Cardiac troponin T measured with a highly sensitive assay for diagnosis and monitoring of heart injury in chronic chagas disease.
The cardiac troponins I and T (cTnI, cTnT) are established markers for diagnosis, risk stratification, and therapy monitoring in patients with acute coronary syndrome. (7) However, there are numerous other physiologic heart stressors, for example, exercise, (8) general pathologies affecting the heart, (9) and cardiac diseases, such as stable angina, myocarditis, and heart failure, (10) which are accompanied by serum cardiac troponin values clearly different from those of healthy controls, although they may be less than or near the established cutoff values for acute coronary syndromes. Therefore, cardiac troponin measurement could be used as a tool for diagnosis, risk assessment, and monitoring of patients with chronic Chagas disease who develop heart injury. To date, there have been only 2 studies and a single patient observation, to our knowledge, that analyzed cardiac troponin in Chagas heart disease. (11-13) These studies--which, in our view, used assays with insufficient sensitivity, mainly in the lower range ([less than or equal to] 99th percentile of the reference population)--did not indicate a profound relationship between Chagas heart disease and cardiac troponin release.
With the highly sensitive cTnT assay manufactured by Roche Diagnostics GmbH (Mannheim, Germany), a test is now available with 10-fold increased sensitivity compared with the previously available cTnT assay. Consequently, we designed a study to test the potential of using cTnT measurements with a highly sensitive assay for diagnosis of Chagas heart disease. In a parallel test, cTnT was also measured with the presently used, conventional assay. To characterize the pathophysiologic background of the cTnT release in chronic Chagas disease, C-reactive protein (CRP) and interleukin 6 (IL-6), as markers of inflammation, were also measured.
MATERIALS AND METHODS
This retrospective study was approved by the authorities of the Santa Barbara Hospital (Sucre, Bolivia). A total of 26 healthy subjects, the control group, and 179 patients with chronic Chagas disease were enrolled in the study. Control subjects and patients signed informed-consent forms. For study enrollment, subjects attending the hospital for blood donation were routinely analyzed for serologic confirmation of chronic Chagas disease. The control group was recruited from subjects who presented with negative Chagas serology results and who did not present with any other criteria that excluded them from blood donation. Patients with chronic Chagas disease (subjects with positive serology results) were classified by clinical investigation, electrocardiogram (ECG) mapping, and radiologic imaging as having no sign of heart or gastrointestinal disease (the indeterminate group [I]), as suffering exclusively from cardiomyopathy or from cardiomyopathy combined with megacolon (the cardiomyopathy group [CM]), or as suffering exclusively from megacolon (the megacolon group [M]).
Furthermore, patients with known Chagas cardiomyopathy and/or megacolon who were hospitalized for routine checks or for elective pacemaker implantation or colon surgery were also enrolled in groups CM and M. None of the patients enrolled in the study suffered from acute coronary syndrome, acute myocarditis, or distinct renal failure.
Group CM was subdivided with respect to the severity of the cardiomyopathy. The presence of at least one of the following criteria classified the cardiomyopathy as mild: mild electrocardiographic changes in ventricular repolarization or sinus bradycardia; as moderate: left anterior fascicular block, incomplete left bundle branch block, right bundle branch block, second-degree atrioventricular block-Mobitz type I, or atrial fibrillation in patients older than 50 years; and as severe: cardiomegaly, dilatative cardiomyopathy, complete left bundle branch block, atrioventricular block-Mobitz type II, complete atrioventricular block, or atrial fibrillation in patients younger than 50 years. For group composition, see the Table.
Serum was sampled and stored at -20[degrees]C until measurement from patients whose Chagas disease was diagnosed for the first time and from patients with known, chronic Chagas disease admitted for routine examination before any treatment was started or changed. In patients admitted for surgical intervention (pacemaker implantation, colon surgery), serum was sampled 48 to 72 hours after the intervention.
