Ryotaro Takahashi

Circulating omentin is associated with coronary artery disease in men

OBJECTIVE Obesity is closely associated with an increased risk for cardiovascular morbidity and mortality. Omentin is a fat-derived secreted factor that is downregulated in obesity. We investigated whether circulating omentin associates with the prevalence of coronary artery disease (CAD). METHODS The consecutive 78 male subjects were enrolled from patients who underwent coronary angiography. Sixty one age-matched male subjects served as controls. Plasma omentin concentration was measured by enzyme-linked immunosorbent assay. RESULTS Plasma levels of omentin correlated negatively with body mass index (BMI), systolic blood pressure, hemoglobin A1c and total cholesterol levels, and positively with HDL cholesterol and adiponectin levels. Circulating omentin was independently associated with hemoglobin A1c and HDL cholesterol in a multiple regression analysis. Plasma levels of omentin were markedly lower in CAD patients than in control subjects (CAD: 102.8 ± 69.0 ng/ml, control: 454.7 ± 128.6 ng/ml, P < 0.001). Multiple logistic regression analysis with BMI, systolic blood pressure, glucose, hemoglobin A1c, HDL cholesterol, adiponectin and omentin revealed that plasma omentin levels were independently correlated with CAD. CONCLUSION These data indicate that low levels of omentin are closely linked with the presence of CAD and that omentin serves as a novel biomarker for CAD.

Omentin as a novel biomarker of metabolic risk factors

BackgroundOmentin is an adipocytokine that is abundantly expressed in visceral fat tissue. We investigated the association of omentin with the number of metabolic risk factors.FindingThe study population comprised 201 Japanese men who underwent annual health checkups. Plasma omentin levels were determined by enzyme-linked immunosorbent assay. We divided the subjects into 4 groups according to omentin levels. A reduction of plasma omentin levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, dyslipidemia, high blood pressure and glucose intolerance.ConclusionsCirculating omentin levels negatively correlated with the multiplicity of metabolic risk factors, suggesting that omentin acts as a biomarker of metabolic disorders.

Association of a fat-derived plasma protein omentin with carotid artery intima-media thickness in apparently healthy men

Obesity is causally linked with the development of atherosclerosis. Omentin is an adipocytokine whose concentrations are reduced in obese individuals. Here we examined the relationship between plasma omentin levels and carotid intima-media thickness (IMT), a marker of early atherosclerosis, in apparently healthy Japanese men. Participants were 100 Japanese men who underwent a medical checkup. Maximal IMT (max-IMT) and mean-IMT in common carotid artery were measured by high-resolution carotid ultrasound system. Plasma omentin concentrations were determined by enzyme-linked immunosorbent assay. Circulating omentin levels correlated negatively with body mass index, waist circumference, fasting glucose, creatinine, max-IMT and mean-IMT, and positively with estimated glomerular filtration rates (eGFR). Single regression analysis demonstrated that max-IMT associated with age, eGFR and omentin levels, and that mean-IMT associated with age, fasting glucose, eGFR and omentin levels. Multiple regression analysis revealed that omentin levels, together with age, correlated with max-IMT and mean-IMT. Our data document that circulating omentin levels independently and negatively associate with carotid IMT in this population, suggesting that measurement of omentin may be useful for assessment of carotid IMT.

Circulating cathepsin K as a potential novel biomarker of coronary artery disease.

BACKGROUND Cathepsin K (CatK) is one of the most potent mammalian collagenases involved in atherosclerosis-based vascular disease. We investigated whether circulating CatK is associated with the prevalence of coronary artery disease (CAD). METHODS Two-hundred fifty-two consecutive subjects were enrolled from among patients who underwent coronary angiography and intravascular ultrasound analyses. One-hundred thirty-two age-matched subjects served as controls. Plasma CatK, intact procollagen type I N-terminal propeptide (I-PINP), and linked carboxy-terminal telopeptide of collagen type I (ICTP) were measured. RESULTS Patients with CAD had higher CatK levels (44.0 ± 31.2 versus 15.5 ± 8.3 ng/mL, P < 0.001) and ICTP/I-PINP ratios (0.2 ± 0.1 versus 0.04 ± 0.03, P < 0.001) than the controls. Patients with acute coronary syndrome had higher CatK levels than those with stable angina pectoris. Overall, linear regression analysis showed that the CatK levels correlated positively with ICTP/I-PINP ratios (r = 0.41, P < 0.001). Multiple logistic regression analysis showed that CatK levels were independent predictors of CAD (odds ratio, 1.15; 95% CI, 1.07 to 1.23; P < 0.01). Furthermore, CatK levels were also correlated positively with percent plaque volumes and inversely with percent fibrous volumes by intravascular ultrasound. CONCLUSIONS These data indicated that high levels of CatK are closely linked with the presence of CAD and that CatK serves as a novel biomarker for CAD.

