The epidemic growth in the prevalence of obesity has made the impact of metabolic syndrome on cardiovascular events increasingly significant. Elevated visceral adiposity, the indispensable component of metabolic syndrome, is thought to play a primary role in the increasing incidence of cardiometabolic disorders. Importantly, obesity is not merely the simple expansion of adipose tissue mass; it also involves the activation of inflammatory processes within visceral adipose tissue. Adipose tissue inflammation on the one hand enhances the production of proinflammatory adipokines and on the other hand increases the release of free fatty acids via the activation of lipolysis. The adipokines and free fatty acids secreted from visceral fat then contribute to a cardiometabolic pathology. We herein summarize recent advances in our understanding of the mechanisms by which visceral obesity leads to the activation of inflammation in cardiovascular and metabolic tissues and promotes cardiometabolic disease. Our focus is on Toll-like receptor 4 signaling and free fatty acids as mediators of chronic inflammation in patients with metabolic syndrome and atherosclerosis.

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Aim: Asymmetric dimethylarginine(ADMA) has recently been investigated as a risk marker for cardio- and cerebrovascular diseases. However, it is not currently known whether the ADMA levels are related to the risk of stroke in Japanese women.
Methods: We examined 192 Japanese women(mean age, 55±9 years, range, 40-80 years) who underwent health examinations. The ADMA level and various vascular risk factors of each subject were assessed, and the predicted 10-year stroke risk was calculated using the point-based prediction model provided by the Japan Public Health Center study.
Results: In a correlation coefficient analysis, age was found to be the only factor significantly correlated with the ADMA level. A significant odds ratio (OR) for a high predicted stroke risk(10-year risk, ≥5%) was noted in the highest ADMA level tertile(6.24; 95% CI, 1.13-34.5; p=0.036) compared with the lowest tertile, after adjusting for potential confounding factors. A significant OR for a high predicted stroke risk was also found for each increment in the ADMA tertile and standard deviation(adjusted OR, 2.42; 95% CI, 1.09-5.34; p=0.029; and 2.51; 95% CI, 1.24-5.11; p=0.011, respectively).
Conclusions: An elevated ADMA level is significantly associated with an increased predicted stroke risk, suggesting that measuring the ADMA level is useful for identifying Japanese women with an elevated stroke risk.

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Aim: Probucol is a lipid-lowering drug that is often prescribed for the treatment of familial hypercholesterolemia. However, it is not known whether probucol can change the lesion quality of atherosclerosis.
Methods: We examined this possibility using WHHL rabbits, a model of human familial hypercholesterolemia. Three-month-old male WHHL rabbits were treated with either probucol(85 mg/kg/day) or atorvastatin(6 mg/kg/day) for 16 weeks, and their plasma lipid levels and atherosclerotic lesions were compared with those of a control group.
Results: We found that probucol treatment reduced the plasma cholesterol levels, but less remarkably than atorvastatin treatment. In spite of this, probucol treatment led to a prominent reduction of aortic en face lesions by 39%(P＜0.01), whereas atorvastatin reduced these by 16%(P＞0.05), compared with those in the control. Histological examinations revealed that the aortic lesions of probucol-treated rabbits were characterized by reduced macrophages and increased smooth muscle cells compared with those from both the control and atorvastatin groups. Furthermore, probucol treatment reduced the coronary artery stenosis and increased the plaque stability.
Conclusions: These results suggest that probucol treatment may have beneficial effects on the plaque stability of hypercholesterolemic patients.

