Arrhythmogenesis in heart cells involves reverse E–C coupling and reverse electrotonic conduction along T-tubules

Early afterdepolarization (EAD) is an aberrant cardiac afterpotential that underlies the development of life-threatening ventricular arrhythmias. It is believed that the development of EAD is caused by the reactivation of L-type Ca2+ current during the period of the action potential plateau; however, the cellular mechanisms that underlie the development of EAD is still controversial. One favorable alternative is the depolarizing reverse-mode operation of the Na+/Ca2+ exchanger, which is activated by aberrant Ca2+ release from the sarcoplasmic reticulum in the process of reverse E–C coupling. Since EADs develop preferentially in damaged heart cells with abnormal Ca2+-signaling, here I studied the causal link between the development of EADs and aberrant intracellular Ca2+ level ([Ca2+]i) dynamics in mouse heart cells using the whole-cell clamp technique. My results show (1) the generation of EADs was preceded by the development of depolarizing membrane potential (Vm) fluctuation, (2) the depolarizing Vm fluctuation is associated with [Ca2+]i elevation, suggesting an involvement of reverse E–C coupling via the Na+/Ca2+ exchanger, and (3) that extending the T-tubules’ length constant by decreasing the extracellular K+ level facilitated the development of the Vm fluctuation and EADs. Taken together, I conclude that EADs are caused by the depolarizing Vm fluctuation, which is induced locally in the T-tubule membrane by aberrant [Ca2+]i elevation and is conducted back electrotonically along the T-tubules.

Bifurcation Analysis on a Generation of Early Afterdepolarization in a Mathematical Cardiac Model

Electrical activity occurs in the cell membrane of cardiomyocytes. This electrical activity forms the action potential that generates pumping of the heart. An abnormality in the action potential turns into arrhythmia, which may cause sudden death. Studies of arrhythmias using mathematical models are important to reduce the risk of sudden death. In this study, we investigate bifurcations related to the generation of early afterdepolarizations (EADs) in a mathematical model. We clarify the transition process from a normal state to a persistent EAD through a transient EAD while changing only one parameter (multiple of conductance of L-type calcium channel current) value. The dependence of the transient EAD generation on parameters is shown through bifurcation analysis in a [Na]i-parameterized system.

Transmural and rate-dependent profiling of drug-induced arrhythmogenic risks through in silico simulations of multichannel pharmacology

In vitro human ether-à-go-go related gene (hERG) inhibition assay alone might provide insufficient information to discriminate “safe” from “dangerous” drugs. Here, effects of multichannel inhibition on cardiac electrophysiology were investigated using a family of cardiac cell models (Purkinje (P), endocardial (Endo), mid-myocardial (M) and epicardial (Epi)). We found that: (1) QT prolongation alone might not necessarily lead to early afterdepolarization (EAD) events, and it might be insufficient to predict arrhythmogenic liability; (2) the occurrence and onset of EAD events could be a candidate biomarker of drug-induced arrhythmogenicity; (3) M cells are more vulnerable to drug-induced arrhythmias, and can develop early afterdepolarization (EAD) at slower pacing rates; (4) the application of quinidine can cause EADs in all cell types, while INaL is the major depolarizing current during the generation of drug-induced EAD in P cells, ICaL is mostly responsible in other cell types; (5) drug-induced action potential (AP) alternans with beat-to-beat variations occur at high pacing rates in P cells. These results suggested that quantitative profiling of transmural and rate-dependent properties can be essential to evaluate drug-induced arrhythmogenic risks, and may provide mechanistic insights into drug-induced arrhythmias.

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

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 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.