Japanese Journal of Clinical Oncology 34:262-268 (2004)
© 2004 Foundation for Promotion of Cancer Research
Evaluation of Cardiotoxicity of a Combined Bolus plus Infusional 5-Fluorouracil/Folinic Acid Treatment by Echocardiography, Plasma Troponin I Level, QT Interval and Dispersion in Patients with Gastrointestinal System Cancers
1 Institute of Oncology, 2 Faculty of Medicine, Department of Cardiology and 3 Faculty of Medicine, Department of Biochemistry, University of Dokuz Eylul, Inciralti-Izmir, Turkey
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: To evaluate the cardiotoxicity of LV5FU2 regimen (bolus plus infusional 5-fluorouracil/folinic acid) treatment by non-invasive methods such as echocardiography, plasma troponin I (TnI) level, QT interval and QT dispersion on ECG.
Methods: Twenty-two patients with gastrointestinal cancer who received LV5FU2 chemotherapy were evaluated prospectively during 12 cycles of chemotherapy. Plasma TnI assay and ECG recording analyses were performed before the first cycle, at 24 h, before each cycle until cycle 6 and every three cycles thereafter. The longest QT interval measurement on each recording corrected with Bazzett’s formula was considered as QTmax and the difference between the QTmax and the shortest corrected QT interval was considered as QT dispersion (QTd). A complete M-mode, 2D and color Doppler echocardiogram was performed at baseline and at the first, third and sixth months of treatment.
Results: Echocardiography did not show any significant change in either systolic or diastolic functions. Also, TnI measurements were found to be below detectable level in all patients and in all measurements. Meanwhile, significant prolongations of QTmax and QTd were observed as early as 24 h after first administration of chemotherapy. These events persisted and became more important over the duration of chemotherapy (P < 0.05).
Conclusions: The clinical implication of these findings as predictive factors for subsequent events such as malignant arrhythmias in patients taking 5-fluorouracil-based chemotherapy need longer follow-up and further detailed evaluations.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Prospective studies have demonstrated that treatment with 5-fluorouracil (5-FU) chemotherapy leads to cardiac adverse events with an incidence ranging from 1.6 to 8.0% (1–4). This incidence was found to be about 10 times higher in patients with a history of cardiac disease compared to those without cardiac problems (15.1 versus 1.5%, respectively) (5). This cardiac toxicity consists generally of an angina accompanied by ST segment changes and/or left ventricle dysfunction. Myocardial infarction, rhythm abnormalities and sudden death have also been reported (1,4,6).
ST segment changes resolve rapidly and left ventricle dysfunction, which is the most common abnormality secondary to 5-FU, reverses within 6 months after the completion of treatment. Thus, cardiac events secondary to 5-FU are generally reversible, but severe damage to cardiac tissues or death are encountered, although rarely (6,7). Several methods have been proposed to identify early cardiac changes which lead to higher risk of irreversible and serious cardiac events. Monoclonal antimyosin antibody imaging (8,9), study of cardiac autonomic function (10) and endomyocardial biopsy (11) were used for this purpose. The complexity and high cost of these methods limit their use in daily clinical practice.
Troponin I (TnI) is a protein specific to myocardial tissue. An increase of its level in serum is an early, sensitive and specific marker of myocardial injury, including minor myocardial damage (12). It has been observed that this cell-structural protein is detected in the blood of patients with acute coronary syndrome (13), after coronary angioplasty (14), in heart failure (15), acute myocarditis (16) and other clinical situations in which conventional markers of myocyte necrosis are often negative (17).
Electrocardiography (ECG) is a simple method which records the electrical potential changes of the myocardium represented on the body surface. It is a very useful tool to evaluate cardiac rhythm and myocardial ischemia.
