Seizures following hippocampal kindling induce QT interval prolongation and increased susceptibility to arrhythmias in rats

doi:10.1016/j.eplepsyres.2013.01.002

Epilepsy Research

Volume 105, Issues 1–2, July 2013, Pages 216-219

https://doi.org/10.1016/j.eplepsyres.2013.01.002 Get rights and content

Summary

The prolonged seizures of status epilepticus produce chronic arrhythmogenic changes in cardiac function. This study was designed to determine if repeated, self-limiting seizures administered to kindled rats induce similar cardiac dysfunction. Multiple seizures administered to rats following hippocampal kindling resulted in cardiac QT interval prolongation and increased susceptibility to experimental arrhythmias. These data suggest that multiple, self-limiting seizures of intractable epilepsy may have cardiac effects that can contribute to sudden unexpected death in epilepsy (SUDEP).

Introduction

Sudden unexpected death in epilepsy (SUDEP) is a major cause of premature death in patients. Although the mechanisms contributing to SUDEP have not been definitively determined, a number of studies have suggested that respiratory distress may be a predominant, precipitating factor, which interacts with cardiac abnormalities to produce potentially lethal arrhythmias. For example, recent reports demonstrate that ictal hypoxemia resulting from depressed respiration is associated with cardiac repolarization abnormalities characterized by QT interval prolongation (Seyal et al., 2011). In addition, another study suggests that ictal hypoventilation contributes to arrhythmias in SUDEP (Bateman et al., 2010). Repolarization abnormalities, such as QT interval prolongation, could provide the cardiac substrate for ictal hypoxemia to induce arrhythmias resulting in SUDEP.

We have previously demonstrated that the protracted seizures of status epilepticus result in long lasting changes in cardiac function that increase susceptibility to arrhythmias, including QT interval prolongation (Bealer et al., 2010, Metcalf et al., 2009). However, the effects of multiple, self-limiting seizures, characteristic of epilepsy, on cardiac function have not been fully defined. The purpose of these experiments was to determine if administration of self-limiting seizures in rats following hippocampal kindling results in a cardiac repolarization abnormality, characterized by QT prolongation, and increased susceptibility to experimental arrhythmias.

Section snippets

Methods

The University of Utah Institutional Animal Care and Use Committee approved all procedures used in these experiments.

Results

K-MS animals were administered between 35 and 48 total seizures during the seizure period.

Heart rates were not different between experimental groups (Cont, 384 ± 13 bpm; K-Cont, 380 ± 17 bpm; K-MS, 395 ± 25 bpm; F_2,20 = 0.13, p = 0.34).

Fig. 1 shows QTc intervals for Cont, K-Cont, and K-MS animals. K-MS rats demonstrated significant QTc interval prolongation compared to both Cont and K-Cont animals (F_2,21 = 11.94, p = 0.0003).

Fig. 2 illustrates the latencies between the initiation of aconitine infusion and the

Discussion

These studies demonstrate that repeated, self-limiting seizures in a kindled rat model of epilepsy can result in long lasting QTc interval prolongation. In addition, the results show that this seizure-induced cardiac repolarization abnormality is associated with enhanced susceptibility to experimental ventricular arrhythmias. It has been proposed that prolongation of the QT interval may increase the potential for SUDEP in patients with chronic epilepsy (Surges et al., 2009, Surges et al., 2010

Conflict of interest

The authors have no disclosures.

Acknowledgements

The authors acknowledge the expert technical assistance of Bethany Pelton. This research was supported by a grant from Citizens United for Research in Epilepsy.

