OBJECTIVE: Dravet syndrome is a severe form of intractable pediatric epilepsy 
with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac 
arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility 
and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. 
The majority of Dravet syndrome patients have de novo mutations in SCN1A, 
resulting in haploinsufficiency. We propose that, in addition to neuronal 
hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function 
and produces arrhythmias, providing a potential mechanism for SUDEP.
METHODS: Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing 
a human Dravet syndrome mutation, were used to investigate a possible cardiac 
phenotype. A combination of single cell electrophysiology and in vivo 
electrocardiogram (ECG) recordings were performed.
RESULTS: We observed a 2-fold increase in both transient and persistent Na(+) 
current density in isolated Dravet syndrome ventricular myocytes that resulted 
from increased activity of a tetrodotoxin-resistant Na(+) current, likely 
Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action 
potential duration prolongation, and triggered activity. Continuous 
radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, 
idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and 
focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third 
became moribund and required euthanasia.
INTERPRETATION: These data from single cell and whole animal experiments suggest 
that altered cardiac electrical function in Dravet syndrome may contribute to 
the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights 
may lead to critical risk assessment and intervention in human patients.