Association between physical activity, occupational sitting time and mortality in a general population: An 18-year prospective survey in Tanushimaru, Japan.

AIMS: It is well known that a decline in physical activity is associated with an increase of all-cause death including cardiovascular events and cancer. Few studies have examined the association between occupational sitting time and mortality. Therefore, we investigated this issue in a general population. METHODS: Physical activity and occupational sitting time were measured using the Baecke physical activity questionnaire in 1999. The questionnaire generated indices in three physical activity categories: work, sport and leisure-time. A total physical activity index was calculated by adding these three indices. The Baecke physical activity questionnaire was able to evaluate occupational sitting time. Hazard ratios and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard regression models. RESULTS: We enrolled a total of 1680 participants, who were followed up for 15.9 ± 3.8 years. The final follow-up rate was 93%. During the follow-up period, 397 subjects died. A significant inverse association (p < 0.0001) was found between physical activity and mortality after adjustment for age and sex. Compared with lower levels of physical activity, the adjusted hazard ratio for mortality at higher levels of physical activity was 0.85 (95% CI: 0.78-0.92). Longer occupational sitting time was also significantly associated with higher mortality (p < 0.01). The adjusted hazard ratio for mortality at longer occupational sitting time was 1.16 (95% CI: 1.05-1.27). These findings were observed in males, but not in females. CONCLUSIONS: Our data demonstrated that higher levels of physical activity are associated with a reduced risk of cancer and cardiovascular death. Further, longer occupational sitting time is associated with increased mortality.

Thrombospondin-2 as a Potential Risk Factor in a General Population.

Serum thrombospondin-2 (TSP-2) is a glycoprotein expressed in the extracellular matrix (ECM), which increases during tissue remodeling. It has been shown in recent studies that TSP-2 is a useful predictor of cardiovascular death in patients with heart failure (HF). However, the clinical importance of serum TSP-2 levels in a general population is still unknown. Therefore, we aimed to clarify the association between TSP-2 and clinical risk factors. A periodic epidemiological survey was performed in a community dwelling in the town of Uku, Nagasaki, Japan. A total of 445 residents received a health checkup examination including blood tests such as fasting serum levels of TSP-2. Uni- and multivariate analyses were performed to examine the relationship between TSP-2 and clinical risk factors. All statistical analyses were performed using SAS v9.4 program. The mean ± standard deviation of age was 67.0 ± 9.4 years old. Although serum TSP-2 levels (mean: 20.9 ± 8.5 ng/mL) showed no significant sex difference, they were significantly correlated with the levels of plasma glucose (P < 0.001), insulin (P < 0.01), homeostasis model assessment of insulin resistance (HOMA-IR) (P < 0.001), estimated glomerular filtration rate (eGFR) (P < 0.01, inversely), high-sensitivity C-reactive protein (hs-CRP) (P < 0.001), history of atrial fibrillation (P < 0.001), history of cardiovascular diseases (P < 0.001), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (P < 0.001). Moreover, in the multiple stepwise linear regression analysis, the levels of TSP-2 were independently and significantly associated with the history of atrial fibrillation (P < 0.0001), HOMA-IR (P < 0.001), high-sensitivity CRP (P = 0.011), and NT-proBNP (P = 0.043). These results indicated the significant relationship between TSP-2 and clinical risk factors in a general population, suggesting its role as a predictor of heart disease morbidity and mortality.

Twenty-four-Hour Urinary Potassium Excretion, But Not Sodium Excretion, Is Associated With All-Cause Mortality in a General Population.

