Abstracts

Rationale: Mutations in voltage-gated Na⁺ channels (VGSCs) are associated with epileptic encephalopathies (EE), and affected individuals are at increased risk for Sudden Unexpected Death in Epilepsy (SUDEP). While the underlying mechanisms of SUDEP remain elusive, a growing body of evidence suggests that cardiac arrhythmias resulting from mutant VGSCs expressed in autonomic nerve and/or cardiac myocytes play an important role. Early Infantile Epileptic Encephalopathy Type 13 (EIEE13) is linked to mutations in SCN8A, encoding the TTX-sensitive VGSC Nav1.6. In the heart, Nav1.6 is preferentially expressed at the t-tubules where it modulates excitation-contraction coupling. Our published work in the Scn8a^N1768D/+ (D/+) mouse model of EIEE13 demonstrated increased susceptibility to cardiac arrhythmias. In addition, D/+ mice had decreased heart rate (HR) compared to WT, suggesting parasympathetic hyperexcitability, and showed dramatic bradycardia ~36 h prior to SUDEP. Thus, cardiac arrhythmias and altered autonomic tone may impact SUDEP risk in EIEE13 mice. Methods: 2 WT and 3 Scn8a^N1768D/+ littermate mice were implanted with radiotelemetry ECG devices  and continuously recorded for up to 60 days post implantation. A 24-hour recording period was evaluated once per week for at least 2 weeks. Results: WT and D/+ mice demonstrated normal circadian changes in HR, with HR peaking in during the dark cycle. During the 2 weeks of recordings analyzed, no differences in HR between the 2 D/+ mice that were later observed to undergo SUDEP vs. the one that did not over the entire 60 day recording period. Analysis of 24-hour ECG data in the D/+ mouse that did not undergo SUDEP showed multiple runs of ventricular tachycardia throughout the day. In contrast,  there were only minimal premature ventricular complexes and only a single isolated run of short-lived ventricular tachycardia in either of the WT mice investigated. When arrhythmias were scored based on frequency and severity, D/+ mice had a higher score than WT. Further analysis of one of the D/+ mice that underwent SUDEP demonstrated that motion artifacts in response to seizures were associated with episodes of bradycardia, which transitioned to tachycardia that persisted following the seizure. Over the same 24 hour period, WT mice had higher HR variability (HRV) than D/+ mice, with the lowest HRV observed in D/+ mice that later underwent SUDEP. Analysis of HRV over a 1-hour period at times of minimal and maximal heart rates, respectively, suggested that the LF/HF ratio is reduced in D/+ mice compared to WT, suggesting sympathetic/parasympathetic imbalance in addition to increased arrhythmia susceptibility. Conclusions: In this study, we show that EIEE13 mouse hearts are intrinsically more susceptible to arrhythmogenic substrates and EIEE13 mice have cardiac arrhythmias that include ventricular tachycardia. In addition, reduced HRV may be associated with SUDEP in this mouse model. Taken together with our previously published results, we propose that cardiac arrhythmias and autonomic imbalance may contribute to the mechanism of SUDEP in EIEE13. Funding: This work was funded by Wishes for Elliot/American Epilepsy Society postdoctroal fellowship to CRF and U01 NS090364 to LLI.