Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve
Abstract In the heart, electrophysiological dysregulation arises from defects at many biological levels (from point mutations in ion channel proteins to gross structural abnormalities). These defects disrupt the normal pattern of electrical activation, producing ectopic activity and reentrant arrhyt...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-11110-1 |
| _version_ | 1818263847416365056 |
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| author | Karoline Horgmo Jæger Andrew G. Edwards Wayne R. Giles Aslak Tveito |
| author_facet | Karoline Horgmo Jæger Andrew G. Edwards Wayne R. Giles Aslak Tveito |
| author_sort | Karoline Horgmo Jæger |
| collection | DOAJ |
| description | Abstract In the heart, electrophysiological dysregulation arises from defects at many biological levels (from point mutations in ion channel proteins to gross structural abnormalities). These defects disrupt the normal pattern of electrical activation, producing ectopic activity and reentrant arrhythmia. To interrogate mechanisms that link these primary biological defects to macroscopic electrophysiologic dysregulation most prior computational studies have utilized either (i) detailed models of myocyte ion channel dynamics at limited spatial scales, or (ii) homogenized models of action potential conduction that reproduce arrhythmic activity at tissue and organ levels. Here we apply our recent model (EMI), which integrates electrical activation and propagation across these scales, to study human atrial arrhythmias originating in the pulmonary vein (PV) sleeves. These small structures initiate most supraventricular arrhythmias and include pronounced myocyte-to-myocyte heterogeneities in ion channel expression and intercellular coupling. To test EMI’s cell-based architecture in this physiological context we asked whether ion channel mutations known to underlie atrial fibrillation are capable of initiating arrhythmogenic behavior via increased excitability or reentry in a schematic PV sleeve geometry. Our results illustrate that EMI’s improved spatial resolution can directly interrogate how electrophysiological changes at the individual myocyte level manifest in tissue and as arrhythmia in the PV sleeve. |
| first_indexed | 2024-12-12T19:25:31Z |
| format | Article |
| id | doaj.art-b8676228161f4e678ffb91bee85f052b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-12T19:25:31Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-b8676228161f4e678ffb91bee85f052b2022-12-22T00:14:31ZengNature PortfolioScientific Reports2045-23222022-04-0112111810.1038/s41598-022-11110-1Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeveKaroline Horgmo Jæger0Andrew G. Edwards1Wayne R. Giles2Aslak Tveito3Simula Research LaboratorySimula Research LaboratorySimula Research LaboratorySimula Research LaboratoryAbstract In the heart, electrophysiological dysregulation arises from defects at many biological levels (from point mutations in ion channel proteins to gross structural abnormalities). These defects disrupt the normal pattern of electrical activation, producing ectopic activity and reentrant arrhythmia. To interrogate mechanisms that link these primary biological defects to macroscopic electrophysiologic dysregulation most prior computational studies have utilized either (i) detailed models of myocyte ion channel dynamics at limited spatial scales, or (ii) homogenized models of action potential conduction that reproduce arrhythmic activity at tissue and organ levels. Here we apply our recent model (EMI), which integrates electrical activation and propagation across these scales, to study human atrial arrhythmias originating in the pulmonary vein (PV) sleeves. These small structures initiate most supraventricular arrhythmias and include pronounced myocyte-to-myocyte heterogeneities in ion channel expression and intercellular coupling. To test EMI’s cell-based architecture in this physiological context we asked whether ion channel mutations known to underlie atrial fibrillation are capable of initiating arrhythmogenic behavior via increased excitability or reentry in a schematic PV sleeve geometry. Our results illustrate that EMI’s improved spatial resolution can directly interrogate how electrophysiological changes at the individual myocyte level manifest in tissue and as arrhythmia in the PV sleeve.https://doi.org/10.1038/s41598-022-11110-1 |
| spellingShingle | Karoline Horgmo Jæger Andrew G. Edwards Wayne R. Giles Aslak Tveito Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve Scientific Reports |
| title | Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve |
| title_full | Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve |
| title_fullStr | Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve |
| title_full_unstemmed | Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve |
| title_short | Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve |
| title_sort | arrhythmogenic influence of mutations in a myocyte based computational model of the pulmonary vein sleeve |
| url | https://doi.org/10.1038/s41598-022-11110-1 |
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