Sex-specific differences in mortality and neurocardiac interactions in the Kv1.1 knockout mouse model of sudden unexpected death in epilepsy (SUDEP)

Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy with possible sex-specific risk factors, although the exact relationship between sex and SUDEP remains unclear. To investigate this, we studied Kcna1 knockout (Kcna1^-/-) mice, which lack voltage-gated Kv1.1 channel subunits and are widely used as a SUDEP model that mirrors key features in humans. To assess sex differences, we first performed survival analysis, EEG-ECG recordings, seizure threshold testing and retrospective analysis of previous intracardiac pacing data. We then applied a novel modelling approach across organs (organomics) to uncover potential sex-specific differences in brain-heart communication. Our findings revealed female Kcna1^-/- mice have significantly longer lifespans than males, suggesting lower SUDEP rates. Although no sex differences were found in seizure frequency, duration, burden, susceptibility or interictal heart rate variability, females showed a higher incidence of bradycardia during spontaneous seizures than males, as well as resistance to inducible ventricular tachyarrhythmias in response to programmed electrical stimulation. Two captured SUDEP events, one per sex, displayed similar patterns of ictal bradycardia in both sexes, progressing to postictal cardiorespiratory failure. Going beyond traditional seizure and cardiac metrics, organomics analysis revealed that seizures affect brain-heart communication differently between sexes. Females exhibited more effective resetting of brain-heart interactions postictally than males. This finding may contribute to the lower SUDEP risk in females and underscores the complex interplay between sex, cardiac function and brain-heart communication in determining SUDEP susceptibility. Furthermore, seizure-resetting measures could represent a promising class of biomarkers for SUDEP risk stratification. KEY POINTS: Female Kcna1^-/- mice live longer than males, suggesting lower sudden unexpected death in epilepsy (SUDEP) rates. There are no sex differences in seizure metrics or interictal heart rate variability. Females show more bradycardia during seizures and are resistant to inducible ventricular tachyarrhythmias. Seizures affect brain-heart communication differently between the sexes. Seizures in females reset brain-heart interactions more effectively postictally, potentially lowering SUDEP risk.