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A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes

In atrial cardiomyocytes without a well-developed T-tubule system, calcium diffuses from the periphery toward the center creating a centripetal wave pattern. During atrial fibrillation, rapid activation of atrial myocytes induces complex remodeling in diffusion properties that result in failure of c...

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Autores principales: Vagos, Márcia R., Arevalo, Hermenegild, Heijman, Jordi, Schotten, Ulrich, Sundnes, Joakim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063103/
https://www.ncbi.nlm.nih.gov/pubmed/33897459
http://dx.doi.org/10.3389/fphys.2021.651428
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author Vagos, Márcia R.
Arevalo, Hermenegild
Heijman, Jordi
Schotten, Ulrich
Sundnes, Joakim
author_facet Vagos, Márcia R.
Arevalo, Hermenegild
Heijman, Jordi
Schotten, Ulrich
Sundnes, Joakim
author_sort Vagos, Márcia R.
collection PubMed
description In atrial cardiomyocytes without a well-developed T-tubule system, calcium diffuses from the periphery toward the center creating a centripetal wave pattern. During atrial fibrillation, rapid activation of atrial myocytes induces complex remodeling in diffusion properties that result in failure of calcium to propagate in a fully regenerative manner toward the center; a phenomenon termed “calcium silencing.” This has been observed in rabbit atrial myocytes after exposure to prolonged rapid pacing. Although experimental studies have pointed to possible mechanisms underlying calcium silencing, their individual effects and relative importance remain largely unknown. In this study we used computational modeling of the rabbit atrial cardiomyocyte to query the individual and combined effects of the proposed mechanisms leading to calcium silencing and abnormal calcium wave propagation. We employed a population of models obtained from a newly developed model of the rabbit atrial myocyte with spatial representation of intracellular calcium handling. We selected parameters in the model that represent experimentally observed cellular remodeling which have been implicated in calcium silencing, and scaled their values in the population to match experimental observations. In particular, we changed the maximum conductances of ICaL, INCX, and INaK, RyR open probability, RyR density, Serca2a density, and calcium buffering strength. We incorporated remodeling in a population of 16 models by independently varying parameters that reproduce experimentally observed cellular remodeling, and quantified the resulting alterations in calcium dynamics and wave propagation patterns. The results show a strong effect of ICaL in driving calcium silencing, with INCX, INaK, and RyR density also resulting in calcium silencing in some models. Calcium alternans was observed in some models where INCX and Serca2a density had been changed. Simultaneously incorporating changes in all remodeled parameters resulted in calcium silencing in all models, indicating the predominant role of decreasing ICaL in the population phenotype.
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spelling pubmed-80631032021-04-24 A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes Vagos, Márcia R. Arevalo, Hermenegild Heijman, Jordi Schotten, Ulrich Sundnes, Joakim Front Physiol Physiology In atrial cardiomyocytes without a well-developed T-tubule system, calcium diffuses from the periphery toward the center creating a centripetal wave pattern. During atrial fibrillation, rapid activation of atrial myocytes induces complex remodeling in diffusion properties that result in failure of calcium to propagate in a fully regenerative manner toward the center; a phenomenon termed “calcium silencing.” This has been observed in rabbit atrial myocytes after exposure to prolonged rapid pacing. Although experimental studies have pointed to possible mechanisms underlying calcium silencing, their individual effects and relative importance remain largely unknown. In this study we used computational modeling of the rabbit atrial cardiomyocyte to query the individual and combined effects of the proposed mechanisms leading to calcium silencing and abnormal calcium wave propagation. We employed a population of models obtained from a newly developed model of the rabbit atrial myocyte with spatial representation of intracellular calcium handling. We selected parameters in the model that represent experimentally observed cellular remodeling which have been implicated in calcium silencing, and scaled their values in the population to match experimental observations. In particular, we changed the maximum conductances of ICaL, INCX, and INaK, RyR open probability, RyR density, Serca2a density, and calcium buffering strength. We incorporated remodeling in a population of 16 models by independently varying parameters that reproduce experimentally observed cellular remodeling, and quantified the resulting alterations in calcium dynamics and wave propagation patterns. The results show a strong effect of ICaL in driving calcium silencing, with INCX, INaK, and RyR density also resulting in calcium silencing in some models. Calcium alternans was observed in some models where INCX and Serca2a density had been changed. Simultaneously incorporating changes in all remodeled parameters resulted in calcium silencing in all models, indicating the predominant role of decreasing ICaL in the population phenotype. Frontiers Media S.A. 2021-04-09 /pmc/articles/PMC8063103/ /pubmed/33897459 http://dx.doi.org/10.3389/fphys.2021.651428 Text en Copyright © 2021 Vagos, Arevalo, Heijman, Schotten and Sundnes. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Vagos, Márcia R.
Arevalo, Hermenegild
Heijman, Jordi
Schotten, Ulrich
Sundnes, Joakim
A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes
title A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes
title_full A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes
title_fullStr A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes
title_full_unstemmed A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes
title_short A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes
title_sort computational study of the effects of tachycardia-induced remodeling on calcium wave propagation in rabbit atrial myocytes
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063103/
https://www.ncbi.nlm.nih.gov/pubmed/33897459
http://dx.doi.org/10.3389/fphys.2021.651428
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