Abstracts

Rationale:
Status epilepticus (SE) is a prevalent disorder associated with significant morbidity, including the development of epilepsy and mortality. Studies indicate that lethal cardiac arrhythmias contribute to death following SE as well as sudden unexpected death in epilepsy (SUDEP). A wide range of potentially lethal cardiac arrhythmias (i.e. tachycardia, bradycardia, asystole, and atrioventricular blocks) are observed in SE and epilepsy patients. Tachycardia is the most commonly reported seizure related arrhythmia, but asystole and bradycardia have also been observed and predominantly occur ictally in people with temporal lobe epilepsy (TLE). We previously characterized ictal and interictal cardiac arrhythmogenesis following SE using continuous electrocardiography (EKG) and video electroencephalography (vEEG) recordings throughout a 14-day monitoring period in an intrahippocampal chemoconvulsant mouse model that develops epilepsy and mimics TLE. SE animals had an increased mortality rate, interictal tachycardia, and heart rhythm abnormalities when compared to control mice during the 14-day monitoring period. Our current study examines whether abnormalities persist in the months following SE.
Method:
Intrahippocampal administration of kainate results in SE followed by the development of epilepsy associated with hippocampal neuron loss and mossy fiber sprouting and closely models what occurs in humans with TLE. Male C57BL/6J mice were anesthetized with isoflurane and placed on a stereotaxic apparatus for implantation of a guide cannula and electrodes at 2-4 months of age. The guide cannula was placed into the hippocampus for the administration of kainate in a freely moving and awake animal. To simultaneously investigate alterations in EKG and vEEG signals following SE, recording and reference electrodes were placed on the chest for EKG and three electrodes implanted to record hippocampal and cortical activity. After a week of recovery, mice were recorded continuously for baseline EKG and vEEG activity. Then, animals received saline or kainate via the intrahippocampal cannula and were EKG and vEEG monitored. Recordings were analyzed at day (d)33 and d60 following SE-induction.
Results:
Persistent seizure and spike activity was present in SE animals when compared to a control animal at d33 and d60 post-SE. SE animals also had an increased heart rate and number of cardiac arrhythmias compared to control animals. Premature ventricular contractions, premature atrial contractions, sinus arrhythmias, and sinus pauses were observed interictally at d33 and d60 following SE-induction.
Conclusion:
Our preliminary findings in these later timepoints are similar to what we found at d14 following SE-induction. All timepoints demonstrated tachycardia, cardiac arrhythmias, and epileptiform activity in SE compared to control animals. These data suggest that the early cardiac arrythmias are persistent and potentially permanent changes in cardiac regulation. Further research into persistent electrophysiological alterations will give insight and direction for candidate cardiac molecular mechanisms with the aim of preventing or ameliorating cardiac dysfunction in epilepsy patients.
Funding:
:This work was supported by National Institutes of Health (NIH) Neurological Disorders and Stroke (NINDS) R21-NS104665.