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In medicine, as in all human communication, clear definitions are essential. The history of medicine is filled with examples of communication failures that result when poor definitions of specific disease entities are used. In clinical practice, as in clinical science, a clear definition of the disease diagnosed or studied is the initial, critical step in managing that illness. Accurate, clear definitions of a disease entity enable clinicians to communicate among themselves, to study the disease, and ultimately to explain to patients the specific condition from which the patient suffers. A clinical scientist’s diagnostic criteria must also be accurate and reproducible so that similar patients with the disease are studied and entered into clinical trials. When accurate, reproducible definitions of a specific disease entity are used, results from one clinical trial can be compared with the results from other trials, and clinicians can communicate accurately among themselves concerning a specific disease.
Given the worldwide importance of morbidity and mortality of cardiovascular disease, considerable scientific effort has been expended in order to identify laboratory tools for clearly and accurately defining the various syndromes of acute ischaemic heart disease. One such modern tool involves the use of biomarkers. Biomarkers are adjunctive tests employed alongside clinical findings to aid physicians in making accurate clinical diagnoses.w1 Various biomarkers have been used for decades in patients with acute ischaemic heart disease; however, the advent of highly specific troponin assays has significantly improved identification of patients with acute ischaemic heart disease. Risk stratification of these patients has also been aided by the use of the troponin measurements in daily clinical practice. The biomarker troponin is the most sensitive and specific test yet devised for identifying myocardial cell necrosis.
The use of troponin blood assays to define various syndromes of acute ischaemic heart disease has gained worldwide use. Currently, in an appropriate clinical setting, an elevated blood troponin value represents the “gold standard” for identifying acute ischaemic myocardial necrosis—that is, acute myocardial infarction (MI).
Until recently, the ideal of a universally applied definition involving biomarker determination did not exist for patients with acute MI. With respect to public health statistics, similar problems have existed with different studies employing varying definitions for MI. Statistics based on hospital discharge diagnoses of MI are also inaccurate since the definitions of MI employed vary from one physician to another and from one hospital to another.
More than 30 years ago, the World Health Organization sought to prepare a standardised definition of MI for use by physicians throughout the world.w2 The criteria employed in this definition, however, were epidemiologically based and in a clinical setting were too non-specific, as well as open to important interpretation bias. For example, a patient’s clinical chest discomfort, or an equivalent symptom such as sudden onset of unexplained dyspnoea, might be interpreted differently by different observers. Similarly, ECG readings might vary from one observer to another. Since the biomarker assays employed in the past to identify myocardial necrosis were quite non-specific and not highly reproducible, biomarker measurement was not an important component of the original WHO definition for acute MI.
Box 1 Definition of myocardial infarction
Criteria for acute myocardial infarction (MI)
Any one of the following criteria meets the diagnosis for MI:
Detection of elevated values of cardiac biomarkers (preferably troponin) above the 99th centile of the upper reference limit (URL) together with evidence of myocardial ischaemia with at least one of the following:
ECG changes indicative of new ischaemia (new 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.
Sudden unexpected cardiac death, including cardiac arrest, with symptoms suggestive of myocardial ischaemia, accompanied by new ST elevation, or new LBBB, or definite new thrombus by coronary angiography but dying before blood samples could be obtained, or in the lag phase of cardiac biomarkers in the blood.
For percutaneous coronary interventions (PCI) in patients with normal baseline values, elevations of cardiac biomarkers above the 99th centile URL are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers greater than 3 × 99th centile URL have been designated as defining PCI related MI.
For coronary artery bypass grafting (CABG) in patients with normal baseline values, elevations of cardiac biomarkers above the 99th centile URL are indicative of periprocedural myocardial necrosis. By convention, increases of biomarkers greater than 5 × 99th centile URL plus either new pathological Q waves or new LBBB, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium have been designated as defining CABG related MI.
Pathological findings postmortem of an acute MI.
Criteria for prior MI
Any one of the following criteria meets the diagnosis for prior MI:
Development of new pathological Q waves with or without symptoms.
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischaemic cause.
Pathological findings postmortem of a healed or healing MI.
