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Alternans

The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform

Zhilin Qu – 1st expert on this subject based on the ideXlab platform

  • t tubule disruption promotes calcium Alternans in failing ventricular myocytes mechanistic insights from computational modeling
    Journal of Molecular and Cellular Cardiology, 2015
    Co-Authors: Michael Nivala, James N. Weiss, Zhen Song, Zhilin Qu

    Abstract:

    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.

  • calcium Alternans in cardiac myocytes order from disorder
    Journal of Molecular and Cellular Cardiology, 2013
    Co-Authors: Zhilin Qu, Michael Nivala, James N. Weiss

    Abstract:

    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”.

  • Controlling cardiac Alternans.
    Heart Rhythm, 2012
    Co-Authors: Zhilin Qu

    Abstract:

    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

James N. Weiss – 2nd expert on this subject based on the ideXlab platform

  • stochastic pacing reveals the propensity to cardiac action potential Alternans and uncovers its underlying dynamics
    The Journal of Physiology, 2016
    Co-Authors: Yann Prudat, James N. Weiss, Alan Garfinkel, Roshni V Madhvani, Marina Angelini, Nils P Borgstom, Hrayr S Karagueuzian, Enno Lange, Riccardo Olcese, Jan Kucera

    Abstract:

    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.

  • t tubule disruption promotes calcium Alternans in failing ventricular myocytes mechanistic insights from computational modeling
    Journal of Molecular and Cellular Cardiology, 2015
    Co-Authors: Michael Nivala, James N. Weiss, Zhen Song, Zhilin Qu

    Abstract:

    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.

  • calcium Alternans in cardiac myocytes order from disorder
    Journal of Molecular and Cellular Cardiology, 2013
    Co-Authors: Zhilin Qu, Michael Nivala, James N. Weiss

    Abstract:

    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”.

Alan Garfinkel – 3rd expert on this subject based on the ideXlab platform

  • Eight (or more) kinds of Alternans.
    Journal of electrocardiology, 2020
    Co-Authors: Alan Garfinkel

    Abstract:

    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.

  • stochastic pacing reveals the propensity to cardiac action potential Alternans and uncovers its underlying dynamics
    The Journal of Physiology, 2016
    Co-Authors: Yann Prudat, James N. Weiss, Alan Garfinkel, Roshni V Madhvani, Marina Angelini, Nils P Borgstom, Hrayr S Karagueuzian, Enno Lange, Riccardo Olcese, Jan Kucera

    Abstract:

    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.

  • t wave Alternans and arrhythmogenesis in cardiac diseases
    Frontiers in Physiology, 2010
    Co-Authors: Zhilin Qu, Alan Garfinkel, James N. Weiss

    Abstract:

    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.