Cardiac troponins I and T in patients with suspected acute coronary syndrome: a comparative study in a routine setting

Departments of
¹ Clinical Chemistry and
² Medicine, Section for Cardiology, Rogaland Central Hospital, 4011 Stavanger, Norway.
^a Author for correspondence. Fax 47-51519907.

	Abstract

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We compared cardiac troponin I (cTnI), using Access®, Sanofi Pasteur, and cardiac troponin T (cTnT), using Elecsys®, Boehringer Mannheim, in the first two routine blood samplings in a routine panel of cardiac markers for the biochemical diagnostic evaluation of patients with symptoms of acute myocardial infarction (AMI). No significant differences in the overall clinical performances of cTnI and cTnT were observed for the diagnosis of AMI (n = 68), but cTnI demonstrated lower initial sensitivity and higher specificity compared with cTnT. cTnT was increased to higher relative values than cTnI (P = 0.023). Discordances were found between cTnI and cTnT in sample I but not in sample II; positive cTnT/negative cTnI was more common than the opposite discordance (P = 0.027). cTnT was more frequently increased in patients with unstable angina pectoris (UAP) than cTnI (P = 0.038), with no significant differences between sample I and sample II; discordant results with respect to cTnI and cTnT appeared in 6 (33%) of these patients, all of which were positive for cTnT and negative for cTnI. Four patients with UAP (22%) developed AMI within 4 months; three were associated with increased cTnI and cTnT at the time of initial testing, and one was discordant (positive cTnT). In patients classified with no acute coronary syndrome (n = 84), five concordant positives for cTnI and cTnT were observed, indicating the existence of a myocardial injury of recent origin in these patients. AMI evolved in one of these patients 5 months later. We conclude that cTnT and cTnI detect acute myocardial injury with equal clinical performance in AMI patients classified by WHO criteria. cTnT was more frequently increased in patients with UAP than cTnI, but the clinical significance of this discordance could not be determined from this study.

	Introduction

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In recent years, cardiospecific proteins of the troponin-tropomyosin complex in the contractile system of the cardiomyocytes [cardiac troponin I (cTnI)¹ and cardiac troponin T (cTnT)] have challenged creatine kinase isoenzyme MB (CK-MB) as the "gold standard" for the early biochemical detection of acute myocardial injury (1)(2)(3), and they appear also to be superior to LD-1 in the late diagnosis of acute myocardial infarction (AMI) (4). An additional feature of cTnT is the ability to detect myocardial injury in some of the patients with unstable angina pectoris (UAP) (5)(6)(7). Because these patients bear a substantial risk for developing adverse events such as AMI, cTnT and, more recently, cTnI have been proposed to be of value in risk stratification of patients with UAP in view of the possible benefit of an early intervention with antithrombotic therapy (8)(9)(10).

The cardiospecificity of cTnT compared with cTnI has recently been questioned (11). cTnT is regularly increased in patients with end-stage renal failure (12). In some instances, re-expression in skeletal muscle of the fetal gene for cTnT may occur and form a potential source of nonspecific cTnT with respect to myocardial injury (13). Such re-expressions seem to be possible in such chronic myopathies as muscle dystrophy and polymyositis (14). The first generation of the cTnT assay lacked absolute specificity for the cardiac isoform and allowed interference by skeletal muscle troponin T (TnT) in conditions such as rhabdomyolysis (15). The second generation of the assay system is claimed to be absolutely specific for the myocardial isoform of TnT (16). However, cTnT is still detectable in many cases of end-stage renal failure, to a lesser extent than the first generation but to an extent far more frequent than cTnI (17). The mechanism behind this situation is unclear at the present time; however, a recent report indicates the presence of some cTnT in skeletal muscle biopsies from patients with end-stage renal failure (13). The specificity of cTnT for the detection of myocardial injury has therefore been debated from both a practical and a theoretical point of view (11). However, studies in unselected patients are few, and the practical impact of these specificity considerations is not known at the present time.

