New computer model for prediction of individual 10-year mortality on the basis of conventional atherosclerotic risk factors.

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.

High level of plasma remnant-like particle cholesterol may predispose to development of hypertension in normotensive subjects.

BACKGROUND: Remnant-like lipoprotein particle cholesterol (RLP-C) is a highly atherogenic factor. RLP-C induces endothelial dysfunction and is associated with hyperinsulinemia. This study was designed to determine whether high plasma RLP-C levels predispose to the development of hypertension in subjects with normal blood pressure (BP). METHODS: A total of 1,485 subjects aged >40 years in a Japanese Cohort of the Seven Countries Study received health examinations. We examined BP, anthropometric parameters, and blood chemistries, including fasting RLP-C levels. RLP-C levels were measured by an immune-separation method. We excluded from the analysis 676 subjects who had hypertension (BP ≥ 140/90mm Hg), or were on antihypertensive medication, and/or were on antihyperlipidemic medication at baseline. Ten years later, 681 subjects were re-examined. RESULTS: Of 681 normotensive subjects at baseline, 303 subjects had developed hypertension 10 years later. Baseline RLP-C level was significantly higher (P < 0.01) in the subjects who developed hypertension than in those who remained normotensive (3.7±1.9 vs. 3.3±1.6mg/dl). Multivariable logistic regression analysis demonstrated that baseline RLP-C was a significant factor for incident hypertension after adjustments for homeostasis model assessment index and other hypertension-related factors (odds ratio = 1.05, 95% CI = 1.00-1.10; P = 0.04). CONCLUSIONS: A high level of plasma RLP-C in normotensive subjects may predispose to the development of hypertension in a population of community-dwelling Japanese.

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.

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.

Plasma aldosterone levels and development of insulin resistance: prospective study in a general population.

Aldosterone plays a role in hypertension, and hypertension is prevalent in patients with insulin resistance. Cross-sectional studies have reported that plasma aldosterone levels are higher in patients with insulin resistance. However, it is not known whether plasma aldosterone levels predict the development of insulin resistance. Subjects of the present study were 1235 local residents (490 men and 745 women) who participated in health screenings in Japan in 1999. Plasma aldosterone levels were measured by radioimmunoassay. We investigated the cross-sectional relationship between plasma aldosterone levels and insulin resistance (homeostasis model assessment index ≥1.73 according to the diagnostic criteria used in Japan) in 1088 nondiabetic participants. At the 10-year follow-up, 141 subjects had died, and 260 subjects refused re-examination. We performed a prospective analysis of 564 subjects to predict incident insulin resistance. We found a significant (P<0.001) cross-sectional relationship between plasma aldosterone and homeostasis model assessment index at baseline. In the prospective analysis, a significantly higher (P<0.05) relative risk (1.71 [95% CI: 1.03-2.84]) was observed in the highest tertile versus lowest tertile of plasma aldosterone for the development of insulin resistance, after adjustment for confounding factors. This 10-year prospective study demonstrated that plasma aldosterone levels predicted the development of insulin resistance in a general population.

LDL-C/HDL-C Ratio Predicts Carotid Intima-Media Thickness Progression Better Than HDL-C or LDL-C Alone.

High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are strong predictors of atherosclerosis. Statin-induced changes in the ratio of LDL-C to HDL-C (LDL-C/HDL-C) predicted atherosclerosis progression better than LDL-C or HDL-C alone. However, the best predictor of subclinical atherosclerosis remains unknown. Our objective was to investigate this issue by measuring changes in carotid intima-media thickness (IMT). A total of 1,920 subjects received health examinations in 1999, and were followed up in 2007. Changes in IMT (follow-up IMT/baseline IMT × 100) were measured by ultrasonography. Our results showed that changes in IMT after eight years were significantly related to HDL-C (inversely, P < 0.05) and to LDL-C/HDL-C ratio (P < 0.05). When the LDL-C/HDL-C ratios were divided into quartiles, analysis of covariance showed that increases in the ratio were related to IMT progression (P < 0.05). This prospective study demonstrated the LDL-C/HDL-C ratio is a better predictor of IMT progression than HDL-C or LDL-C alone.

High white blood cell count and low estimated glomerular filtration rate are independently associated with serum level of monocyte chemoattractant protein-1 in a general population.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) plays a role in cardiovascular disease (CVD) and renal injury. Recent clinical studies have suggested that circulating levels of MCP-1 could be a biomarker of atherosclerosis and future cardiovascular events in humans. Because chronic kidney disease (CKD) is one of the risk factors of CVD, it is conceivable that elevated MCP-1 levels may link the increased risk of CVD in CKD patients. However, as far as we know, in addition to well-known traditional risk factors for atherosclerosis, whether renal dysfunction could be independently associated with the elevation of MCP-1 levels in a general population remains unknown. Therefore, we examined here which anthropometric and metabolic variables, including renal function, could be independent correlates of circulating levels of MCP-1 in a general population. HYPOTHESIS: We hypothesized that renal function was one of the independent correlates of serum MCP-1 levels. METHODS: A total of 860 Japanese residents (318 males and 542 females, mean age 65.4 ± 9.8 years) in a small fishing community underwent a complete history and physical examination with determination of blood chemistries, including serum levels of MCP-1. RESULTS: Mean MCP-1 levels were 281.4 pg/mL. Multiple stepwise regression analyses revealed that male sex (P<0.0001), age (P=0.03), estimated glomerular filtration rate (eGFR) (P<0.0001, inversely), and white blood cell count (P=0.037) were independently associated with MCP-1 levels. CONCLUSIONS: The present study demonstrated for the first time that other than white blood cell count, eGFR was an independent correlate of serum levels of MCP-1 in a Japanese general population. Elevated MCP-1 levels may partly explain the increased risk of CVD in CKD patients.

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.

High level of plasma endothelin-1 predicts development of hypertension in normotensive subjects.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor derived from the endothelium. However, most large scale cross-sectional studies in humans have indicated no relationship between plasma ET-1 levels and hypertension. The present study was designed to determine whether high plasma ET-1 levels predict the development of hypertension. METHODS: A total of 1,492 subjects received a health examination in the Japanese cohort of Seven Countries Study in 1999, when, we examined blood pressure (BP), body mass index (BMI), and blood chemistries. Data on fasting ET-1 were obtained from 1,451 individuals. Seven years later, 1,261 subjects (494 males and 767 females) were re-examined (follow-up rate = 87%). RESULTS: Of 814 normotensives (BP <140/90 mm Hg without antihypertensive medications) at baseline, 222 subjects developed hypertension. We divided the baseline plasma ET-1 levels into quartiles. The odds ratio for the development of hypertension after 7 years was 1.79 (95% confidence interval (CI): 1.08-2.96) in the highest quartile vs. the lowest quartile of ET-1 level after adjustment for confounding factors. CONCLUSION: A high level of plasma ET-1 predicted the development of hypertension in normotensive subjects.