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Clinical Chemistry 49: 248-252, 2003; 10.1373/49.2.248
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(Clinical Chemistry. 2003;49:248-252.)
© 2003 American Association for Clinical Chemistry, Inc.

Minor Increases in Plasma Troponin I Predict Decreased Left Ventricular Ejection Fraction after High-Dose Chemotherapy

Maria Teresa Sandri1a, Daniela Cardinale2, Laura Zorzino1, Rita Passerini1, Paola Lentati1, Alessandro Martinoni2, Giovanni Martinelli3 and Carlo Maria Cipolla2

1 Division of Pathology, Laboratory Medicine Unit,
2 Cardiology Unit, and
3 Division of Hematoncology, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy.

aAuthor for correspondence. Fax 39-02-57489417; e-mail maria.sandri{at}ieo.it.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Increased cardiac troponin I (cTnI) in patients treated with high-dose chemotherapy (HDCT) for aggressive malignancy has been proposed as an early marker of late HDCT-induced cardiac dysfunction. We investigated whether cTnI measured by the Stratus CS (Dade Behring) would allow detection of minimal cTnI increases in patients treated with HDCT.

Methods: Plasma cTnI concentrations were determined in 179 consecutive patients before HDCT, at the end of the treatment, and after 12, 24, 36, and 72 h. Cardiac function was explored by echocardiography, and left ventricular ejection fraction (LVEF) was recorded during follow-up. The greatest variation in LVEF from the baseline value was used as a measure of cardiac damage.

Results: In 99 healthy volunteers, the 99th percentile was at 0.07 µg/L. On the basis of ROC curve analysis (area under the curve, 0.89), a cutoff of 0.08 µg/L was chosen (sensitivity, 82%; specificity, 77%). cTnI >=0.08 µg/L occurred in 57 patients (32%) with echocardiographic monitoring revealing a mean decrease in LVEF of 18%. In comparison, the group of cTnI-negative patients had a mean decrease in LVEF of 2.5% (P <0.001).

Conclusions: Plasma cTnI, as measured with the Stratus CS, can detect minor myocardial injury in patients treated with HDCT.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cardiac troponin I (cTnI)1 and troponin T (cTnT) are well-established biochemical markers of myocardial injury (1)(2). In the last decade, cTnT and cTnI assays have been developed to assure the highest specificity and analytical sensitivity for the detection of minor myocardial injury (3)(4)(5)(6)(7). The first commercially available ELISA system for the determination of cTnI was introduced in 1995 (Stratus II; Dade), and it can detect minor myocardial injury in patients with acute coronary syndromes (8). On the basis of the high sensitivity and specificity of cTnI and cTnT, a new definition of myocardial infarction has recently been proposed, emphasizing that "there is a continuity from minimal myocardial damage, characterized by elevation of cardiac troponin without apparent elevation of other biomarkers, to the classic large myocardial infarction" (9). Confirming earlier studies that showed that increased cTnI identified patients with very mild myocardial damage (10)(11)(12)(13)(14)(15), this document (9) emphasizes that troponins play a key role in the diagnosis of acute coronary disease, allowing the identification of small myocardial injuries.

Increases in cTnI, cTnT, and creatine kinase MB in up to 56% of patients undergoing coronary revascularization were reported by Harris et al. (16), and cTnI was found to be the most sensitive marker for the detection of minor myocardial injury in that setting. Several authors have reported on the usefulness of cTnI in assessing myocardial damage in clinical conditions other than coronary heart disease. La Vecchia et al. (17) showed that acute heart failure could be associated with detectable cTnI in patients with adverse prognosis, whereas patients with improving clinical conditions exhibited a progressive disappearance of cTnI. The measurement of cTnI may also assist in the diagnosis of myocarditis (18).

Cardiac toxicity, with the development of left ventricular dysfunction, may be a late complication in patients treated with high-dose chemotherapy (HDCT), especially when anthracyclines are used (19). Increased cTnT has been reported as an early marker of cardiac damage in both children and adults (20). Recently, we reported that increased cTnI (Stratus II) at the end of the infusion of chemotherapeutic drugs in patients treated with HDCT identified a subset of patients most likely to develop ventricular dysfunction months after the end of the treatment (21).

In this study we prospectively evaluated whether the improved precision of the second-generation Stratus CS cTnI assay (Dade Behring) at low concentrations would improve the early prediction of minor myocardial damage after chemotherapy as detected by echocardiography during later follow-up.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
study population
The study population included 179 consecutive patients [42 men and 137 women; mean (SD) age, 47 ± 11 years] treated with HDCT for aggressive malignancy between November 1999 and December 2000 in our Institute. Patients with a history of heart disease (angina, hypertension, or valvular disease), with a left ventricular ejection fraction (LVEF) <50%, or with renal (creatinine >133 µmol/L) or liver (bilirubin, 34.2 µmol/L; aspartate aminotransferase more than two times the upper limit of normal) function impairment were excluded from the study.

