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.
Highlights
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
To develop a predictive human cardiotoxicity model to address risk of cardiac arrhythmias, we adapted a scaffold-free cardiac microtissue model we previously developed with rat primary cardiac cells[35,36]
For microtissues generated from lactate-purified Human induced pluripotent stem cell (hiPSC)-CMs, a plating density of 13,500 cells per microtissue (95% hiPSC-CMLP and 5% human cardiac fibroblasts (hCFs)) yielded spherical microtissues 359.4 ± 32.4 μm in diameter after 1d in 3D culture that compacted to 290.4 ± 29.5 μm in diameter after 5d
Summary
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. We show that the environmental endocrine disrupting chemical bisphenol-A (BPA) causes acute and sensitive disruption of human action potentials in the nanomolar range 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. New initiatives in toxicity screening call for the development and implementation of non-animal approaches to assess potential hazards associated with acute and chronic exposures to industrial chemicals and medical products Groups such as the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) were assembled in response to new laws across the globe and point to a strong value in platforms based on a mechanistic understanding of toxicity[23,24]. Continued development of new approach methodologies (NAMs) to enhance predictive capabilities for prioritization, hazard screening, and risk assessment of cardiotoxicity is w arranted[25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
