In vitro and in vivo examination of cardiac troponins as biochemical markers of drug-induced cardiotoxicity.
Cardiac troponin T (cTnT) and troponin I (cTnI) are becoming acknowledged as useful biochemical markers of drug-induced cardiotoxicity. In this study we examined the release kinetics of cTnT and cTnI using an in vitro model of isolated rat neonatal ventricular cardiomyocytes (NVCM, 72h treatment with 0.1-3microM of daunorubicin) and compared it with data from a rabbit model of chronic anthracycline-induced cardiomyopathy in vivo (3mg/kg of daunorubicin weekly, 10 weeks). In cell-culture media, the cTnI and cTnT concentrations were concentration- and time-dependently increasing in response to daunorubicin exposure and were negatively exponentially related to cardiomyocyte viability. With 3microM daunorubicin, the relative increase of AUC of cTnT and cTnI was 2.4- and 5.3-fold higher than the increase of LDH activity, respectively. In rabbits, the daunorubicin-induced cardiomyopathy was associated with progressive increase of both cTnT and cTnI. Although the correlation between cTnT and cTnI cumulative release (AUCs) was found (R=0.81; P<0.01) and both cardiac troponins corresponded well with the echocardiographically-assessed systolic dysfunction (R=0.83 and 0.81 for cTnT and cTnI, respectively; P<0.001), the first significant increase in cTnI levels was observed earlier (at a cumulative daunorubicin dose of 200mg/m(2)) than with cTnT (350mg/m(2)). In conclusion, our study has confirmed cTnT and cTnI as very sensitive and specific markers of anthracycline-induced cardiotoxicity. The troponins can become not only the bridge between the clinical and experimental studies of drug-induced cardiotoxicity but also the linkage between the preclinical experiments in vitro and in vivo.
Adamcová
Michaela
M
Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
Šimůnek
Tomáš
T
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: simunekt@faf.cuni.cz.
Kaiserová
Helena
H
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
Popelová
Olga
O
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
Štěrba
Martin
M
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
Potáčová
Anna
A
Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
Vávrová
Jaroslava
J
Department of Clinical Biochemistry and Diagnostics, University Hospital, Sokolská 581, 500 05 Hradec Králové, Czech Republic.
Maláková
Jana
J
Department of Clinical Biochemistry and Diagnostics, University Hospital, Sokolská 581, 500 05 Hradec Králové, Czech Republic.
Geršl
Vladimír
V
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, 500 38 Hradec Králové, Czech Republic.
D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003630:Daunorubicin / Q000009:adverse effects*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D051381:Rats; D019210:Troponin I / Q000097:blood*; D020107:Troponin T / Q000097:blood*
D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D019210:Troponin I; D020107:Troponin T; D003630:Daunorubicin