Doxorubicin-treated patient plasma EV miRNA profiles distinctly cluster high-risk cardiotoxicity patients with signatures matching DOX-treated cardiac cell models, indicating plasma EV miRNAs as potential early biomarkers for doxorubicin-induced cardiotoxicity.
Does doxorubicin-induced paracrine signaling via small extracellular vesicles propagate cardiotoxicity in cardiac cells?
Doxorubicin-induced cardiotoxicity is propagated by paracrine signaling through small extracellular vesicles, suggesting plasma EV miRNAs could serve as noninvasive biomarkers for early risk stratification.
Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. While most of these deaths are the result of chronic heart diseases, some CVDs are induced artificially. Doxorubicin (DOX) is a chemotherapeutic that is commonly used to treat breast cancer which is one of the most common types of cancer in the United States. While DOX is an effective anti-cancer agent, over 10% of treated women show signs of acute cardiotoxicity immediately following treatment, and approximately 2% develop severe cardiotoxicity up to 10 years after the end of treatment. Despite this prevalence, the mechanism by which the onset of this cardiotoxicity occurs over time is not well understood. Here, we show that treatment of cardiac cells with DOX changes the cardiac function and the resulting paracrine signaling profile. Subsequent exposure of healthy cells to these altered paracrine agents can recapitulate the effects of direct DOX exposure in 2D and 3D in vitro models. We suggest that this is the result of an altered paracrine miRNA profile and other paracrine factors that propagate the initial disruption caused by direct DOX exposure. Plasma EV miRNA profiling of blinded patient samples revealed distinct clustering by DOX-cardiotoxicity risk, with high-risk patients exhibiting miRNA signatures similar to those from DOX-treated tissue-engineered models. Pathway analysis of the most distinguishing miRNAs linked them to cardiac homeostasis and cardiotoxicity-related mechanisms, supporting the potential of plasma EV miRNAs as noninvasive biomarkers for early risk stratification and personalized cardioprotective interventions in oncological care, and the targeting of key clusters of miRNAs to enhance both understanding of and intervention strategies for preventing the onset of DOX cardiotoxicity.
Ronan et al. (Fri,) conducted a other in Patients undergoing doxorubicin chemotherapy for breast cancer at high or low risk of cardiotoxicity. Doxorubicin chemotherapy and plasma EV miRNA profiling vs. Low cardiotoxicity risk patients was evaluated on Distinction of doxorubicin-induced cardiotoxicity risk via plasma extracellular vesicle (EV) miRNA signatures. Doxorubicin-treated patient plasma EV miRNA profiles distinctly cluster high-risk cardiotoxicity patients with signatures matching DOX-treated cardiac cell models, indicating plasma EV miRNAs as potential early biomarkers for doxorubicin-induced cardiotoxicity.