Evaluation of Compounds in LQT3 Mice

Long QT syndrome (LQTS) is arrhythmogenic disorder that can cause sudden cardiac death. LQTS type 3 (LQT3) is caused by “gain-of-function” mutations in the voltage-gated Na+ channel gene Scn5a. The majority of LQT3 linked mutations increase the “late” Na current that flows inward during the ventricular action potential plateau phase. This causes a prolongation in the ventricular depolarization and increases the likelihood of early after depolarizations (EADs). The goal of this project is to determine the in vivo therapeutic potential of an experimental drug derived from a parent compound (mexilitine) that blocks sodium current in the heart. Our laboratory recently described time-of-day differences in electrocardiographic (ECG) properties of transgenic knock-in mice that are heterozygous for the LQT3-linked Scn5a deletion mutation ÄKPQ (Scn5a+/ÄKPQ). In this project we will collaborate with the Human BioMolecular Research Institute (HBMR) to test if mexitiline or their derivative normalize the ECG properties of the Scn5a+/ÄKPQ. Preliminary data suggests that this compound normalizes the in vitro LQT3-related phenotype at concentrations considered sub-therapeutic for mexilitine. Therefore, we propose to compare the ECG properties for 3 groups of Scn5a+/ÄKPQ mice: one group treated with sub-therapeutic levels of mexilitine; one group with HBMR compound at analogous concentrations; and a third group at therapeutic levels of mexilitine. The prediction is that the HBMR compound and therapeutic levels of mexilitine will normalize the LQT3-related ECG phenotype.