Predictive Metabolism Based Model of Cardiomyopathy Using Human Embryonic Stem Cell Derived Cardiac Precursers [ASMS 2010]

Cardiomyopathy is a broad term to describe the deterioration of function of the myocardium (heart muscle) that disrupts the heart’s ability to pump blood. Cardiomyopathy can be a serious chemotherapy-related cardiac dysfunction that can lead to chronic heart failure. The underlying mechanism of chemotherapeutics (anthracyclines, taxanes) and kinase inhibitor-induced cardiomyopathies is unclear. While certain compounds exert their toxicity primarily by interfering with proper function of cardiac ion channels (which translate into changes to the action potential duration), others that may cause cardiomyopathy are known disruptors of cellular metabolism. The anthracyclines are thought to induce toxicity by the formation of free radicals leading to changes in mitochondrial function and lipid peroxidation. In order to evaluate changes in metabolism associated with chemotherapeutics we treated hES cell derived cardiac precursors with a training set of drugs with known toxicity. We evaluated whether a metabolomics based approach could detect changes in metabolism that could be used to identify a metabolic signature of cardiotoxicity. A metabolic signature of toxicity could offer a novel means to predict the cardiotoxicity of pharmaceutical compounds and create a more quantitative measure of cardiac damage.

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