Chronic Effects of Adaptive Servo-Ventilation Therapy on Mortality and the Urgent Rehospitalization Rate in Patients Experiencing Recurrent Admissions for Heart Failure　- A Multicenter Prospective Observational Study (SAVIOR-L).

BACKGROUND: This study investigated whether the chronic use of adaptive servo-ventilation (ASV) reduces all-cause mortality and the rate of urgent rehospitalization in patients with heart failure (HF).Methods and Results: This multicenter prospective observational study enrolled patients hospitalized for HF in Japan between 2019 and 2020 who were treated either with or without ASV therapy. Of 845 patients, 110 (13%) received chronic ASV at hospital discharge. The primary outcome was a composite of all-cause death and urgent rehospitalization for HF, and was observed in 272 patients over a 1-year follow-up. Following 1:3 sequential propensity score matching, 384 patients were included in the subsequent analysis. The median time to the primary outcome was significantly shorter in the ASV than in non-ASV group (19.7 vs. 34.4 weeks; P=0.013). In contrast, there was no significant difference in the all-cause mortality event-free rate between the 2 groups. CONCLUSIONS: Chronic use of ASV did not impact all-cause mortality in patients experiencing recurrent admissions for HF.

Improvement of physical activity significantly reduced serum hepatocyte growth factor levels in a general population: 10 year prospective study.

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.

Localization of myocardial FDG uptake for prognostic risk stratification in corticosteroid-naïve cardiac sarcoidosis.

BACKGROUND: The localization of myocardial 18F-fluorodeoxyglucose (FDG) uptake affecting long-term clinical outcomes has not been elucidated in patients with corticosteroid-naïve cardiac sarcoidosis (CS). OBJECTIVES: This study sought to investigate the localization of myocardial FDG uptake on positron emission tomography (PET) and myocardial perfusion abnormality to predict adverse events (AEs) for a long-term follow-up in patients with corticosteroid-naïve CS. METHODS: Consecutive 90 patients with clinical suspicion of CS who underwent FDG-PET imaging to assess for inflammation were enrolled. AEs were defined as a composite of sustained ventricular tachycardia (VT), heart transplantation, and all-cause death, which were ascertained by medical records, defibrillator interrogation, and telephone interviews. RESULTS: Of 90 patients, 42 patients (mean age 62.9 ± 12.0 years; 76.2% females) were confirmed active cardiac involvement. Over a median follow-up of 4.9 years, 15 patients with CS experienced AEs including 6 sustained ventricular tachycardias (VT) and 9 deaths. Cox proportional-hazards model after adjustment for left ventricular systolic dysfunction revealed that FDG uptake in the right ventricle (RV) or basal anterolateral area of the left ventricle (LV) with myocardial perfusion abnormality was predictive of AEs. CONCLUSIONS: FDG uptake in the RV or basal anterolateral area of the LV with myocardial perfusion abnormality provides long-term prognostic risk stratification in patients with corticosteroid-naïve CS.

Correlation between estimated plasma remnant-like particle cholesterol and vegetable fat intake in Uku town, Japan.

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 (< 7.5 mg/dL vs. ≥ 7.5 mg/dL) by receiver operating characteristic (ROC) curve. 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.

Lower albumin levels are associated with frailty measures, trace elements, and an inflammation marker in a cross-sectional study in Tanushimaru.

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.

Trends in nutritional intake and coronary risk factors over 60 years among Japanese men in Tanushimaru.

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.

Habitual coffee intake reduces all-cause mortality by decreasing heart rate.

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.

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.

Vascular Inflammation Evaluated by [18F]-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography Is Associated With Endothelial Dysfunction.

