Narrative Review: Alternative Causes for Elevated Cardiac Troponin Levels when Acute Coronary Syndromes Are Excluded

In September 2000, the Joint European Society of Cardiology/American College of Cardiology (ESC/ACC) Committee proposed a new definition of myocardial infarction based predominantly on the detection of the cardiospecific biomarkers troponin T and troponin I in the appropriate clinical setting (1). The rationale of including troponin assays in the diagnostic pathway was based on the assumption that myocardial necrosis, regardless of its magnitude, should be characterized as a myocardial infarction. Contemporary troponin assays are quite sensitive and can detect even very small episodes of myocardial necrosis (<1 g). The Committee's recommendation for the diagnosis of myocardial infarction based on troponin elevation categorizes a cohort of patients whose values exceed the 99th percentile of a reference control group with an acceptable imprecision (coefficient of variation) of 10% or less. Unfortunately, few assays in current clinical use meet this standard. It has therefore been proposed that an increase in cardiac troponin levels above the 10% coefficient of variation be considered indicative of myocardial injury (2). Given that numerous troponin assays are commercially available and in clinical use, each individual laboratory should confirm the range of reference values in their specific setting and define the value that is considered a significant troponin elevation. The ESC/ACC Committee consensus document states that any amount of myocardial damage implies an impaired clinical outcome for the patient and there is no discernible threshold below which an elevated value of cardiac troponin would be deemed harmless (1). This view is also reflected in the updated 2002 ACC/American Heart Association (AHA) practice guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction (3). However, the ACC/AHA guidelines do indicate that the myocardial necrosis signified by troponin elevation may not necessarily be due to atherosclerotic coronary artery disease and that myocardial infarction should therefore be diagnosed in conjunction with other supportive evidence. The implementation of these new guidelines in clinical practice has led to a substantial increase in the frequency of myocardial infarction diagnosis. For example, among 2181 patients presenting with chest pain to an inner-city tertiary care center, diagnoses of myocardial infarction based on cardiac troponin level increased up to 195% as compared with diagnoses made according to creatine kinase-MB criteria (4). Mortality at 30 days was significantly higher among patients with elevated troponin levels at presentation than among patients with no biomarkers detected, but it was not as high as among patients with elevated creatine kinase-MB levels. In several studies of acute coronary syndromes, troponin elevation has likewise been associated with a worse prognosis (5). Furthermore, the risk for subsequent death appears to be related to the degree of troponin elevation: There is a statistically significant increase in mortality with increasing levels of troponin, and the relative risk for death is 7.8 in the group with the highest troponin levels (6). While the presence of thrombus and impaired epicardial blood flow are both associated with troponin elevation (7, 8), impaired myocardial perfusion is a more robust and independent predictor of troponin elevation among patients with acute coronary syndromes (9). Among patients with a high pretest probability or clinical suspicion of thrombotic coronary artery disease, the diagnostic and prognostic value of troponin is clear. However, troponin testing is now also being used as a screening tool among patients with a low pretest probability of thrombotic coronary artery disease. Given the high sensitivity of cardiac troponin for detecting even minimal myocardial-cell necrosis, these markers may become positive even in the absence of thrombotic acute coronary syndromes. This may occasionally be related to a spurious troponin elevation (usually easily detectable by obtaining a second sample) but may also be due to several nonthrombotic cardiac and systemic diseases. In many instances, these troponin elevations may arise from demand ischemia, with or even without significant coronary artery disease or microcirculatory dysfunction, rather than supply-side thrombotic ischemia. For example, among 1000 consecutive patients presenting to the emergency department of a large urban hospital, troponin I level was elevated on admission in 112 patients, and 45% of these patients had a final diagnosis other than acute coronary syndrome (10). Given the high sensitivity but low specificity among these patients with a low pretest probability of disease, the detection of even minimal troponin elevation may divert attention from the true underlying clinical problem and may lead to unnecessary cardiac evaluation, including invasive testing. The goal of