BACKGROUND: Few studies have examined the relationship between accurate monitoring of sodium or potassium consumption and mortality. We aimed to investigate the association between 24-hour urinary sodium or potassium excretion and ≈30-year mortality in a Japanese population using 24-hour urine collection. METHODS AND RESULTS: We enrolled a total of 1291 participants, aged 21 to 85 years, who underwent health checkups, including a blood test and 24-hour urine collection. They were followed up for 27.5±9.9 years by December 31, 2015, and the final follow-up rate was 95.8%. Cox proportional hazards regression analysis was used to assess the association between 24-hour urinary sodium or potassium excretion and all-cause mortality. At baseline, the mean 24-hour urinary sodium and potassium excretions were 5.80±2.28 g/d and 1.85±0.82 g/d, respectively. There were 631 deaths during the follow-up. The cumulative survival rate was significantly decreased in the lowest quartile compared with the other higher groups. In the Cox proportional hazard model after adjustment for age and sex, 24-hour urinary potassium excretion, but not sodium excretion, was inversely associated with all-cause mortality. We divided the 24-hour urinary potassium excretion levels into quartiles. After adjustment for confounding factors, the hazard ratio of all-cause mortality in the highest quartile of 24-hour urinary potassium excretion versus the lowest was 0.62 (95% confidence interval, 0.48-0.79; P<0.001). CONCLUSIONS: The 24-hour urinary potassium excretion, but not sodium excretion, was significantly associated with all-cause mortality in the general population.

Impact of cystatin C and microalbuminuria on cognitive impairment in the population of community-dwelling Japanese.

BACKGROUND AND AIMS: Cognitive impairment is an important element affecting our well-being, and as such, early diagnosis is critical today. We investigated whether serum cystatin C and microalbuminuria are associated with cognitive impairment. METHODS: A total of 1943 subjects (774 males, 1169 females, mean age 65.8 years) took part in the investigation, and underwent a health examination in Tanushimaru, Japan, in 2009. The participants' cognitive function was evaluated using of mini-mental state examination (MMSE). We measured the levels of serum cystatin C using latex nephelometric immunoassay. Spot urine samples were used to measure microalbuminuria levels. Multivariate linear regression analyses were used to assess the relationship between MMSE scores and the level of cystatin C or microalbuminuria. All statistical analyses were performed using the SAS system. RESULTS: The mean values of log-transformed serum cystatin C levels and log-transformed microalbuminuria were 0.95 (range 0.41-7.11) mg/L and 10.7 (range 1.1-2600) mg/g·Cr, respectively. The means of MMSE score were 27.7 ± 2.5. In the multivariate linear regression analyses adjusted for age and sex, MMSE was significantly associated with systolic blood pressure (p = 0.024, inversely), cystatin C (p = 0.046, inversely) and microalbuminuria (p = 0.019, inversely), whereas estimated glomerular filtration rate (eGFR) had an insignificant association (p = 0.197). In the multiple stepwise linear regression analysis, age, history of stroke, systolic blood pressure, serum cystatin C were independently associated with MMSE levels. CONCLUSIONS: We demonstrated for the first time that cognitive function was significantly and inversely associated with cystatin C and microalbuminuria, in the relatively younger general population.

Elevated Plasma Transforming Growth Factor ß1 Levels Predict the Development of Hypertension in Normotensives: The 14-Year Follow-Up Study.

BACKGROUND: Transforming growth factor ß1 (TGF-ß1) is a multifunctional cytokine. There is growing evidence that TGF-ß1 is involved in the pathogenesis of hypertension and the development of target organ damage in hypertensives. Although several studies have shown that TGF-ß1 induced vascular hypertrophy and remodelling in various vascular diseases, there are no longitudinal data on hypertension in the epidemiological studies. The present study tested the hypothesis whether elevated TGF-ß1 levels can predict the development of hypertension. METHODS: In 2002-2004, 528 subjects received health examinations in Uku town, southwestern Japan. We examined blood pressure (BP), body mass index, and blood test. Data on fasting plasma TGF-ß1 were obtained from 528 individuals. Of these, 149 normotensives (BP <140/90 mm Hg without antihypertensive medications) at baseline were followed-up for 14 years. RESULTS: The receiver-operating characteristic curve was used and the calculated cutoff value was 8.9 ng/ml. Of 149 normotensives at baseline, 59 subjects developed hypertension. Plasma TGF-ß1 levels were significantly associated with the development of hypertension after adjustment for confounding factors. To further examine the association between them, we performed logistic regression analysis. We divided the baseline plasma TGF-ß1 levels into 2 groups using a cutoff value. The significant high odds ratio [3.582 (95% confidence interval, 1.025-12.525)] for the development of hypertension was found in the highest group of TGF-ß1 level vs. the lowest group after adjustment for confounders. CONCLUSIONS: This is the first report demonstrating the causal relationship between them. Elevated plasma TGF-ß1 levels predicted the development of hypertension in normotensives in a population of community-dwelling Japanese.