In order to improve the accuracy of the diagnosis of MI for clinicians and clinical scientists, multinational task forces met in 1999–2000 and 2005–2007 under the auspices of the European Society of Cardiology (ESC), the American College of Cardiology (ACC), the American Heart Association, and the World Heart Federation in order to develop a simple, clinically oriented, universal definition for MI that could be employed both in daily clinical practice and in clinical investigation. The report of the original task force was published simultaneously in the European Heart Journal and the Journal of the American College of Cardiology in 2000, and the revised definition was published in October 2007 in the same two journals and 1 month later in Circulation.1 2
Central to the new universal definition of MI was the use of the highly sensitive and specific biomarker, troponin, determined from serial blood samples. This particular biomarker is now employed throughout the world for the diagnosis of MI (fig 1). Determining blood troponin concentrations enables clinicians and clinical scientists to identify even small quantities of necrotic myocardium in an appropriate clinical setting of acute MI. The report of the task force in 2007 revised the criteria set in 2000 (box 1).2
The global definition of MI from the publications of both 2000 and 20071 2 are based on troponin analysis. Troponin assays are so sensitive that they can identify infarcts too small to be seen with the naked eye during routine pathological examinations. Troponin determination in patients with acute ischaemic heart disease aids clinicians and clinical scientists in more ways than merely establishing the diagnosis of myocardial necrosis. Indeed, the presence and degree of elevation of blood troponin concentrations in a patient with an acute ischaemic syndrome confers important prognostic and therapeutic implications.
Since the publication of the ESC/ACC document in 2000, which emphasised the use of troponin for the diagnosis of MI, a number of investigators have explored the implications of the universal definition of MI as compared with older more traditional (and less specific) diagnostic criteria.3–11 w3 w4 These studies have conclusively shown that the modern troponin based definition of MI increases the number of patients identified as having had an MI (fig 2). This is not a surprising finding since troponin is considerably more sensitive compared with earlier biomarkers such as creatine kinase (CK)-MB. Since troponin identifies smaller infarcts than does CK-MB analysis, the acute or short term prognosis for patients with troponin positive, CK-MB negative infarcts is better than that for patients with elevated troponin as well as CK-MB values. These recent observations underscore the fact that troponin analysis increases both the sensitivity and specificity of MI diagnosis.
Thus, patients who formerly would have been labelled as having angina pectoris or even unstable angina pectoris are now diagnosed as having had an MI when troponin biomarker assays are employed to assist clinicians. The diagnosis of MI involves important prognostic, psychological, and social implications for the patient. Treatment may be altered and, depending on the patient’s employment, certain careers may be interdicted by the diagnosis of MI.
THE DEFINITION OF MI IN THE 2007 CONSENSUS DOCUMENT
The pathological definition of MI is myocardial cell death caused by prolonged ischaemia. In the clinical setting these conditions are met when the following criteria are present:
Detection of a rise and/or fall of cardiac biomarkers (troponin preferred) with at least one value above the 99th centile of the upper reference limit (URL) together with evidence of myocardial ischaemia as recognised by at least one of the following:
symptoms of ischaemia
ECG changes of new ischaemia or development of pathological Q waves
or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality (box 1).2
Cardiac troponins (I and T) are the preferred markers for the diagnosis of any type of myocardial injury since this biomarker has nearly absolute myocardial tissue specificity, as well as high sensitivity, reflecting even microscopic zones of myocardial necrosis.w5 Optimal precision at the 99th centile URL for each assay is defined as a coefficient of variation ⩽10%.w6 w7 If troponin assays are not available, the best alternative is the MB fraction of CK measured by mass assay. As with troponin, an increased CK-MB mass value is defined as a measurement above the 99th centile URL using gender appropriate normal ranges.w6 However, given its greater sensitivity and specificity, troponin is greatly preferred for the diagnosis of MI.
Meticulous attention to laboratory technique must be exercised in performing troponin assays.w8 Unfortunately, some assays, including most of those developed for point of care use, are not nearly as sensitive as those that are performed on larger pieces of equipment used in central laboratories. Therefore, one needs to be cautious in using point of care assays to avoid under identification of patients at risk. There are other problems involved with troponin assays that must be considered. Fibrin and antibody interference can occur and cause an occasional spuriously high troponin value.w9 If a single troponin value seems to be out of proportion to other values, it is suggested that the sample be re-spun and re-assayed, especially if serum samples are being used. Erroneous measurements or persistent myocardial injury from a non-ischaemic source can lead to troponin values that are elevated constantly over time.
