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 -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 -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 -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 153Ϯ57 pg/mL, Pϭ0.012 compared with placebo versus decrease of 50Ϯ13 pg/mL in ␣ 2C wild type, Pϭ0.0005 versus placebo; Pϭ0.010 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; Pϭ0.80), 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; Pϭ0.025). Conclusions-In the -Blocker Evaluation of Survival Trial AR polymorphism substudy, the norepinephrine lowering and clinical therapeutic responses to bucindolol were strongly influenced by ␣ 2C receptor genotype. (Circ Heart Fail. 2010;3:21-28.)Key Words: genetics Ⅲ heart failure Ⅲ norepinephrine Ⅲ receptors, adrenergic, alpha Ⅲ -blockers A drenergic activity is a major determinant of outcome in chronic heart failure (CHF). 1,2 Multiple lines of evidence indicate that sustained high levels of -adrenergic activity produce adverse effects on myocardial structure and function. 3,4 These observations form the basis of the rationale for -blocker therapy of heart failure. 4 On the other hand, a certain amount of adrenergic activity is required to support the failing heart, and too rapid or extreme removal of adrenergic drive can result in adverse outcomes. [5][6][7] Clinical Perspective on p 28The regulation of cardiac adrenergic activity is complex, involving mechanisms modulating central sympathetic outflow, norepinephrine (NE) neuronal synthesis, prejunctional NE release, and neuronal reuptake of NE. 3 Adrenergic activity is likely also influenced by genetic variation, particularly in adrenergic receptors (ARs) that regulate NE release. One such receptor is the ␣ 2C -AR, which is present on prejunctional adrenergic nerve terminals where it provides tonic inhibition of NE release. 8 Combin...