(Circulation. 2001;103:1644.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Pharmacogenetic Interactions Between ß-Blocker Therapy and the Angiotensin-Converting Enzyme Deletion Polymorphism in Patients With Congestive Heart Failure
From the Cardiovascular Institute, University of Pittsburgh Medical Center (D.M.M., R.H., K.J., A.P., J.J.W., G.A.M., S.M., W.D.R., B.L., A.M.F.), and the Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh (R.H.), Pittsburgh, Pa.
Correspondence to Dennis M. McNamara, MD, Heart Failure Section, University of Pittsburgh Medical Center, S-558 Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213. E-mail mcnamaradm{at}msx.upmc.edu
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 ß-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 ß-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 ß-blockers, the adverse impact of ACE D allele was dramatically increased (1-year percent survival II/ID/DD=95/75/67; 2-year=81/61/48; P=0.005). In contrast, in patients receiving ß-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 ß-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 ß-blockers in the determination of heart failure survival.
Key Words: receptors, adrenergic, beta • angiotensin • survival • genetics • heart failure
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