Abstract 466: Cardiac Activation of β-catenin in Mice Leads to Prolongation of QRS and Susceptibility to Arrhythmia by Inhibiting Na ⁺ Channel Activity Through Suppression of Na _V 1.5 Expression

Introduction: In vitro studies showed that activation of β-catenin suppresses Na V 1.5 expression by inhibiting SCN5a promoter activity, leading to a decrease of Na + channel activity. How β-catenin regulates cardiac electrophysiological phenotype is unknown. Hypothesis: We hypothesized that cardiac activation of β-catenin regulates electrophysiological phenotype by suppressing Na V 1.5 expression. Methods: Adult mice with cardiac-specific, tamoxifen-induced deletion of β-catenin exon3 , leading to cardiac activation of β-catenin (β-catenin exon3 -/- ) were generated, and the effects of cardiac activation of β-catenin on the electrophysiological remodeling were assessed by electrocardiogram (ECG) recording. Class Ic antiarrhythmic reagent, flecainide, was administered to evaluate susceptibility to ventricular tachycardia (VT). Cardiac structure and function were evaluated by histologic and echocardiographic examinations, respectively. Western blot and qRT-PCR were performed to determine the levels of Na V 1.5 and β-catenin expression in mouse hearts. Whole-cell recording technique was utilized to record Na + currents and action potentials (APs) from ventricular myocytes. Results: Histologic and echocardiographic examinations showed that β-catenin exon3 -/- mice had normal cardiac structure and function. Compared to wild type (WT) mice, the ratio of heart/body weight was not changed and the duration of QRS was significantly prolonged in β-catenin exon3 -/- mice. VT was induced by flecainide in 60% of β-catenin exon3 -/- mice but not in WT mice. Western blot and qRT-PCR showed that Na V 1.5 protein and mRNA were significantly decreased in β-catenin exon3 -/- hearts, compared to WT hearts. Maximal upstroke velocity and amplitude of APs and Na + currents were significantly decreased in β-catenin exon3 -/- ventricular myocytes, compared to WT cells. Conclusion: Cardiac activation of β-catenin leads to prolongation of QRS and susceptibility to VT by decreasing Na V 1.5 expression and Na + channel activity.