Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Herman
E H
EH
Division of Applied Pharmacology Research (HFD-910), Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, MD 20708, USA. hermaneu@cder.fda.gov
Zhang
J
J
Lipshultz
S E
SE
Rifai
N
N
Chadwick
D
D
Takeda
K
K
Yu
Z X
ZX
Ferrans
V J
VJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers; D009202:Cardiomyopathies / Q000097:blood* / Q000139:chemically induced* / Q000473:pathology; D002908:Chronic Disease; D004317:Doxorubicin / Q000633:toxicity*; D016903:Drug Monitoring / Q000379:methods*; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D020107:Troponin T / Q000097:blood*
D000970:Antineoplastic Agents; D015415:Biomarkers; D020107:Troponin T; D004317:Doxorubicin