Chronic Chagas disease was confirmed by detection of antibodies against Trypanosoma cruzi using an enzyme-linked immunosorbent assay (Wiener Laboratorios SAIC, Rosario, Santa Fe, Argentina) and indirect hemagglutination (Polychaco SAIC, Buenos Aires, Argentina).
For cTnT measurement, the conventional, fourth-generation assay and the highly sensitive assay provided by Roche Diagnostics GmbH (Mannheim, Germany) were performed using Elecsys-2010 chemistry analyzer (Roche Diagnostics). Based on the manufacturer's information, the lower limit of detection (LLD) and functional sensitivity (the lowest analyte concentration measurable with an interassay variation [less than or equal to] 10%) of the conventional assay were 10 ng/L (equal to the 99th percentile of the reference population) and 30 ng/L, respectively. The LLD of the highly sensitive assay was 3 ng/L. As the 99th percentile of the reference population, 13 ng/L was established by using the highly sensitive assay. This value was equal with the functional sensitivity of this assay. For CRP (LLD, 0.03 mg/L; functional sensitivity, 0.11 mg/L), we used the highly sensitive assay from Roche Diagnostics adapted to the Modular Analyzer (Roche Diagnostics). For IL-6 (LLD, 2 ng/L; functional sensitivity, <3 ng/L), the assay from Siemens AG (Eschborn, Germany), adapted to the Immulite Analyzer (Siemens), was used.
Patient data and marker levels are represented as median and range. In the figures, marker levels are expressed in box plots that demonstrate the median bar and the 25th and 75th percentiles (interquartile range), and the whisker ends represent the largest and smallest values inside 1.5 times the interquartile range. The outliers (open circles) are values between 1.5 and 3 times the interquartile range, and extremes (stars) are values of more than 3 times the interquartile range. Additionally, the percentages for values greater than the defined cutoff are given. For numeric expression of the undetectable marker concentrations, values were displayed fixed to one-half of the lower limit of detection.
Statistical analysis was performed using the SPSS software package (SPSS Inc, Chicago, Illinois). For binary variables, the [chi square] and Fisher exact test were used; for intergroup comparison and post hoc analysis, the Kruskal-Wallis H test and Mann-Whitney U test, respectively, were used for data analysis.
To indicate the cutoff that best distinguished between asymptomatic patients and patients with cardiomyopathy, the high-sensitivity (HS) cTnT values of both groups were used for constructing the receiver operating characteristic curve.
As listed in the Table, the median age of control subjects was 30 years (range, 19-61 years), and the median age for asymptomatic patients (group I) was also 30 years (range, 18-62 years), so the median age in both groups was significantly younger than the age of patients in the CM group (median, 47 years; range, 18-81 years; control and I group, P < .001) and in the M group (median, 46 years; range, 19-65 years; control group, P = .002; I group, P = .001). However, no relation existed between the age of the patients and the markers analyzed.
Sample collection in 2 patients following pacemaker implantation had no influence on any marker analyzed. The HS cTnT in both patients was less than the LLD; CRP and IL-6 did not exceed the cutoffs, indicating inflammation. In 9 patients of the M group and in 7 patients of the CM group, samples were collected after colon surgery. Such sampling procedure did not influence the serum HS cTnT concentration, which was 1.5 ng/L (range, 1.5-32.9) in patients without surgery versus 1.5 ng/L (range, 1.525.1) in those with surgery. In contrast, the CRP before and after surgery was 2.3 mg/L (range, 0.32-316.3 mg/L) versus 87.4 mg/L (range, 4.4-173 mg/L; P < .001) and the IL-6 before and after surgery was 5.4 ng/L (range, 2.0888 ng/L) versus 25.4 ng/L (range, 4.0-1020 ng/L; P < .001), showing significantly higher levels in the samples collected after surgery. Consequently, for CRP and IL-6 analyses, patients with samples collected after colon surgery were excluded.
