High-Sensitivity Troponin T Concentrations in Acute Chest Pain Patients Evaluated With Cardiac Computed Tomography
Background— For evaluation of patients with chest pain and suspected acute coronary syndrome (ACS), consensus guidelines recommend use of a cardiac troponin cut point that corresponds to the 99th percentile of a healthy population. Most conventional troponin methods lack sufficient precision at this low level.
Methods and Results— In a cross-sectional study, 377 patients (mean age 53.7 years, 64.2% male) with chest pain and low to intermediate likelihood for ACS were enrolled in the emergency department. Blood was tested with a precommercial high-sensitivity troponin T assay (hsTnT) and compared with a conventional cardiac troponin T method. Patients underwent a 64-slice coronary computed tomography coronary angiogram at the time of phlebotomy, on average 4 hours from initial presentation. Among patients with acute chest pain, 37 (9.8%) had an ACS. Using the 99th percentile cut point for a healthy population (13 pg/mL), hsTnT had 62% sensitivity, 89% specificity, 38% positive predictive value, and 96% negative predictive value for ACS. Compared with the cardiac troponin T method, hsTnT detected 27% more ACS cases (P=.001), and an hsTnT above the 99th percentile strongly predicted ACS (odds ratio 9.0, 95% confidence interval 3.9 to 20.9, P<0.001). Independent of ACS diagnosis, computed tomography angiography demonstrated that concentrations of hsTnT were determined by numerous factors, including the presence and severity of coronary artery disease, left ventricular mass, left ventricular ejection fraction, and regional left ventricular dysfunction.
Conclusions— Among low- to intermediate-risk patients with chest pain, hsTnT provides good sensitivity and specificity for ACS. Elevation of hsTnT identifies patients with myocardial injury and significant structural heart disease, irrespective of the diagnosis of ACS.
Received July 12, 2009; accepted December 17, 2009.
Since the advent of testing for cardiac troponins for the diagnosis of myocardial infarction (MI), the use of these assays has continued to evolve. During the past 2 decades, troponins have been adopted as the preferred biomarker for the diagnosis of acute MI, a position reaffirmed in recent consensus guidelines.1,2 As part of this consensus for the preferred use of troponins for the diagnostic evaluation of the patient with suspected or proven acute coronary syndrome (ACS), the use of a troponin cut point for acute MI that equals the 99th percentile of a healthy population has been endorsed, as long as the assay used delivers acceptable precision at this low threshold, because risk for adverse outcome (including death) has been demonstrated repeatedly in the context of values above this level.3–10 However, most commercial assays for troponin were inadequate to deliver such performance, either because of a limit of detection above that of reference populations or unacceptable imprecision (by consensus, more than 10% variation from test to test) at low concentrations.11
Editorial see p 1172
Clinical Perspective on p 1234
Recently, however, newer assays for troponin have been developed, which, through multiple methodological modifications, are now able to detect changes in concentration of the marker at or below the 99th percentile for a normal population. Although these so-called high-sensitivity troponin assays may now achieve consensus-guideline–recommended precision of <10% imprecision at this low reference limit,1,2 a degree of uncertainty regarding their clinical application exists, particularly with respect to the specificity of these tests for the clinical syndrome of acute MI, because they are able to detect even minor degrees of myocardial injury, even in the absence of ACS. Indeed, despite consensus for their adoption for clinical use, only preliminary data exist supporting the use of high-sensitivity troponin assays in populations of patients with chest pain and suspected ACS.3,4,12,13 Furthermore, the anatomic causes of elevation of high-sensitivity troponin and the clinical ramification of an elevated level of such markers in a patient without an ACS remain undefined. With these issues in mind, among a group of patients presenting with chest discomfort and suspected ACS, we examined the diagnostic performance of a new, preclinical high-sensitivity test for troponin T (hsTnT) using the 99th percentile cut point for this assay and correlated hsTnT results both with clinical syndrome and with cardiac structure and function as demonstrated by 64-slice computed tomography (CT) angiography at the time of blood measurement.
All of the study methods were approved by the local institutional review board.
