Holmes, M, Hurley, ME orcid.org/0000-0003-0553-3079, Sheard, TMD orcid.org/0000-0003-4940-3188 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 B: Biological Sciences, 377 (1864). 20210317. ISSN 0962-8436
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
Item Type: | Article |
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Authors/Creators: |
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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: | calcium handling, excitation-contraction coupling, arrhythmia, heterogeneity, serca, heart failure |
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 British Heart Foundation PG/16/74/32374 |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Jan 2022 10:50 |
Last Modified: | 16 Oct 2022 17:44 |
Status: | Published |
Publisher: | The Royal Society |
Identification Number: | 10.1098/rstb.2021.0317 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:182587 |