title: Circulating microRNAs: Potential Markers of Cardiotoxicity in Children and Young Adults Treated With Anthracycline Chemotherapy.
abstract: BACKGROUND
  Biomarkers for early detection of anthracycline (AC)-induced cardiotoxicity may allow cardioprotective intervention before irreversible damage. Circulating microRNAs (miRNAs) are promising biomarkers of cardiovascular disease, however, have not been studied in the setting of AC-induced cardiotoxicity. This study aimed to identify AC-induced alterations in plasma miRNA expression in children and correlate expression with markers of cardiac injury.
  
  
  RESULTS
  Candidate plasma profiling of 24 miRNAs was performed in 33 children before and after a cycle of AC (n=24) or noncardiotoxic chemotherapy (n=9). Relative miRNA changes between the pre- and postcycle time points (6, 12, and 24 hours) were determined within each treatment group and compared across groups. Plasma miRNA expression patterns were further explored with respect to AC dose and high-sensitivity troponin T. Greater chemotherapy-induced dysregulation was observed in this panel of candidate, cardiac-related plasma miRNAs in patients receiving anthracyclines compared with those receiving noncardiotoxic chemotherapy (24-hour MANOVA;P=0.024). Specifically, plasma miRs-29b and -499 were upregulated 6 to 24 hours post-AC, and their postchemotherapy expression significantly correlated with AC dose. Patients with acute cardiomyocyte injury (high-sensitivity troponin T increase ≥5 ng/L from baseline) demonstrated higher expression of miR-29b and miR-499 post-AC compared with those without.
  
  
  CONCLUSIONS
  In this pilot study, cardiac-related plasma miRNAs are dysregulated following ACs. Plasma miR-29b and -499 are acutely elevated post-AC, with dose response relationships observed with anthracycline dose and markers of cardiac injury. Further evaluation of miRNAs may provide mechanistic insight into AC-induced cardiotoxicity and yield biomarkers to facilitate earlier intervention to mitigate cardiotoxicity.
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA kasey.leger@seattlechildrens.org.
authors.forename: Kasey J
authors.initials: KJ
authors.lastname: Leger
authors.affiliation: Department of Clinical Research, Children's Medical Center, Dallas, TX.
authors.forename: David
authors.initials: D
authors.lastname: Leonard
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Danelle
authors.initials: D
authors.lastname: Nielson
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: James A
authors.initials: JA
authors.lastname: de Lemos
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.|Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Pradeep P A
authors.initials: PP
authors.lastname: Mammen
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
mesh_terms: D000293:Adolescent; D000367:Age Factors; D018943:Anthracyclines / Q000009:adverse effects*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D066126:Cardiotoxicity; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D042241:Early Diagnosis; D005260:Female; D005819:Genetic Markers; D006331:Heart Diseases / Q000097:blood* / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013997:Time Factors; D020107:Troponin T / Q000097:blood
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D005819:Genetic Markers; C532045:MIRN29a microRNA, human; C548683:MIRN499 microRNA, human; D035683:MicroRNAs; D020107:Troponin T
keywords: anthracycline; cancer; cardiotoxicity; microRNA; pediatric