An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure

Michael R. Bristow, Guinevere A. Murphy, Heidi Krause-Steinrauf, Jeffrey L. Anderson, John F. Carlquist, Surai Thaneemit-Chen, Vaishali Krishnan, William T. Abraham, Brian D. Lowes, J. David Port, Gordon W. Davis, Laura C. Lazzeroni, Alastair D. Robertson, Phillip W. Lavori, Stephen B. Liggett

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Background-Adrenergic activation is an important determinant of outcomes in chronic heart failure. Adrenergic activity is regulated in part by prejunctional α2C-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 α2C-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 α2C-AR gene polymorphisms (α2C Del322-325 or the wild-type counterpart) were measured by polymerase chain reaction and gel electrophoresis. Patients who were α2C 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 α2C wild type, P=0.0005 versus placebo; P=0.010 by interaction test). α2C 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 α2C-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 α2C receptor genotype.

Original languageEnglish (US)
Pages (from-to)21-28
Number of pages8
JournalCirculation: Heart Failure
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • Adrenergic
  • Alpha
  • Genetics
  • Heart failure
  • Norepinephrine
  • Receptors
  • β-blockers

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Bristow, M. R., Murphy, G. A., Krause-Steinrauf, H., Anderson, J. L., Carlquist, J. F., Thaneemit-Chen, S., Krishnan, V., Abraham, W. T., Lowes, B. D., Port, J. D., Davis, G. W., Lazzeroni, L. C., Robertson, A. D., Lavori, P. W., & Liggett, S. B. (2010). An α2C-adrenergic receptor polymorphism alters the norepinephrine-lowering effects and therapeutic response of the β-Blocker Bucindolol in chronic heart failure. Circulation: Heart Failure, 3(1), 21-28. https://doi.org/10.1161/CIRCHEARTFAILURE.109.885962