A Useful Tool As a Medical Checkup in a General Population-Bioelectrical Impedance Analysis.

Accumulation of visceral fat leads to metabolic syndrome and increases risks of cerebro-cardiovascular diseases, which should be recognized and improved at the early stage in general population. Accurate measurement of visceral fat area (VFA) is commonly performed by the abdominal cross-sectional image measured by computed tomography scan, which is, however, limited due to the radiation exposure. The bioelectrical impedance analysis (OMRON, HDS-2000 DUALSCANR) has been recently developed to measure VFA, which is more easily accessible modality. In the present study, we investigated the clinical usefulness of DUALSCANR in 226 subjects who received health examination, including blood chemistries, electrocardiography, cardio, and carotid ultrasonography. VFA was measured within only just 5 min. Average of VFA was 83.5 ± 36.3 cm2 in men, and 64.8 ± 28.0 cm2 in women, which was correlated to weight (r = 0.7404, p < 0.0001), body mass index (BMI) (r = 0.7320, p < 0.0001), and waist circumstance (r = 0.7393, p < 0.0001). In multivariate analyses, VFA was significantly associated with weight (p < 0.0001), BMI (p < 0.0001), and waist circumstance (p < 0.0001). Compared to the group of smaller waist and normal BMI, VFA was significantly increased (p < 0.0001) in the group of larger waist and obese subjects. In conclusion, these results indicated that DUALSCANR is useful to measure VFA easily in general population, even in a large number of subjects.

Trends in coronary risk factors and electrocardiogram findings from 1977 to 2009 with 10-year mortality in Japanese elderly males - The Tanushimaru Study.

BACKGROUND: An understanding of the trends in regard to coronary risk factors and electrocardiogram (ECG) findings has an important role in public health. We investigated the trends in coronary risk factors and main ECG findings in 1977, 1989, 1999, and 2009 in the Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town on Kyushu Island. METHODS AND RESULTS: A total of 1397 subjects (231 in 1977, 332 in 1989, 389 in 1999, and 445 in 2009) were enrolled in this study, and all of them were males aged over 65 years. In coronary risk factors, total cholesterol levels, diastolic blood pressure, body mass index, and uric acid significantly increased during these 3 decades. The prevalence of smokers markedly decreased from 56.7% in 1977 to 16.8% in 2009. ECG changes during 3 decades were wider QRS interval, increased prevalence of major abnormality, reduced heart rate, shortened PR interval and corrected QT, and decreased prevalence of left ventricular hypertrophy. Age, smoking habits, major and minor abnormalities in ECG were associated with mortality in 1977-1987. Age, total cholesterol levels (inversely) and corrected QT were associated with mortality in 1989-1999. Age, smoking habits, heart rate, and systolic blood pressure were associated with mortality in 1999-2009. CONCLUSIONS: Predictors of mortality have changed with the times. Coronary risk factors such as smoking, increased heart rate, and elevated blood pressure have been recently associated with mortalities in elderly male Japanese general population.

Augmentation index (AI) in a dose-response relationship with smoking habits in males: The Tanushimaru study.

