Myocardial remodeling and susceptibility to ventricular tachycardia in a model of chronic epilepsy

Abstract

SummaryObjectiveSympathetic predominance and ventricular repolarization abnormalities represent epilepsy‐associated cardiac alterations and may underlie seizure‐induced ventricular arrhythmias. Myocardial ion channel and electrical remodeling have been described early in epilepsy development and may contribute to ventricular repolarization abnormalities and excitability. Using the pilocarpine‐induced acquired epilepsy model we sought to examine whether altered myocardial ion channel levels and electrophysiological changes also occur in animals with long‐standing epilepsy.MethodsWe examined myocardial adrenergic receptor and ion channel protein levels of epileptic and age‐matched sham rats (9–20 months old) using western blotting. Cardiac electrical properties were examined using optical mapping ex vivo and electrophysiology in vivo. We investigated the propensity for ventricular tachycardia (VT) and the effects of β‐adrenergic blockade on ventricular electrical properties and excitability in vivo.ResultsIn animals with long‐standing epilepsy, we observed decreased myocardial voltage‐gated K+ channels Kv4.2 and Kv4.3, which are known to underlie early ventricular repolarization in rodents. Decreased β1 and increased α1A adrenergic receptor protein levels occurred in the myocardium of chronically epileptic animals consistent with elevated sympathetic tone. These animals exhibited many cardiac electrophysiological abnormalities, represented by longer QRS and corrected QT (QTc) intervals in vivo, slower conduction velocity ex vivo, and stimulation‐induced VT. Administration of a β‐adrenergic antagonist late in epilepsy was beneficial, as the therapy shortened the QTc interval and decreased stimulation‐induced VT.SignificanceOur findings demonstrate that myocardial ion channel remodeling and sympathetic predominance, risk factors for increased ventricular excitability and arrhythmias, persist in chronic epilepsy. The beneficial effects of β‐adrenergic antagonist treatment late in the course of epilepsy suggest that attenuating elevated sympathetic tone may represent a therapeutic target for ameliorating epilepsy‐associated cardiac morbidity.

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

“…Whole heart myocardial K v 4.2 protein expression was decreased 2 weeks postchemoconvulsant induction of SE in animals . Moreover, this animal model of acquired epilepsy exhibited reductions in both whole heart cardiac K v 4.2 and K v 4.3 expression 7‐18 months post‐SE, a time period modeling established epilepsy . Concurrent electrophysiologic changes included higher heart rate, longer QRS duration, and slower myocardial conduction velocity.…”

“…Emerging evidence from animal studies indicates that epilepsy may alter the transcriptional expression of ion channels in cardiomyocytes. To date, the ion channels implicated include hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, voltage‐gated potassium channels, voltage‐gated sodium channels, and sodium‐calcium exchangers, as illustrated in Figure . Significantly, this may represent a previously unappreciated form of secondary cardiac dysfunction in epilepsy.…”

“…Evidence of altered cardiac ion channel expression secondary to epilepsy in animals. Animals with acquired epilepsy following chemoconvulsant induction of status epilepticus exhibit altered cardiac messenger RNA (mRNA) and protein expression of HCN 2, K v 4.2, K v 4.3, NCX 1, Na v 1.1, and Na v 1.5 . Animal models of genetic epilepsy exhibit altered cardiac mRNA and protein expression of HCN 2, altered mRNA expression of HCN 4 (in ventricles only), but no change in Na v 1.5 channels…”

“…Notably, molecular changes were accompanied by a lengthening of the ventricular action potential consistent with clinical QTc prolongation, attributed to an increase in sustained late sodium current ( I NaL ) . However, Na v 1.5 expression remained unaltered in (a) whole hearts from post‐SE rats at a later time‐point, and (b) ventricular myocytes from an animal model of Dravet syndrome expressing a human SCN1A mutation . Therefore, cardiac dysregulation of voltage‐gated sodium channels may depend on epilepsy etiology or chronicity.…”

“…Significantly, recent animal studies have reported changes in the transcription and translation of cardiac ion channels secondary to epileptogenesis, accompanied by abnormal cardiac electrophysiology . This has led to the hypothesis that epilepsy secondarily alters cardiac ion channel expression, generating a chronic proarrhythmic state that increases the risk of sudden cardiac death or SUDEP.…”