The diagnosis of cardiac emergencies is one of the most crucial tasks delegated to the emergency physician. The broad differential diagnosis of chest pain must be narrowed down quickly and accurately to perform the life-saving treatments patients require. Along with the history and physical exam, there are a number of important diagnostic tools that are used to differentiate the different causes of chest pain. One tool that has become an essential component of cardiac workups and diagnosis is the measurement of troponins. Interval troponin measurements have revolutionized the practice of emergency medicine and the way myocardial ischemia is diagnosed and treated.
Troponins are cardiac regulatory proteins that are found in the cytoplasm of cardiac myocytes. When calcium binds to the protein complex, the structure of troponin changes, and this causes an interaction between the actin and myosin filaments. This interaction leads to cardiac muscle contraction. The troponin complex is made up of 3 subunits: cTnC, cTnI, and cTnT. cTnI and cTnT are the subunits that are identified in laboratory testing looking for cardiac muscle injury. cTnI has been shown to be exclusive to cardiac muscle. Studies have failed to identify cTnI in any body tissue at any point during neonatal development. Small amounts of cTnT have been identified in skeletal muscle but are found in much higher concentrations in cardiac muscle. In clinical studies, there have been no statistically significant differences found when using cTnI vs. cTnT in troponin assays.
Before troponin, there were a number of different cardiac biomarkers that were used to identify myocardial ischemia. In the 1960s and 1970s, biomarkers such as aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine kinase (CK) were used but were phased out due to lack of specificity for cardiac muscle. The next generation of biomarkers was more specific to cardiac muscle and included CK-MB and LDH 1+2. However, these markers still had an unacceptably high false-positive rate, and a new, more specific biomarker was needed. Troponins were first identified in 1965, but a reliable immune-assay to detect its levels in the blood was not developed until the late 1990s. Troponin measurements were found to have a near 100% sensitivity when checked 6 to 12 hours after the start of chest pain and have a significantly improved specificity for cardiac muscle damage when compared to previous biomarkers. Due to its clinical usefulness, serial troponin testing was added to the Third Universal Definition of Myocardial Infarction, which is the current definition used by the American College of Cardiology.
Myocardial infarction occurs when blood flow is blocked in the coronary vessels that supply the heart muscle with oxygen. This causes a mismatch where oxygen supply is not meeting the oxygen demand of the myocytes, leading to necrosis and cell death. During this process, the cell membranes are ruptured, causing intracellular contents to spill into the extracellular space, eventually making their way into the bloodstream. If these cellular contents, including troponins, are spilled in large enough quantities that can be detected in the circulating blood.
There is a basal amount of troponin found in the circulation of healthy individuals from a normal turnover of cardiac myocytes. For a measured troponin to indicate pathophysiologic muscle damage, it must be greater than the 99th percentile of the normal range, which is about 3 standard deviations from the mean. According to the Third Universal Definition of Myocardial Infarction, there also must be a characteristic rise and fall of the troponin level measured over hours and days. Troponin levels typically start to elevate in the circulation within 2 to 3 hours of the onset of chest pain. The levels will continue to rise at that time until a peak is reached, generally between 12 and 48 hours. The troponin level will then begin to fall over the next 4 to 10 days down to a normal level. This expected rise and fall of the troponin is an important factor that can distinguish a myocardial infarction from other causes of elevated troponins.
In the emergency department setting, it is impossible to follow troponin levels completely from rising to peak to fall. When a patient presents complaining of chest pain, a diagnostic decision has to be made promptly. To help guide decision making in the emergency setting, myocardial infarctions are divided into 2 categories using ECG findings; ST-segment elevation myocardial infarctions (STEMI) and non-ST segment elevation myocardial infarctions (NSTEMI). In STEMIs, patients will have an elevated troponin as well as one of the following ECG changes: (1) ST-segment elevations greater than 1 mm in contiguous leads with reciprocal changes, (2) new evidence of a left bundle branch block, or (3) ST-segment elevations noted on a posterior ECG. In this scenario, the diagnostic and therapeutic decisions are simple. The patient likely has a major blockage of a coronary vessel and requires emergent coronary catheterization if available or thrombolytic therapy to open the blocked vessel and reperfuse the cardiac muscle.
