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

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%, 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.