Abstract

Dysfunction of normal calcium dynamics has been implicated in the generation of cardiac arrhythmias. It is thought that spontaneous calcium release events in the myocyte lead to the formation of intracellular calcium waves. These calcium release events occur through opening of the ryanodine receptors (RyRs) in the sarcoplasmic reticulum. In order for this to lead to an arrhythmia, these waves need to depolarize the cardiac myocyte in events know as early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). These aberrant depolarizations must spread to adjacent cells in a propagating wave of depolarization to disrupt the normal pattern of electrical excitation of the heart. Computational compartmental ventricular myocyte models have shown that EADs and DADS can be generated by certain conditions consistent with experiments. We have developed a spatio-temporal computational model of a chain of cardiac myocytes based on the Jafri-Rice-Winslow model of the guinea pig ventricular myocyte. The model includes spatial resolution of the individual myocyte as well as a network of myocytes, calcium dynamics, and the sarcolemmal electrical activity. We use the model to explore how factors such as calcium overload, RyR calcium sensitivity, and other factors affect the generation of calcium waves. Furthermore, we also explore under what conditions the calcium wave can depolarize the myocyte and induce a propagating wave of depolarization to adjacent myocytes. These insights can be used to better understand the basic mechanisms of calcium-entrained cardiac arrhythmias.

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