Third universal definition of myocardial infarction: Update, caveats, differential diagnoses
ABSTRACTUpdated definitions of myocardial infarction (MI) reflect research on measuring cardiac troponin to diagnose MI. Elevations of this biomarker indicate cardiac injury but not always an acute coronary syndrome. Clinical judgment is needed to interpret increasingly sensitive biomarker assays appropriately. Here, we review the new MI definitions and the various causes of elevated troponin to enable physicians to differentiate acute coronary syndromes from other conditions.
KEY POINTS
- Because newer assays for troponin can detect this biomarker at lower concentrations than earlier ones could, they are more sensitive but less specific.
- The high sensitivity of troponin assays makes them valuable for ruling out MI, but less so for ruling it in. Therefore, additional signs are required for the diagnosis.
- MI is categorized into several types, depending on whether it is spontaneous (acute coronary syndromes), caused by supply-demand mismatch, associated with sudden cardiac death, or a complication of percutaneous coronary intervention or of coronary artery bypass grafting.
- In settings in which nonspecific troponin elevations are frequently seen, a less sensitive but more specific test such as creatine kinase MB or troponin using a higher threshold value may be useful.
OTHER CONDITIONS THAT RAISE TROPONIN LEVELS
As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.
Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.18
Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.
Heart failure
Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.19 Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.20 In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.21
Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.23–26
End-stage renal disease
Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.30
Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.31
Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.32,33
In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.34 Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.34
Sepsis
Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.35
Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.
Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.37 However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.1 Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.
Pulmonary embolism
Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.38 It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.
The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.
The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.39 Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.
However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.40
