Abstract 15043: Circulating microRNA as Novel Biomarkers of Doxorubicin Induced Cardiotoxicity
Background: Cardiotoxicity is a well-known side effect of Doxorubicin (Dox), leading to drug-induced heart dysfunction. Early prediction of disease onset is difficult, thus a new class of heart impairment biomarkers is needed. A role for miRNAs as circulating biomarkers of Dox-mediated heart dysfunction has never been tested.
Purpose: To identify differentially expressed circulating miRNAs of early and late Dox-induced cardiotoxicity using an animal model.
Methods: Healthy mice were administered 24 mg/Kg cumulative dose of Dox during a period of 2 weeks followed by 2-month recovery. Cardiotoxicity insurgence was detectable by echocardiography as early as 1 week after treatment. The expression of 367 miRNAs was analyzed in plasma samples from treated and untreated animals (n=6/group) at the end of the treatment (2 weeks) and 2 months post-administration (recovery phase) followed by singleplex qPCR validation of all miRNAs of interest.
Results: We identified 5 Dox-regulated miRNAs of acute phase. MiR-34a, -34c, and -133a showed an upregulation (6.5, 14.9, and 15 folds, respectively, p≤0.01), whereas miR-16 and miR-451 were negatively regulated by the drug (-2.7 and -2.8 folds, respectively, p<0.05). We then investigated the expression of these miRNAs 2 months after the end of the treatment, but none showed a significant modulation. Conversely, miR-326 was positively regulated by Dox in the plasma of mice after 2 months of recovery (1.53 folds, p<0.05).
Conclusions: This is the first study investigating the possible use of circulating miRNAs as biomarkers of both early and post-treatment Dox-induced cardiotoxicity. Our results revealed a strong regulation of 5 plasmatic miRNAs in response to early damage. Early responders returned to basal levels of expression 2 months after drug administration, indicating an acute damage induced release. This prompts for further studies in the clinical setting to test their suitability as toxicity markers beside cardiac troponin. By contrast, we could not identify strong markers of late damage, apart from a marginal difference in miR-326 circulating levels.
Author Disclosures: Y. D’Alessandra: None. M. Pontremoli: None. G. Milano: None. A. Scopece: None. G. Pompilio: None. G.I. Colombo: None.
- © 2014 by American Heart Association, Inc.