Aim: Adipose tissue inflammation induced by macrophage infiltration through the MCP-1/CCR2 pathway is considered to play a pivotal role in the development of visceral obesity and insulin resistance. In the present study, therefore, we examined whether pharmacological inhibition of CCR2 is effective against the development of diet-induced metabolic disorders.
Methods: C57BL/6 mice were fed a high fat and sucrose diet with or without propagermanium (CCR2 inhibitor, 5 or 50 mg/kg BW/day) for 12 weeks from 6 weeks of age. Then we analyzed lipid and glucose metabolism and tissue inflammation in the liver and adipose tissues along with serum markers in those mice.
Results and Conclusion: Propagermanium treatment slightly decreased body weight gain and visceral fat accumulation in diet-induced obese (DIO) mice. Further, propagermanium suppressed macrophage accumulation and shifted adipose tissue macrophage polarization from the pro-inflammatory (M1) state to anti-inflammatory (M2) state in DIO mice. Expressions of TNF-α and MCP-1 mRNA in adipose tissue were reduced by propagermanium treatment, indicating that propagermanim suppressed inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance, insulin sensitivity, and decreased hepatic triglyceride in DIO mice. Thus, propagermanium improved diet-induced obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve diet-induced metabolic disorders, and that propagermanium may be a beneficial drug for the treatment of metabolic syndrome.

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Aim: To investigate whether HDL₂ can inhibit further oxidative modification of partially oxidized LDL (ox-LDL) by interrupting the chain oxidation reaction after lipid hydroperoxides (LOOH) formation.
Methods: Following incubation of LDL 400 μg protein/mL phosphate-buffered saline with Cu²⁺ for 1.75 h (defined as 0 min), incubation was continued after adding HDL₂ 200 μg protein/mL or HDL₂ 800 μg protein/mL to give both ox-LDL+HDL₂ 200 μg protein/mL or ox-LDL+HDL₂ 800 μg protein/mL. As a control, ox-LDL 200 μg protein/mL and native LDL were prepared. Each sample was subjected to agarose gel electrophoresis and the LOOH in each sample was measured.
Results: When the electrophoretic mobility of native LDL was designated 1, the relative electrophoretic mobility (REM) of ox-LDL increased significantly over time.The REMs of ox-LDL+HDL₂ 800 μg protein/mL from 10 min to 9 h were significantly lower than the REM of ox-LDL at the respective times (p<0.01). LOOH of ox-LDL+HDL₂ 800 μg protein/mL at 1, 3, 6 and 9 h was significantly higher than LOOH in ox-LDL at the respective times (p<0.01). The results of ox-LDL+HDL₂ 200 μg protein/mL were almost the same but to a lesser extent than the results of ox-LDL+HDL₂ 800 μg protein/mL.
Conclusion:The present findings suggest that HDL₂ can inhibit further oxidative modification of partially oxidized LDL by interrupting the chain oxidation reaction after LOOH formation in a concentration-dependent manner.

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Aim: Central pulse pressure and measures of arterial stiffness (augmentation index (AIx) and aortic pulse wave velocity (PWV)) predict morbidity and mortality in patients with stage 2-4 chronic kidney disease (CKD). Although statin therapy may be of vascular benefit in patients with CKD, the long-term effect of statins on central pulse pressure and arterial stiffness has not been assessed in this patient population. Hence, the aim of this study was to assess the long-term effects of atorvastatin on arterial stiffness and central blood pressure in patients with CKD.
Methods: We enrolled 37 patients with serum creatinine levels > 1.36 mg/dL into a randomized, double blind trial. Patients were allocated to receive 10 mg of atorvastatin per day (19) or placebo (18) for three years. Aortic PWV, AIx, estimated central and brachial blood pressures and were determined every nine months.
Results: At baseline, there were no significant differences in aortic PWV, AIx, central or brachial blood pressures between atorvastatin-treated and placebo-treated patients. During the trial, aortic PWV significantly (p=0.05) increased in placebo-treated, but not (p=0.10) in atorvastatin-treated patients (0.51±0.95 vs. 0.30±0.75 m/sec/yr; p=0.48). This represented a 41% (but not statistically significant) slowing of the rate of increase in aortic stiffness. There were no significant changes between groups in the rate of change of AIx (atorvastatin -0.15±5.65 vs. placebo 0.39±5.38%/yr, p=0.53) or central pulse pressure (atorvastatin -2.32±7.46 vs. placebo -0.36±6.64 mmHg/yr p= 0.61).
Conclusion: In patients with CKD arterial stiffness measured by aortic PWV showed a significant increase over time in placebo-treated patients but not in atorvastatin-treated patients.

