Why Do They Test for Troponin Again After 3 Hours
Cardiac troponin (cTn) testing is an essential component of the diagnostic workup and management of acute coronary syndromes (ACS). Although over the by 15 years the diagnostic performance of the previous gold-standard assay, creatine kinase-MB, has not changed appreciably, the ever-increasing sensitivity of cTn assays has had a dramatic affect on the utilize of cTn testing to diagnose ACS.1 Here, we present iii recent clinical cases from the emergency department with astute breast discomfort that exemplify the challenges introduced by loftier-sensitivity cTn assays: a 48-year-old man who presented to the emergency department with chest discomfort lasting two hours and a 3-mean solar day history of flu-like symptoms whose ECG showed lengthened ST-segment changes, a 60-year-old adult female with a medical history of heart failure who presented to the emergency section with chest pain lasting i.five hours whose ECG was nondiagnostic, and a 54-year-old man with a medical history of diabetes mellitus who presented with breast discomfort lasting i hour whose ECG was normal.
Cardiac troponin I (cTnI) testing (TnI-Ultra assay on the ADVIA Centaur XP immunoanalyzer, both Siemens Healthcare Diagnostics) was ordered on all 3 patients. The laboratory results were reported equally positive in all three cases, with the reported values beingness 0.05, 0.06, and 0.06 ng/mL, respectively, all just higher up the diagnostic limit of 0.04 ng/mL.
Assays for cTn, namely cTnI and cardiac troponin T (cTnT), are the preferred diagnostic tests for ACS, in detail non–ST-segment–height myocardial infarction, because of the tissue-specific expression of cTnI and cTnT in the myocardium. The results of cTn testing often guide the decision for coronary intervention. However, although the increasing sensitivity of cTn assays lowers the number of potentially missed ACS diagnoses, it presents a diagnostic challenge because the gains in diagnostic sensitivity have inevitably come with a decrease in specificity. For instance, the replacement of the cTn analysis (Siemens Healthcare Diagnostics) past the more sensitive TnI-UItra assay in the Brigham and Women'due south Hospital Clinical Laboratories in early 2007 resulted in a doubling of positive cTn results in samples nerveless in the emergency department2 fifty-fifty though at that place was no alter in the frequency of final diagnoses of ACS.
What Is a High-Sensitivity Troponin Test?
Rapid advances in immunoassay technologies and the international adoption of traceable troponin calibration standards accept allowed manufacturers to develop and calibrate troponin assays with unprecedented analytic sensitivity and precision. Thus, a contemporary cTnI assay such as TnI-Ultra detects plasma cTn levels equally low equally 0.006 ng/mL with an assay range that spans iv orders of magnitude (0.006–fifty ng/mL). Similarly, the limit of detection of a contemporary cTnT analysis (Elecsys TnT-hs, Roche Diagnostics; approved for clinical use in Europe but non yet in the U.s.a.) is as low as 0.005 ng/mL.three Although cTnI and cTnT concentrations correlate to some extent, the numeric values can exist quite different in a given patient, with cTnT readings generally being lower. Between 1995 and 2007, the limit of detection cruel from 0.5 ng/mL for some cTn assays to 0.006 ng/mL for TnI-Ultra, an ≈100-fold comeback in analytic sensitivity (Figure one).
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Figure one. Evolution of the cardiac troponin (cTn) assays and their diagnostic cutoffs. A hypothetical example of astute coronary syndrome is depicted with the earliest times of potential diagnosis corresponding to the diagnostic cutoffs of more than sensitive cTn assays. The years correspond to the availability of the respective assays in the Us market.
Remarkably, the use of contemporary high-sensitivity cTn assays makes it possible to detect low levels of cTn even in plasma from healthy subjects. Indeed, high-sensitivity cTn assays are designated as such on the ground of their ability to find cTns fifty-fifty in healthy individuals. The latest generation of high-sensitivity cTn assays can notice cTn in >95% of a reference population.4 The power to detect cTns in healthy individuals fabricated information technology imperative to define a clinical decision limit for cTn concentration, ie, a "positive" cTn result.
