According to many prospective cohort studies and meta-analyses of those studies, physical inactivity and/or low levels of physical fitness are associated with an elevated risk for the development of metabolic syndrome, type 2 diabetes, hypertension, coronary artery disease (CAD), and stroke, and with an increased risk of cardiovascular disease (CVD) mortality and all-cause mortality. Most of these analyses, however, were conducted on non-Japanese populations in the West. This report summarizes prospective observational and clinical studies in Japan. The annual national nutrition survey has shown a gradual decline in the number of walking steps in both genders and in all age groups over the last 10 years. While exercise habits have been gradually increasing in the elderly, only one-fifth of young and middle-aged people undertake leisure-time physical activity. Prospective cohort studies have shown that increased physical fitness and greater physical activity in either daily life or leisure time are of benefit in preventing all-cause mortality and CVD mortality. The daily number of walking steps is positively associated with HDL cholesterol levels and negatively associated with triglyceride levels. According to a random-effects model meta-analysis of 4 randomized controlled trials comparing supervised aerobic exercise training with non-exercise control in subjects without CAD, exercise resulted in a significant increase in HDL-cholesterol (10.01 mg/dL, 95% CI 5.38 to 14.65, p< 0.0001). While this confirms the importance of physical activity in preventing CVD mortality and all-cause mortality, the levels of physical activity are on a declining trend in Japan, particularly among the young.

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Aim: We aimed to investigate the expression of monocyte chemoattractant proteins (MCPs) and their cognate receptor CC chemokine receptor 2 (CCR2) in aortas of apolipoprotein E-null (apoE^–/–) mice during atherogenesis as well as the possible transcription pathway involved in the early induction of MCP-1 in vascular smooth muscle cells (VSMCs) in vivo.
Methods: Atherosclerotic lesion development, aortic MCPs and CCR2 mRNA expression as well as the cellular localization of MCP-1, CCR2 and MCP-1 related transcription factors in atherosclerotic lesions were analyzed in apoE^–/– mice fed a high fat and cholesterol diet.
Results: MCP-1 and CCR2 mRNA expression was significantly induced during early atherogenesis and peaked after 10 and 12 weeks of diet, respectively, whereas MCP-2 and MCP-3 mRNA expression elevated in the late phases of lesion development. Immunostaining revealed that early MCP-1 expression was localized to VSMCs and that, in advanced lesions, both neointimal VSMCs and intimal macrophages expressed high levels of MCP-1. During the early (0 and 4 weeks of diet) induction of MCP-1 in VSMCs, the regulatory activator protein-1 (AP-1) proteins c-Jun and c-Fos were highly expressed and observed within the VSMCs nuclei, whereas nuclear factor-κB (NF-κB) protein p65 was only observed within the nuclei of VSMCs after 4 weeks of diet. CCR2 was also identified on intimal macrophages, endothelial cells and VSMCs in advanced lesions.
Conclusion: This study provides fundamental information on the expression kinetics of MCPs and CCR2 during atherogenesis and indicates that the earliest induction of MCP-1 in VSMCs of apoE^–/–mice appears to correlate with AP-1 but not NF-κB regulatory pathways.

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Aim: We examined the anti-oxidant mechanisms of combined therapy of eicosapentaenoic acid (EPA) plus statin on the progression of atherosclerosis.
Methods: Patients receiving statin therapy for dyslipidemia and with coronary artery disease (CAD) were assigned randomly in an open-label manner to the EPA (1,800 mg/day) -plus-statin group (n= 25; combined-therapy group) or to the statin-only group (n= 25), and followed for 48 weeks. At baseline and 48 weeks after enrollment, oxidative stress, brachial-ankle pulse wave velocity (baPWV) and stiffness parameter β-index of the carotid were measured.
Results: The lipid profile remained unchanged throughout the study. Although the median value of baPWV increased more in the statin-only group than in the combined-therapy group, this difference was not significant (p= 0.29); however, a decrease in baPWV was associated with combined-therapy treatment by multiple regression analysis adjusted for age and mean blood pressure (p= 0.04). In addition, the β-index of the carotid was lower in the combined-therapy group than in the statin-only group (p= 0.02). Furthermore, although the difference in the reduction of the urinary concentration of 8-isoprostane between the two groups did not reach statistical significance, this concentration was significantly lower in the combined-therapy group with higher baseline levels (≥ 183 pg/mL · Cr) of urinary 8-isoprostane (p= 0.004).
Conclusions: EPA may reduce oxidative stress and inhibit the progression of arterial stiffness more efficiently than statin-only therapy in patients with dyslipidemia and CAD.

