Tools
Cardiac Biomarkers
Introduction
Cardiac biomarkers are endogenous substances released into the bloodstream when the heart muscle is damaged or stressed.[1] Measurement of these biomarkers is used to help diagnose, assess risk, and manage acute coronary syndrome (ACS), a potentially life-threatening condition characterized by the sudden onset of persistent pain in the chest, one or both arms, shoulders, stomach, or jaw, shortness of breath, nausea, sweating and dizziness.[2]
Cardiac enzymes have been in use since the mid-20th century in evaluating patients with suspected acute myocardial infarction (MI). The biomarkers used back then are not clinically relevant today as more sensitive and specific biomarkers have replaced them.[3] Troponins are the key cardiac biomarkers in modern medicine for diagnosing acute myocardial ischemia.[4] In contrast to creatine kinase (CK), which usually elevates 6 to 12 hours after arriving at the emergency department, troponins show elevation in most AMI cases within 2 to 3 hours of arrival.[5]
Specimen Requirements and Procedure
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Specimen Requirements and Procedure
Serum and heparinized plasma are commonly used sample types for most commercially available troponin assays, while some point-of-care (POC) methods utilize whole blood.[6] Yet, several studies highlight notable variances in cardiac troponin I (cTnI) measurements between serum and plasma. Specifically, plasma results have been reported to be roughly up to 30% lower compared to serum measurements.[7] Extra care is essential when preparing specimens for testing from patients on anticoagulant therapy. These samples can take longer to clot, potentially leading to lower levels in plasma. The lower levels in plasma could lead to a failure to detect an early or small AMI.[8]
The preferred specimen for myoglobin is a non-hemolyzed, non-lipemic serum.[9] One study found no significant difference between heparinized plasma and serum, although results from EDTA plasma samples were significantly lower than serum samples. Another study found that different anticoagulants can substantially interfere with myoglobin assays.[10]
Specimens for CK analysis include serum and plasma heparin. Anticoagulants, other than heparin, should not be used in collection tubes because they inhibit CK activity.[11] Specimen collection using gel separator tubes doesn't impact CK activity compared to using tubes without gel.[12] CK activity in serum is relatively unstable and rapidly lost during storage.[13] Average stabilities are less than 8 hours at room temperature, 48 hours at 4 °C, and 1 month at −20 °C.[12] Therefore, the serum specimen should be stored at −80 °C if the analysis is delayed for more than 30 days. Fresh hemolysis-free serum is the specimen of choice to analyze the CK isoenzyme pattern.[11]
Serum or plasma may be used to measure aspartate aminotransferase (AST). Heparin, oxalate, EDTA, and citrate do not cause enzyme inhibition. Anticoagulants with ammonium as the cation should be avoided to reduce the possibility of error. Because of the high activity of AST in red blood cells, hemolyzed samples are unacceptable.[14]
Serum is the preferred specimen for measuring lactate dehydrogenase (LDH) activity. Plasma samples may be contaminated with platelets, which contain high concentrations of LDH. The serum should be separated from the clot as soon as possible after the specimen has been obtained. Hemolyzed serum must not be used because erythrocytes contain 4000 times more LDH activity than serum.[15] The different isoenzymes vary in their sensitivity to cold, with LDH4 and LDH5 being especially labile. The activity of LDH4 and LDH5 is lost if the samples are stored at −20 °C. Thus, serum specimens should be stored at room temperature, at which no activity loss occurs for at least 3 days.[16]
Diagnostic Tests
AST was the first biomarker used to diagnose AMI. In 1954, Ladue et al proposed that AST released from cardiomyocytes undergoing necrosis would be useful in diagnosing AMI.[17] AST increases in the blood 3 to 4 hours after an AMI, peaks at 15 to 28 hours, and returns to baseline within 5 days. In current clinical practice, AST has fallen out of favor for diagnosing acute MI because it is not a specific marker for cardiac myocytes.[18] Elevated AST levels in the blood are associated with hepatic disease (eg, hepatitis, hepatic congestion), pericarditis, pulmonary embolism, and shock; therefore, AST levels are no longer used in an AMI diagnosis.[19]
After discovering that AST was released from ischemic cardiac myocytes, LDH emerged as another potential biomarker for detecting myocardial ischemia. LDH increases in the blood 6 to 12 hours after an AMI, peaks within 24 to 72 hours, and normalizes within 8 to 14 days. In the past, a ratio of LDH1 (an isoform found in the heart) to LDH2 greater than 1 was considered specific for an AMI.[20] Since it is not a specific marker for cardiac myocytes, and its levels can also increase in many other conditions, LDH is no longer used in a myocardial infarction diagnosis. LDH is used solely to differentiate acute from subacute myocardial infarction in patients with elevated troponin levels and normal CK and creatine kinase MB (CK-MB) levels.[21] Blood LDH levels are still valuable for detecting erythrocyte hemolysis and evaluating the management and prognosis of certain tumors, such as testicular germ cell tumors.[22]
