Prevention of atrial fibrillation by bucindolol is dependent on the beta1389 Arg/Gly adrenergic receptor polymorphism

Ryan G. Aleong, William H. Sauer, Gordon Davis, Guinevere A. Murphy, J. David Port, Inder Anand, Mona Fiuzat, Christopher M. O'Connor, William T. Abraham, Stephen B. Liggett, Michael R. Bristow

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35 Scopus citations

Abstract

Objectives: This study assessed the impact of bucindolol, a beta-blocker/sympatholytic agent, on the development of atrial fibrillation (AF) in advanced chronic heart failure with reduced left ventricular ejection fraction (HFREF) patients enrolled in the BEST (Beta-Blocker Evaluation of Survival Trial). Background: β-blockers have modest efficacy for AF prevention in HFREF patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are genetically modulated by β1- and α2c-adrenergic receptor (AR) polymorphisms that can be used to subdivide HFREF populations into those with bucindolol effectiveness levels that are enhanced, unchanged, or lost. Methods: BEST enrolled 2,708 New York Heart Association (NYHA) class III to IV HFREF patients. A substudy in which 1,040 patients' DNA was genotyped for the β1-AR position 389 Arg/Gly and the α2c322-325 wild type (Wt)/deletion (Del) polymorphisms, and new-onset AF was assessed from adverse event case report forms or electrocardiograms at baseline and at 3 and 12 months. Results: In the entire cohort, bucindolol reduced the rate of new-onset AF compared to placebo by 41% (hazard ratio [HR]:0.59[95% confidence interval (CI): 0.44 to 0.79], p= 0.0004). In the 493 β1389 arginine homozygotes (Arg/Arg) in the DNA substudy, bucindolol reduced new-onset AF by 74% (HR: 0.26 [95% CI: 0.12 to 0.57]), with no effect in β1389 Gly carriers (HR: 1.01 [95% CI: 0.56 to 1.84], interaction test= 0.008). When β1389 Gly carriers were subdivided by α2c Wt homozygotes (n=413, HR: 0.94 [95% CI: 0.48 to 1.82], p= 0.84) or Del variant carriers (n= 134, HR: 1.33 [95% CI: 0.32 to 5.64], p=0.70), there was a positive interaction test (p= 0.016) when analyzed with β1389 Arg homozygotes. Conclusions: Bucindolol prevented new-onset AF; β1 and α2c polymorphisms predicted therapeutic response; and the 47% of patients who were β1389 Arg homozygotes had an enhanced effect size of 74%. (Beta-Blocker Evaluation in Survival Trial [BEST]; NCT00000560).

Original languageEnglish (US)
Pages (from-to)338-344
Number of pages7
JournalJACC: Heart Failure
Volume1
Issue number4
DOIs
StatePublished - Aug 1 2013

Keywords

  • Arrhythmia
  • Beta adrenergic receptors
  • Genetics
  • Heart failure
  • Norepinephrine

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