The chemotherapeutic agents and dosages are shown in Table 1 . All the drugs were administered by continuous intravenous infusion via central venous catheter. Before chemotherapy, progenitor cells were collected from peripheral blood after mobilization by growth factors. All of the patients underwent reinfusion of autologous peripheral blood progenitor cells during each course of HDCT (22).


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  		Table 1. HDCT schedules.

As a pilot study, we analyzed the stored samples from nine patients who had been enrolled in the previous study and who did not have increased cTnI as measured by the Stratus II but did show a worsening of LVEF during follow-up. We obtained informed consent from all patients and approval of the protocol by the Ethical Committee of our Institution.

control population
To estimate the upper 99th percentile, values for 99 apparently healthy individuals were ranked nonparametrically.

study protocol
The study protocol was similar to the one described previously (21). Briefly, each patient was treated with three or four cycles of HDCT (depending on the treatment protocol) every 28 days. Blood samples for cTnI determinations were drawn before the start of the chemotherapy, at the end of the infusion, and 12, 24, 36, and 72 h after the end of each treatment cycle. We prospectively measured cTnI in 2281 samples (mean, 12.7 samples/patient; range, 5–24 samples/patient), subdivided in 383 courses of chemotherapy (mean, 2.1 courses/patient; range, 1–4 courses/patient). Cardiac function was investigated by echocardiography at baseline and 1, 2, 3, 4, 7, and 12 months after the end of the treatment, for a total of 953 exams (mean, 5.3 echocardiograms/patient; range, 2–7 echocardiograms/patient). Cardiologists performed the echocardiograms; they were not aware of the troponin results. LVEF was recorded [biplane method according to Simpson’s rule (23)]. The greatest change from the baseline value ({Delta}%) was determined for each patient.

laboratory methods
Blood samples, collected into a Monovette containing a sodium citrate solution (0.106 mol/L) with a dilution ratio after blood collection of 1 in 10 (1 part citrate and 9 parts blood), were centrifuged at 1080g within 60 min, and the plasma was separated and immediately analyzed on the Stratus CS. Assays were performed routinely by technicians in the pathology laboratory. As reported previously, the functional sensitivity (20% CV) of this assay is 0.03 µg/L, and its total imprecision at concentrations of 0.06–0.08 µg/L is 10–14%. The lowest concentration that gives a 10% CV is 0.06 µg/L (7).

statistical analysis
All results are expressed as the mean (SD). Statistical tests were performed using the Student t-test for unpaired data and were considered significant at P <0.05. The {chi}2 test was used for the comparison of proportions. ROC analysis [ROC Analysis for Excel (24)] was used to evaluate the clinical performance of the test, and the results are expressed as the area under the curve (25). Differentiation between "normal" and "clinically relevant" functional impairment was made by considering as a pathologic value a decrease in LVEF below the 10th percentile of the distribution of the changes of LVEF. According to previous experience (21)(26), values below the 10th percentile are associated with clinically relevant decreases in ejection fraction (27).

To maximize the sum of sensitivity and specificity of cTnI, a cutoff threshold was determined based on the analysis of the ROC curve.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The 99th percentile for cTnI in 99 healthy individuals was 0.07 µg/L. The 10th percentile of LVEF decrease variation distribution corresponded to -21%. Using these values, the ROC curve analysis (Fig. 1 ) gave an area under the curve of 0.89 (95% confidence interval, 0.82–0.94), with a sensitivity of 82% (56–95%) and a specificity of 77% (68–85%) at a concentration of 0.08 µg/L. For decision-making purposes, a concentration >=0.08 µg/L was considered as the threshold. The cTnI results for the stored samples showed increases in three of nine patients, with values ranging from 0.08 to 0.17 µg/L. In the present study, at baseline cTnI was below the cutoff in all patients investigated. After HDCT, the patients were divided into two groups, the troponin-positive group [cTnI+: 57 patients; mean (SD), 0.63 ± 0.54 µg/L; range, 0.08–1.98 µg/L] and the troponin-negative group [cTnI-: 122 patients; mean (SD), 0.039 ± 0.019 µg/L; range, 0–0.07 µg/L]. Among the 57 cTnI-positive patients, the mean number of positive samples per patient was 2.7 (range, 1–9), with 35 patients (61%) having 2 or more positive results. The positive results were homogeneously distributed along the six time points of the cTnI curve (positivity at baseline found only after the first cycle of chemotherapy). Only the last time point (72 h) showed a slightly lower rate of positivity. Moreover, the increases in cTnI were progressively more frequent from the first cycle to the last (20% after the first cycle; 33% after the second cycle; and 48% after the third cycle; first vs second cycle and second vs third cycle, not statistically significant; first vs third cycle, P = 0.018).



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  		Figure 1. ROC curve for cTnI as indicator of minimal myocardial damage after chemotherapy.

Three cTnI concentrations (µg/L) are designated on the curve.

