PO-01-241 ROLE OF THE TWO-PORE K+CHANNEL TREK1 IN REGULATING HEART FAILURE-INDUCED VENTRICULAR ARRHYTHMIA

Abstract

Despite therapeutic advances, heart failure (HF) remains a leading cause of death in the United States and is growing in prevalence. Although disease-induced defects in ion channel excitability and expression put patients at higher risk for life-threatening ventricular arrhythmias, the exact mechanisms by which HF leads to proarrhythmic ion channel dysfunction are not completely understood. Notably, several recent studies have identified important roles for the two-pore background K+ channel TREK1 in regulating sinus rhythm, atrial arrhythmia, and ventricular excitability. In the present study, we examined a putative role for TREK1 dysfunction in promoting heart failure-induced ventricular arrhythmia. We subjected wild type (WT) mice and mice with cardiac-specific TREK1 deficiency (TREK1cKO) to transaortic constriction (TAC) surgery as a model of heart failure or to a sham procedure. Over the course of 6-12 weeks following surgery, we examined structural and electrical remodeling via echocardiography and subsurface ECGs. At the end of the time course, ventricular cells were isolated and used for patch clamp, Ca2+/contractility imaging, and immunostaining. A subset of hearts were isolated for optical voltage mapping. We observed that TREK1cKO mice experienced greater reductions in cardiac function earlier in the development of pressure overload compared to WT mice, which was maintained throughout the time course. Additionally, TREK1cKO mice exhibited proarrhythmic changes to ECG parameters over 6-12 weeks of pressure overload including action potential duration (APD) prolongation, QTc prolongation, and QRS widening. However, the TREK1cKOs also experienced faster conduction, lower APD heterogeneity, and lower ventricular arrhythmia inducibility at 6 weeks post-surgery. Overall, these results demonstrate a potentially complex role of TREK1 in regulating ventricular excitability, ion dynamics, and arrhythmia susceptibility in the context of pressure overload-induced heart failure.