Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells

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Show simple item record Bai, Jieyun en Gladding, PA en Stiles, MK en Fedorov, VV en Zhao, Jichao en 2019-03-05T02:39:15Z en 2018-10-23 en
dc.identifier.citation Scientific reports 8(1):15642 23 Oct 2018 en
dc.identifier.issn 2045-2322 en
dc.identifier.uri en
dc.description.abstract Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility to AF in patients with TBX5/PITX2 insufficiency remain unclear. In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF. Using our TPA model, we have demonstrated that spontaneous diastolic depolarization observed in atrial myocytes with TBX5-deletion can be explained by altered intracellular calcium handling and suppression of inward-rectifier potassium current (IK1). Additionally, our computer simulation results shed new light on the novel cellular mechanism underlying AF by indicating that the imbalance between suppressed outward current IK1 and increased inward sodium-calcium exchanger current (INCX) resulted from SR calcium leak leads to spontaneous depolarizations. Furthermore, our simulation results suggest that these arrhythmogenic triggers can be potentially suppressed by inhibiting sarcoplasmic reticulum (SR) calcium leak and reversing remodeled IK1. More importantly, this study has clinically significant implications on the drugs used for maintaining SR calcium homeostasis, whereby drugs such as dantrolene may confer significant improvement for the treatment of AF patients with TBX5/PITX2 insufficiency. en
dc.publisher Nature Publishing Group en
dc.relation.ispartofseries Scientific Reports en
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. en
dc.rights.uri en
dc.rights.uri en
dc.title Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells en
dc.type Journal Article en
dc.identifier.doi 10.1038/s41598-018-33958-y en
pubs.issue 1 en
pubs.volume 8 en
dc.rights.holder Copyright: The authors en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 755257 en Bioengineering Institute en ABI Associates en
pubs.number 15642 en
pubs.record-created-at-source-date 2018-10-25 en
pubs.dimensions-id 30353147 en

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