Key result
Acute high-dose doxorubicin elicited substantial cardiac necrosis, diminished cardiac output and mass, and inhibited autophagic flux, failing to recapitulate the typical human cardiotoxicity phenotype.
Why the study?
Despite studies describing regulated cell death in doxorubicin-mediated cardiotoxicity, the predominant form of cell death remains unclear, partly due to a lack of model standardization.
Acute high-dose doxorubicin induces cardiotoxicity via necrosis and inhibition of autophagic flux, resulting in a smaller heart with reduced ventricular volumes rather than the dilated cardiomyopathy typically observed in humans.
Acute doxorubicin animal models may not mimic human cardiotoxicity; leaves open the need for better preclinical models.
Doxorubicin (DOX) is an effective anthracycline used in chemotherapeutic regimens for a variety of haematological and solid tumors. However, its utility remains limited by its well-described, but poorly understood cardiotoxicity. Despite numerous studies describing various forms of regulated cell death and their involvement in DOX-mediated cardiotoxicity, the predominate form of cell death remains unclear. Part of this inconsistency lies in a lack of standardization of in vivo and in vitro model design. To this end, the objective of this study was to characterize acute low- and high-dose DOX exposure on cardiac structure and function in C57BL/6N mice, and evaluate regulated cell death pathways and autophagy both in vivo and in cardiomyocyte culture models. Acute low-dose DOX had little impact on cardiac structure or function; however, acute high-dose DOX elicited substantial cardiac necrosis resulting in diminished cardiac mass and volume, with a corresponding reduced cardiac output, and without impacting ejection fraction or fibrosis. Low-dose DOX consistently activated caspase-signaling with evidence of mitochondrial permeability transition. However, acute high-dose DOX had only modest impact on common necrotic signaling pathways, but instead led to an inhibition in autophagic flux. Intriguingly, when autophagy was inhibited in cultured cardiomyoblasts, DOX-induced necrosis was enhanced. Collectively, these observations implicate inhibition of autophagy flux as an important component of the acute necrotic response to DOX, but also suggest that acute high-dose DOX exposure does not recapitulate the disease phenotype observed in human cardiotoxicity.
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Kawalec et al. (2022) studied Doxorubicin-induced cardiotoxicity (n=10). Doxorubicin vs. Saline was evaluated on Cardiac mass, cardiac output, and cell death pathways. Acute high-dose doxorubicin elicited substantial cardiac necrosis, diminished cardiac output and mass, and inhibited autophagic flux, failing to recapitulate the typical human cardiotoxicity phenotype.
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