Dihydropyridine calcium channel blockers (CCBs) are widely used agents for patients with hypertension. Dihydropyridine CCBs lower blood pressure mainly through vasodilation and reduction of peripheral resistance, and several clinical studies have demonstrated that they have clinical benefits in patients with cardiovascular diseases. In addition, some studies have indicated that dihydropyridine CCBs have anti-atherogenic effects beyond their blood pressure-lowering effects. In fact, several studies using atherosclerotic model animals have revealed that dihydropyridine CCBs suppress atherosclerotic lesion formation. It is well known that the production of reactive oxygen species (ROS) is involved in the progression of atherosclerosis by stimulating the production of inflammatory factors such as chemokines, cytokines and adhesion molecules. Dihydropyridine CCBs can suppress ROS generation and subsequent inflammatory actions in vascular cells and arterial walls. Furthermore, several reports have revealed that dihydropyridine CCBs suppress the expression of adhesion molecules, thereby inhibiting monocyte adhesion to endothelial cells, which is thought to be an early step in the pathogenesis of atherosclerosis. In smooth muscle cells, dihydropyridine CCBs suppress cell proliferation and migration in vitro and in vivo. In macrophages, dihydropyridine CCBs decrease cholesterol accumulation and intracellular cholesterol esterification, and increase cholesteryl ester hydrolysis. Moreover, dihydropyridine CCBs suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. Interestingly, recent studies have revealed that the anti-atherosclerotic effects of dihydropyridine CCBs are mediated, at least in part, via the activation of peroxisome proliferator-activated receptor-γ. In this review, we focus on the anti-atherosclerotic effects of dihydropyridine CCBs beyond their blood pressure-lowering effects.

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In vivo evidence for the pleiotropic effects of simvastatin on the nitric oxide synthase system is limited.
Aims: To determine if simvastatin can affect the endothelial nitric oxide synthase cascade.
Methods: New Zealand white rabbits (n=15) were divided: Group 1 (control) was fed a normal rabbit diet; Group 2 (MC) received a normal rabbit diet with 1% methionine (M) plus 0.5% cholesterol (C) and 5% peanut oil (atherogenic diet); Group 3 received the same diet as the MC group plus 5 mg/kg/ day simvastatin (S) orally (MCS). After 4 weeks, the abdominal aorta was collected and analyzed.
Results: Total cholesterol (TC) and total homocysteine (tHcy) were not significantly different between MCS and MC. Endothelial function was only reduced in MC (p<0.05). Although eNOS significantly increased in MC and MCS (p<0.01), simvastatin treatment significantly reduced endothelial caveolin-1 by 35% (p=0.038), causing a 2.5-fold (p=0.026) increase in the eNOS: caveolin-1 ratio. The phosphorylation of eNOS at the threonine 495 site or serine 1177 site was not affected by diet or treatment; however, a positive correlation between the two phosphorylation sites was observed (r²= 0.5, p=0.01).
Conclusion: in vivo pleiotropic effects of statin therapy include decreasing endothelial caveolin-1. Other therapies designed to affect eNOS phosphorylation in vivo might be useful in further preventing CVD.

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Aims:To evaluate the prognostic significance of oxidative stress on the rate of major adverse cardiovascular events (MACEs: cardiac and all-cause death, nonfatal myocardial infarction, coronary revascularization-PTCA/CABG) in CAD.
Methods: We studied 97 angiographically proven CAD patients (78 males, age: 67±11 years, mean± SD). Reactive oxygen metabolites and total antioxidant status, assessed by commercially assays (d-ROMs and OXY-Adsorbent Test; Diacron, Grosseto, GR, Italy), were used to calculate the oxidant/antioxidant balance. Patient data were collected from the Institute's electronic databank, which saves demographic, clinical, instrumental and follow-up data of all patients admitted to our department.
Results: Kaplan-Meier survival estimates showed a significantly worst outcome in patients presenting with elevated oxidative stress levels (>75th percentile, p<0.01). Multivariate Cox models showed that a higher level of oxidative stress was an independent predictor of developing MACEs (hazard ratio=2.1, confidence intervals 1.2-3.6, p<0.01).
Conclusion: Oxidative stress may represent a useful additional tool in the prediction of MACE in CAD.