NSTEMIs are defined as an injury to the cardiac muscle that results in an elevated troponin but lacks the ECG changes that define a STEMI. NSTEMIs usually represent less myocardial tissue damage than STEMIs, and an emergent coronary catheterization is not needed initially. NSTEMIs are generally treated with medical management including dual antiplatelet therapy as well as full anticoagulation such as heparin. NSTEMIs present a difficult challenge to the emergency physician. It is possible that a patient with chest pain can have a negative troponin initially with no ECG changes but can still have an NSTEMI because troponin levels do not start to rise until at least 2 to 3 hours after the initial insult. This emphasizes the importance of getting serial troponins spaced 3 to 6 hours apart in patients suspected of having an ischemic event but have a troponin that is initially normal.
One problem with using troponins to diagnose acute myocardial infarctions is that troponins can be elevated in other conditions as well. Anything that causes damage to cardiac muscle can cause troponin to spill into the circulation. The most common cause of injury is oxygen supply and demand mismatch, which is seen in acute myocardial infarction. However, many other conditions can cause this mismatch to occur, and therefore can cause elevated troponins. For example, tachycardia can cause decreased perfusion due to the decreased diastolic time, which is when coronary blood flow occurs, and oxygen demand increases. Patients in shock can also have a supply and demand mismatch due to low blood volume, and elevated troponins in these patients have been shown to be indicative of worse outcomes. Another cause of elevated levels of troponin is cardiac muscle injury due to non-ischemic causes. Direct, blunt trauma to the chest can cause significant myocardial damage, and in turn can lead to increased troponin. In a study done on 333 blunt chest trauma patients, elevated troponin was found in 144 (44%) patients. Inflammatory conditions such as viral myocarditis and infiltrative diseases such as sarcoidosis have also been shown to cause elevations in troponins. Troponin leak can also occur with processes outside of the heart. For example, troponin elevations have been seen frequently in patients with acute strokes although they have no evidence of coronary artery disease. One proposed mechanism for this phenomenon is that there is disrupted autonomic function after a cerebrovascular accident (CVA), which can cause an increased catecholamine response that acts on the cardiac myocytes.
Another issue that complicates the measurement of troponins for the diagnosis of acute myocardial infarctions is chronic kidney disease (CKD). Patients with CKD have been shown to have elevated troponin levels greater than the 99th percentile with no evidence of cardiac disease. Although the mechanism for increased troponins is not completely understood, it is thought to be due to underlying structural abnormalities of the cardiac tissue and chronic myocardial injury. There have also been studies that suggest that the kidneys have some role in clearing troponin from the circulation, although there is no evidence of troponin found in urine. This can complicate the diagnosis of a CKD patient who presents to the emergency department complaining of chest pain with an elevated troponin. A meta-analysis of 14 different studies showed that the specificity of an elevated troponin over the 99th percentile was drastically decreased in patients with CKD. In these patients, it is crucial to know if the troponins are trending over time, looking to see if there is a rise and fall in the levels. The troponin levels in CKD patients are usually steady, so a rise and fall of the troponin would be more indicative of a cardiac cause of the elevated troponin. One accepted recommendation is if there is a change in the troponin level of 20% during serial testing, it is likely due to a cardiac cause, although the research for this recommendation is lacking.
The accurate diagnosis and treatment of cardiac events is an essential component of working in the emergency department. The development and implementation of troponin testing have had a massive influence on the way emergency medicine is practiced. It is important to recognize the drawbacks and potential flaws when using troponin testing and to keep the entire clinical picture in mind when making medical decisions. Troponin testing has changed the way emergency medicine is practiced and having a deep understanding of its clinical implications is key to the success of emergency physicians.
All healthcare workers including the nurse practitioner should be familiar with biological markers for a heart attack. However, one should never negate the history and physical exam. The final confirmation of a heart attack utilizes many other parameters like an ECG, ECHO and a chest x-ray. One should never just rely on a single serum test because of false positives and false negatives.
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