T he importance of angiotensin II in the pathophysiology of heart failure is well established. 1 Although angiotensin- converting enzyme (ACE) inhibitors are effective in reducing angiotensin II syn- thesis acutely in patients with heart fail- ure, concentrations eventually return to pretreatment levels. 2 Because of this phe- nomenon, it has been hypothesized that a dual blockade of the renin–angiotensin– aldosterone system (RAAS) with an- giotensin II receptor blockers (ARBs) and ACE inhibitors may have additional ben- eficial effects in patients with heart fail- ure. Such a strategy would also maintain the benefit of bradykinin accumulation produced by ACE inhibition. 1 These po- tential benefits of dual angiotensin II suppression were demonstrated in 2 large randomized trials. 3,4 However, not all patients showed benefit from the ad- dition of an ARB. It is currently difficult to predict which patients with heart fail- ure will benefit from pharmacotherapy with both an ACE inhibitor and an ARB. Current data suggest an important her- itability to heart failure. 5 Similarly, the degree of RAAS activity also appears to Effects of AGTR1 A1166C Gene Polymorphism in Patients with Heart Failure Treated with Candesartan Simon de Denus, Marcin Zakrzewski-Jakubiak, Marie-Pierre Dubé, François Bélanger, Serge Lepage, Marie-Hélène Leblanc, Denis Gossard, Anique Ducharme, Normand Racine, Lucette Whittom, Joel Lavoie, Rhian M Touyz, Jacques Turgeon, and Michel White The Annals of Pharmacotherapy ■ 2008 July/August, Volume 42 ■ 925 www.theannals.com Cardiology Author information provided at the end of the text. RESEARCH REPORTS 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 hemo- dynamic, 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. Ann Pharmacother 2008;42:925-32. Published Online, 1 Jul 2008, www.theannals.com, DOI 10.1345/aph.1K657 by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from