Colman, MA orcid.org/0000-0003-2817-8508, Saxena, P, Kettlewell, S et al. (1 more author) (2018) Description of the Human Atrial Action Potential Derived From a Single, Congruent Data Source: Novel Computational Models for Integrated Experimental-Numerical Study of Atrial Arrhythmia Mechanisms. Frontiers in Physiology, 9. 1211. ISSN 1664-042X
Abstract
Introduction: The development of improved diagnosis, management, and treatment strategies for human atrial fibrillation (AF) is a significant and important challenge in order to improve quality of life for millions and reduce the substantial social-economic costs of the condition. As a complex condition demonstrating high variability and relation to other cardiac conditions, the study of AF requires approaches from multiple disciplines including single-cell experimental electrophysiology and computational modeling. Models of human atrial cells are less well parameterized than those of the human ventricle or other mammal species, largely due to the inherent challenges in patch clamping human atrial cells. Such challenges include, frequently, unphysiologically depolarized resting potentials and thus injection of a compensatory hyperpolarizing current, as well as detecting certain ion currents which may be disrupted by the cell isolation process. The aim of this study was to develop a laboratory specific model of human atrial electrophysiology which reproduces exactly the conditions of isolated-cell experiments, including testing of multiple experimental interventions.
Methods: Formulations for the primary ion currents characterized by isolated-cell experiments in the Workman laboratory were fit directly to voltage-clamp data; the fast sodium-current was parameterized based on experiments relating resting membrane potential to maximal action potential upstroke velocity; compensatory hyperpolarizing current was included as a constant applied current. These formulations were integrated with three independent human atrial cell models to provide a family of novel models. Extrapolated intact-cell models were developed through removal of the hyperpolarizing current and introduction of terminal repolarization potassium currents.
Results: The isolated-cell models quantitatively reproduced experimentally measured properties of excitation in both control and pharmacological and dynamic-clamp interventions. Comparison of isolated and intact-cell models highlighted the importance of reproducing this cellular environment when comparing experimental and simulation data.
Conclusion: We have developed a laboratory specific model of the human atrial cell which directly reproduces the experimental isolated-cell conditions and captures human atrial excitation properties. The model may be particularly useful for directly relating model to experiment, and offers a complementary tool to the available set of human atrial cell models with specific advantages resulting from the congruent input data source.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 Colman, Saxena, Kettlewell and Workman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | Atrial Fibrillation, human atrial model, Ion channel currents, computational model, cellular variability |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number MRC MR/M014967/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 22 Aug 2018 13:17 |
Last Modified: | 12 Sep 2018 13:22 |
Published Version: | https://www.frontiersin.org/articles/10.3389/fphys... |
Status: | Published |
Publisher: | Frontiers Media |
Identification Number: | 10.3389/fphys.2018.01211 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:134786 |