In vivo assessment of the off-target metabolic effects of chemotherapy on the heart and liver using hyperpolarized 13C magentic resonance imaging

Cardiotoxic side-effects of common chemotherapeutics like doxorubicin pose a major health risk to cancer-survivors, however, the molecular pathology of this is poorly understood. Preliminary data shows early metabolic changes in the heart after doxorubicin treatment are dominated by decreased pyruvate dehydrogenase flux, which we hypothesize could result in impaired cardiac bioenergetics. With this project, we intend to further investigate the metabolic effects of doxorubicin on the myocardium using isolated cardiomyocytes, the perfused rat heart and an in vivo rat model of doxorubicin-induced cardiotoxicity. Metabolic studies will be undertaken using hyperpolarised magnetic resonance imaging and findings will be supported by magnetic resonance based assessment of cardiac structure, function and energetics. Validation of results will be undertaken using metabolomics, lipidomics and biochemical analysis of tissue extracts. Finally, therapies like dichloroacetate that promote TCA cycle flux will be explored to assess if cardiotoxicity can be prevented without disturbing the anti-cancer effects of doxorubicin.