Image-Based Monte Carlo Modeling of Ca2+ sparks in Ventricular Myocytes

Abstract

The geometry of a dyadic calcium release unit (CRU) plays a critical role in regulating intracellular Ca2+ spark generation and furthermore the excitation-contraction (E-C) coupling in ventricular myocytes. A number of computational models have showed how the geometries of T-tubules and junctional sarcoplasmic reticulum (jSR) and distributions of L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs) could affect local Ca2+ signaling, but almost all of them were based on simple domain geometries such as rectangular or cylindrical shapes. For this reason, incorporating image-based realistic geometric models into mathematical simulation is timely and expected to provide more accurate simulation of many biological processes, in particular, the Ca2+ spark formation in ventricular myocytes.The present study has two goals. First, we adopt a chain of image and geometric processing approaches to construct realistic 3D models (represented by high-quality surface and volumetric meshes) of both T-tubules and junctional SR from electron microscopy images of adult mouse cardiomyocytes. The distributions of LCCs and RyRs are obtained in two ways: random assignment and image-based localization (for RyRs only). The second goal of the present study is the use of Monte Carlo methods to model the randomness of release and diffusion of individual Ca2+ ions within a narrow dyadic cleft. To this end, the M-Cell software package, combined with the realistic geometries obtained in the first goal, is used to simulate how Ca2+ sparks are generated in a single dyad (or CRU) and how they change temporally and spatially with different geometries of membrane structures and distributions of channeling proteins.