In recent years, several studies have used the measurement of carotid intima-media thickness (IMT) as a marker of early atherosclerosis: IMT has been shown to correlate significantly with the presence of coronary artery disease (CAD) and to predict fatal and not fatal cerebro- and cardio-vascular events. These findings highlight the importance of recognizing and managing early stages of atherosclerosis for effective cardiovascular prevention. Beyond traditional established cardiovascular risk factors, inflammation has been shown to be crucial throughout atherosclerosis from endothelial dysfunction to plaque rupture and thrombosis. Several studies have shown the existence of a strong relation between CAD and fibrinogen or highly sensitive C-reactive protein (hs-CRP) levels and their predictive role has been examined through stratification or multivariable statistical analyses: levels of these markers of inflammation have been independently associated with the incidence of coronary events after adjusting for traditional cardiovascular risk factors. Recent studies have further addressed the importance of therapeutical modulation of hs-CRP levels in high-risk patients for the prevention of vascular events. The strong relationship between hs-CRP and IMT may potentially account for the complex role of hs-CRP and IMT in the pathogenesis of cardiovascular events. However, beyond the utility of measuring markers of inflammation to assess patients with subclinical carotid atherosclerosis at higher risk of vascular events, further studies are needed to evaluate the therapeutic implications in this category of patients.

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Aim: It is well established that people gain weight after smoking cessation; however, changes in cardiovascular risk factors and the estimated risk of coronary heart disease following smoking cessation have yet to be fully clarified.
Methods: The participants were 1,995 Japanese male workers at 11 workplaces who participated continuously in the High-risk and Population Strategy for Occupational Health Promotion (HIPOPOHP) study. Participants with a smoking habit had cardiovascular risk factors measured at baseline and over a 4-yr period. Their estimated incidence risk of coronary heart disease was calculated by a formula based on a previous cohort study.
Results: Successful abstainers who had stopped smoking for at least 6 months at the end of the follow-up period had weight gains of approximately 2 kg. These subjects had significant worsening of the following factors compared to continuing smokers: systolic and diastolic blood pressure, total cholesterol, triglyceride and fasting blood sugar levels. In contrast, HDL-cholesterol levels improved significantly. When the overall instantaneous incidence risk of coronary heart disease prior to smoking cessation was assumed to be 1.00, the estimated risk was 0.76 (95%CI: 0.68-0.85) in successful abstainers due mainly to smoking cessation, despite weight gain.
Conclusion: Although smoking cessation leads to weight gain, the estimated risk of coronary heart disease was decreased markedly by smoking cessation.

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Aim: Enhancement of lipoprotein lipase (LPL) activity through drug administration has been shown to increase pre-heparin serum LPL concentrations; however, pre-heparin serum LPL responses to exercise training have not been determined. The present study was undertaken to investigate the effects of 12 weeks of supervised aerobic exercise training on pre-heparin serum LPL concentrations in overweight/obese men.
Methods: Fifteen overweight/obese middle-aged men were assigned to one of two 12-week supervised exercise interventions: a walking group (eight participants gradually increasing brisk walking to 60 min/day 3 days a week) or a jogging group (seven participants gradually increasing jogging to 60 min/day 3 days a week). All participants maintained ad libitum diets. Blood samples were collected at baseline and immediately after 12 weeks. The primary outcome was pre-heparin serum LPL.
Results: Pre-heparin serum LPL concentrations were increased in the jogging group after 12 weeks compared with the baseline values (mean±SEM: 37.6±4.7 vs. 51.0±6.6 ng/mL, respectively, p= 0.033). In the walking group, pre-heparin serum LPL concentrations remained unchanged after 12 weeks.
Conclusions: This study demonstrates that 12 weeks of jogging training increases pre-heparin serum LPL concentrations in overweight/obese middle-aged men.

