Cardiac Injury during Kainic Acid Induced Seizures: Effects of Gender on ECG

Abstract

Epilepsy is associated with an increased mortality rate. In 7 to 17% of epileptics, the cause of death is unknown and this has been termed sudden unexplained death in epilepsy (SUDEP). Seizure-induced cardiac changes have been implicated in the pathophysiology of SUDEP and impaired autonomic regulation is not uncommon in epilepsy. Epileptic patients generally present with a higher heart rate than healthy individuals and tachycardia is frequently reported during seizure activity. Ictal bradycardia is rare, occurring in ~2% of seizures. It is hypothesised that seizures result in a surge of sympathetic activity which leads to tachycardia and heart damage. SUDEP is more prevalent in males than females and oestrogen is associated with cardio- and neuro- protective effects. Therefore it is expected that seizure severity, arrhythmias and cardiac pathology will be higher in males. In this study, kainic acid (KA, 10 mg/kg, s.c.) was used to induce seizures in male and female Sprague-Dawley rats. Electrocardiograph (ECG), electrocorticograph (ECoG) and behavioural data were recorded simultaneously for 3 hours post KA administration. KA administration resulted in a rapid significant decrease in heart rate (>30%) which lasted for 30-60 min. Bradycardia was associated with hypoactivity and low seizure behaviours. At 100 min post KA dosing, seizure severity increased resulting in an elevated cumulative behavioural seizure score (Level 3+) in conjunction with an increase in heart rate (20%). Wet dog shakes were the most commonly observed behaviour in males while females exhibited higher seizure behaviours such as myoclonic jerks, foaming and rearing. Tonic-clonic seizures were only observed in female KA animals. ECoG traces were analysed by Fast Fourier Transformation of different frequency bands. Females showed greater increases in power across all ECoG frequency bands. The greatest increase occurred in the theta band (4.75-6.75 Hz) which is associated with hippocampal activity. The P wave showed the largest ECG change during seizure activity. In males the P wave duration significantly decreased by 30-40% while no change was observed in females. In females significant decreases in P wave amplitude of up to 50% were observed while no significant changes occurred in males following KA administration. A prolonged PR interval was also present in females during bradycardia and tachycardia. Gender specific alterations in the QTc interval were also observed, with QTc prolongation occurring in males and QTc shortening in females. Histological examination of apical and mid-plane myocardium found that KA induced seizures resulted in left ventricular pathology observed by the presentation of oedema, inflammatory cell infiltration, intra-cardiac haemorrhage and myofibril vacuolisation 48 hours post KA. The results from this study demonstrate that KA induced seizures were associated with altered cardiac activity as observed by heart rate and ECG changes. Seizure induced tachycardia may predispose the subject to fatal arrhythmias and myocardial damage, whereas bradycardia leading to asystole could also be implicated in SUDEP. Gender differences were also apparent with females exhibiting more severe seizure activity and greater alterations in ECG variables which is in contrast to preliminary clinical data. The findings from this study suggest that either testosterone has a protective effect or oestrogen may have pro-convulsant effects which enhance seizure induced changes.