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This is a repository copy of Multi-scale approaches for the simulation of cardiac electrophysiology: I -sub-cellular and stochastic calcium dynamics from cell to organ.

The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

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A fundamental problem of cellular biology is to understand the mechanisms underlying cellular locomotion. Bacterial organisms may use appendages such as flagellae or cilia to facilitate motion. Amoeboid motion [6], exhibited by eucaryotic cells are seen to flatten onto surfaces and extend thin sheets of cytosol called lamellipodia. These in turn make attachments to the surface and by the initiation of internal contractions within the cell, a forward motion is achieved. The processes which govern this behaviour are extremely complex, however, key ingredients have been identified which may provide a sufficient basis for persistent cellular motion. These factors are osmotichydrostatic expansion and cellular contraction mediated by intracellular calcium ca2+. In this paper, we develop a simple two dimensional model for a non-muscle motile cell based on these two key factors. We show it is capable of producing persistent cellular motion and chemotactic behaviour.