans. High levels of marine-derived n-3 FAs in Japanese in Japan partly accounted for the difference in incidence.

Introduction Intracranial subclinical vessel diseases are considered important indicators of cognitive impairment. However, a comprehensive assessment of various types of vessel disease, particularly in Asian populations, is lacking. We aimed to compare multiple types of intracranial vessel disease in association with cognitive function among a community-based Japanese male population. Methods The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) randomly recruited and examined a community-based cohort of Japanese men from Shiga, Japan. We analyzed those who underwent the Cognitive Abilities Screening Instrument (CASI) assessment and cranial magnetic resonance imaging/angiogram (MRI/MRA) in 2010–2015. Using MRI/MRA, we assessed lacunar infarction, microbleeds, periventricular hyperintensity (PVH), deep and subcortical white matter hyperintensity (DSWMH), and intracranial artery stenosis (ICAS). We divided these subclinical cerebrovascular diseases (SCDs) into three categories according to severity. Using linear regression, we calculated the CASI score according to the grade of each vessel disease, adjusted for age and years of education. Results In the adjusted models, CASI scores were significantly associated with both PVH and DSWMH. Specifically, multivariable-adjusted CASI scores declined across increasing severity categories of DSWMH (91.7, 91.2, and 90.4; P for trend = 0.011) and PVH (91.5, 90.4, and 89.7; P for trend = 0.006). Other SCDs did not show significant associations. In stratified analyses based on the presence or absence of each SCD, both DSWMH and PVH demonstrated significant inverse trends with CASI scores in the absence of lacunar infarcts and microbleeds and in the presence of ICAS. Additionally, among participants with PVH (+), ≥Moderate ICAS was significantly associated with lower CASI scores. Conclusions PVH and DSWMH showed significant dose-response relationships with cognitive function among community-based Japanese men. These findings suggest that white matter lesions may be an important indicator of early cognitive impairment, and severe ICAS may also play a role in those with PVH.

BACKGROUND:While cholesterol-lowering trials have consistently demonstrated cardiovascular disease (CVD) benefits, some observational studies showed an elevated mortality risk from all-cause, CVD, and cancer in those with low total cholesterol (TC). This inconsistency is likely due to confounding. OBJECTIVE:We explored potential confounders through various analytical approaches such as exclusion and adjustment. METHODS:Using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, we analyzed all-cause, CVD, and cancer mortality in individuals aged 35 to 69, not on cholesterol-lowering medication at baseline. We applied cohort-stratified Cox proportional hazards models to estimate the hazard ratio (HR) and 95% CI of the lowest TC group (<160 mg/dL) in reference to 160 to <200 mg/dL, after excluding self-reported CVD and cancer at baseline. RESULTS:A total of 55,677 participants were followed over 10.1 years. Initially, the lowest TC group, compared to the reference group, had significantly elevated risks for all-cause and cancer mortality. Excluding liver diseases and adjusting for serum albumin at baseline attenuated the association to non-significant; HR (95% CI) of all-cause, cancer mortality in men: 1.37 (0.99-1.87), 1.06 (0.66-1.71), respectively. The corresponding values for women were 0.96 (0.46-2.02), 1.39 (0.58-3.34). For CVD mortality, the HR in men with low TC remained elevated, while women were nonsignificant regardless of liver diseases exclusion and albumin-adjustment. CONCLUSION:Elevated all-cause and cancer mortality in low TC individuals was likely confounded by baseline liver diseases and serum albumin. Further research is needed to identify additional confounders.

BACKGROUND:Deterioration in lifestyle associated with poor mental health could be an important concern during the coronavirus disease 2019 (COVID-19) pandemic. However, few studies have investigated the association between mental health status and lifestyle changes during the pandemic in nationwide Japanese general population. METHODS:This cross-sectional study was conducted using the data among 1,546 participants of the follow-up study of NIPPON DATA2010 in 2021. Recent mental status, as assessed using the Kessler 6 (K6) scale, and lifestyle changes compared to before the pandemic were determined using self-reported questionnaires. Some lifestyle changes such as decreased physical activity were defined as undesirable, whereas others such as decreased alcohol drinking were defined as desirable. The participants were divided into three groups based on the K6 scores: the K6<5, 5≤K6<9, and K6≥9 groups. The odds ratios (ORs) and 95% confidence intervals (CIs) of the K6 groups for each lifestyle change compared with that in the K6<5 group were estimated after adjusting for possible confounders. RESULTS:The ORs of the K6≥9 group for all undesirable lifestyle changes were significantly high, especially increased alcohol drinking (OR 4.64; 95% CI, 2.71-7.93), and decreased physical activity (OR 4.63; 95% CI, 3.29-6.52). Among the desirable changes, the OR of the 5≤K6<9 group was significantly high for increased eating home cooking. CONCLUSIONS:Poor mental health showed a significant association with undesirable lifestyle changes, especially increased alcohol drinking and decreased physical activity, in a nationwide general Japanese population during the COVID-19 pandemic.

