This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schieffer, B. Articles by Drexler, H. Search for Related Content PubMed PubMed Citation Articles by Schieffer, B. Articles by Drexler, H.

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

This article has been cited by other articles:

				R. N. Willette, M. E. Eybye, A. R. Olzinski, D. J. Behm, N. Aiyar, K. Maniscalco, R. G. Bentley, R. W. Coatney, S. Zhao, T. D. Westfall, et al. Differential Effects of p38 Mitogen-Activated Protein Kinase and Cyclooxygenase 2 Inhibitors in a Model of Cardiovascular Disease J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 964 - 970. [Abstract] [Full Text] [PDF]

				S. Peters, B. Behnisch, T. Heilmann, and C. Richter First-in-man use of polymer-free valsartan-eluting stents in small coronary vessels: a comparison to polymer-free rapamycin (2%)-eluting stents Journal of Renin-Angiotensin-Aldosterone System, June 1, 2009; 10(2): 91 - 95. [Abstract] [PDF]

				M. I. Yilmaz, J. Axelsson, A. Sonmez, J. J. Carrero, M. Saglam, T. Eyileten, K. Caglar, A. Kirkpantur, T. Celik, Y. Oguz, et al. Effect of Renin Angiotensin System Blockade on Pentraxin 3 Levels in Type-2 Diabetic Patients With Proteinuria Clin. J. Am. Soc. Nephrol., March 1, 2009; 4(3): 535 - 541. [Abstract] [Full Text] [PDF]

				A Williams, S Davies, A G Stuart, D G Wilson, and A G Fraser Medical treatment of Marfan syndrome: a time for change Heart, April 1, 2008; 94(4): 414 - 421. [Abstract] [Full Text] [PDF]

				D. B. Matchar, D. C. McCrory, L. A. Orlando, M. R. Patel, U. D. Patel, M. B. Patwardhan, B. Powers, G. P. Samsa, and R. N. Gray Systematic Review: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers for Treating Essential Hypertension Ann Intern Med, January 1, 2008; 148(1): 16 - 29. [Abstract] [Full Text] [PDF]

				J. Li, Y. Doerffel, B. Hocher, and T. Unger Inflammation in the genesis of hypertension and its complications the role of angiotensin II Nephrol. Dial. Transplant., November 1, 2007; 22(11): 3107 - 3109. [Full Text] [PDF]

				F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]

				G. A. Rodriguez-Granillo, S. de Winter, N. Bruining, J. M.R. Ligthart, H. M. Garcia-Garcia, M. Valgimigli, P. J. de Feyter, and on behalf of the EUROPA/PERSPECTIVE Investigators Effect of perindopril on coronary remodelling: insights from a multicentre, randomized study Eur. Heart J., October 1, 2007; 28(19): 2326 - 2331. [Abstract] [Full Text] [PDF]

				M. S. Sabatine, D. A. Morrow, K. A. Jablonski, M. M. Rice, J. W. Warnica, M. J. Domanski, J. Hsia, B. J. Gersh, N. Rifai, P. M Ridker, et al. Prognostic Significance of the Centers for Disease Control/American Heart Association High-Sensitivity C-Reactive Protein Cut Points for Cardiovascular and Other Outcomes in Patients With Stable Coronary Artery Disease Circulation, March 27, 2007; 115(12): 1528 - 1536. [Abstract] [Full Text] [PDF]

				J. Ruef, M. Browatzki, C. A. Pfeiffer, J. Schmidt, and R. Kranzhofer Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2 Vascular Medicine, February 1, 2007; 12(1): 23 - 27. [Abstract] [PDF]

				F. Persson, P. Rossing, P. Hovind, C. D.A. Stehouwer, C. Schalkwijk, L. Tarnow, and H.-H. Parving Irbesartan Treatment Reduces Biomarkers of Inflammatory Activity in Patients With Type 2 Diabetes and Microalbuminuria: An IRMA 2 Substudy Diabetes, December 1, 2006; 55(12): 3550 - 3555. [Abstract] [Full Text] [PDF]

				S. G. de Vinuesa, M. Goicoechea, J. Kanter, M. Puerta, V. Cachofeiro, V. Lahera, F. Gomez-Campdera, and J. Luno Insulin Resistance, Inflammatory Biomarkers, and Adipokines in Patients with Chronic Kidney Disease: Effects of Angiotensin II Blockade J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S206 - S212. [Abstract] [Full Text] [PDF]

				J. M. Luther, J. V. Gainer, L. J. Murphey, C. Yu, D. E. Vaughan, J. D. Morrow, and N. J. Brown Angiotensin II Induces Interleukin-6 in Humans Through a Mineralocorticoid Receptor-Dependent Mechanism Hypertension, December 1, 2006; 48(6): 1050 - 1057. [Abstract] [Full Text] [PDF]

				P. M Ridker, E. Danielson, N. Rifai, R. J. Glynn, and for the Val-MARC Investigators Valsartan, Blood Pressure Reduction, and C-Reactive Protein: Primary Report of the Val-MARC Trial Hypertension, July 1, 2006; 48(1): 73 - 79. [Abstract] [Full Text] [PDF]

				A. R. Lucas, R. Korol, and C. J. Pepine Inflammation in Atherosclerosis: Some Thoughts About Acute Coronary Syndromes Circulation, May 2, 2006; 113(17): e728 - e732. [Full Text] [PDF]

				P. Pauletto and M. Rattazzi Inflammation and hypertension: the search for a link Nephrol. Dial. Transplant., April 1, 2006; 21(4): 850 - 853. [Full Text] [PDF]

				C. J. Boos, R. A. Anderson, and G. Y.H. Lip Is atrial fibrillation an inflammatory disorder? Eur. Heart J., January 2, 2006; 27(2): 136 - 149. [Abstract] [Full Text] [PDF]

				S. M. Grundy, J. I. Cleeman, S. R. Daniels, K. A. Donato, R. H. Eckel, B. A. Franklin, D. J. Gordon, R. M. Krauss, P. J. Savage, S. C. Smith Jr, et al. Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement Circulation, October 25, 2005; 112(17): 2735 - 2752. [Full Text] [PDF]

				A. G. Herman and S. Moncada Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis Eur. Heart J., October 1, 2005; 26(19): 1945 - 1955. [Abstract] [Full Text] [PDF]

				J.-J. Li and C.-H. Fang Effects of 4 Weeks of Atorvastatin Administration on the Antiinflammatory Cytokine Interleukin-10 in Patients with Unstable Angina Clin. Chem., September 1, 2005; 51(9): 1735 - 1738. [Full Text] [PDF]

				Z. T. Bloomgarden Second World Congress on the Insulin Resistance Syndrome: Hypertension, cardiovascular disease, and treatment approaches Diabetes Care, August 1, 2005; 28(8): 2073 - 2080. [Full Text] [PDF]

				A. H. Berg and P. E. Scherer Adipose Tissue, Inflammation, and Cardiovascular Disease Circ. Res., May 13, 2005; 96(9): 939 - 949. [Abstract] [Full Text] [PDF]

				H. Morawietz Beyond Blood Pressure: Endothelial Protection Against Hypercholesterolemia by Angiotensin II Type-1 Receptor Blockade Hypertension, February 1, 2005; 45(2): 185 - 186. [Full Text] [PDF]