We investigated the relationship between augmentation index (AI) and smoking habits in community-dwelling Japanese.This cross-sectional study enrolled 1926 subjects (769 males and 1157 females) aged 40 to 95 years who underwent a health check-up in a Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town in Kyushu Island in 2009. The subjects' medical history, alcohol intake, smoking habit, and current medications for hypertension, dyslipidemia, and diabetes were ascertained by questionnaire. Radial arterial pressure wave analysis was used to obtain AI. We analyzed the data stratified by gender.Age-adjusted means of AI in males showed a clear dose-response relationship in 4 categories of smoking habits (P = 0.010). There was no significant relationship between AI and smoking habits in females (P = 0.127). The significant dose-response relationship (P = 0.036) in males between AI and 4 categories of smoking habits still remained even after adjustment for age, body mass index, systolic blood pressure, estimated glomerular filtration rate, glucose, hypertensive medication, and alcohol intake.The present study demonstrated that AI values were significantly associated with smoking habits in a dose-dependent manner in Japanese males.

Serum Albumin and Cerebro-cardiovascular Mortality During a 15-year Study in a Community-based Cohort in Tanushimaru, a Cohort of the Seven Countries Study.

Objective There is little long-term data on the association between the serum albumin levels and mortality in community-based populations. We aimed to determine whether the serum albumin level is an independent risk factor for all-cause and cause-specific death in a community-based cohort study in Japan. Methods In 1999, we performed a periodic epidemiological survey over a 15-year period in a population of 1,905 healthy subjects (783 males, 1,122 females) who were older than 40 years of age and who resided in Tanushimaru, a rural community, in Japan. Over the course of the study, we periodically examined the blood chemistry of the study subjects, including their serum albumin levels. Their baseline serum albumin levels were categorized into quartiles. Results The baseline albumin levels were significantly associated with age (inversely), body mass index (BMI), diastolic blood pressure, lipid profiles [high density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c) and triglycerides] and estimated glomerular filtration rate (eGFR). After adjusting for confounders, a Cox proportional hazards regression analysis demonstrated that a low serum albumin level was an independent predictor of all-cause death [hazard ratio (HR): 0.39, 95% confidence interval (CI): 0.24-0.65], cancer death (HR: 0.43, 95% CI: 0.18-0.99), death from infection (HR: 0.21, 95% CI: 0.06-0.73) and cerebro-cardiovascular death (HR: 0.19, 95% CI: 0.06-0.63). The HRs for all-cause and cerebro-cardiovascular death in the highest quartile vs. the lowest quartile of albumin after adjusting for confounders were 0.59 (95%CI:0.39-0.88) and 0.15 (95%CI: 0.03-0.66), respectively. Conclusion The serum albumin level was thus found to be a predictor of all-cause and cerebro-cardiovascular death in a general population.

Plasma heat shock protein 27 is increased in renal dysfunction and habitual smoking in a Japanese general population.

BACKGROUND: Heat shock proteins (HSPs) work as "chaperones" to affect protein folding of newly synthesized or denatured proteins. HSP 27 plays an important role in coronary artery disease or renal disease as the result of oxidative stress. Although habitual smoking is well known to induce oxidative stress, there is no epidemiological evidence between plasma HSP 27 and renal dysfunction or smoking habits. METHODS: A total of 451 residents (167 men and 284 women, age 65.7 years) underwent a history and physical examination, and determination of blood chemistries, including plasma levels of HSP 27. HSP 27 levels were measured by using enzyme-linked immunosorbent assay kits. RESULTS: Elevated HSP 27 levels were independently associated with estimated glomerular filtration rate (eGFR) (p<0.001) and smoking habits (p<0.05). HSP 27 levels were significantly decreased stratified by groups of eGFR (p<0.001 for trend) by analysis of co-variance (ANCOVA) adjusted for age, sex, and smoking habits. HSP 27 levels were increased with more smoking of cigarettes. In particular, HSP 27 levels were increased in the heavy smokers (≥20cigarettes/day) by ANCOVA adjusted for age, sex, and eGFR compared with non-smokers and light smokers (p<0.05 for trend). CONCLUSIONS: The present study demonstrated that HSP 27 levels were strongly related to renal dysfunction and habitual smoking in a dose-response manner in a Japanese general population.

Ezetimibe combined with standard diet and exercise therapy improves insulin resistance and atherosclerotic markers in patients with metabolic syndrome.

