title: 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.
authors.affiliation: Department of Medicine, University of Maryland, Baltimore, MD 21201, USA. sligg001@umaryland.edu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mialet-Perez
authors.forename: Surai
authors.initials: S
authors.lastname: Thaneemit-Chen
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Weber
authors.forename: Scott M
authors.initials: SM
authors.lastname: Greene
authors.forename: Danielle
authors.initials: D
authors.lastname: Hodne
authors.forename: Bradley
authors.initials: B
authors.lastname: Nelson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Morrison
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Domanski
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagoner
authors.forename: William T
authors.initials: WT
authors.lastname: Abraham
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Krause-Steinrauf
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.forename: J David
authors.initials: JD
authors.lastname: Port
authors.forename: Philip W
authors.initials: PW
authors.lastname: Lavori
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D006224:Cricetinae; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology*; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic; D011412:Propanolamines / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; C024307:bucindolol