Published online before print October 30, 2009, doi: 10.1161/CIRCHEARTFAILURE.109.885962
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Original Articles |
An 
2C-Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the β-Blocker Bucindolol in Chronic Heart Failure
From the University of Colorado (M.R.B., B.D.L., J.D.P., A.D.R.), Denver, Colo; ARCA Biopharma Inc (M.R.B., G.A.M., J.D.P., G.W.D.), Broomfield, Colo; University of Maryland (S.B.L.), Baltimore, Md; VA Cooperative Studies Program (H.K.-S., S.T.-C., V.K.), Palo Alto, Calif; LDS Hospital (J.L.A., J.F.C.), Salt Lake City, Utah; and Ohio State University (W.T.A.), Columbus, Ohio; and Stanford University (L.C.L., P.W.L.), Stanford, Calif.
Correspondence to Michael R. Bristow, MD, PhD, University of Colorado Health Sciences Center, 12700 E. 19th Ave, P-15, Mail Stop B-139, Aurora, CO 80045. E-mail michael.bristow{at}ucdenver.edu
Received June 9, 2009; accepted October 22, 2009.
Background— Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional 
2C-adrenergic receptors (ARs), which exhibit genetic variation in humans. Bucindolol is a novel β-AR blocking agent that also lowers systemic norepinephrine and thus is also a sympatholytic agent. This study investigated whether 2C-AR polymorphisms affect sympatholytic effects of bucindolol in patients with heart failure.
Methods and Results— In the β-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 β-Blocker Evaluation of Survival Trial AR polymorphism substudy, DNA was collected from 1040 of the 2708 randomized patients, and 2C-AR gene polymorphisms (2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were 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 2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). 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 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 β-Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by 2C receptor genotype.
Key Words: genetics • heart failure • norepinephrine • receptors, adrenergic, alpha • β-blockers
CLINICAL PERSPECTIVE
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