Abstract
In cardiac cells, calcium is the mediator of excitation-contraction coupling. Dysfunctions in calcium handling have been identified as the origin of some cardiac arrhythmias. In the particular case of atrial myocytes, recent available experimental data has found links between these dysfunctions and structural changes in the calcium handling machinery (ryanodine cluster size and distribution, t-tubular network, etc). To address this issue, we have developed a computational model of an atrial myocyte that takes into account the detailed intracellular structure. The homogenized macroscopic behavior is described with a two-concentration field model, using effective diffusion coefficients of calcium in the sarcoplasmic reticulum (SR) and in the cytoplasm. The model reproduces the right calcium transients and dependence with pacing frequency. Under basal conditions, the calcium rise is mostly restricted to the periphery of the cell, with a large concentration ratio between the periphery and the interior. We have then studied the dependence of the speed of the calcium wave on cytosolic and SR diffusion coefficients, finding an almost linear relation with the former, in agreement with a diffusive and fire mechanism of propagation, and little dependence on the latter. Finally, we have studied the effect of a change in RyR cluster microstructure. We find that, under resting conditions, the spark frequency decreases slightly with RyR cluster spatial dispersion, but markedly increases when the RyRs are distributed in clusters of larger size, stressing the importance of RyR cluster organization to understand atrial arrhythmias, as recent experimental results suggest (Macquaide et al., 2015).
Highlights
Calcium is one of the most important intracellular messengers, and the mechanisms that control the intracellular free calcium concentration are of fundamental physiological importance (Berridge, 1997)
Because of the high spatial resolution, the model allows us to study in detail the dynamics in the surroundings of the Calcium Release Units (CaRU), that is, the local calcium concentrations and the spark activity
Important differences have been noticed using different spatial configurations of RyRs, showing that the resulting calcium dynamics is highly dependent on the spatial distribution
Summary
Calcium is one of the most important intracellular messengers, and the mechanisms that control the intracellular free calcium concentration are of fundamental physiological importance (Berridge, 1997). AF duplicates the mortality rate and increases the risk of ictus (in which poor blood flow to the brain results in cell death) 5-fold. In spite of this the treatment of AF remains deficient or inefficient, because of the incomplete knowledge of the complex pathophysiology of this disease. In the last ten years, the refinement of the experimental techniques, such as STED and dSTORM (Hell and Wichmann, 1994; Izu et al, 2006; Soeller and Baddeley, 2013) has provided, for instance, a link between the calcium handling microstructure and the occurrence of cardiac diseases, as AF (Macquaide et al, 2015), prompting the quest for more detailed models of calcium handling, able to mechanistically explain this relation
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