Biochemical Markers for Diagnosis of Myocardial Infarction—Cardiac Troponin

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Accurate and timely biochemical marker testing for aiding the diagnosis of myocardial infarction (MI) has been important for the appropriate disposition and treatment of patients for the past several decades. Creatine kinase (CK) muscle and brain (CK-MB) mass and myoglobin measurements were the standard up to the mid-1990s, when assays for the cardiac-specific isoforms of troponin I and troponin T—hereafter referred to collectively as cardiac troponins (cTn)—became available. The data for cTn were so compelling that in 2000 a global task force comprising representatives from the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) was convened to redefine the diagnosis of MI based on cTn measurements.1 Recently, the National Academy of Clinical Biochemistry (NACB) has published updated guidelines for clinical utilization of biochemical markers in the context of acute coronary syndrome (ACS) and MI diagnosis.2,3 Also, this NACB committee developed guidelines for logistics, measurement specifications, and point-of-care testing of these biochemical markers.4 The recommendations and strength of scientific data supporting each NACB guideline statement were rated using scoring criteria adopted from the American Heart Association (AHA)/American College of Cardiology (ACC), which are summarized in Table 1. For each recommendation, the designations I, IIa, IIb, and III describe the indications, and the upper-case letters A to C describe the weight of evidence.5

Who Should Be Tested with Biochemical Markers?

It is well known that the clinical signs and symptoms of patients presenting with suspected ACS are frequently vague and non-specific, and mimic a number of other conditions. For this reason, measurement of biomarkers should be obtained in all patients presenting with ACS symptoms, as indicated in Recommendation 1 in Table 2. Although quantitative measurement of biochemical markers is important for objectifying the diagnostic process of the MI work-up, Recommendation 2 in Table 2 is a reminder that the patient’s clinical presentation (history, physical examination) and electrocardiogram (ECG) must be used in conjunction with biomarkers in the diagnostic evaluation of suspected MI.

Which Biochemical Markers and When?

In brief, cTn is the cornerstone of biochemical marker testing for evaluation of MI in the suspected ACS patient. The data for cTn have been so convincing that it has emerged as the preferred biomarker for use in the diagnosis of MI (see Table 2, Recommendation 3). Given the high prevalence and increased risk profile of MI, cTn should be available in virtually every urgent care venue. However, if for some reason cTn testing is not available, CK-MB by mass assay is an acceptable alternative (see Table 2). cTn is a structural protein and several hours are usually required for its release into the blood after myocardial necrosis. It is therefore not an early biomarker of myocardial damage. For this reason the recommended sampling strategy includes collection at hospital presentation followed by serial sampling, with timing based on the clinical circumstances. Ideally, the temporal sampling sequence would begin at the time of the acute onset. However, patients and bystanders are frequently unable to provide an accurate account of precisely when the suspected cardiac event occurred. For this reason, in routine clinical practice blood collections should be referenced relative to the time of presentation and, if available, the reported time of symptom onset should be noted as well (see Recommendation 4, Table 2). Serial sampling up to six to nine hours after presentation is necessary to evaluate the MI diagnosis with high clinical sensitivity and specificity (see Recommendation 5, Table 2). However, testing should continue for up to 12–24 hours if earlier samples are negative and the clinical index of suspicion remains intermediate or high.2 Given the relatively late release profile for cTn, an early marker of necrosis such as myoglobin may be useful in addition to a cTn for patients who present within the first hours after symptom onset. Also, a rapid ‘rule-in’ protocol with frequent early sampling of markers of myocardial necrosis may be appropriate if tied to therapeutic strategies. Note that Recommendations 6 and 7 in Table 2 are both considered Class IIb, because their usefulness/efficacy is less well established by evidence/opinion.

What Is the Cardiac Troponin Decision Point (Cut-off) to Use?

There has been no shortage of controversy and confusion regarding what cut-off should be used for indicating the diagnosis of MI. Outcomes show that even a small release of cTn confers a high risk profile in the setting for ACS. This evidence justifies a low cTn cut-off.2 It is of interest that both clinicians and the laboratory prefer quantitative rather than qualitative results (see Recommendation 8, Table 2). The ESC/ACC global task force was the first to designate a low cTn decision point, specified as the 99th percentile of a reference control population.1 The NACB guidelines are confluent with the notion of a low cut-off. They state that, in the context of ACS, a maximal concentration of cTn exceeding the 99th percentile for a reference control group on at least one occasion during the first 24 hours after the clinical event is indicative of myocardial necrosis consistent with MI. In the event that CK-MB must be utilized, the guidelines state that the maximal concentration must exceed the 99th percentile of values for a sex-specific reference control group on two successive samples (see Recommendation 9, Table 2).

What Is the ‘Need for Speed’?

The consensus among cardiology and emergency medicine (EM) physicians is that cardiac markers should be available within one hour of specimen collection, and optimally within 30 minutes or less (see Recommendation 10, Table 2). To meet this stringent requirement, several measures are necessary. First, the specimen for analysis should be either anticoagulated whole blood, so that centrifugation and handling is not necessary, or plasma, to avoid a delay due to the clotting process (see Recommendation 11, Table 3). Second, institutions that cannot consistently deliver cardiac marker turnaround times of approximately one hour should implement point-of-care testing devices (see Recommendation 12, Table 2). Although it should go without saying, the guidelines remind us that members of EM, cardiology, primary care, hospital administrations, and laboratory medicine should work to develop an accelerated protocol for the use of biochemical markers in the evaluation of patients with possible ACS (see Table 2).

Summary and Path Forward

cTn measurements are an essential part of the MI evaluation and should be measured in all patients with signs and symptoms of ACS. Sampling is necessary at presentation and at six to nine hours, and in some cases again at 12–24 hours. The troponin cut-off that should be used is the 99th percentile of a reference control population. cTn results should be available within one hour after specimen collection, and optimally in 30 minutes or less. Use of anticoagulated whole blood or plasma facilitates shorter turnaround times, and point-of-care testing is an attractive alternative when turnaround times are suboptimal.


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