The interval between Q and the end of T corresponds to the period from the beginning of depolarization until the end of repolarization of the cardiac muscle. The differences in QT interval, i.e. QT dispersion (QTd) reflect a functional heterogeneity between different regions of the myocardium when it is larger than normal. It has been shown that the QTd is predictive of mortality in normal subjects (18) and different groups of patients including those suffering from diabetes (19–21) and myocardial infarction (22). QTd has also been related to subsequent occurrence of arrhythmias in these patients and in healthy subjects (18).
Echocardiography is a non-invasive tool of imaging which explores the cardiac structures. With the assistance of computers, it also enables observation and measurement of systolic and diastolic functions of the heart and is widely used in daily clinical practice for these purposes.
It has been claimed that cardiac toxicity is more common when higher doses of 5-FU are administered as longer infusions instead of regimens based on bolus administration (1,6). The administration method of LV5FU2, called the de Gramont schedule, is one of the preferred chemotherapy regimens in the treatment of colorectal cancer because of its lower hematological and gastrointestinal toxicity. In this study, we aimed to evaluate the cardiac effects of this regimen with non-invasive methods, namely physical examination, ECG, echocardiography and serum TnI level measurements.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Study Population
Patients receiving LV5FU2 chemotherapy regimen for gastrointestinal cancer in our institute from September 2002 to March 2003 were enrolled into the study. Those with a history of heart disease (angina, hypertension or valvular diseases), with a left ventricular ejection fraction (LVEF) < 50%, or with renal (serum creatinine > 1.5 mg/dl) or liver (bilirubin > 2 mg/dl, aspartate aminotransferase > 2x the upper limit of normal) disease were excluded. Twenty-two patients were included in the study. None of the patients were receiving medication affecting cardiac function and QT interval such as class Ia or class III antiarrhythmic agents.
The LV5FU2 chemotherapy regimen consisted of classical de Gramont regimen (LV 200 mg/m2 2 h infusion; 5-FU 400 mg/m2 bolus and 5-FU 600 mg/m2 22 h infusion, on days 1 and 2, repeated every 2 weeks). Twenty patients received adjuvant, and two patients received palliative treatment. All patients took granisetron 1 mg/day p.o., a 5-HT3 antagonist, as antiemetic prophylaxis each day of chemotherapy.
Before enrolment , patients were informed on the methods and aims of the study and written consent was obtained. Enrolment into the study did not affect treatment regimen.
Study Protocol
Clinical examination, plasma TnI assay, ECG, chest X-ray and echocardiography were part of the baseline evaluation. Chemotherapy was administered intravenously with the schedule mentioned above, via a central venous catheter. Plasma TnI assay and ECG analyses were performed before the first cycle, at 24 h, before each cycle until cycle 6 and every three cycles thereafter. A complete M-mode, 2D and color Doppler echocardiogram was performed at baseline and at the first, third and sixth months of therapy. For all patients, the duration of chemotherapy and follow-up was planned as 6 months.
Electrocardiography
Twelve-lead ECGs were recorded before, and 24 h after, the beginning of the first cycle, and in consecutive cycles before the administration of chemotherapy using the same ECG device. Parameters such as heart rate and rhythm, QRS duration (QRSd), presence of ST abnormalities, QT interval and total QRS voltage were analyzed. QT interval was corrected as described below according to heart rate. The QRS voltage was measured by summating the distance from the peak of R wave to the nadir of S wave in each of the six standard limb leads. These leads were chosen to minimize variability in QRS voltage due to lead placement.
QT Interval Duration
RR and QT intervals were measured with a ruler on the resting ECG tracing: five consecutive beats were considered on each lead. The QT interval was measured from the beginning of the QRS complex to the end of the down slope of the T wave where it reaches the isoelectric line. When a U wave was present, the QT interval was measured to the nadir of the curve between the T and U waves. The QT interval corrected for the previous cardiac cycle length (QTc) was calculated according to Bazzett’s formula [QTc = QT/(RR)1/2] (23). Two observers who were unaware of the state of the patients measured all of the intervals. The QTc for each subject was considered to be the mean value of the five calculated intervals and the mean of reading of both observers to minimize inter observer variability. In any lead, QTc > 440 ms was considered abnormally prolonged. The maximum QTc (QTmax) of each recording was considered for comparisons and calculation of means.
