Genetic polymorphisms of the adrenergic system and implantable cardioverter-defibrillator therapies in patients with heart failure

Abstract

We investigated whether the combination of beta(1)-Gly389Arg and GNB3 C825T, two genetic polymorphisms strictly related to adrenergic system modulation, could act as predictors of appropriate therapies in patients with heart failure (HF) using implantable cardioverter-defibrillators (ICDs). Patients with HF and ICD implantation for primary and secondary prevention were studied. All ICD therapies were registered and classified as appropriate (secondary to ventricular tachycardia) or inappropriate (others). Genetic analysis was performed by polymerase chain reaction and restriction fragment length polymorphism methods. Seventy-three patients with mean left ventricular ejection fraction of 35 +/- 11% were evaluated. Overall, 35 ICD therapies occurred during follow-up in 31 (42.5%) patients. Twenty-four therapies (33%) were appropriate, and 11 (15%) were inappropriate. Individual analysis of each polymorphism only identified T825 carriers of GNB3 C825T as predictor of appropriate shocks. The combined presence of risk genotypes (Arg389 of the beta(1)-Gly389Arg and T825 of the GNB3 C825T) identified patients with higher risk of appropriate shocks. Patients with two at-risk genotypes had a survival rate free of appropriate shocks lower than those with none or only one of these markers (87 vs. 54%, respectively; log-rank statistic = 0.006). Using a Cox regression model, each at-risk genotype was associated with an increment of risk of appropriate ICD shocks (odds ratio = 3.9, 95% confidence interval of 1.3-12.0; P = 0.02). Genetic polymorphisms of the adrenergic system may help to identify HF patients who are more likely to receive appropriate ICD therapies. Further studies are necessary to determine the clinical applicability of these polymorphisms as predictors of arrhythmias.