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Aim: Moderate to severe renal insufficiency and albuminuria have been shown to be independent risk factors for atherosclerosis. However, the association between renal function and intima media thick-ness (IMT) in non-diabetic individuals is less clear. We therefore investigated the relation between renal function, established cardiovascular risk factors and carotid intima media thickness in non-diabetic individuals.
Methods: 853 non-diabetic participants were included in this project. Renal function was estimated using the simplified Modification of Diet in Renal Disease (MDRD) formulae, a refit MDRD equation for healthy persons (MDRD-1) or the Jellife 2 formula, an age independent estimate of glomerular filtration rate (GFR). Carotid arterial intima-media thickness was measured at the posterior wall of the common carotid artery and the bulbus (IMT_ACC, IMTB_Bulbus).
Results: Weak correlations between IMT_ACC or IMTB_Bulbus and MDRD were found (r=-0.105, p= 0.002; r=-0.127, p<0.001). and similiar results were found for MDRD-1. However, adjustment of that relation for age modified the picture. While age was an independent predictor, MDRD or MDRD-1 were not further informative. Further adjustment for cardiovascular risk factors confirmed that relation. Correspondingly, GFR estimated by the age-independent formula Jellife 2 was not correlated with IMT.
Conclusions: The results of this study indicate that variation of renal function within the normal range is not independently associated with carotid intima media thickness in non-diabetic individuals. Crude correlations between MDRD and IMT appear to reflect the inter-relation among age, eGFR and IMT.

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Aim: The cardio-ankle vascular index (CAVI) has been proposed as a new noninvasive marker of arterial stiffness independent of blood pressure. We investigated the association of the CAVI with coronary atherosclerosis and left ventricular (LV) systolic and diastolic function in patients with ischemic heart disease (IHD).
Methods: A total of 206 consecutive subjects undergoing coronary angiography were enrolled. CAVI measurement and echocardiography were performed simultaneously. Patients having significant coronary stenosis were classified into the IHD group.
Results: CAVI in the IHD group (n=133) was significantly higher than in the non-IHD group(n=73)(9.1±1.3 vs. 8.7±1.2, p=0.02). In all IHD patients, CAVI was negatively correlated with LV ejection fraction (LVEF)(r=-0.31, p<0.01), LV mass index (r=0.24, p<0.01) and angiographic scores of coronary atherosclerosis. Stepwise regression analysis revealed that CAVI was independently associated with LVEF, along with a history of myocardial infarction, LV mass index, and left atrial diameter in all IHD patients (p<0.01). In the sub-analysis of IHD patients with preserved LVEF, CAVI was correlated with echocardiographic parameters regarding LV diastolic function. Multivariate analysis demonstrated that the increased CAVI was significantly associated with LV diastolic dysfunction in patients with preserved LVEF.
Conclusion: CAVI, a new parameter of aortic stiffness, was independently associated with LV systolic and diastolic function as well as coronary artery disease in IHD patients.

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Aim: The aim of this study was to investigate the role of uric acid (UA) in coronary endothelial function via its effects on renal function, other coronary risk factors and asymmetric dimethylarginine (ADMA) in men and women.
Methods: The study population consisted of 194 consecutive patients (119 men and 75 women) without coronary artery disease. The relationships between UA and coronary endothelial function, estimated glomerular filtration rate (eGFR), ADMA or other biochemical or anthropometric parameters were investigated.
Results: Monovariate analysis of female participants demonstrated that % change in coronary blood flow (CBF) induced by acetylcholine (ACh) was inversely correlated with UA, ADMA and age (r=-0.32, p<0.01; r=-0.31, p<0.05; r=-0.23, p<0.05, respectively), and positively correlated with eGFR (r=0.27, p<0.05). Stepwise regression analysis showed that UA was the only independent predictor of % change in CBF induced by ACh (F value 4.969, p<0.05). Similar analysis of male participants failed to show significant correlations of these variables except for age in monovariate analysis (r=-0.19, p<0.05). Meanwhile, UA was inversely correlated with eGFR in both men and in women (r=-0.25, p<0.01; r=-0.59, p<0.0001, respectively), and ADMA was positively correlated with UA and inversely correlated with eGFR (r=0.36, p<0.05; r=-0.42, p<0.01, respectively) in women but not in men.
Conclusion: High concentrations of UA correlate with coronary endothelial microvascular dysfunction in women. Further, serum UA concentration is related to eGFR and ADMA only in women, which may result in impaired endothelial function in resistance coronary arteries in women but not in men.

