Üçüncü Evrensel Miyokard Enfarktüsü Tanımı (İng)

Third Universal Definition of Myocardial Infarction

Kristian Thygesen, Joseph S. Alpert, Allan S. Jaffe, Maarten L. Simoons, Bernard R. Chaitman, Harvey D. White

Oct 26, 2012

J Am Coll Cardiol. 2012;60(16):1581-1598. © 2012  Elsevier Science, Inc.

Abstract and Introduction

Definition of Myocardial Infarction

Criteria for Acute Myocardial Infarction

The term acute myocardial infarction (MI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI:
•Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following:
•Symptoms of ischemia.
•New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB).
•Development of pathological Q waves in the ECG.
•Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
•Identification of an intracoronary thrombus by angiography or autopsy.

•Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased.
•Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by elevation of cTn values (>5 × 99th percentile URL) in patients with normal baseline values (≤99th percentile URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia or (ii) new ischemic ECG changes or (iii) angiographic findings consistent with a procedural complication or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required.
•Stent thrombosis associated with MI when detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile URL.
•Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by elevation of cardiac biomarker values (>10 × 99th percentile URL) in patients with normal baseline cTn values (≤99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Criteria for Prior Myocardial Infarction

Any one of the following criteria meets the diagnosis for prior MI:
•Pathological Q waves with or without symptoms in the absence of non-ischemic causes.
•Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause.
•Pathological findings of a prior MI.

Introduction

Myocardial infarction (MI) can be recognized by clinical features, including electrocardiographic (ECG) findings, elevated values of biochemical markers (biomarkers) of myocardial necrosis, and by imaging, or may be defined by pathology. It is a major cause of death and disability worldwide. MI may be the first manifestation of coronary artery disease (CAD) or it may occur, repeatedly, in patients with established disease. Information on MI rates can provide useful information regarding the burden of CAD within and across populations, especially if standardized data are collected in a manner that distinguishes between incident and recurrent events. From the epidemiological point of view, the incidence of MI in a population can be used as a proxy for the prevalence of CAD in that population. The term ‘myocardial infarction’ may have major psychological and legal implications for the individual and society. It is an indicator of one of the leading health problems in the world and it is an outcome measure in clinical trials, observational studies and quality assurance programs. These studies and programs require a precise and consistent definition of MI.

In the past, a general consensus existed for the clinical syndrome designated as MI. In studies of disease prevalence, the World Health Organization (WHO) defined MI from symptoms, ECG abnormalities and cardiac enzymes. However, the development of ever more sensitive and myocardial tissue-specific cardiac biomarkers and more sensitive imaging techniques now allows for detection of very small amounts of myocardial injury or necrosis. Additionally, the management of patients with MI has significantly improved, resulting in less myocardial injury and necrosis, in spite of a similar clinical presentation. Moreover, it appears necessary to distinguish the various conditions which may cause MI, such as ‘spontaneous’ and ‘procedure-related’ MI. Accordingly, physicians, other healthcare providers and patients require an up-to-date definition of MI.

In 2000, the First Global MI Task Force presented a new definition of MI, which implied that any necrosis in the setting of myocardial ischemia should be labeled as MI.^[1] These principles were further refined by the Second Global MI Task Force, leading to the Universal Definition of Myocardial Infarction Consensus Document in 2007, which emphasized the different conditions which might lead to an MI.^[2] This document, endorsed by the European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and the World Heart Federation (WHF), has been well accepted by the medical community and adopted by the WHO.^[3] However, the development of even more sensitive assays for markers of myocardial necrosis mandates further revision, particularly when such necrosis occurs in the setting of the critically ill, after percutaneous coronary procedures or after cardiac surgery. The Third Global MI Task Force has continued the Joint ESC/ACCF/AHA/WHF efforts by integrating these insights and new data into the current document, which now recognizes that very small amounts of myocardial injury or necrosis can be detected by biochemical markers and/or imaging.

Pathological Characteristics of Myocardial Ischemia and Infarction

MI is defined in pathology as myocardial cell death due to prolonged ischemia. After the onset of myocardial ischemia, histological cell death is not immediate, but takes a finite period of time to develop—as little as 20 min, or less in some animal models.^[4] It takes several hours before myocardial necrosis can be identified by macroscopic or microscopic post-mortem examination. Complete necrosis of myocardial cells at risk requires at least 2–4 h, or longer, depending on the presence of collateral circulation to the ischemic zone, persistent or intermittent coronary arterial occlusion, the sensitivity of the myocytes to ischemia, pre-conditioning, and individual demand for oxygen and nutrients.^[2] The entire process leading to a healed infarction usually takes at least 5–6 weeks. Reperfusion may alter the macroscopic and microscopic appearance.