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Aim: The INK4b-ARF-INK4a locus in the chromosome 9p21 region is known to play an important role in the development of atherosclerosis. The INK4/ARF transcript p16^INK4a inhibits the activity of the cyclin-dependent kinases CDK4/CDK6 and arrests cell-cycle progression. CDK inhibitors also regulate G1/S phase progression in vascular smooth muscle cells(VSMCs) and may modulate the early stages of atherosclerosis. Therefore, we aimed to study the expression of the INK4/ARF locus genes CDKN2A and CDKN2BAS in order to examine the p16^INK4a protein expression and the level of cell proliferation in carotid plaques and saphenous tissue samples.
Methods: A total of 50 patients(33 symptomatic subjects and 17 asymptomatic subjects) with carotid atherosclerosis CA) were studied. The CDKN2A and CDKN2BAS gene expression levels were determined using quantitative real-time polymerase chain reaction(qRT-PCR). All tissue sections were also analyzed for the p16^INK4a and proliferating cell nuclear antigen(PCNA) protein expression using immunohistochemistry(IHC).
Results: The CDKN2A gene expression was significantly higher in the carotid plaques than in the saphenous tissues(p=0.009), whereas no such differences were observed in the CDKN2BAS transcripts(p=0.157). The carotid plaque CDKN2A mRNA levels were higher in the symptomatic patients than in the asymptomatic patients(p=0.050); this finding was also associated with the severity of internal carotid artery(ICA) stenosis(p=0.034). The p16^INK4a immune(＋) cell counts in the carotid plaques were higher in the symptomatic patients than in the asymptomatic patients (p=0.056), as was the cell proliferation index(p=0.001).
Conclusions: An increased CDKN2A gene expression in carotid plaques may increase the severity of ICA stenosis, thus raising the risk of atherosclerosis and contributing to the development of symptoms. In addition, the p16^INK4a expression is associated with carotid atherosclerosis in various patient subgroups.

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Aim: Circulating adiponectin comprises high, medium and low molecular weight (HMW, MMW, and LMW) forms. Decreased adiponectin levels have been demonstrated to correlate with the atherogenic lipoprotein profile in patients with metabolic syndrome(MS). However, the associations of these isoforms with the atherogenic lipoprotein profiles in the healthy population remain unclear.
Methods: Apparently healthy male subjects were divided into non-MS(n=132) and MS(n=63) groups. We measured the total, HMW, MMW and LMW adiponectin levels by ELISA, and determined the detailed lipoprotein profiles by high-performance liquid chromatography.
Results: The total and HMW adiponectin levels in the MS group were significantly lower than those in the non-MS group(3.8±1.9 vs. 4.9±2.4μg/mL, p＜0.001 and 1.6±1.2 vs. 2.5±1.9μg/mL, p＜0.001, respectively), whereas the MMW and LMW levels did not differ significantly between the groups. The total and HMW adiponectin levels correlated with the atherogenic lipoprotein profiles, including the following: 1) increased cholesterol levels in the small LDL subclasses; 2) decreased cholesterol levels in the larger HDL subclasses; 3) increased triglycerides(TGs) in almost all VLDL and LDL subclasses and 4) decreased TGs in the large HDL and increased TGs in the small HDL subclasses. In addition, a multivariate analysis demonstrated that the HMW adiponectin level was an independent predictor of the small LDL and HDL levels(p=0.02 for both).
Conclusions: The HMW, but not MMW or LMW, adiponectin levels are associated with the typical atherogenic lipoprotein profiles, independent of MS components. Measurement of the HMW adiponectin levels could be useful for identifying the atherogenicity in apparently healthy males.

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Aim: Genome-wide association studies have identified a series of susceptibility loci for coronary artery disease(CAD). The present study attempted to replicate the results for eight of these loci, CDKN2A/B(rs1333049), ADTRP(rs6903956), PDGFD(rs974819), TCF21(rs12190287), COL4A1-A2(rs4773144), HHIPL1(rs2895811), ADAMTS7(rs4380028) and UBE2Z(rs46522), in patients with pathologically defined atherosclerosis of the coronary arteries.
Methods: Autopsy cases of elderly Japanese subjects were enrolled in the JG-SNP study(n=1,536). Polymorphisms were genotyped, and their associations with the coronary stenosis index(CSI) and incidence of pathological myocardial infraction(MI) were investigated. The potential combinatorial effects of the susceptibility loci were also assessed.
Results: Among the eight loci tested, three exhibited signs of positive associations. CDKN2A/B showed the most robust associations with CSI and MI(p=0.007 and OR=1.843, 95% CI 1.293-2.629, p=0.001, for CC＋CG vs. GG). In addition, ADTRP demonstrated associations with CSI and MI, although the risk allele was opposite from that observed in the original report(p=0.008 and OR=1.652, 95% CI 1.027-2.656, p=0.038 for GG vs. AA＋AG). Meanwhile, PDGFD displayed a suggestive association with CSI in women, but not men(p=0.023). CDKN2A/B and ADTRP were also found to be significantly associated with the severity of the CSI in a case-control setting. The cumulative risk allele counting of CDKN2A/B, ADTRP and PDGFD indicated an increased number of risk alleles to be associated with a higher CSI(p=4.61E-05).
Conclusions: The present study confirmed the association between CDKN2A/B and CAD and identified a different associated risk allele of ADTRP. PDGFD was found to exhibit a gender-specific association with CAD. The combination of multiple risk alleles may be associated with a higher risk of CAD.