QT Interval Dispersion
The difference between the maximum and minimum corrected QT intervals on any of the standard 12 leads on the same ECG was considered as QTd. The measurements were performed as mentioned above by two investigators, who were ignorant as to the identity of the patient and to which cycle of chemotherapy would be administered. The mean of the measurement of both observers was adopted as the final result. QTc dispersion > 60 ms was considered abnormally prolonged.
Echocardiographic Evaluation
Standard 2D and M-mode echocardiographs were obtained with a Hewlett-Packard model Sonos 2000 imaging system using 2.7 and 3.5 MHz transducer. M-mode, pulsed-wave and continuous-wave Doppler recordings were made with a speed of 100 mm/s. Cardiac dimensions were measured according to the recommendations of the American Society of Echocardiography (24). To assess left ventricular diastolic function, mitral flow velocity was recorded using pulse-wave Doppler in the apical 4-chamber position with the sampling window placed at the tip of the mitral leaflets. The angle between the cursor line and the direction of diastolic flow was kept as small as possible and was determined to be <20° in each record. Measurements included peak early mitral valve filling velocity (E wave), peak atrial filling velocity (A wave), ratio of peak early and atrial filling velocity (E/A) and deceleration of the E wave (DT). The isovolumetric relaxation time (IVRT) was measured by moving the sampling window to a position between the anterior mitral leaflet and left ventricular outflow tract. A complete M-mode, 2D and color Doppler echocardiogram were performed at baseline and at first, third and sixth months of chemotherapy. Left ventricle ejection fraction (LVEF%) was calculated according to modified 20-disks Simpson formula.
Laboratory Methods
Blood samples were collected into a Monovette containing a sodium citrate solution (0.106 mol/l) with a dilution ratio after blood collection of 1/10 and were centrifuged at 1080 r.p.m. within 60 min to separate the plasma, which was immediately analyzed. The laboratory analysis for the determination of TnI was performed by immuno-enzymatic fluorescent assay (Immulite Turbo, International Inc., Miami, FL). This method utilizes two TnI-specific monoclonal antibodies for independent epitopes and has no detectable cross reactivity with skeletal muscle TnI. The lowest limit of detection was 0.50 ng/ml.
Statistical Analysis
All results are expressed as the mean (±SD). Statistical tests were performed using the Friedman Variant Analysis (non-parametric tests – K related samples) and Wilcoxon Signed Ranks Analysis (non-parametric tests – two related samples), and were considered significant at P < 0.05. Variations in LVEF values and E/A ratios were analyzed using a generalized linear model.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The study population included 22 patients treated with LV5FU2 regimen for colorectal and stomach cancers in our Institute. The median age of the patients was 63 (range, 44–76). Other characteristics of these patients are shown in Table 1. All the patients completed the planned chemotherapy.
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Clinical Course
Baseline cardiac functions were within normal limits in all patients. None of the patients had a clinically evident acute cardiological event during or soon after administration of the drugs. They did not develop symptoms of either ischemic heart disease or heart failure during the follow-up.
Cardiac TnI
A total of 198 blood samples were collected during 264 treatment cycles from 22 patients for TnI measurements. At the baseline evaluation, as well as before and at 24 h of the first cycle, before each cycle until cycle 6 and every three cycles thereafter, the TnI value was within the normal ranges in all cases.
ECG
No rhythm abnormality, ischemic ST segment or QRS duration or voltage changes in ECG records were observed either before or after chemotherapy. Baseline QTd was also within normal limits in all patients except three. However, significant increases in QTmax and QTd were observed as early as 24 h after administration of chemotherapy (P < 0.05). These persisted and became increasingly marked in subsequent cycles. Sample ECG tracings showing recordings at the start and at the end of study follow-up can be seen in Fig. 1. When each QTmax and QTd measurements performed every three cycles were compared to the previous ones, the differences were statistically significant (Fig. 2) (Table 2).
