Mechanism for Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos

Chen, Diandian Diana; Gray, Richard A.; Uzelac, Ilija; Herndon, Conner; Fenton, Flavio H.

doi:10.1103/physrevlett.118.168101

Cited by 25 publications

(18 citation statements)

References 37 publications

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“…In experiments, alternans in voltage develops gradually, appearing to be more consistent with a border-collision bifurcation (Cherry and Fenton, 2007 , 2008 ; Zhao et al, 2008 ), where small changes in duration grow slowly and mostly linearly, whereas in the model alternans grows much faster, as with a pitchfork bifurcation (Cherry and Fenton, 2008 ). Furthermore, the model does not yield action potential amplitude (APA) alternans as observed in the experiments when the tissue is paced at very short pacing cycle lengths (see Supplementary Figure 4 for the APA bifurcation map from experiment), an important additional pro-arrhythmic mechanism recently described by Myles et al ( 2011 ); Chen et al ( 2017 ). On the other hand, while intracellular calcium does display amplitude alternans in both experiments and simulations, in experiments amplitude alternans develops slowly, while in the model a large difference in amplitude appears as soon as alternans develops and persists with a similar amplitude for all periods where alternans is present, as shown in Figure 6 .…”

Section: Discussionmentioning

confidence: 88%

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Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in Langendorff-Perfused Rabbit Hearts and Inconsistencies with Models of Cardiac Action Potentials and Ca Transients

Uzelac

Hornung

et al. 2017

Front. Physiol.

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Rationale: Discordant alternans, a phenomenon in which the action potential duration (APDs) and/or intracellular calcium transient durations (CaDs) in different spatial regions of cardiac tissue are out of phase, present a dynamical instability for complex spatial dispersion that can be associated with long-QT syndrome (LQTS) and the initiation of reentrant arrhythmias. Because the use of numerical simulations to investigate arrhythmic effects, such as acquired LQTS by drugs is beginning to be studied by the FDA, it is crucial to validate mathematical models that may be used during this process.Objective: In this study, we characterized with high spatio-temporal resolution the development of discordant alternans patterns in transmembrane voltage (V m ) and intracellular calcium concentration ([Ca i ] +2 ) as a function of pacing period in rabbit hearts. Then we compared the dynamics to that of the latest state-of-the-art model for ventricular action potentials and calcium transients to better understand the underlying mechanisms of discordant alternans and compared the experimental data to the mathematical models representing V m and [Ca i ] +2 dynamics. Methods and Results:We performed simultaneous dual optical mapping imaging of V m and [Ca i ] +2 in Langendorff-perfused rabbit hearts with higher spatial resolutions compared with previous studies. The rabbit hearts developed discordant alternans through decreased pacing period protocols and we quantified the presence of multiple nodal points along the direction of wave propagation, both in APD and CaD, and compared these findings with results from theoretical models. In experiments, the nodal lines of CaD alternans have a steeper slope than those of APD alternans, but not as steep as predicted by numerical simulations in rabbit models. We further quantified several additional discrepancies between models and experiments.Uzelac et al. Simultaneous Quantification of Voltage and Intracellular CalciumConclusions: Alternans in CaD have nodal lines that are about an order of magnitude steeper compared to those of APD alternans. Current action potential models lack the necessary coupling between voltage and calcium compared to experiments and fail to reproduce some key dynamics such as, voltage amplitude alternans, smooth development of calcium alternans in time, conduction velocity and the steepness of the nodal lines of APD and CaD.

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Section: Discussionmentioning

confidence: 88%

“…This is in contrast to experiments, where at very short cycle lengths alternans in amplitude is readily observed (Figure 2A ). Recent experiments and theory predict that the presence of amplitude alternans is key in the development of reentrant arrhythmias (Myles et al, 2011 ; Chen et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in Langendorff-Perfused Rabbit Hearts and Inconsistencies with Models of Cardiac Action Potentials and Ca Transients

Uzelac

Hornung

et al. 2017

Front. Physiol.

