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This content will become publicly available on April 22, 2026

Title: Mechanism of Arrhythmogenesis Driven by Early After Depolarizations in Cardiac Tissue
Early-after depolarizations (EADs) are changes in the action potential plateau that can lead to cardiac arrhythmia. At the cellular level, these oscillations are irregular and change from beat to beat due to the sensitivity of voltage repolarization to subcellular stochastic processes. However, the behavior of EADs in tissue, where cells are strongly coupled by gap junctions, is less understood. In this study, we develop a computational model of EADs caused by a reduction in the rate of calcium-induced inactivation of the L-type calcium channel. We find that, as inactivation decreases EADs occur with durations varying randomly from beat to beat. In cardiac tissue, however, gap junction coupling between cells dampens these fluctuations, and it is unclear what dictates the formation of EADs. In this study we show that EADs in cardiac tissue can be modeled by the deterministic limit of a stochastic single-cell model. Analysis of this deterministic model reveals that EADs emerge in tissue after an abrupt transition to alternans, where large populations of cells suddenly synchronize, causing EADs on every other beat. We analyze this transition and show that it is due to a discontinuous bifurcation that leads to a large change in the action potential duration in response to very small changes in pacing rate. We further demonstrate that this transition is highly arrhythmogenic, as the sudden onset of EADs on alternate beats in cardiac tissue promotes conduction block and reentry. Our results highlight the importance of EAD alternans in arrhythmogenesis and suggests that ectopic beats may not be required.  more » « less
Award ID(s):
2320846
PAR ID:
10631750
Author(s) / Creator(s):
; ; ;
Editor(s):
Marsden, Alison
Publisher / Repository:
PLOS
Date Published:
Journal Name:
PLOS Computational Biology
Volume:
21
Issue:
4
ISSN:
1553-7358
Page Range / eLocation ID:
e1012635
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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