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Severe hypertension in pregnancy is a hypertensive crisis that requires urgent and intensive care due to its high maternal and fetal mortality. However, there is still a conflict of opinion on the recommendations of antihypertensive therapy. This study aimed to identify the optimal blood pressure (BP) levels to prevent severe hypertension in pregnant women with nonsevere hypertension. Ovid MEDLINE and the Cochrane Library were searched, and only randomized controlled trials (RCTs) were included if they compared the effects of antihypertensive drugs and placebo/no treatment or more intensive and less intensive BP-lowering treatments in nonsevere hypertensive pregnant patients. A random effects model meta-analysis was performed to estimate the pooled risk ratio (RR) for the outcomes. Forty RCTs with 6355 patients were included in the study. BP-lowering treatment significantly prevented severe hypertension (RR, 0.46; 95% CI, 0.37-0.56), preeclampsia (RR, 0.82; 95% CI, 0.69-0.98), severe preeclampsia (RR, 0.38; 95% CI, 0.17-0.84), placental abruption (RR, 0.52; 95% CI, 0.32-0.86), and preterm birth ( 37 weeks; RR, 0.81; 95% CI, 0.71-0.93), while the risk of small for gestational age infants was increased (RR, 1.25; 95% CI, 1.02-1.54). An achieved systolic blood pressure (SBP) of 130 mmHg reduced the risk of severe hypertension to nearly one-third compared with an SBP of ≥ 140 mmHg, with a significant interaction of the BP levels achieved with BP-lowering therapy. There was no significant interaction between the subtypes of hypertensive disorders of pregnancy and BP-lowering treatment, except for placental abruption. BP-lowering treatment aimed at an SBP 130 mmHg and accompanied by the careful monitoring of fetal growth might be recommended to prevent severe hypertension.

Introduction: Sarcopenia is a core contributor to falls, fractures and disability. Previous cohort studies showed that healthy dietary pattern like plant-focused diets had beneficial effects on cognitive and physical health. However, few longitudinal studies have investigated the association between dietary patterns and future gait speed, which is strongly related to sarcopenia. Therefore, we aimed to evaluate the relationship between dietary patterns and gait speed in a 9-year follow-up. Methods: We recruited 1943 men and women aged 40 to 95 years in the prospective Tanushimaru cohort study in Japan in 2009. Their dietary intake was assessed using a brief self-administered diet history questionnaire (BDHQ). Principal component analysis (PCA) identified the main dietary patterns. In 976 participants re-examined in 2018, walk time for 5m was examined and Results: The prevalence of slow gait speed in 2018 was 46.9%. The PCA revealed three major dietary patterns: vegetable pattern (vegetables, potatoes, mushrooms and seaweeds); rice pattern (rice, bread and miso soup); and alcohol pattern (alcoholic beverages, cakes and snacks). The higher vegetable pattern score was significantly associated with slower gait speed (p=0.002), while other patterns were not. Estimated risk for slow gait speed in the fully-adjusted model was 39.1% in the highest versus 55.8% in the lowest tertile of vegetable dietary pattern scores (p=0.001). Conclusions: The vegetable pattern was significantly associated with a lower risk for slow gait speed in a 9-year follow-up.

Introduction: Chronic kidney disease (CKD) is a growing public health problem with aging society and a progression to end-stage renal disease is associated with a higher risk of death. Previous studies have suggested that healthy dietary patterns like vegetable-based diet may reduce risk of incident CKD in general populations. However, there is less evidence on whether dietary patterns have impact on early stage of renal dysfunction (RD). Therefore, we investigated the longitudinal association between dietary patterns and early stage of RD in a general population. Methods: We recruited 1943 men and women aged 40 to 95 years in the prospective Tanushimaru cohort study in Japan in 2009. Their dietary intake was assessed using a brief self-administered diet history questionnaire (BDHQ). Principal component analysis (PCA) identified the main dietary patterns. In 984 participants re-examined in 2018, estimated glomerular filtration rate (eGFR) was calculated by CKD-EPI method in 2009 and 2018. RD and early RD were defined as eGFR < 60 and < 90 mL/min/1.73m 2 , respectively . Multivariable linear and logistic regression analyses were performed to examine the association of the main dietary patterns in 2009 with RD and early RD in 2018. Covariates included cardiovascular risk factors and eGFR at baseline. Results: Mean levels of eGFR in 2009 and 2018 were 94.0 and 84.3 mL/min/1.73m 2 . The prevalence of RD and early RD in 2018 were 8.8% (n=87) and 58.5% (n=576), respectively. The PCA revealed three major dietary patterns: vegetable pattern (vegetables, mushrooms and seaweeds); rice pattern (rice, bread and miso soup); and alcohol pattern (alcoholic beverages, cakes and snacks). The higher vegetable pattern score was significantly associated with higher eGFR in 2018 (p=0.006) and modestly associated with lower risk of early RD (p=0.06), but not RD (p=0.1) in the fully-adjusted models. Conclusions: The vegetable pattern was significantly associated with higher eGFR and may prevent an early stage of RD in a 9-year follow-up.

