Doxorubicin (DOX) is a commonly used chemotherapeutic agent for the treatment of many cancers. However, DOX has serious cardiotoxic side effects culminating in congestive heart failure. We have previously shown in a clinically-relevant rat model of DOX-induced heart failure (DOX-HF), that this is due to loss and dysfunction of mitochondria. We show here that 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, can prevent heart failure in DOX-treated rats. This cardioprotective effect appears to be, at least in part, achieved through improved fatty acid oxidation in cardiac mitochondria which can be indirectly assessed with hyperpolarized [2-13C]pyruvate MRS.