OBJECTIVE: Endothelial dysfunction is an initial step in atherosclerotic cardiovascular disease. However, involvement of vascular inflammation in endothelial dysfunction is not fully investigated in humans because of the lack of diagnostic modality to noninvasively evaluate vascular inflammation. We assessed the relationship between endothelial function and vascular inflammation evaluated by [(18)F]-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging. APPROACH AND RESULTS: We examined endothelial function and vascular inflammation by flow-mediated dilation (FMD) of the brachial artery and [(18)F]-fluorodeoxyglucose-positron emission tomography/computed tomographic imaging of carotid arteries, respectively, in 145 subjects (95 men and 50 women; mean age, 61.8±9.5 years) who underwent a risk-screening test for cardiovascular disease in Kurume University Hospital. Vascular inflammation was measured by blood-normalized standardized uptake value, known as a target:background ratio (TBR). We investigated whether absolute changes from baseline of %FMD after antihypertensive treatment for 6 months (Δ%FMD) were correlated with those of TBR in 33 drug-naive patients with essential hypertension. Multiple logistic regression analysis revealed that age (odds ratio, 1.767 for 10-year increase), male sex (odds ratio, 0.434), low-density lipoprotein-cholesterol (odds ratio, 1.630 for 26-mg/dL increase), and TBR values (odds ratio, 1.759 for 0.2 increase) were independently associated with %FMD in 145 patients. There was an inverse correlation between Δ%FMD and ΔTBR; ΔTBR was a sole independent associate of Δ%FMD in hypertensive patients (r=-0.558; P<0.001). CONCLUSIONS: The present study showed that vascular inflammation in the carotid arteries evaluated by [(18)F]-fluorodeoxyglucose-positron emission tomography/computed tomography was one of the independent correlates of decreased %FMD, thus suggesting the association of vascular inflammation with endothelial dysfunction in humans.

Serum uric acid is associated with the left ventricular mass index in males of a general population.

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.

Independent association of elevated serum hepatocyte growth factor levels with development of insulin resistance in a 10-year prospective study.

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 < 0·05), age (P < 0·001), homoeostasis model assessment index (P < 0·001), HDL-c (P < 0·05; inversely) and hypertensive medication (P < 0·05) were significantly associated with the development of IR by multivariate stepwise logistic regression analysis. A significant (P < 0·05) relative risk [1·75 (95%CI: 1·01-3·12)] for the development of IR was observed in the highest (≥0·30 ng/ml) vs the lowest categories (<0·15 ng/ml) of HGF after adjustments for confounders. CONCLUSIONS: Our 10-year prospective study suggests that elevated serum HGF levels were significantly associated with the development of IR.

A J-shaped Relationship between Sleep Duration and the Risk of Insulin Resistance in a General Japanese Population.

Objective Data on the role of sleep in the risk of insulin resistance (IR) are lacking. We therefore examined the association between sleep duration and IR in a general Japanese population. Methods Data of 1,344 individuals 34 to 89 years old from the Tanushimaru Study were analysed. IR was calculated using the fasting plasma glucose level×fasting insulin level/405, i.e. the homeostasis model assessment of IR (HOMA-IR). IR was defined as a HOMA-IR ≥1.73 based on the diagnostic criteria used in Japan. Information regarding sleep duration was collected via questionnaire. Results The frequencies of IR and metabolic syndrome (MetS) were 36.7% and 26.9%, respectively. A J-shaped relationship between sleep duration and IR was observed, and the same relationship was also shown between sleep duration and MetS; however, the relationship with MetS disappeared after adjusting for age, sex, and other confounding factors. Conclusion A J-shaped relationship was observed between sleep duration and the risks of IR in a general Japanese population.

Plasma endothelin-1 level is a predictor of 10-year mortality in a general population: the Tanushimaru study.

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 1 pg/ml difference]. The hazard ratio of all-cause death in the highest quartile of plasma ET-1 (≥5.9 pg/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.

Serum hepatocyte growth factor and cancer mortality in an apparently healthy Japanese population.

