Autonomic and cellular mechanisms mediating detrimental cardiac effects of status epilepticus

Abstract

Prolonged seizure activity (status epilepticus; SE) can result in increased susceptibility to lethal ventricular arrhythmias for an extended period of time following seizure termination. SE is accompanied by acute, intense activation of the sympathetic nervous system (SymNS) and results in myocyte myofilament damage, arrhythmogenic alterations in cardiac electrical activity, and increased susceptibility to ventricular arrhythmias. However, the mechanisms mediating the changes in cardiac function, and the specific arrhythmogenic substrate produced during SE are unknown. To determine if detrimental cardiac effects of SE are mediated by SymNS stimulation of the heart, we examined the effects of B-adrenergic blockade (atenolol) during seizure activity on blood pressure, heart rate, myocyte myofilament injury (cardiac troponin I, cTnI), electrocardiographic activity, and susceptibility to arrhythmias. Furthermore, we determined if SE was associated with altered expression of the Kv4.x potassium channels, which are critical for action potential repolarization and thereby contribute significantly to normal cardiac electrical activity. Lithium-pilocarpine induced SE was associated with acute tachycardia, hypertension, and cardiomyocyte damage. Arrhythmogenic alterations in cardiac electrical activity accompanied by increased susceptibility to experimentally induced arrhythmias were evident during the first 2 weeks following SE. Both were prevented by atenolol treatment during seizures. Furthermore, one and two weeks after SE, myocyte ion channel remodeling, characterized by a decreased expression of cardiac Kv4.2 potassium channels, was evident. These data suggest that the cardiac effects of prolonged and intense SymNS activation during SE induce myofilament damage and downregulation of Kv4.2 channels, which alter cardiac electrical activity and increase susceptibility to lethal arrhythmias.

Figure 1

Maximum mean arterial blood pressure (MABP; top panel) and heart rate (beats/minute; bpm; bottom panel) observed during the seizures or a comparable time in control animals (Cont; n=7), control rats administered atenolol (Cont+AT; n=4), vehicle treated animals undergoing status epilepticus (SE; n=10), and status epilepticus animals treated with atenolol (SE+AT; n=5). †, p<0.01 compared to Cont and Cont +AT; **, p<0.01 compared to all other groups.

Figure 2

Concentrations of troponin I in plasma obtained 60 min following the onset of seizures (SE; n=6) and SE animals treated with atenolol (SE+AT; n=6) rats, and at comparable time points in control animals treated with vehicle (Cont; n=4) and atenolol (Cont+AT; n=4) animals. **, p<0.01 compared to all other groups.

Figure 3

QTc duration (top panel) and QTc dispersion (QTcd; bottom panel) observed 12–14 days following treatment in control animals (Cont; n=7), control rats administered atenolol (Cont+AT; n=7), vehicle treated animals undergoing SE (n=8), and SE animals treated with atenolol (SE+AT; n=7). **, p<0.01 compared to all other groups.

Figure 4

Latency between the initiation of aconitine infusion and the 1^st premature ventricular contraction (1^st PVC), ventricular tachycardia (VT), and ventricular fibrillation (VF) measured 12–14 days following treatment in control animals (Cont; n=4), control rats administered atenolol (Cont+AT; n=7), vehicle treated animals undergoing SE (n=6), and SE animals treated with atenolol (SE+AT; n=5). **p<0.01 compared to all other groups.

Figure 5

Western blot analyses of Kv4.2 and Kv4.3 potassium channel proteins in cardiac tissue obtained 1 week (Cont, n=5; SE, n=8) and 2 weeks (Cont, n=8; SE, n=9) following seizure SE or control (Cont) procedures. †, p<0.01 compared to Cont.

Figure 6

Panel A. Confocal photomicrographs showing positive fluorojade-B stained neurons in representative sections of hippocampus obtained from control rats (Cont) and animals undergoing SE and treated with either vehicle (Veh) or atenolol (AT). Panel B. Mean number of fluorojade-B positive neurons per section of hippocampus from control animals (Cont; n=4), control rats administered atenolol (Cont+AT; n=4), vehicle-treated animals undergoing SE (n=5), and SE animals treated with atenolol (SE+AT; n=5). †, p<0.01 compared to Cont and Cont+AT.