Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology committee for the redefinition of myocardial infarction

The Joint European Society of Cardiology/ American College of Cardiology Committee

1. pathology

Myocardial infarction is defined as myocardial cell death due to prolonged ischemia. Cell death is categorized pathologically as either coagulation or contraction band necrosis, or both, which usually evolves through oncosis, but can result to a lesser degree from apoptosis. Careful analysis of histologic sections by an experienced observer is essential to distinguish these entities.

After the onset of myocardial ischemia, cell death is not immediate but takes a finite period to develop (as little as 15 min in some animal models, but even this may be an overestimate). It takes 6 h before myocardial necrosis can be identified by standard macroscopic or microscopic postmortem examination. Complete necrosis of all myocardial cells at risk requires at least 4 h to 6 h or longer, depending on the presence of collateral blood flow into the ischemic zone, persistent or intermittent coronary artery occlusion and the sensitivity of the myocytes.

Infarcts are usually classified by size—microscopic (focal necrosis), small (<10% of the left ventricle), medium (10% to 30% of the left ventricle) or large (>30% of the left ventricle)—as well as by location (anterior, lateral, inferior, posterior or septal or a combination of locations). The pathologic identification of myocardial necrosis is made without reference to morphologic changes in the epicardial coronary artery tree or to the clinical history.

The term MI in a pathologic context should be preceded by the words “acute, healing or healed.” An acute or evolving infarction is characterized by the presence of polymorphonuclear leukocytes. If the interval between the onset of infarction and death is brief (e.g., 6 h), minimal or no polymorphonuclear leukocytes may be seen. The presence of mononuclear cells and fibroblasts and the absence of polymorphonuclear leukocytes characterize a healing infarction. A healed infarction is manifested as scar tissue without cellular infiltration. The entire process leading to a healed infarction usually requires five to six weeks or more. Furthermore, reperfusion alters the gross and microscopic appearance of the necrotic zone by producing myocytes with contraction bands and large quantities of extravasated erythrocytes.

Infarcts are classified temporally according to the pathologic appearance as follows: acute (6 h to 7 days); healing (7 to 28 days), healed (29 days or more). It should be emphasized that the clinical and ECG timing of an acute ischemic event may not be the same as the pathologic timing of an acute infarction. For example, the ECG may still demonstrate evolving ST-T segment changes, and cardiac troponin may still be elevated (implying a recent infarct) at a time when, pathologically, the infarct is in the healing phase.

2. biochemical markers of myocardial necrosis

Myocardial necrosis results in and can be recognized by the appearance in the blood of different proteins released into the circulation due to the damaged myocytes: myoglobin, cardiac troponins T and I, creatine kinase, lactate dehydrogenase, as well as many others (Fig. 2). Myocardial infarction is diagnosed when blood levels of sensitive and specific biomarkers, such as cardiac troponin and the MB fraction of creatine kinase (CK-MB), are increased in the clinical setting of acute ischemia. These biomarkers reflect myocardial damage but do not indicate its mechanism. Thus, an elevated value in the absence of clinical evidence of ischemia should prompt a search for other causes of cardiac damage, such as myocarditis.

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Figure 2

Timing of release of various biomarkers following acute, ischemic myocardial infarction.

Peak A, early release of myoglobin or CK-MB isoforms after AMI; peak B, cardiac troponin after AMI; peak C, CK-MB after AMI; peak D, cardiac troponin after unstable angina. Data are plotted on a relative scale, where 1.0 is set at the AMI cutoff concentration.

AMI = acute myocardial infarction; CAD = coronary artery disease; CK = creatine kinase.

Reproduced with permission, WU AH, et al. Clin Chem 1999;45:1104–1121.

The most recently described and preferred biomarker for myocardial damage is cardiac troponin (I or T), which has nearly absolute myocardial tissue specificity, as well as high sensitivity, thereby reflecting even microscopic zones of myocardial necrosis. An increased value for cardiac troponin should be defined as a measurement exceeding the 99th percentile of a reference control group. Reference values must be determined in each laboratory by studies using specific assays with appropriate quality control, as reported in peer-reviewed journals. Acceptable imprecision (coefficient of variation) at the 99th percentile for each assay should be defined as ≤10%. Each individual laboratory should confirm the range of reference values in their specific setting. In addition, meticulous laboratory practice must be maintained. Because cardiac troponin values may remain elevated for 7 to 10 days or longer after myocardial necrosis, care should be exercised in attribution of elevated cardiac troponin levels to very recent clinical events (Table 2).