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Aim: Was to evaluate the role of seven matrix metalloproteinase (MMP) polymorphisms in the genetic susceptibility to develop myocardial infarction in Mexican individuals.
Methods: Seven polymorphisms in the MMP genes were genotyped by 5' exonuclease TaqMan genotyping assays in 300 patients with myocardial infarction and 300 healthy unrelated controls.
Results: A similar distribution of MMP2-1306 (rs243865), MMP2-790 (rs243864), MMP2-735 (rs22850553), MMP7-153(rs11568819), MMP7-181(rs11568818), and MMP12-82(rs2276109) polymorphisms was observed in both studied groups. On the other hand, patients showed increased frequencies of MMP2-1575 A allele and AA genotype when compared to controls (pC= 0.001; OR= 1.58 and pC= 0.036; OR= 2.37, respectively). According to the dominant model, individuals with AG+AA genotypes had a 1.65-fold increased risk of developing the disease (p= 0.002). After adjusting for known risk factors, we found a significant contribution of gender, BMI, smoking habit, diabetes mellitus, and hypertension to the inheritance model. In this analysis, individuals with the-1575 AA genotype had a 4.23-fold increased risk of developing MI (p= 0.003). On the other hand, an association of the MMP12-82 polymorphism with the extent of coronary artery disease (CAD) was observed. In our study, it was possible to distinguish two risk haplotypes and one protective haplotype for this disease in the MMP2 gene.
Conclusions: The results suggest that the MMP2-1575 (rs243866) gene polymorphism could be involved in the risk of developing myocardial infarction in Mexican individuals.

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Aim: Visceral adiposity is linked with sleep-disordered breathing (SDB) (called Syndrome Z), and both correlate with coronary artery disease (CAD). The aim of the present study was to determine the significance of excess visceral fat, SDB and circulating levels of biomarkers in CAD in Japanese men.
Methods: SDB, visceral fat area (VFA), and circulating levels of biomarkers were assessed in 60 Japanese male patients who underwent coronary angiography and overnight cardiorespiratory monitoring.
Results: Age-adjusted logistic analysis showed a significant relationship between CAD and diabetes, hypertension, dyslipidemia, SDB (AHI ≥5 events/hour), visceral fat accumulation (VFA ≥100 cm²), the combination of visceral fat accumulation and hypertension or dyslipidemia, as well as the combination of visceral fat accumulation and SDB. Patients with VFA ≥100 cm² and SDB had significantly lower serum adiponectin levels and higher serum soluble CD40 ligand levels than those with VFA<100 cm² and SDB. The prevalence of CAD was significantly higher in patients with VFA ≥100 cm² and SDB than in patients with VFA <100 cm² and AHI <5 events/hour, patients with VFA<100 cm² and AHI ≥5 events/hour or patients with VFA ≥100 cm² and AHI <5 events/hour (93% versus 14%, p <0.001, 53%, p <0.01 or 63%, p <0.01, respectively).
Conclusions: The present study indicates that patients with both visceral fat accumulation and SDB develop CAD in association with hypoadiponectinemia and inflammatory activity.

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Aim: Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for the regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on the regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice.
Methods and Results: Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose candesartan caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose candesartan. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol: cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after treatment with high-dose candesartan, while biglycan and ACAT1 expressions were decreased.
Conclusion: These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose candesartan, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

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Aims: Oxidative stress has been recently postulated to be an important factor in the pathogenesis and development of arteriosclerosis. Although urinary 8-hydroxydeoxyguanosine (8-OHdG) is clinically used as a marker of oxidative stress, its usefulness in diagnosing arteriosclerosis has not been fully examined. This study aimed to evaluate the association between urinary 8-OHdG and the cardioankle vascular index (CAVI) as a marker of arterial stiffness in hypertensive patients.
Methods: We enrolled 100 hypertensive patients (70±10 years) who had been taking antihypertensive medications for at least one year. Urinary 8-OHdG levels were measured by an immunochromatographic assay (ICR-001; Selista Inc., Tokyo, Japan). CAVIs were measured at the same visit.
Results: Urinary 8-OHdG was correlated with smoking habits (r=0.382, p<0.001) and CAVIs (r= 0.223, p= 0.026). Multiple linear regression analysis revealed two independent determinants of urinary 8-OHdG: smoking habits (β=0.501, p<0.001) and CAVI (β=0.325, p=0.001). In addition, CAVIs were correlated with age (r= 0.600, p<0.001), BMI (r=−0.348, p<0.001), systolic blood pressure (r= 0.343, p<0.001), pulse pressure (r= 0.358, p<0.001), serum creatinine level (r=0.408, p<0.001), urinary 8-OHdG level (r= 0.223, p= 0.026), and diabetes (r= 0.210, p=0.036). Multiple linear regression analysis revealed two independent determinants of CAVI: age (β= 0.568, p<0.001) and 8-OHdG (β=0.357, p<0.001).
Conclusion: Elevated CAVI is independently associated with an elevated urinary 8-OHdG level in hypertensive patients.

