The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Zhilin Qu - One of the best experts on this subject based on the ideXlab platform.
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t tubule disruption promotes calcium Alternans in failing ventricular myocytes mechanistic insights from computational modeling
Journal of Molecular and Cellular Cardiology, 2015Co-Authors: Michael Nivala, Zhen Song, James N. Weiss, Zhilin QuAbstract:In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the mechanisms of TT disruption and other HF remodeling factors on Ca Alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in “orphaned” RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted Alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, Alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca Alternans; 2) for down-regulated SERCA, Alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca Alternans. In conclusion, the mechanisms of Ca Alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca Alternans by both mechanisms, which may contribute to Alternans at different stages of HF.
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calcium Alternans in cardiac myocytes order from disorder
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Zhilin Qu, Michael Nivala, James N. WeissAbstract:Abstract Calcium Alternans is associated with T-wave Alternans and pulsus Alternans, harbingers of increased mortality in the setting of heart disease. Recent experimental, computational, and theoretical studies have led to new insights into the mechanisms of Ca Alternans, specifically how disordered behaviors dominated by stochastic processes at the subcellular level become organized into ordered periodic behaviors. In this article, we summarize the recent progress in this area, outlining a holistic theoretical framework in which the complex effects of Ca cycling proteins on Ca Alternans are linked to three key properties of the cardiac Ca cycling network: randomness, refractoriness, and recruitment. We also illustrate how this ‘3R theory’ can reconcile many seemingly contradictory experimental observations. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.
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Controlling cardiac Alternans.
Heart Rhythm, 2012Co-Authors: Zhilin QuAbstract:TWA is an electrocardiogram (ECG) manifestation ofrepolarization or action potential duration (APD) Alternans.Because of the close association between TWA and ven-tricular arrhythmias, an interesting question arises: Canprevention of APD Alternans prevent arrhythmias? Oneway to prevent Alternans is to use control theories ofnonlinear systems to control APD Alternans by electricalpacing. The first such control algorithm was proposed byChristini and Collins
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t wave Alternans and arrhythmogenesis in cardiac diseases
Frontiers in Physiology, 2010Co-Authors: Zhilin Qu, Alan Garfinkel, James N. WeissAbstract:T-wave Alternans, a manifestation of repolarization Alternans at the cellular level, is associated with lethal cardiac arrhythmias and sudden cardiac death. At the cellular level, several mechanisms can produce repolarization Alternans, including: 1) electrical restitution resulting from collective ion channel recovery, which usually occurs at fast heart rates but can also occur at normal heart rates when action potential is prolonged resulting in a short diastolic interval; 2) the transient outward current, which tends to occur at normal or slow heart rates; 3) the dynamics of early afterdepolarizations, which tends to occur during bradycardia; and 4) intracellular calcium cycling Alternans through its interaction with membrane voltage. In this review, we summarize the cellular mechanisms of Alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease.
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dynamic origin of spatially discordant Alternans in cardiac tissue
Biophysical Journal, 2007Co-Authors: Hideki Hayashi, Yohannes Shiferaw, Motoki Nihei, Alan Garfinkel, James N. Weiss, Daisuke Sato, Peng Sheng Chen, Zhilin QuAbstract:Alternans, a condition in which there is a beat-to-beat alternation in the electromechanical response of a periodically stimulated cardiac cell, has been linked to the genesis of life-threatening ventricular arrhythmias. Optical mapping of membrane voltage (Vm) and intracellular calcium (Cai) on the surface of animal hearts reveals complex spatial patterns of Alternans. In particular, spatially discordant Alternans has been observed in which regions with a large-small-large action potential duration (APD) alternate out-of-phase adjacent to regions of small-large-small APD. However, the underlying mechanisms that lead to the initiation of discordant Alternans and govern its spatiotemporal properties are not well understood. Using mathematical modeling, we show that dynamic changes in the spatial distribution of discordant Alternans can be used to pinpoint the underlying mechanisms. Optical mapping of Vm and Cai in paced rabbit hearts revealed that spatially discordant Alternans induced by rapid pacing exhibits properties consistent with a purely dynamical mechanism as shown in theoretical studies. Our results support the viewpoint that spatially discordant Alternans in the heart can be formed via a dynamical pattern formation process which does not require tissue heterogeneity.