Equol is a metabolite produced by the gut microbiota from the soy isoflavone daidzein. Previous studies identified bacteria capable of converting daidzein to equol. We investigated whether equol producers among Japanese with a high soy intake contained these bacteria. We also examined differences in equol production status between urine and serum and how the gut microbiota differs between these statuses. To minimize the potential confounding effects of hormonal variability in women, this cross-sectional study analyzed 853 Japanese men. Urinary and serum isoflavones were collected in the morning after fasting and were analyzed using LC-MS/MS. By applying a finite mixture model for each log(10) equol/daidzein ratio, we defined equol producers and non-producers from urine and serum. Among 669 participants with fecal microbial measurements, the 16S rRNA gene was sequenced on a MiSeq System. The cut-off values for the log(10) equol/daidzein ratio were -0.94 for urine and -0.95 for serum. Equol production status in urine and serum matched in 97 %, and equol producers from urine or serum were 42 %. The microbiota was more diverse in producers than in non-producers; the genus Senegalimassilia included strains with high sequence identity (>98 %) to daidzein reductase. The family Oscillospiraceae and class Clostridia also had approximately 46 %-48 % sequence identity. The equol production status of fasting urine and serum almost matched among a general population of Japanese men. Although we did not detect a microbiota with known daidzein reductase in equol producers, several shared similar sequences; these may include equol-producing bacteria that have not yet been identified.

AIM:The aim of this study was to clarify the association between serum total cholesterol and fatal subarachnoid hemorrhage in Japanese men and women. METHODS:The study involved a pooled analysis of individual data from 12 well-qualified cohort studies conducted in Japan. The participants were classified according to their serum total cholesterol levels: ＜4.14 mmol/L (＜160 mg/dL), 4.14-4.64 mmol/L (160-180 mg/dL), 4.65-5.16 mmol/L (180-199 mg/dL), 5.17-5.68 mmol/L (200-219 mg/dL), 5.69-6.20 mmol/L (220-239 mg/dL), and ≥ 6.21 mmol/L (≥ 240 mg/dL). The outcome of the analysis was death from subarachnoid hemorrhage. RESULTS:A total of 120,973 participants (70,947 women and 50,026 men) aged 18-96 years at baseline underwent follow-up for a median of 12.7 years, and 261 participants died from subarachnoid hemorrhage during this period. In women, both low (＜5.69 mmol/L [＜220 mg/dL]) and high (≥ 6.21 mmol/L [≥ 240 mg/dL]) serum total cholesterol levels were significantly associated with a higher risk of fatal subarachnoid hemorrhage compared with the reference group (5.69-6.20 mmol/L [220-239 mg/dL]). These associations remained significant after adjustment for confounding factors. In contrast, no associations were observed in men. CONCLUSION:Both low and high serum total cholesterol levels were associated with a higher risk of fatal subarachnoid hemorrhage in 70,947 female participants from 12 cohort studies throughout Japan.

AIM:Sedentary behavior and physical inactivity increase the risk of cardiometabolic diseases. It is important to evaluate physical activity in daily life and understand the influence of these factors on cardiometabolic diseases in the Japanese population, which tends to have a prolonged sitting time. We examined the association between sedentary behavior and physical inactivity, characterized by extended television (TV) viewing and low step counts, which are easily monitored and modifiable, and cardiometabolic risk factors in the Japanese population. METHODS:This cross-sectional study included 2,531 Japanese adults (1,087 men and 1,444 women) 20-91 years old, randomly selected throughout Japan. TV viewing was assessed using a self-reported questionnaire, and step counts were measured using pedometers. Cardiometabolic risk factors were determined using physical examinations or blood samples. The association between sedentary behavior and physical inactivity with each risk factor was examined using a cross-sectional analysis with multivariate-adjusted logistic regression models. RESULTS:In both sexes, longer TV viewing positively correlated with low high-density lipoprotein (HDL) cholesterol and high triglycerides (TG). In women, TV viewing time is associated with obesity and increased abdominal circumference (AC). Conversely, in men, lower step counts were positively associated with obesity and increased AC, low HDL cholesterol, and high TG levels. CONCLUSIONS:The association between prolonged TV viewing and cardiometabolic risk factors was more pronounced in women than in men, whereas the influence of lower step counts was stronger in men than in women. These findings contribute to the improvement of cardiovascular health by monitoring and managing individual screen times and step counts in daily life.

Background: Increasing physical activity may prevent cognitive decline. Previous studies primarily focused on older adults and used self-reported questionnaires to assess physical activity. We examined the relationship between step count, an objective measure of physical activity, and cognitive function in community-based middle-aged and older Japanese men. Methods: The Shiga Epidemiological Study of Subclinical Atherosclerosis randomly recruited communitydwelling healthy men aged 40-79 years from Shiga, Japan, and measured their step counts over 7 consecutive days using a pedometer at baseline (2006-2008). Among men who returned for follow-up (2009-2014), we assessed their cognitive function using the Cognitive Abilities Screening Instrument (CASI) score. We restricted our analyses to those with valid 7-day average step counts at baseline and those who remained free of stroke at follow-up (n = 676). Using analysis of covariance, we calculated the adjusted means of the CASI score according to the quartiles of the average step counts. Results: The mean (standard deviation) of age and unadjusted CASI score were 63.8 (9.1) years and 90.8 (5.8), respectively. The CASI score was elevated in higher quartiles of step counts (90.2, 90.4, 90.6, and 91.8 from the lowest to the highest quartile, respectively, [p for trend = 0.004]) in a model adjusted for age and education. Further adjustment for smoking, drinking, and other cardiovascular risk factors resulted in a similar pattern of association (p for trend = 0.005). Conclusion: In apparently healthy middle-aged and older Japanese men, a greater 7-day average step count at baseline was associated with significantly higher cognitive function score.