Abstracts

Rationale: Dravet Syndrome (DS) is the most severe form of genetic childhood epilepsy. In addition to seizures, patients exhibit developmental delay, cognitive decline, and sudden death. Death may be due to epilepsy-related causes or SUDEP: Sudden Unexpected Death in Epilepsy. Cardiac arrhythmias are one of the proposed causes of SUDEP, however, the susceptibility to and mechanisms of arrhythmogenesis in DS remain unknown. More than 70% of DS patients have de novo mutations in SCN1A, encoding the α-subunit of the voltage-gated sodium channel, Nav1.1, a channel that is critical for the activation of neurons and cardiac myocytes. We hypothesized that DS mutations in SCN1A that produce haploinsufficiency result in altered cardiac electrical function, arrhythmias, and a potential cardiac mechanism for SUDEP. Methods: Single cell voltage clamp Na+ channel and current clamp action potential recordings were acquired from acutely isolated juvenile (15-21 days old, P15-21) DS (heterozygous for R1407X) and WT mice. Radiotelemetry ECG, temperature, and activity recordings (DSI ETA-F10) were obtained from conscious free moving mice (P16-62). Results: DS mice recapitulate the DS patient neuronal phenotype, yet their cardiac phenotype remains unknown. We observed a 2-fold increase in transient and persistent Na+ current (INa) density in DS ventricular myocytes (p<0.01). There was a leftward shift in the voltage dependence of INa availability and conductance (p<0.05), consistent with increased Nav1.5, the predominant cardiac Na+ channel α-subunit. In agreement with increased INa, DS myocytes exhibited increased excitability (assessed by minimum stimulus threshold and upstroke velocity), and prolongation of the action potential duration. In addition, we observed a 2-fold increase in the incidence of early after-depolarizations, which are predicted to promote the initiation of arrhythmias. Twenty one percent of DS mice in our experiments died by P152, with 69% of these dying by P52. In contrast, none of the WT mice died up to 360 days (n=75 for each WT and DS). Finally, continuous radiotelemetric ECG recordings recapitulated the multisystem DS phenotype of seizures, cardiac triggered activity (e.g., premature ventricular complexes), cardiac arrhythmias, bradycardia, and sudden death. Conclusions: These results shed significant insights into how changes in INa may establish a substrate for the initiation of arrhythmias, and provide a potential mechanism for SUDEP in DS.