Clinical and genetic modifiers of long-term survival in heart failure

J Am Coll Cardiol. 2009 Jul 28;54(5):432-44. doi: 10.1016/j.jacc.2009.05.009.

Abstract

Objectives: This study sought to identify genetic modifiers of beta-blocker response and long-term survival in heart failure (HF).

Background: Differences in beta-blocker treatment effect between Caucasians and African Americans with HF have been reported.

Methods: This was a prospective cohort study of 2,460 patients (711 African American, 1,749 Caucasian) enrolled between 1999 and 2007; 2,039 patients (81.7%) were treated with a beta-blocker. Each was genotyped for beta1-adrenergic receptor (ADRB1) Arg389>Gly and G-protein receptor kinase 5 (GRK5) Gln41>Leu polymorphisms, which are more prevalent among African Americans than Caucasians. The primary end point was survival time from HF onset.

Results: There were 765 deaths during follow-up (median 46 months). beta-blocker treatment increased survival in Caucasians (log-rank p = 0.00038) but not African Americans (log-rank p = 0.327). Among patients not taking beta-blockers, ADRB1 Gly389 was associated with decreased survival in Caucasians (hazard ratio [HR]: 1.98, 95% confidence interval [CI]: 1.1 to 3.7, p = 0.03) whereas GRK5 Leu41 was associated with improved survival in African Americans (HR: 0.325, CI: 0.133 to 0.796, p = 0.01). African Americans with ADRB1 Gly389Gly GRK5 Gln41Gln derived a similar survival benefit from beta-blocker therapy (HR: 0.385, 95% CI: 0.182 to 0.813, p = 0.012) as Caucasians with the same genotype (HR: 0.529, 95% CI: 0.326 to 0.858, p = 0.0098).

Conclusions: These data show that differences caused by beta-adrenergic receptor signaling pathway gene polymorphisms, rather than race, are the major factors contributing to apparent differences in the beta-blocker treatment effect between Caucasians and African Americans; proper evaluation of treatment response should account for genetic variance.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Adrenergic beta-Antagonists / therapeutic use
  • African Americans
  • Aged
  • Cohort Studies
  • European Continental Ancestry Group
  • Female
  • G-Protein-Coupled Receptor Kinase 5 / genetics
  • Genotype
  • Heart Failure / drug therapy
  • Heart Failure / genetics*
  • Heart Failure / mortality*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Prospective Studies
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / genetics*
  • Signal Transduction / genetics
  • Survival Rate
  • Time Factors
  • Treatment Outcome

Substances

  • Adrenergic beta-Antagonists
  • Receptors, Adrenergic, beta
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human