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Echocardiography
Baseline echocardiographic parameters were within normal range in all patients. Any significant abnormality was observed after the chemotherapy including the parameters concerning systolic and diastolic functions. Baseline and follow-up echocardiographic findings are shown in Table 3.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, 22 patients receiving LV5FU2 chemotherapy regimen were evaluated with serial echocardiographic examinations, plasma TnI assays and ECG recordings. Echocardiography did not show any significant changes in either systolic or diastolic functions. Also, TnI measurements were found to be below detectable level in all patients and in all measurements. Neither did ECG recordings show any change in favor of a coronary ischemia, injury or other serious rhythm abnormalities. Meanwhile, significant prolongations of both QTmax and QTd were observed as early as 24 h after administration of chemotherapy. These events persisted and became more important over the duration of chemotherapy.
The cardiac toxicity of 5-FU can be serious, but is not frequent. In the absence of previous history of cardiac disease, it can be observed in as few as 1.5% of patients despite careful clinical follow-up (5). It is very probable that clinical evidence of an event occurring in only a small proportion of patients would not be observed in such a small group of patients.
In contrast, the cardiac toxicity of 5-FU is at least ten times more frequent in patients with a previous history of cardiovascular disease (5). So, it can be supposed that 5-FU has some effects on cardiac function which are frequently translated into clinical symptoms or signs when a pre-existing abnormality exists. It is important to elucidate these subclinical events in order to understand the mechanisms underlying the cardiac toxicity of 5-FU, which is one of the most widely used chemotherapeutic agents.
In children receiving anthracycline chemotherapy (25) and in patients with hematological malignancies receiving anthracycline chemotherapy, an increase in TnI has been reported (26,27). Recently some authors have reported that the elevation of TnI in patients treated with high-dose chemotherapy (HDCT) for aggressive malignancy accurately predicts the development of future left ventricle ejection fraction depression (17,28–30). However, we did not observe either detectable increase of TnI in serial plasma assays or any left ventricular dysfunctions, systolic or diastolic, by echocardiographic evaluation. Although all of our patients had taken 5-FU/LV treatment with a probably more cardiotoxic schedule, i.e. as longer duration infusion, left ventricular dysfunction was not observed in any of them. These results can be explained by the fact that none of the patients had pre-existing cardiac disease and the study population comprised a limited number of patients.
The QT interval reflects the repolarization of myocardium and is affected by the heart rate. It is corrected for the heart rate and is most commonly used in the assessment of abnormalities of myocardial repolarization, which can be secondary to an increase in cardiac muscle mass or prolongation of synchronization inside the heart muscle (31). It has been shown that a prolonged QT interval is associated with sudden death and poor survival in healthy subjects (18) and in a variety of clinical conditions, including newly diagnosed type 2 diabetes (20), nephropathy (32) and type 1 diabetes (33,34). The observation that the QT interval exhibits a certain degree of spatial variability on the epicardial surface (35) has led to the hypothesis that differences in the duration of the QT interval between ECGs may reflect heterogeneity in recovery of excitability (36). Non-uniformity of repolarization provides a basis for the development of malignant ventricular arrhythmias (37).
The measurement of QT interval can sometimes be difficult because of the changes in T waves, the occasional presence of U waves and the effect of electrical axis. Automated measurement had been tried to avoid these problems, but was not found to be superior to manual measurement. No particular lead had been suggested as the lead showing the QTmin or QTmax, but to simplify QT comparisons, V2 or V3 can be considered to be sufficient as the leads to measure the representative QT interval for each ECG recording (38).
