TY - JOUR
T1 - Prevention of atrial fibrillation by bucindolol is dependent on the beta1389 Arg/Gly adrenergic receptor polymorphism
AU - Aleong, Ryan G.
AU - Sauer, William H.
AU - Davis, Gordon
AU - Murphy, Guinevere A.
AU - Port, J. David
AU - Anand, Inder S.
AU - Fiuzat, Mona
AU - O'Connor, Christopher M.
AU - Abraham, William T.
AU - Liggett, Stephen B.
AU - Bristow, Michael R.
N1 - Funding Information:
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.
PY - 2013/8
Y1 - 2013/8
N2 - 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).
AB - 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).
KW - Arrhythmia
KW - Beta adrenergic receptors
KW - Genetics
KW - Heart failure
KW - Norepinephrine
UR - https://www.scopus.com/pages/publications/84881556522
U2 - 10.1016/j.jchf.2013.04.002
DO - 10.1016/j.jchf.2013.04.002
M3 - Article
C2 - 24159564
AN - SCOPUS:84881556522
SN - 2213-1779
VL - 1
SP - 338
EP - 344
JO - JACC: Heart Failure
JF - JACC: Heart Failure
IS - 4
ER -