Departments of 1 Medical Oncology and 2 Cardiology, Hacettepe University Faculty of Medicine, Ankara, Turkey
* Correspondence to: Dr S. Kilickap, Department of Medical Oncology, Hacettepe University Institute of Oncology, Sihhiye, 06100, Ankara, Turkey. Tel: +90-312-3052937; Fax: +90-312-3092905; Email: skilickap{at}yahoo.com
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Abstract |
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Patients and methods:: Forty-one patients who had been scheduled to receive anthracycline-containing combination chemotherapy were included in the study. Serum cTnT levels were measured before (baseline) and after the first cycle of chemotherapy, and again, after the last cycle of chemotherapy. In all patients, the left ventricular ejection fraction (LVEF), fractional shortening (FS), early peak flow/atrial flow velocity (E/A) ratio, and the isovolemic relaxation time (IRT) were measured echocardiographically, both before and after the completion of chemotherapy.
Results:: LVEF and FS did not change in any patients. In 21 patients (49%), the E/A ratio decreased after therapy as compared to the pre-treatment values. The decrease in E/A ratio was more prominent in patients who were older than the mean age of our study group, which was 44 years. The post-treatment IRT was prolonged compared with the pretreatment IRT (94.0 ± 2.0 versus 85.6 ± 10.5 ms, respectively). cTnT levels after completion of therapy were elevated in 14 (34%) patients, and exceeded the upper limit of the normal range (>0.1 ng/ml) in only one patient. cTnT levels measured after completion of therapy were significantly higher, compared with those measured at baseline and after the first cycle of therapy. In the younger age group (44 years old), there was a two-fold decrease in the E/A ratio in those patients whose cTnT levels increased during the therapy, when compared with those whose cTnT levels did not change (21% versus 43%, respectively).
Conclusion:: Increased serum cTnT level can be detected in the early stages of anthracycline therapy and it is associated with diastolic dysfunction of the left ventricle. Therefore, serum cTnT level could be a useful measure for early detection of anthracycline-induced cardiotoxicity.
Key words: anthracycline, cardiotoxicity, cardiac troponin-T, diastolic dysfunction
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Introduction |
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Cardiac troponin-T (cTnT), a component of the troponin complex of muscle cells, is used as a marker of myocardial damage [3, 4
]. The serum cTnT level elevates in conditions such as acute myocardial infarction, unstable angina pectoris, and acute myocarditis [3
, 4
]. Serum cTnT level increases within 46 h after the onset of myocardial infarction and peaks at about 24 h. This increase lasts for 1014 days [5
]. Increased cTnT levels have been informative in the early detection of anthracycline cardiotoxicity in rats [6
]. The aim of this study was to determine whether cTnT levels could prove to be a useful marker for the early detection of anthracycline cardiotoxicity in human beings.
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Patients and methods |
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The Ethical Committee of Hacettepe University Faculty of Medicine approved the protocol (Project number: LUT 02/2, Approval number: LUT 02/24). All patients gave written informed consent before participation in the study.
Cardiac evaluation
The cardiac function of all patients who were enrolled in the study was assessed by complete physical examination, electrocardiography and echocardiography. Echocardiographically, systolic function parameters such as LVEF and FS, diastolic function parameters such as E/A ratio and isovolemic relaxation time (IRT), were measured before and after the treatment by an experienced cardiologist (EA). The cardiologist who performed echocardiograms had no knowledge of the patient's cTnT serum level and cumulative anthracycline dose. Echocardiographic evaluations were performed by Wingmed-Norvea® two-dimensional, M-mode echocardiography.
Biochemical analysis
All the blood samples for cTnT evaluation were obtained from the antecubital vein. Routine blood chemistry was performed in all patients. Those cases having serum creatinine level >1.5 mg/dl, and/or serum bilirubin level >2.0 mg/dl, and/or elevated liver enzymes were excluded from the study. Serum cTnT levels were measured before the anthracycline therapy, on the 3rd to 5th days following the first dose of anthracycline administration, and after the last course of the chemotherapy. The cTnT levels were assessed by Elecsys Troponin T STAT Immunoassay, Elecsys® 1010/2010 systems. The electrochemiluminescence immunoassay was performed on an Elecsys 2010 immunoassay analyzer (Roche® Diagnostics GmbH, Manheim, Germany) with a lower limit of 0.010 ng/ml. Any value below this limit was considered to be zero. The upper limit of the test was 25.00 ng/ml. The normal values of cTnT with analyzer were 0.0100.100 ng/ml.
Statistics
Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) for Windows, version 10.0. Oneway ANOVA test was used to assess the relationship between LVEF, FS, IRT, age and the decrease in the E/A ratio. Wilcoxon signed rank test was used to assess the relationship between pre- and post-therapy serum cTnT levels. Pearson's correlation coefficient was used to evaluate the relationship between age and the E/A ratio. Partial correlation coefficients were used to evaluate the relationship between serum cTnT levels and the E/A ratio.
