CLINICAL STUDIES
Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy
Daniela Cardinale, MDa,
Maria Teresa Sandri, MD ,
Alessandro Martinoni, MDa,
Alessio Tricca LabTech,
Maurizio Civelli, MDa,
Giuseppina Lamantia, MDa,
Saverio Cinieri, MD*,
Giovanni Martinelli, MD*,
Carlo M. Cipolla, MDa and
Cesare Fiorentini, MDa
a Cardiology Unit, Istituto Europeo di Oncologia, University of Milan, Milan, Italy
* Hematoncology Unit, Istituto Europeo di Oncologia, University of Milan, Milan, Italy
Laboratory Medicine, Istituto Europeo di Oncologia, University of Milan, Milan, Italy
Manuscript received October 25, 1999;
revised manuscript received February 11, 2000,
accepted March 30, 2000.
Reprint requests and correspondence: Dr. Daniela Cardinale, Cardiology Unit, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141 Milan, Italy
daniela.cardinale{at}ieo.it
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Abstract
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OBJECTIVES
We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC).
BACKGROUND
High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need.
METHODS
We measured, in 204 patients (45 ± 10 years) affected by cancer resistant to conventional treatment, the cTnI plasma concentration after every single cycle of HDC. According to the cTnI value ( or >0.4 ng/ml), patients were divided into a troponin positive (cTnI+, n = 65) and a troponin negative (cTnI–, n = 139) group. All patients underwent echocardiographic examination during the following seven months.
RESULTS
In the cTnI– group, left ventricular ejection fraction (LVEF) progressively decreased after HDC, reaching a maximal reduction after three months; however, myocardial depression was transient and no longer detectable at later follow-up. By contrast, in the cTnI+ group LVEF reduction was more marked and still evident at the end of the follow-up. In cTnI+ patients, a close relationship between the short-term cTnI increment and the greatest LVEF reduction was found (r = –0.87, p < 0.0001).
CONCLUSIONS
The elevation of cTnI in patients undergoing HDC for aggressive malignancies accurately predicts the development of future LVEF depression. In this setting, cTnI can be considered a sensitive and reliable marker of acute minor myocardial damage with relevant clinical and prognostic implications.
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Abbreviations and Acronyms
| | CK | = creatine kinase | | CK-MB | = creatine kinase, MB fraction | | cTnI | = cardiac troponin I | | EDV | = end-diastolic volume | | ESV | = end-systolic volume | | HDC | = high-dose chemotherapy | | LVEF | = left ventricular ejection fraction |
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High-dose chemotherapy (HDC) is a therapeutic approach for several aggressive malignancies resistant to the traditional chemotherapy schedules (1–3). This kind of treatment can favorably affect survival of patients with cancer disease; however, its use is limited by considerable side effects, in particular cardiotoxicity (4,5). Beyond early cardiotoxicity, which occurs during or soon after treatment (6), the development of heart failure many years after the last administration of chemotherapeutic drugs is increasingly recognized (7,8). Cardiac involvement may become clinically manifest late in the course of the natural history of the disease and lead to overt heart failure. Moreover, with the increasing availability of echocardiography, it has become evident that chemotherapy-induced left ventricular impairment often occurs without symptoms, and, though it is generally considered to be irreversible, some reports on complete recovery of cardiac dysfunction have been reported (9,10). Hence, the possibility of identifying an early marker of cardiac injury, able to predict late ventricular dysfunction after HDC, remains a stimulating incentive. This would permit clinicians to identify higher-risk patients needing a close monitoring of cardiovascular function and in which oncological therapeutic adjustments and supporting cardiological treatment could be required.
Cardiac troponin I (cTnI) is a new specific marker of minor myocardial damage released by cardiac cells in proportion to the degree of myocardial injury (11). While its role in acute coronary syndromes is well appreciated, the possible application of this peptide in the detection of HDC-induced cardiac damage, as well as in the short- and long-term risk stratification of cancer patients undergoing this kind of treatment, has never been investigated before.
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Methods
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Study population.
All consecutive patients undergoing HDC for aggressive malignancies who were evaluated at our Institute between August 1, 1997 and November 1, 1998 were asked to participate in the study. Patients with a history of ischemic, valvular and hypertensive heart disease, uncontrolled hypertension, left ventricular ejection fraction (LVEF) <50%, acute or chronic renal insufficiency (serum creatinine > 1.5 mg/dl) and liver disease (bilirubin > 2.0 mg/dl, AST > two times the upper limit of normal) were excluded from the study.