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Aims: Metabolic syndrome (MetS) is characterized by a group of defects of metabolic origin which are possibly involved in mitochondrial DNA (mtDNA) alteration of mtDNA content [Lee et al. Exp Biol Med, 2007; 232(5):592-606]. The present study was undertaken to ascertain whether alteration of leukocyte mtDNA copy number is related to MetS.
Methods: Eighty non-MetS subjects and 50 subjects with MetS were recruited. The mtDNA copy number of leukocytes from each group of subjects was measured using quantitative polymerase chain reaction.
Results: The mtDNA copy number of leukocytes in subjects with MetS was significantly lower than that of non-MetS subjects. Depleted mtDNA copy number is correlated with lower plasma HDL, higher triglyceride, higher HOMA-IR and hypertension, and is even more sensitive to MetS criteria.
Conclusions: Depleted leukocyte mtDNA copy number is related to the severity of MetS. Alteration of mtDNA copy number in leukocytes is proposed as a MetS biomarker involved in the bioenergetic change of mitochondria.

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Aim: The serotonin level in platelet-poor plasma (PPP) is an important clinical marker for monitoring platelet activation accompanying vascular endothelial injury. We previously developed an HPLC method that combines column-switching with a post-column reaction to measure serotonin in PPP. This study determined serotonin levels in healthy volunteers and evaluated the possible relationship of serotonin levels with lipid markers and Framingham 10-year risk scores (FRS) for coronary heart disease.
Methods: Serotonin was isolated from samples using our HPLC method and converted into a fluorescent derivative with benzylamine for specific and sensitive detection. Lipid fractionation was also performed by HPLC. FRS was calculated using the following: age, sex, LDL cholesterol, HDL cholesterol, blood pressure, and smoking and diabetes status.
Results: The PPP serotonin to whole blood serotonin ratio (PPP/WB) and the PPP serotonin level correlated significantly with HDL cholesterol levels: r= 0.187, p< 0.05 and r= 0.184, p< 0.05, respectively. The PPP/WB ratio also correlated significantly with FRS (r= 0.176, p< 0.05). The reference range (95% confidence interval) of PPP and WB serotonin levels in healthy subjects were 0.86-16.96 and 385-1319 nmol/L, respectively.
Conclusions: Significant positive correlations between the serotonin PPP/WB ratio and FRS suggest that the PPP/WB ratio can serve as a biomarker for estimating atherosclerotic cardiovascular risk.

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Aim: A recent clinical trial showed the preventive effect of cilostazol on cerebrovascular diseases. We compared the effects of cilostazol with aspirin on circulating endothelial progenitor cells (EPCs), a surrogate marker for cardiovascular disease, and lipid metabolism in a randomized controlled trial (UMIN000000537).
Methods: Forty-nine diabetic outpatients with leukoaraiosis or asymptomatic old cerebral infarction were enrolled in the study with written informed consent. They were randomly assigned to a cilostazol (200 mg daily, n= 24) or aspirin group (100 mg daily, n= 25), and followed for 16 weeks. Changes in circulating CD34⁺ CD45^low CD133⁺ VEGFR2⁺ EPCs (ΔEPC) were a primary endpoint. Changes in CD34⁺ CD45^low CD133⁺ progenitor cells (ΔPC), p-selectin-positive platelet, platelet-monocyte binding measured by flow cytometry, LDL-, HDL-, small dense LDL (sdLDL)-cholesterol and triacylglycerol were the secondary endpoints.
Results: Twenty patients in each group completed the study. ΔEPC were significantly higher in the cilostazol group than aspirin group at 16 weeks, while ΔPC were already significantly higher at 4 weeks in the cilostazol group. Changes in p-selectin-positive platelets and platelet-monocyte binding were similar in both groups. The cilostazol group showed significantly less sdLDL- and higher HDL-cholesterol than the aspirin group at both 4 and 16 weeks. ΔEPC were significantly and inversely correlated with changes of sdLDL, while positively with those of HDL. Analysis of covariance showed that a significant relation of ΔEPCs with cilostazol treatment was confounded by changes in HDL- and sdLDL-cholesterol.
Conclusion: Cilostazol increases circulating EPCs and decreases small-dense LDL in diabetic patients with cerebral ischemia.

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Aim: To compare the acute effects of shortly pre- vs. postprandial exercise on postprandial lipid metabolism in healthy but sedentary young Japanese women.
Methods: Healthy young Japanese women with a sedentary lifestyle, normal weight (18.5 ≤ BMI < 25), normal ovarian cycle, and apolipoprotein E3/3 were selected as participants. A single bout of walking exercise was performed 20 min after (Exp. 1) or 50 min before (Exp. 2) the intake of oral fat tolerance test (OFTT) cream (1 g/kg body weight) at about 50% Vo₂max for 30 min on a motorized treadmill. A control trial without exercise was also performed in each experiment. Each subject performed 2 trials in a randomized, cross-over design. Venous blood samples were drawn before the preprandial exercise (−1 h, Exp. 1 only) and before (0 h) and 1, 2, 4 and 6 h after the fat intake for the determination of triglyceride (TG), apolipoprotein B-48 (apoB48), remnant-like particle-TG (RLP-TG), lactate, free fatty acid (FFA), insulin, and glucose.
Results: In both experiments, postprandial serum TG concentrations in the exercise group were lower, but not significantly, than those in the control. In Exp. 1, incremental areas under the curve (IAUC) for TG and RLP-TG were slightly, but not significantly, smaller in the postprandial exercise group than the control. The values of apoB48, a marker of the chylomicron particle number, at 2, 4, and 6 h after the fat intake and IAUC for apoB48 were significantly lower in the postprandial exercise group than the control. In Exp. 2, IAUC for TG, RLP-TG, and apoB48 were not significantly different between the two groups.
Conclusion: The present findings suggest that postprandial, but not preprandial, exercise may reduce the number of chylomicrons and chylomicron remnants and improve exogenous lipoprotein metabolism. Postprandial exercise is more effective for improving postprandial lipoprotein metabolism than preprandial exercise.

