Multiscale mechanistic modelling of heterogeneity in cardiac sub‐cellular calcium handling accounting for variable t‐system density

Spatial properties of subcellular calcium handling in cardiac myocytes underpin both normal and abnormal functions. The structure and density of the transverse and axial tubular system (t-system) strongly determine the spatiotemporal synchrony of calcium-induced-calcium-release, and arrhythmogenic behaviours such as calcium transient alternans and subcellular calcium waves inherently depend on stochastic calcium spark initiation and spatial diffusion. Although detailed three-dimensional cellular models can reproduce these processes, they are computationally prohibitive for the tissue-scale simulations required to investigate arrhythmia mechanisms or inform patient-specific modelling. In this study, we develop a computationally efficient model that reproduces a broad range of spatially dependent subcellular calcium-handling phenomena. The model tracks the population occupancy of distinct states of calcium release units (CRUs), with activation rates that capture the different mechanisms of calcium spark initiation (triggered, spontaneous and spatially recruited). The model has been designed as an independent module that can be integrated into existing cell models and enables the simulation of variable t-system density. We demonstrate in three established cell models that this framework captures normal and abnormal pacing dynamics, including centripetal calcium waves in cells lacking a robust t-system, multiple mechanisms of calcium transient alternans, delayed triggered calcium sparks, and spontaneous calcium release mediated early and delayed after depolarisations. The model achieves this while maintaining a computational efficiency sufficient for large-scale tissue simulations, suitable for mechanistic and clinical applications. Key points Spatial features of sub-cellular calcium handling are integral to physiological and pathophysiological dynamics. This is particularly true for myocytes without a robust sub-cellular transverse and axial tubule system. Traditional computational models of cardiac myocytes do not capture these important features; detailed spatiotemporal models of sub-cellular calcium handling are computationally intensive and unsuitable for large-scale tissue simulation. We develop a novel model that captures spatial features of the sub-cellular calcium handling system without requiring explicit spatial modelling. The model was capable of reproducing normal and abnormal calcium handling dynamics, including centripetal calcium waves, calcium transient alternans, and spontaneous calcium sparks and waves, while being sufficiently efficient to perform tissue-scale simulations.