# Cardiogenic and chronobiological mechanisms in seizure-induced sinus arrhythmias

## TL;DR

This study shows that seizure-induced heart rhythm changes can occur due to heart-specific mechanisms and are influenced by sleep-wake and circadian patterns.

## Contribution

The study introduces a new framework showing intrinsic cardiac and circadian mechanisms in seizure-induced arrhythmias, beyond autonomic changes.

## Key findings

- Seizure-induced arrhythmias can arise from intrinsic cardiac dynamics without autonomic changes.
- Daytime sleep increases postictal arrhythmia risk, while nighttime wakefulness increases ictal arrhythmia risk.
- Misalignment of sleep-wake and circadian rhythms disrupts these patterns, highlighting their direct role.

## Abstract

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.

Seizure-induced sinus arrhythmias are potential triggers for sudden unexpected death in epilepsy. Traditionally, these arrhythmias have been considered as secondary effects resulting from changes in autonomic balance. However, our research suggests that the heart itself may play a more active role. Using a mathematical model of pacemaker cells in the mouse heart, we found that seizure-induced sinus arrhythmias can occur without transient autonomic changes during or after seizures. We also investigated the influence of sleep-wake patterns and circadian rhythms on these arrhythmias. Our findings indicate that daytime sleep increases the risk of post-seizure arrhythmias, while nighttime wakefulness makes arrhythmias more likely during a seizure. Importantly, these circadian patterns can be disrupted when sleep-wake cycles are misaligned with circadian rhythms, underscoring the critical role of sleep-wake patterns in shaping seizure-induced sinus arrhythmias. These mechanistic insights may help pave the way for developing novel strategies to manage the risk of sudden unexpected death in epilepsy.