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Enzymes and Protein Markers |
1
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
2
Duke Clinical Research Institute, Durham, NC.
3
Department of Medicine, University of Edmonton,
Edmonton, AB, Canada.
4
Medizinische Klinik II, Medizinische
Universität Lübeck, Lübeck, Germany.
5
The Cleveland Clinic Foundation, Cleveland, OH.
a Address correspondence to this author at: Clinical Pathology, University of Maryland Medical Center, 22 South Greene St., Baltimore, MD 21201. Fax 410-328-5880; e-mail rchriste{at}umms001.ab.umd.edu.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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2 = 18.0, P
<0.001) with 30-day mortality than cTnI (2 =
12.5, P = 0.002). The area of the ROC curve for
predicting 30-day mortality was significantly larger
(Z = 2.08; P = 0.0375) for cTnT, at
0.68 [95% confidence interval (CI) 0.60–0.75], compared with cTnI,
at 0.64 (95% CI 0.56–0.72). When cTnI and the electrocardiogram (ECG)
were put in a logistic multiple regression model, cTnT added
significant information (2 = 8.03,
P = 0.045); however, cTnI did not add to a model
containing cTnT and the ECG (2 = 0.84,
P = 0.657). cTnT provided more information than cTnI
for predicting 30-day mortality early after presentation with acute
coronary syndromes. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Troponin T and troponin I function together as essential components of the contractile apparatus in striated muscle (10). Although the troponin complex functions similarly in all striated muscle, isoforms of both troponin T and troponin I differ in cardiac vs skeletal muscle because these proteins are coded by separate genes in these tissues (11). Both the myocardial and skeletal isoforms of troponins T and I show striking differences that include biological function, amino acid sequences, and molecular weight. Further, the proportion of total troponins T and I representing the "cytosolic pool" available for rapid release and time of increase after myocardial necrosis differ (12)(13). Therefore, the characteristics of these proteins may differ with regard to risk stratification. Antibodies specific to the cardiac isoforms are the basis for sensitive cTnT and cTnI assays (14)(15).
Both cTnT and cTnI are sensitive markers of myocardial necrosis (12)(13)(16)(17). Measurement of cTnT was shown to be useful for the objective risk assessment in patients presenting with unstable angina on the basis of conventional criteria including the ECG, creatine kinase (CK), and CK-MB in both the short term and long term (1)(18)(19)(20) and in MI patients with and without ECG changes (4)(21). There is an emerging literature for cTnI that indicates that this marker may also be useful for risk stratification (5)(6)(22).
We have shown in the Global Use of the Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIa) troponin T substudy that the baseline serum cTnT concentration provides more prognostic information than the baseline serum CK-MB concentration (4). Part of the design of this substudy was to collect and appropriately archive samples for further testing with newer marker assays as they became available. Recently, cTnI was shown to be useful for risk stratification in acute coronary syndromes (5). We compared the ability of an early cTnT or cTnI concentration to risk-stratify patients with acute coronary syndromes in a large cohort of patients, all of whom were enrolled in a large trial of an antithrombotic agent.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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0.05 mV ST-segment
elevation or depression, left bundle branch block, or 0.05 mV T-wave
inversion). Patients having active bleeding, stroke within 1 year, or
contraindications to heparin therapy were excluded from the GUSTO-IIa
trial. Also excluded from the main trial were patients having serum
creatinine values >221 µmol/L (25 mg/L).
biochemical marker analysis
The specimens analyzed for cTnI were first obtained in the
prospective cTnT substudy of the GUSTO-IIa trial (4).
Immediately after enrollment, blood specimens were collected in tubes
containing no anticoagulant or preservative. After the samples were
allowed to clot and centrifuged at 1000g for 10 min, the
resulting serum aliquots were poured into freezer vials, stored at
-20 °C or lower, and shipped on dry ice to the core laboratory,
where they were stored at -70 °C until analysis. Specimens were
assayed in batches within 8 h of thawing. The cTnT measures were
performed within 60 days after collection (4). The cTnI
measurements were performed 12 to 18 months after collection, with
sample aliquots that had remained frozen since collection. Thawing
after storage periods of as long as several years has been shown not to
result in degradation of the cTnI (5). All cTnT and cTnI
measurements were performed at a core laboratory by personnel blinded
to patient information and other marker results.
