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CARDIOLOGY

Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant

Professor of Medicine, Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada

Heather Ross, MD FRCPC

Associate Professor of Medicine, Fenwick Family Professor in Advanced Heart Failure, Deputy Director MultiOrgan Transplant; Medical Director of Cardiac Transplantation, University Health Network, Toronto, Ontario, Canada

Sylvie Levesque, MSc

Statistician, Montreal Heart Institute Coordinating Center, Montreal

Lucette Whittom, RN BSc

Clinical Research Assistant, Montreal Heart Institute, Montreal

Guy B Pelletier, MD

Clinical Specialist, Department of Medicine, Montreal Heart Institute

Normand Racine, MD, FRCPC

Physician-in-Chief, Department of Medicine and Cardiology; Assistant Professor of Medicine, Montreal Heart Institute and University of Montreal

Sylvain Meloche, PhD

Canada Research Chair in Cellular Signaling, Professor of Pharmacology, Institute for Research in immunology and Cancer, University of Montreal

Laure Voisin, PhD

Associated Researcher, Institute for Research in Immunology and Cancer, University of Montreal

Reprints: Dr. White, Department of Medicine, Montreal Heart Institute and Université de Montréal, 5000 Belanger St., Montréal, Québec, H1T 1C8 Canada, fax 514/376-1355, m_white{at}icmmhi.com

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied.

OBJECTIVE: To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart.

METHODS: Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting.

RESULTS: The mean dose of valsartan was 114 ± 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group.

CONCLUSIONS: Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

Key Words: angiotensin-converting enzyme inhibitor, mitogen-activated protein kinase, myocytes, transplantation

Published Online, May 5, 2009. www.theannals.com, DOI 10.1345/aph.1L602