The aim was to give on overview of the profile of cardiovascular disease, vascular pathology and the relationships between lifestyle and cardiovascular disease in Japanese. Compared with the United States and Europe, the higher mortality from stroke and lower mortality from coronary heart disease constitute a unique cardiovascular profile for Japan.
A selective review of population-based pathology, trend and prospective cohort studies was performed to clarify the characteristics of cardiovascular disease and vascular pathology, trends in the incidence and mortality of cardiovascular disease, and the relationships between lifestyle and cardiovascular disease among Japanese adults. Since the 1970s, mortality from coronary heart disease as well as stroke has declined substantially in Japan, probably due to a major decline in blood pressure levels and for men a more recent decline in smoking, in spite of an increase in body mass index and total cholesterol levels. However, the decline in mortality was smaller and plateaued in middle-aged men aged 30-49 in the metropolitan cities of Tokyo and Osaka. The incidence of coronary heart disease has increased among middle-aged men residing in the suburbs of Osaka. As for the associations between lifestyle and cardiovascular disease, higher sodium, lower calcium and lower animal protein content in the diet and for men higher alcohol consumption may account for the higher prevalence of hypertension and higher risk of stroke for Japanese than for western populations. On the other hand, lower saturated fat (meat) and higher n3 polyunsaturated fat (fish) in the Japanese diet may contribute to the lower prevalence of hypercholesterolemia and lower risk of coronary heart disease among Japanese.
Japan is unique among developed countries in that coronary heart disease mortality has been low and has continued to decline, while stroke mortality has declined substantially. However, a recent trend for coronary heart disease incidence to increase among urban men is a cause for concern as a potential source of future problems for public health and clinical practice in Japan.

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Aim: To examine and compare the predictive value of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C and LDL-C/HDL-C ratios for future cardiovascular outcomes in the general Japanese population.
Methods: A total of 24,566 eligible participants aged 18 years or older, without cardiovascular disease, were enrolled through multiphase health screening and divided into quartile groups based on lipoprotein levels or ratios. Primary endpoints of the study were definitive acute myocardial infarction (AMI) and ischemic stroke, and cases of sudden death with unknown causes were not included. We used Cox proportional hazard models to examine the relationships between the quartiles and incidences of AMI or ischemic stroke, adjusting for traditional risk factors.
Results: Mean age was 63.7 years for males and 60.7 years for females. Mean follow-up period was 2.7 years, and 40 cases of AMI and 182 cases of ischemic stroke were recorded. The hazard ratio (HR) for AMI was significantly higher in the top quartile of the LDL-C/HDL-C ratio and LDL-C levels, and third quartile of TC among male participants. The HR of male participants with a LDL-C/HDL-C ratio of 2.6 or higher was significantly higher than other quartiles. No association between lipoprotein levels or their ratio quartiles and ischemic stroke was seen for either sex after adjusting for risk factors.
Conclusions: Our results indicated that the LDL-C/HDL-C ratio is an independent predictor for AMI, and the importance of better management of cardiovascular risks among people with high LDLC/HDLC ratios for the prevention of future cardiovascular disease.

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Aim: The Japan EPA Lipid Intervention Study (JELIS) was the first prospective randomized clinical trial to demonstrate prevention of coronary events by pure eicosapentaenoic acid (EPA). The aim of this study was to examine the relationships between various plasma fatty acid concentrations and the risk of coronary events in JELIS participants.
Methods: In 15,534 participants, we calculated the hazard ratio for major coronary events (sudden cardiac death, fatal or nonfatal myocardial infarction, unstable angina pectoris, and angioplasty/stenting or coronary artery bypass grafting) relative to the on-treatment average level of plasma fatty acids with the Cox proportional hazard model.
Results: As a result of EPA intervention, the plasma EPA concentration increased, but the docosahexaenoic acid (DHA) concentration did not. The other fatty acids measured decreased slightly. The higher plasma level of EPA (hazard ratio=0.83, p=0.049, in all participants and hazard ratio=0.71, p=0.018, in the EPA intervention group), but not of DHA, was inversely associated with the risk of major coronary events. The associations between other fatty acids and the risk of major coronary events were not significant. In all JELIS participants, the risk of major coronary events was significantly decreased (20%) in the group with high (150 µg/mL or more) on-treatment plasma EPA concentration compared with that in the low (less than 87 µg/mL) group.
Conclusion: The risk of coronary artery disease is influenced by variations in plasma fatty acid composition. Among n-3 polyunsaturated fatty acids, EPA and DHA exhibited differences in the correlation with the risk of major coronary events.

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Aim: Resistin is an adipocytokine that may link inflammation and atherosclerosis.We studied the associations of resistin levels with cardiovascular events and restenosis.
Methods: We measured pre-procedural serum resistin levels in 140 patients with coronary artery disease undergoing elective percutaneous coronary intervention (PCI), of whom 97 had a stent. Restenosis was defined as > 50% stenosis at follow-up angiography. Patients were followed for 3 years for major adverse cardiovascular events (MACE).
Results: At 8±6 months after PCI, reangiography was performed in 94 (67%) patients, of whom 42 had restenosis. Between 42 patients with restenosis and 52 without restenosis, resistin (4.5±2.6 vs. 4.5±2.5 ng/mL) and Creactive protein (CRP) (median 0.70 vs. 0.70 mg/L) levels did not differ. During 3-year follow-up, MACE occurred in 24 patients (1 death, 21 unstable angina, 2 stroke). Compared with 116 patients without MACE, 24 with MACE had higher resistin (5.4±2.4 vs. 4.3±2.5 ng/mL) and CRP (1.30 vs. 0.60 mg/L) levels (p< 0.05). Patients with MACE more often had resistin >4.0 ng/mL than without MACE (75% vs. 35%, p< 0.001). Resistin correlated with CRP levels (r= 0.31). To clarify the association between MACE and resistin, patients were divided into 2 groups by resistin levels. Kaplan-Meier analysis showed a lower event-free survival rate in patients with resistin > 4.0 ng/mL than without it (p< 0.001). On multivariate analysis, resistin, but not CRP, was an independent predictor of MACE. The hazard ratio for MACE was 3.6 (95%CI=1.4-9.2) for resistin > 4.0 ng/mL.
Conclusion: Serum resistin levels were found to be associated with further cardiovascular events in patients undergoing PCI.

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Aim: Although the mean body mass index (BMI) of Japanese patients with type 2 diabetes was within the normal range, we have previously shown that approximately half of all patients classified as normal weight had been formerly obese. The present study examined the clinical features of Japanese type 2 diabetic patients who are currently of normal weight but had formerly been obese (NWFO).
Methods: Body weight history with selfreported body weight was obtainable for 108 of 114 type 2 diabetic outpatients who had been regularly attending our department. Common carotid artery intimamedia thickness (IMT) was also measured.
Results: At the time of the examinations, 5 (5%) and 36 (33%) of 108 type 2 diabetic patients were lean (BMI <18.5 kg/m²) and obese (BMI ≥25 kg/m²), respectively, whereas normal weight (BMI ≥18.5-<25 kg/m²) was found in 67 (62%) patients. Among 108 patients, 67 (62%) were normal weight, of which 32 (48%) were formerly obese (NWFO). NWFO patients with a mean age of 65 years old at the clinic visit had reached their lifetime maximum body weight at age 45 and became diabetic at age 51 years. Obese patients aged 62 years at the clinic visit became diabetic at age 50 and had reached their maximum weight at age 51 years. Diabetes duration was 11 years in patients who had never been obese. Thus, NWFO patients had been exposed to obesity-related metabolic abnormalities and/or hyperglycemia for 20 years on average whereas obese and never obese patients had been exposed for 11-12 years. Although obese patients had higher fasting TG and greater BMI than NWFO, both obese and NWFO patients had similarly lower HDL cholesterol levels than those who had never been obese; however, there was no difference among the 3 groups in diabetic treatment, diabetes duration, HbA1c levels, and prevalence of atherosclerotic risk factors, including smokers, users of statins and antihypertensive drugs. Carotid max IMT was thicker in NWFO type 2 diabetic patients (0.86±0.04mm) than either obese patients (0.78±0.03mm, p=0.041) or those who had never been obese (0.78±0.02mm, p=0.046).
Conclusion: This report confirms that approximately half of 108 Japanese type 2 diabetic patients who are currently normal weight were formerly obese and shows that these patients had a thicker carotid IMT than either obese patients or those who had never been obese. Formerly obese diabetic patients who have lost weight and are currently normal weight might have been exposed to long-term obesity-related cardiometabolic abnormalities and/or hyperglycemia, resulting in increased common carotid IMT. We therefore suggest that an improved clinical screening tool would include the assessment of body weight history for all Japanese type 2 diabetic patients at their first clinic visit.

