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Acquired cardiac channelopathies in epilepsy: Evidence, mechanisms, and clinical significance
Author(s) -
Li Michael C. H.,
O'Brien Terence J.,
Todaro Marian,
Powell Kim L.
Publication year - 2019
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16301
Subject(s) - channelopathy , epilepsy , sodium channel , dravet syndrome , medicine , neuroscience , sudden cardiac death , cardiac arrhythmia , epilepsy syndromes , ion channel , sudden death , bioinformatics , biology , atrial fibrillation , chemistry , receptor , sodium , organic chemistry
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 (Na v 1.1, Na v 1.5), voltage‐gated potassium channels (K v 4.2, K v 4.3), sodium‐calcium exchangers ( NCX 1), and nonspecific cation‐conducting channels ( HCN 2, HCN 4). 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 .