Despite these findings, there is still little information about the exact mechanisms responsible for the cTnT release, especially with regard to the gradual development of myocardial injury, and the role of cTnT in diagnosis and monitoring of cardiac damage remains controversial. Moreover, the lack of evaluation of diastolic heart function represents a negative point of design of the study by Lipshultz and colleagues. Therefore the question immediately arises as to whether the diastolic heart function may have a non-negligible power for prediction of chronic/late cardiotoxicity of anthracyclines. As a consequence, the identification of a reliable serum indicator of early diastolic dysfunction in cardiomyocytes after doxorubicin treatment could be advisable.
Doxorubicin cardiomyopathy is typically associated with myofibrillar deterioration and intracellular calcium overload, which may trigger indiscriminate activation of calcium-dependent proteases resulting in degradation of key myofibrillar proteins. In animal models, oxidative damage to the sarcoplasmic reticulum (SR) and activation of the sarcolemmal L-type calcium channels or the SR ryanodine receptors would result in calcium accumulation in the cytosol, which alone may be sufficient for activation of calpains. In adult rat ventricular myocytes, calpain-mediated proteolysis of the elastic domain of titin, whose extensible segment underlies the passive and restoring forces of the cardiomyocyte and helps to maximize myocardial efficiency, can predictably lead to impaired diastolic or systolic function, both of which can occur acutely after doxorubicin treatment [4].
Because dexrazoxane reduces free-radical injury, the findings by Lipshultz et al. [1] suggest that doxorubicin-associated myocardial injury may be related, at least in part, to oxidative damage. The attenuating effect of dexrazoxane on doxorubicin-induced cardiotoxicity may be attributable to intracellular conversion to its active form (ADR-925), which binds free iron or removes it from the doxorubiciniron complex, thus preventing the formation of oxygen radicals. However, chronic cardiomyopathy develops after summation and mutual feedback of multifactorial processes. Whether, and how, these processes contribute to inducing cardiotoxicity in patients is controversial, and it is not clear how precisely iron and reactive species of the oxygen intervene in these multiple settings [5
].
Thus, the exclusive use of cTnT as an indicator of subclinical doxorubicin-related myocardial injury in children with cancer cannot completely reflect the acute contractile dysfunction caused by doxorubicin. On the contrary, since the stretch-sensitization response is essential to the regulation of heart contractility, calpain-mediated proteolysis of the elastic domain of titin may have acute physiological consequences, predisposing cardiomyocytes to diastolic dysfunction, myofilament instability and necrosis [4]. Unfortunately, this finding has been demonstrated only in a rat myocyte model. Reliable serum markers capable of early detection of the disassembly of the myofilament complex during the normal sarcomere turnover are urgently needed, and may offer a novel diagnostic tool for the acute contractile dysfunction associated with doxorubicin-induced myocardial calcium overload and oxidative stress.
1 Department of Medical Oncology, Regina Elena Cancer Institute, Rome; 2 Division of Medical Oncology, Treviglio Hospital, Treviglio, Italy
(* Email: gia.fer{at}flashnet.it)
References
1. Lipshultz SE, Rifai N, Dalton VM et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004; 351: 145153.
2. Herman EH, Zhang J, Lipshultz SE et al. Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 1999; 17: 22372243.
3. Herman EH, Zhang J, Rifai N et al. The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 2001; 48: 297304.[CrossRef][ISI][Medline]
4. Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, Eppenberger HM, Suter TM, Liao R, Sawyer DB. Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 2004; 279: 82908299.
5. Minotti G, Menna P, Salvatorelli E et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004; 56: 185229.
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