An In-Silico Study on Integrated Mechanisms of Mechano-Electric Coupling in Ischaemic Arrhythmogenesis
| Autor: | Timmermann, Viviane, Wall, Samuel T., Sundnes, Joakim, Lawen, Tarek, Baumeister, Peter A., Quinn, T. Alexander, McCulloch, Andrew D., Edwards, Andrew G. |
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| Rok vydání: | 2023 |
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| Druh dokumentu: | Working Paper |
| Popis: | Heterogeneous mechanical dyskinesis during acute myocardial ischaemia is thought to contribute to arrhythmogenic alterations to cardiac electrophysiology. Various forms of mechano-electric coupling (MEC) mechanisms have been suggested to contribute to these changes, with two primary mechanisms being: (1) myofilament-dependent calcium release events, and (2) the activation of stretch-activated currents (SACs). In this computational investigation, we assessed the collective impact of these processes on mechanically-induced alternans that create an arrhythmogenic substrate during acute ischaemia. To appraise the potential involvement of MEC in ischaemia-induced arrhythmias, we developed a coupled model of ventricular myocyte electrophysiology and contraction including SACs and stretch-dependent calcium buffering and release. The model, reflecting observed electrophysiological changes during ischaemia, was exposed to a series of stretch protocols that replicated both physiological and pathological mechanical conditions. Pathologically realistic myofiber stretch variations revealed calcium sensitivity changes dependent on myofilament, leading to alterations in cytosolic calcium concentrations. Under calcium overload conditions, these changes resulted in electrical alternans. The study implies that strain impacts cellular electrophysiology through myofilament calcium release and SAC opening in ventricular mechano-electrical models, parameterised to available data. This supports experimental evidence suggesting that both calcium-driven instability via MEC and SAC-induced effects contribute to electrical alternans in acute ischaemia. Comment: 20 pages; 8 figures; original paper |
| Databáze: | arXiv |
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