Endothelial Protection, AT1 blockade and Cholesterol-Dependent Oxidative Stress: the EPAS trial.
ABSTRACT Statins and angiotensin type 1 (AT1) receptor blockers reduce cardiovascular mortality and morbidity. In the Endothelial Protection, AT1 blockade and Cholesterol-Dependent Oxidative Stress (EPAS) trial, impact of independent or combined statin and AT1 receptor blocker therapy on endothelial expression of anti-atherosclerotic and proatherosclerotic genes and endothelial function in arteries of patients with coronary artery disease were tested.
Sixty patients with stable coronary artery disease undergoing elective coronary artery bypass grafting (CABG) surgery were randomized 4 weeks before surgery to: (A) control without inhibition of renin-angiotensin system or statin; (B) statin (pravastatin 40 mg/d); (C) AT1 blockade (irbesartan 150 mg/d); or (D) combination of statin and AT1 blocker in same dosages. Primary end point was a priori therapy-dependent regulation of an anti-atherosclerotic endothelial expression quotient Q including mRNA expression (in arbitrary units measured by real-time polymerase chain reaction) of endothelial nitric oxide synthase and C-type natriuretic peptide, divided by expression of oxidized low-density lipoprotein receptor LOX-1 and NAD(P)H oxidase subunit gp91phox in left internal mammary arteries biopsies obtained by CABG surgery; 49 patients completed the study. Statin therapy increased lnQ from 3.2+/-0.4 to 4.4+/-0.4 significantly versus control. AT(1) blockade showed a trend to increase lnQ to 4.2+/-0.5. Combination of statin and AT1 blocker further increased lnQ to 5.1+/-0.6, but a putative interaction of both therapies in lnQ was not significant. Furthermore, preoperative therapy with statin, AT1 blocker and their combination improved endothelial function in internal mammary artery rings.
Statin and AT1 blocker therapy independently and in combination improve an anti-atherosclerotic endothelial expression quotient and endothelial function.
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ABSTRACT: Significance: Endothelial dysfunction and the imbalance between nitric oxide (NO) and reactive oxygen species (ROS) production in the vascular endothelium are important early steps in atherogenesis, a major socioeconomic health problem. Statins have well-established roles in primary and secondary prevention of cardiovascular disease (CVD), due to both their lipid-lowering capacity and their pleiotropic properties. It is therefore important to understand the mechanisms by which statins can modify endothelial function and affect atherogenesis. Recent Advances: In the last decade, the concept of statin pleiotropy has been reinforced by a large number of cell culture, animal and translational studies. Statins have been shown to suppress the activity of pro-oxidant enzymes (such as NADPHoxidase) and pro-inflammatory transcriptional pathways in the endothelium. At the same time, they enhance endothelial nitric oxide synthase (eNOS) expression and activity while they also improve its enzymatic coupling. This leads to increased NO bioavailability and improved endothelial function. Critical Issues: Despite significant recent advances, the exact mechanisms of statin pleitropy are still only partially understood. The vast majority of the published literature relies on animal studies, while the actual mechanistic studies in humans are limited. Future Directions: The success of statins as endothelium redox-modifying agents with a direct impact on clinical outcome highlights the importance of the endothelium as a therapeutic target in CVD. Better understanding of the mechanisms underlying endothelial dysfunction could lead to the design of novel therapeutic strategies targeting the vascular endothelium for the prevention and treatment of CVD.Antioxidants & Redox Signaling 10/2013; · 8.20 Impact Factor
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ABSTRACT: Blood pressure is one of the most important and frequent risk factors for cardiovascular disease morbidity and mortality; however, it is largely uncontrolled in the population. Inhibition of the renin--angiotensin--aldosterone system provides beneficial effects in the hypertensive population. Association of low-dosed diuretics in drug combinations with renin--angiotensin--aldosterone system-blocking agents allows maximum benefit from potassium depletion and control of the compensatory increase in renin secretion, thus increasing the efficacy and safety of the renin--angiotensin--aldosterone system blockers. Irbesartan is a potent and selective angiotensin II subtype 1 receptor antagonist indicated for use in patients with hypertension, including those with Type 2 diabetes mellitus and nephropathy. Once-daily irbesartan administration provides 24-h control of blood pressure. In patients with mild-to-moderate hypertension, irbesartan was as effective as enalapril, atenolol and amlodipine, and more effective than losartan and valsartan (but not olmesartan), in terms of absolute reduction in blood pressure and response rate. Irbesartan also induced regression of left ventricular hypertrophy. Moreover, irbesartan 300 mg/day exerted a significant renoprotective effect in hypertensive Type 2 diabetics. The relative risk of doubling of serum creatinine was significantly lower with irbesartan than with amlodipine or placebo. It was also found to be effective in nondiabetic nephropaties. Furthermore, irbesartan has peroxisome proliferator-activated receptor agonistic effects in in vitro studies and also demonstrated beneficial effects on inflammatory markers of atherosclerosis and endothelial function. The overall incidence of adverse events is similar to that of placebo. A fixed-dose combination of hydrochlorothiazide and irbesartan show additive antihypertensive effects in a dose-dependent manner up to hydrochlorothiazide 25 mg and irbesartan 300 mg, with high tolerability in diverse patient groups. Effects of combination on end-organ protection must be evaluated by broad-spectrum studies. Ongoing trials with irbesartan and its combination with diuretics may provide necessary data to interpret the value of this association among others.Therapy 11/2006; 3(6):733-749.
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ABSTRACT: Vascular endothelial dysfunction is determined by both genetic and environmental factors that cause decreased bioavailability of the vasodilator nitric oxide. This is a hallmark of atherosclerosis, hypertension, and coronary heart disease, which are major complications of metabolic disorders, including diabetes and obesity. Several therapeutic interventions, including changes in lifestyle as well as pharmacologic treatments, are useful for improving endothelial dysfunction in the face of lipotoxicity. This review discusses the current understanding of molecular and physiologic mechanisms underlying lipotoxicity-mediated endothelial dysfunction as well as relevant therapeutic approaches to ameliorate dyslipidemia and consequent endothelial dysfunction that have the potential to improve cardiovascular and metabolic outcomes.Heart Failure Clinics 10/2012; 8(4):589–607.