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(Circulation. 2006;114:I-296 – I-301.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Endothelial Protection, AT₁ Blockade and Cholesterol-Dependent Oxidative Stress

The EPAS Trial

Henning Morawietz, PhD; Sandra Erbs, MD; Jürgen Holtz, MD; Andreas Schubert, PhD; Michael Krekler, PhD; Winfried Goettsch, PhD; Oliver Kuss, PhD; Volker Adams, PhD; Karsten Lenk, MD; Friedrich W. Mohr, MD; Gerhard Schuler, MD; Rainer Hambrecht, MD

From the Department of Vascular Endothelium and Microcirculation (H.M., W.G.), Medical Faculty Carl Gustav Carus, University of Technology Dresden, Dresden, Germany; Department of Cardiology (S.E., V.A., K.L., G.S., R.H.), University of Leipzig, Heart Center Leipzig, Leipzig, Germany; the Institute of Pathophysiology (J.H.), Martin Luther University Halle-Wittenberg, Halle, Germany; the Department of Cardiac Surgery (A.S., F.W.M.), University of Leipzig, Heart Center Leipzig, Leipzig, Germany, Department of Cardiovascular Research (M.K.), Bristol-Myers Squibb, Munich, Germany, and Institute of Medical Epidemiology, Biostatistics, and Informatics (O.K.), Martin Luther University Halle-Wittenberg, Halle, Germany.

Correspondence to Henning Morawietz, Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstr. 74, D-01307 Dresden, Germany. E-mail Henning.Morawietz{at}tu-dresden.de

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.

Key Words: angiotensin • cardiopulmonary bypass • lipoproteins • nitric oxide synthase • trials