August 24, 2021
by Marjory Moreau
Recently I attended a webinar on “Cardiac toxicity Evaluation with a human tissue-engineered model” by Kareen Coulombe, professor at Brown University. I am still blown away every time I hear Dr. Coulombe speak on this subject. In addition to being an excellent speaker, the work she and her team are doing is incredible. I recently wrote a blog on the brain and all its complexity because the brain is not an organ I had worked with in PBPK modeling. But the heart is equally interesting, and this is my first opportunity to work with a heart! Aristotle identified the heart as the most important organ of the body. As cardiovascular disease is the leading cause of death globally, killing 33% of the world’s population, the identification seems accurate. The importance of the Brown Heart Microtissue Team’s work should not be underestimated. They are developing predictive models for environmental cardiotoxicity which will help all of us since we are regularly exposed to everyday compounds like pesticides, flame retardants, and others where little is known about their impact on cardiovascular function.
Arrhythmia is a sensitive measure of serious cardiac effects of chemicals that increases risk of stroke, heart attack, sudden cardiac death, and other forms of heart failure. A handful of models for cardiotoxicity testing have been developed but the goal of Dr. Coulombe’s team—which includes her co-principal investigators Bum-Rak Choi and Ulrike Mende—was to develop a fit-for-purpose and predictive platform for arrhythmia suitable for testing environmental toxicants. They developed a human 3D cardiac microtissue platform for predicting arrhythmia generation and cardiotoxicity as an alternative to animal testing. A human-specific arrhythmia response requires expression of multiple ion channels in ratios unique to the human heart, which is accomplished experimentally using human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) in a 3D myocardial-like environment that contains cardiac fibroblasts. See the group’s recent publication for more information1.
For models like this to be useful for determining the impacts compounds have on human health; one requires a framework for relating the results of experiments in a lab setting to equivalent chemical exposures in the real world. Our goal at ScitoVation is to use a generalized physiological based pharmacokinetic (PBPK) model to do in vitro to in vivo extrapolation (IVIVE) to interpret these in vitro experiments results in human exposure context. Chemical concentration active in their experimental system will be converted to equivalent exposure levels in vivo by using a PBPK model. IVIVE converts active concentrations from an in vitro assay to a human equivalent dose or human exposure that would be expected to produce internal heart concentrations in an exposed person equal to the active concentration from the in vitro study. In collaboration with Dr. Coulombe and the Cardiac team at Brown, ScitoVation is developing a PBPK framework that will allow for this IVIVE. We are developing the model using several compounds with well-established proarrhythmic activity. Because these compounds are also therapeutic tools, we have information on what dose leads to what concentration in the heart. Showing that the PBPK model predicts the relationship between dose and concentration in the heart will serve as a proof of concept, giving us confidence that we can apply the model to environmental toxicants with unknown cardiac toxicity. PBPK modeling serves as an integration and translation tool by incorporating pharmacokinetic factors that are not reflected in the in vitro experiments like absorption, distribution, metabolism, and excretion. We are in the process of finalizing the PBPK model to use for IVIVE so stay tuned for the upcoming article.
1Kofron CM, Kim TY, Munarin F, Soepriatna AH, Kant RJ, Mende U, Choi BR, Coulombe KLK. A predictive in vitro risk assessment platform for pro-arrhythmic toxicity using human 3D cardiac microtissues. Sci Rep. 2021 May 13;11(1):10228. doi: 10.1038/s41598-021-89478-9. PMID: 33986332; PMCID: PMC8119415.