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, Hrayr S Karagueuzian, Alan Garfinkel, Riccardo Olcese, James N. Weiss, Enno Lange, 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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t tubule disruption promotes calcium Alternans in failing ventricular myocytes mechanistic insights from computational modeling
Journal of Molecular and Cellular Cardiology, 2015Co-Authors: Michael Nivala, Zhen Song, James N. Weiss, Zhilin QuAbstract:In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the mechanisms of TT disruption and other HF remodeling factors on Ca Alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in “orphaned” RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted Alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, Alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca Alternans; 2) for down-regulated SERCA, Alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca Alternans. In conclusion, the mechanisms of Ca Alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca Alternans by both mechanisms, which may contribute to Alternans at different stages of HF.
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calcium Alternans in cardiac myocytes order from disorder
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Zhilin Qu, Michael Nivala, James N. WeissAbstract:Abstract Calcium Alternans is associated with T-wave Alternans and pulsus Alternans, harbingers of increased mortality in the setting of heart disease. Recent experimental, computational, and theoretical studies have led to new insights into the mechanisms of Ca Alternans, specifically how disordered behaviors dominated by stochastic processes at the subcellular level become organized into ordered periodic behaviors. In this article, we summarize the recent progress in this area, outlining a holistic theoretical framework in which the complex effects of Ca cycling proteins on Ca Alternans are linked to three key properties of the cardiac Ca cycling network: randomness, refractoriness, and recruitment. We also illustrate how this ‘3R theory’ can reconcile many seemingly contradictory experimental observations. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.
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t wave Alternans and arrhythmogenesis in cardiac diseases
Frontiers in Physiology, 2010Co-Authors: Zhilin Qu, Alan Garfinkel, James N. WeissAbstract:T-wave Alternans, a manifestation of repolarization Alternans at the cellular level, is associated with lethal cardiac arrhythmias and sudden cardiac death. At the cellular level, several mechanisms can produce repolarization Alternans, including: 1) electrical restitution resulting from collective ion channel recovery, which usually occurs at fast heart rates but can also occur at normal heart rates when action potential is prolonged resulting in a short diastolic interval; 2) the transient outward current, which tends to occur at normal or slow heart rates; 3) the dynamics of early afterdepolarizations, which tends to occur during bradycardia; and 4) intracellular calcium cycling Alternans through its interaction with membrane voltage. In this review, we summarize the cellular mechanisms of Alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease.
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dynamic origin of spatially discordant Alternans in cardiac tissue
Biophysical Journal, 2007Co-Authors: Hideki Hayashi, Yohannes Shiferaw, Motoki Nihei, Alan Garfinkel, James N. Weiss, Daisuke Sato, Peng Sheng Chen, Zhilin QuAbstract:Alternans, a condition in which there is a beat-to-beat alternation in the electromechanical response of a periodically stimulated cardiac cell, has been linked to the genesis of life-threatening ventricular arrhythmias. Optical mapping of membrane voltage (Vm) and intracellular calcium (Cai) on the surface of animal hearts reveals complex spatial patterns of Alternans. In particular, spatially discordant Alternans has been observed in which regions with a large-small-large action potential duration (APD) alternate out-of-phase adjacent to regions of small-large-small APD. However, the underlying mechanisms that lead to the initiation of discordant Alternans and govern its spatiotemporal properties are not well understood. Using mathematical modeling, we show that dynamic changes in the spatial distribution of discordant Alternans can be used to pinpoint the underlying mechanisms. Optical mapping of Vm and Cai in paced rabbit hearts revealed that spatially discordant Alternans induced by rapid pacing exhibits properties consistent with a purely dynamical mechanism as shown in theoretical studies. Our results support the viewpoint that spatially discordant Alternans in the heart can be formed via a dynamical pattern formation process which does not require tissue heterogeneity.
Alan Garfinkel - One of the best experts on this subject based on the ideXlab platform.
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Eight (or more) kinds of Alternans.
