Sudden Cardiac Death in a Severe Form of Childhood Epilepsy: Mice & Men

Dravet Syndrome (DS) is a severe form of epilepsy and SUDEP: S udden U nexplained D eath in EP ilepsy. Cardiac arrhythmias are a proposed cause of SUDEP in DS, yet, the incidence and mechanisms remain unknown. Over 80% of DS patients have SCN1A mutations, encoding the Na + channel, Nav1.1. We hypothesized DS SCN1A mutations result in altered cardiac electrical function, arrhythmias, and a cardiac mechanism for SUDEP. Cardiomyocyte Na + current (I Na ), action potentials (APs), and ECG recordings were acquired from DS and WT juvenile mice, and Control and DS (DS1&2) patient induced‐pluripotent stem cell derived cardiomyocytes (iPSC‐CMs). DS mice have increased I Na , excitability, AP prolongation, and incidence of early after‐depolarizations, a substrate for arrhythmias. While no WT mice died, 21% of DS mice died by P152, 69% of these deaths by P52. DS mice exhibited seizures, QT prolongation, ventricular ectopic foci, beat‐to‐beat variability, arrhythmias, bradycardia, and death. Also, iPSC‐CMs from DS1 exhibited increased I Na vs Control, while no change in DS2. This demonstrates the differing DS disease penetrance. In DS, increased I Na is a substrate for arrhythmogenesis, may provide non‐invasive SUDEP biomarkers, and provide a potential mechanism for SUDEP.