A description of the patient population in the present study was reported recently.14 In brief, between May 2005 and May 2007, a convenience sample of 377 low- to intermediate-risk subjects presenting to the Massachusetts General Hospital emergency department between the weekday hours of 7 am and 7 pm with a chief complaint of chest discomfort and clinical suspicion for ACS were enrolled; detailed inclusion/exclusion criteria are provided in Table I in the online-only Data Supplement. After enrollment, patients were followed up for 6 months for clinical course, and end points were ascertained. A final diagnosis of ACS (including either acute MI or unstable angina) was made retrospectively based on the judgment of 2 physicians with access to the history and nature of the presenting symptoms, past medical history, results of physical examination, and all of the medical records available from index hospitalization (including the results of standard troponin testing) through 180 days from presentation. Events subsequent to 180 days from enrollment did not influence the final diagnosis. Disagreement in final diagnosis occurred in 4% of cases and was resolved by consensus with a third reviewer.15 For the purposes of the present analysis, patients were categorized as having unstable angina with a cardiac troponin T (cTnT) value of <0.03 ng/mL measured at any time during hospitalization, as per consensus guidelines.2
Cardiac Biomarker Testing
A sample of blood for biomarker testing (hsTnT and cTnT) was taken at the time of CT angiography, at a median of 4.2 hours from initial presentation. Blood was processed immediately and frozen at −80°C until it was assayed by a precommercial hsTnT method (Roche Diagnostics, Penzberg, Germany) on an Elecsys 2010 platform. Given enhanced sensitivity, this assay is reported with units of picograms per milliliter (rather than nanograms per milliliter for conventional troponin T [cTnT]) and is reported to have a coefficient of variation of 8% at 10 pg/mL16; the 99th percentile for a normal reference population is reported to be 13 pg/mL,17 which was the cut point used for the present analysis. For the present analysis, hsTnT had an interrun coefficient of variation of 3.6% and 2.9% at concentrations of 42 and 2820 pg/mL, respectively.
In addition to hsTnT, conventional cTnT (Stat T, Roche Diagnostics) was measured with a fourth-generation immunoassay on an Elecsys 2010 platform. This assay is reported in nanograms per milliliter and has a 99th percentile of 0.01 ng/mL and a recommended diagnostic threshold for acute MI of 0.03 ng/mL. For the present analysis, cTnT had an interrun coefficient of variation of 6.6% and 3.8% at concentrations of 0.07 and 2.2 ng/mL, respectively. Lastly, amino-terminal pro-B–type natriuretic peptide (Roche Diagnostics), and cystatin C (Siemens Diagnostics, Eschborn, Germany) were also measured. All blood was tested on the first freeze/thaw cycle.
Cardiac CT imaging and interpretation were performed with a 64-slice scanner (Sensation 64, Siemens Medical Solutions, Forcheim, Germany) as described previously.14 Interpretation of the CT angiogram included assessment for presence and extent of coronary artery disease (CAD) according to the American Heart Association 17-segment coronary artery model; the number of segments affected by atherosclerotic plaque was noted, and plaque was further coded as calcified or noncalcified. The presence of significant coronary stenosis was defined as a luminal obstruction of >50% of the diameter of the reference coronary segment. In addition, cardiac structure and function were assessed, including measures of chamber volume in end systole and end diastole, left ventricular ejection fraction, left ventricular mass, and regional left ventricular dysfunction.
Baseline demographics of patients with and without ACS were compared with the χ2 test for dichotomous variables and the Student t test or the Wilcoxon rank sum test for continuous variables, as appropriate. For comparisons of concentrations of hsTnT between multiple diagnostic groups (no ACS, unstable angina, and acute MI), the Kruskal-Wallis test was used.
The diagnostic performance of the hsTnT assay was assessed with receiver operator characteristic curves, with area under the curve estimated as a function of the gold standard diagnosis of ACS (which included both unstable angina and acute MI). Curves for hsTnT versus cTnT were compared for significant differences. Net reclassification improvement and integrated discrimination improvement analyses were performed as described by Pencina et al.18 The optimal cut point for hsTnT was identified in the receiver operator characteristic curve with the value that provided maximal sensitivity and specificity. Furthermore, sensitivity and specificity, as well as positive and negative predictive values (all with 95% confidence intervals [CI]), for unstable angina, acute MI, or all ACS with an hsTnT of 13 pg/mL (the 99th percentile cut point) were evaluated and compared with a cTnT of 0.01 ng/mL (the 99th percentile and limit of detection for this method) and 0.03 ng/mL (the lowest cTnT cut point that delivered <10% imprecision). The sensitivity and specificity for ACS from an hsTnT ≥13 pg/mL was compared with that of a cTnT ≥0.03 ng/mL with the McNemar test.
