Characterization of a novel LQT3 variant with a selective efficacy of mexiletine treatment

Abstract

Pathogenic variants in the human SCN5A gene encoding the a-subunit of the principle Na+ channel (Nav1.5) are associated with long QT syndrome (LQTS) 3. LQT3 patients display variable responses to Na+ channel blockers demanding for the development of variant-specific therapeutic strategies. Here we performed a combined electrophysiological analysis with in silico simulation of variant channel to elucidate mechanisms of therapeutic responsiveness. We identified a novel SCN5A variant (A1656D) in a LQTS patient with a distinct response to mexiletine resulting in suppression of non-sustained ventricular tachycardia and manifestation of premature atrial contraction. Patch clamp analysis revealed that A1656D variant exerted gain-of-function effects including hyperpolarizing shift of the voltage-dependence of activation, depolarizing shift in the voltage-dependence of inactivation, and slowing of fast inactivation. Among ranolazine, flecainide, and mexiletine, only mexiletine restored inactivation kinetics of A1656D currents. In silico simulation to assess the effect of A1656D variant on ventricular cardiac cell excitation predicted a prolonged action potential which is consistent with the prolonged QT and non-sustained ventricular tachycardia of the patient. It also predicted that only mexiletine suppressed the prolonged action potential of human ventricular myocytes expressing A1656D. These data elucidate the underlying mechanism of the distinct response to mexiletine in this patient.

Effects of Mexiletine on a Race-specific Mutation in Nav1.5 Associated With Long QT Syndrome

“…Mexiletine is a voltage-gated sodium channel blocker, and the binding sites of mexiletine were proposed to be located at the intracellular side of the channel ( Li et al, 2020 ). Mexiletine belongs to class IB antiarrhythmic agents, previous studies reported that mexiletine exerted a direct effect on LQTS mutations and modified Na v 1.5 mutation currents ( Kim et al, 2019 ; Li et al, 2020 ). A recent study reported differential gating properties of wild-type Na v 1.5 and Na v 1.7 channels in response to mexiletine and another drug ( Wang et al, 2015 ).…”

Effects of Allicin on Late Sodium Current Caused by ΔKPQ-SCN5A Mutation in HEK293 Cells

“…This finding provides an experimental basis for the clinical application of Allicin in treating LQT3. Class I antiarrhythmic sodium channel blockers, such as mexiletine and flecainide, have been found to effectively shorten the repolarization duration in LQT3 patients with sodium channel mutation and increased late sodium current, which is often used as gene-specific drugs in the treatment of congenital LQT3 ( Benhorin et al, 2000 ; Windle et al, 2001 ; Chorin et al, 2018 ; Kim et al, 2019 ). Recent evidence shows that in patients with LQT3, not all sodium channel blockers play a therapeutic role-they could even induce new arrhythmias ( Mocayar Maron et al, 2020 ; Schwartz et al, 2012 ).…”

Verification of the Efficacy of Mexiletine Treatment for the A1656D Mutation on Downgrading Reentrant Tachycardia Using a 3D Cardiac Electrophysiological Model

“…In this context, a better knowledge of the mechanism of sodium blockers for treating LQT3 patients has become a top goal. The efficacy of mexiletine for treating LQT3 patients has recently been demonstrated in a previous study [ 14 , 23 , 24 ]. Despite the extensive experimental evaluation of mexiletine for treating LQT3 patients, their findings require more investigation into the effects of mexiletine on a 3D ventricular model of the heart.…”

“…In a newborn baby with QT prolongation and non-sustained ventricular tachycardia (NSVT), a unique SCN5A variation known as A1656D was recently discovered [ 14 ]. Kim et al reported that under the influence of mexiletine, A1656D exhibited a distinct response that resulted in the suppression of NSVT and the appearance of premature atrial contraction.…”

“…Deo et al [ 27 ] combined an experimental study of the mutation (E299V) in the KCNJ2 gene that encodes the strong inward rectifier K+ channel protein (Kir2.1) and 3D computational modeling of the heart incorporating the His-Purkinje network to predict the 20% reduction of sodium current that can cause reduction of ventricular excitability and increase the vulnerability of ventricular tachyarrhythmia. Kim et al [ 14 ] also produced a computational model of the A1656D mutation, which demonstrated how various medications affect the AP shape of the ventricular cell. One of their significant discoveries is that mexiletine can reduce the APD of the A1656D mutation by restoring late sodium current inactivation kinetics.…”