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Aim: Few studies have investigated the association between insulin resistance and arterial stiffness in Chinese. We aimed to investigate this relationship in a population-based study of middle-aged Chinese.
Methods: A total of 2,188 subjects aged 40 years and older were recruited in 2004 in Taiwan. The association between arterial stiffness (measured by brachial-ankle pulse wave velocity (baPWV)) and insulin resistance (represented by homeostasis model assessment (HOMA-IR) and fasting glucose levels) was studied by multiple logistic and linear regression analyses.
Results: The respective prevalence of diabetes and impaired fasting glucose (IFG) was 13.9% and 30.6% in males and 10.4% and 20.8% in females. Using multiple linear regression analyses, we found baPWV to be strongly associated with age, gender, body mass index (BMI), waist circumference (WC), systolic blood pressure (BP), diastolic BP, fasting glucose, and triglycerides. Compared to the lowest HOMA-IR tertile I and adjusting for age, BMI, WC, gender, triglycerides, systolic BP, diastolic BP, smoking, alcohol drinking, betel nut chewing, and physical activity, the odds ratios (95% confidence interval) of arterial stiffness for the higher HOMA-IR tertiles II and III were 1.15 (0.77-1.71) and 1.60 (1.05-2.46), respectively. Using a general linear model with adjustment for age, systolic BP, diastolic BP, BMI, WC, and triglycerides, baPWV was significantly lower in the diabetic group by 90.3 cm/sec in males and 100.5 cm/sec in females compared to the IFG group. When comparing the IFG group to the normal glucose group, baPWV was 28.5 cm/sec lower in males and 14.4 cm/sec lower in females.
Conclusions: Arterial stiffness is independently associated with insulin resistance in Chinese middle-aged adults. Subjects with diabetes or IFG have higher baPWV than normoglycemic subjects.

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Aim: It remains unclear whether the decrease in the ADMA level associated with statin treatment results from the LDL-C-lowering effect or the pleiotropic effects of statins. A prospective, controlled study was conducted to examine whether statin treatment affects serum ADMA concentrations in ischemic stroke patients.
Methods: Consecutive outpatients with non-cardiogenic ischemic stroke who had never been treated with statins and whose LDL-cholesterol level was higher than 140 mg/dL were enrolled and compared with control patients whose LDL-cholesterol level was lower than 140 mg/dL. Overall, 114 patients were enrolled in the study (56 and 58 in statin-treated and non-statin-treated groups, respectively). Patients in the statin group were treated with pravastatin 10 mg/day (n=15), fluvastatin 20 mg/day (n=14), pitavastatin 1 mg/day (n=14), or atorvastatin 10 mg/day (n=13).
Results: The serum ADMA concentration and LDL-C level were significantly decreased by statin treatment (p=0.003 and p< 0.001, respectively), and the ADMA concentration in subjects treated with statins was significantly lower than that of the control (p=0.028). Multiple linear regression analysis showed that age (β=0.26, p< 0.05) and statin use (β=-0.20, p< 0.05) were independently associated with the ADMA level.
Conclusions: A significant relation between statin treatment and decreased levels of ADMA was demonstrated in ischemic stroke patients with an adequately controlled lipid profile, suggesting the statin treatment might prevent atherosclerotic disease in ischemic stroke patients through suppression of ADMA concentration.

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Aim: Platelet-derived growth factor (PDGF)-BB plays a crucial role in atherosclerosis and vascular remodeling by promoting the migration and proliferation of vascular smooth muscle cells. The objective of this study was to clarify the pleiotropic effect of peroxisome proliferator-activated receptor α (PPARα) activators on PDGF-BB expression in megakaryocytes and platelets.
Methods and Results: The expression of PPARα in a human erythroleukemia (HEL) cells was clearly detected by reverse transcriptase-PCR and immunofluorescence microscopy. The expression level of PPARα in HEL cells was unchanged regardless of differentiation into megakaryocytic cells by treatment with phorbol 12-myristate 13 acetate (TPA). The TPA-induced expression of PDGF-B mRNA and PDGF-BB protein levels in culture media was significantly decreased by treatment with PPARα activators, Wy14643 and fenofibric acid, in a dose-dependent manner. PDGF-BB expression induced by inflammatory cytokines, including interleukin-1β or interleukin-6, was also significantly suppressed by treatment with PPARα activators. Immunohistochemistry of human bone marrow showed the expression of PPARα in both the nucleus and cytoplasm of megakaryocytes. In addition, PDGF-BB levels in platelets were significantly decreased from 1,800±870 to 1,470±840 pg/10⁵ platelets (mean±SD, p<0.05) by treatment with 300 mg fenofibrate once daily for 4 weeks in 13 patients with dyslipidemia.
Conclusions: Activation of PPARα in megakaryocytes reduces PDGF-BB expression in platelets. PPARα activators may exert vasculo-protective action through suppression of PDGF-BB production in a megakaryocyte/platelet pathway.

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Aim: Recent clinical studies have reported that low lipoprotein lipase mass in preheparin serum (s-LpL) and hypoadiponectinemia are important risk factors for acute myocardial infarction (AMI). The aim of this study was to elucidate the relationship between low s-LpL and hypoadiponectinemia, both of which are risk factors for AMI.
Methods: One hundred and thirty-seven male patients with AMI and fifty-three males with normal coronary arteries (NCA) were enrolled in the study. Coronary risk factors, including s-LpL and serum total adiponectin concentrations (t-adiponectin), were compared.
Results: Both s-LpL and t-adiponectin were significantly lower in patients with AMI than in subjects with NCA (s-LpL, NCA: 48.1±11.0 ng/mL, AMI: 38.9±11.1 ng/mL, p< 0.01; t-adiponectin, NCA: 7.7±2.9 μg/mL, AMI: 6.1±3.3 μg/mL, p< 0.01). In AMI patients, there was a significant positive correlation between s-LpL and t-adiponectin (r=0.46, p< 0.01). Furthermore, multivariate analysis indicated that both s-LpL and t-adiponectin were independent variables for AMI (s-LpL: p< 0.05, t-adiponectin: p< 0.05).
Conclusion: These results indicate that although low s-LpL and hypoadiponectinemia are associated with each other, they are independent risk factors for AMI.

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Aim: Aortic dilatation is a well-known phenomenon in the elderly. We therefore aimed to study the pathobiological determinants of aortic dilatation.
Methods: Retrospective chart review. The subjects were 833 consecutive autopsy cases (616 men and 217 women) of community deaths. The age at death ranged from 20 to 94 years, with an average of 59.2 years. We measured the internal circumference of the aortic root, arch, descending portion, abdominal portion, and bifurcation in unfixed opened aorta at the time of autopsy.
Results: The simple correlation between age and aortic circumference was strongest for the descending portion, followed by the arch, abdominal portion, root, and bifurcation. The simple correlation coefficient reached 0.836 for the descending portion (p < 0.001). The circumference of the descending portion increased significantly as the severity of aortic atherosclerosis increased (p for trend < 0.001). Multiple regression analysis showed that age, sex, and body height were significantly correlated with the aortic circumference at all five measurement sites, while severe atherosclerosis was correlated with the aortic circumference at the root, and descending and abdominal portions. Six contributing factors (age, sex, body height, smoking history, hypertension, and severe atherosclerosis) explained 68.5% of the variance in circumference in the descending portion; age explained 57.5%; sex 8.4%; body height 1%; and severe atherosclerosis 0.8%.
Conclusion: The contribution of atherosclerosis to aortic dilation was very weak, representing less than one seventieth of the contribution of age. The aortic circumference, especially in the descending portion, serves as an excellent age-related marker.

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Aim: We previously reported significant associations between mitochondrial single nucleotide polymorphisms (mtSNPs) and myocardial infarction, atherothrombotic cerebral infarction, metabolic syndrome and type 2 diabetes. Here, we assessed the hypothesis that mtSNPs may confer a risk for atherosclerosis, the most important intermediate phenotype of ischemic cardiovascular events.
Methods: The subjects were 1,536 consecutive autopsy cases (827 men and 709 women). The average age at death was 80 years. The severity of coronary atherosclerosis was semi-quantitatively examined on cut sections. We examined 149 mtSNPs using the PCR-Luminex method, with a success rate of 97%. Phylogenetic tree analysis yielded 36 haplogroups. Multiple logistic regression analysis was performed after adjustments for sex, age, and conventional cardiovascular risk factors.
Results: Among the 45 mtSNPs with minor genotype frequencies >0.05, 6 mtSNPs were associated with coronary atherosclerosis. Among 10 haplogroups with frequencies >0.04, haplogroups A and M7a were significantly associated with coronary atherosclerosis, with odds ratios (95% confidence intervals) of 1.80 (1.09-2.97; p=0.023) and 1.92 (1.23-3.01; p=0.004), respectively. Haplogroup D4a, which was previously reported to be associated with extreme longevity in a Japanese population, was associated with pathological myocardial infarction in men with an odds ratio of 2.05 (1.01-4.14; p=0.046).
Conclusions: The mitochondrial haplogroups A and M7a confer a significant risk for coronary atherosclerosis in the Japanese. The mitochondrial haplogroup may contribute some genetic risk for coronary heart disease.

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