Myoglobin is a heme protein found in cardiac and skeletal muscle tissue. Due to its low molecular weight, myoglobin can be detected in the blood 1 hour after myocardial injury, peaks within 4 to 12 hours, and immediately returns to baseline levels.[23] As a result, myoglobin has some diagnostic value alongside CK-MB for faster detection of AMI. Although troponins have largely replaced myoglobin in detecting AMI, myoglobin is still valuable in evaluating skeletal muscle injury due to rhabdomyolysis.[24]
Heart-type fatty acid-binding protein (H-FABP) is involved in fatty acid metabolism in cardiac myocytes. In a study by Kabekkodu et al, the sensitivity of H-FABP in detecting AMI in patients who present within 4 hours of symptom onset was 60%, which was significantly higher than that of troponin (18.8%) and CK-MB (12.5%). The sensitivity of H-FABP in detecting AMI between 4 to 12 hours after symptom onset was 86.96%, comparable to troponin (90.9%) and higher than CK-MB (77.3%).[25] However, it is also important to note that the specificity of H-FABP in detecting AMI was less than that of troponin and CK-MB.[26] Despite its high sensitivity in detecting myocardial ischemia, H-FABP is not clinically used in the United States and has yet to undergo rigorous testing against high-sensitivity troponin (hs-TnT) assays. Thus, H-FABP is unsuitable as a stand-alone test for diagnosing AMI but may have some value as an adjunctive test in specific patient populations.[27]
CK-MB still holds some diagnostic value in cardiac and noncardiac conditions. CK-MB is detected in the serum 4 hours after myocardial injury, peaks by 24 hours, and normalizes within 48 to 72 hours.[28] CK-MB is a useful biomarker for detecting AMI as it has a relative specificity for cardiac tissue but can still become elevated in noncardiac conditions, such as skeletal muscle injury, hypothyroidism, chronic renal failure, and severe exercise.[29] The ratio of CK-MB2 to CK-MB1 ≥ 1.5 and a CK-MB relative index (CK-MB/total CK x 100) ≥ 2.5 improve cardiac tissue specificity and indicate acute MI.[30] As CK-MB levels typically normalize within 48 to 72 hours after myocardial ischemia (in contrast to troponins, which can persist for days), monitoring CK-MB can be beneficial in identifying if levels rise again after initially declining.[28]
A cardiac troponin test is the first-line test for evaluating patients with suspected AMI. Troponin is a protein found in cardiac and skeletal muscles that plays a role in muscle contraction. Troponin comprises 3 subunits—troponin C, troponin I, and troponin T. Troponin I and troponin T in the heart are structurally different than those found in skeletal muscle, making them specific and sensitive biomarkers of cardiac myocyte injury. As a result, the European Society of Cardiology and American College of Cardiology guidelines released in September 2000, defined AMI as an elevation in serum troponin greater than the level expected from the 99 percentile of a healthy reference population supported by signs and symptoms of cardiac ischemia.[31] This was also corroborated by the 2007 World Task Force definition of myocardial infarction, which stated that AMI is accurately determined based on at least 1 troponin value over the 99th percentile of the upper reference limit in tandem with signs and symptoms of cardiac ischemia, electrocardiogram changes, and/or imaging findings suggestive of wall motion abnormalities or the loss of viable myocardium.[32]
Troponin T and troponin I levels in the blood rise as early as 4 hours from the AMI symptom onset, peak in 24 to 48 hours, and remain elevated for multiple days, thereby making them useful for detecting initial ischemic events but not reliable for detecting reinfarction.[33] The hs-TnT assay was developed to detect troponin at much lower concentrations than conventional troponin tests can detect, allowing for more rapid diagnosis in patients admitted to the hospital with suspected AMI. In a Japanese multicenter study, hs-TnT was found to have superior diagnostic value, compared to other cardiac biomarkers, in diagnosing AMI within the first 3 hours of admission in patients with negative initial troponin T levels. Researchers also noted that the hs-TnT test had 100% sensitivity and negative predictive value in diagnosing AMI, but the specificity was limited.[34]
Testing Procedures
Several assays for troponin are commercially available. Various quantitative and semiquantitative POC methods have also been developed. Current assays for cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are 2- or 3-site immunoassays.[35] In these assays, known as capture assays, a specific immobilized antibody binds to the troponin present in the serum or plasma sample. Following this capture, the troponin is then exposed to a second antibody and, in certain assays, a third antibody linked to an indicator molecule. The assays vary by the types of antibody used, the epitopes to which they bind, and the type of indicator molecule used.[36]
