The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Wayne R Giles - One of the best experts on this subject based on the ideXlab platform.
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour
The Journal of Physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, Action Potential height and duration are key physiological variables. In addition, rate-dependent changes in ventricular Action Potential duration (APD), and variations in APD at a fixed heart rate, are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for Safety Pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence also draws attention to the early repolarization phase of the Action Potential (and the J wave of the ECG) as a biomarker for arrhythmogenesis. Here we provide mechanistic background to this Early Repolarization Syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds; and demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as ‘repolarization reserve’. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram as well as alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). This article is protected by copyright. All rights reserved
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour.
The Journal of physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the Action Potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).
James N. Weiss - One of the best experts on this subject based on the ideXlab platform.
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stochastic pacing reveals the propensity to Cardiac Action Potential alternans and uncovers its underlying dynamics
The Journal of Physiology, 2016Co-Authors: Yann Prudat, Roshni V Madhvani, Marina Angelini, Nils P Borgstom, Enno Lange, Hrayr S Karagueuzian, James N. Weiss, Riccardo Olcese, Alan Garfinkel, Jan KuceraAbstract:KEY POINTS: Beat-to-beat alternation (alternans) of the Cardiac Action Potential duration is known to precipitate life-threatening arrhythmias and can be driven by the kinetics of voltage-gated membrane currents or by instabilities in intracellular calcium fluxes. To prevent alternans and associated arrhythmias, suitable markers must be developed to quantify the susceptibility to alternans; previous theoretical studies showed that the eigenvalue of the alternating eigenmode represents an ideal marker of alternans. Using rabbit ventricular myocytes, we show that this eigenvalue can be estimated in practice by pacing these cells at intervals varying stochastically. We also show that stochastic pacing permits the estimation of further markers distinguishing between voltage-driven and calcium-driven alternans. Our study opens the perspective to use stochastic pacing during clinical investigations and in patients with implanted pacing devices to determine the susceptibility to, and the type of alternans, which are both important to guide preventive or therapeutic measures. ABSTRACT: Alternans of the Cardiac Action Potential (AP) duration (APD) is a well-known arrhythmogenic mechanism. APD depends on several preceding diastolic intervals (DIs) and APDs, which complicates the prediction of alternans. Previous theoretical studies pinpointed a marker called λalt that directly quantifies how an alternating perturbation persists over successive APs. When the propensity to alternans increases, λalt decreases from 0 to -1. Our aim was to quantify λalt experimentally using stochastic pacing and to examine whether stochastic pacing allows discriminating between voltage-driven and Ca(2+) -driven alternans. APs were recorded in rabbit ventricular myocytes paced at cycle lengths (CLs) decreasing progressively and incorporating stochastic variations. Fitting APD with a function of two previous APDs and CLs permitted us to estimate λalt along with additional markers characterizing whether the dependence of APD on previous DIs or CLs is strong (typical for voltage-driven alternans) or weak (Ca(2+) -driven alternans). During the recordings, λalt gradually decreased from around 0 towards -1. Intermittent alternans appeared when λalt reached -0.8 and was followed by sustained alternans. The additional markers detected that alternans was Ca(2+) driven in control experiments and voltage driven in the presence of ryanodine. This distinction could be made even before alternans was manifest (specificity/sensitivity >80% for -0.4 > λalt > -0.5). These observations were confirmed in a mathematical model of a rabbit ventricular myocyte. In conclusion, stochastic pacing allows the practical estimation of λalt to reveal the onset of alternans and distinguishes between voltage-driven and Ca(2+) -driven mechanisms, which is important since these two mechanisms may precipitate arrhythmias in different manners.
