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Mechano‐Electric Coupling and Arrhythmogenic Current Generation in a Multi‐Scale Computational Model of Coupled Myocytes
Author(s) -
Timmerman Viviane
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06806
Subject(s) - myofilament , calcium , coupling (piping) , myocyte , sarcomere , electrophysiology , biophysics , calcium in biology , chemistry , voltage dependent calcium channel , neuroscience , materials science , medicine , biology , metallurgy , organic chemistry
Heterogeneous mechanical activity during acute myocardial ischemia is thought to contribute to arrhythmogenic alterations in cardiac electrophysiology. Stretch‐induced perturbations to cardiomyocyte electrophysiology may trigger arrhythmias via a variety of mechano‐electric coupling (MEC) mechanisms. While the role of stretch‐activated ionic currents has been investigated intensively using computational models, experimental studies have shown that mechanical strain can also trigger intra‐ and inter‐cellular calcium waves. To assess whether the inherent stretch dependence of myofilament calcium affinity may promote ischemia‐induced arrhythmogenic intra‐ and inter‐cellular calcium waves, we coupled a mathematical model of excitation‐contraction coupling in rabbit ventricular myocytes to a model of myofilament activation and force development. The model was modified to mimic observed electrophysiological alterations during ischemia, and was subjected to systolic stretch. We compared a zero‐dimensional (0D) and one‐dimensional (1D) compartmental analysis, for which multiple myocytes were electrically and mechanically coupled in series. In the 1D model each myocyte consisted of 50 bi‐directionally coupled electromechanical models in addition to calcium diffusion and strain transfer between adjacent units. Both, the 0D and 1D model, were fitted to calcium alterations during homogeneous stretch transient. The addition of end‐to‐end mechanical interactions of inter‐ and/or intracellular sarcomeres enabled the model to capture: (1) the effects of MEC on intracellular calcium dynamics at the sarcomeric scale; and (2) the effects of mechanical heterogeneities on calcium dynamics at the cellular scale. The simulation results suggest that in the 0D only the triggers of calcium‐mediated delayed after depolarizations (DADs) could be observed. In the 1D model, in conditions of calcium overload and only for the non‐ischemic myocytes, an increase in stretch or an increase in sarcomere heterogeneity increase the susceptibility for myofilament triggered calcium waves causing DADs. Additionally, the specific sarcomere heterogeneity can modulate intracellular calcium dynamics which may increase susceptibility to pro‐arrhythmic intra‐ and inter‐cellular calcium wave propagation, but only for spatially explicit myocyte models.