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Sudden Cardiac Death in a Severe Form of Childhood Epilepsy: Mice & Men
Author(s) -
Auerbach David S,
Shi Huilin,
Jones Julie,
Clawson Brittany C,
Ogiwara Ikuo,
Yamakawa Kazuhiro,
Meisler Miriam H,
Parent Jack M,
Isom Lori L
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.706.4
Subject(s) - medicine , epilepsy , cardiology , sudden cardiac death , long qt syndrome , induced pluripotent stem cell , sudden death , bradycardia , afterdepolarization , qt interval , anesthesia , repolarization , electrophysiology , biology , heart rate , biochemistry , embryonic stem cell , psychiatry , blood pressure , gene
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.