Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome

AIMS: SCN5A mutations are associated with various cardiac phenotypes, including long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), and cardiac conduction disease (CCD). Certain mutations, such as SCN5A-1795insD, lead to an overlap syndrome, with patients exhibiting both features of BrS/CCD [decreased sodium current (I(Na))] and LQT3 (increased late I(Na)). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late I(Na) and chronically increase peak I(Na) associated with SCN5A loss-of-function mutations. However, most studies have so far employed heterologous expression systems and high mexiletine concentrations. We here investigated the effects of a therapeutic dose of mexiletine on the mixed phenotype associated with the SCN5A-1795insD mutation in HEK293A cells and human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: To assess only the chronic effects on trafficking, HEK293A cells transfected with wild-type (WT) SCN5A or SCN5A-1795insD were incubated for 48 h with 10 µm mexiletine followed by wash-out, which resulted in an increased peak I(Na) for both SCN5A-WT and SCN5A-1795insD and an increased late I(Na) for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 µm mexiletine did not impact on peak I(Na) but significantly decreased SCN5A-1795insD late I(Na). Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak I(Na), action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak I(Na) or AP upstroke velocity, but significantly decreased AP duration. CONCLUSION: These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome.