third universal definition of myocardial infarctionthird universal deﬁnition of myocardial...

Journal of the American College of Cardiology Vol. 60, No. 16, 2012© 2012 by the European Society of Cardiology, American College of Cardiology Foundation, ISSN 0735-1097/$36.00

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EXPERT CONSENSUS DOCUMENT

Third Universal Definition of Myocardial Infarction

Kristian Thygesen, Joseph S. Alpert, Allan S. Jaffe, Maarten L. Simoons, Bernard R. Chaitman andHarvey D. White: the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force forthe Universal Definition of Myocardial Infarction

American Heart Association, Inc., and the World Heart Federation http://dx.doi.org/10.1016/j.jacc.2012.08.001ublished by Elsevier Inc.

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Authors/Task ForceMembersChairpersons

Kristian Thygesen (Denmark)*Joseph S. Alpert (USA)*Harvey D. White (New Zealand)*Biomarker Subcommittee:Allan S. Jaffe (USA)Hugo A. Katus (Germany)Fred S. Apple (USA)Bertil Lindahl (Sweden)David A. Morrow (USA)ECG Subcommittee:Bernard R. Chaitman (USA)Peter M. Clemmensen (Denmark)Per Johanson (Sweden)Hanoch Hod (Israel)Imaging Subcommittee:Richard Underwood (UK)Jeroen J. Bax (The Netherlands)Robert O. Bonow (USA)Fausto Pinto (Portugal)Raymond J. Gibbons (USA)Classification Subcommittee:Keith A. Fox (UK)Dan Atar (Norway)L. Kristin Newby (USA)Marcello Galvani (Italy)Christian W. Hamm (Germany)Intervention Subcommittee:Barry F. Uretsky (USA)Ph. Gabriel Steg (France)William Wijns (Belgium)Jean-Pierre Bassand (France)Phillippe Menasche (France)Jan Ravkilde (Denmark)

Trials & Registries Subcommittee:E. Magnus Ohman (USA)Elliott M. Antman (USA)Lars C. Wallentin (Sweden)Paul W. Armstrong (Canada)Maarten L. Simoons (The Netherlands)Heart Failure Subcommittee:James L. Januzzi (USA)Markku S. Nieminen (Finland)Mihai Gheorghiade (USA)Gerasimos Filippatos (Greece)Epidemiology Subcommittee:Russell V. Luepker (USA)Stephen P. Fortmann (USA)Wayne D. Rosamond (USA)Dan Levy (USA)David Wood (UK)Global Perspective Subcommittee:Sidney C. Smith (USA)Dayi Hu (China)Jose-Luis Lopez-Sendon (Spain)Rose Marie Robertson (USA)Douglas Weaver (USA)Michal Tendera (Poland)Alfred A. Bove (USA)Alexander N. Parkhomenko (Ukraine)Elena J. Vasilieva (Russia)Shanti Mendis (Switzerland)

*Corresponding authors/co-chairpersons: Professor Kristian Thygesen,Department of Cardiology, Aarhus University Hospital, Tage-HansensGade 2, DK-8000 Aarhus C, Denmark. Tel: �45 7846-7614; fax: �45846-7619: E-mail: [email protected]. Professor Joseph S. Alpert, De-artment of Medicine, Univ. of Arizona College of Medicine, 1501 N.ampbell Ave., P.O. Box 245037, Tucson AZ 85724, USA, Tel: �1

20 626 2763, Fax: �1 520 626 0967, Email: [email protected] Harvey D. White, Green Lane Cardiovascular Service, Aucklandity Hospital, Private Bag 92024, 1030 Auckland, New Zealand. Tel:64 9 630 9992, Fax: �64 9 630 9915, Email: harveyw@adhb.

ovt.nz. For permissions, please contact Elsevier’s permission de-artment: [email protected]/.

mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]/

1582 Thygesen et al. JACC Vol. 60, No. 16, 2012Expert Consensus Document October 16, 2012:1581–98

ESCCommitteefor PracticeGuidelines(CPG)

Jeroen J. Bax (CPG Chairperson)(The Netherlands)

