| Title | An {alpha}2C-Adrenergic Receptor Polymorphism Alters the Norepinephrine Lowering Effects and Therapeutic Response of the Beta Blocker Bucindolol in Chronic Heart Failure. | | Author(s) | Bristow MR, Murphy GA, Krause-Steinrauf H, Anderson JL, Carlquist JF, Thaneemit-Chen S, Krishnan V, Abraham WT, Lowes BD, Port JD, Davis GW, Lazzeroni LC, Robertson AD, Lavori PW, Liggett SB | | Institution | 1 University of Colorado, Denver and ARCA Biopharma Inc., Broomfield, CO; | | Source | Circ Heart Fail 2009 Oct 30. | | 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 (alpha(2C)-AR), which exhibit genetic variation in humans. Bucindolol is a novel beta-adrenergic receptor blocking agent that also lowers systemic norepinephrine (NE) and thus is also a sympatholytic agent. This study investigated whether alpha(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 alpha(2C)-AR gene polymorphisms (alpha(2C) Del322-325 or the wild type counterpart) were measured by PCR and gel electrophoresis. Patients who were alpha(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 alpha(2C) wild type, p = 0.0005 vs. placebo; p = 0.010 by interaction test). alpha(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 alpha(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 alpha(2C) receptor genotype. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19880803 |
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