Dissecting the roles of calcium cycling and its coupling with voltage in the genesis of early afterdepolarizations in cardiac myocyte models

Early afterdepolarizations (EADs) are abnormal depolarizations during the plateau phase of the action potential, which are known to be associated with lethal arrhythmias in the heart. There are two major hypotheses for EAD genesis based on experimental observations, i.e., the voltage (Vm)-driven and intracellular calcium (Ca)-driven mechanisms. In ventricular myocytes, Ca and Vm are bidirectionally coupled, which can affect each other's dynamics and result in new dynamics, however, the roles of Ca cycling and its coupling with Vm in the genesis of EADs have not been well understood. In this study, we use an action potential model that is capable of independent Vm and Ca oscillations to investigate the roles of Vm and Ca coupling in EAD genesis. Four different mechanisms of EADs are identified, which are either driven by Vm oscillations or Ca oscillations alone, or oscillations caused by their interactions. We also use 5 other ventricular action potential models to assess these EAD mechanisms and show that EADs in these models are mainly Vm-driven. These mechanistic insights from our simulations provide a theoretical base for understanding experimentally observed EADs and EAD-related arrhythmogenesis.