The SCN5A polymorphism S1103Y alters the response to mexiletine by increasing late sodium current and prolonging action potentials, creating a paradoxical proarrhythmic phenotype.
Does the SCN5A S1103Y polymorphism alter the pharmacological response to mexiletine in human cardiomyocytes?
The common SCN5A S1103Y polymorphism alters the pharmacological response to mexiletine, leading to enhanced sodium current block and paradoxical action potential prolongation, highlighting the need for genotype-informed antiarrhythmic therapy.
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Several common variants have been identified in SCN5A, which encodes the cardiac sodium channel -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.This work exemplifies a New Approach Methodology (NAM) framework for cardiac pharmacology, replacing population-averaged drug testing with a patient-derived, genotype-informed in vitro platform capable of prospectively identifying adverse druggenotype interactions.
Marras et al. (Sun,) reported a other. The SCN5A polymorphism S1103Y alters the response to mexiletine by increasing late sodium current and prolonging action potentials, creating a paradoxical proarrhythmic phenotype.