BACKGROUND: In patients with cancer, hepatocyte growth factor (HGF) is elevated and is a predictor of prognosis. We investigated whether serum HGF was a predictive marker for cancer death in a population of community-dwelling Japanese. METHODS: We studied 1492 apparently healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of liver disease or malignancy on a baseline questionnaire were excluded, and plasma HGF was measured in the remaining 1470 participants, who were followed periodically for 10 years. Multivariate proportional hazards regression was used to estimate cancer mortality. RESULTS: A total of 169 participants died during follow-up (61 from cancer, 32 from cerebrocardiovascular disease, and 76 from other diseases). Mean HGF at baseline was significantly higher among decedents than among survivors (0.26 ± 0.11 vs 0.23 ± 0.09 ng/ml, respectively; P < 0.01). The Cox proportional hazards model showed that age, systolic blood pressure, HGF (hazard ratio, 1.27; 95% CI, 1.06-1.52; P = 0.009), albumin level, smoking status, and creatinine were independent predictors of all-cause death. Age, HGF (hazard ratio, 1.31; 95% CI, 1.04-1.65; P = 0.02), and total cholesterol were independent predictive markers for cancer death. CONCLUSIONS: Serum HGF was a predictor of cancer death in an apparently healthy population of community-dwelling Japanese.

Factors associated with plasma ghrelin level in Japanese general population.

OBJECTIVE: Ghrelin is a novel gastric peptide identified in 1999 as a 'hunger hormone'. Plasma ghrelin level is decreased in human obesity. Factors associated with ghrelin have been mainly investigated in western countries where the prevalence of obesity is high. The aim of this study is to examine factors associated with plasma ghrelin in a Japanese general population where obesity is not so common. METHODS: Fasting ghrelin levels were measured by ELISA in 638 subjects in 2005-2007. We measured body mass index (BMI), waist circumference and blood pressure. Blood was drawn in the morning after a 12-h fast for determinations of ghrelin, lipid, glucose (FPG), insulin, estimated glomerular filtration rate (eGFR) and uric acid levels. Univariate and multiple stepwise regression analyses were performed to find out factors associated with ghrelin. RESULTS: In our population, the mean BMI was 23·8 kg/m(2) , indicating a nonobese population. Results of univariate analysis showed that age (P<0·001), BMI (P<0·001), waist (P<0·001), triglycerides (P<0·01), FPG (P<0·01), insulin (P<0·001) and uric acid (P<0·05) were inversely associated with ghrelin. High-density lipoprotein (HDL) cholesterol (P<0·001) and eGFR (P<0·05) were positively associated with ghrelin. Men had lower ghrelin levels than women (P<0·001). Results of the multiple stepwise regression analysis revealed that age (P<0·001; inversely), female gender (P<0·001), insulin (P<0·001; inversely), HDL cholesterol (P=0·005), BMI (P=0·01; inversely) and uric acid (P=0·045; inversely) were significantly and independently associated with ghrelin. CONCLUSIONS: The present study demonstrated that age and gender affected plasma ghrelin levels more than BMI. This may well be because of the low prevalence of overweight in our population.

Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance, Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population.

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.

Differential impacts of 24 hour urinary sodium excretion on cardiovascular diseases or cancer mortality in a general population.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We found that impacts of 24 h sodium excretion on CV and cancer mortalities were much different in the general population.

Impact of combined elevations of homocysteine and asymmetric dimethylarginine on all-cause death - The Tanushimaru Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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; p<0.001). 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. CONCLUSIONS: 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.

Increased Urinary Levels of Pentosidine Measured by a Newly Developed Enzyme-Linked Immunosorbent Assay Are Independently Correlated with Fracture After Fall.

Although we have found that increased serum levels of glyceraldehyde-derived advanced glycation end products (AGEs) are associated with numerous aging-related disorders, it remains unclear which structurally distinct AGEs 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 (ELISA) 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 gender-adjusted log urine pentosidine-to-creatinine ratio stratified by smile frequency grade was 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 ELISA kit may be useful for identifying high-risk patients for fall-related fractures.