Determinants of early afterdepolarization properties in ventricular myocyte models

Early afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf-homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development.Author summary: Early afterdepolarizations (EADs) are abnormal depolarizations during the plateau phase of action potential in cardiac myocytes, arising from a dual Hopf-homoclinic bifurcation. The same bifurcations are also responsible for certain types of bursting behaviors in other cell types, such as beta cells and neuronal cells. EADs are known to play important role in the genesis of lethal arrhythmias and have been widely studied in both experiments and computer models. However, a detailed comparison between the properties of EADs observed in experiments and those from mathematical models have not been carried out. In this study, we performed theoretical analyses and computer simulations of different ventricular action potential models as well as different species to investigate the properties of EADs and compared these properties to those observed in experiments. While the EAD properties in the action potential models capture many of the EAD properties seen in experiments, the inter-EAD intervals in the computer models differ a lot from model to model, and some of them show very large discrepancy with those observed in experiments. This discrepancy needs to be addressed in future cardiac action potential model development.