Cardiac markers are used for the diagnosis and risk stratification of patients with chest pain and suspected acute coronary syndrome (ACS) and for management and prognosis in patients with acute heart failure, pulmonary embolism, and other disease states. Cardiac markers can be classified into those that signify myocardial necrosis (creatine kinase-MB [CK-MB] fraction, myoglobin and cardiac troponins), those that indicate myocardial ischemia (ischemia modified albumin), those that suggest myocardial stress (natriuretic peptides), and those markers of inflammation and prognosis (C-reactive protein [CRP], soluble CD40 ligand [sCD40L], and homocysteine).
The cardiac troponins, in particular, have become the cardiac markers of choice for patients with ACS, eclipsing CK-MB and myoglobin in terms of clinical value. Indeed, cardiac troponin is central to the definition of acute myocardial infarction (MI) in the consensus guidelines from the European Society of Cardiology (ESC) and the American College of Cardiology (ACC): These guidelines recommend that cardiac biomarkers should be measured at presentation in patients with suspected MI, and that the only biomarker that is recommended to be used for the diagnosis of acute MI at this time is cardiac troponin due to its superior sensitivity and accuracy.
For example, patients with elevated troponin levels but negative CK-MB values who were formerly diagnosed with unstable angina or minor myocardial injury are now reclassified as non–ST-segment elevation MI (NSTEMI), even in the absence of diagnostic electrocardiographic (ECG) changes.
Similarly, only one elevated troponin level above the established cutoff is required to establish the diagnosis of acute MI, according to the ACC guidelines for NSTEMI.
These changes were instituted following the introduction of increasingly sensitive and precise troponin assays. Up to 80% of patients with acute MI will have an elevated troponin level within 2-3 hours of emergency department (ED) arrival, versus 6-9 hours or more with CK-MB and other cardiac markers.
Accordingly, most have advocated relying solely on troponin and discontinuing the use of CK-MB and other markers. Nevertheless, CK-MB and other markers continue to be used in some hospitals to rule out MI and to monitor for additional cardiac muscle injury over time.
Note that cardiac markers are not necessary for the diagnosis of patients who present with ischemic chest pain and diagnostic ECGs with ST-segment elevation. These patients may be candidates for thrombolytic therapy or primary angioplasty. Treatment should not be delayed to wait for cardiac marker results, especially because the sensitivity is low in the first 6 hours after symptom onset. ACC/American Heart Association (AHA) guidelines recommend immediate reperfusion therapy for qualifying patients with ST-segment elevation MI (STEMI), without waiting for cardiac marker results.
The troponins are regulatory proteins found in skeletal and cardiac muscle. Three subunits have been identified: troponin I (TnI), troponin T (TnT), and troponin C (TnC). The genes that encode for the skeletal and cardiac isoforms of TnC are identical; thus, no structural difference exists between them. However, the skeletal and cardiac subforms for TnI and troponin TnT are distinct, and immunoassays have been designed to differentiate between them.
Two different reference ranges are used in troponin assays. The upper percentile reference limit gives the upper limit of what can be expected in a normal, healthy, adult population, whereas the coefficient of variation (CV) is the percentage variation in assay results that can be expected when the same sample is repeatedly analyzed.
Recognizing that cardiac troponin measurements may be elevated in disease states not primarily related to myocardial ischemia, a fourth universal definition of acute MI was developed by the American College of Cardiology (ACC), European Society of Cardiology (ESC), American Hospital Association (AHA), and World Health Federation (WHF) in 2018.
First, myocardial injury is defined as elevated cardiac troponin values with at least one value above the 99th percentile upper reference limit. Myocardial injury is considered acute if there is a rise and/or fall of cardiac troponin values. The term "myocardial infarction" is to be used when there is acute myocardial injury with clinical evidence of acute myocardial ischemia and with detection of a rise and/or fall of cardiac troponin values within at least one value above the 99th percentile upper reference limit and at least one of the following features:
The definition was updated to manage the fact that nonischemic myocardial injury, as occurs in association with heart failure, arrhythmia, myocarditis, renal failure, pulmonary embolism, and percutaneous or surgical coronary procedures, also result in elevated cardiac markers as cardiac troponins become the standard.
The sensitivity, specificity, and precision of the different commercially available troponin assays vary considerably. These differences are related to a lack of standardization, the use of different monoclonal antibodies, the presence of modified TnI and TnT in the serum, and variations in antibody cross-reactivity to the myriad detectable forms of TnI that result from its degradation.
At present, the 99th upper reference limit of cardiac troponin is still the best-established criterion for the diagnosis of acute MI. Only one manufacturer produces the TnT assay, and its 99th percentile cutoffs and the 10% CV are well established. However, up to 20-fold variation has occurred in results obtained with the multitude of commercial TnI assays currently available, each with their own 99th percentile upper reference limits and 10% CV levels.
