Abstract 2021: Adrenergic Receptor Polymorphisms and Prevention of Ventricular Arrhythmias with Bucindolol in Patients with Heart Failure
Background: β-blockers have been shown to prevent ventricular arrhythmias (VT/VF) in patients with low left ventricular ejection fraction (LVEF) and chronic heart failure (CHF). We hypothesized that there may be genotype specific responses to β-blocker therapy for prevention of VT/VF.
Methods: The β-blocker Evaluation of Survival Trial (BEST) is a randomized trial of bucindolol in patients with NYHA Class III – IV CHF and LVEF ≤0.35. From a substudy of 1040 genotyped subjects, we identified those with the high functioning Arg389 β1 adrenergic receptor polymorphism and the loss of function 322–325 α2c adrenergic receptor deletion polymorphism. The incidence of VT/VF was prospectively recorded as an adverse event during the trial.
Results: Of the 1040 subjects in the genotyped cohort, there were a total of 493 Arg389 β1 homozygotes vs. 547 Gly389 carriers and 207 α2c deletion carriers vs. 833 wild-types. The diplotypes included 418 subjects with both Arg/Arg389 β1 receptors and wild type α2c, 484 with one of these, and 134 carrying both the α2c deletion and β1 Gly389. For the genetic substudy, bucindolol was associated with less VT/VF that placebo (5.5% vs. 12.1%; p<0.01) There was a significant drug-gene interaction for prevention of VT/VF with both polymorphisms (β1 overall p<0.01; α2c overall p<0.01). Arg389 homozygotes randomized to bucindolol had a lower incidence of VT/VF during the trial than those randomized to placebo (4.3% vs. 14.4%; P<0.01) as for wild type α2c homozygotes (5.4% vs. 12.7%; p<0.01). This reduction in VT/VF was not significant in other genotypes (β1 Gly389 carriers: 6.6% vs. 10.4%; P=0.13 and α2c deletion carriers: 4.9% vs. 10.6%; P=0.19). Subjects with the Arg/Arg389 β1/wild type α2c receptor diplotype randomized to bucindolol had a lower rate of VT/VF occurrence than those with only one or neither of these genotypes (both: 4.7% vs. 14.6%; p<0.01; one: 4.9% vs. 11.2%; p=0.01; neither: 8.5% vs. 9.3%; p=1.0).
Conclusion: Subjects with CHF and Arg/Arg389 β1 or wildtype α2c adrenergic receptors treated with bucindolol had a lower rate of VT/VF than those randomized to placebo. This treatment effect was not observed in the population of β1 Gly389 or the α2c deletion carriers, indicating a pharmacogenetic interaction.