Common Genetic Variants of The Cardiac Sodium Channel Alter Patient Response to Class 1b Antiarrhythmics

Several common variants have been identified in SCN5A, which encodes the cardiac sodium channel α-subunit Nav1.5 and is targeted by class I antiarrhythmics. Lidocaine and its analog mexiletine both have a primary amine that blocks Na⁺ current. While lidocaine is highly effective in terminating ventricular tachycardia after acute myocardial infarction, mexiletine has been shown to prevent arrhythmia induction in only ~20% of patients. The factors underlying this inconsistent drug response are unclear. Here, we use cardiomyocytes that are derived from induced pluripotent stem cells to observe that a common polymorphism in the SCN5A gene, S1103Y, exhibits an altered pharmacological response to mexiletine, with enhanced use-dependent and tonic block of peak sodium current. In addition, an unexpected increase in late sodium current causes action potential prolongation. This paradoxical proarrhythmic phenotype shifts the paradigm of conventional antiarrhythmic therapy with mexiletine, suggesting that background variants may alter pharmacological responses leading to unanticipated consequences. Our results suggest that the unique genetic background of patients should inform therapeutic approaches to treat and prevent arrhythmias associated with common cardiac pathologies.