Bedside Cardiac Markers Identify Patients at High Risk for Mortality

With the new guidelines for the management of patients with unstable angina and non-ST-elevation MI published by the American College of Cardiology and the European Society of Cardiology last summer, there is no doubt that the troponins have become the markers of choice for the diagnosis of myocardial necrosis. The simple fact is that there is a normal level of CK-MB in the circulating blood of healthy individuals, but troponins are proof of a problem, largely accounting for the troponins' popularity. The enzyme CK-MB is found not only in cardiac muscle but in skeletal muscle and the brain as well. This is an undesirable characteristic for the detection of minor myocardial injury. Minor myocardial damage resulting from platelet emboli showered downstream by an ulcerated coronary artery plaque goes unnoticed by current CK-MB assays. The presence of troponin, however, identifies these patients with ongoing myocardial damage who are at high risk for a coronary occlusion. Although skeletal and cardiac muscles both have a tropomyocin complex, the troponin I and troponin T found in the heart complex are coded by genomes different from their skeletal muscle counterparts. There is no antigenic cross-reactivity between the skeletal muscle and the cardiac muscle troponins using the currently available immunoassays. Troponin C, however, is the same in both muscle groups, and is not of value in differentiating myocardial from skeletal muscle injury. The bottom line is that if any troponin I or T is detected in an ED chest pain patient, there is a problem. You simply don't send these patients home. High Mortality Risk Because the presence of troponin I or troponin T identifies unstable angina patients at high risk for mortality and who could probably benefit from GP IIb/IIIa inhibitor therapy in the ED, one needs to become familiar with the different cardiac marker assays. There are several troponin assays on the market, which are used in hospital central laboratories. These are quantitative mass immunoassays and their results are reported in mcg/L concentrations. Quantitative troponin lab results are by no means a gold standard for the evaluation of a chest pain patient. This is because the number you get depends on the assay used. Different brands of assays don't necessarily give the same number. In myocardial necrosis, troponins are released as a large troponin I-troponin T-troponin C complex. What you find in the serum of a patient undergoing myocardial injury are large complexes, smaller complexes, free troponin, or small peptide fragments of any of the above. How can anyone put an accurate mass measurement on this? The fact is that when you run the same serum sample on several of the different quantitative troponin assays out there, you get up to a 50-fold difference in reported concentrations per ml. There also exists an alarming number of positive reports on one quantitative assay with a negative report on another when using the same reference sample. Most of these lab assays are rife with false positives. This is because of the presence of heterophile antigens, fibrin strands, Rheumatoid factor, or other substances within the sample. This problem is compounded by the fact that each different immunoassay uses a different antibody to target a different epitope on the troponin molecule. If the targeted epitope is hidden by complexation, is changed by ongoing chemical processes within the sample, or is cleaved from the molecule by enzymatic degradation, it could be missed altogether. The clinical chemistry journals are full of this information. Because troponins should not be present in the blood of healthy individuals, there is again a bottom line. Any reliable qualitative detection of troponin I or troponin T is of extreme clinical significance, especially when the quantitative laboratory assays have so many problems. Quantitative assays are far from the last word. There are references in the cardiology literature, which give a cutoff for differentiating between unstable angina and non-ST elevation MI based on blood concentrations of troponin. This assumption is only valid for one particular assay. There is, however, an ongoing effort to attempt to standardize all these different tests. It is valuable to realize that once a sample is drawn from a patient, there is a rapid degradation of the troponins in serum through phosphorylation of amino acids, oxidation of sulfhydryl groups, as well as proteolytic cleavage of the peptides themselves. This process is slower in plasma, but it still could create a problem. A sample sitting in the lab for an extended time before being analyzed is subject to all of this. A rapid turnaround time is essential, especially when the new ACC/AHA guidelines (officially endorsed by the American College of Emergency Physicians) state: “When a central laboratory is used, results should be available within 60 minutes, preferably within 30 minutes.” The guidelines also state: “Point-of-care systems, if implemented at the bedside, have the advantage of reducing delays due to transportation and processing in a central laboratory, and can eliminate delays due to the lack of availability of central laboratory assays at all hours.” When using troponin to evaluate a patient, the simple presence of cardiac troponin at detectable levels is significant. If this is done by a qualitative bedside device, free from false positives, it is as good as if not superior to central laboratory tests. Just because the lab provides a number doesn't guarantee it to be accurate. Bedside cardiac marker determinations are available that run on a few drops of the patients' blood at the point-of-care. These are small plastic devices that look much like a home pregnancy test. Myoglobin, CK-MB, and Troponin I antibodies are present on the same test strip, and will give a positive result if these markers are present in concentrations above a predetermined cutoff. These tests are simple to run, accurate, and can give immediate information, if the test is positive. For a negative, you need to wait a timed 15 minutes to make sure that none of the capture antibody lines on the test strip becomes visible. Myoglobin as Marker Myoglobin is the most sensitive marker for myocardial injury. It is released into the blood as early as two hours post-injury and drops below detectable levels in about 12 hours. A negative test is useful four to eight hours after the onset of symptoms to rule out myocardial necrosis. Unfortunately, many conditions can give a positive myoglobin test. CK-MB has been a reliable marker in the past for myocardial infarction, but requires a significant elevation to make a diagnosis. It is slower in release than myoglobin, and requires about six hours to reach significant levels after myocardial injury. Troponin I and T are powerful tools for risk stratification, as stated in the current ACC/AHA guidelines. Cardiac troponins have greater specificity and sensitivity than CK-MB and can be detected in the blood for up to two weeks post-MI. Using the known timing of the rise and fall of these markers, one is able to differentiate between new injury, old injury, and re-injury. Not only are bedside cardiac marker determinations fast and accurate, they are easy to use as well. I have found them especially useful in evaluating elderly patients with non-specific complaints of dyspnea or nausea who have a normally abnormal EKG. These devices also are useful in evaluating cocaine users who have had chest pain in the preceding few hours. Only time will tell if the use of these devices will cut down that scary four percent of missed myocardial infarctions being sent home from this country's EDs. Current recommendations for the immediate management of patients presenting to an emergency department with suspected acute coronary syndrome include a history, physical examination, a 12-lead EKG, and an initial cardiac marker determination. This is done to assign patients to one of four categories: a non-cardiac diagnosis, chronic stable angina, possible acute coronary syndrome, and definite acute coronary syndrome. Having the initial cardiac marker determination at the bedside greatly reduces the time in the emergency department. Although bedside markers are useful tools in the evaluation of patients with suspected acute coronary syndrome, there is still no substitute for clinical judgment. A test is used along with clinical judgment and experience to make a diagnosis. The physician makes the diagnosis, not the lab test.