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repolarization reserve evolves dynamically during the Cardiac Action Potential effects of transient outward currents on early afterdepolarizations
Circulation-arrhythmia and Electrophysiology, 2015Co-Authors: Thao P Nguyen, Neha Singh, Yuanfang Xie, James N. WeissAbstract:Background— Transient outward K currents (Ito) have been reported both to suppress and to facilitate early afterdepolarizations (EADs) when repolarization reserve is reduced. Here, we used the dynamic clamp technique to analyze how Ito accounts for these paradoxical effects on EADs by influencing the dynamic evolution of repolarization reserve during the Action Potential. Methods and Results— Isolated patch-clamped rabbit ventricular myocytes were exposed to either oxidative stress (H2O2) or hypokalemia to induce bradycardia-dependent EADs at a long pacing cycle length of 6 s, when native rabbit Ito is substantial. EADs disappeared when the pacing cycle length was shortened to 1 s, when Ito becomes negligible because of incomplete recovery from inactivation. During 6-s pacing cycle length, EADs were blocked by the Ito blocker 4-aminopyridine, but reappeared when a virtual current with appropriate Ito-like properties was reintroduced using the dynamic clamp (n=141 trials). During 1-s pacing cycle length in the absence of 4-aminopyridine, adding a virtual Ito-like current (n=1113 trials) caused EADs to reappear over a wide range of Ito conductance (0.005–0.15 nS/pF), particularly when inactivation kinetics were slow (τinact≥20 ms) and the pedestal (noninactivating component) was small (<25% of peak Ito). Faster inactivation or larger pedestals tended to suppress EADs. Conclusions— Repolarization reserve evolves dynamically during the Cardiac Action Potential. Whereas sufficiently large Ito can suppress EADs, a wide range of intermediate Ito properties can promote EADs by influencing the temporal evolution of other currents affecting late repolarization reserve. These findings raise caution in targeting Ito as an antiarrhythmic strategy.
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electrical refractory period restitution and spiral wave reentry in simulated Cardiac tissue
American Journal of Physiology-heart and Circulatory Physiology, 2002Co-Authors: Fagen Xie, Alan Garfinkel, James N. WeissAbstract:Theoretical and experimental studies have shown that restitution of the Cardiac Action Potential (AP) duration (APD) plays a major role in predisposing ventricular tachycardia to degenerate to vent...
Beatriz Trenor - One of the best experts on this subject based on the ideXlab platform.
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour
The Journal of Physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, Action Potential height and duration are key physiological variables. In addition, rate-dependent changes in ventricular Action Potential duration (APD), and variations in APD at a fixed heart rate, are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for Safety Pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence also draws attention to the early repolarization phase of the Action Potential (and the J wave of the ECG) as a biomarker for arrhythmogenesis. Here we provide mechanistic background to this Early Repolarization Syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds; and demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as ‘repolarization reserve’. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram as well as alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). This article is protected by copyright. All rights reserved
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour.
The Journal of physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the Action Potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).
Karen Cardona - One of the best experts on this subject based on the ideXlab platform.
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour
The Journal of Physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, Action Potential height and duration are key physiological variables. In addition, rate-dependent changes in ventricular Action Potential duration (APD), and variations in APD at a fixed heart rate, are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for Safety Pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence also draws attention to the early repolarization phase of the Action Potential (and the J wave of the ECG) as a biomarker for arrhythmogenesis. Here we provide mechanistic background to this Early Repolarization Syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds; and demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as ‘repolarization reserve’. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram as well as alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). This article is protected by copyright. All rights reserved
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour.
The Journal of physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the Action Potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).
Javier Saiz - One of the best experts on this subject based on the ideXlab platform.
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour
The Journal of Physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, Action Potential height and duration are key physiological variables. In addition, rate-dependent changes in ventricular Action Potential duration (APD), and variations in APD at a fixed heart rate, are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for Safety Pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence also draws attention to the early repolarization phase of the Action Potential (and the J wave of the ECG) as a biomarker for arrhythmogenesis. Here we provide mechanistic background to this Early Repolarization Syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds; and demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as ‘repolarization reserve’. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram as well as alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). This article is protected by copyright. All rights reserved
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Cardiac Action Potential repolarization revisited: early repolarization shows all-or-none behaviour.
The Journal of physiology, 2017Co-Authors: Beatriz Trenor, Karen Cardona, Javier Saiz, Denis Noble, Wayne R GilesAbstract:In healthy mammalian hearts the Action Potential (AP) waveform initiates and modulates each contrAction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the Action Potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the Cardiac Action Potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of Action Potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).