cTnI was assayed with the Stratus II system (Dade International) according to the manufacturer's instructions. This is a two-site immunoassay in which any cTnI in the sample is "captured" by an antibody affixed to a paper solid phase. After a wash step in which potential contaminants are removed by radial partition chromatography, excess fluorescently labeled antibody is added, forming a capture antibody–cTnI–labeled antibody complex immobilized on the solid phase. After another wash step to remove uncomplexed antibody, fluorescent substrate is added and the resulting signal measured. The assay time for the Stratus II system is 10 min; the upper reference limit determined from clinical studies as described in the package insert is 1.5 µg/L, and the minimum detection limit is 0.35 µg/L. The interassay CV was 7% in the range of 2.0 µg/L, 8% at 1.5 µg/L, and 15% at 0.7 µg/L.
cTnT was measured with the ES-300 system with Cardiac-T ELISA reagents (both from Boehringer Mannheim Corp.). All cTnT assays were carried out in accordance with the manufacturer's instructions, as described (4)(14). Briefly, in this automated assay cTnT in the sample reacts with a reagent containing a biotin-labeled antibody, which then binds to streptavidin attached to a solid phase. A second antibody labeled with peroxidase is then added, which binds to the immobilized cTnT-containing complexes to yield a biotin antibody–cTnT-labeled antibody complex. After washing, peroxide substrate is added and the resulting signal measured. Although some investigators have shown the minimum detection limit to be 0.015 µg/L (24), the assay's detection limit is quoted as 0.04 µg/L by the manufacturer. The cutoff recommended in the manufacturer's package insert is 0.1 µg/L; the CV was 13% at this concentration, 7% at 0.3 µg/L, and 18% at 0.06 µg/L.
ecg analysis
Core laboratory personnel analyzed all 12-lead ECGs while blinded
to patient information. Patients underwent ECG at randomization, 8
h, 16–24 h, and before discharge. Tracings were categorized by the
predominant feature of ST-segment elevation, ST-segment depression,
T-wave inversion, or confounding factors that impair the detection of
ischemia (bundle branch block, paced rhythms) as described
(4).
statistical analysis
Continuous variables are presented as mean ± SD or medians
with 25th and 75th percentiles. Discrete variables are expressed as
frequencies and percentages. Matched enrollment cTnT and cTnI samples
were available for 770 (90%) of the 855 patients enrolled in this
substudy; only these patients were included in the analysis. Baseline
characteristics of the 770 patients with both samples vs the other 85
patients did not differ significantly.
Logistic multiple regression was used to construct predictive models for the substudy's primary end point, a 30-day composite of death, (re)infarction, or revascularization (bypass surgery or angioplasty), and for each component of the composite outcome. The following models were constructed: one each for the continuous cTnT and cTnI variables alone, one in which the continuous cTnI concentration was forced in the model first followed by that for cTnT, and one in which the continuous cTnT concentration was forced in the model first followed by that for cTnI. Another model was constructed to assess the relative values of continuous cTnT and cTnI concentrtations and the ECG category, before and after adjustment for the other two variables, in the prediction of 30-day mortality. All analyses were performed with SAS (version 6.09) and S-Plus (version 3.3) software.
The area and standard error of the ROC curve were calculated for cTnT and for cTnI to evaluate the relation between concentrations of each of these markers and 30-day mortality (25). The ROC areas for cTnT and cTnI were compared by using the method of Hanley and McNeil (26).
The frequencies of discordant results—patients for whom cTnT was negative and cTnI was positive or those with positive cTnT results but negative cTnI—were analyzed by the McNemar test (27). In all analyses, P <0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. Patients who were cTnT positive or cTnI positive had a
somewhat higher-risk profile than patients with negative results; they
were slightly older, presented more often with Killip class II or
higher, more often had a history of cerebral or peripheral vascular
disease, and less often had previous hypercholesterolemia or
revascularization. Although an effort was made to exclude patients with
chronic renal insufficiency from GUSTO-IIa, Table 1
shows that 21 such
patients were enrolled, 11 of whom were cTnT positive and 8 of whom
were cardiac cTnI positive ( = 0.865,
P = 0.35).
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Of the 770 total patients, 642 (83.4%) died, suffered an infarction,
or underwent revascularization within 30 days of enrollment (Table 2
). Considering the 30-day mortality and infarction end point
only, 26.4% of the patient population (203 of 770) were free from
these events. Patients with negative cTnT results were less likely to
have in-hospital complications than those with negative cTnI results
( = 15.7, P <0.001).
