Arrhythmias & electrophysiologyResearch article
Genotype-Specific Electrophysiological Remodeling in PLN R14del Cardiomyopathy: Implications for Precision Antiarrhythmic Therapy
- Preclinical in vitro study of human induced pluripotent stem cell-derived cardiomyocytes
- isogenic
- CRISPR-edited
- high-throughput optical action potential (AP) recordings
- deep learning framework for AP morphology classification
- graded drug concentrations
Authors' conclusion
PLN R14del cardiomyopathy creates a distinct electrophysiological substrate that fundamentally alters antiarrhythmic drug responsiveness, such that agents beneficial in WT contexts may be ineffective or proarrhythmic in this genotype. Preclinical antiarrhythmic evaluation should incorporate genotype-specific, patient-derived human induced pluripotent stem cell models to enable precision medicine strategies in inherited cardiomyopathies.
Study context
- Population
- Isogenic wild-type (WT) and CRISPR-edited PLN R14del human induced pluripotent stem cell-derived cardiomyocytes
- Comparison
- WT (HD.15S1) vs PLN R14del
Main finding
As reported in the abstract
Arrhythmogenic phenotype: proportion of normal APs, AP duration, and early afterdepolarizations in PLN R14del versus isogenic WT · baseline
- Subtle but significant arrhythmogenic phenotype, consistent with impaired calcium handling and diminished repolarization reserve
- PLN R14del vs isogenic WT: reduced proportion of normal APs, prolonged AP duration, and increased early afterdepolarizations compared with isogenic WT
Further findings
| Outcome | WT (HD.15S1) | PLN R14del |
|---|---|---|
| Response to the transient outward potassium current activator NS-5806 | ||
| Response | biphasic, dose-dependent response, transiently destabilizing and then restoring normal AP morphology | marked proarrhythmic remodeling and near-complete loss of normal APs at higher doses |
| Response to the selective late sodium current blocker GS-967 (eleclazine) | ||
| Response | Not reported in the abstract | paradoxically exacerbated arrhythmic features in the mutant line, including AP duration prolongation and suppression of normal APs |
| Response to the transient outward potassium current inhibitor acacetin | ||
| Response | preserved stability | failed to rescue normal AP morphology |
Original publication
Genotype-Specific Electrophysiological Remodeling in PLN R14del Cardiomyopathy: Implications for Precision Antiarrhythmic Therapy. Circ Arrhythm Electrophysiol. Published 8 July 2026. doi:10.1161/circep.125.014684
Summarised from the published abstract; every number is checked against it