Identification of Biomarkers of Cardiotoxicity using Metabolomics of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Cardiac safety is one of the leading causes of late-stage compound attrition in the pharmaceutical industry and accounts for the withdrawal of 28% of FDA-approved drugs from the market. The development of better screening assays to predict cardiotoxicity is needed to enable the placement of safer drugs in the market and reduce adverse effects. Current methods for cardiotoxicity screening of new drugs are based largely on electrophysiological assessment and have proven insufficient. Cardiotoxicity is a well-established adverse side effect of several drugs across multiple therapeutic indications. It is particularly prevalent following anti-cancer therapy.  In addition, tricyclic antidepressants (TCAs) are a well-known cause of cardiotoxicity. The training set used in this study is comprised of four classes of pharmaceuticals (3 anti-cancer classes and tricyclic antidepressants) that cause cardiomyopathy, in addition to other types of cardiotoxicity. In order to evaluate the changes in metabolism associated with cardiotoxicity, we treated iPS cell-derived cardiomyocytes with a training set of drugs with known toxicity. We then analyzed the spent medium from the treated cell culture with the goal of identifying a metabolic signature of cardiotoxicity using discovery based metabolomics. Metabolomics, the global profiling of small molecule metabolites generated through cellular metabolism, is an alternative to identify predictive biomarkers of cardiotoxicity since it measures the direct products of toxic response, i.e. endogenous cell-derived small molecule metabolites that are the products of functionally active biochemical pathways. We evaluated whether a metabolomics based approach could detect changes in metabolism that could be used to identify a metabolic signature of cardiotoxicity. The metabolic signature of toxicity may offer a novel approach to predicting the cardiotoxic potential of pharmaceutical compounds.

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