Clinical and Genetic Modifiers of Long-Term Survival in Heart Failure

Sharon Cresci, Reagan J. Kelly, Thomas P. Cappola, Abhinav Diwan, Daniel Dries, Sharon L.R. Kardia, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Objectives: This study sought to identify genetic modifiers of β-blocker response and long-term survival in heart failure (HF). Background: Differences in β-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 β-blocker. Each was genotyped for β1-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). β-blocker treatment increased survival in Caucasians (log-rank p = 0.00038) but not African Americans (log-rank p = 0.327). Among patients not taking β-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 β-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 β-adrenergic receptor signaling pathway gene polymorphisms, rather than race, are the major factors contributing to apparent differences in the β-blocker treatment effect between Caucasians and African Americans; proper evaluation of treatment response should account for genetic variance.

Original languageEnglish
Pages (from-to)432-444
Number of pages13
JournalJournal of the American College of Cardiology
Volume54
Issue number5
DOIs
StatePublished - Jul 28 2009

Keywords

  • G-protein receptor kinase
  • beta adrenergic receptor
  • beta-blocker
  • gene polymorphism
  • heart failure

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