If cardiac troponin assays are not available, the best alternative is CK-MB (measured by mass assay). This is less tissue-specific than cardiac troponin, but the data documenting its clinical specificity for irreversible injury are more robust. As with cardiac troponin, an increased CK-MB value (i.e., above the decision limit for MI) is defined as one that exceeds the 99th percentile of CK-MB values in a reference control group. In most situations, elevated values for biomarkers should be recorded from two successive blood samples to diagnose MI.

Measurement of total CK is not recommended for the routine diagnosis of acute MI, because of the wide tissue distribution of this enzyme. Nevertheless, total CK has a long history, and some physicians may opt to continue to employ it for epidemiologic or scientific purposes. In such a setting, total CK should be combined with a more sensitive biomarker, such as cardiac troponin or CK-MB, for more accurate clinical diagnosis of acute MI. The cut-off limits for total CK should be relatively higher than those for cardiac troponin or CK-MB (at least twice the upper reference limit for CK). Glutamic-oxaloacetic transaminase (ASAT [aspartate amino transferase]), lactate dehydrogenase and lactate dehydrogenase isoenzymes should not be used to diagnose cardiac damage. Along with other clinical factors (e.g., residual left ventricular function), the degree of biomarker elevation is related to clinical risk. A classification for the extent of myocardial damage (microscopic, small, medium or large) should be employed, although no generally accepted grading system of infarct size exists.

For most patients, blood should be obtained for testing on hospital admission, at 6 to 9 h and again at 12 to 24 h if the earlier samples are negative and the clinical index of suspicion is high. For patients in need of an early diagnosis, a rapidly appearing biomarker (such as CK-MB isoforms or myoglobin), plus a biomarker that rises later (e.g., cardiac troponin), is recommended for confirmation of the diagnosis (Fig. 1).

Detection of reinfarction is clinically important because it carries incremental risk for the patient. Reinfarction may present special diagnostic difficulties, because an increase of cardiac troponin can be long-lasting, and when cardiac troponin is persistently high, the timing of the initial myocardial damage is difficult to ascertain. If the first sample on presentation has a high cardiac troponin value, then sequential samples of a biomarker with a shorter time course, such as CK-MB or myoglobin, could be employed to clarify the timing of the infarct.

3. electrocardiography

The ECG may show signs of myocardial ischemia, specifically ST segment and T wave changes, as well as signs of myocardial necrosis, specifically changes in the QRS pattern. A working definition for acute or evolving MI in the presence of a clinically appropriate syndrome, as demonstrated by standard 12-lead ECG, has been established by using data from clinical and pathoanatomic correlative studies. The following ECG criteria (in the absence of QRS confounders [i.e., bundle branch block, left ventricular hypertrophy, Wolff-Parkinson-White syndrome]) have emerged as robust determinants for the diagnosis of myocardial ischemia (Table 3). Such ischemic changes may be associated with evolving MI, as discussed subsequently (Fig. 1).

The ECG criteria in Table 3 reflect myocardial ischemia and are not sufficient by themselves to define MI. The final diagnosis of myocardial necrosis depends on the detection of elevated levels of cardiac biomarkers in the blood, as discussed earlier. ST segment elevation in patients with suspected acute MI can resolve rapidly either spontaneously or after therapy. The effect of reperfusion therapy on ST segment changes should be taken into consideration when using the ECG to diagnose MI. Some patients with rapid reversal of ST segment elevation will not develop myocardial necrosis. Moreover, ST segment depression, which is maximal in leads V₁ through V₃, without ST segment elevation in other leads, should be considered as indicative of posterior ischemia or infarction, or both, but imaging studies are usually needed to confirm the presence of ischemia or infarction in an individual patient. In the presence of new or presumed new left bundle branch block, ST segment elevation can accompany the bundle branch block, making it difficult or impossible to recognize an acute infarction, and criteria indicative of acute MI need to be defined by further research. Tall and peaked T waves (hyperacute T waves) have been noted during the very early phases of acute MI.

