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

2020 ◽  
Vol 10 ◽  
Author(s):  
Yasutaka Kurata ◽  
Kunichika Tsumoto ◽  
Kenshi Hayashi ◽  
Ichiro Hisatome ◽  
Yuhichi Kuda ◽  
...  
Keyword(s):  
Ventricular Myocyte ◽  
Phase 2 ◽  
Early Afterdepolarizations

scholarly journals Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models

2017 ◽  
Vol 312 (1) ◽  
pp. H106-H127 ◽  
Author(s):  
Yasutaka Kurata ◽  
Kunichika Tsumoto ◽  
Kenshi Hayashi ◽  
Ichiro Hisatome ◽  
Mamoru Tanida ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Equilibrium Points ◽  
Pump Current ◽  
Myocardial Cell ◽  
Delayed Rectifier ◽  
Ventricular Myocyte ◽  
Phase 2 ◽  
Early Afterdepolarization ◽  
Bifurcation Structures ◽  
Dynamic States

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.

scholarly journals Electrotonic suppression of early afterdepolarizations in the neonatal rat ventricular myocyte monolayer

2013 ◽  
Vol 591 (21) ◽  
pp. 5357-5364 ◽  
Author(s):  
Herman D. Himel ◽  
Alan Garny ◽  
Penelope J. Noble ◽  
Raj Wadgaonkar ◽  
Joseph Savarese ◽  
...  
Keyword(s):  
Neonatal Rat ◽  
Ventricular Myocyte ◽  
Early Afterdepolarizations ◽  
Rat Ventricular Myocyte

scholarly journals Why Pacing Frequency Affects the Production of Early Afterdepolarizations in Cardiomyocytes: An Explanation Revealed by Slow/Fast Analysis of a Minimal Model

2019 ◽  
Author(s):  
Theodore Vo ◽  
Richard Bertram
Keyword(s):  
Action Potential ◽  
Intermediate Frequency ◽  
Tissue Level ◽  
Phase 2 ◽  
Fast Analysis ◽  
Early Afterdepolarizations ◽  
Low Frequencies ◽  
Pharmacological Agents ◽  
Intracellular Ca ◽  
Biophysical Mechanism

AbstractEarly afterdepolarizations (EADs) are pathological voltage oscillations in cardiomyocytes that have been observed in response to a number of pharmacological agents and disease conditions. Phase-2 EADs consist of small voltage fluctuations that occur during the plateau of an action potential, typically under conditions in which the action potential is elongated. Although a single-cell behavior, EADs can lead to tissue-level arrhythmias, including ventricular tachycardia. Much is currently known about the biophysical mechanisms (i.e., the roles of ion channels and intracellular Ca2+ stores) for the various forms of EADs, due partially to the development and analysis of mathematical models. This includes the application of slow/fast analysis, which takes advantage of timescale separation inherent in the system to simplify its analysis. We take this further, using a minimal 3D model to demonstrate that the phase-2 EADs are canards that are formed in the neighborhood of a folded node singularity. This knowledge allows us to determine the number of EADs that can be produced for a given parameter set without performing computer simulations, and provides guidance on parameter changes that can facilitate or inhibit EAD production. With this approach, we demonstrate why periodic stimulation, as would occur in an intact heart, preferentially facilitates EAD production when applied at low frequencies,. We also explain the origin of complex alternan dynamics that can occur with intermediate-frequency stimulation, in which varying numbers of EADs are produced with each stimulation. These revelations fall out naturally from an understanding of folded node singularities, but are hard or impossible to glean from a knowledge of the biophysical mechanism for EADs alone. Therefore, an understanding of the canard mechanism is a useful complement to an understanding of the biophysical mechanism that has been developed over years of experimental and computational investigations.

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

2019 ◽  
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.

Rationalization and internalization

2001 ◽  
Vol 60 (4) ◽  
pp. 215-230 ◽  
Author(s):  
Jean-Léon Beauvois
Keyword(s):  
Phase 1 ◽  
Facilitatory Effect ◽  
Phase 2 ◽  
Causal Explanations ◽  
Reduction Effect ◽  
Dissonance Reduction

After having been told they were free to accept or refuse, pupils aged 6–7 and 10–11 (tested individually) were led to agree to taste a soup that looked disgusting (phase 1: initial counter-motivational obligation). Before tasting the soup, they had to state what they thought about it. A week later, they were asked whether they wanted to try out some new needles that had supposedly been invented to make vaccinations less painful. Agreement or refusal to try was noted, along with the size of the needle chosen in case of agreement (phase 2: act generalization). The main findings included (1) a strong dissonance reduction effect in phase 1, especially for the younger children (rationalization), (2) a generalization effect in phase 2 (foot-in-the-door effect), and (3) a facilitatory effect on generalization of internal causal explanations about the initial agreement. The results are discussed in relation to the distinction between rationalization and internalization.

Idalopirdin bei Alzheimererkrankung: nicht besser als Plazebo

2018 ◽  
Vol 86 (08) ◽  
pp. 456-457
Keyword(s):  
Phase 2 ◽  
Phase 3 ◽  
Alzheimer Demenz

Die Blockade von Serotoninrezeptoren, insbesondere des Serotonin-Rezeptortyps 5-HT6, als Zusatztherapie in Kombination mit Cholinesterasehemmer, hat in experimentellen Versuchen sowie in einer Phase-2-Studie positive Effekte bei Demenz gezeigt. Im Rahmen eines Phase-3 Entwicklungsprogramms wurde nun die Effektivität des selektiven Serotoninrezeptor-Antagonisten Idalopirdin bei leichter bis mittelschwerer Alzheimer Demenz geprüft.

Sign in / Sign up

Export Citation Format

Share Document