第三版心肌梗死定义英文版.doc

Clinical BiochemistryVolume 46, Issues 12, January 2013, Pages 14Third Universal Definition of Myocardial Infarction Allan S. Jaffe, IntroductionThe Third Universal Definition of Myocardial Infarction (MI) was recently published conjointly by the major cardiology organizations throughout the world and in the journals of the World Health Organization (WHO). This definition builds on two previous two iterations which were developed to make the diagnosis of myocardial infarction (MI) more consistent.The efforts started originally in 1999 in the conference in Nice stimulated by the innovation of Dr. Kristian Thygesen and Dr. Joseph Albert who had recognized this problem and who developed a task force jointly sponsored by the ACC (American College of Cardiology) and the ESC (European Society of Cardiology) to attempt to standardize the definition of MI 1. This major step led to the first document which moved the field from the epidemiologically oriented definition of MI which had been developed by the WHO to track the incidence of coronary disease and therefore was oriented towards specificity to a more clinically oriented definition which relied on biomarkers as a key feature of the diagnosis. This resulted in a paradigm shift where the diagnosis required documentation of myocardial necrosis with biomarkers and especially cardiac troponin (cTn) which was emerging at the time in the proper clinical situation. A second iteration in 2007 2 updated the guidelines and the 2012 definition refines the definition still further particularly as it relates to biomarkers 3 which have in the past decade become progressively more and more sensitive. Intrinsically, increases in sensitivity of this sort tend to result in a diminution of specificity since increasingly sensitive measurements often unmask new etiologies for in this instance, elevations of these sensitive cTn biomarkers.Areas of the 2012 definition that remains important but unchangedThe definition of MI from the pathologic circumstance obviously is not going to change. The definition mandates the finding of cardiomyocyte necrosis defined pathologically due to myocardial ischemia. However, the clinical definition since pathology is not readily available to guide clinical care relies on a surrogate marker for cardiac injury; i.e., cardiac biomarkers and particularly, cTn. As in previous iterations, cTn is the biomarker of choice and strongly preferred for the overall guidelines as well as for each specific guideline. The definition of MI from the clinical perspective has not changed substantively. It requires detection of a rise and/or a fall of a cardiac biomarker, preferably cTn, with at least one value above the 99th percentile reference limit in the appropriate clinical setting (see Table1 for criteria). There are additional types of MI which will be covered subsequently but the guidelines rely heavily on clinical signs or symptoms, a clinical situation where ischemia is suspected even if signs and symptoms are absent or imaging information suggestive of ischemia in the presence of a changing pattern of elevated biomarkers.Table1. Criteria for acute myocardial infarction (Third Universal Definition of Myocardial Infarction). Detection of a rise and/or a fall of cardiac biomarker values (preferably cardiac troponin (cTn) with at least one value above the 99th percentile upper reference limit (URL) and at least one of the following: Ischemic symptoms ECG changes of new ischemia (new STT changes or new LBBB) Development of pathologic 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 autopsyFull-size tableTable optionsThe metrics for the use of these biomarkers remain the same. One needs a value above the 99th percentile of the upper reference limit with a rising and/or a falling pattern of values. However, as cTn assay sensitivity has improved, the ability to consistently operationalize these criteria has become more problematic as will be discussed below. The document also recognizes a variety of special clinical circumstances which require unique handling. Some of these are related to cardiac procedures such as percutaneous interventions (PCI) or coronary artery bypass graft (CABG) surgery but others to novel procedures that are being developed such as transcutaneous aortic valve interventions (TAVI). The document discusses as well subsets of patients who are critically ill, those with heart failure, and those undergoing non-cardiac surgery as well. These classifications are not new from the 2007 document but are considered in greater detail.Issues related to biomarkersAs in the past, cTn is the marker of choice and a rise and/or a fall in values is necessary to define an acute event such as MI. It is recognized that there is some tension about how one defines the 99th percentile. It is assay dependent and is often defined based on convenience samples. Therefore, there is concern that perhaps they are not as reliable as if the sample populations were more intensively studied 4. The values for these assays should be expressed in ng/L so that they are whole numbers because as assays become more complicated and more sensitive, the number of zeros could lead to clinical dysfunction. The assays should be precise and the document prefers assays that have excellent precision with a CV of 10% or less of the 99th percentile to allow detection of changing values. However, the document allows for assays with CVs up to 20% to be used 5. It also is noted that analytic and pre-analytic problems can be problematic and lead to false-positive and false-negative values especially with more sensitive assays. It is also recommended that sex dependent values may be used with high sensitivity assays.Sampling should be done at 0, 3, and 6h and later if additional episodes occur or if the timing of the initial symptoms is unclear. The diagnosis requires a rising and