Cardiac dysfunction in epilepsy: a candidate mechanism in sudden unexpected death

描述（由申请人提供）：癫痫猝死（SUDEP）的特征是癫痫患者的突然意外、非创伤性和非溺水死亡。SUDEP是癫痫患者死亡的最常见原因。有报告称，在重度癫痫患者中，SUDEP的发生率高达1/200。然而，这可能是一个低估，因为SUDEP病例的实际数量被认为是少报的。在SUDEP的候选机制中，心脏病因是一个很大的可能性。由心律失常如室性心动过速和纤维性颤动引起的心脏性猝死与负责调节心率和节律的心脏离子通道的改变有关。这些类型的变化也与心脏病理学相关，这被认为是心律失常的风险因素。自主神经系统，特别是交感神经系统活动的不平衡被认为是室性快速性心律失常发生的重要因素。许多临床研究支持癫痫患者存在自主神经改变的概念，并且这在SUDEP组中可能更明显。因此，可能与自主神经功能失调和心脏离子通道重塑相关的心脏致心律失常事件是SUDEP的一个强有力的潜在机制。在概述的研究中，我们将利用获得性癫痫的毛果芸香碱模型，该模型概括了人类慢性癫痫的许多特征，包括无端癫痫发作、心动过速和猝死风险增加。我们在这些动物中的初步研究表明，存在心脏血管生成和离子通道重塑。通过来自癫痫和心脏电生理学领域的研究人员之间的跨学科合作，我们将测试癫痫导致心脏分子重塑和相关的心脏发生倾向的假设。我们认为，异常的自主神经系统功能是这些变化的候选调解人。

DESCRIPTION (provided by applicant): Sudden unexpected death in epilepsy (SUDEP) is characterized by sudden unexpected, nontraumatic, and nondrowning deaths in epileptic patients. SUDEP is the most common cause of mortality in individuals with epilepsy. There are reports of the incidence of SUDEP being as high as 1 in 200 in patients with severe epilepsy. However, this is likely to be an underestimate as the actual number of SUDEP cases is thought to be underreported. Among the candidate mechanisms for SUDEP, cardiac etiologies are a strong possibility. Sudden cardiac death resulting from cardiac arrhythmia such as ventricular tachycardia and fibrillation is associated with alterations in cardiac ion channels responsible for the regulation of the heart rate and rhythm. These types of changes also occur in association with cardiac pathology, which is considered a risk factor for arrhythmia. Imbalance in the autonomic nervous system, specifically sympathetic nervous system activity is considered an important player in the development of ventricular tachyarrhythmias. A number of clinical studies support the concept that autonomic alterations exist in individuals with epilepsy and that this may be more pronounced in the group with SUDEP. Thus, cardiac arrhythmogenic events, possibly related to autonomic dysregulation and cardiac ion channel remodeling represent a strong candidate mechanism underlying SUDEP. In the studies outlined we will utilize the pilocarpine model of acquired epilepsy that recapitulates a number of the features of chronic epilepsy in humans, including unprovoked seizures, tachycardia, and an increased risk of sudden death. Our pilot studies in these animals reveal that there is cardiac arrhythmogenesis and ion channel remodeling. Through an interdisciplinary collaboration between investigators from the fields of epilepsy and cardiac electrophysiology we will test the hypothesis that epilepsy results in cardiac molecular remodeling and an associated propensity for arrhythmogenesis. We propose that aberrant autonomic nervous system function is a candidate mediator for these changes.