Journal of electrocardiology, 2020Co-Authors: Alan GarfinkelAbstract:Cardiac electrical Alternans is an alternating rhythm in the electrical properties of the heart, such as cellular action potential duration, conduction velocity, and/or intracellular calcium (Ca) concentrations. These alternations can initiate reentrant arrhythmias and can also break up ongoing reentry, creating ventricular fibrillation. Alternans can take several forms. The alternation in time can be uniform in space (concordant Alternans) or can have regions that are out of phase with other regions (discordant Alternans). Alternans can be driven by voltage instabilities (involving electrical restitution) or by Ca instabilities. In addition, the relation between voltage and Ca can be positive or negative. Anatomical factors can play a role in generating spatially discordant Alternans, but there is also a critical role for instabilities that are dynamically generated and can only be understood as the response of a nonlinear medium to periodic excitation. This is especially true of spatially discordant Alternans, the most deadly form. We will review the role of factors such as action potential duration, conduction velocity, and Ca, which interact with each other to produce Alternans. Simulations of cardiac conduction support these conclusions, as do experiments in a variety of animal and human preparations.
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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, Hrayr S Karagueuzian, Alan Garfinkel, Riccardo Olcese, James N. Weiss, Enno Lange, 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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t wave Alternans and arrhythmogenesis in cardiac diseases
Frontiers in Physiology, 2010Co-Authors: Zhilin Qu, Alan Garfinkel, James N. WeissAbstract:T-wave Alternans, a manifestation of repolarization Alternans at the cellular level, is associated with lethal cardiac arrhythmias and sudden cardiac death. At the cellular level, several mechanisms can produce repolarization Alternans, including: 1) electrical restitution resulting from collective ion channel recovery, which usually occurs at fast heart rates but can also occur at normal heart rates when action potential is prolonged resulting in a short diastolic interval; 2) the transient outward current, which tends to occur at normal or slow heart rates; 3) the dynamics of early afterdepolarizations, which tends to occur during bradycardia; and 4) intracellular calcium cycling Alternans through its interaction with membrane voltage. In this review, we summarize the cellular mechanisms of Alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease.
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dynamic origin of spatially discordant Alternans in cardiac tissue
Biophysical Journal, 2007Co-Authors: Hideki Hayashi, Yohannes Shiferaw, Motoki Nihei, Alan Garfinkel, James N. Weiss, Daisuke Sato, Peng Sheng Chen, Zhilin QuAbstract:Alternans, a condition in which there is a beat-to-beat alternation in the electromechanical response of a periodically stimulated cardiac cell, has been linked to the genesis of life-threatening ventricular arrhythmias. Optical mapping of membrane voltage (Vm) and intracellular calcium (Cai) on the surface of animal hearts reveals complex spatial patterns of Alternans. In particular, spatially discordant Alternans has been observed in which regions with a large-small-large action potential duration (APD) alternate out-of-phase adjacent to regions of small-large-small APD. However, the underlying mechanisms that lead to the initiation of discordant Alternans and govern its spatiotemporal properties are not well understood. Using mathematical modeling, we show that dynamic changes in the spatial distribution of discordant Alternans can be used to pinpoint the underlying mechanisms. Optical mapping of Vm and Cai in paced rabbit hearts revealed that spatially discordant Alternans induced by rapid pacing exhibits properties consistent with a purely dynamical mechanism as shown in theoretical studies. Our results support the viewpoint that spatially discordant Alternans in the heart can be formed via a dynamical pattern formation process which does not require tissue heterogeneity.
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Inferring the Cellular Origin of Voltage and Calcium Alternans from the Spatial Scales of Phase Reversal during Discordant Alternans
Biophysical Journal, 2006Co-Authors: Daisuke Sato, Yohannes Shiferaw, Alan Garfinkel, James N. Weiss, Zhilin Qu, Alain KarmaAbstract:Beat-to-beat alternation of the action potential duration (APD) in paced cardiac cells has been linked to the onset of lethal arrhythmias. Both experimental and theoretical studies have shown that Alternans at the single cell level can be caused by unstable membrane voltage (Vm) dynamics linked to steep APD-restitution, or unstable intracellular calcium (Ca) cycling linked to high sensitivity of Ca release from the sarcoplasmic reticulum on sarcoplasmic reticulum Ca load. Identifying which of these two mechanisms is the primary cause of cellular Alternans, however, has remained difficult since Ca and Vm are bidirectionally coupled. Here, we use numerical simulations of a physiologically detailed ionic model to show that the origin of Alternans can be inferred by measuring the length scales over which APD and Cai Alternans reverse phase during spatially discordant Alternans. The main conclusion is that these scales are comparable to a few millimeters and equal when Alternans is driven by APD restitution, but differ markedly when Alternans is driven predominantly by unstable Ca cycling. In the latter case, APD Alternans still reverses phase on a millimeter tissue scale due to electrotonic coupling, while Ca Alternans reverses phase on a submillimeter cellular scale. These results show that experimentally accessible measurements of Cai and Vm in cardiac tissue can be used to shed light on the cellular origin of Alternans.
