PMID- 24159564
OWN - NLM
STAT- MEDLINE
DCOM- 20141117
LR  - 20211021
IS  - 2213-1787 (Electronic)
IS  - 2213-1779 (Print)
IS  - 2213-1779 (Linking)
VI  - 1
IP  - 4
DP  - 2013 Aug
TI  - Prevention of atrial fibrillation by bucindolol is dependent on the beta(1)389 
      Arg/Gly adrenergic receptor polymorphism.
PG  - 338-344
LID - S2213-1779(13)00127-3 [pii]
LID - 10.1016/j.jchf.2013.04.002 [doi]
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: beta-blockers have modest efficacy for AF prevention in HFREF 
      patients. Bucindolol's effects on HF and ventricular arrhythmic endpoints are 
      genetically modulated by beta(1)- and alpha(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 beta(1)-AR position 389 
      Arg/Gly and the alpha(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 beta(1)389 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 beta(1)389 Gly carriers (HR: 1.01 [95% CI: 0.56 to 1.84], interaction test = 
      0.008). When beta(1)389 Gly carriers were subdivided by alpha(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 beta(1)389 Arg homozygotes. CONCLUSIONS: Bucindolol 
      prevented new-onset AF; beta(1) and alpha(2c) polymorphisms predicted therapeutic 
      response; and the 47% of patients who were beta(1)389 Arg homozygotes had an enhanced 
      effect size of 74%. (Beta-Blocker Evaluation in Survival Trial [BEST]; 
      NCT00000560)
FAU - Aleong, Ryan G
AU  - Aleong RG
AD  - Section of Cardiac Electrophysiology, University of Colorado Denver, Denver, 
      Colorado. Electronic address: ryan.aleong@ucdenver.edu.
FAU - Sauer, William H
AU  - Sauer WH
AD  - Section of Cardiac Electrophysiology, University of Colorado Denver, Denver, 
      Colorado.
FAU - Davis, Gordon
AU  - Davis G
AD  - ARCA Biopharma, Inc., Broomfield, Colorado.
FAU - Murphy, Guinevere A
AU  - Murphy GA
AD  - ARCA Biopharma, Inc., Broomfield, Colorado.
FAU - Port, J David
AU  - Port JD
AD  - ARCA Biopharma, Inc., Broomfield, Colorado; Division of Cardiology, University of 
      Colorado Anschutz Medical Campus, Denver, Colorado.
FAU - Anand, Inder S
AU  - Anand IS
AD  - Veterans Affairs Medical Center, University of Minnesota, Minneapolis, Minnesota.
FAU - Fiuzat, Mona
AU  - Fiuzat M
AD  - Duke Clinical Research Institute, Duke University Medical Center, Durham, North 
      Carolina.
FAU - O'Connor, Christopher M
AU  - O'Connor CM
AD  - Duke Clinical Research Institute, Duke University Medical Center, Durham, North 
      Carolina.
FAU - Abraham, William T
AU  - Abraham WT
AD  - Division of Cardiovascular Medicine, Ohio State University, Columbus, Ohio.
FAU - Liggett, Stephen B
AU  - Liggett SB
AD  - Center for Personalized Medicine and Genomics, University of South Florida, 
      Morsani College of Medicine, Tampa, Florida.
FAU - Bristow, Michael R
AU  - Bristow MR
AD  - 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.
LA  - eng
SI  - ClinicalTrials.gov/NCT00000560
GR  - R01 HL048013/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - JACC Heart Fail
JT  - JACC. Heart failure
JID - 101598241
RN  - 0 (Adrenergic beta-Antagonists)
RN  - 0 (Propanolamines)
RN  - 0 (Receptors, Adrenergic, beta-1)
RN  - E9UO06K7CE (bucindolol)
SB  - IM
MH  - Adrenergic beta-Antagonists/*therapeutic use
MH  - Atrial Fibrillation/etiology/*genetics/*prevention & control
MH  - Female
MH  - Heart Failure/complications
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - *Polymorphism, Genetic
MH  - Propanolamines/*therapeutic use
MH  - Prospective Studies
MH  - Receptors, Adrenergic, beta-1/*genetics
MH  - Treatment Outcome
PMC - PMC3804380
MID - NIHMS482208
EDAT- 2013/10/26 06:00
MHDA- 2014/11/18 06:00
PMCR- 2014/08/01
CRDT- 2013/10/26 06:00
PHST- 2013/10/26 06:00 [entrez]
PHST- 2013/10/26 06:00 [pubmed]
PHST- 2014/11/18 06:00 [medline]
PHST- 2014/08/01 00:00 [pmc-release]
AID - S2213-1779(13)00127-3 [pii]
AID - 10.1016/j.jchf.2013.04.002 [doi]
PST - ppublish
SO  - JACC Heart Fail. 2013 Aug;1(4):338-344. doi: 10.1016/j.jchf.2013.04.002.