Colman, M. A. | bioRxiv Science

bioRxiv2018

Arrhythmia Mechanisms and Spontaneous Calcium Release: II - From Calcium Spark to Re-entry and Back

MotivationThe role of sub-cellular spontaneous calcium release events (SCRE) in the development of arrhythmia associated with atrial and ventricular tachycardia and fibrillation has yet to be investigated in detail. SCRE may underlie the emergence of spontaneous excitation in single cells, resulting in arrhythmic triggers in tissue. Furthermore, they can promote the substrate for conduction abnormalities. However, the potential interactions with re-entrant excitation have yet to be explored. The primary aim of this study was therefore to apply a novel computational approach to understand the multi-scale coupling between re-entrant excitation and SCRE.\n\nMethodsA general implementation of Spontaneous Release Functions - which reproduce the calcium dependent SCRE dynamics of detailed cell models at a significantly reduced computational cost - was used to reproduce SCRE in tissue models. Arrhythmic dynamics, such as rapid pacing and re-entry, were induced in the tissue models and the resulting interactions with SCRE were analysed.\n\nResultsIn homogeneous tissue, the emergence of a spontaneous beat from a single source was observed and the positive role of coupling was demonstrated. Conduction block could be promoted by SCRE by both inactivation of the fast sodium channel as well as focal pacing heterogeneity interactions. Sustained re-entrant excitation promoted calcium overload, and led to the emergence of focal excitations both after termination of re-entry and also during re-entrant excitation. These results demonstrated a purely functional mechanism of re-entry and focal activity localisation, related to the unexcited spiral wave core.\n\nConclusionsSCRE may interact with tissue excitation to promote and perpetuate arrhythmia through multiple mechanisms, including functional localisation and mechanism switching. These insights may be particularly relevant for successful pharmacological management of arrhythmia.

physiology↗

bioRxiv2018

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

MotivationSpontaneous 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.\n\nMethodsThe 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.\n\nResultsThe 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.\n\nConclusionsA 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.

physiology↗