David S. Rosenbaum - One of the best experts on this subject based on the ideXlab platform.
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cellular mechanisms of arrhythmogenic cardiac Alternans
Progress in Biophysics & Molecular Biology, 2008Co-Authors: Kenneth R Laurita, David S. RosenbaumAbstract:Despite the strong association between mechanical dysfunction of the heart and sudden death due to arrhythmias, the causal relationship is not well understood. Cardiac Alternans has been linked to arrhythmogenesis and can be mediated by intracellular calcium handling. Given the integral role intracellular calcium plays in contractile function, calcium-mediated Alternans may represent an important mechanistic link between mechanical dysfunction and electrical instability. This relationship, however, is not well understood due to complex feedback between membrane currents, intracellular calcium, and contraction. This manuscript describes the cellular mechanisms of cardiac Alternans. Through several pathways, calcium transient Alternans is coupled to repolarization Alternans that can form a substrate for reentrant excitation. Abnormal intracellular calcium cycling, either impaired release or impaired reuptake of sarcoplasmic reticulum calcium, is a cellular mechanism of calcium transient Alternans. Thus, cardiac Alternans is an important mechanistic link between mechanical dysfunction and sudden cardiac death.
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Mechanisms of arrythmogenic cardiac Alternans.
Europace, 2007Co-Authors: Lance D Wilson, David S. RosenbaumAbstract:T-wave Alternans, a powerful marker for the risk of sudden cardiac death is directly related to Alternans of the cellular action potential. When action potential Alternans is first initiated, it occurs with identical phase in all cells of a particular region of the heart. However, above a critical heart rate threshold, action potential Alternans switches phase in some cells but not in others, such that some cells undergo a prolongation of action potential duration (APD), whereas neighbouring cells undergo APD shortening on the same beat (i.e. discordant Alternans). Discordant Alternans is linked to a mechanism of arrhythmogenesis because when ventricular action potentials from neighbouring cells are alternating out of phase, repolarization gradients are amplified, producing conduction block and re-entrant excitation. In this review, we discuss potential mechanisms which may underlie discordant Alternans in the heart, including (i) conduction velocity restitution, (ii) spatial heterogeneities of calcium cycling and the sarcolemmal ionic currents which govern repolarization, and (iii) intercellular uncoupling.
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role of calcium cycling versus restitution in the mechanism of repolarization Alternans
Circulation Research, 2004Co-Authors: Etienne Pruvot, Rodolphe P Katra, David S. Rosenbaum, Kenneth R LauritaAbstract:T-wave Alternans, a powerful marker of arrhythmic events, results from alternation in action potential duration (APD). The underlying cellular mechanism of APD Alternans is unknown but has been attributed to either intracellular calcium (Ca 2+ ) cycling or membrane ionic currents, manifested by a steep slope of cellular APD restitution. To address these mechanisms, high-resolution optical mapping techniques were used to measure action potentials and Ca 2+ transients simultaneously from hundreds of epicardial sites in the guinea pig model of pacing-induced T-wave Alternans (n=7). The pacing rates (ie, Alternans threshold) at which T-wave (369±11 bpm), APD (369±21 bpm), and Ca 2+ (371±29 bpm) Alternans first appeared were comparable. Importantly, the site of origin of APD Alternans and Ca 2+ Alternans consistently occurred together near the base of the left ventricle, not where APD restitution was steepest. In addition, APD and Ca 2+ Alternans were remarkably similar both spatially and temporally during discordant Alternans. In conclusion, the mechanism underlying T-wave Alternans in the intact heart is more closely associated with intracellular Ca 2+ cycling rather than APD restitution.
