Hyperthermia-Induced Ventricular Tachycardia and Sudden Death in Mouse Model of Dravet Syndrome

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Introduction: Dravet syndrome (DS) is a severe type of childhood epilepsies, in which SCN1A mutation is found in 80% of cases. Sudden unexpected death in epilepsy (SUDEP) is frequently seen in DS, but its mechanisms remain unknown. We electrophysiologically characterized DS model mouse with heterozygous knock-in (KI) of Scn1a mutation (R1407X). Methods: In KI and wild-type (WT) mice, electrocardiogram and electroencephalogram were monitored under normo- or hyperthermia (38–43°C). During ex vivo optical mapping of Langendorff perfused hearts, ventricular tachycardia (VT) induction was attempted by programmed electrical stimulation and hyperthermia (42–43°C). Quantitative RT-PCR was done in 2-, 4-, and 8-week-old mice. Results: In vivo, KI mice exhibited seizures with VT or bradycardia induced by hyperthermia, resulting in sudden death in some mice. During optical mapping, VT was reproducibly induced by hyperthermia and eliminated by normothermia only in KI mice (3/7). Programmed stimulation failed to induce VT in either group. The Scn1a expression level declined with age, whereas the expression of Scn5a increased. Histological analysis exhibited no difference between KI and WT. Conclusions: VT and subsequent sudden death induced by hyperthermia in vivo and ex vivo may, at least partly, explain the cause of SUDEP in DS.