The Na<sup>+</sup>/K<sup>+</sup> pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue

Sánchez, Carlos; Corrias, Alberto; Bueno‐Orovio, Alfonso; Davies, Mark; Swinton, Jonathan; Jacobson, Ingemar; Laguna, Pablo; Pueyo, Esther; Rodriguez, Blanca

doi:10.1152/ajpheart.00668.2011

Cited by 44 publications

(47 citation statements)

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“…5). A recent modeling paper 44 analyzed systematically the relative importance of ionic currents and transporters in modulating excitability, refractoriness, and rotor dynamics in human atrial tissue. Results underscored the important role of the Na/K pump in modulating APD, restitution, and dominant frequency (DF) of the reentrant activity, providing comparisons between behavior in sinus rhythm and persistent AF; I K1 and I Na were both found to strongly affect rotor stability.…”

Section: Exploring Atrial Fibrillation Mechanisms: Insights From Mmentioning

confidence: 99%

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation

Trayanova

2014

Circulation Research

109

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Atrial fibrillation (AF) is the most common sustained arrhythmia in humans. The mechanisms that govern AF initiation and persistence are highly complex, of dynamic nature, and involve interactions across multiple temporal and spatial scales in the atria. This articles aims to review the mathematical modeling and computer simulation approaches to understanding AF mechanisms and aiding in its management. Various atrial modeling approaches are presented, with descriptions of the methodological basis and advancements in both lower-dimensional and realistic geometry models. A review of the most significant mechanistic insights made by atrial simulations is provided. The article showcases the contributions that atrial modeling and simulation have made not only to our understanding of the pathophysiology of atrial arrhythmias, but also to the development of AF management approaches. A summary of the future developments envisioned for the field of atrial simulation and modeling is also presented. The review contends that computational models of the atria assembled with data from clinical imaging modalities that incorporate electrophysiological and structural remodeling could become a first line of screening for new AF therapies and approaches, new diagnostic developments, and new methods for arrhythmia prevention.

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Section: Exploring Atrial Fibrillation Mechanisms: Insights From Mmentioning

confidence: 99%

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation

Trayanova

2014

Circulation Research

109

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“…Such a mechanism is indeed expected to be of greater importance in the ventricles, where Ca 2+ currents play a greater role in modulating rate dependence as compared to the more triangular APs in the atria (Sánchez et al, 2012). These results thus mechanistically explain the good performance of class Ic anti-arrhythmics in terminating atrial fibrillation, but at the cost of increased susceptibility to ventricular arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation

Lawson

Burrage

et al. 2018

Front. Physiol.

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Purpose: Rotor stability and meandering are key mechanisms determining and sustaining cardiac fibrillation, with important implications for anti-arrhythmic drug development. However, little is yet known on how rotor dynamics are modulated by variability in cellular electrophysiology, particularly on kinetic properties of ion channel recovery.Methods: We propose a novel emulation approach, based on Gaussian process regression augmented with machine learning, for data enrichment, automatic detection, classification, and analysis of re-entrant biomarkers in cardiac tissue. More than 5,000 monodomain simulations of long-lasting arrhythmic episodes with Fenton-Karma ionic dynamics, further enriched by emulation to 80 million electrophysiological scenarios, were conducted to investigate the role of variability in ion channel densities and kinetics in modulating rotor-driven arrhythmic behavior.Results: Our methods predicted the class of excitation behavior with classification accuracy up to 96%, and emulation effectively predicted frequency, stability, and spatial biomarkers of functional re-entry. We demonstrate that the excitation wavelength interpretation of re-entrant behavior hides critical information about rotor persistence and devolution into fibrillation. In particular, whereas action potential duration directly modulates rotor frequency and meandering, critical windows of excitability are identified as the main determinants of breakup. Further novel electrophysiological insights of particular relevance for ventricular arrhythmias arise from our multivariate analysis, including the role of incomplete activation of slow inward currents in mediating tissue rate-dependence and dispersion of repolarization, and the emergence of slow recovery of excitability as a significant promoter of this mechanism of dispersion and increased arrhythmic risk.Conclusions: Our results mechanistically explain pro-arrhythmic effects of class Ic anti-arrhythmics in the ventricles despite their established role in the pharmacological management of atrial fibrillation. This is mediated by their slow recovery of excitability mode of action, promoting incomplete activation of slow inward currents and therefore increased dispersion of repolarization, given the larger influence of these currents in modulating the action potential in the ventricles compared to the atria. These results exemplify the potential of emulation techniques in elucidating novel mechanisms of arrhythmia and further application to cardiac electrophysiology.

