Browsing Theses and Dissertations School of Pharmacy by Author "Rogers, Hobart Lee"
The Role of the Beta-1,2-adrenergic and GRK5 Receptor Single-Nucleotide-Polymorphisms (SNPs) on the Treatment of Heart Failure with Beta-blockersRogers, Hobart Lee; Dowling, Thomas C. (2010)Despite recent advances in medical treatment, heart failure still remains a primary cause of mortality in the U.S. Pharmacologic β-blockade using carvedilol, metoprolol succinate, or bisoprolol in heart failure is associated with reduced mortality and morbidity and considered a class I recommendation in the consensus guidelines for the treatment of systolic heart failure. Nevertheless, β-blockers are still underused in this patient population. Additionally, significant interpatient variability in response to these agents exists. The differential response to β-blockade may be due to genetic heterogeneity of the β-adrenergic receptor (β-AR), in the form of single-nucleotide-polymorphisms (SNPs). SNPs with functional differences have been identified on the β1-AR at positions 49 (Ser/Gly) and 389 (Arg/Gly) and β2-AR at positions 16 (Gly/Arg) and 27(Gln/Glu). Furthermore, a functional SNP on the G-protein coupled receptor kinase (GRK) has also been identified. These SNPs have all been linked to significant differences in receptor expression and function in experimental models. The objective of this study was to characterize the clinical implications of the β1,2-AR and GRK SNPs on the treatment of heart failure with β-blockers. Eighty-six NYHA class II-III heart failure patients receiving maximum titrated doses of either carvedilol or metoprolol succinate were enrolled in this study. Heart rate (HR) was measured at rest and immediately following a 6-minute walk test, and a blood sample was obtained for genotyping. Genotypes were determined by Taqman genotyping assays. To account for plasma β-blocker concentrations, two novel enantioselective HPLC assays with fluorescence detection were developed. Our primary finding was that metoprolol-treated patients who were homozygous for Arg at position 389 on the β1-AR had both an enhanced negative chronotropic and antihypertensive response to β-blockade when corrected for plasma S-metoprolol concentrations. When evaluating the β2-AR SNPs, both the carvedilol-treated Gly16 homozygotes and the Glu27 carriers had a significantly enhanced antihypertensive response compared to their subsequent counterparts. These findings suggest that SNPs in both the β1,2-ARs are associated with clinical response to either carvedilol or metoprolol succinate. Moreover, our findings emphasize the importance of accounting for pharmacokinetic differences when evaluating pharmacodynamic relationships.