The clinical characteristics of the study population are shown in Table 2 . No difference was observed between the two groups, except for previous treatment with anthracyclines, which was more frequent in the cTnI+ group ({chi}2 test, P <0.05). No difference was observed for baseline LVEF data. No adverse patient events were encountered from performance of the cTnI or echocardiographic tests.


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  		Table 2. Clinical characteristics in cTnI+ and cTnI- groups.

Analysis of the echocardiographic data showed no differences in LVEF at baseline between the two groups [cTnI-negative patients, 63% (5%); cTnI-positive patients, 63% (4.2%)]. After treatment with HDCT, the decrease in LVEF was more evident in the group of cTnI-positive patients (Table 3 ). In this group, a significant decrease in LVEF was observed after the first month (P = 0.0003), and it became increasingly pronounced during the following months [from -6.8% (10.1%) after 1 month to -18.2% (9.8%) after 12 months; P = 0.0004]. Twenty patients with increases in cTnI <0.17 µg/L did not show a significant decrease in LVEF. In the cTnI- group, only a slight decrease was observed, and no significant changes were detected during follow-up [from -1.5% (8.7%) after 1 month to -2.5% (8.6%) after 12 months].


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  		Table 3. Change in LVEF in cTnI+ and cTnI- groups.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study confirms earlier observations that increased plasma cTnI may be considered an early marker of cardiac toxicity induced by HDCT. Specifically, a cTnI concentration >=0.08 µg/L (Stratus CS) after HDCT is predictive of lower left ventricular systolic performance during follow-up. Cardiac toxicity is a potentially severe complication of antineoplastic treatments (28). In particular, cytostatic drugs of the anthracycline class (epirubicin, doxorubicin) affect the myocardium and may lead to the development of heart disease. Although the mechanisms inducing heart damage are still unclear, generation of free radicals seems to be involved (29). The severity of the injury is directly related to the cumulative doses of anthracycline administered (28). In addition to anthracyclines, alkylating agents such as cyclophosphamide, cisplatin, busulfan, and mitomycin have also been associated with cardiotoxicity, as have paclitaxel, etoposide, the vinca alkaloids, fluorouracil, and other drugs. Early and late phases of anthracycline toxicity have been identified, although cardiotoxicity likely occurs along a continuum of time (29), ending in congestive heart failure. The identification of early markers of cardiotoxicity would be pivotal to prevent the progression toward cardiac dysfunction.

Echocardiography is more commonly used to monitor the development of heart dysfunction, but it lacks specificity and sensitivity for early myocardial damage.

Few and discordant reports have evaluated the possible use of cardiac troponin assays for the early detection of myocardial damage induced by chemotherapeutic agents. Some studies (31)(32)(33)(34) have reported that cTnI and cTnT are significantly increased in patients treated with anthracyclines and are potentially good markers of cardiac toxicity, but other authors (35)(36) failed to find significant associations. We showed previously that cTnI was increased in patients whose LVEF decreased during follow-up (21). The method used (Stratus II; Dade Behring) had a detection limit of 0.35 µg/L, with CVs of 9–14% at 0.5–1.5 µg/L (37). In a comparison of the Stratus II and the Stratus CS (37), the latter had improved analytical sensitivity that may increase the likelihood of a positive test result for patients with minimal myocardial damage. In the present study, in which a profile of six cTnI determinations was performed for each HDCT patient treatment, the Stratus CS showed increased cTnI (>0.08 µg/L) in three of the nine patients with normal cTnI by Stratus II but decreased LVEF during follow-up.

Our results in the present study indicate a correlation between increased cTnI and decreased LVEF, confirming our earlier data (21). We observed a significant decrease in LVEF in the cTnI-positive patients by 1 month after therapy, and the decrease became more pronounced later (Table 3Up ). We observed no such decrease in the cTnI-negative group, however, and there was no trend to a progressive decrease in the follow-up period. The fact that 20 (35%) patients with increased cTnI did not show any worsening of LVEF could be explained by a very small myocardial injury, not severe enough to induce an early (within 12 months) impairment of left ventricular function. A longer follow-up period is needed to rule out the possible appearance of late echocardiographic dysfunction.

Lack of standardization (38) may hamper the use of cTnI in this clinical setting and can make the comparison of results obtained by different methods difficult. In our study, we used a method with good precision (CV <15%) at very low cTnI concentrations (<0.1 µg/L); the method thus could detect very small myocardial injuries that may eventually lead to the development of cardiac dysfunction.

In conclusion, the measurement of cTnI released from damaged myocytes during anthracycline therapy may represent the first reliable marker of early cardiac toxicity, far earlier than any significant functional echocardiographic changes. These results may help the clinician in managing treated patients by identifying a "high-risk" group of patients who may benefit from closer observation or supportive cardiac therapy.


   Acknowledgments
 
We thank Anna Visconti and Teresa Roth for assisting in the collection and tabulation of clinical data and for their technical support.


   Footnotes
 
1 Nonstandard abbreviations: cTnI and cTnT, cardiac troponin I and troponin T; HDCT, high-dose chemotherapy; and LVEF, left ventricular ejection fraction.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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