on October 30, 2009
Published online before print October 30, 2009, doi: 10.1161/CIRCHEARTFAILURE.109.885962
Original Article |
An 
2C-Adrenergic Receptor Polymorphism Alters the Norepinephrine Lowering Effects and Therapeutic Response of the Beta Blocker Bucindolol in Chronic Heart Failure
1 University of Colorado, Denver and ARCA Biopharma Inc., Broomfield, CO;
2 ARCA Biopharma Inc., Broomfield, CO;
3 VA Cooperative Studies Program, Palo Alto, CA;
4 LDS Hospital, Salt Lake City, UT;
5 Ohio State University, Columbus, OH;
6 University of Colorado, Denver, CO;
7 Stanford University, Stanford, CA;
8 University of Maryland, Baltimore, MD
* Corresponding author; email: michael.bristow{at}ucdenver.edu
Background—Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional 
2C adrenergic receptors (2C-AR), which exhibit genetic variation in humans. Bucindolol is a novel β-adrenergic receptor blocking agent that also lowers systemic norepinephrine (NE) and thus is also a sympatholytic agent. This study investigated whether 2C-AR polymorphisms affect bucindolol's sympatholytic effects in heart failure patients.
Methods and Results—In the Beta-Blocker Evaluation of Survival Trial ("BEST"), adrenergic activation was estimated by systemic venous norepinephrine measured at baseline, 3 months and 12 months post-treatment in patients treated with placebo or bucindolol. In the BEST Adrenergic Receptor Polymorphisms 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 PCR and gel electrophoresis. Patients who were 2C Del carriers (heterozygotes or homozygotes) exhibited a much greater sympatholytic response to bucindolol (decrease in NE at 3 months of 153±57 (SEM) pg/ml, p = 0.012 compared to placebo vs. decrease of 50±13 pg/ml in 2C wild type, p = 0.0005 vs. placebo; p = 0.010 by interaction test). 2C Del carriers had no evidence of a favorable survival benefit from bucindolol (mortality compared to placebo hazard ratio = 1.09; 95% confidence intervals (CIs) 0.57, 2.08; p = 0.80), whereas bucindolol-treated subjects who were wild type for the 2C-AR had a 30% reduction in mortality (HR = 0.70; 95% CIs 0.51, 0.96; p = 0.025).
Conclusions—In the BEST Adrenergic Receptor Polymorphism Substudy, the NE-lowering and clinical therapeutic responses to bucindolol were strongly influenced by 2C receptor genotype.
Key Words: genetics • heart failure • norepinephrine • receptors, adrenergic, alpha • beta-blockers