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HEART FAILURE AND PHARMACOGENETICS

Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure

Dennis M. McNamara, MD^*,*, Richard Holubkov, PhD, Lisa Postava, MBA^*, Karen Janosko, MSN^*, Guy A. MacGowan, MD^*, Michael Mathier, MD^*, Srinivas Murali, MD^*, Arthur M. Feldman, MD, PhD and Barry London, MD, PhD^*

^* Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
Department of Family and Preventive Medicine, School of Medicine, University of Utah, Salt Lake City, Utah
Department of Medicine, Thomas Jefferson Medical Center, Philadelphia, Pennsylvania

Manuscript received November 22, 2003; revised manuscript received August 13, 2004, accepted August 17, 2004.

^* Reprint requests and correspondence: Dr. Dennis M. McNamara, Director, Heart Failure/Transplantation Program, Cardiovascular Institute, University of Pittsburgh Medical Center, 558 Scaife Hall, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213 (Email: mcnamaradm{at}upmc.edu).

OBJECTIVES: We evaluated the interaction of angiotensin-converting enzyme (ACE) inhibitor therapy with the effect of the ACE D/I polymorphism on heart failure survival.

BACKGROUND: The ACE deletion allele, ACE-D, is associated with increased ACE activity. The utilization of ACE genotyping to predict the impact of ACE inhibitor dose has not been previously evaluated.

METHODS: We prospectively studied 479 subjects with systolic dysfunction (left ventricular ejection fraction 0.25 ± 0.08). Subjects were divided on the basis of ACE inhibitor therapy into low dose (50% of target dose, n = 227), standard (high) dose (>50%, n = 201), or those receiving angiotensin receptor antagonists (n = 51). Patients were genotyped for the ACE D/I polymorphism, followed to the end point of death or cardiac transplantation, and transplant-free survival compared by genotype.

RESULTS: The ACE-D allele was associated with an increased risk of events (p = 0.026). In analysis by ACE inhibitor dose, this effect was primarily in the low-dose group (1-year percent event-free survival: II/ID/DD = 86/77/71,2-year = 79/66/59, p = 0.032). In the standard-dose group, the impact was markedly diminished (1-year: II/ID/DD = 91/81/80, 2-year: 77/70/71, p = 0.64). The impact of beta-blockers and high dose ACE inhibitors was greatest in subjects with the ACE DD genotype (p = 0.001) and was less apparent with the II and ID genotypes (p = 0.38).

CONCLUSIONS: Higher doses of ACE inhibitors diminished the impact of the ACE-D allele, and the benefits of beta-blockers and high-dose ACE inhibitors appeared maximal for DD patients. Determination of ACE genotype may help target therapy for patients with heart failure.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ARB = angiotensin receptor blocker   CI = confidence interval   LVEF = left ventricular ejection fraction   NYHA = New York Heart Association

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