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Aim: Beta-blockers are not considered to be contraindicated in patients with peripheral artery disease, and carvedilol and bisoprolol are commonly used in patients with PAD in Japan. Because there have been only a few reported comparative studies of the effects of different beta-blockers, we compared the clinical outcomes in patients treated with these beta-blockers after undergoing femoropopliteal stenting.
Methods: Between January 2004 and December 2011, 2911 consecutive patients who had undergone their first femoropopliteal stenting were enrolled in this study. Of these patients, 438 patients(532 limbs) on carvedilol(187 patients, 229 limbs) or bisoprolol(251 patients, 303 limbs) were identified and analyzed retrospectively. The primary outcome was the primary patency and the secondary outcomes were the secondary patency and overall survival and freedom from major adverse limb events(MALE; including any repeated revascularization and major amputation), and these were compared between the groups. The mean follow-up interval of the survivors was 27±17 months.
Results: The primary patency was significantly higher in the bisoprolol-treated group than in the carvedilol-treated group(82.4% vs. 73.6% at 2 years, p=0.0006) as were the secondary patency (93.5% vs. 88.1% at two years, p=0.0004) and freedom from MALE (unadjusted: 79.6% vs. 67.9% at two years, p＜0.0001). However, the two-year overall survival was similar between the groups(91.2% vs. 89.9% at two years, p=0.44). Even after adjusting for baseline differences, bisoprolol was still found to be significantly more effective for the primary patency (HR 0.56, 95% CI 0.37 to 0.83, adjusted p=0.005).
Conclusion: Our retrospective study suggests that bisoprolol is associated with more favorable outcomes for vessel patency and avoidance of MALE than is carvedilol.

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Aim: To examine the relationship between the type of work and the number of metabolic syndrome diagnostic components(MetS-DC), as well as the risk of MetS, with adjustment for lifestyle habits in Japanese workers.
Methods: We examined the baseline data from 4,427 participants(81.4% male) aged 19 to 69 years old. The physical activity of each participant was classified according to the International Physical Activity Questionnaire(IPAQ). We defined the four MetS-DC in this study as follows: 1) high blood pressure(BP): systolic BP ≥130 mmHg, or diastolic BP ≥85 mmHg, or the use of antihypertensive drugs; 2) dyslipidemia: high-density lipoprotein-cholesterol concentration ＜40 mg/dl or triglyceride concentration ≥150 mg/dl, or on medication for dyslipidemia; 3) dysglycemia: fasting blood sugar level ≥110 mg/dl, or if less than eight hours after meals ≥140mg/dl, or on medication for diabetes mellitus; 4) overweight: a body mass index ≥25kg/m². We defined MetS as overweight plus two or more of the MetS-DC.
Results: There were 3,094 subjects in the daytime work group, 73 in the fixed nighttime work group, 1,017 in the shift work group and 243 in the day-to-night work group. The Poisson regression analysis revealed that fixed nighttime (regression coefficient [b]=−0.233, P=0.028) and shift work (b=0.098, P=0.034) independently contributed to the number of MetS-DC, compared to daytime work. The multivariate logistic analysis not including sleep hours in the model showed that shift work was positively related to MetS (odd ratio=1.47, P＜0.01).
Conclusion: Shift work were significantly associated with the number of MetS-DC, and was related to risk of MetS compared to daytime work.

