Spatial remodelling of calcium release units may impair cardiac electro-mechanical function: A simulation study

Excitation-contraction coupling (E-C coupling) is thought to be based on elementary calcium release units (CRUs) in which clusters of ryanodine receptors (RyRs) localized on the sarcoplasmic reticulum (SR) are in close apposition to L-type Ca2+ channels (LCCs) on the transverse tubules (TTs). However, a fraction of LCC-RyR structure may be uncoupled due to the remodelling of TTs, which would tend to destroy the E-C coupling in the failing heart. Here we proposed a multiscale model of the ventricular myocyte to investigate the relationship between LCC-RyR structure and cardiac electro-mechanical function. The mathematical model consisted of a two-dimensional (2D) subcellular Ca2+ reaction-diffusion sub-model, a cellular electrophysiological sub-model and a cardiomyocyte contraction sub-model. The simulation results showed that the remodelling of CRU microstructure would disturb Ca2+ homeostasis, leading to a dyssynchronous Ca2+ transient, and postpone the generation of isometric force. Our study suggests that structural remodelling is an important mechanism for dysfunction of Ca2+ handling, cellular electrophysiology and contractility in failing heart.