AIMS/INTRODUCTION: Ezetimibe lowers serum lipid levels by inhibiting intestinal absorption of dietary and biliary cholesterol. However, the effect of ezetimibe on insulin resistance remains unclear. The aim of the present study was to examine this issue in patients with metabolic syndrome in local-dwelling Japanese, who were not being treated with lipid-lowering drugs. MATERIALS AND METHODS: In 2009, 1,943 participants received a health examination in the Tanushimaru Study, a Japanese cohort of the Seven Countries Study, of whom 490 participants had metabolic syndrome. Among them, 61 participants (41 men and 20 women) were examined in the present study. They were treated with 10 mg of ezetimibe once a day for 24 weeks, combined with standard diet and exercise therapy. RESULTS: Bodyweight (P < 0.001), body mass index (P < 0.001), systolic blood pressure (P = 0.003), diastolic blood pressure (P < 0.001), triglycerides (P = 0.002), non-high-density lipoprotein cholesterol (P = 0.001), low-density lipoprotein cholesterol (P < 0.001) and homeostasis model assessment of insulin resistance (P = 0.011) significantly decreased after the observational period. There were no statistically significant differences in the effects of ezetimibe between men and women. Univariate analysis showed that the reduction of homeostasis model assessment of insulin resistance was not associated with the improvement of other metabolic components. CONCLUSIONS: Ezetimibe combined with standard diet and exercise therapy improves not only bodyweight and atherogenic lipid profiles, but also insulin resistance, blood pressure and anthropometric factors in metabolic syndrome in local-dwelling Japanese. Interestingly, the improvement of insulin resistance had no correlation with other metabolic components.

Association of serum eicosapentaenoic acid to arachidonic acid ratio with microalbuminuria in a population of community-dwelling Japanese.

BACKGROUND: Epidemiological evidence suggests that the increased intake of omega-3 polyunsaturated fatty acids can prevent atherosclerosis-related cardiovascular diseases. Recently, serum eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio has been reported to be a predictive marker of cardiovascular events. Accordingly, we examined the relationship between serum EPA/AA ratio and microalbuminuria. METHODS: We enrolled 444 residents (174 males and 270 females, mean age 66.6 ± 9.3 years) who underwent a physical examination in Uku town (fishing area) in Japan. They received blood tests including serum levels of EPA and AA, and urine test to examine microalbuminuria. Eating and drinking patterns were evaluated by a brief self-administered diet history questionnaire. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g Cr. RESULTS: The mean EPA/AA ratio was 0.66 ± 0.3 in males and 0.51 ± 0.2 in females. Multiple stepwise regression analyses revealed that systolic blood pressure (p < 0.0001), high sensitive C-reactive protein (p < 0.01), serum EPA/AA ratio (p < 0.01, inversely), and hemoglobin A1c (p < 0.05) were significantly associated with microalbuminuria. In the group with low serum EPA/AA ratio, the prevalence of microalbuminuria was significantly higher than the other, after the adjustments for confounding factors (odds ratio, 3.45; 95% confidence interval, 1.47-8.13; p < 0.01). CONCLUSION: The present study demonstrated that serum EPA/AA ratio was strongly associated with microalbuminuria.

Plasma Renin Activity and Resting Heart Rate in a Population of Community-Dwelling Japanese: The Tanushimaru Study.

BACKGROUND: Heart rate is a strong predictor of mortality and development of obesity and diabetes. The renin-angiotensin-aldosterone system plays an important role in blood pressure control and volume homeostasis. Although many studies have indicated the association between aldosterone and hypertension or insulin resistance, epidemiological evidence of the association of heart rate with plasma renin activity (PRA) remains scant. Therefore, we investigated whether heart rate is associated with PRA. METHODS: A total of 1,943 subjects were enrolled, who underwent a health examination in Tanushimaru in 2009. Plasma renin and aldosterone concentrations were measured by radioimmunoassay. PRA and the homeostasis model assessment (HOMA) were used by natural-log transformed. Resting heart rate was measured using electrocardiography. RESULTS: We divided the subjects into four groups by heart rate (<60/min, 60-69/min, 70-79/min, ≥80/ min), and analyzed an association between PRA and heart rate by analysis of covariance after adjustments for age and sex. The adjusted mean PRA and HOMA index showed a significant trend (P < 0.01) as higher heart rate, although there was no significant trend between aldosterone and heart rate (P = 0.26). In multiple linear regression analysis adjusted for age, sex, systolic blood pressure, HOMA index, and hypertensive medication, PRA was positively and strongly associated with elevated heart rate (P < 0.01). CONCLUSIONS: This epidemiological study demonstrated that PRA, but not aldosterone, is significantly and positively associated with higher resting heart rate in a general population.