this article is to review potential causes of troponin elevation that are unrelated to coronary thrombosis (Table) and to provide guidance on the evaluation and management of patients with nonthrombotic troponin elevation. Table. Nonthrombotic Causes and Presumed Mechanism for Elevated Cardiac Troponin Level Cardiac Troponins Cardiac troponins are regulatory proteins that control the calcium-mediated interaction of actin and myosin. The troponin complex consists of 3 subunits: troponin T, which binds to tropomyosin and facilitates contraction; troponin I, which binds to actin and inhibits actin-myosin interactions; and troponin C, which binds to calcium ions (11). The amino acid sequences of the skeletal and cardiac isoforms of cardiac troponin T and troponin I are sufficiently dissimilar and therefore detectable by monoclonal antibody-based assays (3). Troponin C is not used clinically because both cardiac and smooth muscle share troponin C isoforms. The release of cardiac troponin from the myocyte to the blood can be due to reversible or irreversible cell damage. In prolonged ischemia, cells are irreversibly damaged as the cell membrane degrades, followed by the gradual release of myofibril-bound cytosolic complexes (11). However, the notion that troponin is increased only after irreversible myocardial necrosis has recently been challenged by the observation that some patients with unstable angina have only transient troponin elevations, with values returning to baseline within a few hours (12). This pattern of troponin increase may not be consistent with permanent myocardial damage. It is, therefore, conceivable that myocardial troponin can also be released in the setting of increased membrane permeability. For example, it is thought that myocardial depressive factors (released in the setting of sepsis and other inflammatory states) cause degradation of free troponin in situ to lower-molecular-weight fragments (13). With increased membrane permeability, those smaller troponin fragments could be released into the systemic circulation. In this setting, myocyte damage may not be permanent, and thus cell necrosis does not occur. This notion is also supported by the clinical observation that myocardial depression during sepsis is a fully reversible process in most surviving patients (14). Nonthrombotic Mechanisms of Troponin Elevation Demand Ischemia The concept of demand ischemia without significant coronary artery disease refers to a mismatch between myocardial oxygen demand and supply in the absence of flow-limiting epicardial stenosis. Although theoretically the same pathophysiologic principle may be valid in the presence of coronary artery disease, it may be more difficult to identify the predominant mechanism that accounts for myocardial ischemia in that clinical scenario. Myocardial oxygen demand frequently increases in the setting of sepsis or septic shock and the systemic inflammatory response syndrome (15-17), hypotension or hypovolemia (18), and atrial fibrillation or other tachyarrhythmias (19, 20). All of these clinical scenarios are either due to or can lead to tachycardia with various loading conditions on the heart. This increases myocardial oxygen demand while decreasing myocardial oxygen supply by shortening diastolic time, a period during which the majority of the myocardial perfusion occurs. In addition, sepsis and other systemic inflammatory processes may lead to myocardial depression, greatly increased oxygen consumption, reduced perfusion pressure, and decreased oxygen delivery to the heart, ultimately resulting in the release of troponin into the systemic circulation (16). Among 20 septic patients treated in an intensive care unit, 85% were noted to have elevated troponin levels (16). The majority (59%) had no evidence of significant coronary artery disease. Similarly, Guest and colleagues found that elevated cardiac troponin level is a common finding among critically ill patients and is associated with a significant increase in mortality (15). In a more recent study, Ammann and colleagues evaluated 58 patients who were admitted to the intensive care unit for diagnoses other than acute coronary syndromes (17). Among the 55% of patients with elevated troponin levels, tumor necrosis factor-, interleukin-6, and C-reactive protein levels were significantly higher than among patients with undetectable troponin, and mortality was fourfold higher in the troponin-positive group. Of note, significant coronary artery disease was excluded in 72% of troponin-positive patients. Thus, troponin elevation among patients with sepsis and the systemic inflammatory response syndrome with or without shock in the intensive care unit setting is common and largely affects patients without significant coronary artery disease. Troponin elevation is associated with a worse prognosis, but whether any cardiovascular intervention could improve outcomes among these patients is unclear. Although a causal relationship has yet to be established, infl