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

Background-Activation of the renin-angiotensin and sympathetic nervous systems adversely affect heart failure progression. The ACE deletion allele (ACE D) is associated with increased renin-angiotensin activation; however, its influence on patient outcomes remains uncertain, and the pharmacogenetic interactions with beta -blocker therapy have not been previously evaluated. Methods and Results-We prospectively followed 328 patients (age, 56.1 +/- 11.9 years) with systolic dysfunction (left ventricular ejection fraction, 0.24 +/-0.08) to assess the impact of the ACE D allele on transplant-free survival (median follow-up, 21 months). Transplant-free survival was compared by genotype for the whole cohort and separately in patients with (n = 120) and those without beta -blocker therapy (n = 208) at the time of entry. Transplant-free survival was significantly poorer for patients with the D allele (1-year percent survival II/ID/DD=94/77/75; 2-year 78/65/60; ordered log-rank test, P=0.044). In patients not treated with beta -blockers, the adverse impact of ACE D allele was dramatically increased (l-year percent survival II/ID/DD=95/75/67; 2-year=81/61/48; P=0.005), In contrast, in patients receiving P-blocker therapy, no influence of ACE genotype on transplant-free survival was evident (1-year percent survival II/ID/DD=91/80/86; 2-year=70/71/77; P=0.73). Conclusions-In a cohort of patients with systolic dysfunction, the ACE D allele was associated with a significantly poorer transplant-free survival. This effect was primarily evident in patients not treated with beta -blockers and was not seen in patients receiving therapy. These findings suggest a potential pharmacogenetic interaction between the ACE D/I polymorphism and therapy with beta -blockers in the determination of heart failure survival.