Abstract
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. 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.
Publication types
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Comparative Study
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II Type 1 Receptor Blockers / administration & dosage
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Angiotensin II Type 1 Receptor Blockers / therapeutic use*
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Atherosclerosis / etiology
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Atherosclerosis / genetics
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Atherosclerosis / prevention & control
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Biphenyl Compounds / administration & dosage
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Biphenyl Compounds / therapeutic use*
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Blood Pressure / drug effects
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Cholesterol / blood
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Cholesterol, LDL / blood
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Coronary Artery Bypass*
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Coronary Disease / surgery*
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Drug Therapy, Combination
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Elective Surgical Procedures
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Gene Expression Regulation / drug effects
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
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Hypercholesterolemia / complications
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Hypercholesterolemia / drug therapy
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Irbesartan
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Mammary Arteries / metabolism
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / genetics
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Muscle, Smooth, Vascular / drug effects
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NADPH Oxidase 2
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NADPH Oxidases / biosynthesis
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NADPH Oxidases / genetics
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Natriuretic Peptide, C-Type / biosynthesis
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Natriuretic Peptide, C-Type / genetics
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Nitric Oxide Synthase Type III / biosynthesis
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Nitric Oxide Synthase Type III / genetics
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Oxidative Stress
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Polymerase Chain Reaction
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Pravastatin / administration & dosage
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Pravastatin / therapeutic use*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptor, Angiotensin, Type 1 / physiology
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Renin-Angiotensin System / drug effects
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Renin-Angiotensin System / physiology
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Scavenger Receptors, Class E / biosynthesis
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Scavenger Receptors, Class E / genetics
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Tetrazoles / administration & dosage
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Tetrazoles / therapeutic use*
Substances
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Angiotensin II Type 1 Receptor Blockers
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Biphenyl Compounds
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Cholesterol, LDL
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Membrane Glycoproteins
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OLR1 protein, human
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RNA, Messenger
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Receptor, Angiotensin, Type 1
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Scavenger Receptors, Class E
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Tetrazoles
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Natriuretic Peptide, C-Type
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Cholesterol
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Nitric Oxide Synthase Type III
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CYBB protein, human
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NADPH Oxidase 2
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NADPH Oxidases
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Irbesartan
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Pravastatin