What Is a Positive Troponin Issue? The 99th Percentile Rule
The National Academy of Clinical Biochemistry issued a guideline in 2007 that stated that "in the presence of a clinical history suggestive of ACS, the following is considered indicative of myocardial necrosis consistent with myocardial infarction: maximal concentration of cTn exceeding the 99th percentile of values (with optimal precision divers by full c.five. [coefficient of variation] <10%) for a reference control grouping on at least 1 occasion during the first 24 hours after the clinical outcome."v This guideline provides the framework for determining the determination limit or a "positive" troponin result.
Based on the 99th percentile dominion, troponin decision limits of several loftier-sensitivity cTn assays tin can be set equally low every bit 0.01 ng/mL.6 This makes it possible to identify patients with ACS before, enabling earlier coronary intervention (Figure 2). Nonetheless, while improving clinical sensitivity for the diagnosis of myocardial infarction, the increased analytic sensitivity has come at the toll of reduced specificity, thus presenting an additional diagnostic challenge for clinicians.
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Figure 2. Cardiac troponin I (cTnI) levels in a healthy reference population and in an acute coronary syndrome (ACS) population. Top, Frequency histograms of real TnI levels (blue filled) in good for you reference controls are shown, along with the distribution of the same TnI levels as measured with a less precise cTnI (green) and the more precise TnI-Ultra (bluish) assay for comparison. In practice, the values below the assay detection threshold (dashed portions of the histogram plots) cannot be distinguished from one some other. Note how the 99th percentile decision limits decrease with increased assay precision. Bottom, Hypothetical frequency histograms of cTnI concentrations in individuals with ACS <2, 2 to 3, or iii to four hours after the onset of symptoms. The decision limits (dashed vertical lines) for the contemporary high-sensitivity cTnI assays are based on the 99th percentile in a healthy reference population. Annotation the bear on of decreased diagnostic cutoffs of the newer cTnI assays on the fraction of acute myocardial infarctions diagnosed at earlier time intervals. (All frequency histograms in this figure are hypothetical and for illustrative purposes but.)
The Specificity of a Troponin Test for ACS
The employ of the 99th percentile cutoff for cTn positivity does not imply that 1% of the population suffers from myocardial damage. Rather, this cutoff is useful only when practical to patients with a high pretest probability of ACS. The clinician must interpret cTn results in the context of clinical history, ECG findings, and possibly cardiac imaging to found the right diagnosis. A positive troponin in the setting of a depression pretest probability for ACS may be suggestive but clearly is not indicative of a coronary effect. Unfortunately, the pressure to avoid malpractice litigation forces many clinicians to order comprehensive panels of laboratory tests, including cTn, for patients with a very low pretest probability of ACS, which adversely affects the positive predictive value of cTn assays for diagnosing myocardial infarction.
Traditional wisdom, before the advent of high-sensitivity cTn assays, held that troponins do not announced in the circulation of individuals with a healthy myocardium. These levels used to be considered indicative of myocardial necrosis. Notwithstanding, with high-sensitivity troponin assays, circulating cTnT or cTnI can be establish in the plasma as a result of transient ischemic or inflammatory myocardial injury. Thus, elevated cTn may be detected in weather other than ACS (the Table), including heart failure, cardiomyopathies, myocarditis, renal failure, tachyarrhythmias, and pulmonary embolism, and even after strenuous do in salubrious individuals.8
| Cardiac Causes | Noncardiac Causes |
|---|---|
| Cardiac contusion resulting from trauma | Pulmonary embolism |
| Cardiac surgery | Severe pulmonary hypertension |
| Cardioversion | Renal failure |
| Endomyocardial biopsy | Stroke, subarachnoid hemorrhage |
| Astute and chronic center failure | Infiltrative diseases, eg, amyloidosis |
| Aortic autopsy | Cardiotoxic drugs |
| Aortic valve affliction | Disquisitional illness |
| Hypertrophic cardiomyopathy | Sepsis |
| Tachyarrhythmia | Extensive burns |
| Bradyarrhythmia, heart block | Extreme exertion |
| Apical ballooning syndrome | |
| Post–percutaneous coronary intervention | |
| Rhabdomyolysis with myocyte necrosis | |
| Myocarditis or endocarditis/pericarditis |
The Need for Serial Troponin Testing
In addition to the absolute level of cTn in plasma or serum above the decision limit, a critical component of the diagnosis of ACS is cTn kinetics. This was reiterated in the current universal definition of myocardial infarction adopted in 2007.5 Although absolute cTn elevations are seen in multiple chronic cardiac and noncardiac conditions, a rise or fall in serial cTn levels strongly supports an acutely evolving cardiac injury such as, about normally, acute myocardial infarction.
