A polymorphism within a conserved beta sub(1)-adrenergic receptor motif alters cardiac function and beta -blocker response in human heart failure

Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta sub(1)-adrenergic receptor ( beta sub(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 sub(1)-Arg-389 had respective 2.8 plus or minus 0.3- and 4.3 plus or minus 2.1-fold greater agonist-promoted contractility vs. beta sub(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 plus or minus 80 vs. 115 plus or minus 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 sub(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.