Thus, it has become clear that a changing pattern of troponin values is the key to distinguishing acute problems from more chronic ones. The ability to detect such changes is heavily dependent on the precision of the troponin assay. A 10% coefficient of variability at the 99th centile of a normal population has been advocated for troponin assays.2 w7
If one utilises sensitive assays and the 99th centile URL, troponin values rise more rapidly than CK-MB measurements. Consequently, the use of biomarkers such as myoglobin and other rapidly rising markers is no longer necessary in order to establish the diagnosis of acute MI.w10–12 In addition, myoglobin is not specific for the diagnosis of myocardial necrosis. The 99th centile URL value for troponin maximises the sensitivity and specificity of this biomarker for patients with MI.w13 The diagnosis of an acute MI can be made in as many as 80% of patients within 3 h of presentation, even in an early presenting cohort (within 4 h) of patients.w14 Late detection of MI is also facilitated since troponin values often remain elevated for 4–7 days following infarction.w15
Box 2 ECG manifestations of acute myocardial ischaemia (in absence of left ventricular hypertrophy and left bundle branch block)w2
New ST elevation at the J point in two contiguous leads with the cut-off points:
⩾0.2 mV in men or ⩾0.15 mV in women in leads V2–V3 and/or ⩾0.1 mV in other leads.
ST depression and T wave changes
New horizontal or downsloping ST depression ⩾0.05 mV in two contiguous leads and/or
T inversion ⩾0.1 mV in two contiguous leads with prominent wave or R/S ratio >1.
Both cTnI and cTnT, assuming good assays and appropriate cut-off values, perform comparably in terms of diagnostic accuracy. The one difference between these two troponin assays occurs in patients with renal failure in whom there are greater numbers of elevations of cTnT compared with cTnI.12 Pathologic studies suggest that these elevated values denote prognostic cardiac abnormalities12 in these patients with renal insufficiency. Moreover, they are highly prognostic.12 13 w16 w17 Thus, patients with renal insufficiency who have elevated concentrations of cTnT require further clinical evaluation. It is important to emphasise that these individuals may have elevated troponin values that are not the result of acute ischaemic heart disease. Patients with renal failure and an acute MI may present with troponin concentrations that rise from an already elevated baseline value.w17 A rising pattern of cTn values distinguishes those who have acute ischaemic heart disease from those with chronic elevations secondary to presumed myocardial injury resulting from some aspect of renal failure.
Box 3 ECG changes associated with prior myocardial infarctionw2
Any Q wave in leads V2–V3 ⩾0.02 s or QS complex in leads V2 and V3.
Q waves ⩾0.03 s and ⩾0.1 mV deep or QS complex in leads I, II, aVL, aVF or V4–V6 in any two leads of a contiguous lead grouping (I, aVL,V6; V4–V6; II, III, aVF).
R wave ⩾0.04 s in V1–V2 and R/S ⩾1 with a concordant positive T wave in the absence of a conduction defect.
ELECTROCARDIOGRAPHIC DETECTION OF MI
The ECG criteria utilised for the diagnosis of acute myocardial ischaemia that may lead to infarction are listed in box 2.2 The J point is used to determine the height of the ST elevation. The term “posterior” to reflect the basal part of the left ventricular wall that lies on the diaphragm is no longer a recommended ECG term. It is preferable to refer to this territory as inferobasal.
As shown in box 3,w2 Q waves or QS complexes are usually diagnostic of a prior MI in the absence of QRS confounders. ST or T wave deviations alone are not specific findings for myocardial necrosis since they may reflect ischaemia without myocardial cell death. However, when these abnormalities occur in the same leads as the Q waves, the likelihood of MI is increased.
Imaging techniques can be useful in the diagnosis of MI because of their ability to detect wall motion abnormalities which, in the presence of elevated cardiac biomarkers, are diagnostic of an acute MI. If, for some reason, biomarkers have not been measured or may have normalised, demonstration of new loss of myocardial viability alone, in the absence of non-ischaemic causes of myocardial cell injury, meets the criteria for MI (fig 3). However, if biomarkers have been measured at appropriate time intervals and, if biomarker values are normal, then MI has not occurred.w2
Echocardiography is useful in the diagnosis of many non-ischaemic causes of acute chest pain such as perimyocarditis, valvular heart disease, cardiomyopathy, pulmonary embolism or aortic dissection. Moreover, echocardiography is the imaging technique of choice for the detection of complications of acute infarction such as myocardial free wall rupture, acute ventricular septal defect, and mitral regurgitation secondary to papillary muscle rupture or ischaemia. Unfortunately, echocardiography cannot distinguish regional wall motion abnormalities due to myocardial ischaemia from those that are the result of infarction.
An important role for urgent echocardiography or radionuclide imaging is in patients with suspected MI and a non-diagnostic ECG. A normal echocardiogram or resting ECG gated scintigram rules out infarction with a 95–98% negative predictive value.2 Thus, imaging techniques can be used for early triage and discharge of patients with suspected MI.2 High resolution, contrast enhanced MRI can be employed to delineate areas of late enhancement that correlate well with areas of fibrosis that represent a prior MI.
