Synergistic polymorphisms of beta1 and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure.

OBJECTIVES: The Arg389Gly polymorphism (Arg389Gly) in the beta1-adrenergic receptor gene (ADRB1) has been associated with improvement in left-ventricular remodeling with beta-blocker treatment. One study of risk for heart failure suggested a synergistic effect of ADRB1 Arg389Gly with the insertion/deletion polymorphism in the alpha2C-adrenergic receptor gene (ADRA2C). We tested whether the ADRA2C insertion/deletion polymorphism was associated with beta-blocker response in heart failure, either alone or in combination with the ADRB1Arg389Gly polymorphism. METHODS: Fifty-four beta-blocker naive heart failure patients underwent echocardiography before and after 5-6 months of metoprolol CR/XL therapy. Multivariant linear regression modeling was performed to assess the impact of genotypes and other variables on changes in left-ventricular function in response to metoprolol therapy. RESULTS: Deletion carriers had a significantly greater negative chronotropic response. Predictors of the end of study ejection fraction were baseline ejection fraction, deletion carrier status and Arg389Arg genotype. Patients with Arg389Arg/Del-carrier status showed the greatest ejection fraction increase with metoprolol CR/XL. Adjusting for baseline ejection fraction, final S-metoprolol plasma concentration and race, final ejection fraction in patients with this genotype combination was significantly higher than all other genotype combination groups. CONCLUSION: ADRB1 and ADRA2C polymorphisms synergistically influence the ejection fraction response to beta-blocker therapy of heart failure patients.