Abstract
Pharmaceutical agents despite their efficacy to treat disease can cause additional unwanted cardiovascular side effects. Cardiotoxicity is characterized by changes in either the function and/or structure of the myocardium. Over recent years, functional cardiotoxicity has received much attention, however morphological damage to the myocardium and/or loss of viability still requires improved detection and mechanistic insights. A human 3D cardiac microtissue containing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), cardiac endothelial cells and cardiac fibroblasts was used to assess their suitability to detect drug induced changes in cardiac structure. Histology and clinical pathology confirmed these cardiac microtissues were morphologically intact, lacked a necrotic/apoptotic core and contained all relevant cell constituents. High-throughput methods to assess mitochondrial membrane potential, endoplasmic reticulum integrity and cellular viability were developed and 15 FDA approved structural cardiotoxins and 14 FDA approved non-structural cardiotoxins were evaluated. We report that cardiac microtissues provide a high-throughput experimental model that is both able to detect changes in cardiac structure at clinically relevant concentrations and provide insights into the phenotypic mechanisms of this liability.
Highlights
Cardiovascular diseases are currently recognized as the leading cause of death in the world, in 2013 accounting for >17 million deaths[1]
All expected cell types were positively identified within the microtissue and importantly the approximate proportions of each cell type was consistent with the anticipated starting cell ratios of 4:2:1
To further complement this morphological assessment, known soluble cardiac biomarkers (cTnI, creatine phosphokinase muscle/brain (CK-MB) and fatty acid binding protien-3 (FABP-3)) were monitored over the same time course (Fig. 1D). These biomarkers are released from cardiomyocytes upon damage, and significantly elevated levels would be suggestive of morphological damage
Summary
Cardiovascular diseases are currently recognized as the leading cause of death in the world, in 2013 accounting for >17 million deaths[1]. Over recent years significant progress in antineoplastic compounds, include tyrosine kinase inhibitors and proteasome inhibitors, has increased cancer patient survival These agents significantly reduce cancer cell survival, proliferation and migration but are all associated to some degree with cardiotoxicities. Structural cardiotoxicity can be viewed as a continuum progressing from degeneration, necrosis leading to inflammatory changes and fibrosis, affecting multiple cardiac cell types. Throughout this process the ability of the heart to contract and function is highly dependent on the number, severity and distribution of www.nature.com/scientificreports/.
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