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As shown for cTnT (4), an increased cTnI concentration was
associated with a greater risk of mortality at 30 days across all ECG
categories. Among the 413 patients who had ST-segment elevation, 30-day
mortality was 11.5% with an increased cTnI concentration vs 5.5% for
a concentration 
1.5 µg/L. The corresponding rates for the other
categories were: ST-segment depression, 12.9% vs 5.5% (n = 86);
T-wave inversion or normal tracing, 5.0% vs 0% (n = 132); and
confounding ECG factors, 19.4% vs 5.4% (n = 68).
There was a substantial correlation between cTnT and cTnI results
(r = 0.83, P = 0.0001). As shown in
Table 3
, of the 770 patients, 696 (90%) had cTnT and cTnI results that
were in concordance (both were either positive or negative). Of the 74
patients with discordant results, 66 (89%) were cTnT positive and cTnI
negative; the other 8 patients (11%) showed a negative cTnT result but
were positive for cTnI. The proportion of discordant patients who were
cTnT positive and cTnI negative vs the reverse differed significantly
( = 43.9, P <0.0003).
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Only 1.1% of the overall population (n = 8) showed cTnT-negative
and cTnI-positive results. Of these, 7 of the 8 patients (88%) had
cTnT results that were within the 95% confidence interval (CI) of the
cTnT assay's 0.1 µg/L cutoff. On the other hand, 66 patients (8.7%
of the overall population) had cTnT-positive and cTnI-negative results;
16 of these patients (24%) had cTnI values within the 95% CI of
the cTnI assay's 1.5 µg/L cutoff ( =
13.3, P = 0.0003).
Among the 8 patients with cTnT-negative and cTnI-positive results, 7 (87.5%) had an infarction or revascularization; none of these patients died during 30-day follow-up. In contrast, 56 (84.9%) of the 66 cTnT-positive and cTnI-negative patients had a clinical event within 30 days: 5 died, 46 had an infarction, and 36 underwent revascularization.
For an outcome of 30-day mortality, the area of the ROC curve for cTnT was larger at 0.68 (95% CI 0.60–0.75) compared with cTnI, which had a ROC area of 0.64 (95% CI 0.56–0.72). Statistical analysis revealed that the ROC area for cTnT was significantly larger than that for cTnI (Z = 2.08; P = 0.0375).
Considering each biochemical marker alone with logistic multiple
regression modeling (Table 4
), cTnT was a slightly better predictor of 30-day mortality, as
shown by the larger and lower
P-value results. After adjusting the model for cTnI
first, cTnT added significantly to the model's ability to predict
30-day mortality (P = 0.014); cTnI did not add
significantly to a model that first incorporated cTnT
(P = 0.23). None of the other outcomes studied showed a
substantial difference between cTnT and cTnI.
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In a model that combined the continuous values of cTnT and cTnI and the
ECG category (Table 5
), cTnT showed a greater ability to predict 30-day mortality
than did the ECG category or cTnI. After adjusting for the other
variables, the ECG category contributed more to the model than either
of the biochemical markers. cTnT retained a significant ability to
predict death by 30 days after adjustment of the model for cTnI and the
ECG category ( = 8.03, P =
0.045). However, after adjustment of the model for cTnT and ECG
category, cTnI did not add significantly to the ability for predicting
30-day mortality ( = 0.84, P =
0.657).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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These results confirm the findings of a recent retrospective analysis
of the Thrombolysis in Myocardial Infarction (TIMI) IIIb database
(5). In this study, a cTnI concentration of 0.4 mg/L was
associated with significantly higher mortality at 42 days than lower
concentrations among patients with unstable angina or non-Q-wave
infarction and was an independent predictor of short-term mortality
after adjustment for age 65 years and the presence of ST-segment
depression. Our results show the ability of the cTnI concentration
to risk-stratify not only the type of patients included in the
TIMI-IIIb study (5) but also those with ST-segment
elevation infarction. Patients with ST-segment elevation who were cTnI
positive in our study had twice the mortality of such patients who were
cTnI negative.
cTnT and cTnI are similar in that both are structural proteins present in stoichiometrically equal quantities in the contractile apparatus of striated muscle (10)(11). Further, although the exact nature of release has not been fully elucidated, both are probably released from the cytosolic pool into circulation after necrosis (12)(13)(29). The proteins differ in the proportion contained in the cytosolic pool, however, representing 6% to 8% of total cTnT (13) but only about 2.5% of total cTnI (12). Other differences include their physiological role in muscle contraction, amino acid composition, molecular weight, time of increase after myocardial necrosis (10)(12)(15), and, more importantly, their time of release after myocardial injury (13)(24)(28). The apparent earlier release of cTnT after any myocardial necrosis and its increase with even minor myocardial damage may explain its superior ability to predict 30-day mortality. Because of its smaller cytosolic compartment, cTnI may not be as sensitive to early minor necrosis.
