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Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study
Genetic mutations in genes encoding for potassium channel protein structures have been recently associated with episodes of atrial fibrillation in asymptomatic patients. The aim of this study is to investigate the potential arrhythmogenicity of three gain-of-function mutations related to atrial fibr...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201780/ https://www.ncbi.nlm.nih.gov/pubmed/34135774 http://dx.doi.org/10.3389/fphys.2021.681943 |
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author | Belletti, Rebecca Romero, Lucia Martinez-Mateu, Laura Cherry, Elizabeth M. Fenton, Flavio H. Saiz, Javier |
author_facet | Belletti, Rebecca Romero, Lucia Martinez-Mateu, Laura Cherry, Elizabeth M. Fenton, Flavio H. Saiz, Javier |
author_sort | Belletti, Rebecca |
collection | PubMed |
description | Genetic mutations in genes encoding for potassium channel protein structures have been recently associated with episodes of atrial fibrillation in asymptomatic patients. The aim of this study is to investigate the potential arrhythmogenicity of three gain-of-function mutations related to atrial fibrillation—namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M—using modeling and simulation of the electrophysiological activity of the heart. A genetic algorithm was used to tune the parameters’ value of the original ionic currents to reproduce the alterations experimentally observed caused by the mutations. The effects on action potentials, ionic currents, and restitution properties were analyzed using versions of the Courtemanche human atrial myocyte model in different tissues: pulmonary vein, right, and left atrium. Atrial susceptibility of the tissues to spiral wave generation was also investigated studying the temporal vulnerability. The presence of the three mutations resulted in an overall more arrhythmogenic substrate. Higher current density, action potential duration shortening, and flattening of the restitution curves were the major effects of the three mutations at the single-cell level. The genetic mutations at the tissue level induced a higher temporal vulnerability to the rotor’s initiation and progression, by sustaining spiral waves that perpetuate until the end of the simulation. The mutation with the highest pro-arrhythmic effects, exhibiting the widest sustained VW and the smallest meandering rotor’s tip areas, was KCNE3-V17M. Moreover, the increased susceptibility to arrhythmias and rotor’s stability was tissue-dependent. Pulmonary vein tissues were more prone to rotor’s initiation, while in left atrium tissues rotors were more easily sustained. Re-entries were also progressively more stable in pulmonary vein tissue, followed by the left atrium, and finally the right atrium. The presence of the genetic mutations increased the susceptibility to arrhythmias by promoting the rotor’s initiation and maintenance. The study provides useful insights into the mechanisms underlying fibrillatory events caused by KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M and might aid the planning of patient-specific targeted therapies. |
format | Online Article Text |
id | pubmed-8201780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82017802021-06-15 Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study Belletti, Rebecca Romero, Lucia Martinez-Mateu, Laura Cherry, Elizabeth M. Fenton, Flavio H. Saiz, Javier Front Physiol Physiology Genetic mutations in genes encoding for potassium channel protein structures have been recently associated with episodes of atrial fibrillation in asymptomatic patients. The aim of this study is to investigate the potential arrhythmogenicity of three gain-of-function mutations related to atrial fibrillation—namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M—using modeling and simulation of the electrophysiological activity of the heart. A genetic algorithm was used to tune the parameters’ value of the original ionic currents to reproduce the alterations experimentally observed caused by the mutations. The effects on action potentials, ionic currents, and restitution properties were analyzed using versions of the Courtemanche human atrial myocyte model in different tissues: pulmonary vein, right, and left atrium. Atrial susceptibility of the tissues to spiral wave generation was also investigated studying the temporal vulnerability. The presence of the three mutations resulted in an overall more arrhythmogenic substrate. Higher current density, action potential duration shortening, and flattening of the restitution curves were the major effects of the three mutations at the single-cell level. The genetic mutations at the tissue level induced a higher temporal vulnerability to the rotor’s initiation and progression, by sustaining spiral waves that perpetuate until the end of the simulation. The mutation with the highest pro-arrhythmic effects, exhibiting the widest sustained VW and the smallest meandering rotor’s tip areas, was KCNE3-V17M. Moreover, the increased susceptibility to arrhythmias and rotor’s stability was tissue-dependent. Pulmonary vein tissues were more prone to rotor’s initiation, while in left atrium tissues rotors were more easily sustained. Re-entries were also progressively more stable in pulmonary vein tissue, followed by the left atrium, and finally the right atrium. The presence of the genetic mutations increased the susceptibility to arrhythmias by promoting the rotor’s initiation and maintenance. The study provides useful insights into the mechanisms underlying fibrillatory events caused by KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M and might aid the planning of patient-specific targeted therapies. Frontiers Media S.A. 2021-05-31 /pmc/articles/PMC8201780/ /pubmed/34135774 http://dx.doi.org/10.3389/fphys.2021.681943 Text en Copyright © 2021 Belletti, Romero, Martinez-Mateu, Cherry, Fenton and Saiz. https://creativecommons.org/licenses/by/4.0/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) and the copyright owner(s) 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. |
spellingShingle | Physiology Belletti, Rebecca Romero, Lucia Martinez-Mateu, Laura Cherry, Elizabeth M. Fenton, Flavio H. Saiz, Javier Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study |
title | Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study |
title_full | Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study |
title_fullStr | Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study |
title_full_unstemmed | Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study |
title_short | Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study |
title_sort | arrhythmogenic effects of genetic mutations affecting potassium channels in human atrial fibrillation: a simulation study |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201780/ https://www.ncbi.nlm.nih.gov/pubmed/34135774 http://dx.doi.org/10.3389/fphys.2021.681943 |
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