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They can also be used to help understand pathophysiological processes during and following seizures. Experimental models divide into: acute interventions on normal animals (Jefferys et al., 2019; Stewart, 2018; Villiere et al., 2017), chronic models where an experimental intervention induces a chronic epileptic state (Bealer and Little, 2013; Jefferys et al., 2020; Powell et al., 2014; Walker et al., 2017), and genetic models which replicate specific mutations associated with clinical epilepsy and in some cases with cardiac pathophysiology (Glasscock, 2014). We will start with acute models, make some comments on genetic models, and consider chronic models associated with repeated time-limited seizures in the final part of this paper.
The risk factors for SUDEP are undoubtedly heterogenous but the main factor is the frequency of generalized tonic-clonic seizures with apnoea and/or cardiac abnormalities likely precipitating the lethal event. By its very nature modelling SUDEP experimentally is challenging, yet insights into the nature of the lethal event and precipitating factors are vital in order to understand and prevent fatalities. Acute animal models, which induce status epilepticus (SE), can be used to help understand pathophysiological processes during and following seizures, which sometimes lead to death. The most commonly used method to induce seizures and status epilepticus is systemic administration of an ictogenic agent. Microinjection of such agents into restricted regions within the brain induces a more localised epileptic focus and circumvents the risk of direct actions on cardiorespiratory control centres. Both approaches have revealed substantial cardiovascular and respiratory consequences, including death as a result of apnoea, which may be of central origin, obstructive due to laryngospasm or, at least in genetically modified mice, a result of spreading depolarisation to medullary respiratory control centres.
SUDEP is by definition a result of epilepsy, which in turn is diagnosed on the basis of two or more unprovoked seizures. The incidence of tonic-clonic seizures is the main risk factor, raising the possibility that repeated seizures cause cumulative pathological and/or pathophysiological changes that contribute to the risk of SUDEP. Chronic experimental models, which induce repeated seizures that in some cases lead to death, do show progressive development of pathophysiological changes in the myocardium, e.g. prolongation of QT the interval of the ECG or, over longer periods, ventricular hypertrophy. However, the currently available evidence indicates that seizure-related deaths are primarily due to apnoeas, but cardiac factors, particularly cumulative cardiac pathophysiologies due to repeated seizures, are potential contributing factors.
Pediatric Sudden Unexpected Death in Epilepsy: What Have we Learned from Animal and Human Studies, and Can we Prevent it?
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Citation Excerpt :
Several studies have indicated that ictal hypoxemia resulting from depressed respiration can acutely result in cardiac repolarization abnormalities and in SUDEP.13,14 In addition, the study by Bealer and Little15 showed that repeated self-limited seizures in rats, following hippocampal kindling, result in cardiac QT interval prolongation and in increased susceptibility to experimental arrhythmias. This suggests that chronic seizure activity can have cardiac rhythm effects that predispose to SUDEP.
Several factors, such as epilepsy syndrome, poor compliance, and increased seizure frequency increase the risks of sudden unexpected death in epilepsy (SUDEP). Animal models have revealed that the mechanisms of SUDEP involve initially a primary event, often a seizure of sufficient type and severity, that occurs in a brain, which is vulnerable to SUDEP due to either genetic or antecedent factors. This primary event initiates a cascade of secondary events starting, as some models indicate, with cortical spreading depolarization that propagates to the brainstem where it results in autonomic dysfunction. Intrinsic abnormalities in brainstem serotonin, adenosine, sodium-postassium ATPase, and respiratory-control systems are also important. The tertiary event, which results from the above dysfunction, consists of either lethal central apnea, pulmonary edema, or arrhythmia. Currently, it is necessary to (1) continue researching SUDEP mechanisms, (2) work on reducing SUDEP risk factors, and (3) address the major need to counsel families about SUDEP.
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Others have found increased susceptibility to VF by aconitine infusion in the period following status epilepticus or kindling (Bealer and Little, 2013; Metcalf et al., 2009a) in rats. The change in VF susceptibility was found to accompany decreased vagal tone (Metcalf et al., 2009b), QT interval prolongation (Bealer and Little, 2013), and cardiac myofilament damage (Metcalf et al., 2009a). While risk factors for VF have been identified in these models, they do not imply VF is a chief cause of death in these animals.
Cardiac autonomic, conduction, and structural changes may occur in epilepsy and may contribute to sudden unexpected death in epilepsy (SUDEP), e.g. by increasing the risk for ventricular fibrillation (VF). In a model of chronic seizures in rats, we sought to study (1) cardiac and autonomic derangements that accompany the epileptic state, (2) whether chronically seizing rats experienced more significant cardiac effects after severe acute seizures, and (3) the susceptibility of chronically seizing rats to VF arising from autonomic and hypoxemic changes, which commonly occur during seizures. Sprague-Dawely rats were injected with saline or kainic acid to induce chronic seizures. At 2–3 months or 7–11 months after injection, these rats were studied with both 12-lead electrocardiography (to assess heart rate variability and QT dispersion) and echocardiography under ketamine/xylazine or urethane anesthesia. Hearts were subsequently excised, weighed, and examined histologically. Epileptic rats exhibited decreased vagal tone, increased QT dispersion, and eccentric cardiac hypertrophy without significant cardiac fibrosis, especially at 7–11 months post-injection. Of these three findings, vagal tone was inversely correlated with heart weights. Epileptic rats exhibited diminished systolic function compared to controls after severe acute seizures. However, animals with long-standing chronic seizures were less susceptible to autonomic/hypoxemia-driven VF, and their susceptibility inversely correlated with mean left ventricular wall thickness on histology. On the basis of this model, we conclude that cardiac changes accompany epilepsy and these can lead to significant seizure-associated cardiac performance decreases, but these cardiac changes actually lower the probability of VF.
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2013, Epilepsy and Behavior
Seizure-related deaths in children: The expanding spectrum
2021, Epilepsia
Cardiac dysregulation following intrahippocampal kainate-induced status epilepticus
2020, Scientific Reports

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Short communicationSeizures following hippocampal kindling induce QT interval prolongation and increased susceptibility to arrhythmias in rats

Summary

Introduction

Section snippets

Methods

Results

Discussion

Conflict of interest

Acknowledgements

Epilepsy Res.

Life Sci.

Seizure

Brain Res.

Epilepsy Res.

Electroencephalogr. Clin. Neurophysiol.

Lancet Neurol.

Ictal hypoventilation contributes to cardiac arrhythmia and SUDEP: report on two deaths in video-EEG-monitored patients

Epilepsia

Lengthening of corrected QT during epileptic seizures

Epilepsia

Determinants of prolonged QT interval and their contribution to sudden death risk in coronary artery disease: the Oregon sudden unexpected death study

Circulation

Effects of meformin on QT and QTc interval dispersion in diabetic rats

Arq. Bras. Cardiol.

Short communication
Seizures following hippocampal kindling induce QT interval prolongation and increased susceptibility to arrhythmias in rats