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“…Qu et al [86] have previously shown that reduction in the Na + channel conductance or slowing its recovery prolongs ERP, alters APD restitution, reduces CV, and broadens CV restitution, promoting discordant APD alternans. It may also cause cellular APA alternans that is linked to QRS alternans [87], contributing to initiation of spiral waves and complex dynamics of re-entrant excitations. Whilst our simulation results are consistent with those findings in demonstrating the role of a reduced I Na in promoting alternans genesis, we also provide new findings suggesting that an abnormally augmented Na + channel conductance also promotes alternans.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia—A simulation study

Wang

Zhang

et al. 2018

PLoS Comput Biol

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Cardiac electrical alternans (CEA), manifested as T-wave alternans in ECG, is a clinical biomarker for predicting cardiac arrhythmias and sudden death. However, the mechanism underlying the spontaneous transition from CEA to arrhythmias remains incompletely elucidated. In this study, multiscale rabbit ventricular models were used to study the transition and a potential role of INa in perpetuating such a transition. It was shown CEA evolved into either concordant or discordant action potential (AP) conduction alternans in a homogeneous one-dimensional tissue model, depending on tissue AP duration and conduction velocity (CV) restitution properties. Discordant alternans was able to cause conduction failure in the model, which was promoted by impaired sodium channel with either a reduced or increased channel current. In a two-dimensional homogeneous tissue model, a combined effect of rate- and curvature-dependent CV broke-up alternating wavefronts at localised points, facilitating a spontaneous transition from CEA to re-entry. Tissue inhomogeneity or anisotropy further promoted break-up of re-entry, leading to multiple wavelets. Similar observations have also been seen in human atrial cellular and tissue models. In conclusion, our results identify a mechanism by which CEA spontaneously evolves into re-entry without a requirement for premature ventricular complexes or pre-existing tissue heterogeneities, and demonstrated the important pro-arrhythmic role of impaired sodium channel activity. These findings are model-independent and have potential human relevance.

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“…VF results from unstable reentrant waves of electrical activity throughout the heart (Winfree, 1994; Gray et al, 1995, 1998) that quickly leads to death if not terminated by an electric shock. Although high-resolution “optical mapping” has demonstrated organized electrical activity on the surface of small and large mammalian hearts in the form of spiral waves (Gray et al, 1995, 1998; Gray and Chattipakorn, 2005; Park and Gray, 2015), the detailed three-dimensional structure of such waves remains incompletely understood (Baxter et al, 2001; Fenton et al, 2018). Computer simulations of reentrant electrical waves in cardiac tissue continue to be an important tool to study the complex dynamics during fibrillation.…”

Section: Introductionmentioning

confidence: 99%

Effect of Heart Structure on Ventricular Fibrillation in the Rabbit: A Simulation Study

et al. 2019

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Ventricular fibrillation (VF) is a lethal condition that affects millions worldwide. The mechanism underlying VF is unstable reentrant electrical waves rotating around lines called filaments. These complex spatio-temporal patterns can be studied using both experimental and numerical methods. Computer simulations provide unique insights including high resolution dynamics throughout the heart and systematic control of quantities such as fiber orientation and cellular kinetics that are not feasible experimentally. Here we study filament dynamics using two bi-ventricular 3-D high-resolution rabbit heart geometries, one with detailed fine structure and another without fine structure. We studied filament dynamics using anisotropic and isotropic conductivities, and with four cellular action potential models with different recovery kinetics. Spiral wave dynamics observed in isotropic two-dimensional sheets were not predictive of the behavior in the whole heart. In 2-D the four cell models exhibited stable reentry, meandering spiral waves, and spiral-wave breakup. In the whole heart with fine structure, all simulation results exhibited complex dynamics reminiscent of fibrillation observed experimentally. In the whole heart without fine structure, anisotropy acted to destabilize filament dynamics although the number of filaments was reduced compared to the heart with structure. In addition, in isotropic hearts without structure the two cell models that exhibited meandering spiral waves in 2-D, stabilized into figure-of-eight surface patterns. We also studied the sensitivity of filament dynamics to computer system configuration and initial conditions. After large simulation times, different macroscopic results sometimes occurred across different system configurations, likely due to a lack of bitwise reproducibility. The study conclusions were insensitive to initial condition perturbations, however, the exact number of filaments over time and their trends were altered by these changes. In summary, we present the following new results. First, we provide a new cell model that resembles the surface patterns of VF in the rabbit heart both qualitatively and quantitatively. Second, filament dynamics in the whole heart cannot be predicted from spiral wave dynamics in 2-D and we identified anisotropy as one destabilizing factor. Third, the exact dynamics of filaments are sensitive to a variety of factors, so we suggest caution in their interpretation and their quantitative analyses.

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Mechanism for Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos

Cited by 25 publications

References 37 publications

Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in Langendorff-Perfused Rabbit Hearts and Inconsistencies with Models of Cardiac Action Potentials and Ca Transients

Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in Langendorff-Perfused Rabbit Hearts and Inconsistencies with Models of Cardiac Action Potentials and Ca Transients

Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia—A simulation study

Effect of Heart Structure on Ventricular Fibrillation in the Rabbit: A Simulation Study

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