To better understand the association between hsTnT and ACS diagnosis, logistic regression analyses were performed to examine the final gold standard diagnosis as a function of hsTnT tertiles; 2 models were used in this analysis, the first adjusted for age and sex and the second fully adjusted for age, sex, hypertension, hyperlipidemia, diabetes mellitus, and prior CAD. In both models, the first tertile served as the referent, with odds ratios (ORs) and 95% CIs generated for the second and third tertiles. Furthermore, with an hsTnT cutoff of 13 pg/mL, the OR and 95% CI for a final diagnosis of ACS were generated in a similar fashion with models that included age and sex, as well as the fully adjusted model described above.
In an effort to better understand the meaning of hsTnT concentrations (especially with respect to the presence and extent of CAD, as well as ventricular structure and function), continuous variables and log-transformed concentrations of hsTnT were correlated with Spearman analysis; afterward, independent predictors of hsTnT concentrations were identified by multivariable linear regression that included candidate variables with P≤0.10 in univariable analysis. Only those variables with P<0.05 were retained in the final model. In addition, associations between hsTnT above and below the 99th percentile in individuals without ACS were examined. Finally, linear regression analysis was then repeated, constrained to only those patients without ACS and an hsTnT >13 pg/mL.
All of the statistical analyses were performed with SAS software (version 9.2, SAS Institute Inc, Cary, NC). All of the probability values were 2-sided, with a value <0.05 considered significant.
The mean (±SD) age of the study population overall was 53.7±12.0 years; 242 (64.1%) were male. Of the overall study population, 37 (9.8%) were judged to have ACS, of whom 25 had unstable angina according to standard criteria. Baseline characteristics of study subjects as a function of ACS, including CT angiogram results, are detailed in Table 1.
The median hsTnT value for the group as a whole was 5.4 pg/mL (interquartile range [IQR] 2.7 to 9.0] pg/mL). Overall, 62 (16.4%) had an hsTnT ≥13 pg/mL. Median concentrations of hsTnT were significantly higher among those patients judged to have an ACS than among those without (28.0 [IQR 8.6 to 68.7] versus 7.0 [IQR 2.5 to 8.1] pg/mL, P<0.001). When categorized as acute MI, unstable angina, and noncardiac chest pain, median concentrations of hsTnT were highest in patients with acute MI (112.0 [IQR 60.7 to 211.5] pg/mL), intermediate in those with unstable angina (12.3 [IQR 4.9 to 31.9] pg/mL), and lowest in those without ACS (7.0 [IQR 2.7 to 9.0] pg/mL; P<0.001 for trend across groups).
Receiver operator characteristic testing demonstrated an area under the curve for the diagnosis of ACS of 0.79 for hsTnT compared with 0.74 for cTnT (P=0.28). The net reclassification improvement from the addition of hsTnT to cTnT was 0.74 (95% CI 0.49 to 0.99, P<0.001), whereas the integrated discrimination improvement was 0.24 (95% CI 0.14 to 0.33, P<0.001). The probability of correctly identifying ACS when hsTnT was added to cTnT improved from 18.7% to 40.7% (P change for events=22.0%). The probability of nonevents from the addition of hsTnT to cTnT changed from 8.6% to 6.6% (P change for nonevents −2.0%); the relative integrated discrimination improvement overall was 2.37, which translated to a 237% improvement from the addition of hsTnT to cTnT.
Compared with the cTnT cut point of 0.03 ng/mL, an hsTnT ≥13 pg/mL had statistically superior sensitivity (Table 2; P=0.002), detecting nearly 50% more cases of ACS (23 of 37 cases versus 12 of 37 cases); this relates to the identification of patients judged to have unstable angina (by definition, with a conventional cTnT <0.03 ng/mL) with hsTnT. Although hsTnT had excellent specificity for ACS (89%), it was significantly less specific than cTnT (Table 2; P<0.001). The positive predictive value and negative predictive value of an hsTnT of 13 pg/mL were 38% and 96%, respectively. The receiver operator characteristic optimal cut point for hsTnT was 8.62 pg/mL, which delivered 76% sensitivity, 78% specificity, and a 27% positive predictive value for ACS.
