Award Title: Mitochondrial function in doxorubicin-induced cardiotoxicity
Funder: The Academy of Medical Sciences

Abstract: Doxorubicin (DOX) is a chemotherapeutic drug that can cause serious cardiotoxic side effects leading to heart failure. Different mechanisms have been proposed for this toxicity, though there is no specific cardioprotective drug available to prevent functional decline. I previously established a clinically-relevant rat model of DOX-induced heart failure and characterised metabolic changes with non-invasive in vivo hyperpolarized magnetic resonance spectroscopy (MRS). These data show that cardiac oxidative metabolism is impaired before functional decline. I have furthermore shown that activation of the adenosine monophosphate-activated kinase (AMPK) with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) prevents functional decline, but the mechanism for this remains elusive. AICAR is known to increase fatty acid uptake and oxidation, thereby improving mitochondrial function. This could make mitochondrial energy generation more efficient, leading to adequate energy provision to maintain cardiac function. Improved mitochondrial function could also prevent reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) opening, indicative of the early stages of cell death. I therefore propose to purchase a state-of-the-art mitochondrial bioanalyzer, the Oroboros O2k FluoRespirometer, which allows simultaneous measurements of mitochondrial substrate oxidation, ATP generation, ROS production and mPTP opening. I will assess mitochondrial function in isolated cardiac mitochondria of saline control, DOX and DOX+AICAR rats at three time points in the chemotherapy regimen. Before mitochondrial isolation I will measure cardiac function with CINE MRI and cardiac metabolic fluxes with hyperpolarized MRS to establish a clear picture of functional, metabolic and mitochondrial changes in the heart during DOX-chemotherapy and to elucidate the cardioprotective mechanism of AICAR.

Lay Abstract: Chemotherapy has greatly improved cancer survival rates, especially in breast cancer patients. However, some chemotherapeutic drugs such as doxorubicin have side effects on the heart and cancer survivors can end up developing heart failure as a consequence of their cancer treatment. Unfortunately, it is still poorly understood what exactly happens in the heart that causes this toxicity and decline in function. It is also impossible to predict which patients will suffer long-term heart problems due to their cancer therapy. An imaging tool to screen patients regularly to check for early signs of toxicity on the heart would therefore be desirable to detect any changes early and intervene with appropriate treatment. I have previously established in rats that a non-invasive and non-radioactive imaging technique called hyperpolarized magnetic resonance can detect early changes in how the heart generates energy after chemotherapy. This could potentially be translated as a screening tool into cancer patients. In order to fully understand what underlies the early changes in energy generation that hyperpolarized magnetic resonance can detect I now want to perform a study using an Oroboros O2k FluoRespirometer. This device can accurately assess in the cellular powerhouses, the mitochondria, how energy is made and whether there are any signs of toxic radicals forming that may impact their function. Assessing mitochondrial function with this device will be vital to fully understand the underlying pathology of doxorubicin cardiotoxicity and may lead to a cardioprotective drug that can boost mitochondrial energy generation and protection from heart failure.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CARDIOVASCULAR