title: An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure.
abstract: BACKGROUND
  Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional alpha(2C)-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel beta-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether alpha(2C)-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure.
  
  
  RESULTS
  In the beta-Blocker Evaluation of Survival Trial, adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months, and 12 months posttreatment in patients treated with placebo or bucindolol. In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and alpha(2C)-AR gene polymorphisms (alpha(2C) Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were alpha(2C) Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in norepinephrine at 3 months of 153+/-57 pg/mL, P=0.012 compared with placebo versus decrease of 50+/-13 pg/mL in alpha(2C) wild type, P=0.0005 versus placebo; P=0.010 by interaction test). alpha(2C) Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared with placebo hazard ratio, 1.09; 95% CI, 0.57 to 2.08; P=0.80), whereas bucindolol-treated subjects who were wild type for the alpha(2C)-AR had a 30% reduction in mortality (hazard ratio, 0.70; 95% CI, 0.51 to 0.96; P=0.025).
  
  
  CONCLUSIONS
  In the beta-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by alpha(2C) receptor genotype.
authors.affiliation: University of Colorado Health Sciences Center, Aurora, CO 80045, USA. michael.bristow@ucdenver.edu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
authors.forename: Guinevere A
authors.initials: GA
authors.lastname: Murphy
authors.forename: Heidi
authors.initials: H
authors.lastname: Krause-Steinrauf
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
authors.forename: Surai
authors.initials: S
authors.lastname: Thaneemit-Chen
authors.forename: Vaishali
authors.initials: V
authors.lastname: Krishnan
authors.forename: William T
authors.initials: WT
authors.lastname: Abraham
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lowes
authors.forename: J David
authors.initials: JD
authors.lastname: Port
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Davis
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Robertson
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Lavori
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000494:pharmacology*; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*
chemical_list: C547774:ADRA2C protein, human; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018341:Receptors, Adrenergic, alpha-2; C024307:bucindolol; D009638:Norepinephrine