Series cTn testing helped establish final diagnoses in our iii patients. Patient i (Effigy iii, top) had a steady but relatively slow increase in cTnI with a peak value of 0.9 ng/mL. The findings of acute dilated cardiomyopathy and global ventricular dysfunction on echocardiography were consistent with a diagnosis of acute myocarditis.
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Figure 3. Troponin kinetics in the index cases. Plasma cardiac troponin I (cTnI) values in the 3 alphabetize cases. The cutoff for the TnI assay (0.04 ng/mL) is indicated with a dashed horizontal line. See the text for detailed description.
Patient 2 (Figure iii, center) had modest cTn elevations fluctuating just above the decision limit in the 0.05 to 0.09 ng/mL range. She was diagnosed with acutely decompensated middle failure. Additional TnI testing did not provide evidence of ACS.
TnI levels in patient iii (Figure 3, lesser) rose to a acme of 53 ng/mL within 24 hours. He was diagnosed with non–ST-segment–pinnacle myocardial infarction when the 2nd cTn result of 6.iii ng/mL was obtained later 6 hours. The rapid, steep increase from the initial barely positive value of 0.06 ng/mL to the half-dozen-hr value of half-dozen.3 ng/mL illustrates that more than frequent testing during the kickoff several hours may be sufficient to detect a diagnostic rise in cTn levels that is eventually destined to increment by a few orders of magnitude such every bit the tiptop of 53 ng/mL in this patient.
Fortunately, simultaneous improvements in contemporary assay sensitivity and precision allow two cTn values with a divergence every bit pocket-size equally a few hundredths of ane ng/mL to be distinguished reliably. This has significant implications for serial cTn testing.
Previously, clinicians often had to wait an boilerplate of 6 hours with the lower-sensitivity, lower-precision cTn assays to run across a conclusive increase in plasma cTn levels after the starting time troponin measurement, but today'due south high-sensitivity cTn tests that are separated by a mere two to 3 hours tin be highly informative. Given the urgent need for early diagnosis of ACS and appropriate emergency intervention, equally well as the ease of performing this relatively cheap assay, clinicians do non need to await vi to viii hours before ordering a second troponin test to rule in ACS. We recommend collecting a 2d specimen for cTn testing inside ii to 3 hours from the collection of the blood sample at presentation to help ostend the diagnosis of MI.
Conclusions
Commenting on the always-increasing sensitivity and decreasing specificity of cTn assays, Robert Jesse quipped, "When troponin was a lousy assay it was a great examination, only at present that it'southward becoming a smashing analysis, it'due south getting to be a lousy exam."9 Even so, frequent monitoring of cTn kinetics, forth with careful attention to the noncoronary causes of cTn elevations, will keep the high-sensitivity cTn assays in the class where they rightfully belong—among the greatest, most useful assays in clinical chemistry laboratories.
Disclosures
Dr Jarolim has research grants from Roche Diagnostics, Siemens Healthcare Diagnostics, Ortho Clinical Diagnostics, Beckman Coulter, Inc, and Amgen, as well every bit honoraria from Ortho Clinical Diagnostics and Roche Diagnostics. Dr Mahajan reports no conflicts.
Footnotes
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Source: https://www.ahajournals.org/doi/10.1161/circulationaha.111.023697
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