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Correlation Between Serum Levels of Cardiac Troponin-T and the Severity of the Chronic Cardiomyopathy Induced by Doxorubicin

From the Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, MD; Division of Pediatric Cardiology, University of Rochester Medical Center, Rochester, NY; Department of Laboratory Medicine, Boston Childrens Hospital and Harvard Medical School, Boston, MA; and Pathology Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

Address reprint requests to Eugene H. Herman, PhD, Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, 8301 Muirkirk Rd, Laurel, MD 20708; email hermaneu{at}cder.fda.gov

PURPOSE: To investigate, over a wide range of cumulative doxorubicin doses, the feasibility of using serum concentrations of cardiac troponin-T (cTnT) as a biomarker for doxorubicin-induced myocardial damage.

MATERIALS AND METHODS: Groups of spontaneously hypertensive rats (SHR) were given 1 mg/kg doxorubicin weekly for 2 to 12 weeks. Cardiomyopathy scores were assessed according to the method of Billingham and serum levels of cTnT were quantified by a noncompetitive immunoassay. Myocardial localization of cTnT was studied by immunohistochemical staining and confocal microscopy.

RESULTS: Increases in serum levels of cTnT (0.03 to 0.05 ng/mL) and myocardial lesions (cardiomyopathy scores of 1 or 1.5) were found in one out of five and two out of five SHR given 2 and 4 mg/kg doxorubicin, respectively. All animals given 6 mg/kg or more of doxorubicin had increases in serum cTnT and myocardial lesions. The average cTnT levels and the cardiomyopathy scores correlated with the cumulative dose of doxorubicin (0.13 v 0.4 ng/mL cTnT and scores of 1.4 v 3.0 in SHR given 6 and 12 mg/kg doxorubicin, respectively). Decreased staining for cTnT was observed in cardiac tissue from SHR receiving cumulative doses that caused only minimal histologic alterations (scores of 1 to 1.5). Staining for cTnT decreased simultaneously with increases in the severity of the cardiomyopathy scores.

CONCLUSION: cTnT is released from doxorubicin-damaged myocytes. Measurements of serum levels of this protein seem to provide a sensitive means for assessing the early cardiotoxicity of doxorubicin.

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