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Aim: The aim of this study was to examine whether non-high-density lipoprotein cholesterol (non-HDL-cholesterol) raises the risk of coronary heart disease in a dose-response fashion in a non-obese population with low total cholesterol levels and high HDL-cholesterol levels, such as Japanese.
Methods: A total of 30,802 men and 60,417 women, aged 40 to 79 years with no history of stroke or coronary heart disease, completed a baseline risk factor survey in 1993 under the auspices of the Ibaraki Prefectural Health Study. Systematic mortality surveillance through 2003 identified 539 coronary heart disease deaths.
Results: The mean values for non-HDL-cholesterol were 140 mg/dL for men and 151 mg/dL for women. The corresponding mean values were 193 mg/dL and 208 mg/dL total cholesterol and 52 mg/dL and 57 mg/dL HDL-cholesterol, respectively. Men with non-HDL-cholesterol ≥180 mg/dL had a two-fold higher age-adjusted risk of mortality from coronary heart disease than did those with non-HDL-cholesterol <100 mg/dL, whereas no such association was found for women. The multivariable hazard ratio for ≥180 mg/dL versus <100 mg/dL of non-HDL-cholesterol was 2.22 (95% confidence interval: 1.37 to 3.62) for men and 0.71 (0.37 to 1.34) for women.
Conclusion: Higher concentrations of non-HDL-cholesterol were associated with an increased risk of mortality from coronary heart disease for men, but not for women.

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Aim: Ezetimibe is a novel cholesterol absorption inhibitor that reduces the level of low-density lipoprotein (LDL)-cholesterol (C). The effects of ezetimibe on remnant-like particle (RLP)-C, lipoprotein (a) [Lp(a)], and oxidized LDL (Ox-LDL) levels have not been examined.
Methods: Fifty patients with dyslipidemia were treated with 10 mg/day of ezetimibe. At baseline and 12 weeks after treatment with ezetimibe, we measured the levels of RLP-C, Lp(a), Ox-LDL, and high-sensitivity C-reactive protein (hs-CRP).
Results: The mean levels of total cholesterol (TC), LDL-C, triglycerides (TG), and apolipoprotein (apo) B, respectively, showed a significant decrease from 229±39 to 191±37 mg/dL (-16%, p<0.0001), from 151±34 to 118±33 mg/dL (-22%, p<0.0001), from 162±82 to 135±55 mg/dL (-7%, p<0.01), and from 116±22 to 94±21 mg/dL (-18%, p<0.0001) after 12 weeks of treat-ment with ezetimibe. The mean level of RLP-C and median level of hs-CRP also decreased signifi-cantly from 6.8±4.0 to 4.8±2.5 mg/dL (-21%, p<0.0001) and from 0.6 to 0.4 mg/L (-33%, p<0.05). The median level of Lp(a) decreased significantly from 14 to 10 mg/dL (-29%, p<0.05) in patients treated with ezetimibe monotherapy.
Conclusions: Ezetimibe was effective for reducing the levels of TC, LDL-C, TG, and RLP-C. Ezeti-mibe could be a potential therapeutic option for decreasing the Lp(a) level.

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Aim: The aim of this study was to investigate the association of T-786C, G894T and 4a/b polymorphisms in the endothelial nitric oxide synthase (eNOS) gene with early-onset ischemic stroke in South Indians.
Methods: We enrolled 177 patients diagnosed with ischemic stroke aged between 15 to 45 years and 219 age- and gender-matched healthy controls. Genotypes of eNOS T-786C, G894T and 4a/b were identified by polymerase chain reaction and restriction fragment length polymorphism.
Results: The allele and genotype frequencies of eNOS 4a/b, T-786C and G894T did not differ significantly in the patient group compared to controls. Logistic regression analysis indicated the 4a allele to be an independent predictor of ischemic stroke in females (dominant model: OR, 2.46; 95% CI, 1.11 to 5.43; p=0.026). Marked differences were found in the prevalence of the minor alleles of the three variants when comparing the South Indian population with the reported frequencies from Caucasians. There was also a contrast in the frequencies of 4ab and T-786C variants from other Asians. The genotypes of all three variants were found to be in Hardy-Weinberg equilibrium. There was a lack of significant linkage disequilibria among the variants, and none of the estimated haplo-types increased or decreased the risk of ischemic stroke.
Conclusion: The eNOS intron 4a/b polymorphism can predict early-onset ischemic stroke in south Indian women.