Biomarker Detection of Myocardial Injury With Necrosis

Myocardial injury is detected when blood levels of sensitive and specific biomarkers such as cTn or the MB fraction of creatine kinase (CKMB) are increased.^[2] Cardiac troponin I and T are components of the contractile apparatus of myocardial cells and are expressed almost exclusively in the heart. Although elevations of these biomarkers in the blood reflect injury leading to necrosis of myocardial cells, they do not indicate the underlying mechanism.^[5] Various possibilities have been suggested for release of structural proteins from the myocardium, including normal turnover of myocardial cells, apoptosis, cellular release of troponin degradation products, increased cellular wall permeability, formation and release of membranous blebs, and myocyte necrosis.^[6] Regardless of the pathobiology, myocardial necrosis due to myocardial ischemia is designated as MI.

Also, histological evidence of myocardial injury with necrosis may be detectable in clinical conditions associated with predominantly non-ischemic myocardial injury. Small amounts of myocardial injury with necrosis may be detected, which are associated with heart failure (HF), renal failure, myocarditis, arrhythmias, pulmonary embolism or otherwise uneventful percutaneous or surgical coronary procedures. These should not be labeled as MI or a complication of the procedures, but rather as myocardial injury, as illustrated in (Figure 1). It is recognized that the complexity of clinical circumstances may sometimes render it difficult to determine where individual cases may lie within the ovals of (Figure 1). In this setting, it is important to distinguish acute causes of cTn elevation, which require a rise and/or fall of cTn values, from chronic elevations that tend not to change acutely. A list of such clinical circumstances associated with elevated values of cTn is presented in (). The multifactorial contributions resulting in the myocardial injury should be described in the patient record.

Table 1.  Elevation of Cardiac Troponin Values Because of Myocardial Injury

Figure 1.

This illustration shows various clinical entities: for example, renal failure, heart failure, tachy- or bradyarrhythmia, cardiac or non-cardiac procedures that can be associated with myocardial injury with cell death marked by cardiac troponin elevation. However, these entities can also be associated with myocardial infarction in case of clinical evidence of acute myocardial ischemia with rise and/or fall of cardiac troponin.

The preferred biomarker—overall and for each specific category of MI—is cTn (I or T), which has high myocardial tissue specificity as well as high clinical sensitivity. Detection of a rise and/or fall of the measurements is essential to the diagnosis of acute MI.^[7] An increased cTn concentration is defined as a value exceeding the 99th percentile of a normal reference population [upper reference limit (URL)]. This discriminatory 99th percentile is designated as the decision level for the diagnosis of MI and must be determined for each specific assay with appropriate quality control in each laboratory.^[8,9] The values for the 99th percentile URL defined by manufacturers, including those for many of the high-sensitivity assays in development, can be found in the package inserts for the assays or in recent publications.^[10–12]

Values should be presented as nanograms per liter (ng/L) or picograms per milliliter (pg/mL) to make whole numbers. Criteria for the rise of cTn values are assay-dependent but can be defined from the precision profile of each individual assay, including high-sensitivity assays.^[10,11] Optimal precision, as described by coefficient of variation (CV) at the 99th percentile URL for each assay, should be defined as <10%. Better precision (CV <10%) allows for more sensitive assays and facilitates the detection of changing values.^[13] The use of assays that do not have optimal precision (CV >10% at the 99th percentile URL) makes determination of a significant change more difficult but does not cause false positive results. Assays with CV >20% at the 99th percentile URL should not be used.^[13] It is acknowledged that pre-analytic and analytic problems can induce elevated and reduced values of cTn.^[10,11]

Blood samples for the measurement of cTn should be drawn on first assessment and repeated 3–6 h later. Later samples are required if further ischemic episodes occur, or when the timing of the initial symptoms is unclear.^[14] To establish the diagnosis of MI, a rise and/or fall in values with at least one value above the decision level is required, coupled with a strong pre-test likelihood. The demonstration of a rising and/or falling pattern is needed to distinguish acute- from chronic elevations in cTn concentrations that are associated with structural heart disease.^{[10,11,15–19]} For example, patients with renal failure or HF can have significant chronic elevations in cTn. These elevations can be marked, as seen in many patients with MI, but do not change acutely.^[7] However, a rising or falling pattern is not absolutely necessary to make the diagnosis of MI if a patient with a high pre-test risk of MI presents late after symptom onset; for example, near the peak of the cTn time-concentration curve or on the slow-declining portion of that curve, when detecting a changing pattern can be problematic. Values may remain elevated for 2 weeks or more following the onset of myocyte necrosis.^[10]

