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

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

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

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

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

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

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

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

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.

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.

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

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

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.

Isolation and characterization of phenolic antioxidants from Plantago herb.

Seven phenolic compounds, including a new phenylethanoid glycoside, were isolated from the ethyl acetate fraction of an aqueous ethanol extract of Plantago Herb (whole part of Plantago asiatica L.), which showed significant antioxidative activity. The new compound was characterized as 2-(3,4-dihydroxyphenyl)ethyl 3-O-ß-D-allopyranosyl-6-O-caffeoyl-ß-D-glucopyranoside on the basis of spectral and chemical evidence, and its antioxidant activity was comparable to that of tea catechins.