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role of structural barriers in the mechanism of Alternans induced reentry
Circulation Research, 2000Co-Authors: Joseph M Pastore, David S. RosenbaumAbstract:Abstract —Previously, using an animal model of T-wave Alternans in structurally normal myocardium, we demonstrated that repolarization can alternate with opposite phase between neighboring myocytes (ie, discordant Alternans), causing spatial dispersions of repolarization that form the substrate for functional block and reentrant ventricular fibrillation (VF). However, the mechanisms responsible for cellular discordant Alternans and its electrocardiographic manifestation (ie, T-wave Alternans) in patients with structural heart disease are unknown. We hypothesize that electrotonic uncoupling between neighboring regions of cells by a structural barrier (SB) is a mechanism for discordant Alternans. Using voltage-sensitive dyes, ventricular action potentials were recorded from 26 Langendorff-perfused guinea pig hearts in the absence (ie, control) and presence of an insulating SB produced by an epicardial laser lesion. Quantitative analysis of magnitude and phase of cellular Alternans revealed that in controls, action potential duration alternated in phase at all ventricular sites above a critical heart rate (269±17 bpm), ie, concordant Alternans. Also, above a faster critical heart rate threshold (335±24 bpm), action potential duration alternated with opposite phase between sites, ie, discordant Alternans. In contrast, only discordant but not concordant Alternans was observed in 80% of hearts with the SB, and discordant Alternans always occurred at a significantly slower heart rate (by 68±28 bpm) compared with controls. Therefore, the SB had a major effect on the Alternans–heart rate relation, which served to facilitate the development of discordant Alternans. Whether a SB was present or not, discordant Alternans produced considerable increases (by ≈170%) in the maximum spatial gradient of repolarization, which in turn formed the substrate for unidirectional block and reentry. However, by providing a structural anchor for stable reentry, discordant Alternans in the presence of a SB led most often to sustained monomorphic ventricular tachycardia rather than to VF, whereas in the absence of a SB discordant Alternans caused VF. SBs facilitate development of discordant Alternans between cells with different ionic properties by electrotonically uncoupling neighboring regions of myocardium. This may explain why arrhythmia-prone patients with structural heart disease exhibit T-wave Alternans at lower heart rates. These data also suggest a singular mechanism by which T-wave Alternans forms a substrate for initiation of both VF and sustained monomorphic ventricular tachycardia.
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mechanism linking t wave Alternans to the genesis of cardiac fibrillation
Circulation, 1999Co-Authors: Joseph M Pastore, Kenneth R Laurita, Steven D Girouard, Fadi G Akar, David S. RosenbaumAbstract:Background—Although T-wave Alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave Alternans and their role, if any, in the mechanism of reentry remain unclear. Methods and Results—T-wave Alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209±46 bpm) that was significantly lower (by 57±36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization Alternans varied substantially between cells across the epicardial surface. T-wave Alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular re...
Alain Karma - One of the best experts on this subject based on the ideXlab platform.
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Inferring the Cellular Origin of Voltage and Calcium Alternans from the Spatial Scales of Phase Reversal during Discordant Alternans
Biophysical Journal, 2006Co-Authors: Daisuke Sato, Yohannes Shiferaw, Alan Garfinkel, James N. Weiss, Zhilin Qu, Alain KarmaAbstract:Beat-to-beat alternation of the action potential duration (APD) in paced cardiac cells has been linked to the onset of lethal arrhythmias. Both experimental and theoretical studies have shown that Alternans at the single cell level can be caused by unstable membrane voltage (Vm) dynamics linked to steep APD-restitution, or unstable intracellular calcium (Ca) cycling linked to high sensitivity of Ca release from the sarcoplasmic reticulum on sarcoplasmic reticulum Ca load. Identifying which of these two mechanisms is the primary cause of cellular Alternans, however, has remained difficult since Ca and Vm are bidirectionally coupled. Here, we use numerical simulations of a physiologically detailed ionic model to show that the origin of Alternans can be inferred by measuring the length scales over which APD and Cai Alternans reverse phase during spatially discordant Alternans. The main conclusion is that these scales are comparable to a few millimeters and equal when Alternans is driven by APD restitution, but differ markedly when Alternans is driven predominantly by unstable Ca cycling. In the latter case, APD Alternans still reverses phase on a millimeter tissue scale due to electrotonic coupling, while Ca Alternans reverses phase on a submillimeter cellular scale. These results show that experimentally accessible measurements of Cai and Vm in cardiac tissue can be used to shed light on the cellular origin of Alternans.