Helmut Baumgartner (Germany)Claudio Ceconi (Italy)Veronica Dean (France)Christi Deaton (UK)Robert Fagard (Belgium)Christian Funck-Brentano (France)David Hasdai (Israel)Arno Hoes (The Netherlands)Paulus Kirchhof (Germany/UK)Juhani Knuuti (Finland)

Philippe Kolh (Belgium)Theresa McDonagh (UK)Cyril Moulin (France)Bogdan A. Popescu (Romania)Zeljko Reiner (Croatia)Udo Sechtem (Germany)Per Anton Sirnes (Norway)Michal Tendera (Poland)Adam Torbicki (Poland)Alec Vahanian (France)Stephan Windecker (Switzerland)

DocumentReviewers

Joao Morais (CPG Review Coordinator)(Portugal)

Carlos Aguiar (Portugal)Wael Almahmeed (United Arab Emirates)David O. Arnar (Iceland)Fabio Barili (Italy)Kenneth D. Bloch (USA)Ann F. Bolger (USA)Hans Erik Botker (Denmark)Biykem Bozkurt (USA)Raffaele Bugiardini (Italy)Christopher Cannon (USA)James de Lemos (USA)Franz R. Eberli (Switzerland)Edgardo Escobar (Chile)

Mark Hlatky (USA)Stefan James (Sweden)Karl B. Kern (USA)David J. Moliterno (USA)Christian Mueller (Switzerland)Aleksandar N. Neskovic (Serbia)Burkert Mathias Pieske (Austria)Steven P. Schulman (USA)Robert F. Storey (UK)Kathryn A. Taubert (Switzerland)Pascal Vranckx (Belgium)Daniel R. Wagner (Luxembourg)

The disclosure forms of the authors and reviewers are available on theESC website www.escardio.org/guidelines.

TABLE OF CONTENTS

Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1583

Definition of myocardial infarction . . . . . . . . . . . . . . . . . . . . .1584

Criteria for acute myocardial infarction. . . . . . . . . . . . . . .1584Criteria for prior myocardial infarction . . . . . . . . . . . . . . . .1584

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1584

Pathological characteristics of myocardial ischemiaand infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1585

Biomarker detection of myocardial injurywith necrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1585

Clinical features of myocardial ischemiaand infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1586

Clinical classification of myocardial infarction . . . . . . .1586

Spontaneous myocardial infarction (MI type 1) . . . . . .1587

Myocardial infarction secondary to an ischaemicimbalance (MI type 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1587Cardiac death due to myocardial infarction(MI type 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1587Myocardial infarction associated withrevascularization procedures (MI types 4 and 5) . . . .1587

Electrocardiographic detection ofmyocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1588

Prior myocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1589

Silent myocardial infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1589

Conditions that confound the ECG diagnosis ofmyocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1589

Imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1589

Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1590Radionuclide imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1590Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . .1590Computed tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1590

Applying imaging in acute myocardial infarction. . . . .1590

http://www.escardio.org/guidelines

1583JACC Vol. 60, No. 16, 2012 Thygesen et al.October 16, 2012:1581–98 Expert Consensus Document

Applying imaging in late presentation ofmyocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1591

Diagnostic criteria for myocardial infarctionwith PCI (MI type 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1591

Diagnostic criteria for myocardial infarctionwith CABG (MI type 5). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1592

Assessment of MI in patients undergoingother cardiac procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1592

Myocardial infarction associated withnon-cardiac procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1592

Myocardial infarction in the intensive care unit . . . . .1593

Recurrent myocardial infarction. . . . . . . . . . . . . . . . . . . . . . . . .1593

Reinfarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1593

Myocardial injury or infarction associatedwith heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1593

Application of MI in clinical trials and qualityassurance programmes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1594

Public policy implications of the adjustmentof the MI definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1594

Global perspectives of the definition ofmyocardial infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1595

Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1595

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1595

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1595

Abbreviations and acronyms

ACCF � American College of Cardiology FoundationACS � acute coronary syndrome

CAD � coronary artery diseaseCABG � coronary artery bypass graftingCKMB � creatine kinase MB isoformcTn � cardiac troponinCT � computed tomographyCV � coefficient of variationECG � electrocardiogramESC � European Society of CardiologyFDG � fluorodeoxyglucoseh � hour(s)HF � heart failureLBBB � left bundle branch blockLV � left ventricleLVH � left ventricular hypertrophyMI � myocardial infarctionmlBG � meta-iodo-benzylguanidinemin � minute(s)MONICA � Multinational MONItoring of trends and

determinants in CArdiovascular diseaseMPS � myocardial perfusion scintigraphyMRI � magnetic resonance imagingmV � millivolt(s)ng/L � nanogram(s) per literNon-Q Ml � non-Q wave myocardial infarctionNSTEMI � non-ST-elevation myocardial infarctionPCI � percutaneous coronary interventionPET � positron emission tomographypg/mL � pictogram(s) per milliliterQ wave Ml � Q wave myocardial infarctionRBBB � right bundle branch blocksec � second(s)SPECT � single photon emission computed tomographySTEMI � ST elevation myocardial infarctionST-T � ST-segment -T waveURL � upper reference limitWHF � World Heart Federation

AHA � American Heart Association WHO � World Health Organization


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 myocardialischemia. 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:y Symptoms of ischemia.y New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB).y Development of pathological Q waves in the ECG.y Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.y 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 cardiacbiomarkers 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 baselinevalues (�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) symptomssuggestive of myocardial ischemia or (ii) new ischemic ECG changes or (iii) angiographic findings consistent with a procedural complication or (iv) imagingdemonstration 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 cardiacbiomarker 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 withnormal baseline cTn values (�99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft ornew 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.

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Introduction

Myocardial infarction (MI) can be recognized by clinicalfeatures, including electrocardiographic (ECG) findings, ele-vated values of biochemical markers (biomarkers) of myocar-dial necrosis, and by imaging, or may be defined by pathology.It is a major cause of death and disability worldwide. MI maybe the first manifestation of coronary artery disease (CAD) orit may occur, repeatedly, in patients with established disease.Information on MI rates can provide useful informationregarding the burden of CAD within and across populations,especially if standardized data are collected in a manner thatdistinguishes between incident and recurrent events. From theepidemiological point of view, the incidence of MI in apopulation can be used as a proxy for the prevalence of CADin that population. The term ‘myocardial infarction’ may havemajor psychological and legal implications for the individualand society. It is an indicator of one of the leading healthproblems in the world and it is an outcome measure in clinicaltrials, observational studies and quality assurance programs.These studies and programs require a precise and consistentdefinition of MI.

In the past, a general consensus existed for the clinicalsyndrome designated as MI. In studies of disease preva-lence, the World Health Organization (WHO) defined MIfrom symptoms, ECG abnormalities and cardiac enzymes.However, the development of ever more sensitive andmyocardial tissue-specific cardiac biomarkers and moresensitive imaging techniques now allows for detection of

very small amounts of myocardial injury or necrosis. Addi- b

tionally, the management of patients with MI has signifi-cantly improved, resulting in less myocardial injury andnecrosis, in spite of a similar clinical presentation. More-over, it appears necessary to distinguish the various condi-tions which may cause MI, such as ‘spontaneous’ and‘procedure-related’ MI. Accordingly, physicians, otherhealthcare providers and patients require an up-to-datedefinition of MI.

In 2000, the First Global MI Task Force presented a newdefinition of MI, which implied that any necrosis in thesetting of myocardial ischemia should be labeled as MI (1).

hese principles were further refined by the Second GlobalI Task Force, leading to the Universal Definition ofyocardial Infarction Consensus Document in 2007, which

mphasized the different conditions which might lead to anI (2). This document, endorsed by the European Society

f Cardiology (ESC), the American College of Cardiologyoundation (ACCF), the American Heart Association

AHA), and the World Heart Federation (WHF), has beenell accepted by the medical community and adopted by theHO (3). However, the development of even more sensi-

ive assays for markers of myocardial necrosis mandatesurther revision, particularly when such necrosis occurs inhe setting of the critically ill, after percutaneous coronaryrocedures or after cardiac surgery. The Third Global MIask Force has continued the Joint ESC/ACCF/AHA/HF efforts by integrating these insights and new data into

he current document, which now recognizes that very smallmounts of myocardial injury or necrosis can be detected by

iochemical markers and/or imaging.