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as an important regulator of low-density lipoprotein (LDL) receptor processing. Evolocumab and alirocumab are PCSK9 inhibitors; however, little is known about the association between PCSK9 levels and lipid profiles in a general population. Because PCSK9 inhibitors have LDL-C lowering effects, we investigated whether there is a positive correlation between serum PCSK9 levels and LDL-C or lipoprotein(a) [Lp(a)]. Methods: In Uku town, 674 residents (mean age; 69.2 ± 8.3 years) received health check-ups. The participants underwent a physical examination and blood tests, including PCSK9 and Lp(a). Serum PCSK9 and Lp(a) were measured by ELISA and Latex methods, respectively. HOMA-IR was calculated by fasting plasma glucose × insulin levels/405. Results: The mean (range) of PCSK9 and Lp(a) were 211.2 (49–601) ng/mL and 60 (1–107) mg/dL, respectively. Because of a skewed distribution, the log-transformed values were used. With univariate linear regression analysis, PCSK9 levels were associated with Lp(a) (p = 0.028), triglycerides (p < 0.001), and HOMA-IR (p < 0.001), but not with LDL-C (p = 0.138) levels. Multiple stepwise regression analysis revealed that serum PCSK9 levels were independently associated with triglycerides (p < 0.001), Lp(a) (p = 0.033) and HOMA-IR (p = 0.041). Conclusions: PCSK-9 is independently associated with triglycerides, Lp(a) levels, and HOMA-IR, but not LDL-C, in a relatively large general population sample.

Hepatocyte growth factor (HGF) is an adipocytokine elevated in obese subjects. We have previously reported that serum HGF levels were significantly associated with insulin resistance or components of the metabolic syndrome. However, it has been unknown how physical activity (PA) affects HGF levels after a long-term follow-up. Our aim was to clarify the association between PA changes and HGF levels as well as cerebro-cardiovascular disease (CVD) development, during a 10 year follow-up period in a Japanese general population. Of 1320 subjects who received a health check-up examination in Tanushimaru town in 1999, 903 subjects (341 males and 562 females), who received the examination both in 1999 and 2009 were enrolled. We evaluated their PA levels by Baecke questionnaire in 1999 and by a simple questionnaire in 2009. We measured the HGF levels by ELISA method in 1999 and 2009. We divided the subjects into four PA groups, stable low PA, increased PA, decreased PA, and stable high PA. Using these questionnaires, we compared their PA and HGF levels after an interval of 10 years. A significant inverse association was found between PA changes and HGF levels at 10 years, after adjustment for age and sex. The HGF levels of the increased PA group were significantly lower than stable low PA (p = 0.038), and the increased PA group showed reduced CVD development compared to the stable low PA group after adjustment for age and sex (p = 0.012). Our data demonstrated that improvement of PA levels was associated with reduced HGF levels and CVD development.

Background The prevalence of sarcopenia and its subtypes, such as sarcopenic obesity, osteosarcopenia, and osteosarcopenic obesity, is little known in patients with cardiovascular diseases (CVD). Methods Physical, motor functional, and nutritional assessments were performed for 230 community-dwelling (CD) adults who came to receive a physical check-up, and 160 patients with CVD who were admitted to our hospital. Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia guidelines. The subtypes of sarcopenia were consecutively diagnosed according to increased body fat percentage and decreased bone density. Results The CVD patients had malnutrition when compared to the CD adults. Impaired motor function of the CVD patients occurred in females as compared with males. The prevalence of sarcopenia, osteosarcopenia, and osteosarcopenic obesity was higher in the CVD patients than in the CD adults (16.9% vs. 4.4%, p Conclusions CVD may accelerate sarcopenia, osteosarcopenia, and osteosarcopenic obesity. Our calculation formula for the easy diagnosis of sarcopenia may help in an early diagnosis and prevent it before worsening the patient's prognosis.