ELEVATED TROPONIN VALUES THAT ARE NOT THE RESULT OF ACUTE ISCHAEMIC HEART DISEASE
It is important to note that a variety of disease entities can injure myocardium (for example, trauma, myocarditis, chemotherapeutic agents, etc), thereby leading to elevated values of troponin. These other entities are not the result of acute ischaemic heart disease and careful clinical evaluation should be used to prevent these patients from being labelled as having had an acute MI (box 4). Injury to myocardium that is not the result of ischaemia has been termed “collateral myocardial injury”. As noted in box 4, a variety of disease states can injure the myocardium leading to elevated blood troponin values.
Box 4 Elevation of troponin in the absence of overt ischaemic heart disease
Cardiac contusion, including ablation, pacing, cardioversion, or endomyocardial biopsy
Congestive heart failure: acute and chronic
Aortic dissection, aortic valve disease or hypertrophic cardiomyopathy
Tachy- or bradyarrhythmias, or heart block
Apical ballooning syndrome
Rhabdomyolysis with cardiac injury
Pulmonary embolism, severe pulmonary hypertension
Acute neurological disease, including stroke, or subarachnoid haemorrhage
Infiltrative diseases—for example, amyloidosis, haemochromatosis, sarcoidosis, and scleroderma
Inflammatory diseases—for example, myocarditis, or myocardial extension of pericarditis
Drug toxicity—for example, doxorubicin, 5-fluorouracil, trastuzumab, snake venoms
Critically ill patients, especially with respiratory failure, or sepsis
Burns, especially if affecting >30% of body surface area
THE SIGNIFICANCE OF ELEVATED BLOOD TROPONIN VALUES IN PATIENTS WITH ACUTE ISCHAEMIC HEART DISEASE AND SUBSETS OF PATIENTS WITH ACUTE MI
In the setting of acute ischaemic heart disease, the prognostic significance of an elevated troponin is clear. In patients with ST segment elevation MI (STEMI), those with elevated troponins at the time of presentation are at increased risk for subsequent adverse events.14 w18 In studies involving primary angioplasty for STEMI, the procedural success rate is lower when troponin is elevated at the time of presentation.w19 In patients with non-STEMI, the finding of an elevated troponin presages an adverse short term outcome and usually indicates the need for aggressive anticoagulation as well as early interventional treatment.15 16 w20–27
There is heterogeneity of causation in patients with acute MI2 (box 1). MI can be a spontaneous event related to plaque rupture, fissuring, or dissection, or nodular plaque rupture, the so-called type I MI.1 2 Alternatively, MI can result from increased myocardial oxygen demand combined with inadequate myocardial supply of oxygen and nutrients. This could be the result of anaemia, arrhythmia, and hyper- or hypotension in the setting of coronary artery disease. Vasoconstriction or arterial spasm, causing a pronounced reduction in myocardial blood flow, can also lead to severe myocardial ischaemia and MI. This latter group of entities are termed type 2 MI (box 1).2 In addition, elevated troponin values (>3 times the URL) following a percutaneous coronary intervention (PCI) has been designated as an acute MI resulting from myocardial ischaemia (type 4a MI). A second category of type 4 MI (type 4b MI) results from stent thrombosis. Finally, elevations of troponin (>5 times the URL) can be used in the diagnosis of a type 5 MI—that is, an infarct associated with coronary bypass surgery (box 1).2
One circumstance in which biomarkers are not involved in the diagnosis of MI is when a patient with a typical presentation for myocardial ischaemia/infarction dies before the time when it is possible to detect blood biomarker elevation, either because blood samples for troponin determination were not obtained or the patient succumbed soon after the onset of symptoms before troponin values could become elevated. Such patients are designated as having a type 3 MI.2
The prognostic significance of an elevated troponin value in a patient with an acute MI is related to the magnitude of the elevation. Smaller degrees of cardiac injury, denoted by small elevations in troponin values, are associated with a better acute prognosis as compared with larger troponin elevations.10 However, long term prognosis is less affected by the degree of troponin elevation noted during the acute phase of an MI.
Universal definition of myocardial infarction: key points
In the past, the criteria used for the diagnosis of acute myocardial infarction (MI) in a clinical setting was not specific and resulted in the use of conflicting definitions.
In 2000 a task force from the European Society of Cardiology and the American College of Cardiology developed a consensus universal clinical definition for acute and established MI.
In 2007, this universal definition was revised by a global task force (European Society of Cardiology, American College of Cardiology, American Heart Association, World Heart Federation).
Changes in the new document from 2007 included new material involving imaging and revised ECG criteria for the diagnosis of MI, as well as criteria relating to patients who died suddenly before blood biomarkers could be measured and individuals who suffered ischaemic myocardial necrosis in the setting of a revascularisation procedure.
