Abstract P2096: Long Qt Syndrome Type 3 Phenotype Dependence On Extracellular Sodium And The Perinexus In A Genetic Mouse Model

Abstract

Background: Long QT Syndrome Type 3 (LQT3) is caused by cardiac voltage-gated sodium channel (Nav1.5) gain of function and characterized by action potential duration (APD) prolongation. A guinea pig model of drug-induced LQT3 demonstrated that elevating sodium and widening the perinexus, an intercalated disc cleft adjacent to gap junctions, individually and synergistically exacerbate APD prolongation. The synergistic effect suggests that high sodium with cardiac edema is a risk factor for LQT3 patients. However, it remains unclear if this synergistic effect occurs in a genetic model of LQT3. Purpose: To investigate individual and combined effects of sodium concentration and perinexal widening in a genetic mouse model of LQT3. Methods: Ventricular action potential duration at 30 (APD30) and 90 (APD90) percent of repolarization was measured from optically mapped, Langendorff-perfused wild type (WT) and ΔKPQ mouse hearts. Hearts were perfused with sodium concentrations of 145 or 160 mM, in the absence or presence of an intercalated disc adhesion inhibitor (βadp1) inducing perinexal widening. Results: At baseline with 145 mM sodium, APD30 and APD90 were significantly greater in ΔKPQ than WT hearts. Surprisingly, increased sodium (160 mM), significantly decreased APD90 in WT but not ΔKPQ hearts, which is inconsistent with results from the drug-induced LQT3 guinea pig model. In contrast, 160mM sodium significantly decreased APD30 in both genotypes suggesting elevated sodium increases the transient outward potassium current (Ito). Interestingly, with 145 mM sodium, βadp1 treatment did not significantly change APD30 or APD90 in either genotype. However, increasing sodium from 145 to 160 mM with βadp1 significantly increased APD90 in ΔKPQ hearts but not WT. Conclusions: Synergistic APD prolongation was modest in a genetic LQT3 mouse when elevating sodium and widening the perinexus relative to drug-induced LQT3 in guinea pig. A significant difference in action potential morphology between mice and guinea pig is the over-expression of Ito in mice and its absence in guinea pig. Future studies will investigate whether transient outward potassium channels contribute to the effect of high sodium on APD shortening during early repolarization.