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Aim: We previously reported that obesity (defined as a body mass index (BMI) ≥25 kg/m²) was not an independent risk factor for coronary heart disease (CHD) in hypercholesterolemic patients without a history of CHD from the Japan Lipid Intervention Trial (J-LIT). In this study, the obese J-LIT subgroup was further analyzed to assess CHD risk.
Methods: In the J-LIT study, patients received simvastatin treatment (usually at 5 mg/day) for 6 years. A total of 38,385 patients (mean age: 57.7±7.9, 12,111 men) without prior CHD and/or stroke were analyzed.
Results: In this cohort, 181 CHD (acute myocardial infarction or sudden cardiac death) were observed. Obesity (n=12,929) was not an independent risk factor for CHD (relative risk; 1.18, 95% confidence interval; 0.87?1.59) after adjustment for the major risk known factors, such as age, sex, hypertension, diabetes mellitus (DM), and smoking. However, blood pressure, triglycerides, and fasting plasma glucose all increased, while high-density lipoprotein-cholesterol decreased, with increased BMI. The percentage of patients having two or three risk factors (such as dyslipidemia, hypertension, and DM) also increased with increased BMI.
Conclusions: Obesity was not an independent risk factor for CHD in hypercholesterolemic patients on statin therapy; however, it is important to control obesity, a condition in which CHD risks accumulate, in order to improve associated risk factors along with the treatment of each risk factor, thus further reducing the risk of CHD.

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Aim: Obesity is a strong risk factor for cardiovascular morbidity and mortality. In addition, decreased central arterial distensibility is recognized as an independent risk factor for cardiovascular disease (CVD). Obese subjects exhibit low arterial distensibillity; however, the mechanism responsible for the decrease in arterial distensibility in obese subjects has not yet been elucidated. Pentraxin 3 (PTX3), a recently identified member of the pentraxin family of proteins, is produced in areas of atherosclerosis. A recent study has revealed that the PTX3 level may indicate the vascular inflammatory status. The aim of this study was to investigate plasma PTX3 concentrations and arterial distensibility in obese subjects.
Methods: Eleven obese men (age: 44±2 years, body mass index [BMI]: 32±1 kg/m²) and 14 nonobese men (age: 42±2 years, BMI: 26±1 kg/m²) participated in this study. We measured arterial compliance (using simultaneous B-mode ultrasound and arterial applanation tonometry of the common carotid artery); β-stiffness index, an index of arterial compliance adjusted for distending pressure; and plasma PTX3 concentrations.
Results: Arterial compliance was significantly lower and the β-stiffness index was significantly higher in obese men than in non-obese men. Plasma PTX3 concentration was markedly higher in obese than non-obese men.
Conclusions: Obese men have lower arterial distensibility and higher circulating PTX3 levels than non-obese men; therefore, higher PTX3 levels and decreased arterial distensibility coexist in obese men. The high PTX3 concentrations in obese men may be involved in the mechanism underlying the obesity-induced decrease in arterial distensibility.