Insulin-like growth factors are polypeptides, with arrays similar to insulin, and insulin-like growth factor 1 (IGF-1) is secreted via stimulation by growth hormone (GH) in the liver. The lack of both GH and IGF-1 leads to physiological age-related changes in the cardiovascular system; however, the role of IGF-1 and GH in hypertension has not been fully elucidated. Thus, we examined the association between plasma IGF-1 and GH levels and hypertension. Among 1368 health check-up examination participants in the town of Tanushimaru, 1094 subjects were analyzed after excluding subjects with diabetes mellitus or impaired liver function. Multiple linear and logistic regression analyses were performed for factors related to systolic and diastolic blood pressures (BPs). Characteristics of participants stratified by IGF-1 and GH quartiles were compared using analysis of covariance. We calculated odds ratios associated with each standard deviation increase in IGF-1 and GH levels for hypertension, which was defined as BP ≥ 140/90 mmHg and/or the use of antihypertensive medication. Multivariable analysis showed that FPG, insulin, HOMA-IR, eGFR, total cholesterol, triglycerides, and the use of medication for hypertension were associated with the Z-score of IGF-1 measurement quartiles. Next, we found that BMI, systolic and diastolic BPs, insulin, HOMA-IR, total cholesterol, HDL-cholesterol, triglycerides, smoking, and alcohol intake were associated with GH quartiles, indicating that hypertension was inversely associated with GH but not IGF-1. A significant and inverse relationship between serum GH and hypertension was found after adjustment for confounders. In conclusion, decreased GH but not IGF-1, was associated with hypertension in a general population.

We investigated the relationship between time trends in nutrient intake and coronary risk factors/mortality rates in Tanushimaru, a Japanese cohort of the Seven Countries Study. All men between the ages of 40 and 64 were enrolled. Subjects numbered 628 in 1958, 539 in 1977, 602 in 1982, 752 in 1989, 402 in 1999, 329 in 2009, and 160 in 2018. Eating patterns were evaluated by 24-h dietary recall from 1958 through 1989, and by a food frequency questionnaire administered from 1999 through 2018. The total daily energy intake decreased from 2,837 kcal in 1958 to 2,096 kcal in 2018. Carbohydrate intake as a percentage of the total decreased remarkably from 84% (1958) to 53% (2018), whereas there was a large increase in fat intake (from 5 to 24%) during the same period. Age-adjusted mean cholesterol levels rose sharply (from 167.9 to 209.4 mg/dl) and body mass index levels also increased (from 21.7 to 24.4 kg/m2), but smoking rate decreased from 69% (1958) to 30% (2018). The mortality rates from stroke and cancer declined, but mortality from myocardial infarction and sudden death remained stable at low levels. The remarkable changes in dietary patterns over the last 60 years can be related to coronary risk factors, but not currently to the mortality of coronary artery disease; more follow-up is needed.

Although we have found that increased serum levels of glyceraldehyde-derived advanced glycation end products are associated with numerous aging-related disorders, it remains unclear which structurally distinct advanced glycation end products could be a reliable biomarker of the healthy life-threatening disorders. Since pentosidine is produced by glyceraldehyde, we measured here urinary pentosidine levels with a newly developed enzyme-linked immunosorbent assay kit, which requires no pretreatment with acid hydrolysis and heat, and examined their correlations with geriatric syndrome, such as musculoskeletal disease, frailty, and cognitive impairment, in a general population. Multiple regression analysis revealed that female, age, history of fracture after fall, and taking medication for diabetes were independent correlates of log urine pentosidine-to-creatinine ratio (R2=0.190). When sex-adjusted log urine pentosidine-to-creatinine ratio stratified by smile frequency grade were compared using analysis of covariance, urine pentosidine-to-creatinine ratio was significantly decreased according to the increase in smile frequency. Our present findings suggest that measurement of urine pentosidine-to-creatinine ratio by a newly developed enzyme-linked immunosorbent assay kit may be useful for identifying high-risk patients for fall-related fractures.

