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bioRxiv · 10.1101/613182

Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of spontaneous SR Ca2+ release

Kurata, Y.·Tsumoto, K.·Hayashi, K.·Hisatome, I.·Kuda, Y.·Tanida, M.
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Abstract

Early afterdepolarization (EAD) is known to cause lethal ventricular arrhythmias in long QT syndrome (LQTS). In this study, dynamical mechanisms of EAD formation in human ventricular myocytes (HVMs) were investigated using the mathematical model developed by ten Tusscher & Panfilov (Am J Physiol Heart Circ Physiol, 2006). We explored how the rapid (IKr) and slow (IKs) components of delayed-rectifier K+ channel currents, L-type Ca2+ channel current (ICaL), Na+/Ca2+ exchanger current (INCX), and intracellular Ca2+ handling via the sarcoplasmic reticulum (SR) contribute to initiation, termination and modulation of phase-2 EADs during pacing in relation to bifurcation phenomena in non-paced model cells. Dynamical behaviors of the non-paced model cell were determined by calculating stabilities of equilibrium points (EPs) and limit cycles, and bifurcation points. EADs during pacing were reproduced by numerical simulations. Results are summarized as follows: 1) A modified version of the ten Tusscher-Panfilov model with accelerated ICaL inactivation could reproduce bradycardia-related EADs and {beta}-adrenergic stimulation-induced EADs in LQTS. 2) Two types of EADs with different initiation mechanisms, ICaL reactivation-dependent and spontaneous SR Ca2+ release-mediated EADs, were detected. 3) Spontaneous SR Ca2+ releases occurred at higher Ca2+ uptake rates, attributable to the instability of steady-state intracellular Ca2+ concentrations. Dynamical mechanisms of EAD formation and termination in the paced model cell are closely related to stability changes (bifurcations) in dynamical behaviors of the non-paced model cell, but they are model-dependent. Nevertheless, the modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of EAD-related arrhythmias in LQTS.\n\nKey pointsO_LIWe investigated dynamical mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of the human ventricular myocyte model developed by ten Tusscher and Panfilov.\nC_LIO_LIA modified version of ten Tusscher-Panfilov model with accelerated inactivation of the L-type Ca2+ channel current could reproduce phase-2 EADs in long QT syndrome type 1 and 2 cardiomyocytes.\nC_LIO_LIDynamical mechanisms of EAD formation in the paced model cell are closely related to stability and bifurcations of the non-paced model cell.\nC_LIO_LIEAD mechanisms in the modified ten Tusscher-Panfilov model are different from those in other human ventricular myocyte models in the following respects: 1) EAD formation is partially attributable to spontaneous sarcoplasmic reticulum Ca2+ releases; and 2) EAD termination (action potential repolarization) during pacing requires the slowly-activating delayed-rectifier K+ channel current.\nC_LIO_LIThe modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of initiation and termination of EAD-related arrhythmias in LQTS.\nC_LI

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Kurata, Y., Tsumoto, K., Hayashi, K., Hisatome, I., Kuda, Y., Tanida, M.. 2019-04-18. Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of spontaneous SR Ca2+ release. https://doi.org/10.1101/613182

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