New or presumed new ST segment depression or T wave abnormalities, or both, should be observed in two or more contiguous leads on two consecutive ECGs at least several hours apart.

Myocardial necrosis or clinically established MI may be defined from standard 12-lead ECG criteria in the absence of QRS confounders (e.g., bundle branch block, left ventricular hypertrophy, Wolff-Parkinson-White syndrome) or immediately after coronary artery bypass graft surgery, utilizing the QRS changes presented in Table 4. A single ECG that meets the Q wave criteria in Table 4 is indicative of a previous MI. Q waves <30 ms in duration associated with ST-T segment depression may represent infarction, but these findings require more research and confirmation. When three or more ECG recordings are obtained, then at least two consecutive ECGs should demonstrate the abnormality in question. Criteria for Q wave depth require more research, as do QRS criteria to establish the diagnosis of posterior MI. Bundle branch block with additional Q waves is included in these descriptions. Right bundle branch block will not interfere with the ability to diagnose Q waves; left bundle branch block usually obscures Q waves; new Q waves in the presence of left bundle branch block should be considered as pathologic.

Not all patients who develop myocardial necrosis exhibit ECG changes. Thus, a normal ECG does not rule out the diagnosis of MI. Since new sensitive biochemical markers enable detection of myocardial necrosis too small to be associated with QRS abnormalities, some patients will have their peak values in the subrange of any QRS changes. Such patients might be considered to have only a microinfarction, but these aspects need further clarification.

4. imaging

Imaging techniques have been used to assist in 1) ruling out or confirming the presence of acute infarction or ischemia in the Emergency Department; 2) identifying nonischemic conditions causing chest pain; 3) defining short- and long-term prognoses; and 4) identifying mechanical complications of acute infarction. The rationale of acute imaging using echocardiographic or nuclear techniques in patients suspected of having acute ischemia is that ischemia results in regional myocardial hypoperfusion, leading to a cascade of events that can include myocardial dysfunction and ultimately cell death. Only conventional methods such as cross-sectional echocardiography, radionuclide angiography and myocardial single-photon emission computed tomographic (SPECT) perfusion imaging are discussed in this document, and not those that are presently being tested in clinical research studies.

One of the major advantages of echocardiography is that it allows assessment of most nonischemic causes of acute chest pain, such as perimyocarditis, valvular heart disease (aortic stenosis), pulmonary embolism and aortopathies (aortic dissection).

Radionuclide techniques enable the physician to assess perfusion at the time of patient presentation; this can be performed with immediate tracer injection, because image acquisition can be delayed for 60 to 90 min. Quantitative analysis is an advantage of this technique. The accuracy of the studies is high when interpreted by skilled observers. These studies also provide simultaneous information on myocardial perfusion and function.

Biomarkers are more sensitive, more specific and less costly than imaging techniques for the diagnosis of myocardial necrosis. Injury involving >20% of myocardial wall thickness is required before a segmental wall motion abnormality can be detected by echocardiography. In general, >10 g of myocardial tissue must be injured before a radionuclide perfusion defect can be resolved. Neither technique can distinguish ischemia from infarction.

1. percutaneous coronary artery intervention

An increase of cardiac biomarkers after coronary angioplasty or implantation of coronary artery stents, or both, is indicative of cell death. Because this necrosis occurs as a result of myocardial ischemia, it should be labeled as an MI according to the new criteria. Large infarcts in this setting may be caused by a complicated procedure and can usually be recognized clinically. In contrast, small or tiny infarcts are more frequent and are probably the result of microemboli from the atherosclerotic lesion that has been disrupted during angioplasty or from the particulate thrombus at the site of the culprit lesion.

