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

Area of Science:

• Cardiovascular Toxicology
• Biomedical Engineering
• Stem Cell Biology

Background:

• Cardiotoxicity from chemicals poses severe health risks, necessitating accurate human response prediction.
• Current methods for assessing cardiotoxicity have limitations in scope, species relevance, and physiological translation.
• Predicting arrhythmia and sudden cardiac death risk is crucial for chemical safety profiling.

Purpose of the Study:

• To develop and validate a robust 3D human in vitro platform for assessing pro-arrhythmic cardiotoxicity.
• To evaluate the efficacy of the platform in differentiating between high-risk and low-risk compounds.
• To assess the impact of environmental toxicants, such as bisphenol-A, on cardiac function.

Main Methods:

• Utilized human induced pluripotent stem cell-derived cardiomyocytes and cardiac fibroblasts in 3D microtissues.
• Employed automated algorithms and statistical analyses on eight cardiac action potential metrics.
• Tested known hERG channel blockers (E4031, ranolazine) and bisphenol-A (BPA).

Main Results:

• The 3D human cardiac microtissues demonstrated appropriate physiological responses and differentiated between high- and low-risk compounds.
• Bisphenol-A (BPA) was shown to disrupt human action potentials at nanomolar concentrations.
• The platform proved robust and reproducible for cardiotoxicity assessment.

Conclusions:

• The novel 3D human in vitro platform effectively assesses pro-arrhythmic cardiotoxicity for environmental and pharmaceutical compounds.
• This platform addresses critical needs in cardiotoxicity testing and can aid in establishing safe human exposure levels.
• The model offers improved physiological relevance compared to existing in vitro and in vivo methods.