Arrhythmia Mechanisms and Spontaneous Calcium Release: I - Multi-scale Modelling Approaches

Motivation Spontaneous sub-cellular calcium release events (SCRE), controlled by microscopic stochastic fluctuations of the proteins responsible for intracellular calcium release, are conjectured to promote the initiation and perpetuation of rapid arrhythmia associated with conditions such as heart failure and atrial fibrillation: SCRE may underlie the emergence of spontaneous excitation in single cells, resulting in arrhythmic triggers in tissue. However, translation of single-cell data to the tissue scale is non-trivial due to complex substrate considerations. Computational modelling provides a viable approach to dissect these multi-scale mechanisms, yet there remains a significant challenge in accurately and efficiently modelling this probabilistic behaviour in large-scale tissue models. The aim of this study was to develop an approach to overcome this challenge. Methods The dynamics of SCRE under multiple conditions (pacing rate, beta-stimulation, disease remodelling) in a computational model of stochastic, spatio-temporal calcium handling were analysed in order to develop Spontaneous Release Functions, which capture the variability and properties of SCRE matched to the full cell model. These functions were then integrated with tissue models, comprising idealised 2D sheets as well as full reconstructions of ventricular and atrial anatomy. Results The Spontaneous Release Functions accurately reproduced the dynamics of SCRE and its dependence on environment variables under multiple different conditions observed in the full single-cell model. Differences between cellular models and conditions where enhanced at the tissue scale, where the emergence of a focal excitation is largely an all-or-nothing response. Generalisation of the approaches was demonstrated through integration with an independent cell model, and parameterisation to an experimental dataset. Conclusions A novel approach has been developed to dynamically model SCRE at the tissue scale, in-line with behaviour observed in detailed single-cell models. Such an approach allows evaluation of the potential importance of SCRE in arrhythmia in both general mechanistic and disease-specific investigation.