Sex Differences in Cardiac Mitochondrial Respiration and Reactive Oxygen Species Production May Predispose 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 , expressed in both the brain and heart. Previously, mutations in have been linked to arrhythmia. We used a 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 hearts had deficits in maximal ( = 0.02) and Complex II-linked respiration ( = 0.03). Male mice were also more susceptible to cardiac arrhythmias under increased workload. When isolated cardiomyocytes were subjected to diamide, cardiomyocytes from male hearts were less resistant to thiol oxidation. They had decreased survivability compared to ( = 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 mitochondria accumulated more ROS during hypoxia/reperfusion. This study determines novel sex-linked differences in mitochondrial and antioxidant function in -linked DS. Importantly, we found that male mice are more susceptible to cardiac arrhythmias than female mice. When developing new therapeutics to address SUDEP risk in DS, sex should be considered.