Sex differences in cardiac mitochondrial respiration and reactive oxygen species production may predispose Scn1a−/+ mice to cardiac arrhythmias and Sudden Unexpected Death in Epilepsy

Dravet Syndrome (DS) is a pediatric-onset epilepsy with an elevated risk of Sudden Unexpected Death in Epilepsy (SUDEP). Most individuals with DS possess mutations in the voltage-gated sodium channel gene Scn1a, expressed in both the brain and heart. Previously, mutations in Scn1a have been linked to arrhythmia. We used a Scn1a^−/+ DS mouse model to investigate changes to cardiac mitochondrial function that may underlie arrhythmias and SUDEP. We detected significant alterations in mitochondrial bioenergetics that were sex-specific. Mitochondria from male Scn1a^−/+ hearts had deficits in maximal (p = 0.02) and Complex II-linked respiration (p = 0.03). Male Scn1a^−/+ mice were also more susceptible to cardiac arrhythmias under increased workload. When isolated cardiomyocytes were subjected to diamide, cardiomyocytes from male Scn1a^−/+ hearts were less resistant to thiol oxidation. They had decreased survivability compared to Scn1a^+/+ (p = 0.02) despite no whole-heart differences. Lastly, there were no changes in mitochondrial ROS production between DS and wild-type mitochondria at basal conditions, but Scn1a^−/+ mitochondria accumulated more ROS during hypoxia/reperfusion. This study determines novel sex-linked differences in mitochondrial and antioxidant function in Scn1a-linked DS. Importantly, we found that male Scn1a^−/+ mice are more susceptible to cardiac arrhythmias than female Scn1a^−/+ mice. When developing new therapeutics to address SUDEP risk in DS, sex should be considered.