Introduction: Elevated cardiovascular disease risk factor burden is a recognized contributor to poorer cognitive function. Recent cohort study suggested that higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels predicted incident dementia. However, there is little study of the longitudinal association between left ventricular (LV) structure and future cognitive decline. Hypothesis: LV structure is associated with cognitive decline. Methods: We recruited 1943 participants (mean age: 65.8±11.3 years, male 39.9%) as a population-based sample of Tanushimaru, Japan in 2009 and followed 837 adults in 2018 after excluding those with heart disease history. The subjects received 2-dimensional echocardiography to quantify LV mass index (LVMI) in 2009. The 30-point Mini-Mental State Examination (MMSE) was used to assess cognitive function in 2009 and in 2018. We classified MMSE scores ≦23, 24-27, ≥28 as dementia, mild cognitive impairment (MCI) and normal cognition (NC). Multivariable logistic regression analyses were performed to examine the association between LVMI and cognitive decline. Results: Mean MMSE scores in 2009 and in 2018 among 837 participants were 28.1±2.0 and 28.4±2.3, respectively. Cognitive status progressed from NC to MCI/dementia in 19.3% (96/498) or from NC/MCI to dementia in 2.9% (24/826). Mean LVMI levels were 81.9±19.7g/m2 in men and 76.5±18.4g/m2 in women. Conversion from NC to MCI/dementia was not associated with LVMI, while larger LVMI was significantly associated with the progression from NC/MCI to dementia (p=0.002). Age, sex-adjusted odds ratio for progression to dementia was 1.50 (95% confidence interval, 1.16-1.97) as LVMI increased by 10 g/m2. The association was independent of body mass index, systolic blood pressure, and microalbuminuria. LVMI > 90.6 g/m 2 in men and > 99.9 g/m 2 in women accurately predicted progression to dementia (p < 0.0001). These cutoff points were smaller in men and larger in women than the current criteria for LV hypertrophy. Conclusions: Larger LVMI was not associated with early stage of cognitive decline, but can be a risk factor for progression to dementia. We recommend to carefully evaluate cognitive function among at-risk individuals with larger LVMI.

Background: We have previously reported that hepatocyte growth factor (HGF) levels were significantly associated with insulin resistance or components of the metabolic syndrome. However, it has been unknown how physical activity (PA) affects HGF levels after a long-term follow-up.Aims: Our aim was to clarify the association between PA changes and HGF levels /cerebro-cardiovascular disease (CVD) development during 10 years follow-up period in a community-dwelling Japanese general population.Methods: Of 1,320 subjects who received a health check-up examination in Tanushimaru town in 1999, 903 subjects (341 males and 562 females) were enrolled, who received the examination both in 1999 and 2009. We evaluated their PA levels by Baecke questionnaire in 1999 and evaluated their PA levels by a simple questionnaire in 2009. We measured the serum HGF levels by ELISA method in 1999 and 2009. We divided into four physical activity groups such as stable low PA, increased PA, decreased PA, and stable high PA. Using these questionnaires, we compared their PA and HGF levels in 10 years.Results: A significant inverse association was found between PA changes and serum HGF levels in 10 years after adjustment for age and sex. The serum HGF levels of increased PA group were significantly lower than stable low PA (p=0.038), and the former group showed the reduced CVD development compared to the latter group after adjustment for age and sex (p=0.012).Conclusions: Our data demonstrated that improvement of PA levels was associated with reduced HGF levels and CVD development.

Introduction: Sarcopenia or slow gait speed (SGS) strongly interact with cognitive impairment (CI), that is cognitive frailty, possibly because of reinforcing common underlying pathophysiologies. We previously reported that renal impairment (RI) was associated with CI and inflammation is said to be important in the association. Associations of RI and inflammation with cognitive frailty has been understudied. Hypothesis: RI and inflammation are associated with cognitive frailty. Methods: We conducted a cross-sectional study in 1368 population-based sample (mean age: 68.7±11.3 years, men:40.5%) of Tanushimaru, Japan in 2018. We measured urinary albumin-creatinine ratio (ACR) and high-sensitivity C-reactive protein (hsCRP) and assessed cognitive function by Mini-Mental State Examination (MMSE) and 5m walking time. RI was defined as ACR ≧30mg/dL and inflammation was defined as higher than median log-hsCRP. MMSE scores ≦27 out of 30-points was classified as CI and SGS was defined as Results: Prevalence of CI and SGS were 29.3% and 44.3%, respectively. SGS was more prevalent in participants with CI than those with normal cognition (64.4% vs 35.7%, p Conclusions: RI and inflammation were associated with cognitive frailty, especially inflammation was strongly associated with frailty.

Background Remnant-like particle cholesterol (RLP-C) is highly atherogenic, which is associated with atherosclerosis. However, RLP-C has not been routinely measured in the clinical practice. We estimated RLP-C levels using conventional lipid profiles and examined the association between estimated RLP-C and related factors including nutrient intake. Methods This study was performed in Uku town, Nagasaki prefecture, Japan in 2019. A total of 225 subjects were enrolled and directly measured RLP-C levels. Estimated RLP-C levels were defined as the following formula [total cholesterol − (LDL-cholesterol) − (HDL-cholesterol)]. Multivariate analyses were used to assess the relationship between estimated RLP-C and atherogenic factors. We calculated cut-off values on dichotomized RLP-C ( Results The mean values of directly measured RLP-C levels and estimated RLP-C were 4.0 mg/dL and 16.4 mg/dL, respectively. In the multiple stepwise linear regression analysis, directly measured and estimated RLP-C levels were independently and commonly associated with apolipoprotein E, triglycerides, and vegetable fat intake (inversely). Using ROC curves, we found the cut-off value of estimated RLP-C was 22.0 mg/dL. Conclusion We demonstrated that the estimated RLP-C levels using conventional lipid profiles may substitute for directly measured RLP-C and these levels were independently and inversely associated with vegetable fat intake in the community-dwelling Japanese 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.