In the 1990s, it was shown that the inter-lead difference of QT interval on standard 12-lead ECG recordings might provide more powerful diagnostic information than the measurement of only the maximum QT interval (39). Despite some problems in the methodology, the majority of studies suggest that increased QTd is a risk marker for future clinical events. It has been demonstrated that QTd is predictive of mortality in normal subjects and different groups of patients, including those with myocardial infarction (22), long QT syndrome (22,39), heart failure (40) and hypertrophic cardiomyopathy (41). Furthermore, a number of studies have shown that increased QTd is a marker for arrhythmic events, sudden cardiac death (40,42,43) and drug-induced proarrhythmia (44,45), in particular, broad QTd seems to predict the occurrence of the drug-induced Torsade de Pointes (46).
In a study conducted in patients receiving high-dose chemotherapy, including high-dose cyclophosphamide with peripheral blood stem-cell transplantation (PBSCT), it was reported that QTd could predict acute heart failure after high-dose cyclophosphamide administration. It was speculated that lengthening of the QTd showed increases in ventricular recovery-time dispersion caused by local damage, or multifocal degeneration of cardiac muscle. QTd is a sensitive marker, which can show abnormalities earlier than they would appear on echocardiography (47).
In patients receiving anthracycline-based chemotherapy, it has been reported that QTd increased with higher cumulative doses of anthracycline (48–51). This increase has shown an important inverse correlation with the decrease of left ventricular ejection fraction in two studies (48,49). This relation was not confirmed by two others studies (50,51). The effect of 5-FU on QTd was not reported previously. In our study, QTd increased after 5-FU-based chemotherapy, but this increase was not accompanied by an evident left ventricular dysfunction.
Unfortunately, it is still difficult to make any conclusive remarks on the possible impact of the QT interval prolongation and QTd increase, corrected or not, on the decisions concerning 5-FU-based chemotherapy and the cardiac outcome of patients. This is because our results concern only a small group of patients followed up only during the treatment. It is very probable that any risk for events such as arrhythmias can disappear with the reversal of the prolongation of the QT interval and QTd. Subsequent studies with longer follow up are being planned in order to answer these questions. However, it can be concluded that, with the knowledge that higher cardiotoxicity secondary to 5-FU is observed in patients with a history of cardiac disease, special attention should be paid to the cardiological follow up of patients when the ECG events mentioned above are observed.
There is no information on the possible role of folinic acid on QT interval and QTd. But it is well documented that the addition of folinic acid to 5-FU does not have any influence on cardiac effects of 5-FU (5,6). However, the increased QTd was reported to be an effect of several medications such as antiemetics. The antiemetic drug taken by our patients was granisetron. Some reports claim that 5-HT3 antagonists can have minor reversible effects on cardiac rhythm (52–54). These are reflected by ECG changes, including QTd. Among these drugs, granisetron was found to have the least effect on cardiac rhythm and is the one proposed for most safety in patients with heart disease (53–56). It is difficult to ignore the contribution of granisetron to the changes of QT interval and QTd of our patients. But any effect of granisetron on cardiac rhythm is expected to be of short duration and rapidly reversible (54). The ECG recordings were taken before the chemotherapy and granisetron administration, and so the interval between the last granisetron dose and ECG recording was at least 12 days. Thus, we conclude that the effect of granisetron on QTd in our patients was negligible, if not absent.
In conclusion, LV5FU2 chemotherapy leads to significant increases in QT interval and QTd in a group of 22 patients without overt cardiac disease. Special care should be taken to observe whether this effect interferes with other medications such as antiarrhythmic agents with some influence on QT interval. Longer follow-up with further detailed evaluations are required to establish the clinical implication of this finding as a predictive factor for subsequent events such as malignant arrhythmias in patients taking 5-FU-based chemotherapy.
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FOOTNOTES |
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+ For reprints and all correspondence: Ugur Yilmaz, Dokuz Eylul Universitesi, Onkoloji Enstitusu, 35340 Inciralti-Izmir, Turkey. E-mail: ugur.yilmaz{at}deu.edu.tr
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1 De Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol 1992;10:1795–801.