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Aim: To examine the impact of C-reactive protein on the risks of stroke and its subtypes, particularly among Asian populations in which median C-reactive protein levels are typically lower than in Western populations.
Methods: A prospective, nested case-control study was conducted to examine the associations between high sensitivity-CRP (hs-CRP) and risks of cardiovascular disease within a cohort of 29,876 men and women aged 40-69 years, with no history of stroke, ischemic heart disease or cancer, who submitted blood samples between 1990 and 1993. Systematic cardiovascular surveillance was performed throughout 2007. One control for each stroke and two controls for each ischemic heart disease were matched for sex, age, date of blood drawing, time since last meal and study location.
Results: We documented 1,132 incident strokes (638 ischemic and 494 hemorrhagic strokes) and 209 ischemic heart diseases (168 myocardial infarctions and 41 sudden cardiac deaths), and observed a linear association between hs-CRP levels and risks of ischemic stroke and ischemic heart disease, more specifically myocardial infarction. The multivariable odds ratios associated with 1-SD increment of logarithmically transformed hs-CRP were 1.13 (0.99-1.29),p= 0.07 for ischemic stroke, 1.16 (0.96-1.41),p= 0.13 for lacunar infarction, 1.41 (0.98-2.01),p= 0.06 for embolic infarction, and 1.28 (1.03-1.59),p= 0.03 for myocardial infarction. The predictive value of hs-CRP for ischemic stroke was reduced primarily after adjustment for hypertensive status and body mass index. No association was found between hs-CRP levels and the risk of hemorrhagic or total stroke.
Conclusions: High serum hs-CRP levels were associated with the risk of myocardial infarction and more weakly with the risk of ischemic stroke among middle-aged Japanese men and women.

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Aim: The use of ethnic-specific cutoff values of waist circumference (WC) has been recently recommended, but they were originally developed on different statistical grounds. We investigated whether different statistical procedures and clinical settings generate different WC cutoff values in one ethnic population.
Methods: We recruited 3810 Japanese subjects and performed the following three statistical analyses: 1) search for WC cutoff points associated with the risk of clustering metabolic abnormalities, 2) calculation of WC associated with certain body mass index (BMI) levels, 3) evaluation with receiver operating characteristic (ROC) curves for the risk. We also simulated population models to evaluate whether WC cutoff values depend on the clinical settings of the study population.
Results: First, in risk analysis, males and females had the same risk when females had 10 cm larger WC than males, although the risk increased almost linearly, without any clear threshold. Second, WC corresponding to BMI of 25 kg/m² was 87 cm in males and 85 cm in females, with a slight sex difference. Third, ROC curves showed that the male optimal cutoff value was 85 cm, larger than the female one (79 cm). However, simulated population models with various WC distributions gave different ROC curves and different WC cutoff values. Furthermore, WC cutoff values varied by age in any of the three statistical procedures.
Conclusions: Different statistical grounds could generate different WC cutoff values. If one plans to establish a unified trans-ethnic diagnostic tool of metabolic syndrome, ethnic-specific WC cutoff values should be primarily provided based on a unified statistical ground.

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Aim: The aim of this study was to investigate the association of cannabinoid receptor 1 (CNR1) 4895 C/T gene polymorphism with obesity and obesity-related cardiovascular disease (CVD) risk factors in Japanese.
Method: This study included 1,452 Japanese (678 men and 774 women, aged 25 to 74) from rural communities in Shimane Prefecture, Japan.
Results: The frequency of the C minor allele of CNR1 4895 C/T polymorphism was 47%. In men, the CC genotype carriers showed significantly greater body mass index (BMI) and waist circumference (WC) values than T allele carriers, even after adjusting for age and medications for hypertension, dyslipidemia and type 2 diabetes. The frequency of obesity (BMI ≥25 kg/m²) in CC genotype carriers was significantly greater than in T allele carriers (31.8% vs 21.5%), but the frequency of central obesity (WC ≥85 for men and WC ≥90 cm for women) was not significant by CNR1 4895 C/T genotype. CC genotype carriers of CNR1 4895 C/T showed, in logistic regression analysis, significantly greater odds for obesity than T allele carriers, even after adjustment for age and the above-mentioned medications. Systolic blood pressure (SBP) values were also significantly different between the CC genotype and T allele carriers after controlling for age, medications for hypertension, dyslipidemia, and type 2 diabetes, and BMI or WC.
Conclusion: This study supports the association of CNR1 4895 C/T with interindividual differences in obesity in men.

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