Background: Non-alcoholic fatty liver disease is increasing in decades and has been recently reported to be associated with cardiovascular disease (CVD). However, the underlying pathophysiology has not been elucidated. Thrombospondin(TSP)-2 is a cardio-protective extracellular matrix, while some clinical studies showed that high serum TSP-2 is a good predictor for adverse events in patients with heart failure. We previously found that in healthy people, serum TSP-2 was associated with insulin resistance, N-terminal pro-brain natriuretic peptide and atrial fibrillation, which suggested a potential CVD risk factor. Therefore, serum thrombospondin-2 can affect on the association between liver fibrosis and CVD. Hypotheses: Serum TSP-2 levels were associated with liver fibrosis in a general population. Methods: We performed a cross-sectional study with a health-check up in 224 participants (mean age: 69.0±7.8 years, men: 42.0%) in Uku, Japan in 2019. Serum TSP was measured by ELISA. Liver fibrosis was defined by the Fibrosis-4 (FIB-4) index ≥2.67, where FIB-4 was calculated as {(ageхaspartate aminotransferase)/(plateletх(alanine aminotransferase) 0.5 )}/10. Continuous serum TSP-2 was modeled using restricted cubic splines with 3 knots (5 th , 50 th , 95th) to allow a nonlinear association with the log odds ratio of liver fibrosis. Results: Mean FIB-4 was 1.92±0.89 and 14.3% of total had liver fibrosis. Age and sex adjusted log odds ratios (ORs) for liver fibrosis was associated with serum TSP-2 non-linearly and the risk accelerate when serum TSP-2 ≥29.5ng/mL(Figure 1). ORs(95% CI) for 29.5 and 31.0 of serum TSP-2 compared to 23.0(median) were 1.57(1.11-2.21) and 1.86(1.25-2.78), respectively. Conclusion: Serum TSP-2, which is a CVD biomarker, was strongly associated with liver fibrosis in the pathological range in a general population. This finding provides a new insight into the pathology in the link between liver fibrosis and CVD.

Introduction: Mild cognitive impairment (MCI) is often a precursor to dementia and is therefore of increasing interest. Some previous studies showed MCI progresses to dementia faster in women than in men. However, sex differences in the progression of cognitive decline requires additional study. Hypothesis: Correlates of changing patterns of cognitive function differ between the sexes. Methods: We recruited 2653 participants (mean age: 59.2±12.0 years, male 41.6%) as a population-based sample of Tanushimaru, Japan in 2009 and conducted a longitudinal study with a follow-up examination in 2018. Mini-Mental State Examination (MMSE) was a 30-point test used to assess cognitive function. We classified cognitive function as dementia, MCI and normal using MMSE cutpoints ≤23, 24-27, and ≥28, respectively. We performed analysis of covariance (ANCOVA) to examine the correlates of change in MMSE scores in 973 people who attended in both 2009 and 2018. Results: Mean MMSE scores in 2009 were 27.7±2.5 (men:27.4±2.8, women:27.8±2.3, p=0.0016) and in 2018 were 28.3±2.3 (men:28.3±2.2, women:28.4±2.5). Changes in MMSE scores were 0.47±3.04 in men and 0.26±3.13 in women. Cognition status progressed from normal to MCI or from MCI to dementia over 9 years in 26.3% (men:24.9%, women:27.2%) and 2.6%(men:2.8%, women:2.5%), respectively. On the other hand, 72.0% of MCI (men:69.7%, women:73.4%) reverted to normal cognitive status. Cognitive improvement for 9 years was associated with higher high-density lipoprotein (HDL) cholesterol, lower log-transformed serum insulin in 2009 in men(p=0.0198, p=0.008),and higher estimated glomerular filtration rate (eGFR) in 2009 in women (p=0.058). Lower serum magnesium levels in 2009 were marginally associated with the progression from MCI to dementia in both sexes. (Figure 1). Conclusions: Cognitive status function was better in women and improved in both sexes during 9 years. A sex-stratified approach for describing correlates of cognitive status may be useful.