Using the conventional cTnT assay (LLD, 10 ng/L = 99th percentile of the reference population), cTnT values greater than the LLD were found in only 2 patients of the CM group, whereas the control subjects and all other patients were cTnT negative. As demonstrated in Figure 1, A, with the HS assay (LLD, 3.0 ng/L), cTnT was detectable in 1 control subject (4%, 1 of 26), in 4 of 86 patients in the I (asymptomatic) group (5%), and in 3 of 22 patients in the M group (14%). None of these values exceeded the 99th percentile cutoff (<13 ng/L). In CM, the HS cTnT was greater than the LLD in 26 of 71 patients (37%), which was significantly higher than that found in the C group (P = .001), the I group (P = .001), and the M group (P = .04). A comparable HS cTnT distribution was found for the HS cTnT levels. The HS cTnT levels did not differ in C, I and M, but a significantly higher level at 1.5 ng/L (range, 1.5-35.9 ng/L) was found in the CM group versus the C group (1.5 ng/L; range, 1.5-11.3 ng/L; P = .003), versus the I group (1.5 ng/L; range, 1.5-12.4 ng/ L; P < .001), and versus the M group (1.5 ng/L; range, 1.55.8 ng/L; P = .03). Based on the receiver operating characteristic curve, the LLD of the HS cTnT assay (3.0 ng/ L) was suggested as the best cutoff (area under the curve, 0.67; sensitivity, 0.37; specificity, 0.97;) to distinguish among patients in the indeterminate (asymptomatic) stage and the cardiomyopathy stage. Cardiomyopathy preva lence was only 30% in patients with chronic Chagas, and a positive predictive value of 0.84 and a negative predictive value of 0.78 were calculated.
For the HS cTnT analysis related to cardiomyopathy severity, patients with mild and moderate cardiomyopathy were combined because of the low percentage of mild cardiomyopathy (10%) in our study cohort. Figure 1, B, shows that the percentage of HS cTnT values greater than the LLD was significantly lower in the group without cardiomyopathy (5%) compared with patients with mild or moderate cardiomyopathy (31%; P < .001) and with patients in the severe cardiomyopathy group (50%; P < .001). None of the values found in patients without cardiomyopathy exceeded the 99th percentile cutoff, but 10% (P = .006) of patients with mild or moderate cardiomyopathy and as much as 25% (P < .001) of patients with severe cardiomyopathy exceeded the cutoff. The relationship between cardiomyopathy severity and cTnT release was further documented by the HS cTnT levels. The HS cTnT was 1.5 ng/L (range, 1.4-12.4 ng/L) in patients without cardiomyopathy, which was significantly lower than in patients with mild or moderate cardiomyopathy (1.5 ng/L; range, 1.5-25.1 ng/L; P < .001) and severe cardiomyopathy (3.0 ng/L; range, 1.5-35.9; P = .001). The HS cTnT increased significantly from mild/ moderate to severe cardiomyopathy (P = .008).
As demonstrated in Figure 2, A, the percentage of CRP values greater than the cutoff of 5 mg/L was comparable in groups C (7%), I (12%), and M (23%), but significantly more CRP values (41%) exceeded the cutoff in group CM versus groups C (P < .001) and I (P < .001). There were also significantly more values greater than the cutoff in group M versus group C (P = .02). The CRP concentration was comparable in groups C, I, and M. Group CM had a CRP level of 2.9 mg/L (range, 0.1-316 mg/L), significantly higher than found in groups C (1.2 mg/L; range, 0.1-10.4 mg/L; P = .004) and I (1.4 mg/L; 0.1-50.2 mg/L; P =.003).
