Mechanism of Arrhythmogenesis Driven by Early After Depolarizations in Cardiac Tissue.
| Autor: | Stein J; Department of Physics and Astronomy, California State University, Northridge., Greene D; Department of Physics and Astronomy, California State University, Northridge., Fenton F; Department of Physics, Georgia Institute of Technology., Shiferaw Y; Department of Physics and Astronomy, California State University, Northridge. |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Nov 14. Date of Electronic Publication: 2024 Nov 14. |
| DOI: | 10.1101/2024.11.14.623585 |
| Abstrakt: | 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 in cardiac tissue promotes conduction block and reentry. Our results highlight the importance of EAD alternans in arrhythmogenesis and suggests that ectopic beats are not required. Competing Interests: Declaration of Interest The authors declare no competing interests. |
| Databáze: | MEDLINE |
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