Endothelial Protection, AT1 Blockade and Cholesterol-Dependent Oxidative Stress The EPAS Trial

Background— 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. Methods and Results— 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. AT1 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. Conclusions— Statin and AT1 blocker therapy independently and in combination improve an anti-atherosclerotic endothelial expression quotient and endothelial function.