Altered cardiac structure and function is related to seizure frequency in a rat model of chronic acquired temporal lobe epilepsy

Powell, Kim L.; Liu, Zining; Curl, Claire L.; Raaijmakers, A.; Sharma, Prerana; Braine, Emma L.; Gomes, Flávia Maria Medeiros; Sivathamboo, Shobi; Macefield, Vaughan G.; Casillas‐Espinosa, Pablo M.; Jones, Nigel C.; Delbridge, L.; O’Brien, Terence J.

doi:10.1016/j.nbd.2021.105505

Cited by 10 publications

(9 citation statements)

References 41 publications

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“…Studies have shown that chronic epilepsy can lead to hypoxemia and the increase of catecholamine, causing damage of the heart and vascular, resulting in cardiac electrical, and mechanical dysfunction [23,24] . Some fatal incentives may be the acidosis caused by persistent hypoxemia and hypercapnia, leading to bradycardia or cardiac arrest, while in others it may be the seizures due to malignant arrhythmias [25] .…”

Section: Discussionmentioning

confidence: 99%

“…Relevant clinical data have found that paroxysmal arrhythmias (including arrest, atrioventricular block, and rare atrial and ventricular fibrillation) usually occur after convulsive episodes and are often associated with (near) SUDEP 37 . Studies have shown that chronic epilepsy can lead to hypoxemia and the increase of catecholamine, causing damage to the heart and vascular, resulting in cardiac electrical, and mechanical dysfunction 38, 39 . Some fatal incentives may be the acidosis caused by persistent hypoxemia and hypercapnia, leading to bradycardia or cardiac arrest, while in others it may be the seizures due to malignant arrhythmias 40 .…”

Section: Discussionmentioning

confidence: 99%

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The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

Lian

et al. 2022

Preprint

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Sudden unexpected death of epilepsy (SUDEP) is the key cause of of death in patients with epilepsy. Due to the complicated pathogenesis of SUDEP, however, the exact mechanism of SUDEP remains elusive. Currently, although it is recognized that the seizure-induced respiratory arrest (S-IRA) may be a main cause for SUDEP, other factors resulting in SUDEP can not be excluded e.g arrhythmias. Our previous findings indicated that the incidence of seizure-induced respiratory arrest S-IRA and SUDEP evoked by acoustic stimulation or pentetrazol (PTZ) injection was significantly reduced by atomoxetine, a norepinephrine reuptake inhibitor (NRI), suggesting that noradrenergic neurotransmission modulates S-IRA and SUDEP. Given that norepinephrine acts on the central and peripheral target to modulate respiratory and circulation function by targeting adrenergic receptor α and beta (a-AR and β-AR) and the arrhythmias can be contributed to SUDEP. Meanwhile, to further test whether cardiac factors are implicated in S-IRA and SUDEP, we choose esmolol hydrochloride, a selective antagonist of beta-1 adrenergic receptor (β1-AR) to test it in our models. Our findings demonstrated that the lower incidence of S-IRA and SUDEP evoked by acoustic stimulation or PTZ in DBA/1 mice by administration with atomoxetine was significantly reversed by intraperitoneal (IP) of esmolol hydrochloride. Importantly, the data of electrocardiogram (ECG) showed that the cardiac arrhythmia evoked by acoustic stimulation including the ventricular tachycardia, ventricular premature beat and atrioventricular block and administration of atomoxetine significantly reduced theses arrhythmias and the incidence of S-IRA and SUDEP in our models. Thus, the dysfunction of respiratory and circulation may be implicated in the pathogenesis of S-IRA and SUDEP hand in hand and enhancing central norepinephrinergic neurotransmission contributes to inhibition of seizure-induced respiratory arrest by targeting β1-AR locating in the cardiomyocytes. Our findings will show a new light on decoding the pathogenesis of SUDEP. Keywords: sudden unexpected death in epilepsy (SUDEP); seizure-induced respiratory arrest S-IRA); esmolol hydrochloride (Esmolol); Electrocardiogram (ECG); locus coeruleus (LC); cardiac arrhythmia; pentetrazol (PTZ)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

Lian

et al. 2022

Preprint

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“…Powell and colleagues 3 turned to a kainic acid–induced rat model of acquired chronic temporal lobe epilepsy (TLE) in order to shed light on cardiac processes that ensue in response to recurrent seizures. The authors performed a detailed analysis of cardiac function and structure in a sample of nine animals with chronic epilepsy and in eight saline treated controls.…”

Section: Commentarymentioning

confidence: 99%

When Seizures Trigger “Extreme (Cardiac) Makeover”

