Cancer Institute A national cancer institute
designated cancer center

Philip W. Lavori

Publication Details

  • An alpha(2C)-Adrenergic Receptor Polymorphism Alters the Norepinephrine-Lowering Effects and Therapeutic Response of the beta-Blocker Bucindolol in Chronic Heart Failure CIRCULATION-HEART FAILURE 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; 3 (1): 21-28

    Abstract:

    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.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).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.

    View details for DOI 10.1161/CIRCHEARTFAILURE.109.885962

    View details for Web of Science ID 000273735100005

    View details for PubMedID 19880803

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