2 Akhtar S, Salim K, Bano Z. Symptomatic cardiotoxicity with high-dose 5-fluorouracil infusion: a prospective study. Oncology 1993;50:441–4.[Web of Science][Medline]
3 Meyer C, Anton Calis K, Burke L,Walawander CA, Grasela TH. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy 1997;17:729–36.[Web of Science][Medline]
4 Labianca R, Beretta G, Clerici M, Fraschini P, Luporini G. Cardiac toxicity of 5-fluorouracil: a study on 1083 patients. Tumori 1982;68:505–10.[Web of Science][Medline]
5 Schober C, Papageorgiou E, Harstrick A, Bokemeyer C, Mugge A, Stahl M, et al. Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer. Cancer 1993;72:2242–7.[CrossRef][Web of Science][Medline]
6 Tsavaris N, Kosmas C, Vadiaka M, Efremidis M, Zinelis A, Beldecos D, et al. Cardiotoxicity following different doses and schedules of 5-fluorouracil administration for malignancy – a survey of 427 patients. Med Sci Monit 2002;8:151–7.
7 Grandi AM, Pinotti G, Morandi E, Zanzi P, Bulgheroni P, Guasti L, et al. Noninvasive evaluation of cardiotoxicity of 5-fluorouracil and low doses of folinic acid: a one-year follow-up study. Ann Oncol 1997;8:705–8.
8 Carrio I, Estorch M, Berna L, Germa JR, Alonso C, Ojeda B, et al. Assessment of anthracycline-induced myocardial damage by quantitative indium-111 myosin-specific monoclonal antibody studies. Eur J Nucl Med 1991;18:806–12.[Web of Science][Medline]
9 Yamada T, Matsumori A, Tamaki N, Morishima S, Watanabe Y, Yonekura Y, et al. Detection of adriamycin cardiotoxicity with indium-111 labeled antimyosin monoclonal antibody imaging. Jpn Circ J 1991;55:377–83.[Medline]
10 Viniegra M, Marchetti M, Losso M, Navigante A, Litovska S, Senderowicz A, et al. Cardiovascular autonomic function in anthracycline-treated breast cancer patients. Cancer Chemother Pharmacol 1990;23:227–31.
11 Billingham ME, Bristow MR. Evaluation of anthracycline cardiotoxicity: predictive ability and functional correlation of endomyocardial biopsy. Cancer Treat Symp 1984;3:71–6.
12 Chapelle JP. Cardiac troponin I and troponin T: recent players in the field of myocardial markers. Clin Chem Lab Med 1999;37:11–20.[CrossRef][Web of Science][Medline]
13 Stubbs P. The cardiac troponins uses in routine clinical practice. Experience from GUSTO and other clinical trials. Eur Heart J 1998;19(Suppl N):N59–63.
14 Stromme JH, Johansen O, Brekke M, Seljeflot I, Amesen H. Markers of myocardial injury in blood following PTCA: a comparison of CKMB, cardiospecific troponin T and troponin I. Scand J Clin Lab Invest 1998;58:693–9.[CrossRef][Web of Science][Medline]
15 La Vecchia L, Mezzena G, Ometto R, Finocchi G, Bedogni F, Soffiati G, Vincenzi M. Detectable serum troponin I in patients with heart failure of non myocardial ischemic origin. Am J Cardiol 1997;80:482–5.
16 Lauer B, Niederau C, Kuhl U, Schannwell M, Pauschinger M, Strauer BE, Schultheiss HP. Cardiac troponin T in patients with clinically suspected myocarditis. J Am Coll Cardiol 1997;30:1354–9.[Abstract]
17 Morandi P, Ruffini PA, Benvenuto GM, La Vecchia L, Mezzena G, Raimondi R. Serum cardiac troponin I levels and ECG/Echo monitoring in breast cancer patients undergoing high-dose (7 g/m2) cyclophosphamide. Bone Marrow Transplant 2001;28:277–82.[CrossRef][Web of Science][Medline]
18 Elming H, Holm E, Jun L, Torp-Pedersen C, Kober L, Kircshoff M, et al. The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens. Eur Heart J 1998;19:1391–400.
