An In-Silico Study on Integrated Mechanisms of Mechano-Electric Coupling in Ischemic Arrhythmogenesis
arxiv(2023)
摘要
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.
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