In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) IV study, a relatively insensitive point-of-care TnI assay was used to screen patients for study eligibility. In a subsequent study, the blood samples were reanalyzed using the 99th percentile cutoff of a far more sensitive central laboratory TnT assay. The more sensitive 99th percentile cutoff of this TnT assay identified an additional 96 (28%) of 337 patients with a positive TnT result but negative point-of-care TnI; these patients had higher rates of death or MI at 30 days.
In a similar reanalysis of the TACTICS-TIMI 18 trial, three different TnI cutoffs were compared on 1821 patients to evaluate the 30-day risk of death or MI: the 99th percentile, 10% CV, and the World Health Organization (WHO) acute MI cutoffs. (The WHO cutoffs define acute MI using creatine kinase-MB [CK-MB] and report troponin levels as either a higher “acute MI level” or a lower “intermediate level” that is correlated with “leak” or “minor myocardial injury.”)
Using the 10% CV cutoff identified, an additional 12% more cases were identified relative to the WHO acute MI cutoff. The 99th percentile cutoff identified an additional 10% of cases relative to the 10% CV cutoff, as well as a 22% increase in the number of cases over the WHO acute MI cutoff. Nevertheless, the odds ratios for the adverse cardiac event rates of death or MI at 30 days were similar for all three cutoffs, suggesting that the lower cutoffs detected more patients with cardiovascular risk without sacrificing specificity.
The American Association for Clinical Chemistry Academy (AACC) (formerly the National Academy of Clinical Biochemistry [NACB]) working with the ACC/ESC guidelines has recommended adoption of the 99th percentile upper reference limit as the recommended cutoff for a positive troponin result. Ideally, the precision of the assay at this cutoff level should be measured by a CV that is less than 10%.
However, most TnI assays are imprecise at the 99th percentile reference limit. Some have therefore recommended that the cutoff level be raised to the slightly higher 10% CV level instead of the 99th percentile reference limit to ensure adequate assay precision.
In addition, studies have shown that populations within the 99th percentile reference limit include patients with low troponin levels who nevertheless have an elevated cardiac risk, and that the true 99th percentile cutoff for a healthy patient population is actually a factor of 10-50 lower. Accordingly, these investigations suggest that higher sensitivity or ultrasensitive troponin assays are necessary. A high-sensitivity cardiac troponin (hs-cTn) can quantify lower cardiac troponin concentrations by up to 10 fold lower than conventional assays while also detecting measurable cardiac troponin values in over 50% of healthy subjects. These tests are very precise in that their CV is below 10% at the 99th percentile upper reference limit. Therefore, the advantage of ultrasensitive troponins is based on the premise that lower cutoff levels achieve higher sensitivity that will allow earlier diagnosis, often within 90 minutes of presentation. High-sensitivity troponins confer additional clinical benefits in that they help detect myocardial injury due to acute ischemia earlier, sometimes before a larger infarct occurs.
Additionally, the introduction of hs-cTn assays into practice necessitates serial measurements to differentiate a number of previously mentioned disease states that cause myocardial injury.
Of note, the 99th percentile upper reference limit has been shown to differ between men and women when measured with high-sensitivity assays.
To optimize use of the assay in the emergency department (ED), it is important to be familiar with the particular troponin assay available in the individual laboratory and to know whether the cutoff is set at the 10% CV level or at the 99th percentile upper reference limit.
The AACC recommendations specify that cardiac markers be available in hospitals on an immediate basis 24 hours per day, 7 days per week, with a turnaround time of 1 hour or less. Point-of-care (POC) devices that provide rapid results should be considered in hospitals whose laboratories cannot meet these guidelines.
POC assays for CK-MB, myoglobin, and the cardiac troponins TnI and TnT are available. Only qualitative TnT assays are available as POC tests, but both quantitative and qualitative POC TnI assays are currently marketed.
In a multicenter trial, the time to positivity was significantly faster for the POC device than for the local laboratory (2.5 h vs 3.4 h).
In another multicenter study, which evaluated the i-STAT POC TnI assay in comparison with the central laboratory in 2000 patients with suspected acute coronary syndrome (ACS), POC testing reduced the length of stay by approximately 25 minutes for patients who were discharged from the ED. POC high-sensitivity assays are available as well. The increasing sensitivity of POC assays coupled with the benefit of rapid turnaround time make them attractive clinical tools in the ED.
In addition to its use in the diagnosis of MI, an elevated troponin level can identify patients at high risk for major adverse cardiac events (MACE). Specifically, data from a meta-analysis indicated that an elevated troponin level in patients without ST-segment elevation is associated with a nearly four-fold increase in the cardiac mortality rate. In patients without ST-segment elevation who were being considered for thrombolytic therapy, initial TnI levels on admission correlated with mortality at 6 weeks, but CK-MB levels were not predictive of adverse cardiac events and had no prognostic value.
Other studies revealed that an elevated troponin level at baseline was an independent predictor of mortality, even in patients with chest pain and acute MI with ST-segment elevation.
