Patient-Specific Induced Pluripotent Stem Cell Cardiac Myocytes as Predictors of Sudep Risk

Abstract

Dravet syndrome (DS) is a severe and intractable pediatric epileptic encephalopathy that is largely caused by de novo loss-of-function mutations in the voltage-gated sodium channel SCN1A. Approximately 15% of DS patients undergo Sudden Unexpected Death in Epilepsy (SUDEP). A growing body of evidence suggests that cardiac arrhythmia may precede SUDEP in DS. Previous work in DS mouse cardiomyocytes (CMs) demonstrated increased transient and persistent TTX-resistent sodium current (INa), action potential excitability, and incidence of early afterdepolarizations.To test whether cardiac excitability is altered in DS patients, we differentiated induced pluripotent stem cells (iPSCs) from two control and four SCN1A-linked DS patients into CMs. iPSC neurons tested from one of these DS patients was found to be hyperexcitable with increased INa density.Confluent iPSC-CMs from all DS patients had an increased intrinsic beating rate compared to controls (P<0.05, N≥8 per group). Multi-electrode array analysis of iPSC-CMs from DS4 confirmed that beating rate was increased in DS. Consistent with our previous studies in DS mice, we observed a ∼two-fold increase in peak INa in iPSC-CMs from 3 of the 4 DS patients (P<0.05, N≥9 per group). INa density from the remaining patient (DS5) was ∼3 fold higher than control. Due to the high level of INa density, the patient was recommended for a cardiac consultation. The patient presented with sinus tachycardia and repolarization abnormalities that are now being closely monitored.Taken together, our data suggest that alterations in cardiac excitability contribute to the mechanism of SUDEP in DS via increased INa density, which may underlie arrhythmia in DS patients. DS patient-derived iPSC-CMs provide a valuable model for advancing our knowledge of how cardiac arrhythmias contribute to the mechanism of SUDEP and may provide novel biomarkers for SUDEP risk.