Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling

Abstract Atrial fibrillation (AF) is the most common arrhythmia and is associated with inflammation. AF patients have elevated levels of inflammatory cytokines known to promote vascular leak, such as vascular endothelial growth factor A (VEGF). However, the contribution of vascular leak and conseque...

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Autores principales:	Louisa Mezache, Heather L. Struckman, Amara Greer-Short, Stephen Baine, Sándor Györke, Przemysław B. Radwański, Thomas J. Hund, Rengasayee Veeraraghavan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/339058eefeee476198027db5f79e00fe
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spelling	oai:doaj.org-article:339058eefeee476198027db5f79e00fe2021-12-02T12:33:46ZVascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling10.1038/s41598-020-77562-52045-2322https://doaj.org/article/339058eefeee476198027db5f79e00fe2020-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-77562-5https://doaj.org/toc/2045-2322Abstract Atrial fibrillation (AF) is the most common arrhythmia and is associated with inflammation. AF patients have elevated levels of inflammatory cytokines known to promote vascular leak, such as vascular endothelial growth factor A (VEGF). However, the contribution of vascular leak and consequent cardiac edema to the genesis of atrial arrhythmias remains unknown. Previous work suggests that interstitial edema in the heart can acutely promote ventricular arrhythmias by disrupting ventricular myocyte intercalated disk (ID) nanodomains rich in cardiac sodium channels (NaV1.5) and slowing cardiac conduction. Interestingly, similar disruption of ID nanodomains has been identified in atrial samples from AF patients. Therefore, we tested the hypothesis that VEGF-induced vascular leak can acutely increase atrial arrhythmia susceptibility by disrupting ID nanodomains and slowing atrial conduction. Treatment of murine hearts with VEGF (30–60 min, at clinically relevant levels) prolonged the electrocardiographic P wave and increased susceptibility to burst pacing-induced atrial arrhythmias. Optical voltage mapping revealed slower atrial conduction following VEGF treatment (10 ± 0.4 cm/s vs. 21 ± 1 cm/s at baseline, p < 0.05). Transmission electron microscopy revealed increased intermembrane spacing at ID sites adjacent to gap junctions (GJs; 64 ± 9 nm versus 17 ± 1 nm in controls, p < 0.05), as well as sites next to mechanical junctions (MJs; 63 ± 4 nm versus 27 ± 2 nm in controls, p < 0.05) in VEGF–treated hearts relative to controls. Importantly, super-resolution microscopy and quantitative image analysis revealed reorganization of NaV1.5 away from dense clusters localized near GJs and MJs to a more diffuse distribution throughout the ID. Taken together, these data suggest that VEGF can acutely predispose otherwise normal hearts to atrial arrhythmias by dynamically disrupting NaV1.5-rich ID nanodomains and slowing atrial conduction. These data highlight inflammation-induced vascular leak as a potential factor in the development and progression of AF.Louisa MezacheHeather L. StruckmanAmara Greer-ShortStephen BaineSándor GyörkePrzemysław B. RadwańskiThomas J. HundRengasayee VeeraraghavanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Louisa Mezache Heather L. Struckman Amara Greer-Short Stephen Baine Sándor Györke Przemysław B. Radwański Thomas J. Hund Rengasayee Veeraraghavan Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling
description	Abstract Atrial fibrillation (AF) is the most common arrhythmia and is associated with inflammation. AF patients have elevated levels of inflammatory cytokines known to promote vascular leak, such as vascular endothelial growth factor A (VEGF). However, the contribution of vascular leak and consequent cardiac edema to the genesis of atrial arrhythmias remains unknown. Previous work suggests that interstitial edema in the heart can acutely promote ventricular arrhythmias by disrupting ventricular myocyte intercalated disk (ID) nanodomains rich in cardiac sodium channels (NaV1.5) and slowing cardiac conduction. Interestingly, similar disruption of ID nanodomains has been identified in atrial samples from AF patients. Therefore, we tested the hypothesis that VEGF-induced vascular leak can acutely increase atrial arrhythmia susceptibility by disrupting ID nanodomains and slowing atrial conduction. Treatment of murine hearts with VEGF (30–60 min, at clinically relevant levels) prolonged the electrocardiographic P wave and increased susceptibility to burst pacing-induced atrial arrhythmias. Optical voltage mapping revealed slower atrial conduction following VEGF treatment (10 ± 0.4 cm/s vs. 21 ± 1 cm/s at baseline, p < 0.05). Transmission electron microscopy revealed increased intermembrane spacing at ID sites adjacent to gap junctions (GJs; 64 ± 9 nm versus 17 ± 1 nm in controls, p < 0.05), as well as sites next to mechanical junctions (MJs; 63 ± 4 nm versus 27 ± 2 nm in controls, p < 0.05) in VEGF–treated hearts relative to controls. Importantly, super-resolution microscopy and quantitative image analysis revealed reorganization of NaV1.5 away from dense clusters localized near GJs and MJs to a more diffuse distribution throughout the ID. Taken together, these data suggest that VEGF can acutely predispose otherwise normal hearts to atrial arrhythmias by dynamically disrupting NaV1.5-rich ID nanodomains and slowing atrial conduction. These data highlight inflammation-induced vascular leak as a potential factor in the development and progression of AF.
format	article
author	Louisa Mezache Heather L. Struckman Amara Greer-Short Stephen Baine Sándor Györke Przemysław B. Radwański Thomas J. Hund Rengasayee Veeraraghavan
author_facet	Louisa Mezache Heather L. Struckman Amara Greer-Short Stephen Baine Sándor Györke Przemysław B. Radwański Thomas J. Hund Rengasayee Veeraraghavan
author_sort	Louisa Mezache
title	Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling
title_short	Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling
title_full	Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling
title_fullStr	Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling
title_full_unstemmed	Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling
title_sort	vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/339058eefeee476198027db5f79e00fe
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Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling

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