cTnT and cTnI results were concordant for about 90% of the patients. Although no direct comparisons have been done between cTnT vs cTnI in acute coronary syndrome patients, the rise of cTnT after myocardial injury appears to be earlier than that of CK-MB mass (24), which has been shown to occur either simultaneously with or slightly earlier than cTnI measured by the assay used in this study (12)(16). This sequence of marker increase may be responsible for the significantly larger number of patients who were positive for cTnT but negative for cTnI. This issue is clinically important because the patients who were cTnT positive but cTnI negative were more likely to die within 30 days than patients who were cTnT negative and cTnI positive. The importance of this apparent earlier rise was also evident in the patients who were cTnT negative; these patients had significantly fewer clinical events than those who were cTnI negative at enrollment.
The relatively small number of patients (n = 8, 1.1% of the overall population) who were cTnT negative but cTnI positive was probably due to random analytical variability in the cTnT method used in this study. This is shown by the fact that results of 7 of 8 patients were within the 95% analytic CI for the cTnT assay; thus these cTnT "false-negative" results were not significantly lower than the cTnT cutoff. On the other hand, random analytic variability cannot explain the larger number of patients (n = 66, 8.7% of the overall population) who were cTnT positive and cTnI negative—50 of these 66 patient results (76%) were below the 95% analytic CI for the cTnI method. Thus, as stated above, the apparent earlier rise of cTnT appears to be the reason for the significantly larger number of patients who were cTnT positive but cTnI negative.
The cutoff concentrations used in this study were >0.1 µg/L for cTnT and >1.5 µg/L for cTnI, in accordance with the clinical studies presented in the manufacturers' respective package inserts. The choice of the cutoff value is important when comparing the relative performance and value of tests, because they may differ with the population examined and the purpose of the testing and have sometimes been viewed as arbitrary or biased. For this reason, the areas under the ROC curves for cTnT and cTnI were calculated. The area of the ROC curve is independent of the cutoff value, and the larger the area under the curve (up to a maximum of unity), the better the performance of the test (30). For predicting 30-day mortality, cTnT showed a significantly larger ROC curve area than did cTnI (P = 0.0375).
The logistic multiple regression modeling analyses performed in this
study show this point most clearly. Although a model including cTnT
alone showed only a slightly greater association with 30-day mortality
than cTnI (Table 4
), after adjusting for cTnI in a two-variable model,
cTnT added significantly to the ability for predicting death
(P = 0.014). On the other hand, after adjusting the
model for cTnT, cTnI did not add significantly (P =
0.23) to the model's ability for predicting 30-day mortality. Further,
models that included the ECG category (Table 5
) also showed that cTnT
contributed significant information to a model containing cTnI and the
ECG category (P = 0.045), whereas cTnI did not add
significantly (P = 0.657) to a model containing cTnT
and ECG category.
There are several limitations to this study. One is that the characteristics of either the cTnT or the cTnI immunoassays used in this study may be method dependent, as are those for CK-MB (31). Thus, other immunoassays for either analyte may show different properties depending on whether the cTnT or cTnI is released in the free form or complexed form (32), oxidized or reduced, phosphorylated or not, and other factors that may affect the target epitope, antibody properties, and (or) other assay conditions. Although the GUSTO-IIa population included in this substudy was large, only about 10% (74) of the patients showed discordant cTnT and cTnI results. Also, the population used in this study was a high-risk group of acute cardiac ischemia patients, 71% of whom were eventually diagnosed with MI. Studies to examine these and other cardiac tests in a lower-risk population are under way (28).
Although efforts were made to exclude patients with chronic renal insufficiency (creatinine >221 µmol/L, >25 mg/L) from the GUSTO-IIa trial, 21 such patients were included. There have been reports of spurious cTnT increases in such patients (33)(34), and recent studies have also shown increased cTnI values in this group (35)(36). Our study showed no significant difference between cTnT and cTnI results among patients with renal insufficiency presenting with acute coronary syndromes. Further studies in unselected patients are in progress.
A cTnT concentration measured at presentation appears to provide more information than a cTnI concentration measured at the same time in the prediction of 30-day mortality in patients with acute coronary syndromes. This difference, which may reflect the relatively faster release of cTnT after myocardial injury, shows that cTnT and cTnI, when measured with the assays used in the current study, must be viewed as distinct clinical markers among these patients.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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