Sex-dependent values may be recommended for high-sensitivity troponin assays.^[20,21] An elevated cTn value (>99th percentile URL), with or without a dynamic pattern of values or in the absence of clinical evidence of ischemia, should prompt a search for other diagnoses associated with myocardial injury, such as myocarditis, aortic dissection, pulmonary embolism, or HF. Renal failure and other more non-ischemic chronic disease states, that can be associated with elevated cTn levels, are listed in ().^[10,11]

Table 1.  Elevation of Cardiac Troponin Values Because of Myocardial Injury

If a cTn assay is not available, the best alternative is CKMB (measured by mass assay). As with troponin, an increased CKMB value is defined as a measurement above the 99th percentile URL, which is designated as the decision level for the diagnosis of MI.^[22] Sex-specific values should be employed.^[22]

Clinical Features of Myocardial Ischemia and Infarction

Onset of myocardial ischemia is the initial step in the development of MI and results from an imbalance between oxygen supply and demand. Myocardial ischemia in a clinical setting can usually be identified from the patient’s history and from the ECG. Possible ischemic symptoms include various combinations of chest, upper extremity, mandibular or epigastric discomfort (with exertion or at rest) or an ischemic equivalent such as dyspnea or fatigue. The discomfort associated with acute MI usually lasts >20 min. Often, the discomfort is diffuse—not localized, nor positional, nor affected by movement of the region—and it may be accompanied by diaphoresis, nausea or syncope. However, these symptoms are not specific for myocardial ischemia. Accordingly, they may be misdiagnosed and attributed to gastrointestinal, neurological, pulmonary or musculoskeletal disorders. MI may occur with atypical symptoms—such as palpitations or cardiac arrest—or even without symptoms; for example in women, the elderly, diabetics, or post-operative and critically ill patients.^[2] Careful evaluation of these patients is advised, especially when there is a rising and/or falling pattern of cardiac biomarkers.

Clinical Classification of Myocardial Infarction

For the sake of immediate treatment strategies, such as reperfusion therapy, it is usual practice to designate MI in patients with chest discomfort, or other ischemic symptoms that develop ST elevation in two contiguous leads (see ECG section), as an ‘ST elevation MI’ (STEMI). In contrast, patients without ST elevation at presentation are usually designated as having a ‘non-ST elevation MI’ (NSTEMI). Many patients with MI develop Q waves (Q wave MI), but others do not (non-Q MI). Patients without elevated biomarker values can be diagnosed as having unstable angina. In addition to these categories, MI is classified into various types, based on pathological, clinical and prognostic differences, along with different treatment strategies ().

Table 2.  Universal Classification of Myocardial Infarction

Spontaneous Myocardial Infarction (MI Type 1)

This is an event related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries, leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe CAD but, on occasion (5 to 20%), non-obstructive or no CAD may be found at angiography, particularly in women.^[23,24,25]

Myocardial Infarction Secondary to an Ischemic Imbalance (MI Type 2)

In instances of myocardial injury with necrosis, where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, the term ‘MI type 2’ is employed (Figure 2). In critically ill patients, or in patients undergoing major (non-cardiac) surgery, elevated values of cardiac biomarkers may appear, due to the direct toxic effects of endogenous or exogenous high circulating catecholamine levels. Also coronary vasospasm and/or endothelial dysfunction have the potential to cause MI.^[26–28]

Figure 2.

Differentiation between myocardial infarction (MI) types 1 and 2 according to the condition of the coronary arteries.

Cardiac Death Due to Myocardial Infarction (MI Type 3)

Patients who suffer cardiac death, with symptoms suggestive of myocardial ischemia accompanied by presumed new ischemic ECG changes or new LBBB—but without available biomarker values—represent a challenging diagnostic group. These individuals may die before blood samples for biomarkers can be obtained, or before elevated cardiac biomarkers can be identified. If patients present with clinical features of myocardial ischemia, or with presumed new ischemic ECG changes, they should be classified as having had a fatal MI, even if cardiac biomarker evidence of MI is lacking.

Myocardial Infarction Associated With Revascularization Procedures (MI Types 4 and 5)

Periprocedural myocardial injury or infarction may occur at some stages in the instrumentation of the heart that is required during mechanical revascularization procedures, either by PCI or by coronary artery bypass grafting (CABG). Elevated cTn values may be detected following these procedures, since various insults may occur that can lead to myocardial injury with necrosis.^[29-32] It is likely that limitation of such injury is beneficial to the patient: however, a threshold for a worsening prognosis, related to an asymptomatic increase of cardiac biomarker values in the absence of procedural complications, is not well defined.^[33–35] Subcategories of PCI-related MI are connected to stent thrombosis and restenosis that may happen after the primary procedure.