Measurement of blood troponin values remains the “gold standard” for the diagnosis of acute MI.
Troponin is the most sensitive and specific biomarker for myocardial cell death.
Once an elevated troponin value has been noted in a patient with an acute MI, it is difficult to differentiate the effect of the original MI on troponin values from those associated with reinfarction occurring spontaneously or secondary to PCI. In this setting, it is essential to have a pre-PCI baseline troponin value for comparison with post-PCI determinations.2 Traditionally, CK-MB measurements have been used to detect reinfarction. However, recent data suggest that troponin values provide similar information.w28 w29 If a recurrent MI is suspected from clinical signs or symptoms following the initial infarction, an immediate measurement of the employed cardiac marker (preferably troponin) is recommended. A second sample is then obtained 3–6 h later. Recurrent infarction is diagnosed if there is a ⩾20% increase of the value in the second sample compared to the first value.
The diagnosis of reinfarction following an initial infarction by ECG criteria may be confounded by the presence of the initial evolutionary ECG changes. Reinfarction should be considered when either ST elevation ⩾0.1 mV reoccurs in a patient having a lesser degree of ST elevation or new diagnostic Q waves are seen in at least two contiguous leads. Reinfarction is particularly suggested when ECG changes are associated with ischaemic symptoms lasting ⩾20 min.
Recent data suggest that troponin measurement is as accurate as determination of CK-MB for identifying reinfarction.w28
EFFECT OF THE NEW, TROPONIN BASED DEFINITION OF MI
The new criteria for the diagnosis of MI has dramatically increased the frequency of the diagnosis of MI, thereby impacting epidemiological studies and clinical practice. Since smaller infarcts are now identified with the troponin “gold standard”, the overall acute prognosis for MI has improved with the addition of individuals with very small infarcts. However, long term prognosis is affected minimally or not at all. Employment, health insurance and evaluation of health care delivery statistics are also affected.
For example, one study demonstrated an increase in the number of patients with an MI by 26.1% when the new troponin based definition for MI was used as compared with the previously employed WHO classification.4 It is interesting that in this study, the WHO criteria resulted in false positive rates for the diagnosis of MI of approximately 5%.5 Most of the additional patients with the troponin based diagnosis of MI were previously labelled as unstable angina. However, 33% were previously diagnosed as having “other cardiac” or “non-cardiac” diagnoses.
In another prospective US community study involving patients who presented with suspected cardiac discomfort, the use of a troponin T assay resulted in a 74% increase over CK and a 41% increase over CK-MB criteria for the diagnosis of MI.w9 Patients diagnosed with the troponin based definition for MI were at increased risk for morbid and mortal events, but at less risk compared with individuals with elevated troponin and CK-MB values who had presumably suffered larger infarctions.10
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GENERAL IMPLICATIONS OF REDEFINING MI
The revised universal definition of MI has a number of psychological and social implications for individuals as well as for society at large, since more patients will receive the diagnosis of MI and public health statistics will be altered. As noted earlier, the troponin based definition of MI is useful for prognostication as well as for diagnosis. However, it is important for the clinician to characterise other clinical prognostic factors such as the extent of the infarct, residual left ventricular function, and the severity of associated coronary artery disease rather than merely establishing a diagnosis of MI. The information conveyed about the patient’s prognosis and subsequent lifestyle requires more than just the statement that the patient has suffered an infarct. The many other factors just mentioned are also required so that appropriate social, family, and employment decisions can be made. An elevated blood troponin value by itself does not establish the diagnosis of acute MI. Careful clinical correlation is required in order to make this diagnosis.
This was the first attempt to arrive at a universal definition of MI for use by clinicians. The consensus task force was predominantly from Europe and North America.
This represents the current revised universal definition for MI and includes new material on defining MI after revascularisation, with ECG and imaging, and sudden death criteria. The consensus task force was global in nature.
The new troponin based, universal definition for MI results in changing the diagnosis of unstable angina to non-ST elevation MI in a substantial number of patients.
The new universal definition for MI is based on clinical criteria that may not be completely applicable in the setting of a community wide epidemiological study. Other criteria will need to be added to the universal definition for epidemiological studies.
Support for the new definition in terms of accuracy of identification of ischaemic myocardial necrosis in a clinical setting and improved prognostication for patients with an acute ischaemic syndrome.
Troponin is the most sensitive and specific biomarker for identifying myocardial necrosis.
An authoritative and up-to-date review of the use of biomarkers in clinical acute cardiac disease.
In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests.
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