Of the 232 patients screened, 204 patients (165 women, 39 men, mean age 45 ± 10 years) qualified for inclusion in the study. The indications for HDC were advanced or primary resistant breast cancer in 133 cases, relapsed or refractory ovarian carcinoma in 12, small cell lung cancer in 8, high grade non-Hodgkin’s lymphoma in 46 and relapsed or refractory poor prognosis Hodgkin’s disease in 5. Previous treatment with anthracyclines or radiotherapy was present in 111 and 13 cases, respectively. Twenty-one patients were receiving calcium antagonist agents for mild hypertension; none was receiving beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors or diuretics.
Informed consent was obtained from all patients before participation in the study, and the protocol was approved by the Ethical Committee of our Institution.
Study protocol (Fig. 1).
Clinical examination, electrocardiogram, chest x-ray and echocardiogram were part of the preliminary evaluation. All 204 eligible patients who passed the inclusion and exclusion criteria received HDC in different drug combinations, according to our Institute’s medical oncology protocols (Table 1). All drugs were administered intravenously via central venous catheters. In addition, all patients received reinfusion of autologous peripheral blood progenitor cells in order to accelerate hematopoietic recovery and reduce supportive care requirement (1,12). None of the patients received contemporary radiotherapy.
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Figure 1 Study design. Open square = clinical and echocardiographic examination; Open circle = troponin I, creatine kinase (CK) and CK-MB mass determination. EC = epirubicin and cyclophosphamide; ICE = ifosfamide, carboplatin and etoposide; SEQ = sequential therapy (see Table 1); TEC = taxotere, epirubicin and cyclophosphamide; TICE = taxotere, ifosfamide, carboplatin and etoposide.
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Plasma cTnI concentration, creatine kinase (CK) and creatine kinase, MB fraction (CK-MB) mass were measured before, immediately after and then 12, 24, 36 and 72 h after every single cycle of HDC.
Cardiac function was assessed by echocardiography and electrocardiography. In all patients LVEF (biplane method, according to Simpson’s rule), end-diastolic (EDV) and end-systolic (ESV) volumes were evaluated before beginning HDC, one month, two months, three months, four months and seven months after the end of the treatment. Electrocardiogram was performed before and after each HDC cycle and then at all follow-up checks. The duration of the follow-up was nine months from the baseline evaluation for most patients and 10 months for patients undergoing "sequential" therapy. During this period, no one was treated with other chemotherapeutic drugs or radiotherapy, and all patients’ management decisions were made without the knowledge of the patient’s cTnI results.
Laboratory methods.
The blood samples for cTnI determination were centrifuged within 60 min, and plasma was stored immediately at –30°C. Cardiac TnI concentrations were determined by an immunoenzymatic fluorescent assay (Stratus II, Dade International Inc., Miami, Florida) that uses two monoclonal antibodies specific for independent epitopes of cTnI (13) with a lower limit of detection of 0.35 ng/ml; the considered cut off level was 0.5 ng/ml. All blood samples were analyzed in duplicate with an interassay variability 0.1 ng/ml, and all "positive" samples were immediately retested to confirm the result obtained. Total CK activity was determined by an enzymatic method, and CK-MB mass concentration was measured using a commercially available immunoabsorbent assay (Stratus II, Dade International Inc.). The upper limit of the reference interval is 190 U/L for CK and 5 ng/ml for CK-MB mass.
Statistical analysis.
The values of LVEF were analyzed using a repeated measures model taking into account the correlation among the time periods with an unstructured covariance matrix. Time was treated as a factor, and the interaction between time and troponin value was included in the model. We also included the linear effects of the baseline troponin value and its interactions. All interactions were tested using F tests based upon Type 3 sums on squares. Least squares means and corresponding confidence intervals of time by troponin value interactions were calculated. All calculations were performed using PROC MIXED in SAS (SAS for Windows, version 6.11; SAS Institute Inc., Cary, North Carolina). Differences in LVEF values at baseline between the two groups were analyzed using a generalized linear model. A generalized linear model was also used to investigate differences in the maximum percentage change in EDV, ESV and LVEF. A square root transformation was used to achieve normality and homogeneity of variance of the maximum percent changes.
