Abstract 2001: Genetic β-Blockade: A G-Protein Coupled Receptor Kinase-5 Polymorphism That Inhibits Beta-Adrenergic Receptor Signaling is Protective in Heart Failure
Heart failure (HF) is a heterogeneous disorder characterized by variable progression rate, treatment response, and outcome. Genetic variants are thought to contribute to clinical heterogeneity, especially polymorphic β-adrenergic receptors (βAR), which regulate normal cardiac contractility and are downregulated and desensitized in HF. β-blocker therapy confers a mortality benefit in HF, but again, there is inter-individual variability. Since βAR desensitization is regulated by G-protein receptor kinases (GRKs), we hypothesized that genetic variants of these kinases could modify βAR signaling and affect heart failure outcome.
Methods: We resequenced GRKs 2 and 5 in 96 individuals, revealing no nonsynomymous GRK2 variants, but 1 common (Q41L) and 3 rare nonsynonymous variants of GRK5. The phenotype of GRK5 Q41L was studied functionally at multiple levels: in human heart failure in both case-control (n=1323) and prospective studies (n=339), in vitro in transfected CHO cells, and in vivo in cardiac-specific transgenic mice expressing either the Q41 or L41 variant.
Results: In the case-control study GRK5-L41 was~9-fold more common in blacks vs. whites, was not increased in HF, but was associated with delayed HF onset in blacks (P=0.001), demonstrating a modest protective effect. Mechanistically, in comparison with GRK5-Q41, GRK5-L41 enhanced desensitization of βAR signaling and cardiac function in transfected cells, while in transgenic mice L41 accelerated inotropic (+dP/dt) desensitization and delayed resensitization to infused isoproterenol. These effects mimic β-blockers by attenuating βAR signaling. In the prospective human study, GRK5-Q41 HF patients receiving β-blockers had the typical reduced relative risk (RR) of death/transplant of 0.17, 95% CI=0.08 – 0.35, vs. the same genotype without β-blockers. Strikingly, a similar degree of protection was afforded by GRK-L41, even in the absence of β-blockers (RR=0.29, 95% CI=0.11– 0.78). Survival in L41 patients was not further improved by β-blockers.
Conclusions: The GRK5-L41 polymorphism is a genetic equivalent to -blockade in heart failure and improves outcome. Genotyping may identify patients for tailored therapy, particularly those patients intolerant to β-blocker therapy.