Subcellular calcium dynamics in a whole-cell model of an atrial myocyte

摘要

In this study, we present an innovative mathematical modeling approach that allows detailed characterization of Ca~(2+) movement within the three-dimensional volume of an atrial myocyte. Essential aspects of the model are the geometrically realistic representation of Ca~(2+) release sites and physiological Ca~(2+) flux parameters, coupled with a computationally inexpensive framework. By translating nonlinear Ca~(2+) excitability into threshold dynamics, we avoid the computationally demanding time stepping of the partial differential equations that are often used to model Ca~(2+) transport. Our approach successfully reproduces key features of atrial myocyte Ca~(2+) signaling observed using confocal imaging. In particular, the model displays the centripetal Ca~(2+) waves that occur within atrial myocytes during excitation-contraction coupling, and the effect of positive inotropic stimulation on the spatial profile of the Ca~(2+) signals. Beyond this validation of the model, our simulation reveals unexpected observations about the spread of Ca~(2+) within an atrial myocyte. In particular, the model describes the movement of Ca~(2+) between ryanodine receptor clusters within a specific z disk of an atrial myocyte. Furthermore, we demonstrate that altering the strength of Ca~(2+) release, ryanodine receptor refractoriness, the magnitude of initiating stimulus, or the introduction of stochastic Ca~(2+) channel activity can cause the nucleation of proarrhythmic traveling Ca~(2+) waves. The model provides clinically relevant insights into the initiation and propagation of subcellular Ca~(2+) signals that are currently beyond the scope of imaging technology.