The determination of serum myoglobin for diagnosing AMI and other muscle disorders is performed almost exclusively by immunoassay techniques because of their high analytical sensitivity, specificity, precision, and rapid turnaround time.[37] Radioimmunoassay (RIA) procedures have also been described for quantitative measurement of serum myoglobin. However, in clinical laboratories, RIA has largely been replaced by automated 2-site non-isotopic immunoassays.[38] Qualitative and quantitative methods for serum myoglobin have also been developed for POC use.[39]
Most routine methods today use the Karmen coupled enzymatic method for detecting AST and may be traceable to the current International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method.[14] The American Association for Clinical Chemistry proposed a method for the small clinical chemistry laboratory that differs from the IFCC in that (1) a single reagent is used to avoid a 2-step addition procedure, (2) the reaction is read after 150 seconds for the following 180 seconds, and (3) pyridoxal phosphate is not added.[40]
The lactate-to-pyruvate (L→P) reaction is commonly utilized in LDH determination procedures due to its purported reduced reliance on NAD+ concentrations and lactate levels, minimizing the likelihood of NAD+ contamination with inhibitory byproducts.[41] Electrophoretic separation on agarose gels or cellulose acetate membranes is the procedure most commonly used to demonstrate LDH isoenzymes.[42]
Interfering Factors
The cardiac troponin test is the standard, first-line blood test used to diagnose AMI. However, cardiac troponins may be elevated in cases unrelated to cardiac ischemia.[43] Elevated levels of cardiac troponins can occur due to open-heart surgery, post-percutaneous coronary intervention, acute pulmonary embolism, end-stage renal disease, pericarditis, myocarditis, Stanford A aortic dissection, acute or chronic heart failure, strenuous exercise, cardiotoxic chemotherapy, radiofrequency catheter ablation of arrhythmias, cardioversion of atrial fibrillation or atrial flutter, defibrillation for ventricular fibrillation or tachycardia, amyloidosis, cardiac contusion from blunt chest wall trauma, sepsis, and rhabdomyolysis.[44]
A study has shown that aortic valve disease, apical balloon syndrome, bradyarrhythmia, endomyocardial biopsy, hypertrophic cardiomyopathy, tachyarrhythmias, and noncardiac causes such as acute pulmonary edema, chronic obstructive pulmonary disease, pulmonary hypertension, stroke, and subarachnoid hemorrhage can also cause elevated cardiac troponins in the blood.[30] These conditions may increase cardiac troponin concentration in the blood due to a mismatch between cardiac oxygen supply and demand even in the absence of coronary artery disease.[44]
The use of collection tubes with separator gels has been reported to both increase and decrease myoglobin results.[45] A moderate degree of hemolysis (up to 0.32 g/dL of hemoglobin) does not significantly influence the measured CK activity because erythrocytes contain no CK activity. However, severely hemolyzed specimens are unsatisfactory because enzymes and intermediates (AK, ATP, and glucose-6-phosphate) liberated from the erythrocytes may affect the lag phase and the side reactions occurring in the assay system. Turbid and icteric samples can be analyzed; appropriate values are obtained if the starting absorbance is not too high.[46]
Results, Reporting, and Critical Findings
Current recommendations recommend that troponin testing be available in all hospitals 24/7 with a turnaround time of 30 to 60 minutes.[47] In addition to its application as a diagnostic marker for myocardial infarction, elevated levels of troponin also have prognostic significance; high levels suggest an elevated risk for adverse cardiac events. Further, data show that increasing levels of troponin and creatinine are strong predictors of worsening congestive heart failure.[48]
Clinical Significance
Cardiac troponins are specific and sensitive biomarkers of cardiac ischemia and are the preferred biomarkers in evaluating patients suspected to have AMI.[49] There are sensitive and highly sensitive assays to detect cardiac troponin levels in the blood. A highly sensitive troponin assay was approved in the USA in 2017. Although CK-MB has a high sensitivity for cardiac myocytes, testing for CK-MB should not be used as a first-line diagnostic measure if cardiac troponin assays are available.[50] In the absence of cardiac troponin assays, CK-MB can be useful in evaluating AMI, but it is far less sensitive and specific than cardiac troponins. Since cardiac troponin levels remain elevated in the blood for multiple days after an AMI, they are not useful in evaluating for reinfarction of cardiac myocytes (another myocardial infarction). CK-MB levels normalize 48 to 72 hours after an AMI, so a rising level in the blood after normalization can confirm that another myocardial infarction has occurred.[51]