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from pulsus to pulseless the saga of cardiac Alternans
Circulation Research, 2006Co-Authors: James N. Weiss, Alain Karma, Yohannes Shiferaw, Alan Garfinkel, Peng Sheng Chen, Zhilin QuAbstract:Computer simulations and nonlinear dynamics have provided invaluable tools for illuminating the underlying mechanisms of cardiac arrhythmias. Here, we review how this approach has led to major insights into the mechanisms of spatially discordant Alternans, a key arrhythmogenic factor predisposing the heart to re-entry and lethal arrhythmias. During spatially discordant Alternans, the action potential duration (APD) alternates out of phase in different regions of the heart, markedly enhancing dispersion of refractoriness so that ectopic beats have a high probability of inducing reentry. We show how, at the cellular level, instabilities in membrane voltage (ie, steep APD restitution slope) and intracellular Ca (Ca i ) cycling dynamics cause APD and the Ca i transient to alternate and how the characteristics of Alternans are affected by different “modes” of the bidirectional coupling between voltage and Ca i . We illustrate how, at the tissue level, additional factors, such as conduction velocity restitution and ectopic beats, promote spatially discordant Alternans. These insights have illuminated the mechanistic basis underlying the clinical association of cardiac Alternans (eg, T wave Alternans) with arrhythmia risk, which may lead to novel therapeutic approaches to avert sudden cardiac death.
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control of electrical Alternans in canine cardiac purkinje fibers
Physical Review Letters, 2006Co-Authors: David J. Christini, Calin A Culianu, Mark L Riccio, Alain Karma, Robert F GilmourAbstract:: Alternation in the duration of consecutive cardiac action potentials (electrical Alternans) may precipitate conduction block and the onset of arrhythmias. Consequently, suppression of Alternans using properly timed premature stimuli may be antiarrhythmic. To determine the extent to which Alternans control can be achieved in cardiac tissue, isolated canine Purkinje fibers were paced from one end using a feedback control method. Spatially uniform control of Alternans was possible when Alternans amplitude was small. However, control became attenuated spatially as Alternans amplitude increased. The amplitude variation along the cable was well described by a theoretically expected standing wave profile that corresponds to the first quantized mode of the one-dimensional Helmholtz equation. These results confirm the wavelike nature of Alternans and may have important implications for their control using electrical stimuli.
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Spatiotemporal control of cardiac Alternans.
Chaos, 2002Co-Authors: Blas Echebarria, Alain KarmaAbstract:Electrical Alternans are believed to be linked to the onset of life-threatening ventricular arrhythmias and sudden cardiac death. Recent studies have shown that Alternans can be suppressed temporally by dynamic feedback control of the pacing interval. Here we investigate theoretically whether control can suppress Alternans both temporally and spatially in homogeneous tissue paced at a single site. We first carry out ionic model simulations in a one-dimensional cable geometry which show that control is only effective up to a maximum cable length that decreases sharply away from the Alternans bifurcation point. We then explain this finding by a linear stability analysis of an amplitude equation that describes the spatiotemporal evolution of Alternans. This analysis reveals that control failure above a critical cable length is caused by the formation of standing wave patterns of Alternans that are eigenfunctions of a forced Helmholtz equation, and therefore remarkably analogous to sound harmonics in an open ...
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Spatiotemporal control of cardiac Alternans.
Chaos, 2002Co-Authors: Blas Echebarria, Alain KarmaAbstract:Electrical Alternans are believed to be linked to the onset of life-threatening ventricular arrhythmias and sudden cardiac death. Recent studies have shown that Alternans can be suppressed temporally by dynamic feedback control of the pacing interval. Here we investigate theoretically whether control can suppress Alternans both temporally and spatially in homogeneous tissue paced at a single site. We first carry out ionic model simulations in a one-dimensional cable geometry which show that control is only effective up to a maximum cable length that decreases sharply away from the Alternans bifurcation point. We then explain this finding by a linear stability analysis of an amplitude equation that describes the spatiotemporal evolution of Alternans. This analysis reveals that control failure above a critical cable length is caused by the formation of standing wave patterns of Alternans that are eigenfunctions of a forced Helmholtz equation, and therefore remarkably analogous to sound harmonics in an open pipe. We discuss the implications of these results for using control to suppress Alternans in the human ventricles as well as to probe fundamental aspects of Alternans morphogenesis.
