Holmes, M., Sheard, T. orcid.org/0000-0003-4940-3188, Hurley, M. et al. (3 more authors) (2022) Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 377 (1864). ISSN 0080-4622
Abstract
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.
Metadata
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, provided the original author and source are credited. | ||||
Keywords: | heterogeneity; calcium handling; heart failure; arrhythmia; excitation-contraction coupling; serca | ||||
Dates: |
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) | ||||
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 13 Oct 2022 15:47 | ||||
Last Modified: | 13 Oct 2022 15:47 | ||||
Status: | Published | ||||
Publisher: | The Royal Society | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1098/rstb.2021.0317 | ||||
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