Early myocardial metabolic signatures of anthracycline-induced cardiotoxicity

Background/introduction Anthracycline-induced cardiotoxicity (AIC) is a major concern in patients receiving chemotherapy. Despite it seems clear the main damage is mediated through mitochondrial toxicity, the lack of evidence to correlate tissue subtle and overt changes to novel advance imaging techniques and translate to the human scenario remains a main gap in the field. Purpose To evaluate in vivo and ex vivo myocardial metabolic changes in model of AIC and validate the findings in the human patient scenario. Methods Cardiac metabolism was evaluated in a large-animal AIC model (Sus scrofa, large-white strained castrated males, 5 intracoronary cycles of 0.45mg/kg of doxorubicin weekly) in vivo by 18FDG PET and cardiac magnetic resonance spectroscopy (CMRS) and ex vivo by transmission electron microscopy in early (6 weeks) and late stages of the disease (16 weeks). Finally, in vivo results were validated with 18FDG PET data in a cohort of 32 cancer patients with similar doxorubicin regimes obtained in comparable timepoints. Results In the pig model, there was an increase in myocardial glucose uptake measured by PET during non-dysfunctional early stages compared with baseline that were maintained after 16 weeks (Fig. pig, panels A, C), these changes were accompanied by a detrimental reduction in the ATP/PCr in the CMRS (Fig. pig, panel B). In the explanted cardiac tissue, the mitochondrial exhibited a fragmented profile by diminishing its area and increasing the number (Fig. pig, panels D-F). In the human patient cohort, myocardial uptake was increase at the end of the visits (32-38 weeks later, Fig. humans, panels A-C). This elevation occurred mainly in a diffuse pattern (Fig. humans, panel D). Conclusions Subclinical myocardial metabolic changes can be detected in vivo during doxorubicin-based chemotherapy by advance imaging (mainly PET). Those changes are mainly related with mitochondrial fragmented phenotype and metabolic dysregulation, even during the first phases. Metabolic profiling and evaluation in thus critical in order to diagnose the injury prior to irreversible damage.Figure