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Beneficial effects of chronic mexiletine treatment in a human model of SCN5A overlap syndrome.
- Source :
- EP: Europace; Jun2023, Vol. 25 Issue 6, p1-12, 12p
- Publication Year :
- 2023
-
Abstract
- Aims SCN5A 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 (I <subscript>Na</subscript>)] and LQT3 (increased late I <subscript>Na</subscript>). The sodium channel blocker mexiletine may acutely decrease LQT3-associated late I <subscript>Na</subscript> and chronically increase peak I <subscript>Na</subscript> 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 results To 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 µ m mexiletine followed by wash-out, which resulted in an increased peak I <subscript>Na</subscript> for both SCN5A -WT and SCN5A -1795insD and an increased late I <subscript>Na</subscript> for SCN5A -1795insD. Acute re-exposure of HEK293A cells to 10 µ m mexiletine did not impact on peak I <subscript>Na</subscript> but significantly decreased SCN5A -1795insD late I <subscript>Na</subscript>. Chronic incubation of SCN5A -1795insD hiPSC-CMs with mexiletine followed by wash-out increased peak I <subscript>Na</subscript>, action potential (AP) upstroke velocity, and AP duration. Acute re-exposure did not impact on peak I <subscript>Na</subscript> or AP upstroke velocity, but significantly decreased AP duration. Conclusion These findings demonstrate for the first time the therapeutic benefit of mexiletine in a human cardiomyocyte model of SCN5A overlap syndrome. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10995129
- Volume :
- 25
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- EP: Europace
- Publication Type :
- Academic Journal
- Accession number :
- 164654602
- Full Text :
- https://doi.org/10.1093/europace/euad154