For IL-6, a comparable marker distribution existed, as shown in Figure 2, A. Compared with groups C (22%; P < .001) and I (40%; P = .001), the percentage of IL-6 values greater than the cutoff (3.4 ng/L) was 71% in CM, which was significantly higher. A higher percentage of values greater than the cutoff was also found in group M versus C(P = .05). The CM and M (54%) groups did not differ significantly. The IL-6 concentrations in groups C and I were comparable at 2.4 ng/L (range, 2.0-19.6 ng/L) and 2.8 ng/L (range, 2.0-43.3 ng/L), respectively, and in groups CM and M at 4.9 ng/L (range, 2.0-888 ng/L) and 4.2 ng/L (range, 2.0-25.9 ng/L). In contrast, the CM group had significantly higher IL-6 levels than the C group (P < .001) and the I group (P = .002). The IL-6 level in group M (P = .04) versus the C group was also significantly increased. As demonstrated in Figure 2, B, in parallel to the severity of the cardiomyopathy, the percentage of values greater than the CRP and IL-6 cutoffs are indicative of inflammation, and the serum levels of these markers increased continuously as well. The percentage of patients with CRP values greater than the cutoff, compared to the group without cardiomyopathy (12%), was significantly higher in the patients with mild or moderate cardiomyopathy (21%; P = .006) and those with severe cardiomyopathy (47%; P < .001). The percentage of patients with IL6 values greater than the cutoff was 12% in the patients without cardiomyopathy and was significantly higher in the groups of patients with mild or moderate cardiomyopathy (47%; P = .005) and with severe cardiomyopathy (76%; P = .05). The relationship of the cardiomyopathy severity and the serum levels of CRP and IL-6 were also documented by the continuous increase of the serum concentrations of CRP and IL-6. The CRP levels increased from patients without cardiomyopathy (1.4 mg/L; range, 0.2-41.2 mg/L) to those with mild or moderate cardiomyopathy (2.1 mg/L; range, 0.1-316 mg/L) to those with severe cardiomyopathy (4.5 mg/L; range, 2.0-271 mg/L), as did the values for IL-6 from 2.8 ng/L (range, 2.043.3 ng/L) to 4.9 ng/L (range, 2.0-888 ng/L) to 4.5 ng/L (range, 2.0-271 ng/L), respectively. Consequently, CRP and IL-6 results were significantly higher in patients with mild or moderate (CRP, P = .02; IL-6, P = .004) and severe cardiomyopathy (CRP, P = .001; IL-6, P =.005).
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The introduction of cardiac troponin immunoassays with improved sensitivity (highly sensitive assays) now enables cardiac troponin measurements with imprecision rates (<10%) near or even less than the required 99th percentile of the reference population. With such assays, a window was opened that enables the mirroring of minor, but distinct, cardiac troponin elevations with diagnostic and prognostic effect in pathophysiologic conditions of the heart, such as inflammation and cardiomyopathy. (10) With the HS cTnT assay we used, a highly sensitive test for cardiac troponin measurement in patients with chronic Chagas disease is now available for the first time, to our knowledge. The conventional cTnT assay was also used for comparison purposes. Whereas the cTnT values greater than the LLD were seen in patients with chronic Chagas disease only to a negligible extent with the conventional assay, a distinct number of cTnT values greater than the LLD were found with the highly sensitive assay. This advantage of the highly sensitive cTnT assay versus the conventional assay was also recently demonstrated by Latini et al. (14)
In detail, significantly more patients with measurable HS cTnT (>LLD), or even values greater than the 99th percentile, were seen in the group with Chagas cardiomyopathy compared with the healthy controls, the patients in the indeterminate stage, and the patients in the megacolon group. The number of measurable HS cTnT values also increased with the severity of the cardiomyopathy. A comparable picture was seen in the cTnT levels, which were highest in patients in group CM and in the patients with severe cardiomyopathy. The LLD of 3 ng/L was the best cutoff value for distinguishing patients with and without cardiomyopathy.
There is, however, one additional point that has to be discussed. We enrolled patients in our study who were newly diagnosed with Chagas disease and patients with existing Chagas disease who were attending the hospital for routine checks. Additionally, patients with chronic Chagas disease who were hospitalized for elective pacemaker implantation or colon surgery were also enrolled. Sampling in these patients was done 48 to 72 hours after the intervention. Comparing patients with and without intervention, we did not find any indication that the sampling following the intervention influenced the HS cTnT levels. This fact clearly agrees with data (15,16) presented recently that showed that a minor cardiac troponin release peaked between 6 and 12 hours after pacemaker implantation only; at 48 hours after the intervention, normalized levels were observed.