In the setting of percutaneous coronary artery interventions, small infarcts may, and should, be detected by serial blood sampling and analysis before and after the procedure (6 to 8 h and 24 h, respectively). The peak level of the myocardial biomarkers may be pronounced and of relatively greater magnitude because of the reperfusion associated with the procedure. Myocardial cell injury occurring after angioplasty may be a one-time event, as compared with the often repetitive nature of spontaneously occurring episodes of myocardial ischemia and necrosis. However, it is likely that patients who develop a coronary embolism and small infarcts have atherosclerotic lesions that are apparently unstable, and hence represent a subgroup at risk for future events. Indeed, it has been convincingly demonstrated that the risk of subsequent ischemic heart disease events (death or MI) is related to the extent of cardiac troponin or CK-MB increase, and the prognosis for these individuals is usually worse than that for patients who do not develop these small increases in biomarkers after interventional procedures. Accordingly, patients with elevated biomarkers after an otherwise uncomplicated procedure may require particularly careful instructions to respond appropriately to recurrent symptoms.

2. cardiac surgery

Myocardial damage in association with cardiac surgery can be caused by different mechanisms, including direct trauma by sewing needles; focal trauma from surgical manipulation of the heart; global ischemia from inadequate perfusion, myocardial cell protection or anoxia; coronary artery or venous graft embolism; and other complications of the procedure. A portion of this damage may be unavoidable. Moreover, no biomarker is capable of distinguishing damage due to an acute infarction from the usually small quantity of myocardial cell damage associated with the procedure itself. Nevertheless, the higher the value for the cardiac biomarker after the procedure, the greater the amount of damage to the myocardium, irrespective of the mechanism of injury.

1. epidemiology

Monitoring of cardiovascular disease in a population is of utmost importance, because it enables the investigator to analyze possible causal factors and to assess the effect of various preventive measures, such as changes in diet or life-style, as well as the effect of medications. The incidence of a new MI and the prevalence of established infarcts represent important epidemiologic variables. The application of the new, more sensitive diagnostic criteria for MI will cause the recorded incidence of MI to rise and the case fatality rate to fall. Thus, a new definition of MI will confuse efforts to follow trends in disease rates and outcomes that are now being used to monitor the impact of public health measures and treatments. However, this would not be a valid reason to hold onto old definitions of MI which no longer reflect current scientific thinking. In fact, changes in definitions have already occurred, albeit unnoticed—for example, through substitution of newer biomarkers (CK-MB, troponin) for older ones (ASAT, CK). Continued tracking of these trends will require methods for adjusting the new criteria to the old; for example, specific surveillance centers will be needed to measure total CK and CK-MB, together with the newer biomarkers.

Established definitions of MI (e.g., Minnesota code, WHO MONICA) should be retained by specific epidemiologic centers for comparison with previously collected data. At the same time, these centers should use the current biomarker-based definition of acute MI to compare earlier data with subsequent data collected at research centers employing more recent standards for defining acute MI.

2. clinical trials

Myocardial infarction can be used either as an entry criterion or as an end point in a clinical trial. Entry criteria in clinical investigations dealing with suspected acute or evolving MI or unstable angina reflect the initial working diagnosis at the time the patient is enrolled in the trial. This will not necessarily correspond to the final diagnosis of MI, because spontaneous or therapeutically induced changes may alter the likelihood of developing myocardial necrosis. Usually, a combination of chest discomfort of a determined length of time and ECG abnormalities (ST segment elevation or a new bundle branch block) is required for the initial working diagnosis of MI. Trials of long-term management may require a definite or hospital discharge diagnosis of MI, usually on the basis of ECG Q waves and biochemical markers. Independent of the precise entry criteria chosen, the randomization process will ensure balanced groups of patients for comparison of different treatment modalities. Modification of the definition of MI may impact patient selection or the generalizability of the trial outcome, or both.

In many trials of MI or unstable angina, as well as of primary and secondary prevention of coronary heart disease events, MI is one of the trial end points, usually in combination with total mortality or cardiovascular mortality. In recent trials, different definitions of MI as an end point have been employed, thereby hampering comparison of trial results and meta-analyses.