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Pathological characteristics ofmyocardial ischemia and infarction

MI is defined in pathology as myocardial cell death due toprolonged ischemia. After the onset of myocardial isch-emia, histological cell death is not immediate, but takes afinite period of time to develop—as little as 20 min, orless in some animal models (4). It takes several hoursbefore myocardial necrosis can be identified by macro-scopic or microscopic post-mortem examination. Com-plete necrosis of myocardial cells at risk requires at least2-4 h, or longer, depending on the presence of collateralcirculation to the ischemic zone, persistent or intermit-tent coronary arterial occlusion, the sensitivity of themyocytes to ischemia, pre-conditioning, and individualdemand for oxygen and nutrients (2). The entire processleading to a healed infarction usually takes at least 5-6weeks. Reperfusion may alter the macroscopic and mi-croscopic appearance.

Biomarker detection ofmyocardial injury with necrosis

Myocardial injury is detected when blood levels of sensitiveand specific biomarkers such as cTn or the MB fraction ofcreatine kinase (CKMB) are increased (2). Cardiac troponinI and T are components of the contractile apparatus ofmyocardial cells and are expressed almost exclusively in theheart. Although elevations of these biomarkers in the

lood reflect injury leading to necrosis of myocardialells, they do not indicate the underlying mechanism (5).arious possibilities have been suggested for release of

tructural proteins from the myocardium, including nor-al turnover of myocardial cells, apoptosis, cellular

elease of troponin degradation products, increased cel-ular wall permeability, formation and release of mem-ranous blebs, and myocyte necrosis (6). Regardless ofhe pathobiology, myocardial necrosis due to myocardialschemia is designated as MI.

Also, histological evidence of myocardial injury withecrosis may be detectable in clinical conditions associatedith predominantly non- ischemic myocardial injury. Small

mounts of myocardial injury with necrosis may be detected,hich are associated with heart failure (HF), renal failure,yocarditis, arrhythmias, pulmonary embolism or otherwise

neventful percutaneous or surgical coronary procedures.hese should not be labeled as MI or a complication of therocedures, but rather as myocardial injury, as illustrated inigure 1. It is recognized that the complexity of clinicalircumstances may sometimes render it difficult to deter-ine where individual cases may lie within the ovals ofigure 1. In this setting, it is important to distinguish acuteauses of cTn elevation, which require a rise and/or fall ofTn values, from chronic elevations that tend not to change

cutely. A list of such clinical circumstances associated with n

levated values of cTn is presented in Table 1. Theultifactorial contributions resulting in the myocardial

njury should be described in the patient record.The preferred biomarker—overall and for each specific

ategory of MI—is cTn (I or T), which has high myocardialissue specificity as well as high clinical sensitivity. Detec-ion of a rise and/or fall of the measurements is essential tohe diagnosis of acute MI (7). An increased cTn concen-ration is defined as a value exceeding the 99th percentile of

normal reference population [upper reference limitURL)]. This discriminatory 99th percentile is designateds the decision level for the diagnosis of MI and must beetermined for each specific assay with appropriate qualityontrol in each laboratory (8,9). The values for the 99thercentile URL defined by manufacturers, including thoseor many of the high-sensitivity assays in development, cane found in the package inserts for the assays or in recentublications (10–12).Values should be presented as nanograms per liter (ng/L)

r picograms per milliliter (pg/mL) to make whole num-ers. Criteria for the rise of cTn values are assay-dependentut can be defined from the precision profile of eachndividual assay, including high-sensitivity assays (10,11).

ptimal precision, as described by coefficient of variationCV) at the 99th percentile URL for each assay, should beefined as �10%. Better precision (CV �10%) allows forore sensitive assays and facilitates the detection of chang-

ng values (13). The use of assays that do not have optimalrecision (CV �10% at the 99th percentile URL) makesetermination of a significant change more difficult but does

Figure 1. This illustration shows various clinical entities: forxample, renal failure, heart failure, tachy- or bradyarrhythmia,ardiac or non-cardiac procedures that can be associated withyocardial injury with cell death marked by cardiac troponin ele-

ation. However, these entities can also be associated with myo-ardial infarction in case of clinical evidence of acute myocardialschemia with rise and/or fall of cardiac troponin.

ot cause false positive results. Assays with CV �20% at the

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99th percentile URL should not be used (13). It is acknowl-edged that pre-analytic and analytic problems can induceelevated and reduced values of cTn (10,11).

