Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation
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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2018.01114/full |
| _version_ | 1818858459182923776 |
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| author | Brodie A. Lawson Kevin Burrage Kevin Burrage Pamela Burrage Christopher C. Drovandi Alfonso Bueno-Orovio |
| author_facet | Brodie A. Lawson Kevin Burrage Kevin Burrage Pamela Burrage Christopher C. Drovandi Alfonso Bueno-Orovio |
| author_sort | Brodie A. Lawson |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T08:56:37Z |
| format | Article |
| id | doaj.art-3c8389601afb448498a7baca3e3ae5aa |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-19T08:56:37Z |
| publishDate | 2018-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-3c8389601afb448498a7baca3e3ae5aa2022-12-21T20:28:35ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2018-08-01910.3389/fphys.2018.01114351045Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by EmulationBrodie A. Lawson0Kevin Burrage1Kevin Burrage2Pamela Burrage3Christopher C. Drovandi4Alfonso Bueno-Orovio5ARC Centre of Excellence for Mathematical and Statistical Frontiers, School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaARC Centre of Excellence for Mathematical and Statistical Frontiers, School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaDepartment of Computer Science, University of Oxford, Oxford, United KingdomARC Centre of Excellence for Mathematical and Statistical Frontiers, School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaARC Centre of Excellence for Mathematical and Statistical Frontiers, School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaDepartment of Computer Science, University of Oxford, Oxford, United KingdomPurpose: 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.https://www.frontiersin.org/article/10.3389/fphys.2018.01114/fullrotorsarrhythmias (cardiac)fibrillationexcitabilityrefractorinessemulation |
| spellingShingle | Brodie A. Lawson Kevin Burrage Kevin Burrage Pamela Burrage Christopher C. Drovandi Alfonso Bueno-Orovio Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation Frontiers in Physiology rotors arrhythmias (cardiac) fibrillation excitability refractoriness emulation |
| title | Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation |
| title_full | Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation |
| title_fullStr | Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation |
| title_full_unstemmed | Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation |
| title_short | Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation |
| title_sort | slow recovery of excitability increases ventricular fibrillation risk as identified by emulation |
| topic | rotors arrhythmias (cardiac) fibrillation excitability refractoriness emulation |
| url | https://www.frontiersin.org/article/10.3389/fphys.2018.01114/full |
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