Paulhus Kelsey, Kumar Praveen, Kneale Kelly, Hutson T Noah, Gautier-Hall Nicole M, Shiau Deng-Shan, Watts Megan, Trosclair Krystle, Dhaibar Hemangini A, Dominic Paari, Iasemidis Leonidas, Glasscock Edward
Department of Biological Sciences, Southern Methodist University, Dallas, TX, USA.
Departments of Translational Neuroscience and Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.
J Physiol. 2025 Jan 8. doi: 10.1113/JP287582.
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.
癫痫猝死（SUDEP）是癫痫的一种毁灭性并发症，可能存在性别特异性风险因素，尽管性别与SUDEP的确切关系尚不清楚。为了对此进行研究，我们对Kcna1基因敲除（Kcna1）小鼠进行了研究，这些小鼠缺乏电压门控Kv1.1通道亚基，被广泛用作反映人类关键特征的SUDEP模型。为了评估性别差异，我们首先进行了生存分析、脑电图-心电图记录、癫痫发作阈值测试以及对先前心内起搏数据的回顾性分析。然后，我们应用了一种跨器官的新型建模方法（器官组学）来揭示脑-心通讯中潜在的性别特异性差异。我们的研究结果显示，雌性Kcna1小鼠的寿命明显长于雄性，这表明其SUDEP发生率较低。尽管在癫痫发作频率、持续时间、负担、易感性或发作间期心率变异性方面未发现性别差异，但雌性在自发性癫痫发作期间心动过缓的发生率高于雄性，并且对程序性电刺激诱导的室性快速性心律失常具有抗性。捕获的两例SUDEP事件，一男一女，在两性中均表现出类似的发作期心动过缓模式，进而发展为发作后心肺功能衰竭。超越传统的癫痫发作和心脏指标，器官组学分析表明癫痫发作对脑-心通讯的影响在两性之间存在差异。雌性在发作后比雄性更有效地重置脑-心相互作用。这一发现可能有助于解释女性较低的SUDEP风险，并强调了性别、心脏功能和脑-心通讯在决定SUDEP易感性方面的复杂相互作用。此外，癫痫发作重置措施可能代表一类有前景的用于SUDEP风险分层的生物标志物。要点：雌性Kcna1小鼠比雄性寿命长，表明癫痫猝死（SUDEP）发生率较低。癫痫发作指标或发作间期心率变异性方面不存在性别差异。雌性在癫痫发作期间表现出更多心动过缓，并且对诱导的室性快速性心律失常具有抗性。癫痫发作对脑-心通讯的影响在两性之间存在差异。雌性癫痫发作后能更有效地重置脑-心相互作用，可能降低SUDEP风险。
