Methods for ECG Evaluation of Indicators of Cardiac Risk, and Susceptibility to Aconitine-induced Arrhythmias in Rats Following Status Epilepticus

Abstract

Lethal cardiac arrhythmias contribute to mortality in a number of pathological conditions. Several parameters obtained from a non-invasive, easily obtained electrocardiogram (ECG) are established, well-validated prognostic indicators of cardiac risk in patients suffering from a number of cardiomyopathies. Increased heart rate, decreased heart rate variability (HRV), and increased duration and variability of cardiac ventricular electrical activity (QT interval) are all indicative of enhanced cardiac risk. In animal models, it is valuable to compare these ECG-derived variables and susceptibility to experimentally induced arrhythmias. Intravenous infusion of the arrhythmogenic agent aconitine has been widely used to evaluate susceptibility to arrhythmias in a range of experimental conditions, including animal models of depression and hypertension, following exercise and exposure to air pollutants, as well as determination of the antiarrhythmic efficacy of pharmacological agents. It should be noted that QT dispersion in humans is a measure of QT interval variation across the full set of leads from a standard 12-lead ECG. Consequently, the measure of QT dispersion from the 2-lead ECG in the rat described in this protocol is different than that calculated from human ECG records. This represents a limitation in the translation of the data obtained from rodents to human clinical medicine. Status epilepticus (SE) is a single seizure or series of continuously recurring seizures lasting more than 30 min, and results in mortality in 20% of cases. Many individuals survive the SE, but die within 30 days. The mechanism(s) of this delayed mortality is not fully understood. It has been suggested that lethal ventricular arrhythmias contribute to many of these deaths. In addition to SE, patients experiencing spontaneously recurring seizures, i.e. epilepsy, are at risk of premature sudden and unexpected death associated with epilepsy (SUDEP). As with SE, the precise mechanisms mediating SUDEP are not known. It has been proposed that ventricular abnormalities and resulting arrhythmias make a significant contribution. To investigate the mechanisms of seizure-related cardiac death, and the efficacy of cardioprotective therapies, it is necessary to obtain both ECG-derived indicators of risk and evaluate susceptibility to cardiac arrhythmias in animal models of seizure disorders. Here we describe methods for implanting ECG electrodes in the Sprague-Dawley laboratory rat (Rattus norvegicus), following SE, collection and analysis of ECG recordings, and induction of arrhythmias during iv infusion of aconitine. These procedures can be used to directly determine the relationships between ECG-derived measures of cardiac electrical activity and susceptibility to ventricular arrhythmias in rat models of seizure disorders, or any pathology associated with increased risk of sudden cardiac death.