dc.contributor.author |
Bai, Jieyun |
|
dc.contributor.author |
Lo, Andy |
|
dc.contributor.author |
Gladding, Patrick A |
|
dc.contributor.author |
Stiles, Martin K |
|
dc.contributor.author |
Fedorov, Vadim V |
|
dc.contributor.author |
Zhao, Jichao |
|
dc.coverage.spatial |
United States |
|
dc.date.accessioned |
2021-05-11T02:50:07Z |
|
dc.date.available |
2021-05-11T02:50:07Z |
|
dc.date.issued |
2020-2-25 |
|
dc.identifier.citation |
PLoS computational biology 16(2):e1007678 25 Feb 2020 |
|
dc.identifier.issn |
1553-734X |
|
dc.identifier.uri |
https://hdl.handle.net/2292/55069 |
|
dc.description.abstract |
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that paired-like homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na+ channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency. |
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dc.format.medium |
Electronic-eCollection |
|
dc.language |
eng |
|
dc.publisher |
Public Library of Science (PLoS) |
|
dc.relation.ispartofseries |
PLoS computational biology |
|
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
|
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
|
dc.rights.uri |
https://creativecommons.org/licenses/by/4.0/ |
|
dc.subject |
Sarcoplasmic Reticulum |
|
dc.subject |
Heart Atria |
|
dc.subject |
Endoplasmic Reticulum |
|
dc.subject |
Animals |
|
dc.subject |
Mice, Knockout |
|
dc.subject |
Humans |
|
dc.subject |
Mice |
|
dc.subject |
Atrial Fibrillation |
|
dc.subject |
Fibrosis |
|
dc.subject |
Sodium |
|
dc.subject |
Calcium |
|
dc.subject |
Flecainide |
|
dc.subject |
Ryanodine Receptor Calcium Release Channel |
|
dc.subject |
Homeodomain Proteins |
|
dc.subject |
Transcription Factors |
|
dc.subject |
Anti-Arrhythmia Agents |
|
dc.subject |
Electrophysiology |
|
dc.subject |
Gene Expression Regulation |
|
dc.subject |
Action Potentials |
|
dc.subject |
Kinetics |
|
dc.subject |
Phenotype |
|
dc.subject |
Computer Simulation |
|
dc.subject |
Genome-Wide Association Study |
|
dc.subject |
Atrial Remodeling |
|
dc.subject |
Action Potentials |
|
dc.subject |
Animals |
|
dc.subject |
Anti-Arrhythmia Agents |
|
dc.subject |
Atrial Fibrillation |
|
dc.subject |
Atrial Remodeling |
|
dc.subject |
Calcium |
|
dc.subject |
Computer Simulation |
|
dc.subject |
Electrophysiology |
|
dc.subject |
Endoplasmic Reticulum |
|
dc.subject |
Fibrosis |
|
dc.subject |
Flecainide |
|
dc.subject |
Gene Expression Regulation |
|
dc.subject |
Genome-Wide Association Study |
|
dc.subject |
Heart Atria |
|
dc.subject |
Homeodomain Proteins |
|
dc.subject |
Humans |
|
dc.subject |
Kinetics |
|
dc.subject |
Mice |
|
dc.subject |
Mice, Knockout |
|
dc.subject |
Phenotype |
|
dc.subject |
Ryanodine Receptor Calcium Release Channel |
|
dc.subject |
Sarcoplasmic Reticulum |
|
dc.subject |
Sodium |
|
dc.subject |
Transcription Factors |
|
dc.subject |
Science & Technology |
|
dc.subject |
Life Sciences & Biomedicine |
|
dc.subject |
Biochemical Research Methods |
|
dc.subject |
Mathematical & Computational Biology |
|
dc.subject |
Biochemistry & Molecular Biology |
|
dc.subject |
DELAYED AFTERDEPOLARIZATIONS |
|
dc.subject |
IONIC MECHANISMS |
|
dc.subject |
DRUG-THERAPY |
|
dc.subject |
INSIGHTS |
|
dc.subject |
ARRHYTHMOGENESIS |
|
dc.subject |
SYNCHRONIZATION |
|
dc.subject |
SUSCEPTIBILITY |
|
dc.subject |
MODULATION |
|
dc.subject |
FLECAINIDE |
|
dc.subject |
ARRHYTHMIA |
|
dc.subject |
1102 Cardiorespiratory Medicine and Haematology |
|
dc.subject |
Biomedical |
|
dc.subject |
Basic Science |
|
dc.subject |
Cardiovascular |
|
dc.subject |
Heart Disease |
|
dc.subject |
Cardiovascular |
|
dc.subject |
2.1 Biological and endogenous factors |
|
dc.subject |
01 Mathematical Sciences |
|
dc.subject |
06 Biological Sciences |
|
dc.subject |
08 Information and Computing Sciences |
|
dc.title |
In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2. |
|
dc.type |
Journal Article |
|
dc.identifier.doi |
10.1371/journal.pcbi.1007678 |
|
pubs.issue |
2 |
|
pubs.begin-page |
e1007678 |
|
pubs.volume |
16 |
|
dc.date.updated |
2021-04-04T21:44:01Z |
|
dc.rights.holder |
Copyright: The authors |
en |
pubs.author-url |
https://www.ncbi.nlm.nih.gov/pubmed/32097431 |
|
pubs.publication-status |
Published |
|
dc.rights.accessrights |
http://purl.org/eprint/accessRights/OpenAccess |
en |
pubs.subtype |
Research Support, Non-U.S. Gov't |
|
pubs.subtype |
research-article |
|
pubs.subtype |
Journal Article |
|
pubs.elements-id |
796277 |
|
dc.identifier.eissn |
1553-7358 |
|
dc.identifier.pii |
PCOMPBIOL-D-19-01121 |
|
pubs.number |
ARTN e1007678 |
|
pubs.online-publication-date |
2020-2-25 |
|