Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.

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...

Background-Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. Methods and Results-Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the ␤-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the ␤-blocker/ sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (PϽ0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization.In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. Conclusions-In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation ␤-blocker.