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Aim: We investigated the role of endothelin-1 (ET-1) in coronary microvascular spasm in a porcine model.
Methods: A flowmeter was implanted around the left anterior descending coronary artery (LAD), and epicardial coronary artery endothelial denudation (ED) was performed just distal to the flowmeter every 2 weeks (W) until 6 W in 10 pigs (ED group). Ten pigs were chronically treated with endothelin type A receptor (ET_A) antagonist (TA-0201, 0.1 mg/kg/day, ED+ET_A group), while neither ED nor administration of ET_A antagonist was performed in 12 pigs (Control group). We assessed changes in LAD blood flow and the denuded site diameter induced by acetylcholine (ACh, 0.05 μg/kg i.c.).
Results: In the ED group, administration of ACh to LAD induced zero flow without LAD diameter reduction at 8 W. In the ED+ET_A group, the decrease in LAD blood flow response to ACh was suppressed. Chronic administration of TA-0201 suppressed ROS generation in the myocardium. Decreases of eNOS and intimal thickening were smaller in the TA-0201 administration group than the non-TA-0201 administration group.
Conclusion: Chronic administration of ET_A receptor antagonist is effective to prevent coronary microvascular spasm.

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Aim: To clarify the relationship between the accumulation of cardiovascular risk factors and the 5-year decline in instrumental activity of daily living (IADL) among a cohort representative of the Japanese population aged 65 years and over.
Methods: An IADL survey was performed by public health centers throughout Japan. Study subjects were elderly men and women living in districts under the jurisdiction of collaborating health centers. Subjects were invited to participate in the IADL survey assessed by the Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence twice in 1995 and in 2000; 1222 participants were eligible for the analysis. The relationship between the number of cardiovascular risk factors, such as hypertension, hypercholesterolemia, hypertriglycemia, low serum high-density lipoprotein cholesterol, diabetes, obesity and smoking, at baseline and the 5-year difference in IADL scores was examined by linear regression analysis and logistic regression analysis.
Results: Decrease in IADL scores was larger in those with cardiovascular risk factors than in those without. The multivariable odds ratio (OR) for decreased IADL after adding one CVD risk factor was 1.16 (95% confidence interval (CI), 1.04-1.29) after adjusting for age, sex, alcohol consumption and TMIG score at baseline. Among participants who were regarded as physically independent with respect to basic ADL in the baseline survey, the odds ratio was also similar and significant.
Conclusion: Preventive interventions directed against cardiovascular risk factors, especially against their accumulation, may contribute to maintaining IADL in the Japanese elderly.

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Aim: PPARγ (peroxisome proliferator-activated receptor γ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes associated with lipid metabolism. Herein, we show that expression levels of the novel PPARγ transcript exhibit circadian oscillation. To study the mechanisms controlling PPARγ expression, a novel PPARγ gene promoter was cloned and characterized.
Methods: We analyzed the novel PPARγ promoter by luciferase reporter assays and gel shift analysis.
Results: Surprisingly, it was not an intron but rather the novel first exon of PPARγ that was found to have functional minimal promoter activity. Luciferase reporter assays and gel shift assays revealed that the novel first exon is essential for novel PPARγ promoter activation and that DBP (albumin gene D-site binding protein) and E4BP4 (E4 promoter A binding protein 4) bind directly to D-sites in the novel first exon.
Conclusion: Our results demonstrate that the PAR-bZIP (bZIP, basic leucine zipper) family and E4BP4 are the main regulatory factors involved in oscillation of novel PPARγ expression. This regulatory mechanism clearly differs from that of the circadian expression of PPARα.