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Aim: We assessed levels of polyunsaturated fatty acid (PUFA) in serum and red blood cells (RBCs) among groups stratified by generation and its clinical significance in Japanese subjects living in an urban area.
Methods: We enrolled 200 apparently healthy Japanese (126 males, mean age: 50.3±9.2 years) living in an urban area. Levels of PUFA, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) in serum and RBCs were measured for each generation (G1 <35y, G2 35y-<45y, G3 45y-<55y, G4 55y-<65y, G5≥65y).
Results: No significant differences in EPA, DHA, AA, or EPA/AA were observed between males and females. After dividing into generations, stepwise increases in EPA and DHA, but not DGLA or AA, were observed in serum (all p<0.0001). EPA/AA ratios were stepwisely increased in serum (mean: G1:0.26, G2:0.29, G3:0.43, G4:0.58, G5:0.68, p<0.0001) and RBCs (mean: G1:0.10, G2:0.09, G3:0.15, G4:0.20, G5:0.23, p<0.0001). Positive correlations of EPA (r=0.83), DHA (r=0.55), DGLA (r=0.54), AA (r=0.29), and EPA/AA (r=0.91) were demonstrated between serum and RBCs. In addition, a significant positive correlation between EPA/AA ratios and insulin sensitivity as well as a negative correlation between those ratios and insulin resistance were observed in subjects with metabolic syndrome.
Conclusion: Low levels of EPA/AA, which were associated with insulin resistance, were demonstrated in young Japanese adults living in an urban area.

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Aim: There is uncertainty about the association between circulating concentrations of adiponectin and coronary heart disease risk, particularly in patients after acute myocardial infarction (AMI). The goal of this study was to determine whether plasma adiponectin levels could predict future cardiovascular events in patients after AMI, and to elucidate the role of adiponectin in cardioprotection.
Methods: A total of 102 patients with AMI were enrolled. Plasma adiponectin levels were examined from blood samples collected 18 months after AMI. All subjects were followed-up for 43±12 months. The primary endpoint was the combined occurrence of major adverse cardiovascular events (MACE), including rehospitalization due to unstable angina, nonfatal MI, revascularization with percutaneous coronary intervention or coronary artery bypass grafting, ischemic stroke, and cardiovascular death.
Results: A total of 30 MACE occurred, including one case of cardiovascular death, five cases of nonfatal MI, and nine cases of ischemic stroke. Patients with MACE had lower plasma adiponectin levels (p=0.013). In addition, adiponectin was positively associated with changes in left ventricular ejection fraction (p=0.005). All patients were divided into a high-adiponectin group (≥6.46 µg/mL) and a low-adiponectin group (<6.46 µg/mL). The incidence of MACE was significantly reduced in the high-adiponectin group (p=0.021). In multivariate Cox regression analysis that included adiponectin, classical risk factors, and medications, adiponectin was an independent predictor of MACE in patients after AMI (HR, 0.821; 95% CI, 0.691 to 0.974; p=0.024).
Conclusions: The results indicate a potential association between plasma adiponectin levels and future cardiovascular events in patients after AMI. Moreover, plasma adiponectin concentrations appear to play a pivotal role in atherothrombosis and cardioprotection.

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Aim: There is growing evidence that venous thrombotic and arterial atherosclerotic diseases are interrelated. This presumption is supported by the similar ethiopathogenesis, risk factors and clinical appearance of the two diseases. We investigated whether the prevalence of preclinical indicators of atherosclerosis is higher in patients with spontaneous venous thrombosis than in healthy subjects. Further, we studied the extent of preclinical deterioration of the arterial wall in different beds of the arterial system.
Methods: Forty seven patients of both sexes (mean age, 52.3±14.3 years) with idiopathic venous thrombosis and 44-age matched controls were studied. Using ultrasound, bifurcations of the carotid and femoral arteries were investigated and intima-media thickness plus the presence and thickness of atherosclerotic plaques were determined.
Results: The intima-media was on average, and in all beds investigated, significantly thicker in patients than in controls (0.94mm ±0.29 vs. 0.71 mm ±0.15, p<0.001). The prevalence of atherosclerotic plaques was higher in patients (33/47 vs. 15/44, p<0.001). Furthermore, the number of plaques per individual, the number of arterial segments involved, and total plaque thickness were significantly longer in patients than in controls.
Conclusion: The findings showed a close interrelationship between idiopathic venous thrombosis and preclinical atherosclerotic changes in different arterial territories. This could mean that in patients with primary arterial or venous disease, the arterial and venous vessel walls deteriorate simultaneously, and that common local or systemic factors influence the clinical appearance of either or both diseases.

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