title: Adrenergic receptor polymorphisms and prevention of ventricular arrhythmias with bucindolol in patients with chronic heart failure.
abstract: BACKGROUND
  β-blockers prevent cardiac arrhythmias in patients with chronic heart failure and reduced left ventricular ejection fraction, including ventricular tachycardia/ventricular fibrillation (VT/VF). We hypothesized that prevention of ventricular arrhythmias by the β-blocker/sympatholytic agent bucindolol is influenced by genetic variation in adrenergic receptors.
  
  
  RESULTS
  From a substudy of the β-Blocker Evaluation of Survival Trial (n=1040), we identified those with the high functioning 389Arg versus the lower function 389Gly β(1) adrenergic receptor variant, and the loss of function α(2c)322-325 adrenergic receptor deletion versus the 322 to 325 wild-type (Wt)/deletion variant. VT/VF was recorded on case report forms as an adverse event. There were 493 Arg 389 β(1) receptor homozygotes (β(1)389 Arg/Arg) versus 547 Gly389 carriers and 207 α(2c)322-325 deletion carriers versus 833 homozygous Wts (α(2c)322-325 Wt/Wt). In all genotypes bucindolol was associated with a lower incidence of VT/VF (subhazard ratio, 0.42 [0.27-0.64]; P=0.00006). Bucindolol reduced VT/VF in β(1)389 Arg homozygotes (subhazard ratio, 0.26 [0.14-0.50]; P=0.00005) but not in β(1)389 Gly carriers (subhazard ratio, 0.60 [0.34-1.07]; P=0.09). For genotype combinations, the α(2c)322-325 polymorphism altered the VT/VF bucindolol response in β1389 Gly carriers, with α(2c) deletion genotypes associated with complete efficacy loss. A test of interaction was statistically significant (P=0.028) for the treatment group and a β(1)389/α(2c)322-325 three genotype construct, effectively identifying patients who exhibited enhanced response, no substantial response modification and loss of response.
  
  
  CONCLUSIONS
  Bucindolol prevents VT/VF in subjects with heart failure and reduced left ventricular ejection fractions, and this effect is modulated by β(1)389 Arg/Gly and α(2c)322-325 Wt/deletion adrenergic receptor polymorphisms.
authors.affiliation: University of Colorado, Division of Cardiology, Aurora, CO, USA. ryan.aleong@ucdenver.edu
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Aleong
authors.forename: William H
authors.initials: WH
authors.lastname: Sauer
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Robertson
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000627:therapeutic use*; D011446:Prospective Studies; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D013318:Stroke Volume; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left
chemical_list: C547774:ADRA2C protein, human; C547787:ADRB1 protein, human; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; C024307:bucindolol