Linear regression analysis was used for obtaining correlation coefficients. Significance was taken at the 5% level. Results are presented as mean ± standard deviation unless otherwise specified.
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Results
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All patients underwent HDC without clinically evident acute cardiological side effects during or soon after the drugs’ administration. Three patients developed overt heart failure during the follow-up (four, six and seven months after HDC).
At the baseline evaluation, as well as before each cycle of HDC, cTnI value was within the normal range in all cases. Increment in circulating cTnI was detected in 65 (32%) of the 204 treated patients and, when the total number of HDC cycles was considered, in 112/661 (17%) cycles. In particular, in the 112 cycles in which cTnI increased, in 59 (53%) cases the first abnormal cTnI value was observed soon after the end of drug(s) administration, in 10 (9%) after 12 h, in 21 (19%) after 24 h, in 8 (7%) after 36 h and in 14 (12%) after 72 h. When the whole population, as well as every single HDC schedule, was considered, the percentage of cTnI positivity progressively increased in parallel with the increasing number of the cycles performed.
No change in CK serum levels was detected, whereas CK-MB concentration increased in three cases (5.9, 5.7 and 6.3 ng/ml, respectively). In these three patients, the maximal value of cTnI detected was 1.9, 1.9 and 2.0 ng/ml, respectively.
In all patients no significant electrocardiographic changes were observed, both after HDC and at the follow-up checks.
Patients were allocated to two subgroups according to the maximal cTnI value detected after HDC: the troponin negative group (cTnI–; n = 139) and the troponin positive group (cTnI+, n = 65; mean value 1.0 ± 0.5 ng/ml; range 0.5–2.0). The cTnI+ group was defined by a value equal to or greater than 0.5 ng/ml at least at one of the points of measurement considered, while the cTnI– group was defined by a value <0.5 ng/ml in every determination. Table 2 gives the clinical characteristics of the two populations. No difference was observed in regards to age, gender, kind of neoplasm, HDC schedule or other clinical characteristics between the two groups, except for previous treatment with anthracyclines that was more frequent in the cTnI+ group. The time elapsed from previous anthracycline treatment to the enrollment in the study was similar in the two groups (range: 2–6 months).
At the baseline evaluation, LVEF, EDV and ESV were similar in the two groups and in all cases within the normal limits. After HDC, there was a significantly different pattern of LVEF in the cTnI+ compared with the cTnI– group (p < 0.0001) (Fig. 2). Among the patients in the cTnI+ group, there was evidence of a significant reduction in LVEF from three months onwards. Indeed, LVEF impairment was still evident at the end of the follow-up. In the cTnI– group there was also a significant reduction in LVEF at three months, which was not as great as the reduction in the cTnI+ group. This transient decrease was followed by a recovery to baseline levels at four and seven months. In particular, during the entire follow-up, an LVEF value less than 50% was observed in 19/65 (29%) cTnI+ and in 0/139 cTnI– patients, respectively (chi-square p < 0.001). The three patients developing symptoms of heart failure during the follow-up have had positive value of both cTnI and CK-MB after HDC and an LVEF <30% at the last evaluation before symptom onset. Cardiovascular treatment was required only in these three patients.
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Figure 2 Left ventricular ejection fraction (LVEF) at baseline and during the seven months of follow-up of troponin I positive (cTnI+; solid circle) and negative (cTnI–; solid square) patients. *p < 0.001 vs. baseline (month 0);  p < 0.001 vs. cTnI– group. Data are shown as mean ± 95% confidence interval.
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Figure 3 shows the maximal percent of changes in LVEF, in EDV and in ESV observed during the follow-up in the two groups, regardless of the moment in which they were detected. The changes from the baseline value of these parameters were significant in both groups; however, the variations were significantly greater in the cTnI+ than in the cTnI– group.
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Figure 3 Maximal percent changes in end-diastolic volume (EDV), end-systolic volume (ESV) and left ventricular ejection fraction (LVEF) observed during the follow-up in the two groups of patients. cTnI+ = cardiac troponin I > 0.4 ng/ml; cTnI– = cardiac troponin I 0.4 ng/ml. Data are shown as mean ± 95% confidence interval.
