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.
In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),1 replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.
TROPONINS: THE PREFERRED MARKERS
Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.
Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).2 But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.
Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.
Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.
As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.3 There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.
Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.
The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.5 Most assays have been adapted to ensure that they meet such criteria.
High-sensitivity assays
Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.
In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.6 The algorithm had a sensitivity and negative predictive value of 100%.
Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.4 With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.7
Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.8,9
TYPES OF MYOCARDIAL INFARCTION
The task force defines the following categories of MI (Table 1):
Type 1: Spontaneous myocardial infarction
Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.
To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:
- Symptoms of ischemia
- New ST-segment or T-wave changes or new left bundle branch block
- Development of pathologic Q waves
- Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
- Finding of an intracoronary thrombus by angiography or autopsy.
Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.
