Extracellular vesicular microRNAs as potential biomarker for early detection of doxorubicin‐induced cardiotoxicity

BACKGROUND: Long‐term use of doxorubicin (DOX) is limited by cumulative dose‐dependent cardiotoxicity. OBJECTIVES: Identify plasma extracellular vesicle (EV)‐associated microRNAs (miRNAs) as a biomarker for cardiotoxicity in dogs by correlating changes with cardiac troponin I (cTnI) concentrations and, echocardiographic and histologic findings. ANIMALS: Prospective study of 9 client‐owned dogs diagnosed with sarcoma and receiving DOX single‐agent chemotherapy (total of 5 DOX treatments). Dogs with clinically relevant metastatic disease, preexisting heart disease, or breeds predisposed to cardiomyopathy were excluded. METHODS: Serum concentration of cTnI was monitored before each treatment and 1 month after the treatment completion. Echocardiography was performed before treatments 1, 3, 5, and 1 month after completion. The EV‐miRNA was isolated and sequenced before treatments 1 and 3, and 1 month after completion. RESULTS: Linear mixed model analysis for repeated measurements was used to evaluate the effect of DOX. The miR‐107 (P = .03) and miR‐146a (P = .02) were significantly downregulated whereas miR‐502 (P = .02) was upregulated. Changes in miR‐502 were significant before administration of the third chemotherapeutic dose. When stratifying miRNA expression for change in left ventricular ejection fraction, upregulation of miR‐181d was noted (P = .01). Serum concentration of cTnI changed significantly but only 1 month after treatment completion, and concentrations correlated with left ventricular ejection fraction and left ventricular internal dimension in diastole. CONCLUSION AND CLINICAL SIGNIFICANCE: Downregulation of miR‐502 was detected before significant changes in cTnI concentrations or echocardiographic parameters. Further validation using a larger sample size will be required.