Heterogeneity and variability are important determinants of both normal and abnormal function of the heart. Cardiac cells and tissues exhibit heterogeneities and variability across a substantial range of spatial scales, from single dyads (nm) through whole cells (μm) to the whole-heart (mm-cm). Investigation of the interacting mechanisms by which these multi-scale heterogeneities ultimately lead to cardiac dysfunction is a major research challenge which cannot be met through traditional experimental techniques; novel joint computational-experimental approaches need to be developed to achieve this goal. 

This talk will discuss a range of computational approaches to study heterogeneous structure-function relationships across the relevant spatial scales, from models of the single-nanodomain, through detailed models of individual cells, to models of the whole-heart. In particular, we will discuss modelling the mechanisms by which dysfunction of the intracellular calcium handling system is involved in the generation and sustenance of arrhythmia, and image-analysis approaches that facilitate integration between simulation and experiment. We will reveal novel mechanisms by which heterogeneity in the distribution of sub-cellular calcium handling channels can lead to mechanical dysfunction, the mechanisms by which independent cellular spontaneous activity synchronises into a focal excitation, and the interaction between these focal excitations and fibrosis which lead to complex trigger and substrate dynamics.