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.
Highlights
The voltage-gated Na+ channel is an integral membrane protein, a part of a macromolecular complex that is central to signaling in excitable tissues such as hearts
A male infant was born after 37 weeks’ gestation to a 40 years old mother, who had been treated throughout pregnancy with flecainide, 100 mg bid, to treat premature atrial contraction (PAC) and non-sustained atrial tachycardia observed by fetal echocardiographic examination
The results of our study demonstrate that the SCN5A A1656D mutation in a newborn perturbs the Nav1.5 channel inactivation contributing to delayed repolarization in cardiac cells
Summary
The voltage-gated Na+ channel is an integral membrane protein, a part of a macromolecular complex that is central to signaling in excitable tissues such as hearts. Characterization of clinical phenotypes and therapeutic responses for Na+ channel harboring specific mutations is actively pursued; many of the relevant studies have been limited by the fact that they were performed in expression systems rather than native cells To circumvent this limitation, the combined approach of experimental analysis with in silico simulation using human atrial and ventricular myocytes model is beginning to emerge[16,17]. Our data show that out of 3 tested antiarrhythmic drugs, mexiletine effectively recovers the channel function only in ventricular cells while it fails to suppress atrial arrhythmia These are well correlated with the suppression of NSVT and the occurrence of premature atrial contraction (PAC) in the patient post mexiletine therapy, supporting for the importance of understanding the biophysical and pharmacological characterization of a distinct mutant to develop a mutation-specific therapeutic approach to manage arrhythmias
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