Colman, M orcid.org/0000-0003-2817-8508, Alvarez-Lacalle, E, Echebarria, B et al. (3 more authors) (2022) Multi-scale computational modelling of spatial calcium handling from nanodomain to whole-heart: overview and perspectives. Frontiers in Physiology, 13. 836622. ISSN 1664-042X
Abstract
Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is ultimately regulated at the cellular scale, by the interaction of spatially separated but diffusively coupled nanodomains with other sub-cellular and surface-membrane calcium transport channels with strong non-linear interactions; and cardiac electrophysiology and arrhythmia mechanisms are ultimately tissue-scale phenomena, regulated by the interaction of a heterogeneous population of coupled myocytes. Recent advances in imaging modalities and image-analysis are enabling the super-resolution reconstruction of the structures responsible for regulating calcium homeostasis, including the internal structure of nanodomains themselves. Extrapolating functional and imaging data from the nanodomain to the whole-heart is non-trivial, yet essential for translational insight into disease mechanisms. Computational modeling has important roles to play in relating structural and functional data at the sub-cellular scale and translating data across the scales. This review covers recent methodological advances that enable image-based modeling of the single nanodomain and whole cardiomyocyte, as well as the development of multi-scale simulation approaches to integrate data from nanometer to whole-heart. Firstly, methods to overcome the computational challenges of simulating spatial calcium dynamics in the nanodomain are discussed, including image-based modeling at this scale. Then, recent whole-cell models, capable of capturing a range of different structures (such as the T-system and mitochondria) and cellular heterogeneity/variability are discussed at two different levels of discretization. Novel methods to integrate the models and data across the scales and simulate stochastic dynamics in tissue-scale models are then discussed, enabling elucidation of the mechanisms by which nanodomain remodeling underlies arrhythmia and contractile dysfunction. Perspectives on model differences and future directions are provided throughout.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright © 2022 Colman, Alvarez-Lacalle, Echebarria, Sato, Sutanto and Heijman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: | cardiac electrophysiology, calcium handling in cardiomyocytes, excitation-contraction coupling, computational modeling methods, multi-scale model |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number MRC (Medical Research Council) MR/M014967/1 MRC (Medical Research Council) MR/V0150050/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Feb 2022 11:58 |
Last Modified: | 07 Aug 2023 14:58 |
Published Version: | https://www.frontiersin.org/articles/10.3389/fphys... |
Status: | Published |
Publisher: | Frontiers Media |
Identification Number: | 10.3389/fphys.2022.836622 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:184011 |