With respect to the colon surgery, perioperative silent ischemia could potentially affect the heart and consequently produce cTnT release. However, recently published results from a large cohort of elderly patients undergoing noncardiac surgery of at least 30 minutes duration showed that only a few patients (9.7%) presented with perioperative cTnT increases. (17)
The elevated HS cTnT level in cardiomyopathy from Chagas disease agrees with the results we found with a cTnI assay (cTnI adapted to the Stratus CS; Dade Behring, Marburg, Germany) that also worked with acceptable performance in the lower troponin range. Using that assay, we found measurable (>LLD) cTnI values--nevertheless, most values were less than the cutoff represented by the 99th percentile of the reference population in patients with mild myocardial dysfunction, whereas most of the healthy controls were cTnI negative. (18,19) In a study by Latini et al, (14) measurable cTnT values (>LLD) were demonstrated in patients with nonchagasic, chronic, stable heart failure. In that study, (14) cTnT greater than 10 ng/L, which we found predominantly in our patients with severe cardiomyopathy, predicted a 4-fold increase in mortality at 24 months when compared with level less than 10 ng/L.
There were also some patients who were positive for cTnT in the indeterminate and megacolon groups. Because of the restricted diagnostic sensitivity for detection of cardiomyopathy in the ECG, patients with positivity for cTnT who lacked pathologic ECG evidence could be misclassified if diagnosed by echocardiography and belong, rather, to the cardiomyopathy group. This hypothesis is supported by Talvani et al, (20) who found elevated B-type, natriuretic peptides in patients with mild cardiomyopathy that was diagnosable only with echocardiography, but not with ECG.
For the obviously nonthrombotic release of cardiac troponin, as supposed for our patients with cardiac disease, Latini and Masson (21) discussed possible mechanisms, including ongoing cardiomyocyte death. Apoptosis is the main reason for myocyte death in heart failure, but whether and to what extent apoptosis is associated with the release of macromolecules, such as cTnT, into the circulation is still under discussion and is at present doubtful. (22) Other potential mechanisms for release of cardiac troponin have been summarized by Jeremias and Gibson. (10) Demand ischemia in the heart, resulting from tachyarrhythmias and ventricular hypertrophy, stretching of the cardiomyocytes following volume and pressure overload, and inflammation processes, were suspected of disturbing cell membrane integrity, leading to troponin loss, especially from the cytosolic myocyte pool. The cumulative establishment of these mechanisms would explain the increasing cTnT release related to the severity of cardiomyopathy. Oxidative stress has been postulated for the coupling of pathophysiologic events in the failing heart, such as inflammation with membrane leakage, and in that way, causing the troponin release. Oxidative stress related to inflammation has been discussed as being responsible for the cardiac troponin release during strenuous exercise, such as marathon running. (23,24) Recurring inflammation episodes, combined with focal inflammation areas in the heart, are typical in Chagas cardiomyopathy. (4,25) Consequently, inflammation, as documented by our CRP and IL 6 data, which are in agreement with Lopez et al, (26) could drive, possibly via induction of oxidative stress, the cTnT elevation in patients with Chagas cardiomyopathy. Recently, for marathon runners, their minor cTnT release--only preferentially detectable by highly sensitive assays--was found to be in relation to their inflammation. (27)
The relationship of inflammation and cardiac troponin release was also documented for myocarditis, (28) pericarditis, (29) and immune responses after heart transplantation. (30)
With the highly sensitive cTnT assay, a diagnostic tool is now available that supplies data useable in chronic Chagas disease for diagnosis, prognosis, and monitoring of cardiomyopathy. The cTnT measurement could, in our view, supplement ECG or echocardiography in patients with chronic Chagas disease and, in special circumstances, be applied before these other diagnostic tools.