Characteristics of cTnI and cTnT compared in a practical routine setting have not been fully described. In view of the importance of detecting minor myocardial injury in patients with unstable coronary disease, it is clinically relevant to compare cTnT and cTnI in a common population of patients presenting to hospital with chest discomfort suggestive of an acute coronary syndrome. The assay for cTnT has been provided by only one manufacturer (the ES system, Boehringer Mannheim) (18); that same manufacturer has recently provided a new and more rapid system that allows for rapid analytical turnover time (Elecsys system) (19). The situation for cTnI is more complex; several diagnostic assays from different manufacturers have recently appeared, which differ substantially from each other with respect to reference limits and decision limits (cutoff limits) for myocardial injury (20)(21)(22)(23).

In the present study, we compared cTnT (Elecsys system, Boehringer Mannheim) to cTnI (Access system, Sanofi Pasteur) (21) in patients arriving consecutively to the hospital with symptoms of AMI, by including the assays in a routine panel of cardiac markers. CK-MB mass concentration (CK-MBm, Elecsys system) was in part added to the study to relate some of the conclusions regarding the troponins to CK-MB mass, which conventionally has been regarded as the gold standard for the detection of acute myocardial injury (1).

	Materials and Methods

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subjects and samples
All consecutive patients with symptoms of AMI arriving at the coronary care unit in a period of 6 weeks were enrolled in the study on a 24-h basis. Blood samples were drawn for routine cardiac status (CK total and CK-MB) according to the routine sampling system of the hospital: the first blood sample was drawn within 4 h after admission at fixed sampling times at 0800 and 1200, 1600 and 2000, and at admission when this occurred between 2000 and 0800. A second routine sample was drawn 4–8 h after the first sample, according to the patient's history of symptom duration. A third and fourth sample was drawn as clinically appropriate. The blood samples were obtained in evacuated gel tubes for serum preparation and were kept at room temperature to allow clotting before centrifugation to obtain serum. CK and CK-MB activities were analyzed without delay. Serum aliquots were stored at -25 °C for a maximum of 1 week before the analysis of cTnI and cTnT (and CK-MBm when appropriate). Thawed samples were analyzed batchwise within a few hours for cTnI and cTnT, followed by the analysis of CK-MBm in samples associated with a cTnI and/or cTnT concentration of 0.05 µg/L. CK-MBm was therefore initially analyzed in all samples in which cTnI and/or cTnT was >0.05 µg/L, and later (within 2 months) also in the samples from the patients diagnosed with AMI and UAP in which no initial analysis of CK-MBm existed.

A final diagnosis of AMI was established according to the presence of two out of three criteria (WHO) (24): (a) the patient's clinical history and symptom duration (characteristic chest pain of at least 20-min duration), (b) electrocardiogram (ECG) abnormalities, and (c) typical rise and fall pattern of CK-MB activity. The diagnosis of AMI by ECG was based on a 12-lead ECG, with evolution of Q-waves and/or ST-segment elevation/depression of at least 0.1 mV in two or more leads. A final diagnosis of UAP was established in patients with typical angina pain at rest, combined with reversible or persistent ECG changes compatible with ischemia with or without changes in CK-MB activity below the decision limits for AMI.

laboratory analysis
The routine cardiac panel consisted of CK total and CK-MB activity along with a calculated CK-MB index (CK-MB activity in percentage of total CK activity). CK and CK-MB activities were analyzed on a Johnson & Johnson Vitros(TM) 700 analyzer (25). CK-MB activity was analyzed according to the immunoinhibition principle; CK-MB activity was defined as CK-B subunit activity x 2 (26). The upper reference limit (URL) for CK was 200 U/L for men and 150 U/L for women. The URL for CK-MB activity was 12 U/L. The cutoff limit for AMI in serial CK-MB was 16 U/L associated with a rise and fall pattern and a CK-MB index in the range of 4–20% (Johnson & Johnson Diagnostics, Vitros Test Methodologies, MP2–48, 1997). CK-MBm and cTnT were analyzed using the Elecsys 2010 system from Boehringer Mannheim (19). The manufacturer's cutoff limit was 5.0 µg/L (CK-MBm) and 0.10 µg/L (cTnT). cTnI was analyzed by the Access system (Sanofi Pasteur); the manufacturer's cutoff limit was 0.10 µg/L (21). The URLs were 0.05 µg/L (cTnI and cTnT) and 3.1 µg/L (CK-MBm); see the Discussion section for additional details.

