Pharmacogenomics of beta-adrenergic receptors and their accessory signaling proteins in heart failure

Abstract

beta-Adrenergic receptors (betaAR) are widely expressed on cardiovascular cells. Pharmacological stimulation or blockade of betaAR signaling is the therapeutic mainstay in cardiogenic shock, hypertension, ischemia, arrhythmias, and heart failure. Interindividual variability in the response to betaAR agonists and antagonists has prompted examination of variability in the genes encoding betaAR signaling pathway members. Prominent among the genes that have been examined so far in heart failure are the beta(1)AR, beta(2)AR, and G-protein-coupled receptor kinase 5 (GRK5). Each has nonsynonymous polymorphisms that alter amino acid sequence and protein function and regulation in cell-based systems, genetically altered mouse models, or human hearts. Here, we review these phenotypes and results from published clinical studies, with a focus on heart failure pharmacogenomics. Thus far, very few studies have utilized analogous protocols or drugs, and discrepancies in the clinical studies are apparent. A compelling approach is the use of multiple methods to understand the molecular, cellular, and organ phenotypes of a variant and couple these with clinical studies designed to specifically address the relevance of those phenotypes in humans. Undoubtedly, additional loci will be identified, and together, will provide for genetically driven, individualized treatments for heart failure.

Figure 1

Schematic diagram of the principal components of beta‐adrenergic signaling and their cardiac effects. Norepi = norepinephrine, the major endogenous β₁AR agonist; GRK = G‐protein‐coupled receptor kinase.

Figure 2

Phenotypes of theβ₁Arg389‐Gly389 polymorphism in various model systems. (A) Results from transfected CHW cells expressing equal levels of the two receptors. (B and C) Results from transgenic mouse hearts studied in the ex vivo work‐performing mode. At 3 months, basal and maximal agonist‐stimulated contractility are enhanced in Arg389 hearts. At 6 months of age (C), basal contractility for Arg389 remained greater than Gly389, but the response to agonist was essentially absent. (D) Results from young transgenic mice treated with vehicle or propranolol in their drinking water for 1 month. Heart rates were determined by echocardiography and showed that only the Arg389 mice had a reduction in the heart rate from β‐blockade.

Figure 3

Physiologic properties of human right ventricular trabeculae from nonfailing and failing hearts stratified by the β₁AR position 389 variants. Trabecular strips were studied in organ bath experiments by measuring contractile force in response to the indicated drugs. (A) Dose‐response to isoproterenol from human nonfailing hearts (normal hearts not used for transplantation). (B) Dose‐response to isoproterenol from failing hearts (end‐stage, explanted hearts from patients receiving cardiac transplants); note scale difference between (A) and (B). Regardless of whether the hearts were normal or failing, the Arg389 homozygous responses to agonist were greater than Gly389 heterozygotes. (C) Dose‐response to bucindolol in failing hearts. Trabeculae were co‐stimulated with forskolin, which allows for detection of partial and inverse agonist actions. Bucindolol had an inverse agonist effect only in Arg389 hearts.

Figure 4

Kaplan‐Meier survival curves in heart failure patients stratified by bucindolol or placebo treatments and Arg or Gly389 β₁AR genotypes. The Arg389 patients were homozygous, and Gly389 patients were carriers of one or two Gly389 alleles. Comparisons were within genotype between bucindolol and placebo. For Arg389 patients treated with bucindolol compared to placebo (HR = 0.62, 95% CI = 0.40–0.96, p= 0.03), indicating an improvement in survival with bucindolol in those with this genotype. This same comparison in Gly carriers revealed no difference in survival (HR = 0.90, 95% CI = 0.62–1.30, p= 0.57), indicative of no treatment response to bucindolol.

Figure 5

Functional and clinical characteristics of GRK5 Glu41 and Leu41. (A) Tissue culture studies showing GRK5 Leu41 (L41) desensitizing β₁AR‐stimulated cAMP accumulation more rapidly than GRK5 Glu41 (Q41). (B) Isolated perfused heart studies showing that GRK5 Leu41 (L41) desensitizes myocardial β₁AR‐stimulated adenylyl cyclase activity more than GRK5 Glu41 (Q41). (C) Treatment with the β‐blocker propanolol prevents left ventricular remodeling, measured as the increase in left ventricular end‐diastolic dimension (LVEDD), in chronic isoproterenol‐stimulated heart failure. (D) GRK5 L41 transgenic mice are resistant to ventricular remodeling induced by chronic isoproterenol (black bars), similar to propanolol treatment (gray bars). (E and F) Kaplan–Meier survival curves of African Americans stratified by β‐blocker treatment in homozygous GRK5 Q41 (E) and GRK5L41 carriers (F).