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

Abstract

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.

Conflict of interest statement

Conflict of interest statement: S.B.L. and J.D.P. are consultants and M.R.B. is an officer and equity holder in ARCA Discovery (Denver, CO).

Figures

Fig. 1.

The β1AR-389 polymorphism is within a highly conserved intracellular region. Amino acid sequences from diverse species are shown aligned with human residues 379–397, with differences indicated in red. The human polymorphism is located at position 389 (yellow) in patients treated with bucindolol.

Fig. 2.

β1AR genotype and drug-response correlations in nonfailing and failing human ventricles. (A and B) Right ventricular trabeculae were used from 22 nonfailing (A) and 31 failing (B) human hearts as described in Methods. ∗, P < 0.001 for curve slope, P = 0.028 for force response differences vs. Gly. #, P < 0.001 for curve slope, P = 0.013 for force response differences vs. Gly. (C) ISO responses plotted by all β1 389 genotypes; §, P < 0.001 for slope, P = 0.011 for force-response differences among all three curves. (D–F) Failing trabeculae (n = 23) were precontracted with 10 μM forskolin, and the effects of bucindolol, carvedilol, or the partial agonist xamoterol were determined; †, slopes (dashed lines) of curve differ from zero at P < 0.01. See Tables 2 and 3 for patient characteristics.

Fig. 3.

Bucindolol effectively antagonizes the hyperfunctional β1-Arg-389 receptor. Transfected fibroblasts expressing equivalent levels of the receptors were stimulated with 10 μM NE, with simultaneous exposure to the indicated concentrations of bucindolol. ∗, P = 0.008 vs. Gly, n = 4.

Fig. 4.

Kaplan–Meier analysis of endpoints in the placebo–bucindolol study stratified by treatment and β1AR genotype. (A) For survival, Arg homozygotes had an HR = 0.62, 95% C.I. = 0.40–0.96, P = 0.03. In contrast, for β1-Gly-389 carriers, the HR = 0.90, 95% C.I. = 0.62–1.30, P = 0.57. (B) For the combined endpoint of death or HF hospitalization, Arg homozygotes had an HR = 0.66, 95% C.I. = 0.50–0.88, P = 0.004. In contrast, for β1-Gly-389 carriers, the HR = 0.87, 95% C.I. = 0.67–1.11, P = 0.25. In parentheses next to each curve are the number of total subjects enrolled/the number of events at end of study. buc, bucindolol; pla, placebo. (C) Graphical representation of HRs and C.I.s by bucindolol and placebo is shown. Hosp, hospitalization.