statistical analysis
All individual test results for comparisons were grouped according to the sampling system in routine sample I and routine sample II. ROC analysis was performed by the use of a software program for clinical test evaluation: GraphROC for Windows (27). Results of ROC analysis were expressed as areas under the individual ROC curves (and the 95% confidence intervals). The same software program was also used to calculate clinical sensitivities and specificities (and 95% confidence intervals) at different cutoff limits. Differences between relative values (relative to the URL) of different markers in the same sample were evaluated by Wilcoxon's paired signed rank sum test. Discordances were analyzed by McNemar's test (28).

	Results

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patients with ami
AMI was diagnosed in 68 patients; 102 patients (including 18 patients with UAP) were diagnosed without AMI. Table 1 illustrates the patient characteristics. Median values and ranges of cTnI, cTnT, and CK-MBm in sample I and in sample II in the patients with AMI are shown in Table 2 . The overall accuracies of cTnI and cTnT for discrimination between AMI and a diagnosis of no AMI were not distinguishable in either sample I or in sample II as evaluated by ROC analysis (Table 3 ). The clinical sensitivities and specificities at the URLs and at the conventional cutoff limits for AMI (see Discussion) are shown in Table 4 . cTnT demonstrated an overall higher relative increase than cTnI in the patients with AMI (P = 0.023, Wilcoxon's paired rank sum test). cTnI was less sensitive than cTnT in sample I at the lower cutoff value at the URL, as shown in Table 4A , with no overlap in the respective confidence intervals. However, this situation was associated with higher specificity of cTnI, as shown in Table 4B . No significant differences in sensitivities were observed at the cutoff limits of 0.10 µg/L (cTnI and cTnT), and no significant differences in the sensitivities were noted in sample II (substantial overlap in the confidence intervals). The specificity of cTnI was marginally higher than cTnT. (CK-MBm demonstrated higher sensitivity than both troponins at the URL and at the manufacturer's cutoff value, shown in Table 4A ; the clinical specificity, however, was not determined for this marker in the present study.) Discordant results between cTnI and cTnT (relative to cutoff limits at 0.10 µg/L) were observed in 10 samples, 8 of these from routine sampling I (Table 5 ). Discordances associated with increased cTnT were more frequent than the opposite discordance (P = 0.027). However, the small number of samples that were negative for cTnT (n = 1) and cTnI (n = 3) in sample II were all positive when additional routine request samples from these individuals were tested for cTnI and cTnT later within the time-related diagnostic window, yielding an overall concordance of cTnI and cTnT (and CK-MBm) of 100% in the patients diagnosed with AMI.

patients with uap
cTnT and CK-MBm were more frequently increased in patients with UAP than cTnI (Table 6 ). Discordances between cTnT and cTnI were observed in 6 of a total of 18 samples in sample I and persisted in 5 of these in sample II at either cutoff value. All discordances were associated with positive cTnT/negative cTnI in this group of patients with no indications of renal insufficiency or myopathy.

Adverse cardiac events (AMI/cardiac death) occurred in four (22%) of the patients with UAP during the next 4 months after the initial blood samplings/enrollment to the study: in the first 0–30 days, n = 2 (initial cTnI, 0.12 and 0.13 µg/L; cTnT, 0.25 and 0.27 µg/L); 31–60 days, n = 0; 61–90 days, n = 1 (cTnI, 0.07 µg/L; cTnT, 0.17 µg/L); 91–120 days, n = 1 (cTnI, 0.11 µg/L; cTnT, 0.27 µg/L; the maximum concentrations of cTnI andcTnT in the initial blood samplings). Concordance between cTnI and cTnT occurred in three individuals (increased concentrations relative to the cutoff value 0.1 µg/L); discordance occurred in one (increased cTnT).