19 Veglio M, Giunti S, Stevens LK, Fuller JH, Perin PC, The EURODIAB IDDM Complications Study Group. Prevelance of QT interval dispersion in type I diabetes and its relation with cardiac ischemia. Diabetes Care 2002;25:702–7.
20 Naas AAO, Davidson NC, Thompson C, Cummings F, Ogston SA, Jung RT, et al. QT and QTc dispersion are accurate predictors of cardiac death in newly diagnosed non-insulin-dependent diabetes: a cohort study. Br Med J 1998;316:745–6.
21 Sawicki PT, Kiwitt S, Bender M, Berger M. The value of QT interval dispersion for identification of total mortality risk in non-insulin-dependent diabetes mellitus. J Intern Med 1998;243:49–56.[CrossRef][Web of Science][Medline]
22 Van de Loo A, Arendts W, Hohnloser SH. Variability of QT dispersion measurements in the surface electrocardiogram in patients with acute myocardial infarction and in normal subjects. Am J Cardiol 1994;74:1113–8.[CrossRef][Web of Science][Medline]
23 Bazett HC. An analysis of time-relations of electrocardiograms. Hearts 1920;7:353–70.
24 Sahn JD, DeMaria A, Kisslo J, Weyman A. The committee on M-mode Standardization of the American Society of Echocardiography. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–83.
25 Lipshultz SE, Rifai N, Sallan SE, Lipsitz SR, Dalton V, Sacks DB, Ottlinger ME. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997;96:2641–8.
26 Auner HW, Tinchon C, Linkesch W, Tiran A, Quehenberger F, Link H, Sill H. Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol 2003;82:218–22.[Web of Science][Medline]
27 Missov E, Calzolari C, Davy JM, Leclercq F, Rossi M, Pau B. Cardiac troponin I in patients with hematologic malignancies. Coron Artery Dis 1997;8:537–41.[Web of Science][Medline]
28 Cardinale D, Sandri MT, Martinoni A, Borghini E, Civelli M, Lamantia G, et al. Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Ann Oncol 2002;13:710–5.
29 Sandri MT, Cardinale D, Zorzino L, Passerini R, Lentati P, Martinoni A, et al. Minor increases in plasma troponin I predict decreased left ventricular ejection fraction after high-dose chemotherapy. Clin Chem 2003;49:248–52.
30 Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M, Lamantia G, et al. Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy. J Am Coll Cardiol 2000;36:517–22.
31 Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval. Progr Cardiovasc Dis 2001;43(Suppl):1–45.
32 Sawicki PT, Dahne R, Bender R, Berger M. Prolonged QT interval as a predictor of mortality in diabetic nephropathy. Diabetologia 1996;39:77–81.[Web of Science][Medline]
33 Veglio M, Sivieri R, Chinaglia A, Scaglione L, Cavallo-Perin P. QT interval prolongation and mortality in type I diabetic patients. Diabetes Care 2000;23:1381–3.
34 Rossing P, Breum L, Major-Pederesen A, Sato A, Winding H, Pietersen A, et al. Prolonged QTc interval predicts mortality in patients with type I diabetes mellitus. Diabet Med 2001;18:199–205.[CrossRef][Web of Science][Medline]
35 Cowan JC, Hilton CJ, Griffiths CJ. Sequence of epicardial repolarization and configuration of the T wave. Br Heart J 1988;60:424–33.
36 Sylven JC, Horacek BM, Spencer CA, Klassen GA, Montague TJ. QT interval variability on the body surface. J Electrocardiol 1994;17:179–88.
