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
AU - Fiuzat, Mona
AU - O'Connor, Christopher M.
AU - Abraham, William T.
AU - Liggett, Stephen B.
AU - Bristow, Michael R.
PY - 2013/8/1
Y1 - 2013/8/1
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
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UR - http://www.scopus.com/inward/citedby.url?scp=84881556522&partnerID=8YFLogxK
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 -