The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects: the significance of plasma adiponectin levels

OBJECTIVE Genetic variants of the endothelial nitric oxide synthase (eNOS) gene, Glu298Asp and T-786C, have been reported to be associated with cardiovascular disease. Adiponectin is an adipocyte-derived plasma protein with insulin-sensitizing and vascular protective effects; its levels are typically low in metabolic syndrome. Therefore, eNOS gene polymorphisms may also be associated with specific metabolic profiles, including plasma adiponectin levels and atherogenic lipids. METHODS We evaluated the functional significance of eNOS gene Glu298Asp and T-786C polymorphisms on endothelial function and metabolic profiles in 101 healthy young men (mean age 30.3 years) before the progression of atherosclerotic lesions. RESULTS No linkage disequilibrium was found between the two genotypes. The Asp298 allele carriers of the eNOS gene presented significantly higher plasma low density lipoprotein (LDL) cholesterol, LDL particle size, malondialdehyde-modified LDL (MDA-LDL), and fasting insulin levels and lower plasma high density lipoprotein (HDL) cholesterol, apolipoprotein A-I levels, and endothelium-dependent vasodilation when compared with noncarriers. In spite of higher MDA-LDL levels, Asp298 carriers had significantly larger LDL particle size. By contrast, in C-786 allele carriers, systolic blood pressure was significantly higher, and plasma high-molecular-weight adiponectin levels and endothelium-dependent vasodilation were significantly lower than those in non-carriers. CONCLUSIONS Although both eNOS polymorphisms induced endothelial dysfunction, the eNOS T-786C polymorphism may be associated with adiponectin levels, whereas the Glu298Asp polymorphism may be associated with atherogenic lipid levels.

Pressure Overload-Induced Cardiomyopathy in Heterozygous Carrier Mice of Carnitine Transporter Gene Mutation

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

Association of circulating C1q/TNF-related protein 1 levels with coronary artery disease in men.

Objective Obesity is a major risk factor for cardiovascular disease. Recent evidence demonstrates that dysregulation of fat-derived hormones, also known as adipokines, is linked with the pathogenesis of obesity-related disorders including coronary artery disease (CAD). Here, we investigated whether circulating level of an adipokine C1q/TNF-related protein (CTRP) 1 is associated with the prevalence of CAD. Methods and Results Consecutive 76 male CAD patients were enrolled from inpatients that underwent coronary angiography. Sixty four healthy male subjects served as controls. Plasma CTRP1 concentration was determined by enzyme-linked immunosorbent assay. CTRP1 levels were correlated positively with systolic blood pressure (BP) and triglyceride levels, and negatively with HDL cholesterol levels in all subjects. Plasma levels of CTRP1 were significantly higher in CAD patients than in control subjects (CAD: 443.3±18.6 ng/ml, control: 307.8±21.5 ng/ml, p<0.001). Multiple logistic regression analysis with body mass index, systolic BP, glucose, total cholesterol, HDL cholesterol, triglyceride, adiponectin and CTRP1 revealed that CTRP1 levels, together with systolic BP and HDL cholesterol, correlated with CAD. Conclusions Our data indicate the close association of high CTRP1 levels with CAD prevalence, suggesting that CTRP1 represents a novel biomarker for CAD.

Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy nonsmokers

Low folate and high homocysteine levels are emerging as important risk factors for atherosclerosis and predictors of early coronary heart disease. We evaluated folate and homocysteine levels, compared them with endothelial function, and analyzed their association with the methylenetetrahydrofolate reductase (MTHFR) and endothelial nitric oxide synthase genotypes. We recruited 71 young healthy male nonsmokers without overt cardiovascular or renal disease. Plasma homocysteine levels were enhanced 2-fold in the subjects with the MTHFR 677T/T compared with the others (P = .0001) and also enhanced in the subjects with the endothelial nitric oxide synthase -786C allele (P = .031). Homocysteine levels were independently predicted only by the MTHFR genotype. A relationship between folate and homocysteine levels was not significant. Plasma folate levels were associated independently either with high-density lipoprotein cholesterol levels or with endothelial function in the brachial artery. These results suggest that low folate levels may be a risk factor for cardiovascular diseases regardless of homocysteine levels and that the subjects with lower folate levels should be recommended for dietary folic acid supplementation to elevate endothelial function and probably increase high-density lipoprotein cholesterol levels.

Changes in distinct species of 1,2-diacylglycerol in cardiac hypertrophy due to energy metabolic disorder

OBJECTIVE The juvenile visceral steatosis (JVS) mouse, a genetic model of systemic carnitine deficiency resulting from carnitine transport mutation, develops cardiac hypertrophy. We determined two putative lipid messengers, 1,2-diacylglycerol (DAG) and ceramide, in JVS and carnitine palmitoyltransferase-I (CPT-I) inhibitor etomoxir-treated mice because these lipids function as co-messengers in the myocardium via modification of protein kinase C activity. METHODS JVS mice were evaluated at 4 and 8 weeks of age. The effect of long-term etomoxir treatment (45 mg/day) (ET) on mice was investigated in control mice from 4 to 8 weeks of age. As a model of inhibited cardiac hypertrophy, carnitine-treated JVS (CT) mice were produced. Myocardial DAG and ceramide levels and their fatty acid composition were measured. RESULTS The heart/body weight ratio increased by 100% in JVS mice compared with that in controls, while that of CT mice was normalized in comparison with controls at 8 weeks of age. DAG markedly increased in both JVS and ET mice compared with that in controls (1,677+/-84, 1,258+/-49, and 585+/-58 ng/dry wt, respectively; P<0.01 for controls versus JVS or ET mice), whereas it was decreased significantly in CT mice compared with that in JVS mice (1,066+/-54 ng/dry wt, P<0.01). Furthermore, the fatty acid composition of DAG was similar in JVS and ET mice; in particular, 18:1 and 18:2 were significantly elevated in the myocardium (P<0.01 versus controls). On the other hand, that of DAG in CT mice was similar to that of the control group. In contrast, no difference was observed in myocardial ceramide levels among the groups. CONCLUSIONS Pharmacological intervention with etomoxir mimics changes in the lipid second messenger characteristic of genetic JVS mice. The results suggest that the increases in distinct DAG species might be involved in the pathogenesis of cardiac hypertrophy as a result of disorder of fatty acid transport.

Circulating malondialdehyde-modified low-density lipoprotein is strongly associated with very small low-density lipoprotein cholesterol concentrations in healthy men

BACKGROUND Despite the importance of oxidized LDL and small LDL particles as atherogenic lipoproteins, the relationship between oxidized LDL and the distributions of size subclasses of lipoproteins is not fully proved. We investigated the relationship of circulating malondialdehyde-modified (MDA)-LDL, an oxidized form of LDL, and lipoprotein subclasses in healthy men. METHODS The study group consisted of a total of 170 healthy Japanese men (55+/-9 y). Plasma cholesterol concentrations in major lipoproteins and their subclasses were determined by HPLC with gel permeation columns. RESULTS In univariate analysis, body mass index, waist circumference, blood pressure, white blood cell count, C-reactive protein, uric acid, fasting insulin, HOMA-IR, total cholesterol, triglycerides, each VLDL subclass cholesterol, each LDL subclass cholesterol, small HDL cholesterol, and very small HDL cholesterol were positively correlated with MDA-LDL, whereas adiponectin and large HDL cholesterol were inversely correlated with MDA-LDL. In stepwise multiple regression analysis, very small LDL cholesterol, medium VLDL cholesterol, very small HDL cholesterol, small HDL cholesterol, and systolic blood pressure were identified as independent determinants of MDA-LDL (R(2)=0.718, p<0.0001). CONCLUSIONS Circulating MDA-LDL concentrations are strongly associated with very small LDL cholesterol concentrations in healthy men. HDL size heterogeneity has a biphasic effect on MDA-LDL.