Myocardial damage may occur in different clinical settings: spontaneous, during percutaneous intervention, during coronary artery bypass graft surgery or with trauma or myocarditis. It has been uncertain whether a similar amount of damage in different settings has the same prognostic implications. There have been different thresholds for identifying an infarct in trials undertaken up to this time in the U.S.: CK-MB >2 times the upper limit of normal (ULN) for spontaneous MI; CK-MB >3 times the ULN with coronary artery interventions; and CK-MB >5 to 10 times the ULN for bypass surgery. It is important that the background for such choices be subjected to research and verified or rejected from different databases. However, the Joint ESC/ACC Expert Committee reached the consensus opinion that, irrespective of the clinical circumstances (except for coronary artery surgery or intended myocardial lesions such as radiofrequency ablation of arrhythmias or septal ablation for hypertrophic cardiomyopathy), the same discriminative value for each biochemical marker should be applied, as they reflect the same amount of myocardial necrosis.

In clinical trials, as in clinical practice, measurement of cardiac troponin T or I is preferred over measurement of CK-MB, as well as total CK and other biomarkers, for the diagnosis of MI. Assessment of the quantity of myocardial damage (infarct size) is also an important trial end point. The use of cardiac troponin will undoubtedly increase the number of events recorded in a particular trial because of its increased sensitivity for detecting MI. Ideally, data should be presented so that trialists can translate the MI end point chosen in one trial into the end point of another trial. Thus, measurements should be presented in a continuous manner (distribution) to allow independent judgment of the clinical end points.

In the design of a trial, investigators should specify the expected effect of the new treatment under investigation. Factors that must be considered include:

• 1. Reduction in the incidence of spontaneous myocardial damage (events) in treated patients versus control subjects.

• 2. Reduction in the incidence of angioplasty- or bypass surgery–induced myocardial damage.

• 3. Reduction in the amount of myocardial damage (infarct size) under any circumstance. Analysis of the actual distribution of infarct sizes observed (area under the curve of a biomarker or peak values) is more appropriate than analysis of the presence or absence of events only.

Definition of MI

Criteria for acute, evolving or recent MI.

Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI:

• 1. Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following:

  • ischemic symptoms;

  • development of pathologic Q waves on the ECG;

  • ECG changes indicative of ischemia (ST segment elevation or depression); or

  • coronary artery intervention (e.g., coronary angioplasty).

• 2. Pathologic findings of an acute MI.

Pathology

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Biochemistry

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Electrocardiography

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Imaging

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3. Duca MD, Giri S, Wu AHB, et al. Comparison of acute rest myocardial perfusion imaging and serum markers of myocardial injury in patients with chest pain syndromes. J Nucl Cardiol 1999;6:570–6.

4. Gibler WB, Runyon JP, Levy RC, et al. A rapid diagnostic and treatment center for patients with chest pain in the emergency department. Ann Emerg Med 1995;25:1–8.

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6. Machecourt J, Longere P, Fagret D, et al. Prognostic value of thallium-201 single-photon emission computed tomographic myocardial perfusion imaging according to extent of myocardial defect. J Am Coll Cardiol 1994;23:1096–106.

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8. Peels, C, Visser CA, Funkekupper AJ, Visser FC, Roos JP. Usefulness of two-dimensional echocardiography for immediate detection of myocardial ischemia in the emergency room. Am J Cardiol 1990;65:687–91.

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10. Saeian K, Rhyne TL, Sagar KB. Ultrasonic tissue characterization for diagnosis of acute myocardial infarction in the coronary care unit. Am J Cardiol 1994;74:1211–5.

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Epidemiology

1. Burke GL, Edlavitch SA, Crow RS. The effects of diagnostic criteria on trends in coronary heart disease morbidity: the Minnesota Heart Survey. J Clin Epidemiol 1989;42:17–24.

2. Gillum RF, Fortmann SP, Prineas RJ, Kottke TE. International diagnostic criteria for acute myocardial infarction and acute stroke. Am Heart J 1984;108:150–8.

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8. Report of the Joint International Society and Federation of Cardiology/World Health Organization Task Force on Standardization of Clinical Nomenclature. Nomenclature and criteria for diagnosis of ischemic heart disease. Circulation 1979;59:607–9.

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