https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 2Kath. Klinikum Bochum Cellular Physiology Bochum, Deutschland; 3Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland
Introduction:
Short QT Syndrome (SQTS) is a genetic arrhythmia characterized by a shortened QTc interval, associated with a high risk of malignant arrhythmias and sudden cardiac death (SCD). Treatment options for SQTS remain limited. This study aimed to evaluate disopyramide's effects on SQT5 phenotype features.
Methods:
Human iPSC-derived cardiomyocytes (hiPSC-CMs) from an SQT patient with a CACNB2 variant (SQT5) and from a CRISPR-edited line (variant corrected) were used. Patch-clamp assessed the effects of disopyramide on action potentials (APs) and ion channel currents, while calcium transient techniques evaluated its potential to reduce arrhythmia-like events.
Results:
The SQT5 patient-specific cardiomyocytes showed a shortened APD and decreased L-type calcium channel current (ICa-L) due to delayed activation, recovery, and enhanced inactivation of the calcium channel, compared to the variant-corrected cells. Disopyramide significantly prolonged APD and increased ICa-L by reducing inactivation and promoting the recovery phase. The effects were frequency-independent. In the variant-corrected hiPSC-CMs, disopyramide prolonged APD without affecting ICa-L. Calcium transient experiments indicated that disopyramide markedly reduced arrhythmia-like events induced by epinephrine and carbachol in the SQT5 cells and decreased interval variability.
Conclusions:
Disopyramide prolongs APD and increases ICa-L caused by the disease gene; Disopyramide reduces arrhythmia-like events in SQT5 cells, suggesting its benefits for the clinical management of SQT5 patients.