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

Publication ,  Journal Article
Aleong, RG; Sauer, WH; Davis, G; Murphy, GA; Port, JD; Anand, IS; Fiuzat, M; O'Connor, CM; Abraham, WT; Liggett, SB; Bristow, MR
Published in: JACC Heart Fail
August 2013

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 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)

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Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

August 2013

Volume

1

Issue

4

Start / End Page

338 / 344

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Receptors, Adrenergic, beta-1
  • Prospective Studies
  • Propanolamines
  • Polymorphism, Genetic
  • Middle Aged
  • Male
  • Humans
  • Heart Failure
  • Female
 

Citation

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Aleong, R. G., Sauer, W. H., Davis, G., Murphy, G. A., Port, J. D., Anand, I. S., … Bristow, M. R. (2013). Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism. JACC Heart Fail, 1(4), 338–344. https://doi.org/10.1016/j.jchf.2013.04.002
Aleong, Ryan G., William H. Sauer, Gordon Davis, Guinevere A. Murphy, J David Port, Inder S. Anand, Mona Fiuzat, et al. “Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism.JACC Heart Fail 1, no. 4 (August 2013): 338–44. https://doi.org/10.1016/j.jchf.2013.04.002.
Aleong RG, Sauer WH, Davis G, Murphy GA, Port JD, Anand IS, et al. Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism. JACC Heart Fail. 2013 Aug;1(4):338–44.
Aleong, Ryan G., et al. “Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism.JACC Heart Fail, vol. 1, no. 4, Aug. 2013, pp. 338–44. Pubmed, doi:10.1016/j.jchf.2013.04.002.
Aleong RG, Sauer WH, Davis G, Murphy GA, Port JD, Anand IS, Fiuzat M, O’Connor CM, Abraham WT, Liggett SB, Bristow MR. Prevention of atrial fibrillation by bucindolol is dependent on the beta₁389 Arg/Gly adrenergic receptor polymorphism. JACC Heart Fail. 2013 Aug;1(4):338–344.
Journal cover image

Published In

JACC Heart Fail

DOI

EISSN

2213-1787

Publication Date

August 2013

Volume

1

Issue

4

Start / End Page

338 / 344

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Receptors, Adrenergic, beta-1
  • Prospective Studies
  • Propanolamines
  • Polymorphism, Genetic
  • Middle Aged
  • Male
  • Humans
  • Heart Failure
  • Female