Blood samples for the measurement of cTn should bedrawn on first assessment and repeated 3-6 h later. Latersamples are required if further ischemic episodes occur, orwhen the timing of the initial symptoms is unclear (14). Toestablish the diagnosis of MI, a rise and/or fall in valueswith at least one value above the decision level is required,coupled with a strong pre-test likelihood. The demonstrationof a rising and/or falling pattern is needed to distinguish acute-from chronic elevations in cTn concentrations that are associ-ated with structural heart disease (10,11,15–19). For example,patients with renal failure or HF can have significant chronicelevations in cTn. These elevations can be marked, as seen inmany patients with MI, but do not change acutely (7).However, a rising or falling pattern is not absolutelynecessary to make the diagnosis of MI if a patient with ahigh pre-test risk of MI presents late after symptom onset;for example, near the peak of the cTn time-concentrationcurve or on the slow-declining portion of that curve, whendetecting a changing pattern can be problematic. Valuesmay remain elevated for 2 weeks or more following the

Table 1. Elevation of Cardiac Troponin ValuesBecause of Myocardial Injury

Injury related to primary myocardial ischemia

Plaque rupture

Intraluminal coronary artery thrombus formation

Injury related to supply/demand imbalance of myocardial ischemia

Tachy-/brady-arrhythmias

Aortic dissection or severe aortic valve disease

Hypertrophic cardiomyopathy

Cardiogenic, hypovolemic, 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

Cardiac contusion, surgery, ablation, pacing, or defibrillator shocks

Rhabdomyolysis with cardiac involvement

Myocarditis

Cardiotoxic agents, e.g. anthracyclines, herceptin

Multifactorial or indeterminate myocardial injury

Heart failure

Stress (Takotsubo) cardiomyopathy

Severe pulmonary embolism or pulmonary hypertension

Sepsis and critically ill patients

Renal failure

Severe acute neurological diseases, e.g. stroke, subarachnoid

hemorrhage

Infiltrative diseases, e.g. amyloidosis, sarcoidosis

Strenuous exercise

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 patternof values or in the absence of clinical evidence of ischemia,should prompt a search for other diagnoses associated withmyocardial injury, such as myocarditis, aortic dissection,pulmonary embolism, or HF. Renal failure and other morenon-ischemic chronic disease states, that can be associatedwith elevated cTn levels, are listed in Table 1 (10,11).

If a cTn assay is not available, the best alternative isCKMB (measured by mass assay). As with troponin, anincreased CKMB value is defined as a measurement abovethe 99th percentile URL, which is designated as thedecision level for the diagnosis of MI (22). Sex-specificvalues should be employed (22).

Clinical features ofmyocardial ischemia and infarction

Onset of myocardial ischemia is the initial step in thedevelopment of MI and results from an imbalance betweenoxygen supply and demand. Myocardial ischemia in aclinical setting can usually be identified from the patient’shistory and from the ECG. Possible ischemic symptomsinclude various combinations of chest, upper extremity,mandibular or epigastric discomfort (with exertion or atrest) or an ischemic equivalent such as dyspnea or fatigue.The discomfort associated with acute MI usually lasts �20

in. Often, the discomfort is diffuse—not localized, norositional, nor affected by movement of the region—and itay be accompanied by diaphoresis, nausea or syncope.owever, these symptoms are not specific for myocardial

schemia. Accordingly, they may be misdiagnosed andttributed to gastrointestinal, neurological, pulmonary orusculoskeletal disorders. MI may occur with atypical

ymptoms—such as palpitations or cardiac arrest—or evenithout symptoms; for example in women, the elderly,iabetics, or post-operative and critically ill patients (2).areful evaluation of these patients is advised, especiallyhen there is a rising and/or falling pattern of cardiaciomarkers.