in cases where patients present with acute chest pain resembling angina and display ST-segment elevation on an ECG, immediate consideration for primary coronary intervention or thrombolytic therapy is crucial. Clinicians need to recognize that cardiac markers might not exhibit high sensitivity during the early hours after an infarct. Delaying treatment while waiting for these markers may not be beneficial in such critical situations.[52]
Quality Control and Lab Safety
Quality control (QC) of the analytical examination process monitors a measurement procedure to verify that it meets performance specifications appropriate for patient care or that an error condition exists that must be corrected.[53] For non-waived tests, laboratory regulations require, at the minimum, analysis of at least 2 levels of quality control materials once every 24 hours. If necessary, laboratories can assay QC samples more frequently to ensure accurate results. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance.[54] To minimize QC when performing tests for which manufacturers’ recommendations are less than those required by the regulatory agency (such as once per month), the labs can develop an individualized quality control plan (IQCP) that involves performing a risk assessment of potential sources of error in all phases of testing and putting in place a QC plan to reduce the likelihood of errors.[55]
The design of a QC plan must consider the analytical performance capability of a measurement procedure and the risk of harm to a patient that might occur if an erroneous laboratory test result is used for a clinical care decision. An erroneous laboratory test result is a hazardous condition that may or may not cause harm to a patient, depending on what action or inaction a clinical care provider takes based on the erroneous result.[56]
The acceptable range and rules for interpreting QC results are based on the probability of detecting a significant analytical error condition with an acceptably low false alert rate.[55] The desired process control performance characteristics must be established for each measurement before selecting the appropriate QC rules.[57] Westgard multi-rules are usually used to evaluate the quality control runs. If a run is declared out of control, investigate the system (eg, instrument, standards, controls) to determine the cause of the problem. Do not perform any analysis until the problem has been resolved.[58]
Changing reagent lots can have an unexpected impact on QC results. Careful reagent lot crossover evaluation of QC target values is necessary. Because the matrix-related interaction between a QC material and a reagent can change with a different reagent lot, QC results may not be a reliable indicator of a measurement procedure’s performance for patient samples after a reagent lot change.[59] It is necessary to use clinical patient samples to verify the consistency of results between old and new lots of reagents because of the unpredictability of a matrix-related bias being present for QC materials.[60]
The laboratory must participate in the external quality control or proficiency testing (PT) program because it is a regulatory requirement published by the Centers for Medicare and Medicaid Services (CMS) in the Clinical Laboratory Improvement Amendments (CLIA) regulations.[61] It is helpful to ensure the accuracy and reliability of the laboratory concerning other laboratories performing the same or comparable assays. Required participation and scored results are monitored by CMS and voluntary accreditation organizations. The PT plan should be included as an aspect of the quality assessment (QA) plan and the overall quality program of the laboratory.[62]
Consider all specimens, control materials, and calibrator materials as potentially infectious. Exercise the usual precautions required for handling all laboratory reagents. Disposal of all waste material should be in accordance with local guidelines. Wear gloves, a lab coat, and safety glasses when handling human blood specimens. Place all plastic tips, sample cups, and gloves that come into contact with blood in a biohazard waste container.[63] Discard all disposable glassware into sharps waste containers. Protect all work surfaces with disposable absorbent bench top paper, discarded into biohazard waste containers weekly or whenever blood contamination occurs. Wipe all work surfaces weekly.[64]
Enhancing Healthcare Team Outcomes
The correct diagnosis of AMI requires an interprofessional team of healthcare professionals that may include laboratory technologists, nurses, advanced care practitioners, and physicians. Measuring the blood levels of cardiac troponins is one of the first steps in reaching a diagnosis. Swift diagnosis of AMI is crucial, as less time from symptom onset to reperfusion therapy is vital for improved long-term outcomes of heart function.[65] The path to diagnosing AMI starts with the physician ordering a cardiac troponin blood test, the nurses drawing blood and sending it to the appropriate laboratory, and the laboratory technologists accurately measuring blood levels of cardiac troponins and posting the result on the electronic medical records.
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