A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues.
Celinda M Kofron, Tae Yun Kim, Fabiola Munarin, Arvin H Soepriatna, Rajeev J Kant, Ulrike Mende, Bum-Rak Choi, Kareen L K Coulombe
Author Information
Celinda M Kofron: Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA.
Tae Yun Kim: Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Fabiola Munarin: Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA.
Arvin H Soepriatna: Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA.
Rajeev J Kant: Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA.
Ulrike Mende: Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA.
Bum-Rak Choi: Cardiovascular Research Center, Cardiovascular Institute, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI, USA. bum-rak_choi@brown.edu.
Kareen L K Coulombe: Center for Biomedical Engineering, School of Engineering, Brown University, Providence, RI, USA. kareen_coulombe@brown.edu.
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.
