ARG389GLY beta-1 adrenergic receptor polymorphism and left ventricular remodeling changes to beta-blocker therapy

Abstract

The β1-adrenergic receptor (β1AR) contains a common functional polymorphism at codon 389 (Arg389Gly). In vitro studies indicate that Arg389 has greater basal and agonist stimulated adenylyl cyclase activity. We hypothesized that the Arg389Gly polymorphism was associated with left ventricular (LV) remodeling changes to a β-blocker. We prospectively enrolled 47 β-blocker naive patients with ischemic or non-ischemic heart failure (HF). Patients received metoprolol CR/XL (MXL) 12.5–25 mg/d, titrated q 2 weeks (as tolerated) up to 200 mg/d or highest tolerated dose over 8 weeks. Patients completed a 2D echocardiogram at baseline and at the end of study, which occurred 3 months after attainment of highest tolerated MXL dose during titration. An ANCOVA with baseline measures and MXL dose as covariates was used to compare changes in ejection fraction (EF), LV end-diastolic and end-systolic diameters (LVEDD and LVESD, respectively), between genotypes. The % of patients with non-ischemic HF, HF duration, and heart rate reduction was similar between genotypes. The final MXL dose was 136 mg/d for Arg389Arg and 103 mg/d for Gly389 carriers. Gly389 carriers experienced progressive ventricular dilatation reflected by increases in LVEDD and LVESD, while patients with the Arg389Arg genotype had an attenuation of LV remodeling. The difference in LVEDD was statistically significant between groups. In conclusion, the codon 389 genotype is associated with LV remodeling changes from β-blocker therapy. (See Table) Clinical Pharmacology & Therapeutics (2004) 75, P2–P2; doi: 10.1016/j.clpt.2003.11.006 Table 1. Arg389Arg (n=20) Gly389 Carriers (n=27) P* Baseline Final Baseline Final * For comparison of change from baseline between genotypes. Means ± SD. EF (%) 24 ± 6 29 ± 11 22 ± 8 23 ± 11 0.15 LVEDD (mm) 62 ± 12 61 ± 11 63 ± 9 66 ± 9 0.01 LVESD (mm) 53 ± 11 51 ± 13 54 ± 10 56 ± 12 0.12