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Aim: To evaluate the dose-response effects of granulocyte-colony stimulating factor (G-CSF) on atherosclerosis, we examined how G-CSF treatment at different concentrations affects atherosclerotic plaque formation in the aorta of cholesterol-fed rabbits.
Methods: Japanese White rabbits (n=8 each) fed on a 1.5% cholesterol diet were subcutaneously injected with G-CSF at 50 (GL), 100 (GM), or 300 µg/kg/day (GH) for five days, or with 3 cycles of G-CSF at 100 µg/kg/day at 3-week intervals (GM3), or human serum albumin (Control). The extent and composition of atherosclerosis was evaluated 14 weeks after cholesterol feeding.
Results: Although G-CSF treatment did not affect plasma lipid levels, the percentage of aortic surface involvement in the GM3 group was significantly decreased (p<0.05) compared with the Control group. Histological analysis revealed that the intima media ratio was also diminished in GM and GM3 groups. The extent of intimal smooth muscle cell accumulation was higher in GL and GM3 groups than in the Control group. TIMP-2 mRNA expression in the aortic tissue was increased by G-CSF treatment.
Conclusions: Our results suggest that appropriate doses of G-CSF reduced atherosclerotic plaque formation and increased plaque stability in cholesterol-fed rabbits.

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Aim: Angiotensin-converting enzyme inhibitors (ACEIs) have been shown to block matrix metalloproteinase (MMP)-9 activity, which plays a role in atherogenesis. MMP-9 activity of macrophages is increased during foam cell formation. To investigate the contribution of ACEIs to foam cell formation, we studied the effects of an ACEI, imidaprilat, on THP-1 macrophages and the underlying molecular mechanisms in vitro.
Methods and Results: Pre-treatment of THP-1 macrophages with imidaprilat (100 nmol/L, 4 hours) significantly decreased foam cell formation induced by oxidized LDL (OxLDL). Imidaprilat reduced the protein level of MMP-9 in THP-1 macrophages and attenuated OxLDL-induced MMP-9 activity in the culture supernatants. Indeed, pretreatment of THP-1 macrophages with an MMP-2/9 inhibitor (20 µmol/L, 4 hours) attenuated OxLDL-induced foam-cell formation. Imidaprilat or the MMP-2/9 inhibitor blocked OxLDL-induced expressions of LOX-1 and scavenger receptor-A (SR-A), but not that of CD36, in THP-1 macrophages. In addition, OxLDL-induced activation of p38 mitogen-activated protein kinase (MAPK) and ERK, but not JNK, was blunted by imidaprilat or the MMP-2/9 inhibitor. Finally, siRNA against MMP-9 inhibited foam cell formation as well as lipid accumulation in THP-1 macrophages.
Conclusion: These findings suggest that imidaprilat reduces OxLDL-triggered foam-cell formation in THP-1 macrophages via modulation of MMP-9 activity and may indicate a novel antiinflamma-tory mechanism of imidaprilat in atherogenesis.

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Aim: To demonstrate the clinical benefit of inhibiting intestinal cholesterol absorption, we evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis, lipid and glucose metabolism, and markers of obesity and inflammation.
Methods: A total of 120 patients with dyslipidemia (46 men; mean age 66.5 years), who had not achieved the low density lipoprotein cholesterol (LDL-C) goal recommended by the Japan Atherosclerosis Society Guideline despite diet and exercise or any statin therapy, were enrolled and additionally treated with ezetimibe (10 mg/day) for 12 weeks.
Results: Compared to the baseline, LDL-C was reduced by 19.2% (p<0.001) after ezetimibe monotherapy and by 24.7% (p<0.001) after co-administration with ezetimibe and any statin. Ezetimibe therapy decreased cholesterol absorption markers and increased a cholesterol synthesis marker. Treatment with ezetimibe reduced the fasting serum insulin level (p<0.05) and HbA1c (p<0.05), increased serum adiponectin (p<0.01), and showed a significant decrease of high-sensitive C-reactive protein (hsCRP, p<0.01). No adverse events occurred during the study.
Conclusion: Thus, cholesterol absorption inhibition by ezetimibe is an important therapeutic strategy since LDL-C and cholesterol absorption markers had a positive correlation. Ezetimibe not only reduced the serum LDL-C level but also improved glucose metabolism as well as obesity and inflammation markers. These findings support the benefit of ezetimibe as a new option for the treatment of dyslipidemia.

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