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Aims: The effects of eicosapentaenoic acid (EPA) on the levels of inflammatory markers, cardiac function and long-term prognosis in chronic heart failure (CHF) patients with dyslipidemia remain unclear.
Methods: A total of 139 CHF patients with a mean left ventricular ejection fraction (LVEF) of 37.6± 8.0% were divided into two groups based on whether EPA was included in their treatment regimen: the EPA group (n=71) and the no EPA group (n=68). Only patients with dyslipidemia at baseline (entry) were treated with EPA. The monocyte chemoattractant protein (MCP)-1 and asymmetric dimethylarginine (ADMA) levels were measured at baseline and after 12 months of treatment.
Results: At 12 months, in the EPA group, the LVEF had improved and the MCP-1 and ADMA levels had decreased (respectively, p＜0.001); however, in the no EPA group, the LVEF had worsened, while the MCP-1 and ADMA levels had increased (respectively, p＜0.001). Fifty-five patients experienced cardiac events, including 15 cardiac deaths and 40 readmissions for worsening of CHF during a median follow-up period of 28.0 months. The percent change in LVEF from baseline was found to be significantly associated with the percent change in ADMA (r=−0.462, p＜0.001). A multivariate Cox hazard analysis showed EPA treatment (hazard ratio: 0.21, 95% confidence interval: 0.05-0.93, p=0.031) to be an independent predictor of cardiac events.
Conclusions: These data indicate that EPA treatment may improve the cardiac function and long-term prognosis of CHF patients with dyslipidemia, at least in part, due to reductions in inflammation and improvements in the endothelial function.

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Aim: Chronic kidney disease (CKD) is associated with cardiovascular events. Tumor necrosis factor (TNF) and/or its receptors have been postulated to be involved in renal pathophysiology. It is unclear whether an increased TNF system activity is present before the development of apparent CKD.
Methods: Four hundred and twenty non-diabetic Japanese subjects with an estimated GFR (eGFR) greater than 60 ml/min/1.73 m² were recruited for measurement of the HbA1c, insulin, TNF system activity (TNF-α, soluble TNF receptor 1 (sTNF-R1) and sTNF-R2) levels and various parameters, including the lipid, high-sensitivity C-reactive protein (hsCRP), high-molecular-weight (HMW) adiponectin and leptin levels. The subjects were stratified according to the eGFR: the G1 level (eGFR ≧90 ml/min/1.73 m²) and the G2 level (90 ＞eGFR ≧60 ml/min/1.73 m²).
Results: Whereas no significant differences were observed in gender, body mass index (BMI), blood pressure, insulin, TNF-α, hsCRP, HMW adiponectin or leptin between the two groups, the values for age, HbA1c, triglycerides, sTNF-R1 and sTNF-R2 were significantly higher in the subjects with a G2 level of eGFR than in those with a G1 level. In contrast, the HDL cholesterol levels were significantly lower in the subjects with a G2 level than in those with a G1 level. Linear negative correlations were also observed between eGFR and age, BMI, HbA1c, triglycerides, sTNF-R1 and sTNFR2, respectively. A multiple logistic regression analysis revealed that only sTNF-R2 was associated with the presence of a G2 level of eGFR (Odds ratio 1.092, 95% CI 1.013-1.177, P=0.021).
Conclusions: The circulating sTNF-R2 level is closely associated with the kidney function in non-diabetic Japanese subjects.

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Aim: This subanalysis aimed to clarify whether intensive lipid-lowering therapy with statins slows the progression of atherosclerosis in Japanese subjects under treatment for primary prevention of cardiovascular disease.
Methods: This was a subanalysis of the Justification for Atherosclerosis Regression Treatment (JART) Study. We compared the efficacy of intensive lipid-lowering therapy and conventional therapy with respect to changes in the mean intima-media thickness (IMT) and serum lipid levels. We also evaluated changes in the mean IMT over 24 months of treatment and assessed the relationship between these changes and reductions in the LDL-C levels using a post-hoc analysis.
Results: Intensive lipid-lowering therapy with rosuvastatin was associated with significantly smaller changes in the mean IMT and a greater reduction in the serum lipid levels in comparison to conventional therapy with pravastatin. The average net change in the mean IMT was 0.010 mm (n=121) at 12 months and −0.004 mm (n=56) at 24 months. A decrease in LDL-C was found to be associated with a smaller change in the mean IMT (p=0.0009; Jonckheere-Terpstra trend test). A greater reduction in serum LDL-C was found to be associated with a smaller change in the mean IMT. Similar associations were observed for the serum TC and non-HDL-C levels and LDL-C/HDL-C ratio. There were no notable differences in the incidence of serious adverse events among the LDL-C quartiles.
Conclusions: Lowering the LDL-C level with intensive lipid-lowering therapy is associated with reduced changes in the IMT among Japanese subjects at moderate to high risk under treatment for primary prevention. Subjects suitable for primary prevention may receive cardiovascular benefits from intensive lipid-lowering therapy, in association with significantly slower IMT progression than that observed with conventional therapy.

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