Cardiogenic and chronobiological mechanisms in seizure-induced sinus arrhythmias

Seizure-induced cardiac arrhythmias, such as ictal (during seizure) or postictal (post-seizure) sinus arrhythmias, are potential triggers for sudden unexpected death in epilepsy. Traditionally, these arrhythmias have been attributed to changes in autonomic balance during ictal or postictal phases, as per the neurogenic mechanism. However, it remains unclear if these arrhythmias may involve intrinsic cardiogenic mechanisms. Furthermore, while circadian and sleep-wake patterns influence both neurogenic and cardiogenic mechanisms, a direct mechanistic link to seizure-induced arrhythmias remains to be established. In this study, we utilized a mathematical model of mouse sinoatrial nodal cell pacemaking and an autonomic clamping protocol, to dissect neurocardiogenic mechanisms in seizure-induced sinus arrhythmias and to test the hypothesis that circadian and sleep-wake rhythms directly modulate cellular susceptibility to these arrhythmias. Our simulations revealed that, in the context of altered autonomic levels associated with seizure progression, diverse seizure-induced sinoatrial nodal cell firing patterns during ictal or postictal phases can be triggered directly by intrinsic cardiac dynamics, without the need for dynamical changes in within-phase autonomic activities. This finding highlights the distinct roles of neurogenic and cardiogenic mechanisms in shaping sinoatrial nodal cell firing patterns, challenging the predominance of the neurogenic mechanism. This neurocardiogenic framework also successfully captures distinct circadian and vigilance state patterns of seizure-induced arrhythmias. Specifically, while daytime sleep predisposed sinoatrial nodal cells to postictal sinus arrhythmias, nighttime wakefulness promotes ictal sinus arrhythmias. However, these circadian patterns can be disrupted when sleep-wake cycles are decoupled from circadian rhythms, supporting the hypothesis that sleep-wake patterns can directly be a key determinant of seizure-induced sinus arrhythmias. Our findings may facilitate the development of novel therapeutic strategies for managing the risk of sudden unexpected death in epilepsy.