When hsTnT tertiles were considered, a graded association with ACS was found; compared with the first tertile (referent), in age- and sex-adjusted models, the second (OR 2.6, 95% CI 1.4 to 4.6, P=.002) and third (OR 5.1, 95% CI 2.2 to 11.9, P<0.001) tertiles had higher likelihood for ACS. A similar pattern was observed in fully adjusted models (tertile 2: OR 2.4, 95% CI 1.3 to 4.3, P=.005; tertile 3: OR 4.7, 95% CI 2.0 to 11.2, P<0.001). When hsTnT was considered as a function of the 99th percentile cut point of 13 pg/mL and a final diagnosis of ACS was used as the dependent variable, a similar independent association with ACS was noted in both models (age and sex adjusted: OR 9.3, 95% CI 4.2 to 20.5, P<0.001; fully adjusted: OR 9.0, 95% CI 3.9 to 20.9, P<0.001).
Correlations and Predictors of hsTnT in Patients With Chest Pain
Table 3 details predictors of log-transformed hsTnT in all subjects. In multivariable analyses, independent predictors of hsTnT included age, presence/extent of CAD, cardiac structure, cardiac function, and amino-terminal pro-B-type natriuretic peptide values.
Subjects With Elevated hsTnT but Without ACS
When only those patients with an hsTnT above 13 pg/mL were considered (n=61), 38 (62%) did not have an ACS. Compared with those patients without ACS and with negative hsTnT, patients with an elevated value were more likely to have more complex medical histories (including prior CAD) and more cardiac abnormalities, with more prevalent and extensive CAD, as well as larger cardiac chambers and greater left ventricular mass (Table 4). In patients without ACS, stepwise selection of significant variables identified age (β-coefficient=0.0399; P<0.001), left ventricular mass (β-coefficient=0.0117; P<0.001), and amino-terminal pro-B–type natriuretic peptide (β-coefficient=0.00110; P=.03) as predictors of hsTnT values.
The decision to adopt the 99th percentile of troponin from a normal population for the evaluation of patients with suspected ACS was based primarily on the enhanced risk stratification associated with such lower cut points.3–10 Furthermore, use of the 99th percentile for troponin appears to be associated with more robust prediction of benefit from early invasive strategies for ACS management than higher cut points.8,10 Complicating the situation is the fact that until recently, troponin methods were unable to deliver the requisite analytic performance at the 99th percentile,11 an extremely low cut point in a range that is in the range of analytic “noise” for most conventional assays. Furthermore, these assays are well recognized as being able to detect myocardial injury in the absence of a clinical ACS, such as in heart failure.16 Indeed, the diagnostic ramification of a troponin result above the 99th percentile (reflective of significant myocardial injury) in those without a clinically manifest ACS requires further definition.
We have shown that hsTnT was able to more sensitively detect ACS than a corresponding conventional cTnT method in a population of low- to intermediate-risk patients with chest discomfort, and the hsTnT assay delivered excellent specificity as well. Furthermore, because each patient underwent concomitant cardiac CT (including angiography of the coronary arteries), we were able to show that myocardial injury (reflected by concentrations of hsTnT), independent of the presence or absence of ACS, was associated with the presence and severity of a wide range of cardiac abnormalities, including more prevalent CAD and greater left ventricular mass. Importantly, such associations were present in patients without ACS, which illustrates the importance of considering hsTnT values not only as a marker of ACS presence but also as a marker of underlying structural heart disease.
