Circulating microRNAs and cytokines as prognostic biomarkers for doxorubicin-induced cardiac injury and for evaluating the effectiveness of an exercise intervention.

Abstract

To define a set of biomarkers that can be used to identify patients at high risk of developing late DOX-induced cardiac morbidity with the goal of focused monitoring and early interventions. Mice received phosphate buffered saline or DOX 2.5 mg/kg 2x/week for 2 weeks. Blood samples were obtained before and after therapy for quantification of miRNAs (6 and 24 h), cytokines (24 h), and troponin (24 h, 4 and 6weeks). Cardiac function was evaluated using echocardiography before and 24 h after therapy. To assess the effectiveness of exercise intervention in preventing DOX-induced cardiotoxicity blood samples were collected from mice treated with DOX or DOX + exercise. Plasma samples from 13 DOX-treated sarcoma patients were also evaluated before and 24 h after therapy. Elevations in in plasma miRNA-1, miRNA-499 and IL-1α, IL-1β, and IL-6 were seen in DOX-treated in mice with decreased ejection fraction and fractional shortening 24 h after DOX therapy. Troponin levels were not elevated until 4 weeks after therapy. In mice treated with exercise during Dox there was no elevation in these biomarkers and no change in cardiac function. Elevations in these biomarkers were seen in 12 of 13 sarcoma patients treated with Dox. These findings define a potential set of biomarkers to identify and predict patients at risk for developing acute and late cardiovascular diseases with the goal of focused monitoring and early intervention. Further studies are needed to confirm the predictive value of these biomarkers in late cardiotoxicity.