Seizure-induced cardiomyopathy: Benefit of Atenolol
Epilepsy affects 1-2% of the population in New Zealand and is associated with an increased mortality rate of two to three times that of the general population. This thesis examines the effect of seizures on cardiac function, as it is hypothesised that seizure-induced activation of the sympathetic system produces electrographic (ECG) abnormalities, cardiac dysfunction and structural damage. Using a rodent model, seizures were induced using the excitotoxin, kainic acid, either subcutaneously or via an intrahippocampal drug cannula. The first section of this study demonstrated that systemic kainic acid administration produced generalised seizure activity developing to status epilepticus. Kainic acid administration produced an immediate drop in heart rate (by 28%) associated with bradyarrhythmias. This was followed by a progressive increase in seizure severity which coincided with the development of tachycardia, QTc prolongation and T wave elevation. Heart rate variability analysis demonstrated that seizure activity resulted in significant changes in autonomic function. Prophylactic therapy with atenolol or clonidine attenuated seizure-induced ECG changes and preserved normal cardiac morphology. The second half of this thesis used an improved model of seizure in which kainic acid was administered directly into the hippocampus to prevent possible systemic effects. The results in this study clearly demonstrated that seizures produced cardiac dysfunction, particularly changes in heart rate, QTc interval and blood pressure. Seizure-induced cardiac dysfunction resulted in significant structural damage as early as 48 hours which was still present up to 28 days after the original seizure induction. Assessment of autonomic function using various techniques demonstrated that seizures resulted in an increase in plasma noradrenaline levels and enhanced sympathetic dominance at 48 hours. The seizure-induced tachycardia which ensued resulted in the development of dilated cardiomyopathy with significant cardiac structural injury. The formation of cardiac micro-lesions and fibrotic deposition is suggested to contribute to left ventricular dysfunction and an increased susceptibility to arrhythmia induction. Intervention therapy with atenolol, 60 minutes post seizure induction, preserved cardiac function and structure. Importantly, atenolol reduced the susceptibility to arrhythmia onset, which has been reported as a contributor to sudden death in epilepsy. Interestingly, atenolol treatment during seizures also reduced EEG and behavioural score severity and protected the hippocampus from injury. Attenuation of seizure activity with diazepam did not reduce the extent of cardiac dysfunction. Diazepam-treated animals had significantly higher blood pressure, left ventricular dilation and an increased susceptibility to arrhythmia induction. However, combination therapy with atenolol and diazepam, proved effective at protecting both the heart and brain following seizure activity. This thesis has consistently demonstrated that atenolol administration (prophylactic or intervention) offers significant protection against seizure-induced cardiomyopathy. Atenolol, therefore, should be considered for clinical use, prophylactically in epilepsy or as a rescue intervention during status epilepticus. Importantly, this study clearly demonstrates that atenolol in combination with diazepam offers superior therapeutic benefit, over either monotherapy, in an animal model of status epilepticus.
Advisor: Sammut, Ivan; Kerr, Steve
Degree Name: Doctor of Philosophy
Degree Discipline: Pharmacology
Publisher: University of Otago
Keywords: Seizure; Heart; Cardiomyopathy; Atenolol; Diazepam; ECG; Kainic Acid; status epilepticus
Research Type: Thesis