patients without acute coronary syndromes
Increased concentrations of cTnI and/or cTnT (>0.10 µg/L) were observed in 7 patients of a total number of 84 patients in this group. Concordance was observed in five of these and discordance (increased concentration of cTnT) in two patients. Table 7 illustrates the characteristics of these patients. Four of these patients were diagnosed with pneumonia, three of whom had both increased cTnI and cTnT. All of these patients had nondiagnostic values for CK and CK-MB activity, but two had increased CK-MB mass. In one patient with a diagnosis of congestive heart failure (patient C, Table 7 ), the concentrations of both troponins and CK-MB mass rose 5- to 10-fold from sample I to sample II, which indicated acute myocardial injury but was associated with inconclusive values for CK and CK-MB activity because of the CK-MB index, indicating the presence of increased CK activity from skeletal muscle. The same patient suffered a transmural AMI 5 months later. In another patient with an immunopathic disease, both troponins were increased in sample II (below URL in sample I) with no conclusive routine marker status and marginally increased CK-MB mass. Discordances between cTnI and cTnT (increased cTnT) were observed in a patient with amyloid cardiomyopathy and one patient with chronic obstructive pulmonary disease complicated with pneumonia.

	Discussion

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In this study of patients arriving consecutively to a coronary care unit with symptoms of acute coronary disease and for which routine cardiac enzymes were requested, CK-MBm appeared to be more sensitive than both the troponins in the first routine sample after admission, when evaluated on basis of the assay manufacturer's cutoff limits (cTnI and cTnT, 0.10 µg/L; CK-MBm, 5.0 µg/L). The cutoff limit for a test (decision limit for a positive test result with respect to AMI) is often set at a higher concentration than the URL to increase test specificity (2). With respect to cTnT, the provisional cutoff limit from the manufacturer is 0.10 µg/L (16), and this cutoff limit has been used as a conventional cutoff limit in recent studies (7)(12)(14)(29)(30). cTnI measured by the Access system is based on the same numerical cutoff limit for myocardial injury, 0.10 µg/L (21). A recent report concluded with 0.15 µg/L as a cutoff value for cTnI (Access) (31). However, both cTnT (Elecsys) and cTnI (Access) are associated with an URL of ~0.04–0.05 µg/L by conventional nonparametric statistical analysis of a healthy population: cTnT was <0.06 µg/L in >98% of 4955 healthy individuals and 0.04 µg/L in 96% (16). The distribution of cTnI (Access) in a healthy population is quite similar: cTnI is <0.06 µg/L in 98.9% and <0.05 µg/L in 96.3% (Sanofi Pasteur, personal communication). Based on these values, the URL for cTnT and cTnI was set at 0.05 µg/L in the present study for the purpose of clinical performance evaluations and between-test comparisons. Because the cardiac troponins appear to be highly specific for myocardial injury, the "gap" between the URL (0.05 µg/L) and the conventional cutoff value (0.10 µg/L) should be of clinical value, and some recent studies support this view (10)(30).

ROC analysis demonstrated an overall equal accuracy of cTnI and cTnT for the diagnosis of AMI, and both markers (as well as CK-MBm) were associated with an overall equal clinical sensitivity, with 100% concordance of test results in the diagnostic window by cutoff values at 0.10 µg/L (cTnI and cTnT) and 5.0 µg/L (CK-MBm). The initial sensitivity of cTnI (sample I) was lower than cTnT when the lower cutoff values were used at the URL; however, specificity was significantly higher for cTnI in this situation. The same tendency between cTnI and cTnT was noted when the higher cutoff values (0.10 µg/L) were used, but the differences were not significant. However, the observed discordances between cTnI and cTnT were significantly more frequent in favor of increased cTnT than the opposite discordance. One recent study suggested higher initial clinical sensitivity for cTnT than for cTnI (32), but another study concluded that the early sensitivities were equal (29).

