A Stochastic Spatiotemporal Model of Rat Ventricular Myocyte Calcium Dynamics Demonstrated Necessary Features for Calcium Wave Propagation

Abstract

Calcium (Ca2+) plays a central role in the excitation and contraction of cardiac myocytes. Experi-ments have indicated that calcium release is stochastic and regulated locally suggesting the pos-sibility of spatially heterogeneous calcium levels in the cells. This spatial heterogeneity might be important in mediating different signaling pathways. During more than 50 years of computa-tional cell biology, the computational models have been advanced to incorporate more ionic cur-rents, going from deterministic models to stochastic models. While periodic increases in cyto-plasmic Ca2+ concentration drive cardiac contraction, aberrant Ca2+ release can underly cardiac arrhythmia. However, the study of the spatial role of calcium ions has been limited due to the computational expense of using a three-dimensional stochastic computational model. In this pa-per, we introduce a three-dimensional stochastic computational model for rat ventricular myo-cytes at the whole-cell level that incorporate detailed calcium dynamics, with (1) non-uniform re-lease site placement, (2) non-uniform membrane ionic currents and membrane buffers, (3) sto-chastic calcium-leak dynamics and (4) non-junctional or rogue ryanodine receptors. The model simulates spark-induced spark activation and spark-induced Ca2+ wave initiation and propaga-tion that occur under conditions of calcium overload at the closed-cell condition, but not when Ca2+ levels are normal. This is considered important since the presence of Ca2+ waves contribute to the activation of arrhythmogenic currents.