a falling pattern which is essential to differentiate elevations that are acute from those that are chronic and associated with structural heart disease such as patients with renal failure, heart failure, left ventricular hypertrophy, and the like. It is recognized that one needs to be careful because at times one could present sufficiently late as to miss an elevated value or could be near the time of peak values at which point in time one could believe that a change had not occurred when simply the values were similar on both sides of the peak.It is recognized and allowed that there may be circumstances in which cardiac injury could be present but not meet the diagnosis of MI because it is not in the appropriate setting or does not manifest a rise and a fall and there are a large number of such situations in which a diagnosis of cardiac injury may be more appropriate than the diagnosis of acute MI (see Table2).Table2. Elevations of cardiac troponin values because of myocardial injury (Third Universal Definition of Myocardial Infarction). Injury related to primary myocardial ischemia (MI type 1; i.e., plague rupture, intraluminal coronary artery thrombus formation) Injury related to supply/demand imbalance of myocardial ischemia (MI type2;i.e., tachy-/brady-arrhythmias, aortic dissection, or severe aortic valve disease, hypertrophic cardiomyopathy, cardiogenic or septic shock, severe respiratory failure, severe anemia, hypertension with or without LVH, coronary spasm, coronary embolism or vasculitis, coronary endothelial dysfunction without significant CAD) Injury not related to myocardial ischemia (i.e., cardiac contusion, surgery, ablation, pacing, defibrillator shocks, rhabdomyolysis with cardiac involvement, myocarditis, cardiotoxic agents) Multifactorial or indeterminate myocardial injury (i.e., heart failure, stress (takotsubo) cardiomyopathy, severe pulmonary embolism or pulmonary hypertension, sepsis and critically ill patients, renal failure, severe acute neurological (e.g., stroke) infiltrative diseases (e.g., amyloidosis), strenuous exercise)Operationalizing change in cTn values is complex and assay dependent. It should be clear that given previous ways of diagnosing infarction have often not required changes over time that as one starts to implement these changes, one will have differences in both sensitivity and specificity 6. In fact, most of the data in this area suggests that the use of delta change criteria improves specificity but at the cost of sensitivity. There are multiple reasons why this could be the case. The first is that it may be that there are patients being diagnosed with acute infarction who do not have a rising and a falling pattern based on clinical judgment since one can have acute looking plaques even in patients with stable coronary artery disease 7. A second potential issue relates to the situation where there is variation in coronary artery perfusion. Biomarker release is flow dependent and the consequence of that is that there may well be circumstances with closed vessels where it takes much longer for the egress of marker to reach the circulation than in others. Thus, the idea of short periods of one or two hour sampling times looking for change may be inadequate. There also are issues related to the spontaneous change that can occur. This has been termed biological variation and clearly is much more substantial than just the variability associated with the imprecision of the assays 8. Nonetheless, it is clear there is some overlap between the values that one believes are associated with patients with MI and the values that are considered part of the spontaneous biological variation 9. In addition, the optimal values to use with each assay are not clear. One could calculate an ROC curve which many laboratorians are enamored of doing and pick the value that classifies the most patients correctly. However, this may not be what clinicians need. Cardiologists want relatively high specificity to avoid unnecessary procedures in patients who are not at risk, whereas emergency department physicians often want more sensitive criteria so that they do not inadvertently discharge patients who are at risk 10. The balance between these two needs to be found at each institutional level. Thus, the complexity of this issue, with high-sensitivity assays, needs to be discussed at each local site and adjudicated on a case by case by assay basis.Classification of MIsThere are multiple reasons why cTn could be elevated that need to be distinguished from MI. One could have a rising and a falling pattern of cTn due to sepsis or pulmonary embolism, or acute heart failure with myocardial stretch; none of which would be associated, nor should be considered the same as MI. In addition, there are types of MIs as well and it may well be of some importance to distinguish the types as the care of these individuals may be different. The task force recognized multiple types of acute MI 3. They define type 1 which many have called the so called “wild” type as an episode associated with plaque rupture and spontaneous in nature. Thus, these patients most often present after an episode of chest discomfort often with ECG changes, elevated biomarkers, and in the studies of such patients it is clear that having an elevated cTn indicates a beneficial response to an aggressive strategy with anticoagulation and the use of IIb/IIIa agents and early invasive strategy 11. So called type 2 MIs are less typical. They often occur in patients who have fixed atherosclerotic disease who developed tachycardia, hyper- or hypotension, or in individuals who have abnormalities in coronary vasomotion such that they do not improve increased coronary blood flow in response to stress or have overt vasospasm. Such events can even occur in some individuals whose coronary arteries are totally normal but who have such severe supply demand