Elevated blood pressure is a major risk factor for cardiovascular (CV) disease. But the effects of sodium intake or excretion on CV mortality are uncertain. The present study aimed to investigate the association between 24 h urinary sodium excretion, as a marker of dietary salt intake, and CV or cancer mortality in a healthy Japanese population using 24 hurine collection.The baseline study was conducted in 1980. A total of 1291 participants aged 21 to 85 years, underwent health check-ups, which included blood chemistry measurements and the collection of 24 h urine samples. Enrolled 1291 participants were followed up for 27.5 years, in whom the final follow-up rate was 95.8%. Cox proportional hazards regression models were used to assess the association between 24 h urinary sodium excretion and CV or cancer mortality.The mean 24 h urinary sodium excretion was 5.80 ± 2.28 g/day. There were 631 deaths: 153 (27%) from cancer, 142 (26%) from CV disease. In the Cox proportional hazard regression model after adjustment for confounding factors, systolic and diastolic blood pressures, and uric acid were positively associated with CV mortality, and the 24 h urinary sodium and potassium excretions were inversely associated with CV mortality (p 0.05). On the other hand, there were no association between 24 h urinary sodium excretions and cancer mortality. We divided the urinary sodium excretions levels into quartiles. After adjustment for confounding factors, the hazard ratio of CV mortality in the highest quartile of 24 h urinary sodium excretion versus the lowest was 0.46 (p 0.05). The cumulative survival rate for CV death was significantly decreased in the lowest quartile compared with the other higher groups.We found that impacts of 24 h sodium excretion on CV and cancer mortalities were much different in the general population.

Background There is little data on the association between the lower nutrition represented by serum albumin levels and related factors in a general population. The present study aimed to determine whether the albumin level positioned as some kind of biomarker with frailty measures, trace elements, and an inflammation marker. Methods In 2018, we performed an epidemiological survey in 1368 subjects who resided in Tanushimaru, Japan, in which we examined the blood chemistry including albumin, trace elements, hormone levels, and carotid ultrasonography. Albumin levels were categorized into 4 groups (G1 [3.2–3.9 mg/dL], G2 [4.0–4.3 mg/dL], G3 [4.4–4.6 mg/dL], and G4 [4.7–5.3 mg/dL]). The participants underwent measurements of handgrip strength and were tested by asking to walk 5 m. Their cognitive functions were evaluated by the mini-mental state examination (MMSE). Results Multiple stepwise regression analysis demonstrated that albumin levels were significantly and independently associated with age (inversely), systolic blood pressures, estimated glomerular filtration rate (eGFR), MMSE score, frailty measures (handgrip strength), an inflammation marker (high-sensitivity C-reactive protein), hormones (growth hormone (inversely) and insulin-like growth factor-1), and trace elements (calcium, magnesium, iron, and zinc), with a linear trend. Conclusions Lower albumin levels, even in the normal range, were found to be related factors of frailty measures, trace elements, and an inflammation marker in a general population.

Both homocysteine (Hcy) and asymmetric dimethylarginine (ADMA) induce endothelial dysfunction. However, the impact of both elevations on all-cause death is not known. We investigated the association between elevations of Hcy or ADMA and all-cause death in a general population.A total of 517 subjects (224 men, 293 women; mean age, 62.8 years) were recruited from a population-based survey in 1999 in Tanushimaru, and we measured fasting plasma Hcy and ADMA levels. We followed them up for over 20 years and examined the effect on mortality using Cox proportional hazard regression model.The mean follow-up years were 17.7 (1.8-20.8). In this period, 182 subjects have died (35.2%). The correlation between Hcy and ADMA was high (r=0.194; p0.001). With Cox regression analysis after adjustments for age and sex, elevated log transformed Hcy levels were significantly associated with all-cause death (p=0.028). When Hcy and ADMA levels were divided into quintiles, the hierarchical model showed the synergistic effect of Hcy and ADMA on all-cause death.This is the first report that we have measured Hcy and ADMA levels simultaneously in this community-dwelling Japanese, and we demonstrated that combined elevations of Hcy and ADMA had big impact on all-cause death in this epidemiological study.

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 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.

Peripheral arterial disease (PAD) frequently coexists with coronary artery disease (CAD). The ankle-brachial index (ABI) is widely used for the screening for PAD. Low ABI is associated with short-term clinical outcomes in patients receiving coronary drug-eluting stent (DES) implantation. However, there is no report to examine the relationship between lower ABI and long-term clinical outcomes after DES implantation. Thus, we investigated the clinical long-term impact of low ABI after DES implantation.This retrospective analysis included 181 CAD patients treated with DES from April 2010 to March 2013 in our institute. Based on ABI values, we divided the subjects into the low-ABI group (ABI0.9, n=29) and the normal ABI group (0.9≤ABI1.4, n=152). The incidence of target lesion revascularization (TLR), all-cause mortality, and major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of cardiac death, myocardial infarction, stroke, and any repeat revascularization, were compared between the 2 groups.During the median follow-up period of 43 months, the incidences of TLR, all-cause mortality, and MACCE were significantly higher in the low ABI group than in the normal ABI group (TLR: 41.4% vs 9.9%, p0.001, all-cause mortality: 31.0% vs 3.9%, p0.001, MACCE: 48.3% vs 11.2%, p0.001, respectively).Low ABI may predict poor long-term outcomes, including TLR, in CAD patients treated with DES.

