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CARDIOLOGY

Effects of AGTR1 A1166C Gene Polymorphism in Patients with Heart Failure Treated with Candesartan

Assistant Professor, Faculty of Pharmacy, University of Montreal/Montreal Heart Institute, Montreal, QC, Canada

Marcin Zakrzewski-Jakubiak, BPharm MSc

PhD Student, Faculty of Pharmacy, University of Montreal

Marie-Pierre Dubé, PhD

Assistant Professor, Faculty of Medicine, University of Montreal/Montreal Heart Institute

François Bélanger, MSc

Laboratory Coordinator, Centre hospitalier de l'Université de Montréal Research Centre

Serge Lepage, MD

Professor, Faculty of Medicine and Health Sciences, University of Sherbrooke/Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC

Marie-Hélène Leblanc, MD FACC

Clinical Associate Professor, Hôpital Laval, Laval, QC

Denis Gossard, MD

Cardiologist, Hôpital du Haut-Richelieu, Saint-Jean-sur-Richelieu, QC

Anique Ducharme, MD MSc

Director, Heart Failure Clinic, Montreal Heart Institute; Associate Professor of Medicine, Department of Medicine, University of Montreal

Normand Racine, MD

Chief, Department of Medicine and Cardiology, Montreal Heart Institute; Associate Professor of Medicine, Department of Medicine, University of Montreal

Lucette Whittom, RN BSc

Project Leader, Montreal Heart Institute

Joel Lavoie, PhD

Clinical Biochemist; Director, Biochemistry Laboratory, Montreal Heart Institute

Rhian M Touyz, MD PhD

Senior Scientist, Kidney Research Centre, University of Ottawa, Ottawa Health Research Institute/Professor, Department of Medicine, University of Ottawa, Ottawa, ON

Jacques Turgeon, PhD

Director, Centre hospitalier de l'Université de Montréal Research Centre; Professor, Faculty of Pharmacy, University of Montreal

Michel White, MD

Director, Heart Failure Research Program, Montreal Heart Institute; Professor of Medicine, Department of Medicine, University of Montreal

Reprints: Dr. White, Montreal Heart Institute, 5000 Belanger St. East, Montreal, QC, HIT 1C8, Canada, fax 514/593-2575, m_white{at}icm-mhi.com

BACKGROUND: The benefits of angiotensin II receptor blockers (ARBs) in patients with heart failure who are treated with standard pharmacotherapy, including an angiotensin-converting enzyme (ACE) inhibitor, were demonstrated in 2 large randomized trials. It is currently impossible to determine which patient will benefit from the addition of an ARB.

OBJECTIVE: To explore the impact of selected candidate genes on the hemodynamic, neurohormonal, and antiinflammatory effects of candesartan in patients with heart failure who are already being treated with an ACE inhibitor.

METHODS: We investigated the impact of 10 candidate genetic polymorphisms on the effects of candesartan in patients with heart failure who are treated with an ACE inhibitor. We evaluated their impact on acute (2 wk) and long-term (24 wk) changes in blood pressure and N-terminal proB-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) during treatment with candesartan.

RESULTS: Thirty-one patients were included. Homozygotes of the AGTR1 A1166 allele (n = 13) had a greater decrease in systolic (–9.1 ± 4.7 vs 1.1 ± 3.3 mm Hg; p = 0.04 by analysis of variance [ANOVA], adjusting for dose) and diastolic blood pressure (–5.1 ± 1.5 vs 1.9 ± 1.9 mm Hg; p = 0.005 by ANOVA, adjusting for dose) compared with C1166 allele carriers (n = 18) following 2 weeks of treatment. After 6 months of treatment, C1166 carriers experienced a greater decrease in NT-proBNP (–151.4 [–207; –19.8] ng/L vs 147.3 [–61.3; 882.9] ng/L; p = 0.03) and hsCRP (–0.8 [–2.2; –0.03] mg/L) vs 0.2 [–1.8; 5.3] mg/L; p = 0.09) compared with patients carrying the AA1166 genotype. No other significant association was found.

CONCLUSIONS: The results of this proof-of concept study provide the first evidence that the AGTR1 A1166C polymorphism could influence the response to candesartan in patients with heart failure who are receiving ACE inhibitors. Validation of these exploratory findings in larger populations is required before use of the AGTR1 A1166C genotype can be incorporated into clinical practice.

Key Words: angiotensin, candesartan, heart failure, pharmacogenetics

Published Online, July 1, 2008. www.theannals.com, DOI 10.1345/aph.1K657