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

Abstract

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 (1-year percent survival II/ID/DD=95/75/67; 2-year=81/61/48; P:=0.005). In contrast, in patients receiving beta-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.

• Authors: D M McNamara, R Holubkov, K Janosko, A Palmer, J J Wang, G A MacGowan, S Murali, W D Rosenblum, B London, A M Feldman
• Journal: Circulation (Circulation) Vol. 103 Issue 12 Pg. 1644-8 (Mar 27 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11273991 (Publication Type: Clinical Trial, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Antagonists
• Angiotensin-Converting Enzyme Inhibitors
• Peptidyl-Dipeptidase A

Topics

• Adrenergic beta-Antagonists (therapeutic use)
• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Cohort Studies
• Disease-Free Survival
• Female
• Genetic Testing
• Genotype
• Heart Failure (drug therapy, genetics)
• Humans
• Male
• Middle Aged
• Peptidyl-Dipeptidase A (genetics)
• Pharmacogenetics
• Polymorphism, Genetic (genetics)
• Prospective Studies
• Renin-Angiotensin System (drug effects, genetics)
• Sequence Deletion
• Treatment Outcome