It is well known that subjects with metabolic syndrome show an elevated resting heart rate. We previously reported that elevated heart rate was significantly related to all-cause mortality, and that coffee consumption was inversely associated with metabolic syndrome. We hypothesized that higher coffee consumption may decrease all-cause mortality by reducing resting heart rate. We performed a longitudinal epidemiological study in Tanushimaru (a cohort of the Seven Countries Study). A total of 1920 residents aged over 40 years received health checkups in 1999. We measured components of metabolic syndrome, and eating and drinking patterns were evaluated by a food frequency questionnaire. We followed up the participants annually for 15 years. During the follow-up period, 343 of the participants died. Of these, 102 subjects died of cancer, 48 of cerebro-cardiovascular diseases, and 44 of infectious diseases. Multivariate analyses revealed that higher coffee consumption was inversely associated with resting heart rate. Kaplan–Meier curves found lower mortality rates in the higher coffee consumption groups. In the lower coffee consumption groups, elevated hazard ratios of all-cause death were observed in the increased heart rate quintiles, whereas heart rate was not associated with all-cause death in the higher coffee consumption groups. These significant associations remained after further adjustment for confounders. This prospective study suggests that higher coffee consumption may have a protective effect against all-cause death due to reducing resting heart rate.

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

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.

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 Conclusions The 24‐hour urinary potassium excretion, but not sodium excretion, was significantly associated with all‐cause mortality in the general population.

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.

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 (

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

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.

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

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 ± 45.1 μg/ml in males and 262.7 ± 55.8 μg/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.

Objectives Vaspin is a novel adipocytokine with potential insulin-sensitizing properties. Insulin resistance (IR) plays a role in the development and progression of atherosclerosis. However, the relationship between serum vaspin levels and atherosclerosis remains unknown. Therefore, we investigated whether vaspin was correlated with carotid intima-media thickness (c-IMT). Methods Data for fasting vaspin levels of 201 subjects (78 men and 123 women aged over 40 years) were obtained from a general population in Japan. We obtained anthropometric parameters and blood chemistries, and calculated homeostasis model assessment-IR (HOMA-IR) index. C-IMT was measured by B-mode ultrasonography. The mean values of each parameter by tertiles of vaspin were compared with analysis of variance, and the associations of vaspin with IR and c-IMT were evaluated by multiple stepwise regression analysis. Results Univariate analysis revealed that vaspin levels were positively correlated with BMI, insulin, HOMA-IR index, estimated glomerular filtration rate (eGFR), c-IMT and hypertensive medication. Multiple stepwise regression analysis revealed that HOMA-IR index, c-IMT and eGFR were significantly and independently associated with vaspin. We performed multivariate analyses with c-IMT as the dependent variable. Age, hypertensive medication and vaspin were significant for c-IMT. Moreover, a mediation analysis demonstrated that vaspin was significantly related to c-IMT, independently of IR. Conclusions The present study not only confirmed the previous finding of the positive association of vaspin with IR but also demonstrated that serum vaspin level was positively associated with c-IMT, independently of IR in a general population. Our results may suggest a role of vaspin in atherosclerosis in humans.

The association of serum uric acid (UA) with left ventricular hypertrophy (LVH) remains controversial. We investigated this issue in a general population. Participants consisted of 1,943 subjects (774 males and 1,169 females) aged over 40 years, living in Tanushimaru (a Japanese cohort of the Seven Countries Study). Serum UA and other biochemistry parameters were determined by a standard analytical technique. All individuals underwent anthropometric measurements and 2-dimensional echocardiography. Because serum UA levels are much higher in males than in females, they were analyzed separately. When LV mass index (LVMI) levels were stratified according to tertile as low (≤ 80 cm(2): n = 261), middle (81-103 cm(2): n = 261), and high (≥ 104 cm(2): n = 252) in males, there were significant relationships between LVMI and UA, in addition to age, body mass index, systolic blood pressure, medication for hypertension, triglycerides, and alcohol intake. Multiple stepwise regression analysis revealed LVMI was significantly associated with systolic BP (P < 0.0001), medication for hypertension (P < 0.0001), UA (P = 0.003), BMI (P = 0.019), and alcohol intake (P = 0.038) in males. In females, LVMI was not associated with UA. In a multiple logistic regression analysis, a significantly higher odds ratio of LVH (odds ratio: 1.77, 95%CI: 1.01-3.09, P < 0.05) was observed for males in the highest UA tertile versus the lowest UA tertile after adjustments for confounding factors, but not for females. In this cross-sectional study, there was a clear difference in the relation of UA and LVH between males and females. High serum UA was significantly and independently associated with LVH evaluated by echocardiography in only males of a general population.

