Sub-cellular Heterogeneity in SERCA Determines Spatial Calcium Dynamics in Cardiomyocytes

Holmes, Maxx; Hurley, Miriam E.; Sheard, Tom M. D.; Stevenson-Cocks, Harley J.; Benson, Al; Jayasinghe, Izzy; Colman, Michael A.

doi:10.1016/j.bpj.2019.11.1055

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“…Model code and heterogeneous SERCA2a maps are available at Michael Colman's Github repository: (maps are found in the folder MSCSF_Distribution/MSCSF/MSCSF_state_and_geometry_files if you already have the code). Data is also available in the electronic supplementary material [51].…”

Section: Data Accessibilitymentioning

confidence: 99%

Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics

Holmes

Hurley

Sheard

et al. 2022

Phil. Trans. R. Soc. B

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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. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

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Section: Data Accessibilitymentioning

confidence: 99%