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When the incidence of cTnI+ patients was considered according to the degree of left ventricular depression observed at the follow-up, the percentage of cTnI+ patients increased in parallel with the degree of LVEF reduction, up to a 100% incidence for a decrease in LVEF greater than 30%.
In the cTnI+ group, a strong relationship between the cTnI maximal value and the LVEF maximal reduction was found (r = –0.87; p < 0.0001; Fig. 4).
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Figure 4 Scatterplot of left ventricular ejection fraction (LVEF) changes against troponin I value in cTnI+ patients. cTnI = cardiac troponin I.
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Discussion
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Many recent studies have elucidated the value of both troponin T and I in the diagnosis and in the risk assessment of acute coronary syndromes (14–17). Our study addressed the question of whether cTnI measurement gives significant information in a subgroup of patients with aggressive malignancies resistant to conventional chemotherapic regimens and undergoing HDC, in relation to the possible direct cardiotoxic effect (4,5). This study shows that cTnI is a risk marker for future development of significant and prolonged left ventricular dysfunction. This issue is particularly important in patients with cancer disease in which onset of cardiac dysfunction, even asymptomatic, importantly limits the therapeutical opportunities and negatively influences the prognosis of these patients (18,19). Indeed, HDC has contributed considerably to the improvement of survival of patients with poor-prognosis cancer (2,3,20), and cardiotoxicity represents a major limitation to the total dose that can safely be administered (4–5). Hence, the possibility of identifying patients at higher risk of developing late myocardial function depression could permit clinicians to modify or to discontinue the oncologic regimen, to support cardiac function with cardiovascular therapy or cardioprotective agents (21,22) and to accurately monitor the progression of cardiac damage. This last point is particularly relevant, considering that a progressive and cumulative cardiotoxicity occurs during HDC and that the risk of developing cardiac dysfunction, as revealed by troponin positivity, increases in parallel with the number of cycles of HDC completed. Our data confirm previous studies reporting that cardiotoxicity, due to anthracyclines, is cumulative and dose-related (6,8,18,19); further evidence derives from the observation that, in our population, previous treatment with anthracyclines was more frequently associated with cTnI positivity (Table 2). Furthermore, increasing evidence that cardiotoxicity can be reversible, at least in its early phases, exist (9,10). Accordingly, several methods of identifying cardiotoxicity before it causes irreversible depression of myocardial function had been proposed. Among these were: monoclonal antimyosin antibodies imaging (23,24), study of cardiac autonomic function (25) and endomyocardial biopsy (26). In comparison, cTnI appears to be a sensitive, as well as a simple and low-cost, method for the identification of early, and possibly reversible, cardiotoxicity.
Hypothetical mechanism(s) of cardiotoxicity.
Because of the combination of different drugs, the mechanisms by which HDC may generate cardiotoxicity are multifactorial and complex. They include production of free oxygen radicals, disturbance of the mitochondrial energy metabolism, intracellular calcium overloading, increase in lipid peroxidation, etc. (27–29). In addition, cardiac toxic effects deriving from the combination of different drugs, some of which are not classically considered to have cardiotoxic properties, such as ifosfamide and etoposide, cannot be excluded. Indeed, a similar dose-dependent cTnI release was observed in our study whatever the drug composition considered and, in previous reports, congestive heart failure has been described as occurring when intermediate cumulative doses with multiagent chemotherapy were utilized (30).
Comparison with previous studies.
Previous animal studies have consistently shown that troponin T is released into the circulation after anthracycline administration and that the elevated troponin levels were correlated with clinical toxicity (31). Similar observations were reported in children receiving anthracycline chemotherapy (32). In addition, Missov et al. (33) described cTnI increase during the course of anthracycline chemotherapy in patients with hematological malignancies. The small release of cTnI indicates that only a minimal acute necrosis occurs during HDC, as compared with that observed in acute coronary syndromes. However, the clinical interest of this cTnI increment is quite relevant. Indeed, in addition to the impairment in systolic cardiac function predicted by cTnI elevation, a close relationship between the cTnI maximal value observed after HDC and the degree of late LVEF reduction was observed (Fig. 4). This finding strongly amplifies the clinical significance of cTnI in order to individuate patients who will develop late cardiac impairment and, to a greater extent, to predict the degree of the future left ventricular dysfunction.
