A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues

Abstract Cardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critic...

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Autores principales:	Celinda M. Kofron, Tae Yun Kim, Fabiola Munarin, Arvin H. Soepriatna, Rajeev J. Kant, Ulrike Mende, Bum-Rak Choi, Kareen L. K. Coulombe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/75b6c068a5ce412c8a3e790024a14557
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spelling	oai:doaj.org-article:75b6c068a5ce412c8a3e790024a145572021-12-02T16:50:31ZA predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues10.1038/s41598-021-89478-92045-2322https://doaj.org/article/75b6c068a5ce412c8a3e790024a145572021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89478-9https://doaj.org/toc/2045-2322Abstract Cardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critical for defining safety profiles. Currently available approaches have limitations including a focus on single select ion channels, the use of non-human species in vitro and in vivo, and limited direct physiological translation. We have advanced the robustness and reproducibility of in vitro platforms for assessing pro-arrhythmic cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts in 3-dimensional microtissues. Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we demonstrate that tissue-engineered human cardiac microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range. Thus, this novel human 3D in vitro pro-arrhythmic risk assessment platform addresses critical needs in cardiotoxicity testing for both environmental and pharmaceutical compounds and can be leveraged to establish safe human exposure levels.Celinda M. KofronTae Yun KimFabiola MunarinArvin H. SoepriatnaRajeev J. KantUlrike MendeBum-Rak ChoiKareen L. K. CoulombeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Celinda M. Kofron Tae Yun Kim Fabiola Munarin Arvin H. Soepriatna Rajeev J. Kant Ulrike Mende Bum-Rak Choi Kareen L. K. Coulombe A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues
description	Abstract Cardiotoxicity of pharmaceutical drugs, industrial chemicals, and environmental toxicants can be severe, even life threatening, which necessitates a thorough evaluation of the human response to chemical compounds. Predicting risks for arrhythmia and sudden cardiac death accurately is critical for defining safety profiles. Currently available approaches have limitations including a focus on single select ion channels, the use of non-human species in vitro and in vivo, and limited direct physiological translation. We have advanced the robustness and reproducibility of in vitro platforms for assessing pro-arrhythmic cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts in 3-dimensional microtissues. Using automated algorithms and statistical analyses of eight comprehensive evaluation metrics of cardiac action potentials, we demonstrate that tissue-engineered human cardiac microtissues respond appropriately to physiological stimuli and effectively differentiate between high-risk and low-risk compounds exhibiting blockade of the hERG channel (E4031 and ranolazine, respectively). Further, we show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range. Thus, this novel human 3D in vitro pro-arrhythmic risk assessment platform addresses critical needs in cardiotoxicity testing for both environmental and pharmaceutical compounds and can be leveraged to establish safe human exposure levels.
format	article
author	Celinda M. Kofron Tae Yun Kim Fabiola Munarin Arvin H. Soepriatna Rajeev J. Kant Ulrike Mende Bum-Rak Choi Kareen L. K. Coulombe
author_facet	Celinda M. Kofron Tae Yun Kim Fabiola Munarin Arvin H. Soepriatna Rajeev J. Kant Ulrike Mende Bum-Rak Choi Kareen L. K. Coulombe
author_sort	Celinda M. Kofron
title	A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues
title_short	A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues
title_full	A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues
title_fullStr	A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues
title_full_unstemmed	A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues
title_sort	predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3d cardiac microtissues
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/75b6c068a5ce412c8a3e790024a14557
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A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues

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