An alpha2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the beta-blocker bucindolol in chronic heart failure.
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.
Bristow
Michael R
MR
University of Colorado Health Sciences Center, Aurora, CO 80045, USA. michael.bristow@ucdenver.edu
Murphy
Guinevere A
GA
Krause-Steinrauf
Heidi
H
Anderson
Jeffrey L
JL
Carlquist
John F
JF
Thaneemit-Chen
Surai
S
Krishnan
Vaishali
V
Abraham
William T
WT
Lowes
Brian D
BD
Port
J David
JD
Davis
Gordon W
GW
Lazzeroni
Laura C
LC
Robertson
Alastair D
AD
Lavori
Phillip W
PW
Liggett
Stephen B
SB
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*
C547774:ADRA2C protein, human; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018341:Receptors, Adrenergic, alpha-2; C024307:bucindolol; D009638:Norepinephrine