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. Troponins are the most widely recognized and important cardiac enzymes used in the diagnosis of acute myocardial ischemia in modern medicine. The majority of patients with an acute MI will have elevation in troponins within 2 to 3 hours of arrival at the emergency department, versus 6 to 12 hours with creatine kinase.
The first biomarker used to aid in the diagnosis of acute MI was aspartate aminotransferase (AST). In 1954, Ladue et al. proposed that AST released from cardiomyocytes undergoing necrosis would be useful in diagnosing acute MI. AST increases in the blood 3 to 4 hours after an acute MI, 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. AST levels in the blood elevate in hepatic disease (e.g., hepatitis, hepatic congestion), pericarditis, pulmonary embolism, and shock and as a result, is not used in the diagnosis of acute MI anymore.
After discovering that AST was released from ischemic cardiac myocytes, lactate dehydrogenase (LDH) emerged as another potential biomarker for detecting myocardial ischemia. LDH increases in the blood 6 to 12 hours after an acute MI, 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 to be specific for an acute MI. 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 the diagnosis of myocardial infarction. Nowadays, the only usage for LDH in the evaluation of acute MI is to differentiate acute from subacute MI in patients with elevated troponin levels and normal creatine kinase (CK) and CK-MB levels. Blood LDH levels are still valuable for detecting erythrocyte hemolysis and for evaluating the management and prognosis of certain tumors such as testicular germ cell tumors.
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 then immediately return to baseline levels. As a result, it had some diagnostic value alongside CK-MB for faster detection of acute MI. Although troponins have largely replaced myoglobin in the detection of acute MI, myoglobin is still valuable in the evaluation of skeletal muscle injury due to rhabdomyolysis.
Heart-type fatty acid-binding protein (H-FABP) is a protein involved in fatty acid metabolism in cardiac myocytes. In a study by Kabekkodu et al., the sensitivity of H-FABP in detecting acute MI in patients who present within 4 hours of the onset of symptoms was 60%, which was significantly higher than that of troponin (18.8%) and CK-MB (12.5%). The sensitivity of H-FABP in detecting acute MI between 4 to 12 hours after symptom onset was 86.96%, which was comparable to troponin (90.9%) and higher than CK-MB (77.3%). However, it is also important to note that the specificity of H-FABP in detecting acute MI was less than that of troponin and CK-MB. 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 assays. (hs-TnT). Thus, H-FABP is not suitable as a stand-alone test for diagnosing acute MI but may have some value as an adjunctive test in specific patient populations.
CK-MB still holds some diagnostic value in cardiac and non-cardiac conditions. CK-MB is detected in the serum 4 hours after myocardial injury, peaks by 24 hours, and normalizes within 48 to 72 hours. CK-MB is a useful biomarker for detecting acute MI as it has a relative specificity for cardiac tissue but can still become elevated in non-cardiac conditions such as skeletal muscle injury, hypothyroidism, chronic renal failure, and severe exercise. The ratio of CK-MB2 to CK-MB1 greater than or equal to 1.5 and a CK-MB relative index (CK-MB/total CK x 100) greater than or equal to 2.5 improve specificity for cardiac tissue and are indicative of acute MI. Since CK-MB normalizes 48 to 72 hours after myocardial ischemia (vs. troponins, which can persist for days), it can be useful in detecting re-infarction if levels rise again after declining.
Cardiac troponin is currently the first-line test for evaluating patients with suspected acute MI. Troponin is a protein found in both cardiac and skeletal muscles that play a role in muscle contraction. It is comprised up of three subunits, troponin C, troponin I and troponin T. Troponin I and troponin T in the heart are structurally different than the ones 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 acute MI as an elevation in serum troponin greater than the level that expected from the 99 percentile of a healthy reference population supported by signs and symptoms of cardiac ischemia. This was also corroborated by the 2007 World Task Force definition of MI, which stated that acute MI is accurately determined based on at least one 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. Troponin T and troponin I levels in the blood rise as early as 4 hours from the onset of acute MI symptoms, peaks in 24 to 48 hours, and remain elevated for multiple days thereby making them useful for detecting initial ischemic events but not reliable to detect re-infarction. High-sensitivity troponin assay (hs-TnT), a test developed to detect troponin at much lower concentrations than what the conventional troponin tests can detect, allows for more rapid diagnosis in patients admitted to the hospital suspected to have acute MI. In a Japnese multicenter study, hs-TnT was found to have superior diagnostic value, compared to other cardiac biomarkers, in diagnosing acute MI within the first 3 hours of admission in patients with negative initial troponin T levels. Researchers also noted that this test had 100% sensitivity and negative predictive value in diagnosing acute MI, but the specificity was limited.
Cardiac troponins are the standard, first-line blood test used to diagnose acute MI. However, cardiac troponins may be elevated in cases unrelated to cardiac ischemia. 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. Another study has shown that aortic valve disease, apical balloon syndrome, bradyarrhythmia, endomyocardial biopsy, hypertrophic cardiomyopathy, tachyarrhythmias and non-cardiac causes such as acute pulmonary edema, chronic obstructive pulmonary disease, pulmonary hypertension, stroke, and subarachnoid hemorrhage can also cause cardiac troponins to become elevated in the blood. 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.
The diagnosis of myocardial infarction requires that cardiac troponin levels must be above the 99 percentile upper reference limit for the assay in use and that there is clinical evidence of myocardial ischemia. Thus an elevated cardiac troponin level in the blood without clinical evidence of myocardial ischemia (e.g., symptoms of acute MI, ECG abnormalities, wall motion abnormalities) should prompt a search for other underlying conditions.
Results, Reporting, Critical Findings
Current recommendations recommend that troponin testing should be available in all hospitals 24/7 with a turnaround time of 60 minutes.
In addition to its application as a diagnostic marker for MI, 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 of congestive heart failure.
Cardiac troponins are specific and sensitive biomarkers of cardiac ischemia, and they are the preferred blood test in the evaluation of patients suspected to have acute MI. There are sensitive and highly sensitive assays to detect cardiac troponin levels in the blood. The highly sensitive troponin assay obtained approval for use in the USA in 2017. Although CK-MB has a high sensitivity for cardiac myocytes, it should not be used as a first-line diagnostic test if cardiac troponin assays are available. In the absence of cardiac troponin assays, CK-MB can be useful in the evaluation of acute MI, 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 acute MI, they are not useful in evaluating for re-infarction of cardiac myocytes (another MI). CK-MB levels normalize 48 to 72 hours after an acute MI, so a rising level in the blood after normalization can confirm that another MI has occurred.
Clinicians need to understand that cardiac markers are not mandatory in patients who present with acute chest pain mimicking angina and ECG evidence of ST-segment elevation. These individuals are candidates for primary coronary intervention or thrombolytic therapy. One should not delay treatment waiting for cardiac markers because their sensitivity is not high in the early hours after an infarct.
Enhancing Healthcare Team Outcomes
The correct diagnosis of acute MI requires an interprofessional team of healthcare professionals that includes laboratory technologists, nurses, and physicians. Measuring the blood levels of cardiac troponins is one of the first steps in reaching a diagnosis. Swift diagnosis of acute MI is crucial, as the less the time from symptom onset to reperfusion therapy is vital for improved long-term outcome of heart function. The path to diagnosing acute MI 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 titers of cardiac troponins and posting the result on the electronic medical records.