Recent data have been published that demonstrate the augmented sensitivity of high-sensitivity troponin (hsTn) methods for acute MI (and ACS overall).3,4,12,13 In each of these analyses, an hsTn method consistently demonstrated augmented sensitivity compared with conventional assays for these analytes, much as we found in the present analysis, in which nearly 50% more cases of ACS were diagnosed at the time of sampling. These results are consistent with data suggesting that use of the 99th troponin percentile provides earlier recognition of myocardial injury,19–23 with a significant percentage of patients reclassified from unstable angina to acute MI. Although superior to cTnT for diagnosis, hsTnT was not universally elevated in those judged to have ACS, which suggests that even with enhanced sensitivity, many patients with unstable angina or transient myocardial ischemia may still have troponin results below the 99th percentile for a normal population.17
As a counterobservation to increased sensitivity, we did see a 10% reduction in specificity for ACS compared with conventional cTnT, reminiscent of other reports.3,4,12,13 This is not surprising because the gold standard for acute MI diagnosis used in all of the studies was a conventional cTnT method, which partly explains the superior specificity of conventional assays; however, the specificity for ACS of 89% observed with hsTnT is excellent and is expected to be accompanied by enhanced risk stratification, as suggested by other studies that examined the advantages conferred by use of the 99th percentile for cTnT interpretation.3–10
More to this point, looking beyond the specificity or positive predictive value of hsTnT for “acute MI” (and in comparisons with other studies of its kind), a strength of the present study is the mechanistic association between hsTnT and prevalent cardiovascular disease as detected by universal CT angiography in our study subjects. This finding was present not only in subjects with an ACS but also in those without. The present data suggest that an elevated “high-sensitivity” troponin result reflects myocardial injury, irrespective of an ACS, and thus reflects a true signal for structural heart disease, even in the absence of an acute cardiac event. This mechanistically explains its proven ability to prognosticate adverse outcomes across the wide spectrum of patients evaluated with these assays, from apparently well subjects24 to those with chronic CAD,6 ACS,9,10 and heart failure.16
It remains unclear whether myocardial ischemia in the absence of necrosis can be detected with hsTnT or high-sensitivity troponin I. Although a small amount of cardiac troponin is found in the cytosol of myocytes and theoretically could be released without frank myocyte death, such a phenomenon remains unproven. In this setting, however, it is probable that hsTn methods will be superior to conventional troponin methods for detection of such a process. Indeed, in a model of exercise stress testing, high-sensitivity troponin I elevation was detected in parallel with the presence and severity of ischemia.25 Whether this is proof of concept that ischemia without necrosis may lead to elevated hsTn is speculative, without histological evidence to corroborate it.
The present results indicate that clinicians should recognize that elevation of either hsTnT or high-sensitivity troponin I likely identifies a patient with significant heart disease who is at higher risk for an adverse outcome, irrespective of the presence or absence of ACS. Given the ability of these assays to detect myocardial injury above and beyond any other method available, more than ever, we emphasize the crucial need to consider each patient as a function not only of their troponin value but also with respect to their clinical presentation, to avoid overdiagnosis of “acute MI” with these highly sensitive assays. Indeed, hsTn methods should be considered highly accurate tests for myocardial injury, rather than a test for “acute MI,” and only in the correct context should a positive result for these assays be interpreted as consistent with ACS. The growing use of hsTn methods will require a rethinking of the present guidelines for ACS management, as well as of the exact way to manage the patient with an unexpectedly elevated hsTn value. Ultimately, the correct interpretation of hsTn methods should be based on Bayesian considerations, integrating pretest likelihood with posttest results, and with the recognition that higher hsTn values are more likely to reflect higher-risk myocardial injury states, such as acute MI.
The present study has limitations worthy of comment. First, the cohort studied was small, yet the demographics and overall rate of ACS were comparable to real-world analyses of patients presenting to the emergency department with chest discomfort.26 In addition, given the low- to intermediate-risk nature of the present study population, a low 6-month event rate subsequent to presentation was observed, which limits our ability to examine the prognostic value of hsTnT versus cTnT. With respect to comparative performance of hsTnT relative to cTnT, similar data have been published recently by Reichlin and colleagues13 describing a cohort of 786 subjects with a much higher rate of ACS (33% overall); despite the overall higher risk of the study subjects in this latter analysis, the performance of hsTnT for ACS diagnosis in the present study was similar. Moreover, although smaller than the Reichlin study (or a similar analysis of high-sensitivity troponin I by Keller and colleagues12), the present study is set apart by the morphological correlation of hsTnT results with cardiac structure and function using cardiac CT. This aspect of the present study adds a depth of understanding to the results of hsTnT above and beyond clinical analyses of ACS etiology. Indeed, a mechanistic understanding of the predictors of hsTn release is crucially important. Another issue is the timing of the blood draw: The blood samples assayed for hsTnT and cTnT were drawn contemporaneously with the CT scan, yet they were obtained some 4 hours after presentation. Whether an earlier sample for hsTnT would have been less sensitive for diagnosis is possible, particularly if performed within the first hour of ischemia. Additionally, we only had 1 measurement of hsTnT; serial measures would have provided more data regarding the performance of hsTnT versus cTnT and would have allowed for a better assessment of the ramifications of an elevated hsTnT in the absence of ACS. Indeed, serial measurement of hsTnT or high-sensitivity troponin I has been advocated3,5,20 to detect a change in troponin concentration (rising or falling), which would more likely represent an ischemic syndrome. Lastly, our subjects were at low to intermediate risk and thus the present results may not necessarily apply to medically complex or unstable patients. Nonetheless, the present data are applicable to a large population of patients26 in whom troponin assays are particularly important, given their lack of significant ECG changes or clinical instability.