High plasma fetuin-A levels are associated with metabolic syndrome among males but not females in a Japanese general population.

AIMS: Fetuin-A, a protein exclusively secreted from the liver, is associated with insulin resistance and/or metabolic syndrome (MetS). However, few studies have examined this association in Japan. We investigated this issue in a Japanese general population. METHODS: We performed an epidemiological survey in a small community in Japan. The participants consisted of 659 subjects (253 males and 406 females). Fetuin-A levels were measured by a sandwich ELISA method and the modified NCEP-ATP III criteria were adopted to diagnose MetS. The homeostasis model assessment index (HOMA-IR) was calculated as a marker of insulin resistance. RESULTS: Statistically significant characteristics of the 659 subjects stratified by fetuin-A quartiles were male gender (inversely), age (inversely), insulin, HOMA-IR, uric acid (inversely), alcohol intake (inversely) and the prevalence of MetS. Mean fetuin-A levels were 249.7±45.1µg/ml in males and 262.7±55.8µg/ml in females. In males, the prevalence of MetS was 43.1%, and their mean HOMA-IR level was 1.1. In females, the prevalence of MetS was 17.7%, and their mean HOMA-IR level was 0.9. Multiple stepwise regression analyses showed that fetuin-A levels in males but not females were independently associated with MetS and LDL-c. Multiple logistic regression analysis of fetuin-A (quartile 1 vs. quartile 4) in males showed significant odds ratios of 1.009 (95% C.I.: 1.003-1.015) for MetS and 1.376 (95% C.I.: 1.027-1.844) for 1-SD increment increase in LDL-c. CONCLUSIONS: High plasma fetuin-A levels were associated with MetS in community-dwelling Japanese males but not females.

Circulating Inflammatory and Hemostatic Biomarkers are Associated with All-Cause Death and Cancer Death in a Population of Community-Dwelling Japanese: the Tanushimaru Study.

BACKGROUND: In patients with cardiovascular diseases, inflammatory and hemostatic biomarkers are significant indicators of prognosis. We investigated whether circulating inflammatory and hemostatic biomarkers were predictive markers for all-cause death and cancer death in a population of community-dwelling Japanese. METHODS: We studied 1,920 healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of inflammatory diseases and malignancy on a baseline questionnaire were excluded. Inflammatory and hemostatic biomarkers were measured in the remaining 1,862 participants, who were followed up periodically for 10 years. Multivariate proportional hazards regression analysis was used to estimate all-cause and cancer mortality. RESULTS: A total of 258 participants died during follow-up: 87 from cancer, 38 from cerebro-cardiovascular diseases, and 133 from other diseases. Mean C-reactive protein (CRP) levels at baseline were significantly higher in decedents than in survivors. Mean von Willebrand factor (vWF) levels at baseline were significantly higher in decedents than in survivors. The Cox proportional hazards model after adjustments for age and sex showed that CRP (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.06-1.51) and vWF (HR, 1.01; 95% CI, 1.00-1.01) were independent predictors of all-cause death. CRP (HR, 1.40; 95% CI, 1.06-1.86) and vWF (HR, 1.01; 95% CI, 1.00-1.02) were also independent predictive markers for cancer death. CONCLUSIONS: Serum CRP and vWF were predictors of all-cause death and cancer death in the population of community dwelling Japanese.