In patients with unstable coronary disease, cTnT has been shown to provide important prognostic information in a substantial number of studies (33), which have been confirmed in a large multicenter study (30). cTnT concentrations in patients presenting to hospital with chest pain have been compared with coronary angiography, which demonstrated a relationship between cTnT concentration and the extent of obstructive coronary disease associated with ruptured coronary plaques (34)(35). Identification of such patients for anticoagulation therapy with low molecular weight heparin has given promising results (8). The potential of cTnI has not been investigated to the same extent as cTnT, but preliminary studies as well as a larger multicenter study also demonstrate a potential for cTnI in risk stratification of patients with unstable coronary disease (9)(10)(36). However, it is unclear at the present time whether cTnI reflects the same situation as cTnT, and recent observations may indicate some differences in this respect (37).

In the present study, adverse coronary events (AMI) occurred in four of the patients with UAP; cTnI and cTnT were both increased in three of these patients and discordant (increased cTnT) in one. Discordances (increased cTnT) were observed in an additional four patients with UAP who had no adverse events. This situation poses two questions: Is cTnT more sensitive for the detection of minor myocardial injury in this group of patients than cTnI? Or is this situation associated with a lower specificity of cTnT than cTnI for myocardial injury? The reformulated, second generation cTnT assay does not cross-react with the skeletal isoform of TnT (16). Skeletal muscle may in some regeneration processes synthesize the cardiac isoform by activation of fetal genes, as described in some chronic myopathies, including Duchenne's muscle dystrophy (13). The other known interfering clinical situation that may give rise to an increase in cTnT is renal failure (12)(17). To what extent such situations may give rise to false positives in patients with suspected acute coronary disease is not fully known, but these possible confounding co-morbid conditions are not a common clinical problem. A recent study has indicated some higher potential for cTnT compared with cTnI for the risk stratification of patients with acute coronary syndromes (37).

A possible mechanism for the discordances in UAP may be associated with the prolonged increase of cTnT in plasma after AMI, compared with cTnI (3). In the present study, we observed that the plasma concentration of cTnT in AMI and UAP was increased to markedly higher relative values than cTnI. Repetitive episodes of microinfarcts in UAP may give rise to a persistent increased concentration of cTnT because of a possible prolonged time of decay of plasma cTnT compared with cTnI after cardiac injury or by continuing release of immune-detectable cTnT that is not paralleled by immune-detectable cTnI. Both free and complex forms of cTnI have been described after AMI, and some complexes between cTnI and troponin C may hide otherwise immune-reactive epitopes on cTnI in such a way that antibody detection is reduced or blocked (38). cTnT appears to be more commonly existent in free form after AMI, compared with cTnI (39).

The existence of concordant "positive" results of cTnI and cTnT in some patients classified with no acute coronary syndrome suggests that both troponins are able to detect myocardial injury not obviously detected by the use of CK/CK-MB activities and CK-MBm. In view of the superior performance of the cardiac troponins in the detection of minimal myocardial injury compared with the traditional enzyme markers (2)(3), such results are not unexpected. These situations were associated with cases in which the CK/CK-MB system failed to give a clear indication of a cardiac origin by the concomitant increase from skeletal muscle, indicated by a low CK-MB index or by not reaching the cutoff limits specified for this system.

In conclusion, cTnI and cTnT detected AMI with comparable clinical performances in a routine setting. Cases positively concordant for cTnI and cTnT without a diagnosis of AMI/UAP suggest a superior clinical performance of cTnT and cTnI, when compared with CK/CK-MB activity. cTnT was more frequently increased than cTnI in patients with UAP, but the clinical significance of these situations must be determined by future studies.

	Acknowledgments

 
We thank Boehringer Mannheim, Norway, for providing the Elecsys 2010 and reagents for cTnT to the study. We thank Partner Pharma, Norway, and Sanofi Pasteur, France, for providing reagents for the assay of cTnI on the Access system. This study was partly supported by a research grant from the Central Hospital of Rogaland, Stavanger, Norway.

	Footnotes

 
¹ Nonstandard abbreviations: cTnI, cardiac troponin I; cTnT, cardiac troponin T; CK, creatine kinase; CK-MB, creatine kinase MB isoenzyme; AMI, acute myocardial infarction; UAP, unstable angina pectoris; TnT, troponin T; CK-MBm, creatine kinase MB mass concentration; ECG, electrocardiogram; and URL, upper reference limit of a healthy population.

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