In areas of endemic Chagas disease, ECG, echocardiography, and radiologic imaging are still restricted in their availability because they are cost-intensive, require highly qualified personnel, and have to be performed in special units often located a long way from the patients' home, thereby making visits more expensive and time-consuming. These disadvantages could be reduced by measuring cTnT instead because laboratory medicine is superior, from an economic and logistic viewpoint, to the other diagnostic tools. For cTnT measurements, blood could be sampled near the patient's home, thus sparing the patient time and cost. Samples are stable and can be transported to centralized units of laboratory medicine, where the analyses could be performed automatically and economically but with high-quality results.
When cTnT positivity is detected in a patient with chronic Chagas disease, an ECG should be performed for cardiomyopathy verification. In cases lacking ECG evidence, echocardiography should be performed. Patients who are cTnT positive should be monitored for indications of cardiomyopathy progression.
However, this strategy for management of patients with Chagas disease requires further studies to increase the acceptance of low-level cardiac troponin measurements as a promising tool for laboratory medicine.
We are grateful to Deutsche Gesellschaft fur Klinische Chemie und Laboratoriumsmedizin for support awarding the HansBreuer-Stipendium to S. G. Munoz Saravia, PhD, and to Anne Gale, BA, ELS, for editorial assistance.
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Silvia Gilka Munoz Saravia, PhD; Annekathrin Haberland, PhD; Sabine Bartel, PhD; Raul Araujo, MD; Gregorio Valda, MD; Diana Duchen Reynaga, MS; Ivan Diaz Ramirez, MD; Adrian C. Borges, MD; Gerd Wallukat, PhD; Ingolf Schimke, PhD
Accepted for publication April 12, 2010.
From the Department of Cardiology, Charite Universitatsmedizin Berlin, Berlin, Germany (Drs Munoz Saravia, Haberland, Diaz Ramirez, and Schimke); the Department of Immunology of Cardiovascular Diseases, Max-DelbrUck-Centrum Berlin, Berlin, Germany (Drs Bartel and Wallukat); the Departments of Cardiology (Dr Araujo), Gastroenterology (Dr Valda), and Laboratory Medicine (Dr Munoz Saravia and Ms Duchen Reynaga), Santa Barbara Hospital Sucre, Sucre, Bolivia; and the Department of Cardiology, HELIOS Klinikum Emil von Behring, Berlin, Germany (Dr Borges).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Ingolf Schimke, PhD, Department of Cardiology, Campus Charitee Mitte, Universitatsmedizin Berlin, Chariteeplatz 1, 10117 Berlin, Germany (e-mail: firstname.lastname@example.org).
Basic Data on Healthy Subjects (Control Group) and Patients With Chronic Chagas Disease (a) Parameter Control Group Indeterminate Group No. of patients (M/F) 26 (8/18) 86 (19/67) Age, y Median (range) 30 (19-61) 30 (18-62) Categories of cardiomyopathy, % Mild Moderate Severe Cardiomyopathy Parameter Group No. of patients (M/F) 71 (36/35) Age, y Median (range) 47(18-81) (b) Categories of cardiomyopathy, % Mild 10 Moderate 54 Severe 36 Parameter Megacolon Group No. of patients (M/F) 22 (6/16) Age, y Median (range) 46 (19-65) (c) Categories of cardiomyopathy, % Mild Moderate Severe (a) Patients with chronic Chagas disease were subdivided into those who were asymptomatic (indeterminate group), those who had cardiomyopathy (cardiomyopathy group), and those with megacolons (megacolon group). Patients in the cardiomyopathy group were further subdivided by the severity of their cardiomyopathy. (b) Patients in the cardiomyopathy group (P < .001; P < .001) were in the median age significantly older than healthy controls and patients in the indeterminate group. (c) Patients in the megacolon group (P = .002; P = .001) were in the median age significantly older than healthy controls and patients in the indeterminate group.