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Aim: Paraoxanase 1 (PON 1) has been shown to protect against atherosclerosis by modifying lipoproteins. Its activity decreases in dialysis patients but is restored after transplantation. Whether it affects arterial stiffness is unclear. In this study we aimed to investigate the effects of PON 1 on arterial stiffness in renal transplant patients.
Methods: Seventy renal transplant recipients were enrolled. Arterial stiffness was measured using a Syphmocor device. PON-1 activity was assessed from the rate of enzymatic hydrolysis of paraoxon to p-nitrophenol.
Results: Mean age was 39.0±9.6 years and 5.7% of the patients were diabetic. Post-transplant follow-up time was 46.7±37.9 months. Eighty-five percent received anti-hypertensive and 12.9% anti-hyperlipidemic medication. Mean PON1 activity was 75.9±52.4 U/L. PON1 activity was negatively correlated with systolic and diastolic blood pressure, mean arterial pressure, LDL-cholesterol and carotid-femoral pulse wave velocity (cf-PWV). Mean c-f PWV was 8.10±1.39 m/s. Cf-PWV was positively correlated with age, systolic and diastolic blood pressure, mean arterial pressure, proteinuria and negatively correlated with PON1, PON1/HDL ratio and creatinine clearance. In linear regression analysis, PON1 was a predictor of cf-PWV in a model that included age, gender, diabetes, mean arterial pressure, urine protein level, creatinine clearance and PON 1.
Conclusions: Reduced PON1 activity is significantly associated with increased arterial stiffness. The results of this study show the possible role of PON1 for arterial stiffening in renal transplant recipients.

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Aim: The elevation of troponin-T (TnT) and occurrence of transient slow-flow phenomena have been recognized as procedure-related myocardial injuries. Little is known about the characteristics of high-risk plaque resulting in myocardial injury after coronary stenting.
Methods: The culprit plaques in 42 consecutive patients with stable angina undergoing elective coronary stenting were observed by angioscopy. The plaque color upon angioscopic examination was classified as either intense yellow or not yellow. Slow flow was defined as < TIMI grade 3 flow during the procedure. The TnT levels were measured 8, 16, and 24 hours after stenting, and myocardial injury was defined as TnT ≥ 0.03 ng/mL at any time point.
Results: Twenty-four patients (57%) had intense yellow plaques and myocardial injury occurred in 22 patients (52%). The frequency of intense yellow plaque was significantly higher in the patients with myocardial injury than in those without myocardial injury (91% vs. 20%, p < 0.001). Transient slow flow occurred frequently in patients with myocardial injury than in those without myocardial injury (23% vs. 0%, p = 0.049). All patients with transient slow flow had intense yellow plaques at the culprit lesions.
Conclusions: Intense yellow culprit plaque coloration was closely associated with TnT elevation and flow complications following elective coronary stenting. Angioscopically-observed intense yellow coloration may therefore predict high-risk plaque for peri-procedural myocardial injury.

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Aim: Previous studies regarding on-treatment platelet reactivity have focused on response variability to individual antiplatelet agents. There are limited data on [1] response variability to both of these anti-platelet drugs, [2] efficacy of combining two point-of-care tests (POCT) simultaneously and [3] how it predicts the clinical outcome after percutaneous coronary intervention (PCI).
Methods: We analyzed 716 patients, enrolled in the CILON-T prospective randomized controlled trial, with both VerifyNow P2Y12 (PRU) and Aspirin (ARU) data at discharge. Patients were classified according to the tertile of PRU, ARU and the sum of the tertiles of PRU and ARU. The primary endpoint was the composite of cardiac death, nonfatal myocardial infarction (MI) and ischemic stroke at 6 months post-PCI.
Results: Ten patients reached the primary endpoint, four of which were nonfatal MI and six ischemic stroke. When analyzed for the primary endpoint, tertiles of ARU and PRU were not able to discriminate patients with future thrombotic events from the remainder (p= 0.197 for ARU and 0.058 for PRU with the log-rank test, respectively), whereas combining the tertiles of ARU and PRU was significantly effective (p= 0.019 for ARU+PRU with the log-rank test). Multivariate analysis showed that the highest tertile of the sum of ARU and PRU tertiles was the only significant predictor of future thrombotic events after PCI (HR 6.34, 95% confidence interval 1.32-30.47, p= 0.021).
Conclusions: In this post-hoc analysis of the CILON-T trial, combining the results of ARU and PRU simultaneously had a significant role in discriminating patients at highest risk of future thrombotic events after PCI compared with either assay alone.

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