Determinants of early afterdepolarization properties in ventricular myocyte models

Abstract

Early afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf-homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development.

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

“…In the diagram for the slow gating variable-parameterized fast subsystem with a superimposed full system trajectory, gradual increases in the slow variable led the full system trajectory slowly across the stable steady-state branch of qEP and then into the region of the stable periodic branch of qLC through an HB point, resulting in the termination of EADs via a homoclinic bifurcation of qLC. This scenario is known as the Hopf-homoclinic bifurcation mechanism (Tran et al, 2009;Qu et al, 2013;Song et al, 2015;Huang et al, 2018). Consistent with these previous reports, the mTP06b model exhibited slow I Ks activationdependent EADs in the xs 2 regions of stable and unstable qEPs ( Figure 7A); however, a stable qLC region or homoclinic bifurcation to yield EAD termination was not detected for the fast subsystem of the mTP06b model.…”

Mechanisms of phase‐3 early afterdepolarizations and triggered activities in ventricular myocyte models

“…However, phase‐3 EADs and TAs have been rarely observed in isolated ventricular myocytes [low amplitude phase‐3 EADs with take‐off potential around −50 mV but not TAs were reported in isolated mice ventricular myocytes (Edwards et al, 2014; Tazmini et al, 2020)]. This was supported by a literature survey by Huang et al (Huang et al, 2018), which showed that the vast majority of the EADs recorded in experiments of isolated ventricular myocytes are phase‐2 EADs (see table 1 in Huang et al), no phase‐3 EADs and TAs were observed. Moreover, phase‐3 EADs and TAs were also not observed in computer simulations of ventricular AP models, and only phase‐2 EADs were reported [see EAD takeoff potentials in our previous study for different AP models (Huang et al, 2018), as well as EADs shown in many other computer simulation studies (Clancy & Rudy, 1999; Kurata et al, 2017, 2020; Pueyo et al, 2011; Song et al, 2015; Tanskanen et al, 2005; Varshneya et al, 2018)].…”

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

“…Early afterdepolarizations (EADs) occur during the plateau phase of the cardiac AP and are associated with LQTS and ventricular tachyarrhythmias (associated with HF) (Landstrom et al, 2017). They are triggered by a reduction in repolarization reserve as a result of an increase in an inward current or a decrease in an outward current (Huang et al, 2018). A main contributor to EAD initiation is an increase in L-type Ca 2+ current (I CaL ) which drives the EAD upstroke.…”