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 and Panfilov (Am J Physiol Heart Circ Physiol 291, 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. Parameter-dependent dynamical behaviors of the non-paced model cell were determined by calculating stabilities of equilibrium points (EPs) and limit cycles, and bifurcation points to construct bifurcation diagrams. Action potentials (APs) and EADs during pacing were reproduced by numerical simulations for constructing phase diagrams of the paced model cell dynamics. Results are summarized as follows: (1) A modified version of the ten Tusscher-Panfilov model with accelerated ICaL inactivation could reproduce bradycardia-related EADs in LQTS type 2 and β-adrenergic stimulation-induced EADs in LQTS type 1. (2) Two types of EADs with different initiation mechanisms, ICaL reactivation–dependent and spontaneous SR Ca2+ release–mediated EADs, were detected. (3) Termination of EADs (AP repolarization) during pacing depended on the slow activation of IKs. (4) 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.
Highlights
Afterdepolarization (EAD) is well known to trigger lethal ventricular arrhythmias, called Torsades de Pointes (TdP), in patients with long QT syndrome (LQTS) (Weiss et al, 2010; Shimizu and Horie, 2011; Shimizu, 2013)
The aims of this study were (1) to determine whether the ten Tusscher and Panfilov model for human ventricular myocytes (HVMs), which has often been used for simulations of reentrant arrhythmias in the human ventricle, could reproduce Early afterdepolarization (EAD) formation in LQTS, and (2) to define the contributions of individual sarcolemmal and intracellular components to the initiation, termination, and modulation of phase-2 EADs in the TP06 model in comparison with those in other HVM models
We first determined whether the mTP06a/b models can mimic the electrophysiological properties of IKr-reduced LQTS type 2 (LQT2) and IKs-reduced LQTS type 1 (LQT1) HVMs, in which
Summary
Afterdepolarization (EAD) is well known to trigger lethal ventricular arrhythmias, called Torsades de Pointes (TdP), in patients with long QT syndrome (LQTS) (Weiss et al, 2010; Shimizu and Horie, 2011; Shimizu, 2013). There are many experimental studies regarding the mechanisms of EAD formation in cardiomyocytes, suggesting major contribution of reactivation of the L-type Ca2+ channel current (ICaL) to the initiation of EADs during the action potential (AP) phase 2 (e.g., January et al, 1988; January and Riddle, 1989; Guo D. et al, 2007; Weiss et al, 2010; Xie et al, 2010; Milberg et al, 2012a; Shimizu, 2013). Despite many experimental and theoretical studies, how individual membrane and intracellular components contribute to the initiation, termination and modulation of EADs remains controversial
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