Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms, and clinical significance

Abstract

There is growing evidence that cardiac dysfunction in patients with chronic epilepsy could play a pathogenic role in sudden unexpected death in epilepsy (SUDEP). Recent animal studies have revealed that epilepsy secondarily alters the expression of cardiac ion channels alongside abnormal cardiac electrophysiology and remodeling. These molecular findings represent novel evidence for an acquired cardiac channelopathy in epilepsy, distinct from inherited ion channels mutations associated with cardiocerebral phenotypes. Specifically, seizure activity has been shown to alter the messenger RNA (mRNA) and protein expression of voltage‐gated sodium channels (Nav1.1, Nav1.5), voltage‐gated potassium channels (Kv4.2, Kv4.3), sodium‐calcium exchangers (NCX1), and nonspecific cation‐conducting channels (HCN2, HCN4). The pathophysiology may involve autonomic dysfunction and structural cardiac disease, as both are independently associated with epilepsy and ion channel dysregulation. Indeed, in vivo and in vitro studies of cardiac pathology reveal a complex network of signaling pathways and transcription factors regulating ion channel expression in the setting of sympathetic overactivity, cardiac failure, and hypertrophy. Other mechanisms such as circulating inflammatory mediators or exogenous effects of antiepileptic medications lack evidence. Moreover, an acquired cardiac channelopathy may underlie the electrophysiologic cardiac abnormalities seen in chronic epilepsy, potentially contributing to the increased risk of malignant arrhythmias and sudden death. Therefore, further investigation is necessary to establish whether cardiac ion channel dysregulation similarly occurs in patients with epilepsy, and to characterize any pathogenic relationship with SUDEP.

KCNQ2-Neonatal Epileptic Encephalopathy Complicated by Ventricular Tachycardia: A Case Report

“…Another possible explanation for the occurrence of ventricular tachycardia in patients with epilepsy, according to recent literature, is that through certain mechanisms yet unknown, epilepsy has caused a "pro-arrhythmic" state. For example, animal studies have shown that seizure activity alters the expression of ion channels in the heart, leading to abnormal ventricular repolarization and greater susceptibility to ventricular arrythmias and QTc prolongation (15).…”

Sudden cardiac death in children and young adults without structural heart disease: a comprehensive review

“…Recent meta-analysis by Chahal et al suggested potential overlap between SUDEP and arrhythmogenic SCD with a common genetic ion channel abnormality that affects electrophysiology of both neurons and cardiomyocytes (cardiocerebral ion channelopathy) (Chahal et al, 2020), also supported by some case reports (Heron et al, 2010;Parisi et al, 2013). Acquired myocardial alteration secondary to refractory epilepsy may enhance vulnerability to develop lethal ventricular arrhythmias (Li et al, 2019;Verrier et al, 2020). The mechanisms underlying epilepsy-induced SCD are multifactorial and, in part, attributed to a dynamic interplay between heart and CNS (Li et al, 2019;Tolstykh and Cavazos, 2013).…”

“…Acquired myocardial alteration secondary to refractory epilepsy may enhance vulnerability to develop lethal ventricular arrhythmias (Li et al, 2019;Verrier et al, 2020). The mechanisms underlying epilepsy-induced SCD are multifactorial and, in part, attributed to a dynamic interplay between heart and CNS (Li et al, 2019;Tolstykh and Cavazos, 2013). Hefti et al performed detailed neuropathological investigations and reported that nearly half of children with unexplained death (n = 69) had hippocampal malformation (Hefti et al, 2016).…”

Prognostic impact of misdiagnosis of cardiac channelopathies as epilepsy

“…studies have deeply investigated the pathophysiology of SUDEP, and there is agreement that cardiac dysfunction plays a major role. [19] These studies have demonstrated that a severe depression of the cardiac and respiratory centers may arise after a generalized tonic-clonic seizure, particularly among young patients, and this fact can provoke severe hypoxemia and/ or hypotension, leading to an instant death [20]. On the other hand, among cardiac dysfunction causes there is lack of evidence for the existence of malignant ventricular arrhythmias in the context of epilepsy.…”