Abstracts

Rationale: Intractable seizures are a major risk factor for sudden unexpected death in epilepsy (SUDEP). Although the precise mechanism(s) of SUDEP have not been fully elucidated, several lines of investigation suggest that lethal cardiac arrhythmias may contribute. However, the effects of multiple seizures on arrhythmogenic processes in the heart are not known. These studies were designed to determine if repeated seizures in a rat model of epilepsy produce arrhythmogenic electrical activity in the heart, and increase susceptibility to experimentally-induced ventricular arrhythmias. Methods: Male, Spague-Dawley rats underwent hippocampal kindling and were allowed to recover for one week. At this time, some animals were administered additional hippocampal stimulations to induce multiple motor seizures (K-MS), 3 days per week for two weeks. The remaining kindled animals did not receive additional stimulations (K-Cont). Following the final stimulation session, animals were anesthetized and implanted with subcutaneous electrodes in the chest for electrocardiographic (ECG) evaluation of cardiac function, and with a catheter in the femoral vein for infusion of the arrhythmogenic agent aconitine. Mean QT interval (total duration of cardiac ventricular electrical activity/heart beat) was measured from ECG recordings obtained over a 10 min period. QT intervals were corrected for heart rate (QTc), and the mean dispersion of QTc (QTcd = max QTc- min QTc) was calculated. Extended QTc and/or QTcd are both clinically validated predictors of increased risk of ventricular arrhythmias and sudden cardiac death in humans and in animal models of cardiac pathology. Susceptibility to cardiac arrhythmias was subsequently determined directly by measuring latency to the first premature ventricular contraction (multiple ventricular contractions with no associated atrial contraction) during iv infusion of a constant dose of aconitine (5ug/kg/min) for 7 min. These procedures are routinely used to evaluate susceptibility to cardiac arrhythmias in rodents. Results: K-MS animals experienced approximately 60 seizures beyond kindling during the 2 wks of hippocampal stimulations. Both QTc (K-Cont=101±3 ms; K-MS=120±5 ms) and QTcd (K-Cont=8.9±1.1 ms; K-MS=20.0±3.6 ms) were significantly (p<0.05) longer in K-MS animals compared to K-Cont. Furthermore, the latency to the 1st PVC was significantly shorter in K-MS (180±44 sec) than in K-Cont (385±25 sec) rats. Conclusions: These data demonstrate that repeated seizures in an animal model of intractable epilepsy produce alterations in cardiac electrical activity predictive of sudden cardiac death, and increased susceptibility to experimentally-induced ventricular arrhythmias. These findings support the hypothesis that multiple seizures produce progressive, chronic cardiac effects which could culminate in SUDEP.