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 <i>Scn1a</i>, expressed in both the brain and heart. Previously, mutations in <i>Scn1a</i> have been linked to arrhythmia. We used a <i>Scn1a</i> ^-/+ 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 <i>Scn1a</i> ^-/+ hearts had deficits in maximal (<i>p</i> = 0.02) and Complex II-linked respiration (<i>p</i> = 0.03). Male <i>Scn1a</i> ^-/+ mice were also more susceptible to cardiac arrhythmias under increased workload. When isolated cardiomyocytes were subjected to diamide, cardiomyocytes from male <i>Scn1a</i> ^-/+ hearts were less resistant to thiol oxidation. They had decreased survivability compared to <i>Scn1a</i> ^+/+ (<i>p</i> = 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 <i>Scn1a</i> ^-/+ mitochondria accumulated more ROS during hypoxia/reperfusion. This study determines novel sex-linked differences in mitochondrial and antioxidant function in <i>Scn1a</i>-linked DS. Importantly, we found that male <i>Scn1a</i> ^-/+ mice are more susceptible to cardiac arrhythmias than female <i>Scn1a</i> ^-/+ mice. When developing new therapeutics to address SUDEP risk in DS, sex should be considered.