title: The utility of serum biomarkers to detect myocardial alterations induced by Imatinib in rats.
abstract: BACKGROUND
  Imatinib (Imb) is a tyrosine kinase inhibitor with cardiotoxic activity (decreases in left ventricular function and congestive heart failure) in patients. Currently, clinical diagnosis of Imb cardiotoxicity relies primarily on evaluation of left ventricular function, Imb also induces cardiac lesions in rats.
  
  
  OBJECTIVE
  This study, in rats, sought to determine whether monitoring biochemical markers would be a sensitive means to detect Imb-induced changes in cardiomyocyte morphology.
  
  
  METHODS
  Groups of male Sprague-Dawley rats were dosed orally with 50, 100, 200 mg kg(-1) Imb or water daily for 28 days. Tissues and blood samples were collected 24 h after the last dosing. Cardiac biomarkers such as cardiac troponin I (cTnI), cardiac troponin T (cTnT), and fatty acid binding protein 3 (FABP3) were monitored by the Erenna, Elecsys, and Meso Scale immunoassay systems.
  
  
  RESULTS
  Imb caused microscopic myocardial lesions (myofibrillar loss, cytoplasmic vacuolization, and necrosis) at all doses as determined by unbiased histopathology analysis. The severity of the alterations was dose-related with mean lesion scores (based on a scale of 0-3) of 1.2 (50 mg kg(-1)), 2.1 (100 mg kg(-1)) and 2.9 (200 mg kg(-1)). However, the increases in cTnI, cTnT, and FABP3 levels were noted primarily in high-dose Imb treated animals.
  
  
  CONCLUSIONS
  The occurrence of myocardial alterations in animals without consistent changes in cardiac troponin and FABP3 concentrations raises questions regarding the utility of these biomarkers as early indicators of Imb-induced cardiotoxicity. Due to limited numbers of animals the reasons for this discrepancy could not be determined.
authors.affiliation: Division of Drug Safety Research, Food and Drug Administration Silver Spring, Maryland.
authors.forename: Eugene
authors.initials: E
authors.lastname: Herman
authors.affiliation: Division of Drug Safety Research, Food and Drug Administration Silver Spring, Maryland.
authors.forename: Alan
authors.initials: A
authors.lastname: Knapton
authors.affiliation: Division of Drug Safety Research, Food and Drug Administration Silver Spring, Maryland.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Singulex, Inc. Alameda, California.
authors.forename: Joel
authors.initials: J
authors.lastname: Estis
authors.affiliation: Singulex, Inc. Alameda, California.
authors.forename: John
authors.initials: J
authors.lastname: Todd
authors.affiliation: Department of Pediatrics, Mailman Center for Child Development, Leonard A. Miller School of Medicine, University of Miami Miami, Florida.
authors.forename: Steven
authors.initials: S
authors.lastname: Lipshultz
keywords: Cardiac biomarkers; Imatinib cardiotoxicity; rats