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.


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. 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.


CONCLUSIONS
Statin and AT1 blocker therapy independently and in combination improve an anti-atherosclerotic endothelial expression quotient and endothelial function.
Morawietz
Henning
H
Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstr. 74, D-01307 Dresden, Germany. Henning.Morawietz@tu-dresden.de
Erbs
Sandra
S
Holtz
Jürgen
J
Schubert
Andreas
A
Krekler
Michael
M
Goettsch
Winfried
W
Kuss
Oliver
O
Adams
Volker
V
Lenk
Karsten
K
Mohr
Friedrich W
FW
Schuler
Gerhard
G
Hambrecht
Rainer
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000601:surgery*; D004359:Drug Therapy, Combination; D017558:Elective Surgical Procedures; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy; D000077405:Irbesartan; D008323:Mammary Arteries / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics; D020098:Natriuretic Peptide, C-Type / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D017035:Pravastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis / Q000235:genetics; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008562:Membrane Glycoproteins; C495137:OLR1 protein, human; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D051127:Scavenger Receptors, Class E; D013777:Tetrazoles; D020098:Natriuretic Peptide, C-Type; D002784:Cholesterol; D052250:Nitric Oxide Synthase Type III; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000077405:Irbesartan; D017035:Pravastatin