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Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges

The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challen...

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Autores principales: Vagos, Márcia, van Herck, Ilsbeth G. M., Sundnes, Joakim, Arevalo, Hermenegild J., Edwards, Andrew G., Koivumäki, Jussi T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131668/
https://www.ncbi.nlm.nih.gov/pubmed/30233399
http://dx.doi.org/10.3389/fphys.2018.01221
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author Vagos, Márcia
van Herck, Ilsbeth G. M.
Sundnes, Joakim
Arevalo, Hermenegild J.
Edwards, Andrew G.
Koivumäki, Jussi T.
author_facet Vagos, Márcia
van Herck, Ilsbeth G. M.
Sundnes, Joakim
Arevalo, Hermenegild J.
Edwards, Andrew G.
Koivumäki, Jussi T.
author_sort Vagos, Márcia
collection PubMed
description The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology.
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spelling pubmed-61316682018-09-19 Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges Vagos, Márcia van Herck, Ilsbeth G. M. Sundnes, Joakim Arevalo, Hermenegild J. Edwards, Andrew G. Koivumäki, Jussi T. Front Physiol Physiology The pathophysiology of atrial fibrillation (AF) is broad, with components related to the unique and diverse cellular electrophysiology of atrial myocytes, structural complexity, and heterogeneity of atrial tissue, and pronounced disease-associated remodeling of both cells and tissue. A major challenge for rational design of AF therapy, particularly pharmacotherapy, is integrating these multiscale characteristics to identify approaches that are both efficacious and independent of ventricular contraindications. Computational modeling has long been touted as a basis for achieving such integration in a rapid, economical, and scalable manner. However, computational pipelines for AF-specific drug screening are in their infancy, and while the field is progressing quite rapidly, major challenges remain before computational approaches can fill the role of workhorse in rational design of AF pharmacotherapies. In this review, we briefly detail the unique aspects of AF pathophysiology that determine requirements for compounds targeting AF rhythm control, with emphasis on delimiting mechanisms that promote AF triggers from those providing substrate or supporting reentry. We then describe modeling approaches that have been used to assess the outcomes of drugs acting on established AF targets, as well as on novel promising targets including the ultra-rapidly activating delayed rectifier potassium current, the acetylcholine-activated potassium current and the small conductance calcium-activated potassium channel. Finally, we describe how heterogeneity and variability are being incorporated into AF-specific models, and how these approaches are yielding novel insights into the basic physiology of disease, as well as aiding identification of the important molecular players in the complex AF etiology. Frontiers Media S.A. 2018-09-04 /pmc/articles/PMC6131668/ /pubmed/30233399 http://dx.doi.org/10.3389/fphys.2018.01221 Text en Copyright © 2018 Vagos, van Herck, Sundnes, Arevalo, Edwards and Koivumäki. http://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
van Herck, Ilsbeth G. M.
Sundnes, Joakim
Arevalo, Hermenegild J.
Edwards, Andrew G.
Koivumäki, Jussi T.
Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges
title Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges
title_full Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges
title_fullStr Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges
title_full_unstemmed Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges
title_short Computational Modeling of Electrophysiology and Pharmacotherapy of Atrial Fibrillation: Recent Advances and Future Challenges
title_sort computational modeling of electrophysiology and pharmacotherapy of atrial fibrillation: recent advances and future challenges
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131668/
https://www.ncbi.nlm.nih.gov/pubmed/30233399
http://dx.doi.org/10.3389/fphys.2018.01221
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