The authors thank Kevin F. Kennedy, MS, for providing assistance with calculation of net reclassification improvement and integrated discrimination improvement, as well as Gerlinde Trischler for excellent technical assistance. Reagents for troponin assays were provided by Roche Diagnostics.
Sources of Funding
This study was sponsored in part by the National Institutes of Health (RO1 HL080053). Dr Januzzi is supported in part by the Balson Scholar Fund. Dr Truong is supported by National Institutes of Health grants T32HL076136 and L30HL093896. Dr Mohammed is supported by the Dennis and Marilyn Barry Cardiology Fellowship, and Mr Schlett is supported in part by grants from the German Federal Ministry of Education and Research, as well as the Foundation of German Business.
Dr Januzzi reports having received research grant support from Roche Diagnostics, Siemens, and Critical Diagnostics and assay/reagent support from Siemens. Dr Nagurney has received research grant support from Biosite. Dr Hoffmann has received grant support for the ROMICAT 1 and 2 trials from the National Institutes of Health and research grant support from GE Healthcare and Siemens Medical Systems. The remaining authors report no conflicts.
Thygesen K, Alpert JS, White HD, Jaffe AS, Apple FS, Galvani M, Katus HA, Newby LK, Ravkilde J, Chaitman B, Clemmensen PM, Dellborg M, Hod H, Porela P, Underwood R, Bax JJ, Beller GA, Bonow R, Van der Wall EE, Bassand JP, Wijns W, Ferguson TB, Steg PG, Uretsky BF, Williams DO, Armstrong PW, Antman EM, Fox KA, Hamm CW, Ohman EM, Simoons ML, Poole-Wilson PA, Gurfinkel EP, Lopez-Sendon JL, Pais P, Mendis S, Zhu JR, Wallentin LC, Fernandez-Aviles F, Fox KM, Parkhomenko AN, Priori SG, Tendera M, Voipio-Pulkki LM, Vahanian A, Camm AJ, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Widimsky P, Zamorano JL, Morais J, Brener S, Harrington R, Morrow D, Lim M, Martinez-Rios MA, Steinhubl S, Levine GN, Gibler WB, Goff D, Tubaro M, Dudek D, Al-Attar N. Universal definition of myocardial infarction. Circulation. 2007; 116: 2634–2653.
Apple FS, Pearce LA, Smith SW, Kaczmarek JM, Murakami MM. Role of monitoring changes in sensitive cardiac troponin I assay results for early diagnosis of myocardial infarction and prediction of risk of adverse events. Clin Chem. 2009; 55: 930–937.
Apple FS, Smith SW, Pearce LA, Ler R, Murakami MM. Use of the Centaur TnI-Ultra assay for detection of myocardial infarction and adverse events in patients presenting with symptoms suggestive of acute coronary syndrome. Clin Chem. 2008; 54: 723–728.
Eggers KM, Jaffe AS, Lind L, Venge P, Lindahl B. Value of cardiac troponin I cutoff concentrations below the 99th percentile for clinical decision-making. Clin Chem. 2009; 55: 85–92.
Eggers KM, Lagerqvist B, Venge P, Wallentin L, Lindahl B. Persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary syndrome predicts long-term mortality. Circulation. 2007; 116: 1907–1914.
Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub WS, Braunwald E. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA. 2001; 286: 2405–2412.
Venge P, James S, Jansson L, Lindahl B. Clinical performance of two highly sensitive cardiac troponin I assays. Clin Chem. 2009; 55: 109–116.
Panteghini M, Pagani F, Yeo KT, Apple FS, Christenson RH, Dati F, Mair J, Ravkilde J, Wu AH. Evaluation of imprecision for cardiac troponin assays at low-range concentrations. Clin Chem. 2004; 50: 327–332.
Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, Bickel C, Baldus S, Warnholtz A, Frohlich M, Sinning CR, Eleftheriadis MS, Wild PS, Schnabel RB, Lubos E, Jachmann N, Genth-Zotz S, Post F, Nicaud V, Tiret L, Lackner KJ, Munzel TF, Blankenberg S. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med. 2009; 361: 868–877.
Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, Biedert S, Schaub N, Buerge C, Potocki M, Noveanu M, Breidthardt T, Twerenbold R, Winkler K, Bingisser R, Mueller C. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009; 361: 858–867.
Hoffmann U, Bamberg F, Chae CU, Nichols JH, Rogers IS, Seneviratne SK, Truong QA, Cury RC, Abbara S, Shapiro MD, Moloo J, Butler J, Ferencik M, Lee H, Jang IK, Parry BA, Brown DF, Udelson JE, Achenbach S, Brady TJ, Nagurney JT. Coronary computed tomography angiography for early triage of patients with acute chest pain: the ROMICAT (Rule Out Myocardial Infarction using Computer Assisted Tomography) trial. J Am Coll Cardiol. 2009; 53: 1642–1650.
Latini R, Masson S, Anand IS, Missov E, Carlson M, Vago T, Angelici L, Barlera S, Parrinello G, Maggioni AP, Tognoni G, Cohn JN. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation. 2007; 116: 1242–1249.
Kurz K, Giannitsis E, Zehelein J, Katus HA. Highly sensitive cardiac troponin T values remain constant after brief exercise- or pharmacologic-induced reversible myocardial ischemia. Clin Chem. 2008; 54: 1234–1238.
Kavsak PA, MacRae AR, Newman AM, Lustig V, Palomaki GE, Ko DT, Tu JV, Jaffe AS. Effects of contemporary troponin assay sensitivity on the utility of the early markers myoglobin and CKMB isoforms in evaluating patients with possible acute myocardial infarction. Clin Chim Acta. 2007; 380: 213–216.
Kavsak PA, MacRae AR, Yerna MJ, Jaffe AS. Analytic and clinical utility of a next-generation, highly sensitive cardiac troponin I assay for early detection of myocardial injury. Clin Chem. 2009; 55: 573–577.
Kavsak PA, Newman AM, Ko DT, Palomaki GE, Lustig V, MacRae AR, Jaffe AS. Is a pattern of increasing biomarker concentrations important for long-term risk stratification in acute coronary syndrome patients presenting early after the onset of symptoms? Clin Chem. 2008; 54: 747–751.
Macrae AR, Kavsak PA, Lustig V, Bhargava R, Vandersluis R, Palomaki GE, Yerna MJ, Jaffe AS. Assessing the requirement for the 6-hour interval between specimens in the American Heart Association Classification of Myocardial Infarction in Epidemiology and Clinical Research Studies. Clin Chem. 2006; 52: 812–818.
Melanson SE, Morrow DA, Jarolim P. Earlier detection of myocardial injury in a preliminary evaluation using a new troponin I assay with improved sensitivity. Am J Clin Pathol. 2007; 128: 282–286.
Sundstrom J, Ingelsson E, Berglund L, Zethelius B, Lind L, Venge P, Arnlov J. Cardiac troponin-I and risk of heart failure: a community-based cohort study. Eur Heart J. 2009; 30: 773–781.
Sabatine MS, Morrow DA, de Lemos JA, Jarolim P, Braunwald E. Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart J. 2009; 30: 162–169.
Given the fact that in the context of an acute coronary syndrome, very-low-level cardiac troponin release is associated with an increase in the risk for adverse outcomes, current consensus guidelines define acute myocardial infarction by cardiac troponin values in excess of the 99th percentile of a healthy population, assuming the assay used is sufficiently precise at this low threshold value. Most conventional cardiac troponin assays are not able to deliver this performance; however, newly developed “high-sensitivity” troponin assays are able to detect extremely low levels of cardiac troponin, with acceptable precision at low concentrations, meeting specifications from consensus guidelines. Among 377 low- to intermediate-risk patients with chest pain and suspected acute coronary syndrome, we compared the results of a high-sensitivity troponin T method with those of a conventional cardiac troponin T assay. We found the high-sensitivity troponin T method increased sensitivity for acute coronary syndrome compared with cardiac troponin T; furthermore, because every patient had a cardiac computerized tomography angiogram, we demonstrated that high-sensitivity troponin T concentrations correlated strongly with abnormalities in cardiac structure and function, independent of a diagnosis of acute coronary syndrome.
↵*Drs Hoffmann and Koenig contributed equally to this report.
Guest Editor for this article was Sanjay Kaul, MD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.893826/DC1.