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“…5). As shown in various studies, sensitivity analysis can unravel causes and implications of variability in specific properties, as illustrated in the following studies (84,86,89,90).…”

Section: H150 Bridging Experiments Models and Simulations In Electrmentioning

confidence: 99%

“…Those advances are likely to change the landscape of cardiac electrophysiology and to result in novel ways of coconstructing the human electrophysiology MSE system and with it our knowledge of cardiac electrophysiology. The current maturity of the MSE system in cardiac electrophysiology opens up new perspectives for the potential of computational cardiac electrophysiology for the refinement, reduction, and replacement of animal experiments in research as well as in industrial applications such as drug development (29,35,59,89).…”

Section: H150 Bridging Experiments Models and Simulations In Electrmentioning

confidence: 99%

Bridging experiments, models and simulations: an integrative approach to validation in computational cardiac electrophysiology

Carusi

Burrage

Rodríguez

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Carusi A, Burrage K, Rodríguez B. Bridging experiments, models and simulations: an integrative approach to validation in computational cardiac electrophysiology. Am J Physiol Heart Circ Physiol 303: H144 -H155, 2012. First published May 11, 2012; doi:10.1152/ajpheart.01151.2011.-Computational models in physiology often integrate functional and structural information from a large range of spatiotemporal scales from the ionic to the whole organ level. Their sophistication raises both expectations and skepticism concerning how computational methods can improve our understanding of living organisms and also how they can reduce, replace, and refine animal experiments. A fundamental requirement to fulfill these expectations and achieve the full potential of computational physiology is a clear understanding of what models represent and how they can be validated. The present study aims at informing strategies for validation by elucidating the complex interrelations among experiments, models, and simulations in cardiac electrophysiology. We describe the processes, data, and knowledge involved in the construction of whole ventricular multiscale models of cardiac electrophysiology. Our analysis reveals that models, simulations, and experiments are intertwined, in an assemblage that is a system itself, namely the model-simulation-experiment (MSE) system. We argue that validation is part of the whole MSE system and is contingent upon 1) understanding and coping with sources of biovariability; 2) testing and developing robust techniques and tools as a prerequisite to conducting physiological investigations; 3) defining and adopting standards to facilitate the interoperability of experiments, models, and simulations; 4) and understanding physiological validation as an iterative process that contributes to defining the specific aspects of cardiac electrophysiology the MSE system targets, rather than being only an external test, and that this is driven by advances in experimental and computational methods and the combination of both. computational physiology; systems biology; computer simulations; whole ventricular models; cardiac electrophysiology COMPUTATIONAL PHYSIOLOGY belongs to the broad family of research in the life sciences referred to as systems biology. As with other domains of systems biology, it considers biological processes as systems of interacting components, and draws upon mathematical and computational modeling to bring these into new configurations with experimentation. It shares the basic commitments of systems biology to nonreductionist or integrative principles, geared towards the exploration of emergence and nonlinear interactions among components and between levels (12,16,41,49,53,71,88). From a sociological point of view, it is also a mode of research that depends on a high degree of interdisciplinary collaboration, where the increased sophistication of computational modeling in the life sciences can elicit high expectations but also skepticism sometimes, thus making collaboration more difficult (19,20,...

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The Na⁺/K⁺ pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue

Cited by 44 publications

References 70 publications

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation

Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation

Bridging experiments, models and simulations: an integrative approach to validation in computational cardiac electrophysiology

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The Na+/K+ pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue

Cited by 44 publications

References 70 publications

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation

Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation

Bridging experiments, models and simulations: an integrative approach to validation in computational cardiac electrophysiology

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The Na⁺/K⁺ pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue