Human atrial fibrillation and genetic defects in transient outward currents: mechanistic insights from multi-scale computational models
Previous studies have linked dysfunctional arising from mutations to -encoded Kv4.3 and -encoded Kv4.2 to atrial fibrillation. Using computational models, this study aimed to investigate the mechanisms underlying pro-arrhythmic effects of the gain-of-function Kv4.3 (T361S, A545P) and Kv4.2 (S447R) m...
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Published in | Philosophical transactions of the Royal Society of London. Series B. Biological sciences Vol. 378; no. 1879; p. 20220166 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
England
The Royal Society
19.06.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Previous studies have linked dysfunctional
arising from mutations to
-encoded Kv4.3 and
-encoded Kv4.2 to atrial fibrillation. Using computational models, this study aimed to investigate the mechanisms underlying pro-arrhythmic effects of the gain-of-function Kv4.3 (T361S, A545P) and Kv4.2 (S447R) mutations. Wild-type and mutant
formulations were developed from and validated against experimental data and incorporated into the Colman
. model of human atrial cells. Single-cell models were incorporated into one- (1D) and two-dimensional (2D) models of atrial tissue, and a three-dimensional (3D) realistic model of the human atria. The three gain-of-function mutations had similar, albeit quantitatively different, effects: shortening of the action potential duration; lowering the plateau membrane potential, abbreviating the effective refractory period (ERP) and the wavelength (WL) of atrial excitation at the tissue level. Restitution curves for the WL, the ERP and the conduction velocity were leftward shifted, facilitating the conduction of atrial excitation waves at high excitation rates. The mutations also increased lifespan and stationarity of re-entry in both 2D and 3D simulations, which further highlighted a mutation-induced increase in spatial dispersion of repolarization. Collectively, these changes account for pro-arrhythmic effects of these Kv4.3 and Kv4.2 mutations in facilitating AF. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 One contribution of 23 to a theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’. Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.6498564. |
ISSN: | 0962-8436 1471-2970 |
DOI: | 10.1098/rstb.2022.0166 |