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Results |
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Discussion |
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The cTnT and I are thin-filament contractile proteins present in high concentrations in the myocardium. The serum concentration of these proteins increases within 36 h after a myocardial injury and remains elevated for 710 days [35
]. In particular, increased serum cTnT level is a specific marker compared to MB isoenzyme of creatine phosphokinase for myocardial injury [18
]. It has been investigated whether measurement of the serum cTnT level is useful for the detection of anthracycline cardiotoxicity. Lipshultz and colleagues [15
] have shown that an increased serum level of troponin-T may predict both doxorubicin-induced subclinical and clinical cardiotoxicity in 15 children. They found that elevated serum cTnT was indicative of left ventricular dilatation and wall thinning. In addition, they reported that serum cTnT increased during doxorubicin administration in doxorubicin-treated children, and was decreased as a result of dexrazoxane therapy [19
]. They showed that low-level elevations of cTnT could be used as a predictor of late doxorubicin-induced cardiotoxicity. Herman et al. [6
] demonstrated that serum cTnT levels predicted doxorubicin-induced cardiotoxicity in spontaneously hypertensive rats. The authors found that an increase in serum cTnT levels was associated with cumulative doxorubicin doses, and there was a positive correlation between the increase in serum cTnT levels and cardiomyopathy scores based on microscopic examination of cardiac tissue. They further reported that cTnT could be used for the detection of doxorubicin-induced cardiomyopathy [20
]. Similarly, another study showed that serum cTnT is a useful marker for the detection of anthracycline-induced cardiotoxicity in rabbits [21
]. In that study, the authors observed that serum cTnT levels increased pathologically after a cumulative dose of 400 mg/m2. Auner et al. [16
] evaluated whether prolonged monitoring of cTnT was beneficial for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. The authors suggested that serial measurement of serum cTnT might be useful for the detection of subclinical myocardial damage in adult patients, even after low doses of anthracyclines.
Several authors, however, stated that serum cTnT showed no increase in the early stages of anthracycline therapy [22, 23
]. Fink et al. [22
] investigated the correlation between cTnT and doxorubicin infusion in early stage, but found no correlation except that the cut-off value for serum cTnT was markedly high (0.04 ng/ml). In another study, Kismet and colleagues assessed 24 pediatric patients who received doxorubicin [24
]. They found that serum cTnT levels increased in only one patient (0.027 ng/ml) who had abnormal systolic functions. However, the assessment of serum cTnT levels and echocardiographic parameters were evaluated 2.511 months after completion of therapy in the mentioned study.
In the present study, our aim was to seek whether serum cTnT predicts cardiac dysfunction at earlier stages of therapy in patients who are receiving ACC regimens. We did not find a significant difference between pre- and post-therapy LVEF and FS measurements. This may be explained by the short duration of follow-up in our patients. However, the E/A ratio, which is predictive of diastolic dysfunction, was decreased in 20 patients (48.8%). It is known that the E/A ratio decreases with age in healthy persons. In our study, we demonstrated that the E/A ratio decreased with age, and the curve showing this decrease was more clearly defined when stratified according to pre- and post-treatment assessments (Figure 2). These data support the view that diastolic dysfunction may develop in patients who receive ACC. However, IRT, which predicts diastolic dysfunction, was significantly prolonged following treatment compared with the pretreatment value. In patients who had decreased E/A ratio, IRT was prolonged for 15.25 ms compared with those cases in which the E/A ratio did not change. Stoddard et al. [25] found that the mean IRT increased from 66 to 84 ms after doxorubicin therapy. Similarly, Marchandise and colleagues [26
] reported a prolongation of IRT from 65 to 86 ms in patients who had received doxorubicin. Our findings were in accordance with these observations.
There was limited information regarding the usefulness of increased serum cTnT in detecting anthracycline-induced cardiotoxicity in its early stage. In our study, the serum cTnT level after the first dose of anthracycline was elevated in only two patients (4.9%) and the E/A ratio was decreased after treatment in these patients. The level of cTnT measured after completion of therapy was elevated in 14 patients (34%), but it exceeded the upper limit of the normal range (>0.1 ng/ml) in only one case. However, the E/A ratio decreased in only six patients who had increased levels of serum cTnT. In the younger age group (44 years old), there was a two-fold decrease in the E/A ratio in patients whose cTnT levels had increased during the therapy, compared with those cases in whom cTnT levels did not change (21.4% versus 42.9%, respectively) (Table 6).
The values of cTnT may also be affected by hydration of the patients. Yet, we do not believe it to be an issue in the present study, since the patients were hydrated mainly on the first day of chemotherapy, while the serum samples for cTnT assessment were drawn before, on the 3rd to 5th days of, and after, the last course of chemotherapy. Moreover, doxorubicin and the other anthracyclines were administered intravenously either via slow push or infusion in 100500 ml of 5% dextrose or normal saline over 3060 min.
A recent hypothesis postulates that release of troponin and/or troponin degradation products is not specific for necrotic myocardium, but may also occur from the viable myocardium [27]. Moreover, some investigators suggest the diagnostic cut-off of cTnT for acute myocardial infarction to be 0.1 ng/ml, and minor myocardial damage to be 0.03 ng/ml [28
]. Thus, 0.03 ng/ml may possibly be the new threshold for cTnT in future studies on anthracycline cardiotoxicity.
There are several limitations of our study. First, the mean follow-up of the patients is very short (6.3 ± 2.2 months). Since the mean follow-up is shorter than a year, LVEF and the other systolic and diastolic cardiac functions are yet to be decreased. The long-term follow-up of the patients who had increased serum levels of cTnT can clarify whether an increased cTnT level may predict anthracycline cardiotoxicity at the early stage. Secondly, different chemotherapeutic agents from the anthracycline group were used in the present study. In spite of the fact that the equivalent doses of drugs were estimated by using a conversion factor, the use of different anthracyclines may be a confounding factor. Thirdly, the cumulative anthracycline doses that were used in this study were lower than those known to be cardiotoxic (228 ± 126.6 mg/m2). Furthermore, the other drugs combined with anthracyclines might well be cardiotoxic and possibly arrhythmogenic. Of note, the agents other than anthracyclines were used at standard dosages in our study.
In conclusion, cTnT can be elevated in patients who have received anthracyclines and it is associated with diastolic dysfunction of the left ventricle. The measurement of the cTnT level could be useful for the detection of anthracycline cardiotoxicity in the early stages, especially in younger patients.
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Acknowledgements |
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Received for publication September 7, 2004. Revision received December 14, 2004. Accepted for publication December 15, 2004.
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