title: Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism.
abstract: OBJECTIVE
  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 α(2c)-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 α(2c)322-325 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 α(2c) 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 α(2c) 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)
authors.affiliation: Section of Cardiac Electrophysiology, University of Colorado Denver, Denver, Colorado. Electronic address: ryan.aleong@ucdenver.edu.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Aleong
authors.affiliation: Section of Cardiac Electrophysiology, University of Colorado Denver, Denver, Colorado.
authors.forename: William H
authors.initials: WH
authors.lastname: Sauer
authors.affiliation: ARCA Biopharma, Inc., Broomfield, Colorado.
authors.forename: Gordon
authors.initials: G
authors.lastname: Davis
authors.affiliation: ARCA Biopharma, Inc., Broomfield, Colorado.
authors.forename: Guinevere A
authors.initials: GA
authors.lastname: Murphy
authors.affiliation: ARCA Biopharma, Inc., Broomfield, Colorado; Division of Cardiology, University of Colorado Anschutz Medical Campus, Denver, Colorado.
authors.forename: J David
authors.initials: JD
authors.lastname: Port
authors.affiliation: Veterans Affairs Medical Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Inder S
authors.initials: IS
authors.lastname: Anand
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mona
authors.initials: M
authors.lastname: Fiuzat
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.affiliation: Division of Cardiovascular Medicine, Ohio State University, Columbus, Ohio.
authors.forename: William T
authors.initials: WT
authors.lastname: Abraham
authors.affiliation: Center for Personalized Medicine and Genomics, University of South Florida, Morsani College of Medicine, Tampa, Florida.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.affiliation: ARCA Biopharma, Inc., Broomfield, Colorado; Division of Cardiology, University of Colorado Anschutz Medical Campus, Denver, Colorado; Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control*; D005260:Female; D006333:Heart Failure / Q000150:complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000627:therapeutic use*; D011446:Prospective Studies; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; C024307:bucindolol