Eita Kumagai

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.

Factors associated with serum high mobility group box 1 (HMGB1) levels in a general population

High mobility group box 1 (HMGB1), a nonhistone chromatin-associated protein, is implicated as a mediator of both infectious and non-infectious inflammatory conditions. Clinical research on this protein in humans just has begun; serum HMGB1 was reported to be elevated in a small number of critically ill patients suffering from sepsis. However, the kinetics, distribution and factors associated with circulating HMGB1 are unknown in a general population. In this study, we examined these issues in a large population of healthy subjects. Fasting blood samples were obtained from 626 subjects (237 males and 389 females). HMGB1 levels showed a skewed distribution with a mean of 1.65 +/- 0.04 ng/ml. Multiple stepwise regression analyses found that white blood cell (WBC) counts (P = .016) and the soluble form of receptor for advanced glycation end products (sRAGE; P < .001, inversely), which is also known to be a receptor for HMGB1, were independently associated with HMGB1 levels. We demonstrated for the first time that circulating HMGB1 levels were inversely associated with sRAGE levels in a general population. Because RAGE is involved in HMGB1 signaling, our present study suggests that sRAGE may capture and eliminate circulating HMGB1 in humans.

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

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

Serum vaspin levels are positively associated with carotid atherosclerosis in a general population

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.

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.

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

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

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.

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

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

Elevated Plasma Transforming Growth Factor β1 Levels Predict the Development of Hypertension in Normotensives: The 14-Year Follow-Up Study

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 <140/90 mm Hg without antihypertensive medications) at baseline were followed-up for 14 years. RESULTS The receiver-operating characteristic curve was used and the calculated cutoff value was 8.9 ng/ml. Of 149 normotensives at baseline, 59 subjects developed hypertension. Plasma TGF-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.