Adrenergic Receptor Polymorphisms and Prevention of Ventricular Arrhythmias With Bucindolol in Patients With Chronic Heart Failure

Background— β-blockers prevent cardiac arrhythmias in patients with chronic heart failure and reduced left ventricular ejection fraction, including ventricular tachycardia/ventricular fibrillation (VT/VF). We hypothesized that prevention of ventricular arrhythmias by the β-blocker/sympatholytic agent bucindolol is influenced by genetic variation in adrenergic receptors. Methods and Results— From a substudy of the β-Blocker Evaluation of Survival Trial (n=1040), we identified those with the high functioning 389Arg versus the lower function 389Gly β1 adrenergic receptor variant, and the loss of function α2c322-325 adrenergic receptor deletion versus the 322 to 325 wild-type (Wt)/deletion variant. VT/VF was recorded on case report forms as an adverse event. There were 493 Arg 389 β1 receptor homozygotes (β1389 Arg/Arg) versus 547 Gly389 carriers and 207 α2c322-325 deletion carriers versus 833 homozygous Wts (α2c322-325 Wt/Wt). In all genotypes bucindolol was associated with a lower incidence of VT/VF (subhazard ratio, 0.42 [0.27–0.64]; P =0.00006). Bucindolol reduced VT/VF in β1389 Arg homozygotes (subhazard ratio, 0.26 [0.14–0.50]; P =0.00005) but not in β1389 Gly carriers (subhazard ratio, 0.60 [0.34–1.07]; P =0.09). For genotype combinations, the α2c322-325 polymorphism altered the VT/VF bucindolol response in β1389 Gly carriers, with α2c deletion genotypes associated with complete efficacy loss. A test of interaction was statistically significant ( P =0.028) for the treatment group and a β1389/α2c322-325 three genotype construct, effectively identifying patients who exhibited enhanced response, no substantial response modification and loss of response. Conclusions— Bucindolol prevents VT/VF in subjects with heart failure and reduced left ventricular ejection fractions, and this effect is modulated by β1389 Arg/Gly and α2c322-325 Wt/deletion adrenergic receptor polymorphisms.