ArticleEuropace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology2023
Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome.
Article in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 18 citations in OpenAlex.
- Article
- Common genetic variants of the cardiac sodium channel alter patient response to class 1b antiarrhythmics.Journal of precision medicine (Amsterdam, Netherlands) · 2026Article
- Common Genetic Variants of The Cardiac Sodium Channel Alter Patient Response to Class 1b Antiarrhythmics.bioRxiv : the preprint server for biology · 2026Article
- Synergistic antiarrhythmic mechanism of IJournal of translational medicine · 2025Article
- SGLT2 inhibitors to the rescue: restoring cardiac sodium channel membrane function in muscular dystrophy.American journal of physiology. Heart and circulatory physiology · 2025Article
- The sodium/glucose cotransporter 2 inhibitor empagliflozin is a pharmacological chaperone of cardiac NaAmerican journal of physiology. Heart and circulatory physiology · 2025Article
- Practical compendium of antiarrhythmic drugs: a clinical consensus statement of the European Heart Rhythm Association of the European Society of Cardiology.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Review
- Bioengineering Approaches to In Vitro Modeling of Genetic and Acquired Cardiac Diseases.Current cardiology reports · 2025Review
- A Rare Noncoding Enhancer Variant inCirculation · 2025Article
- Investigating Inherited Heart Diseases Using Human Induced Pluripotent Stem Cell-Based Models.Life (Basel, Switzerland) · 2024Review
- Genetic background determines the severity of age-dependent cardiac structural abnormalities and arrhythmia susceptibility in Scn5a-1798insD mice.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2024Article
- Relevance of mexiletine in the era of evolving antiarrhythmic therapy of ventricular arrhythmias.Clinical research in cardiology : official journal of the German Cardiac Society · 2024Review
- Chronic Mexiletine Administration Increases Sodium Current in Non-Diseased Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.Biomedicines · 2024Article
- Unravelling NovelInternational journal of molecular sciences · 2023Article
- Review
- SCN5A-1795insD founder variant: a unique Dutch experience spanning 7 decades.Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation · 2023Review
- Injection of IFrontiers in physiology · 2023Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
aimsSCN5A 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 (INa)] and LQT3 (increased late INa). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late INa and chronically increase peak INa 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
resultsTo 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 INa for both SCN5A-WT and SCN5A-1795insD and an increased late INa for SCN5A-1795insD. Acute re-exposure of HEK293A cells to 10 µm mexiletine did not impact on peak INa but significantly decreased SCN5A-1795insD late INa. Chronic incubation of SCN5A-1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak INa, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak INa or AP upstroke velocity, but significantly decreased AP duration.
conclusionThese findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome.
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