Abstract 18694: Connexin-43 Gene Variants are Associated with Risk of Ventricular Arrhythmias in Patients with a Depressed Ejection Fraction

Background: Despite the life-saving benefits of implantable cardioverter defibrillator (ICD) therapy, only a minority of primary prevention patients ultimately receive ICD therapy for ventricular arrhythmias. Genetic risk factors may improve current risk stratification models. Connexin-43 is the predominant component of gap junctions in ventricular myocardium. Accordingly, we hypothesized that common genetic variants in connexin-43 are associated with risk of ventricular arrhythmias in patients with reduced ejection fraction. Methods: Caucasian individuals with an impaired ejection fraction (< 35%) who had received a primary prevention ICD were identified from the Duke Electrophysiology Genetic Studies (EPGEN) database (N=252). Six connexin-43 single-nucleotide polymorphisms (SNPs) were genotyped using Taqman. Association with ventricular arrhythmia, defined as an appropriate ICD shock or anti-tachycardia pacing for ventricular tachycardia or fibrillation, was tested using univariate and multivariable logistic regression models adjusted for sex, age, hypertension, hyperlipidemia, smoking, diabetes and coronary artery disease status. Results: Over a mean follow-up of 2.3 years, there were 42 cases of ventricular arrhythmia. In univariate analyses, two SNPs in complete linkage disequilibrium, rs11961755 and rs10456940, were associated with risk of ventricular arrhythmia (19% of cases vs. 44% of controls carried at least one copy of the minor allele, p=0.003 in the dominant genetic model). In multivariable models, these SNPs were associated with an odds ratio for ventricular arrhythmia of 0.27 (95% confidence interval 0.11-0.62, p=0.002). These relationships were not observed in African-American subjects (N=124). No other connexin-43 SNPs were associated with events. Conclusions: Genetic variants in connexin-43 are independently associated with risk of ventricular arrhythmia in patients referred for primary prevention ICDs. Prospective studies should address whether these novel markers improve risk stratification.