Human and rabbit inter-species comparison of ionic mechanisms of arrhythmic risk: A simulation study.

Experimental studies of pro-arrhythmic mechanisms are scarcely performed in humans due to the limited availability of human cardiomyocytes. Subsequently, extrapolation of animal experimental research to humans is widely extended. Our aim is to systematically compare the ionic mechanisms of the main cellular biomarkers of arrhythmic risk between human and rabbit using computer simulations. For this purpose four stimulation protocols were applied to the Mahajan et al. rabbit ventricular action potential (AP) model for control conditions and for ± 15 and ± 30% variations in the ionic current conductances of the main repolarization currents to quantify cellular biomarkers. Sensitivity of every simulated biomarker to every parameter modification was compared to that obtained for human in our previous work. Our results show that the ionic mechanisms involved in AP triangulation, systolic intracellular calcium concentration and AP duration (APD) accommodation to abrupt changes of pacing rate are very similar in both species. Unfortunately, significant differences were found in the ionic mechanisms related to APD, restitution properties and rate dependence of intracellular calcium and sodium concentrations. In conclusion, extrapolation of experimental research in rabbit to humans is limited by the existence of species dependent ionic mechanisms. In addition, this analysis is very useful for understanding and improvement of mathematical models.