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Response to “Troponins in prediction of cardiotoxic effects.”
- Saadettin Kilickap, Ibrahim Barista, and Kudret Aytemir (13 June 2005)
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“ Troponins in prediction of cardiotoxic effects.”
- Daniela Cardinale, [Maurizio Civelli] , and [Carlo M.Cipolla] (3 May 2005)
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Saadettin Kilickap, M.D. Hacettepe University Institute of Oncology, Department of Medical Oncology, 06100, Ankara, Turkey, Ibrahim Barista, and Kudret Aytemir
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We have read the interpretation by Cardinale et al. (1) about our study (2). We would like to thank the authors for their interest. The increase in serum levels of cardiac troponin-I and -T (cTnI and cTnT) occur due to myocardial damage and are generally used to detect acute myocardial infarction. Since cardiotoxicity can be a dose-limiting factor during cancer treatment, it is very important to detect chemotherapy- related cardiotoxicity at an earlier stage. There are several studies assessing the use of both cTnI and cTnT for the early prediction of cardiac damage in patients who had received chemotherapy. However, information obtained from these studies is limited and use of troponins in subjects who had undergone chemotherapy is not routinely recommended. Although both cTnI and cTnT are used to detect myocardial damage, measurement of cTnI has an important limitation. There is no standardization of assays measuring cTnI (3). More than 15 companies presently market assays for cTnI measurements by employing different epitope specificities. On the other hand, a third-generation cTnT assay is commercially available only from a single diagnostic manufacturer, so that result standardization for this marker is not a problem. Point-of-care qualitative testing is available for both of these enzymes, but the assay for cTnT has been more uniform and reliable (4). The studies of Cardinale et al. evaluate mainly the utility of cTnI rather than cTnT after chemotherapy. However, our conclusion of limited data was about the value of cTnT after chemotherapy. Although an increase in cTnI or cTnT may be considered equivalent, one should keep in mind that results from different cTnI systems and assay generations may cloud the interpretations of reported data (5). The second comment of Cardinale et al was about the threshold of the cTnT. The consensus documents use 99th percentile of the value distribution of the healthy population as reference cut-off value. However, there is unfortunately no threshold below which elevations of troponins are harmless and without negative implications for prognosis (5). In our study, although there was no change in cTnT level, 12 of the 27 patients developed diastolic dysfunction based on the E/A ratio. By thinking of these results and the results of a substudy of GUSTO-IV ACS (6), we speculate a lower threshold may be appropriate. Although we agree about their idea of using a lower threshold may decrease specificity of this marker for detection of myocardial necrosis, we think whether it has additional clinical advantage requires new studies. We stated the short follow-up period as a limitation of our article. However, we do not think that this underscores our findings of the relationship between increase in cTnT and the development of diastolic dysfunction. But it is clear that clinical relevance of this finding requires long term follow up. Two studies about the use of cTnI to reveal the chemotherapy-related cardiotoxicity were inconclusive. In one study, twenty-two patients who were treated with doxorubicin were evaluated (7). Although the cardiac functions, which were evaluated by using echocardiography, were impaired in three patients, the levels of serum cTnI were found within normal range in all subjects. The authors found no relationship between serum cardiac cTnI, the dose of doxorubicin, and echocardiographical findings. In another study, Morandi et al. investigated the relation between cTnI and cardiac function by using echocardiography in patients receiving high-dose cyclophosphamide (8). Early cTnI elevation and cardiac toxicity were not found. They recorded diastolic dysfunction in only two patients. References: 1-Cardinale D, Civelli M, Cipolla M. Troponins in prediction of cardiotoxic effects. Ann Oncol 2005; E-Letter published on May 3rd, 2005. 2-Kilickap S, Barista I, Aytemir K et al. cTnT can be a useful marker for early detection of antrhacycline cardiotoxicity. Ann Oncol 2005; 16: 798-804. 3- Panteghini M. The measurement of cardiac markers. Where should we focus? Am J Clin Pathol 2002; 118: 354-361. 4-Ohman EM, Armstrong PW, White HD et al. Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. Am J Cardiol 1999; 84: 1281-1286. 5- Panteghini M. Role and importance of biochemical markers in clinical cardiology. Eur Heart J 2004; 25: 1187-1196. 6- Ottervanger JP, Armstrong P, Barnathan ES et al for the GUSTO IV- ACS Investigators. Association of revascularisation with low mortality in non-ST elevation acute coronary syndrome, a report from GUSTO IV-ACS. Eur Heart J 2004; 25: 1494-1501. 7- Koseoglu V, Berberoglu S, Karademir S et al. Cardiac troponin I: is it a marker to detect cardiotoxicity in children treated with doxorubicin? Turk J Pediatr 2005; 47: 17-22. 8-Morandi P, Ruffini PA, Benvenuto GM et al. Serum cardiac troponin I levels and ECG/Echo monitoring in breast cancer patients undergoing high- dose (7g/m2) cyclophosphamide. Bone Marrow Transplant 2001; 28: 277-282. Conflict of Interest:None declared |
