Numerical Analysis of the Effect of T-tubule Location on Calcium Transient in Ventricular Myocytes

George, Uduak Z.; Wang, Jun; Yu, Zeyun

doi:10.3233/bme-130932

Cited by 1 publication

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References 19 publications

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“…Such models are in general idealised (with an idealised structure and dyad distribution), but some have used imaging data to distribute RyRs throughout the cell or cell-portion [ 17 , 18 , 22 , 39 ]; Other models have been created of small regions of the cell (e.g. the volume surrounding a single TT or even a single dyad) and have integrated more detailed imaging data [ 29 , 31 , 32 , 37 ]. However, a spatio-temporal Ca 2+ handling model which accounts for realistic SR structure, TT structure and dyad distribution at the whole-cell scale has not yet been developed and involves significant challenges.…”

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confidence: 99%

A computational model of spatio-temporal cardiac intracellular calcium handling with realistic structure and spatial flux distribution from sarcoplasmic reticulum and t-tubule reconstructions

et al. 2017

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Intracellular calcium cycling is a vital component of cardiac excitation-contraction coupling. The key structures responsible for controlling calcium dynamics are the cell membrane (comprising the surface sarcolemma and transverse-tubules), the intracellular calcium store (the sarcoplasmic reticulum), and the co-localisation of these two structures to form dyads within which calcium-induced-calcium-release occurs. The organisation of these structures tightly controls intracellular calcium dynamics. In this study, we present a computational model of intracellular calcium cycling in three-dimensions (3-D), which incorporates high resolution reconstructions of these key regulatory structures, attained through imaging of tissue taken from the sheep left ventricle using serial block face scanning electron microscopy. An approach was developed to model the sarcoplasmic reticulum structure at the whole-cell scale, by reducing its full 3-D structure to a 3-D network of one-dimensional strands. The model reproduces intracellular calcium dynamics during control pacing and reveals the high-resolution 3-D spatial structure of calcium gradients and intracellular fluxes in both the cytoplasm and sarcoplasmic reticulum. We also demonstrated the capability of the model to reproduce potentially pro-arrhythmic dynamics under perturbed conditions, pertaining to calcium-transient alternans and spontaneous release events. Comparison with idealised cell models emphasised the importance of structure in determining calcium gradients and controlling the spatial dynamics associated with calcium-transient alternans, wherein the probabilistic nature of dyad activation and recruitment was constrained. The model was further used to highlight the criticality in calcium spark propagation in relation to inter-dyad distances. The model presented provides a powerful tool for future investigation of structure-function relationships underlying physiological and pathophysiological intracellular calcium handling phenomena at the whole-cell. The approach allows for the first time direct integration of high-resolution images of 3-D intracellular structures with models of calcium cycling, presenting the possibility to directly assess the functional impact of structural remodelling at the cellular scale.

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