Diverse Mechanisms of Cardiovascular Toxicity
Many drugs can cause adverse effects on the cardiovascular system. Oncology drugs including targeted kinase inhibitors are particularly problematic. Cardiovascular toxicities present in the clinic as high blood pressure, cardiac arrhythmias, heart attacks and strokes. These toxicities can result from injury to heart tissue, damage to blood vessels or disruption to the coagulation system. Given the many cell types and biological processes that contribute to cardiovascular system functions, it should not be surprising that many different mechanisms can cause cardiovascular system toxicities. Because of this, predicting drug-induced cardiotoxicity has been challenging.
The US National Toxicology Program (NTP) is taking on this challenge. Together with the US FDA and HESI (Health and Environmental Sciences Institute), NTP (through NICEATM) is supporting an initiative to design non-animal approaches to assess cardiotoxicity hazard. The goals are to develop human cell- and protein-based assays to more efficiently screen drugs and chemicals for their potential to be toxic to the heart or circulatory system.
To fully capture cardiotoxicity hazard, integration of results from multiple assays that cover different mechanisms will be required. While a few specific targets have been identified, e.g. hERG channel, etc., others remain to be identified. For this, phenotypic assays based on cardiovascular system-relevant biology can be helpful. Cardiomyocyte-based assays have been helpful for identifying effects on heart cell function, while assays using endothelial cells and vascular smooth muscle cells have been used for detecting mechanisms associated with thrombosis-related side effects and vascular toxicity relevant to atherosclerosis biology (see here, here and here for details).
Since combining data from multiple different assays will be necessary to fully capture cardiotoxicity hazard, we have initiated a pilot study using interactive visualizations to make data from different assay platforms more accessible and understandable. For this, published results from testing several kinase inhibitor drugs in cardiomyocyte, endothelial and smooth muscle cell-based assays were used. See the interactive visualization here.
