How to Interpret Elevated Cardiac Troponin Levels

What Is a High-Sensitivity Troponin Test?

Rapid advances in immunoassay technologies and the international adoption of traceable troponin calibration standards have 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 as low as 0.006 ng/mL with an assay range that spans 4 orders of magnitude (0.006–50 ng/mL). Similarly, the limit of detection of a contemporary cTnT assay (Elecsys TnT-hs, Roche Diagnostics; approved for clinical use in Europe but not yet in the United States) is as low as 0.005 ng/mL.³ Although cTnI and cTnT concentrations correlate to some extent, the numeric values can be quite different in a given patient, with cTnT readings generally being lower. Between 1995 and 2007, the limit of detection fell from 0.5 ng/mL for some cTn assays to 0.006 ng/mL for TnI-Ultra, an ≈100-fold improvement in analytic sensitivity (Figure 1).

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Figure 1.

Evolution of the cardiac troponin (cTn) assays and their diagnostic cutoffs. A hypothetical case of acute coronary syndrome is depicted with the earliest times of potential diagnosis corresponding to the diagnostic cutoffs of more 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 basis of their ability to detect cTns even in healthy individuals. The latest generation of high-sensitivity cTn assays can detect cTn in >95% of a reference population.⁴ The ability to detect cTns in healthy individuals made it imperative to define a clinical decision limit for cTn concentration, ie, a “positive” cTn result.

What Is a Positive Troponin Result? 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 defined by total c.v. [coefficient of variation] <10%) for a reference control group on at least one occasion during the first 24 hours after the clinical event.”⁵ This guideline provides the framework for determining the decision limit or a “positive” troponin result.

Based on the 99th percentile rule, troponin decision limits of several high-sensitivity cTn assays can be set as low as 0.01 ng/mL.⁶ This makes it possible to identify patients with ACS earlier, enabling earlier coronary intervention (Figure 2). However, while improving clinical sensitivity for the diagnosis of myocardial infarction, the increased analytic sensitivity has come at the cost 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 healthy 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 (blue) assay for comparison. In practice, the values below the assay detection threshold (dashed portions of the histogram plots) cannot be distinguished from one another. 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 3 to 4 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. Note the impact 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 only.)

The Specificity of a Troponin Test for ACS

The use 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 applied 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 establish the correct diagnosis. A positive troponin in the setting of a low pretest probability for ACS may be suggestive but clearly is not indicative of a coronary event. 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 appear in the circulation of individuals with a healthy myocardium. These levels used to be considered indicative of myocardial necrosis. However, with high-sensitivity troponin assays, circulating cTnT or cTnI can be found in the plasma as a result of transient ischemic or inflammatory myocardial injury. Thus, elevated cTn may be detected in conditions other than ACS (the Table), including heart failure, cardiomyopathies, myocarditis, renal failure, tachyarrhythmias, and pulmonary embolism, and even after strenuous exercise in healthy individuals.⁸

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, most commonly, acute myocardial infarction.

Serial cTn testing helped establish final diagnoses in our 3 patients. Patient 1 (Figure 3, 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 index 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 3, middle) 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 heart failure. Additional TnI testing did not provide evidence of ACS.

TnI levels in patient 3 (Figure 3, bottom) rose to a peak of 53 ng/mL within 24 hours. He was diagnosed with non–ST-segment–elevation myocardial infarction when the second cTn result of 6.3 ng/mL was obtained after 6 hours. The rapid, steep increase from the initial barely positive value of 0.06 ng/mL to the 6-hour value of 6.3 ng/mL illustrates that more frequent testing during the first several hours may be sufficient to detect a diagnostic rise in cTn levels that is eventually destined to increase by a few orders of magnitude such as the peak of 53 ng/mL in this patient.

Fortunately, simultaneous improvements in contemporary assay sensitivity and precision allow 2 cTn values with a difference as small as a few hundredths of 1 ng/mL to be distinguished reliably. This has significant implications for serial cTn testing.

Previously, clinicians often had to wait an average of 6 hours with the lower-sensitivity, lower-precision cTn assays to see a conclusive increase in plasma cTn levels after the first troponin measurement, but today's high-sensitivity cTn tests that are separated by a mere 2 to 3 hours can be highly informative. Given the urgent need for early diagnosis of ACS and appropriate emergency intervention, as well as the ease of performing this relatively inexpensive assay, clinicians do not need to wait 6 to 8 hours before ordering a second troponin test to rule in ACS. We recommend collecting a second specimen for cTn testing within 2 to 3 hours from the collection of the blood sample at presentation to help confirm the diagnosis of MI.

Disclosures

Dr Jarolim has research grants from Roche Diagnostics, Siemens Healthcare Diagnostics, Ortho Clinical Diagnostics, Beckman Coulter, Inc, and Amgen, as well as honoraria from Ortho Clinical Diagnostics and Roche Diagnostics. Dr Mahajan reports no conflicts.