Conditions for the genesis of early afterdepolarization in a model of a ventricular myocyte

Early afterdepolarization (EAD) is known as a cause of ventricular arrhythmias in long QT syndromes. We theoretically investigated 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), Na+-K+ pump current ( INaK), intracellular Ca2+ (Cai) handling via sarcoplasmic reticulum (SR), and intracellular Na+ concentration (Nai) contribute to initiation, termination, and modulation of phase-2 EADs, using two human ventricular myocyte models. Bifurcation structures of dynamical behaviors in model cells were explored by calculating equilibrium points, limit cycles (LCs), and bifurcation points as functions of parameters. EADs were reproduced by numerical simulations. The results are summarized as follows: 1) decreasing IKs and/or IKr or increasing ICaL led to EAD generation, to which mid-myocardial cell models were especially susceptible; the parameter regions of EADs overlapped the regions of stable LCs. 2) Two types of EADs (termination mechanisms), IKs activation–dependent and ICaL inactivation–dependent EADs, were detected; IKs was not necessarily required for EAD formation. 3) Inhibiting INCX suppressed EADs via facilitating Ca2+-dependent ICaL inactivation. 4) Cai dynamics (SR Ca2+ handling) and Nai strongly affected bifurcations and EAD generation in model cells via modulating ICaL, INCX, and INaK. Parameter regions of EADs, often overlapping those of stable LCs, shifted depending on Cai and Nai in stationary and dynamic states. 5) Bradycardia-related induction of EADs was mainly due to decreases in Nai at lower pacing rates. This study demonstrates that bifurcation analysis allows us to understand the dynamical mechanisms of EAD formation more profoundly. NEW & NOTEWORTHY We investigated mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of human ventricular myocyte (HVM) models. EAD formation in paced HVMs basically depended on bifurcation phenomena in non-paced HVMs, but was strongly affected by intracellular ion concentrations in stationary and dynamic states. EAD generation did not necessarily require IKs.

Download Full-text

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

10.1101/613182 ◽

2019 ◽

Cited By ~ 1

Author(s):

Yasutaka Kurata ◽

Kunichika Tsumoto ◽

Kenshi Hayashi ◽

Ichiro Hisatome ◽

Yuhichi Kuda ◽

...

Keyword(s):

Delayed Rectifier ◽

Ventricular Myocyte ◽

Phase 2 ◽

Long Qt ◽

Channel Current ◽

Dynamical Behaviors ◽

Early Afterdepolarization ◽

Model Cell ◽

Intracellular Ca ◽

Qt Syndrome

AbstractEarly 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 β-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.Key pointsWe investigated dynamical mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of the human ventricular myocyte model developed by ten Tusscher and Panfilov.A 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.Dynamical mechanisms of EAD formation in the paced model cell are closely related to stability and bifurcations of the non-paced model cell.EAD 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.The modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of initiation and termination of EAD-related arrhythmias in LQTS.

Download Full-text