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, Ilija; Ji, Yanyan Claire; Hornung, Daniel; Schröder-Scheteling, Johannes; Luther, Stefan; Gray, Richard A.; Cherry, Elizabeth M.; Fenton, Flavio H.

doi:10.3389/fphys.2017.00819

Cited by 41 publications

(33 citation statements)

References 58 publications

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“…We have performed some additional tests for this work but we believe that many open questions still remain in this direction and will therefore dedicate part of our future efforts in addressing these issues. Specific areas of interest involve discordant alternans patterns [61], inherently a spatial quantity, and their period-doubling bifurcation progression as early precursors of arrhythmias and fibrillation [62]. Besides, a quantitative non-local rationale encompassing tissue heterogeneities and anisotropies would close up the picture allowing to introduce patient-specific parameters, e.g., anatomical features and electrophysiological measurements.…”

Section: Limitations and Future Perspectivesmentioning

confidence: 99%

Key aspects for effective mathematical modelling of fractional-diffusion in cardiac electrophysiology: A quantitative study

Cusimano

Gizzi

Fenton

et al. 2020

Communications in Nonlinear Science and Numerical Simulation

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Microscopic structural features of cardiac tissue play a fundamental role in determining complex spatio-temporal excitation dynamics at the macroscopic level. Recent efforts have been devoted to the development of mathematical models accounting for non-local spatio-temporal coupling able to capture these complex dynamics without the need of resolving tissue heterogeneities down to the micro-scale. In this work, we analyse in detail several important aspects affecting the overall predictive power of these modelling tools and provide some guidelines for an effective use of space-fractional models of cardiac electrophysiology in practical applications. Through an extensive computational study in simplified computational domains, we highlight the robustness of models belonging to different categories, i.e., physiological and phenomenological descriptions, against the introduction of non-locality, and lay down the foundations for future research and model validation against experimental data. A modern genetic algorithm framework is used to investigate proper parameterisations of the considered models, and the crucial role played by the boundary assumptions in the considered settings is discussed. Several numerical results are provided to support our claims.

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Section: Limitations and Future Perspectivesmentioning

confidence: 99%

Key aspects for effective mathematical modelling of fractional-diffusion in cardiac electrophysiology: A quantitative study

Cusimano

Gizzi

Fenton

et al. 2020

Communications in Nonlinear Science and Numerical Simulation

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“…Conversely, discordant alternans arise when alternating rhythms in different spatial regions are out of phase. Such heterogeneities can be identified with optical mapping of fluorescence signals from multiple sites across a cardiac preparation with high spatiotemporal resolution(44). One such example is shown in Figure 7, in which ventricular tachycardia was encountered concomitantly with spatially discordant calcium transient alternans following dynamic pacing (S1-S1, 70 msec cycle length, isolated rat heart).…”

Section: Resultsmentioning

confidence: 99%

Lights, Camera, Path Splitter: A New Approach for Truly Simultaneous Dual Optical Mapping of the Heart with a Single Camera

Jaimes

McCullough

Siegel

et al. 2019

Preprint

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1Background: Optical mapping of transmembrane voltage and intracellular calcium is a powerful tool for 3 2 investigating cardiac physiology and pathophysiology. Until recently, the assembly and implementation 3 3 of simultaneous dual mapping of two fluorescent probes has been technically challenging. We 3 4introduce a novel, easy-to-use platform that requires only a single camera and single excitation light to 3 5 simultaneously acquire voltage and calcium signals from whole heart preparations, which can be 3 6expanded and applied to other physiological models -including neurons and isolated cardiomyocytes. 3 7Results: Complementary probes were selected that could be excited with a single wavelength light 3 8source. Langendorff-perfused hearts (rat, swine) were stained and then imaged using a sCMOS 3 9camera outfitted with an optical path splitter to simultaneously acquire two emission fields at high 4 0spatial and temporal resolution. Voltage (RH237) and calcium (Rhod2-AM) signals were acquired 4 1 concurrently on a single sensor, resulting in two 384x256 images at 814 frames per second. At this 4 2 frame rate, the signal-to-noise ratio was 47 (RH237) and 85 (Rhod-2AM). In separate experiments, 4 3 each dye was used independently to assess crosstalk and demonstrate signal specificity. Additionally, 4 4the effect of ryanodine on myocardial calcium transients was validated -with no measurable effect on 4 5the amplitude of optical action potentials. To demonstrate spatial resolution, ventricular tachycardia was 4 6induced and spatially discordant alternans were noted in different regions of the heart. 4 7Conclusions: We present and validate a dual imaging approach that eliminates the need for multiple 4 8 cameras, excitation light patterning or frame interleaving. This imaging platform is comprised entirely of 4

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“…For example, (Gray et al, 2013 ) measured the action potential upstroke shape during propagation and found that it differed from that predicted in tissue simulations using a variety of cell models. (Uzelac et al, 2017 ) show that current cell models when incorporated into tissue level models do not reproduce the voltage and calcium dynamics of alternans. In addition, it is fairly common to adjust cell model parameters in tissue simulations (e.g., to shorten APD when simulating fibrillation Bishop and Plank, 2012 ), without any “re-validation” of the modified cell model; for such cases, it is unclear how much the previous cell model validation results can be relied upon.…”

Section: Credibility Of Cep Models At Different Spatial Scalesmentioning

confidence: 99%

Validation and Trustworthiness of Multiscale Models of Cardiac Electrophysiology

Pathmanathan

Gray

2018

Front. Physiol.

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Computational models of cardiac electrophysiology have a long history in basic science applications and device design and evaluation, but have significant potential for clinical applications in all areas of cardiovascular medicine, including functional imaging and mapping, drug safety evaluation, disease diagnosis, patient selection, and therapy optimisation or personalisation. For all stakeholders to be confident in model-based clinical decisions, cardiac electrophysiological (CEP) models must be demonstrated to be trustworthy and reliable. Credibility, that is, the belief in the predictive capability, of a computational model is primarily established by performing validation, in which model predictions are compared to experimental or clinical data. However, there are numerous challenges to performing validation for highly complex multi-scale physiological models such as CEP models. As a result, credibility of CEP model predictions is usually founded upon a wide range of distinct factors, including various types of validation results, underlying theory, evidence supporting model assumptions, evidence from model calibration, all at a variety of scales from ion channel to cell to organ. Consequently, it is often unclear, or a matter for debate, the extent to which a CEP model can be trusted for a given application. The aim of this article is to clarify potential rationale for the trustworthiness of CEP models by reviewing evidence that has been (or could be) presented to support their credibility. We specifically address the complexity and multi-scale nature of CEP models which makes traditional model evaluation difficult. In addition, we make explicit some of the credibility justification that we believe is implicitly embedded in the CEP modeling literature. Overall, we provide a fresh perspective to CEP model credibility, and build a depiction and categorisation of the wide-ranging body of credibility evidence for CEP models. This paper also represents a step toward the extension of model evaluation methodologies that are currently being developed by the medical device community, to physiological models.

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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

Cited by 41 publications

References 58 publications

Key aspects for effective mathematical modelling of fractional-diffusion in cardiac electrophysiology: A quantitative study

Key aspects for effective mathematical modelling of fractional-diffusion in cardiac electrophysiology: A quantitative study

Lights, Camera, Path Splitter: A New Approach for Truly Simultaneous Dual Optical Mapping of the Heart with a Single Camera

Validation and Trustworthiness of Multiscale Models of Cardiac Electrophysiology

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