Author + information
- Received November 15, 2012
- Revision received March 1, 2013
- Accepted March 3, 2013
- Published online August 1, 2013.
- Ryan G. Aleong, MD∗∗ (, )
- William H. Sauer, MD∗,
- Gordon Davis, MS†,
- Guinevere A. Murphy, PhD†,
- J. David Port, PhD†,‡,
- Inder S. Anand, MD§,
- Mona Fiuzat, PharmD⋮,
- Christopher M. O'Connor, MD⋮,
- William T. Abraham, MD¶,
- Stephen B. Liggett, MD# and
- Michael R. Bristow, MD, PhD†,‡⋮
- ∗Section of Cardiac Electrophysiology, University of Colorado Denver, Denver, Colorado
- †ARCA Biopharma, Inc., Broomfield, Colorado
- ‡Division of Cardiology, University of Colorado Anschutz Medical Campus, Denver, Colorado
- §Veterans Affairs Medical Center, University of Minnesota, Minneapolis, Minnesota
- ⋮Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
- ¶Division of Cardiovascular Medicine, Ohio State University, Columbus, Ohio
- #Center for Personalized Medicine and Genomics, University of South Florida, Morsani College of Medicine, Tampa, Florida
- ↵∗Reprint requests and correspondence:
Dr. Ryan G. Aleong, Section of Cardiac Electrophysiology, University of Colorado Hospital, 12401 East 17th Avenue, B136, Aurora, Colorado 80045.
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)
This study was supported by the VA Cooperative Studies Program, National Institutes of Health National Heart, Lung, and Blood Institute, and ARCA Biopharma. Dr. Bristow is CEO and a shareholder of ARCA Biopharma, Inc., which owns rights to bucindolol. Dr. Port is an employee of ARCA. Mr. Davis and Dr. Murphy are consultants to ARCA. Dr. Fiuzat is a consultant to ARCA Biopharma, Inc. All other authors report that they have no relationships relevant to the contents of this paper to disclose. Jeffrey L. Anderson, MD, served as Guest Editor for this paper.
- Received November 15, 2012.
- Revision received March 1, 2013.
- Accepted March 3, 2013.
- 2013 American College of Cardiology Foundation