Goldman

2022

Epilepsy Curr

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Objective This study aimed to prospectively examine cardiac structure and function in the kainic acid-induced post-status epilepticus (post-KA SE) model of chronic acquired temporal lobe epilepsy (TLE), specifically to examine for changes between the pre-epileptic, early epileptogenesis and the chronic epilepsy stages. We also aimed to examine whether any changes related to the seizure frequency in individual animals. Methods Four hours of SE was induced in 9 male Wistar rats at 10 weeks of age, with 8 saline treated matched control rats. Echocardiography was performed prior to the induction of SE, two- and 10-weeks post-SE. Two weeks of continuous video-EEG and simultaneous ECG recordings were acquired for two weeks from 11 weeks post-KA SE. The video-EEG recordings were analyzed blindly to quantify the number and severity of spontaneous seizures, and the ECG recordings analyzed for measures of heart rate variability (HRV). PicroSirius red histology was performed to assess cardiac fibrosis, and intracellular Ca2+ levels and cell contractility were measured by microfluorimetry. Results All 9 post-KA SE rats were demonstrated to have spontaneous recurrent seizures on the 2-week video- EEG recording acquired from 11 weeks SE (seizure frequency ranging from .3 to 10.6 seizures/day with the seizure durations from 11 to 62 s), and none of the 8 control rats. Left ventricular wall thickness was thinner, left ventricular internal dimension was shorter, and ejection fraction was significantly decreased in chronically epileptic rats, and was negatively correlated to seizure frequency in individual rats. Diastolic dysfunction was evident in chronically epileptic rats by a decrease in mitral valve deceleration time and an increase in E/E′ ratio. Measures of HRV were reduced in the chronically epileptic rats, indicating abnormalities of cardiac autonomic function. Cardiac fibrosis was significantly increased in epileptic rats, positively correlated to seizure frequency, and negatively correlated to ejection fraction. The cardiac fibrosis was not a consequence of direct effect of KA toxicity, as it was not seen in the 6/10 rats from separate cohort that received similar doses of KA but did not go into SE. Cardiomyocyte length, width, volume, and rate of cell lengthening and shortening were significantly reduced in epileptic rats. Significance The results from this study demonstrate that chronic epilepsy in the post-KA SE rat model of TLE is associated with a progressive deterioration in cardiac structure and function, with a restrictive cardiomyopathy associated with myocardial fibrosis. Positive correlations between seizure frequency and the severity of the cardiac changes were identified. These results provide new insights into the pathophysiology of cardiac disease in chronic epilepsy, and may have relevance for the heterogeneous mechanisms that place these people at risk of sudden unexplained death.

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“…Seizure-related dysfunction including repetitive ischemia and catecholaminergic toxicity can potentially lead to myocardial remodeling and fibrosis, which may form the substrate for cardiac arrhythmias. 8,9 Patients with a history of chronic and drug-resistant epilepsy may therefore be at greater risk of cardiac rhythm disturbances, which may go undetected in routine epilepsy and cardiac investigations. We conducted a prospective cohort study of long-term cardiac monitoring in patients with chronic drug-resistant epilepsy with video-EEG–confirmed epilepsy to determine the incidence of serious cardiac arrhythmias in this population.…”

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confidence: 99%

Serious Cardiac Arrhythmias Detected by Subcutaneous Long-term Cardiac Monitors in Patients With Drug-Resistant Epilepsy

et al. 2022

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Background:Epilepsy is associated with an increased risk of cardiovascular disease and premature mortality, including sudden unexpected death in epilepsy (SUDEP). Of concern, serious cardiac arrythmias might go undetected from routine epilepsy and cardiac investigations.Methods:This prospective cohort study aimed to detect cardiac arrhythmias in patients with chronic drug-resistant epilepsy (≥5 years duration) using subcutaneous cardiac monitors for a minimum follow-up duration of 12 months. Participants with known cardiovascular disease or those with abnormal 12-lead electrocardiograms were excluded. The device was programmed to automatically record episodes of tachycardia ≥140 beats per minute (bpm), bradycardia ≤40 bpm for ≥3 seconds, or asystole ≥3 seconds.Findings:Thirty-one patients underwent subcutaneous cardiac monitoring for a median recording duration of 2.2 years (range 0.5 to 4.2). During this time, 28 (90.3%) patients had episodes of sustained (≥30s) sinus tachycardia, 8/31 (25.8%) had sinus bradycardia, and 3 (9.7%) had asystole. Three (9.7%) patients had serious cardiac arrhythmias requiring additional cardiac interventions. Among them, two patients had prolonged sinus arrest and ventricular asystole (>6 seconds), leading to pacemaker insertion in one; and another patient with an epileptic encephalopathy had multiple episodes of recurrent non-sustained polymorphic ventricular tachycardia and bundle branch conduction abnormalities. The time to first detection of a clinically significant cardiac arrhythmia ranged between 1.2 to 26.9 months following cardiac monitor insertion.Conclusions:Implantable cardiac monitors detected a high incidence of clinically significant cardiac arrhythmias in patients with chronic drug resistant epilepsy, which may contribute to the incidence of premature mortality including SUDEP.

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Altered cardiac structure and function is related to seizure frequency in a rat model of chronic acquired temporal lobe epilepsy

Cited by 10 publications

References 41 publications

The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

The Interaction Between The Noradrenergic Neurons In The Locus Coeruleus And Beta-1 Adrenergic Receptor (β1-AR) In The Cardiomyocytes Was Implicated In Modulating SUDEP

When Seizures Trigger “Extreme (Cardiac) Makeover”

Serious Cardiac Arrhythmias Detected by Subcutaneous Long-term Cardiac Monitors in Patients With Drug-Resistant Epilepsy

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