Rabbit models as tools for preclinical cardiac electrophysiological safety testing: Importance of repolarization reserve.

It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. We suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations. In addition to healthy animals and tissues, the use of animal models (e.g. those with impaired repolarization reserve) is suggested that more closely resemble subsets of patients exhibiting increased vulnerability towards the development of ventricular arrhythmias and sudden cardiac death.