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Daniela Cardinale, Cardiology Unit European Institute of Oncology - Via Ripamonti 435, 20141 Milan, Italy, [Maurizio Civelli] , and [Carlo M.Cipolla]
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We read the work by Kilickap et al. with great interest [1].These authors affirm that troponin T (cTnT) could be useful for the early detection of anthracycline-related cardiotoxicity. However, the role of cardiac troponins, as indicators of early cardiotoxicity, and as predictors of myocardial dysfunction have already been extensively demonstrated in animal models, as well as in children and adult patient populations treated with chemotherapy. We previously demonstrated that troponin I (cTnI) is a sensitive and specific marker for myocardial injury after high-dose chemotherapy, able to predict, in a very early phase, the development and severity of ventricular dysfunction [2]. More recently, these observations were extended to a larger population of more than 700 patients undergoing high-dose chemotherapy. During a follow-up of more than 3 years, a wide spectrum of adverse cardiac events was considered [3]. These data clearly show that cTnI release pattern identifies patients at different risk of cardiac events. It is quite surprising that the authors completely ignored these recent advances about the clinical and prognostic relevance of troponin increase after chemotherapy, and their statement “there was limited information regarding the usefulness of increased serum cTnT in detecting anthracycline-induced cardiotoxicity in its early stage” appears not appropriated, and not updated. Notably, the pathophysiological and clinical meaning of cTnT and cTnI are equivalent from a cardiological point of view. In addition, the interest of troponins in the oncologic setting has recently moved to a further step of investigation. Troponins have been proposed to the assess the safety of new antineoplastic treatments, and to evaluate the effectiveness of cardioprotective strategies aimed at preventing, or blunting, troponin rise after chemotherapy [4]. The authors describe a relationship between cTnT levels and E/A ratio. cTnT values exceeded the upper limit of the normal range in only two patients, leading the authors to suggest the use of a new lower threshold for cTnT positivity for future studies on anthracycline cardiotoxicity. However, it must be considered that previous studies which had demonstrated a close correlation between troponin levels increase and cardiac events occurrence, utilized the standard cut-off for myocardial damage. Therefore, in our opinion the reduction of the diagnostic cut-off in this setting would only lead to decrease the marker specificity without additional clinical advantages. Moreover, Auner et al. [5] demonstrated the importance of serial measurement of troponins, especially after anthracycline standard dose. In our studies, repeated curves of cTnI samples, associated with a late measurement (1 month after the end of chemotherapy) were utilized, and a predictive negative value of 99%, and a positive predictive value of 84%, were found. Thus, the timing of detection of chemotherapy-induced cardiac injury, as revealed by troponins, more than their actual thresholds, represents the point we have to focus on in future studies. Finally, we found the possible correlation between cTnT increase and the development of diastolic dysfunction very interesting. Unfortunately, because of the short follow-up, and of the small study population, no conclusive information on the possible clinical relevance of this relationship can be drawn. References 1. Kilickap S, Barista I, Akgul E, et al. cTnT can be a useful marker for early detection of antrhacycline cardiotoxicity. Ann Oncol 2005; 16: 798-804. 2. Cardinale D, Sandri MT, Martinoni A, et al. Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Ann Oncol. 2002; 13: 710-15 3. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of Troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004; 109: 2749-2754 4. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukaemia. N Engl J Med 2004: 351: 145-153. 5. Auner HW, Tinchon C, Linkesch W, et al. Prolonged monitoring of troponin T for detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol. 2003; 82: 218-222. Conflict of Interest:None declared |
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