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Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several...

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Autores principales: Fu, Fumin, Pietropaolo, Michael, Cui, Lei, Pandit, Shilpa, Li, Weiyan, Tarnavski, Oleg, Shetty, Suraj S., Liu, Jing, Lussier, Jennifer M., Murakami, Yutaka, Grewal, Prabhjit K., Deyneko, Galina, Turner, Gordon M., Taggart, Andrew K. P., Waters, M. Gerard, Coughlin, Shaun, Adachi, Yuichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741011/
https://www.ncbi.nlm.nih.gov/pubmed/34995278
http://dx.doi.org/10.1371/journal.pone.0256512
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author Fu, Fumin
Pietropaolo, Michael
Cui, Lei
Pandit, Shilpa
Li, Weiyan
Tarnavski, Oleg
Shetty, Suraj S.
Liu, Jing
Lussier, Jennifer M.
Murakami, Yutaka
Grewal, Prabhjit K.
Deyneko, Galina
Turner, Gordon M.
Taggart, Andrew K. P.
Waters, M. Gerard
Coughlin, Shaun
Adachi, Yuichiro
author_facet Fu, Fumin
Pietropaolo, Michael
Cui, Lei
Pandit, Shilpa
Li, Weiyan
Tarnavski, Oleg
Shetty, Suraj S.
Liu, Jing
Lussier, Jennifer M.
Murakami, Yutaka
Grewal, Prabhjit K.
Deyneko, Galina
Turner, Gordon M.
Taggart, Andrew K. P.
Waters, M. Gerard
Coughlin, Shaun
Adachi, Yuichiro
author_sort Fu, Fumin
collection PubMed
description The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.
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spelling pubmed-87410112022-01-08 Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models Fu, Fumin Pietropaolo, Michael Cui, Lei Pandit, Shilpa Li, Weiyan Tarnavski, Oleg Shetty, Suraj S. Liu, Jing Lussier, Jennifer M. Murakami, Yutaka Grewal, Prabhjit K. Deyneko, Galina Turner, Gordon M. Taggart, Andrew K. P. Waters, M. Gerard Coughlin, Shaun Adachi, Yuichiro PLoS One Research Article The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF. Public Library of Science 2022-01-07 /pmc/articles/PMC8741011/ /pubmed/34995278 http://dx.doi.org/10.1371/journal.pone.0256512 Text en © 2022 Fu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Fu, Fumin
Pietropaolo, Michael
Cui, Lei
Pandit, Shilpa
Li, Weiyan
Tarnavski, Oleg
Shetty, Suraj S.
Liu, Jing
Lussier, Jennifer M.
Murakami, Yutaka
Grewal, Prabhjit K.
Deyneko, Galina
Turner, Gordon M.
Taggart, Andrew K. P.
Waters, M. Gerard
Coughlin, Shaun
Adachi, Yuichiro
Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
title Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
title_full Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
title_fullStr Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
title_full_unstemmed Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
title_short Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
title_sort lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741011/
https://www.ncbi.nlm.nih.gov/pubmed/34995278
http://dx.doi.org/10.1371/journal.pone.0256512
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