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CLINICAL RESEARCH: ANTI-INFLAMMATORY THERAPY IN CORONARY ARTERY DISEASE

Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease

Bernhard Schieffer, MD^*,*, Christoph Bünte, MS^*, Jana Witte, MS^*, Kirsten Hoeper, RN^*, Rainer H. Böger, MD, Edzard Schwedhelm, PhD and Helmut Drexler, MD^*

^* Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Germany
Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Germany

Manuscript received November 7, 2003; revised manuscript received February 25, 2004, accepted March 16, 2004.

^* Reprint requests and correspondence: Dr. Bernhard Schieffer, Department of Cardiology and Angiology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Schieffer.Bernhard{at}MH-Hannover.de

OBJECTIVES: We evaluated whether renin-angiotensin system (RAS) blockade attenuates cardiovascular events.

BACKGROUND: Because inflammation and enhanced thrombogenesis are hallmarks of atherosclerosis, we assessed whether RAS inhibition elicits anti-inflammatory and anti-aggregatory effects.

METHODS: Interleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), metalloprotease 9 (MMP-9), and interleukin 10 (IL-10) were determined in patients with coronary artery disease (CAD) and arterial hypertension six to eight weeks after coronary angioplasty (low-density lipoprotein serum levels <150 mg/dl). Patients were randomized double-blind to either 20 mg enalapril (ENAL, n = 27) or 300 mg irbesartan (IRB, n = 21) for 3 months. Blood samples were drawn at baseline and at three months. Thromboxane A2-induced platelet aggregation was determined turbidimetrically; urine bicyclo-prostaglandin E2 (PGE₂) and inflammatory markers were measured by enzyme-linked immunosorbent assay technique.

RESULTS: Both treatment regimens enhanced serum IL-10 levels (IRB p < 0.001, ENAL p < 0.03) and reduced serum MMP-9 protein (IRB p < 0.001, ENAL p < 0.05) and MMP-9 activity (IRB p < 0.005, ENAL p < 0.05). Only IRB reduced serum IL-6 and hsCRP levels significantly compared with baseline (p < 0.01), whereas ENAL did not (hsCRP p < 0.02 IRB vs. ENAL, p < 0.01 IRB vs. ENAL). Platelet aggregation was only reduced by IRB (p < 0.001, ENAL p < 0.06, IRB vs. ENAL p < 0.001) while urine PGE₂ levels remained unchanged.

CONCLUSIONS: Angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) blockade reduced serum MMP-9 protein/activity to a similar extent, and only AT1 blockade reduced hsCRP, IL-6, and platelet aggregation in patients with CAD. Thus, AT1-blockade appears to exert stronger systemic anti-inflammatory and anti-aggregatory effects compared with ACE inhibition.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ANG II = angiotensin II   AT1 = angiotensin II type 1 receptor   BP = blood pressure   CAD = coronary artery disease   COX = cyclooxygenase   ENAL = enalapril   EUROPA = European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease   hsCRP = high-sensitivity C-reactive protein   HOPE = Heart Outcome and Prevention Evaluation   IL = interleukin   IRB = irbesartan   MMP = metalloprotease   PG = prostaglandin   RAS = renin-angiotensin system   TXA2 = thromboxane A2

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