Clinical implications.
As our group of patients was less symptomatic, the detection of elevated cTnI levels would seem to substantially increase the information regarding the risk of heart failure. This information could not be obtained by conventional criteria such as symptoms, electrocardiographic and echocardiographic changes. The rise in cTnI indicates minor myocardial damage, which seems to precede left ventricular systolic impairment. The time course of this cardiac damage is unclear, and further studies are needed to clarify whether patients with acute minor myocardial injury, attested by cTnI increment and prolonged LVEF reduction, will develop an irreversible dilated cardiomyopathy. On the other hand, normal cTnI values, after HDC, seem to identify patients at lower risk in which no cardiac damage, or only transient subclinical dysfunction, occurs. Finally, the three patients who developed overt heart failure during the follow-up of our study had, in addition to cTnI elevation, also CK-MB positivity. This finding emphasizes the clinical importance of cardiac enzymes in revealing the extension of acute myocardial necrosis during HDC. Therefore, the relationship between extension of enzyme elevation, both cTnI and CK-MB, and cardiac damage allows us to anticipate a continuum spectrum of future clinical events, namely only transient left ventricular impairment in cTnI– patients, prolonged and more marked cardiac dysfunction in cTnI+ patients and symptomatic heart failure in patients with positivity of both cTnI and CK-MB.
Conclusions.
Elevation of cTnI in cancer patients undergoing HDC for aggressive malignancies accurately predicts the development of ventricular systolic dysfunction in the months following. In such a patient population, cTnI can be considered a sensitive and reliable marker of acute minor cardiac damage with relevant clinical and prognostic implications.
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Acknowledgments
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We would like to express our gratitude to Dr. Sara Gandini of the Division of Epidemiology and Biostatistics for assistance with the statistical analysis and to Mrs. Angela Cocquio and the nursing staff of the Hematoncology Unit for their help in the research protocol.
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M. T. Sandri, M. Salvatici, D. Cardinale, L. Zorzino, R. Passerini, P. Lentati, M. Leon, M. Civelli, G. Martinelli, and C. M. Cipolla
N-Terminal Pro-B-Type Natriuretic Peptide after High-Dose Chemotherapy: A Marker Predictive of Cardiac Dysfunction?
Clin. Chem.,
August 1, 2005;
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A. Jeremias and C. M. Gibson
Narrative Review: Alternative Causes for Elevated Cardiac Troponin Levels when Acute Coronary Syndromes Are Excluded
Ann Intern Med,
May 3, 2005;
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[Abstract]
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Y Sato, T Kita, Y Takatsu, and T Kimura
Biochemical markers of myocyte injury in heart failure
Heart,
October 1, 2004;
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S Sharma, P G Jackson, and J Makan
Cardiac troponins
J. Clin. Pathol.,
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M. Panteghini
Role and importance of biochemical markers in clinical cardiology
Eur. Heart J.,
July 2, 2004;
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D. Cardinale, M. T. Sandri, A. Colombo, N. Colombo, M. Boeri, G. Lamantia, M. Civelli, F. Peccatori, G. Martinelli, C. Fiorentini, et al.
Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy
Circulation,
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I. Oztop, M. Gencer, T. Okan, A. Yaren, E. Altekin, S. Turker, and U. Yilmaz
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
Jpn. J. Clin. Oncol.,
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T. B. Horwich, J. Patel, W. R. MacLellan, and G. C. Fonarow
Cardiac Troponin I Is Associated With Impaired Hemodynamics, Progressive Left Ventricular Dysfunction, and Increased Mortality Rates in Advanced Heart Failure
Circulation,
August 19, 2003;
108(7):
833 - 838.
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M. T. Sandri, D. Cardinale, L. Zorzino, R. Passerini, P. Lentati, A. Martinoni, G. Martinelli, and C. M. Cipolla
Minor Increases in Plasma Troponin I Predict Decreased Left Ventricular Ejection Fraction after High-Dose Chemotherapy
Clin. Chem.,
February 1, 2003;
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248 - 252.
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A. van der Laarse
Hypothesis: troponin degradation is one of the factors responsible for deterioration of left ventricular function in heart failure
Cardiovasc Res,
October 1, 2002;
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Abstract
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