BACKGROUND Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine. There is growing evidence that TGF-β1 is involved in the pathogenesis of hypertension and the development of target organ damage in hypertensives. Although several studies have shown that TGF-β1 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-β1 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-β1 were obtained from 528 individuals. Of these, 149 normotensives (BP 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-β1 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-β1 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-β1 level vs. the lowest group after adjustment for confounders. CONCLUSIONS This is the first report demonstrating the causal relationship between them. Elevated plasma TGF-β1 levels predicted the development of hypertension in normotensives in a population of community-dwelling Japanese.

Summary Objective Hepatocyte growth factor (HGF) receptors form a hybrid complex with insulin receptors in the liver of mice, which lead to robust signalling to regulate glucose metabolism. Serum HGF levels are high in subjects with metabolic syndrome and/or obesity. Accordingly, we prospectively investigated the relationship between HGF and the development of insulin resistance (IR) in a general population without IR at baseline. Methods A total of 1492 subjects received health examinations. After excluding subjects with diabetes and/or IR (n = 402) at baseline, the remaining subjects (n = 1090) were followed-up 10 years later. Complete data sets were available from 716 subjects for prospective analysis. Logistic regression was performed to determine factors associated with the development of IR after 10 years. Results In subjects without diabetes at baseline, serum HGF levels were higher (0·26 ± 0·10 ng/ml, n = 259) in subjects with IR than without it (0·22 ± 0·09 ng/ml, n = 1090). After deleting subjects who developed liver disease during follow-up, 188 were found to have developed IR at 10 years after the original screening. HGF (P

Background Large cohort studies have revealed that subjects with atherosclerotic risk factors have high mortality. However, there has been no method to predict individual mortality based on these risk factors. Accordingly, we developed a computer model predicting the 10-year mortality of an individual with atherosclerotic risk factors. Methods We enrolled two different cohorts in Japan. One was from Tanushimaru-town and the other was from Uku-town. Residents over the age of 40 underwent baseline examinations and were followed-up for ten years. 1851 Subjects in Tanushimaru-town were randomly divided into 1486 training samples and 365 test samples. We applied supervised statistical pattern recognition (SSPR) techniques to develop, using the training samples, a computer model to predict the 10-year mortality of an individual based on 6 conventional risk factors. The test samples were then used to evaluate the predictive accuracy. Results There were 49 deaths and 316 survivors in the test samples in Tanushimaru-town. The correctly simulated number of deaths and survival was 36 and 250, respectively. The predictive accuracy of death was 73.5% (36/49) and that of survival was 79.1% (250/316) with c -statistics of 0.827. In order to verify our model, we predicted death and survival for the other test samples (Uku-town, n = 170). The predictive accuracy of death was 72.9% (35/48) and that of survival was 76.2% (93/122) with c -statistics of 0.848. Conclusions This is the first computer model to use SSPR methods to estimate individual 10-year mortality based on conventional risk factors with high accuracy.

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor and an elevated plasma level is a prognostic marker in patients with cardiovascular diseases and/or malignancies. We hypothesized that an elevated plasma level might be a prognostic marker even in subjects without apparent cardiovascular disease or malignancy at baseline. Methods and Results: We measured plasma ET-1 levels in 1,440 healthy subjects over 40 years of age (580 men, 860 women) who were periodically followed for 10 years. The follow-up rate was 96.8%. Baseline plasma ET-1 levels were categorized into quartiles. Baseline plasma ET-1 levels were significantly associated with age, blood pressure, high-density lipoprotein-cholesterol, renal function, uric acid and all-cause death, but not with cardiovascular or cancer death. Kaplan-Meier curves demonstrated that all-cause mortality was significantly higher in the highest quartile of ET-1 than in the lowest quartile. Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause death [hazard ratio: 1.11, 95% confidence interval (CI) 1.01–1.23 per 1pg/ml difference]. The hazard ratio of all-cause death in the highest quartile of plasma ET-1 (≥5.9pg/ml) vs. the lowest quartile after adjusting for confounding factors was 1.54 (95% CI 1.09–2.20). Conclusions: The plasma ET-1 level may be a predictor of all-cause death in a healthy population. (Circ J 2012; 76: 2779–2784)