37 Kautzner J, Malik M. QT interval dispersion and its clinical utility. PACE 1997;20:2625–40.
38 Kautzner J. QT interval measurements. Cardiac Electrophysiol Rev 2002;6:273–7.[CrossRef][Medline]
39 Day CP, MeComb JM, Cambell RW. QT dispersion: An indication of arrhythmic risk in patients with long QT intervals. Br Heart J 1990;63:342–4.
40 Barr CS, Naas A, Freeman M, Lang CC, Struthers AD. QT dispersion and sudden unexpected death in chronic heart failure. Lancet 1994;343:327–9.[CrossRef][Web of Science][Medline]
41 Buja G, Miorelli M, Turrini P, Melacini P, Nava A. Comparison of QT dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. Am J Cardiol 1993;72:973–6.[CrossRef][Web of Science][Medline]
42 Zareba W, Moss AJ, Le Cessie S. Dispersion of ventricular repolarization and arrhythmic cardiac death in coronary artery disease. Am J Cardiol 1994;74:550–3.[CrossRef][Web of Science][Medline]
43 Pye M, Quinn AC, Cobbe SM. QT interval dispersion: a non-invasive marker of susceptibility to arrhythmia in patients with sustained ventricular arrhythmias? Br Heart J 1994;71:511–4.
44 Campbell RW, Furniss SS. Practical considerations in the use of sotalol for ventricular tachycardia and ventricular fibrillation. Am J Cardiol 1993;72:80A–85A.[CrossRef][Medline]
45 Hii JT, Wyse DG, Gillis AM, Duff HJ, Solylo MA, Mitchell LB. Precordial QT interval dispersion as a marker of torsades de pointes. Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 1992;86:1376–82.
46 Malik M, Batchvarov VN. Clinical potential of QT dispersion. J Am Coll Cardiol 2000;36:1749–66.
47 Nakamae H, Tsumura K, Hino M, Hayashi T, Tatsumi N. QT dispersion as a predictor of acute heart failure after high-dose cyclophosphamide. Lancet 2000;355:805–6.[CrossRef][Web of Science][Medline]
48 Bender KS, Shematek JP, Leventhal BG, Kan JS. QT interval prolongation associated with anthracycline cardiotoxicity. J Pediatr 1984;105:442–4.[CrossRef][Web of Science][Medline]
49 Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 1993;11:1906–10.
50 Ferrari S, Figus E, Cagnano R, Iantorno D, Bacci G. The role of corrected QT interval in the cardiologic follow-up of young patients treated with adriamycin. J Chemother 1996;8:232–6.[Web of Science][Medline]
51 Nousiainen T, Vanninen E, Rantala A, Jantunen E, Hartikainen J. QT dispersion and late potentials during doxorubicin therapy for non-Hodgkin’s lymphoma. J Int Med 1999;245:359–64.[CrossRef][Web of Science][Medline]
52 Keefe DL. The cardiotoxic potential of the 5-HT3 receptor antagonist antiemetics: Is there cause for concern? Oncologist 2002;7:65–72.
53 Jantunen IT, Kataja VV, Muhonen TT, Parviainen T. Effects of granisetron with doxorubicin or epirubicin on ECG intervals. Cancer Chemother Pharmacol 1996;5:502–4.
54 Navari RM, Koeller JM. Electrocardiographic and cardiovascular effects of the 5-hydroxytryptamine 3 receptor antagonists. Ann Pharmacother 2003;9:1276–86.
55 Carmichael J, Philip PA, Forfar C, Harris AL. An open study to assess the safety, tolerance and pharmacokinetics of an intravenous infusion of granisetron given at 3 mg over 30 s in patients receiving chemotherapy for malignant disease. Cancer Chemother Pharmacol 1995;37:134–8.[Web of Science][Medline]
56 Aapro M, Bourke JP. Rapid intravenous administration of granisetron prior to chemotherapy is not arythmogenic: results of a pilot study. Eur J Cancer 2003;39:927–31.[CrossRef][Web of Science][Medline]
Received January 9, 2004; accepted March 9, 2004
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