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Karl-Franzens-University A-8036 Graz, Austria
Arola et al. (1) , in a recent issue of Cancer Research, reported on CA1 after the administration of doxorubicin in an animal model. Male Wistar rats were exposed to doxorubicin at increasing dosages (from 1.25 mg/kg as a single injection up to a total cumulative dose of 15 mg/kg over 2 weeks) and killed 1–18 days after the last doxorubicin administration. A significant induction of CA was noted shortly after doxorubicin administration, with a peak after 24–48 h and a return to baseline levels within a week. In addition, alterations of the cytoskeleton were demonstrated by immunohistochemical staining of desmin. The authors concluded that CA plays a major role in the development of anthracycline cardiomyopathy and "may be of key importance in the ensuing heart failure." We wish to comment on the work of Arola et al. (1) and present our own data on anthracycline cardiotoxicity in humans.
The data reported by Arola et al. (1) add valuable information to our understanding of anthracycline-induced cell damage. However, their interpretation lacks the essential distinction between acute and chronic anthracycline cardiotoxicity. Acute cardiotoxicity comprises mostly transient electrophysiological changes seen immediately after administration of the drug. Chronic cardiotoxicity is characterized by gradually developing, usually progressive, and irreversible heart failure occurring months to years after anthracycline treatment and is more worrisome to clinicians. We caution against an interpretation of the data that CA is essential to the development of chronic doxorubicin-induced cardiomyopathy. First, in the study by Arola et al. (1) , the follow-up period during which clinical signs of cardiotoxicity became evident was very short. It is also noteworthy that clinically overt heart failure occurred only in rats exposed to 15 mg/kg doxorubicin over 2 weeks. This constitutes a dose intensity that far exceeds that of any treatment protocol for human malignancies. Furthermore, of the several features that histologically characterize anthracycline-induced late cardiotoxicity (2) , Arola et al. (1) found only cardiomyocyte vacuolization. The findings of Arola et al. (1) are also in contrast to those of another study that did not find increased CA in spontaneously hypertensive rats after prolonged and less intense exposure to doxorubicin (3) . Moreover, in patients with idiopathic dilated and ischemic cardiomyopathy, chronic heart failure was found to be accompanied by ongoing, increased CA years after onset of the disease (4) , whereas in the discussed study (1) , the number of apoptotic cardiomyocytes rapidly returned to baseline. For these reasons, it does not seem justifiable to attribute doxorubicin-induced heart failure mainly to CA.
cTnT has emerged as a specific and sensitive biomarker of myocardial damage in various cardiac diseases. Elevations of serum levels of cTnT after anthracycline chemotherapy have recently been reported to indicate early myocardial damage and were found to predict subsequent cardiac dysfunction in children (5, 6, 7)
. Therefore, the cellular events leading to elevated cTnT levels may be of considerable importance in the development of late-onset cardiomyopathy, and assessing the exact time course of cTnT elevations could furthermore facilitate the identification of the underlying pathogenetic mechanism. We performed serial cTnT measurements in 41 patients with hematological malignancies (acute myeloid leukemia, n = 22; aggressive non-Hodgkin’s lymphoma, n = 18; Hodgkin’s disease, n = 1; median age, 53 years; age range, 17–68 years; male, n = 23; female, n = 18) who received anthracycline-containing polychemotherapy regimens. A total of 85 treatment courses (36 mg/m2 body surface area idarubicin over 3 days, n = 24; 30 mg/m2 mitoxantrone over 3 days, n = 22; 35–50 mg/m2 doxorubicin over 1 day, n = 7; 30–35 mg/m2 pegylated liposomal doxorubicin over 1 day, n = 32) were analyzed. Serum concentrations of cTnT were determined by immunoassay (Elecsys Troponin T Stat; Roche, Indianapolis, IN). According to the manufacturer’s protocol, the detection limit of the assay, which represents the lowest cTnT concentration that can be distinguished from zero, is 0.01 ng/ml. The functional sensitivity of the assay is 0.03 ng/ml; therefore, the determination of a cTnT concentration 
0.03 was considered to represent an elevated serum cTnT. For all chemotherapy cycles analyzed, pretreatment values served as controls and were <0.01 ng/ml, and patients were also required to have normal serum creatinine levels. cTnT was elevated in eight patients (20%; median age, 59.5 years; age range, 35–64 years) during 10 treatment cycles (12%; mitoxantrone, n = 5; doxorubicin, n = 2; idarubicin, n = 2; pegylated liposomal doxorubicin, n = 1). Peak cTnT levels occurred on day 18 (median; range, days 6–35) and were 0.04 ng/ml (median; range, 0.03–0.11 ng/ml). The earliest elevated cTnT was measured on day 13 (median; range, days 4–35). The duration of cTnT elevations per cycle was 4.5 days (median; range, 1–14 days). The number of anthracycline-containing treatment cycles that the patients had received before the treatment cycle in which cTnT elevation was noted was two (median; range, 0–7 cycles).
These data reveal a clearly delayed release of cTnT from cardiomyocytes after anthracycline exposure, suggesting prolonged damage to the myofibrillar system. A number of studies, including that by Arola et al. (1) , have already demonstrated severe alterations of the contractile apparatus after anthracycline exposure in cell lines (8) , animal models (6 , 7 , 9) , and humans (2) . Several mechanisms including increased degradation of myofibrils may be involved in this process. Therefore, our data suggest that prolonged toxicity to the myofibrillar system rather than acute CA is largely responsible for the late cardiomyopathies seen in patients treated with these highly effective antineoplastic drugs.
FOOTNOTES
1 The abbreviations used are: CA, cardiomyocyte apoptosis; cTnT, cardiac troponin T. 
Received 6/12/00. Accepted 12/21/00.
REFERENCES
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  R. J. Bennink, M. J. van den Hoff, F. J. van Hemert, K. M. de Bruin, A. L. Spijkerboer, J.-L. Vanderheyden, N. Steinmetz, and B. L. van Eck-Smit Annexin V Imaging of Acute Doxorubicin Cardiotoxicity (Apoptosis) in Rats J. Nucl. Med., May 1, 2004; 45(5): 842 - 848. [Abstract] [Full Text] [PDF]
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