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

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. 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. 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. ADRB1 and ADRA2C polymorphisms synergistically influence the ejection fraction response to beta-blocker therapy of heart failure patients.