imbalance due to extreme tachycardia, hyper- or hypotension. These scenarios can become complex. One could suggest that there is a continuum between myocardial injury which might be diagnosed, for example, in a young person with tachycardia who had an elevated cTn than who was totally asymptomatic, to a similar patient who might have more typical chest pain who might be called a type 1 MI, to an individual who might have vague symptoms that are difficult to classify in whom a diagnosis of type 2 MI might be made. This is an area where clinical judgment will be important for clinicians but it should be clear that solitary elevation of cTn even with a rising and a falling pattern does not mandate a diagnosis of MI. These distinctions are made more difficult by the fact that in certain circumstances such as the elderly, the diabetic, and patients who are postoperative classic findings may not be observed.Type 3 MI subsumes that circumstance where there is a patient with a classic MI documented either by electrocardiography or angiography where the biomarkers have not been obtained or have not had sufficient time to be elevated. This is rarely a problem except in those patients who succumb at a very early time during the process.There also are myocardial infarctions associated with revascularization procedures such as PCI or CABG. These are complex and will be covered below.Electrocardiographic changesThe electrocardiographic changes that should be observed for did not change markedly but looking for evidence of circumflex coronary artery ischemia is emphasized. Posterior leads (V7V9) should be recorded in patients who may have circumflex involvement. This may be suspected if there is ST segment depression in V1V3. The ECG criteria for acute MI and common ECG pitfalls in diagnosing infarction are detailed in the Third Universal Definition of Myocardial Infarction 3.Periprocedural myocardial infarctionsThis is an area of intense controversy. It is clear that myocardial injury can occur after percutaneous procedures. This can be due to emboli, whether they are a clot of atherosclerotic, occlusion of a side branch, or simply prolonged ischemia. What has been problematic has been the ability to know for sure that these events are associated with an adverse prognosis 12. The criteria provided do not attempt to make that distinction since such a distinction requires outcome data. The thought with that is that for many such elevations, elevations prior to the procedure are present but have been ignored 12. Indeed in recent meta-analysis, not one study that claimed to have a normal baseline had such a baseline. Therefore, the proponents of this particular point of view would argue that there is rarely prognostic significance. If so, the question arises as to whether or not diagnosing these patients with acute MI is of value. The opposing view is that prior studies, particularly done with less sensitive markers where one could ignore the baseline changes because markers like CK-MB were insensitive and did not detect very many such elevations suggested that there was prognostic significance to these events. Given the task force has moved strongly toward a cTn oriented structure and did not have to, nor did, dwell on the issue of prognostic significance, the question then was viewed as how to define a distinction between the cardiac injury that might have led to the procedure and some sort of additional insult caused by the procedure itself. The task force then decided to mandate the need for a normal cTn value or documentation of a stable or a falling pattern at baseline and then to rely on a 5 fold elevation of cTn when there was a clear cut abnormality induced by the procedure itself or marked symptoms occurred. The criteria uses previously of a threefold was increased to fivefold along with these ancillary criteria given the increase in assay sensitivity that has occurred since 2007 but it should be clear that given the heterogeneity of present day cardiac troponin assays that this will be a moving target depending upon the assay that one utilizes in any given situation.A similar statement can be made for CABG. Unfortunately, given the heterogeneity of assays, there is no single cutoff value that can be utilized. However, it is clear that individuals who start with an elevated cTn preoperatively elaborate more cTn 3. Thus, a normal baseline value is important for comparative information. It is also clear that the more cTn that is elaborated, the more adverse the prognosis; thus, making many more comfortable with this diagnosis than with the post-PCI diagnosis 13. However, there also is an obligatory amount of injury that is indigenous to the cardiac surgical procedure and the question is how much should be or should not be included. An arbitrary decision was made to suggest that above a tenfold increase from the URL value for any given cTn assay should be considered abnormal and lead to investigation looking to see if the additional criteria were present. These could be provided by imaging or by the electrocardiogram.Novel circumstancesSeveral other circumstances are recognized in the guidelines that are of relevance. For example, any procedure done on the heart is likely to cause elevations of cTn. Therefore, transcatheter aortic valve implantations, the so called TAVI or mitral clip procedures are likely to cause such cardiac injury. The task force suggested that the criteria for CABG be applied in that circumstance. In non-cardiac surgical procedures, there often are cTn elevations. Many of these appear to be the so called type 2 events although definitive information in this area is lacking and it is not clear that we have defined well enough the appropriate clinical criteria to distinguish type 1 and type 2 MI 3. Nonetheless, it appears that at least based on an earlier data and vascular surgery patients that pati