Clinical classificationof myocardial infarction

For the sake of immediate treatment strategies, such asreperfusion therapy, it is usual practice to designate MI inpatients with chest discomfort, or other ischemic symptomsthat develop ST elevation in two contiguous leads (see ECGsection), as an ‘ST elevation MI’ (STEMI). In contrast,patients without ST elevation at presentation are usuallydesignated as having a ‘non-ST elevation MI’ (NSTEMI).Many patients with MI develop Q waves (Q wave MI), butothers do not (non-Q MI). Patients without elevated bio-

marker values can be diagnosed as having unstable angina. In

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addition to these categories, MI is classified into various types,based on pathological, clinical and prognostic differences, alongwith different treatment strategies (Table 2).

Spontaneous myocardial infarction (MI type 1)

This is an event related to atherosclerotic plaque rupture,ulceration, fissuring, erosion, or dissection with resultingintraluminal thrombus in one or more of the coronaryarteries, leading to decreased myocardial blood flow or distalplatelet emboli with ensuing myocyte necrosis. The patientmay have underlying severe CAD but, on occasion (5 to20%), non-obstructive or no CAD may be found at angiog-raphy, particularly in women (23–25).

Myocardial infarction secondaryto an ischemic imbalance (MI type 2)

In instances of myocardial injury with necrosis, where acondition other than CAD contributes to an imbalancebetween 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 thedirect toxic effects of endogenous or exogenous high circu-lating catecholamine levels. Also coronary vasospasm and/orendothelial dysfunction have the potential to cause MI(26–28).

Cardiac death due tomyocardial infarction (MI type 3)

Patients who suffer cardiac death, with symptoms suggestiveof myocardial ischemia accompanied by presumed newischemic ECG changes or new LBBB—but without avail-

Table 2. Universal Classification of Myocardial Infarction

Type 1: Spontaneous myocardial infarction

Spontaneous myocardial infarction related to atherosclerotic plaque rupture,one or more of the coronary arteries leading to decreased myocardial bloounderlying severe CAD but on occasion non-obstructive or no CAD.

Type 2: Myocardial infarction secondary to an ischemic imbalance

In instances of myocardial injury with necrosis where a condition other than Ce.g. coronary endothelial dysfunction, coronary artery spasm, coronary emhypertension with or without LVH.

Type 3: Myocardial infarction resulting in death when biomarker values are una

Cardiac death with symptoms suggestive of myocardial ischemia and presumsamples could be obtained, before cardiac biomarker could rise, or in rare

Type 4a: Myocardial infarction related to percutaneous coronary intervention (PC

Myocardial infarction associated with PCI is arbitrarily defined by elevation of(�99th percentile URL) or a rise of cTn values �20% if the baseline valuesmyocardial ischemia, or (ii) new ischemic ECG changes or new LBBB, or (iipersistent slow- or no-flow or embolization, or (iv) imaging demonstration orequired.

Type 4b: Myocardial infarction related to stent thrombosis

Myocardial infarction associated with stent thrombosis is detected by coronarand/ or fall of cardiac biomarkers values with at least one value above the

Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG)

Myocardial infarction associated with CABG is arbitrarily defined by elevationbaseline cTn values (�99th percentile URL). In addition, either (i) new pathnative coronary artery occlusion, or (iii) imaging evidence of new loss of via

able biomarker values—represent a challenging diagnostic

group. These individuals may die before blood samples forbiomarkers can be obtained, or before elevated cardiacbiomarkers can be identified. If patients present with clinicalfeatures of myocardial ischemia, or with presumed newischemic ECG changes, they should be classified as havinghad a fatal MI, even if cardiac biomarker evidence of MI islacking.

Myocardial infarction associated withrevascularization procedures (MI types 4 and 5)

Periprocedural myocardial injury or infarction may occur atsome stages in the instrumentation of the heart that isrequired during mechanical revascularization procedures,either by PCI or by coronary artery bypass grafting(CABG). Elevated cTn values may be detected following

tion, Assuring, erosion, or dissection with resulting intraluminal thrombus inor distal platelet emboli with ensuing myocyte necrosis. The patient may have

ntributes to an imbalance between myocardial oxygen supply and/or demand,, tachy-/brady-arrhythmias, anemia, respiratory failure, hypotension, and

le

w ischemic ECG changes or new LBBB, but death occurring before bloodcardiac biomarkers were not collected.

lues �5 x 99th percentile URL in patients with normal baseline valueslevated and are stable or falling. In addition, either (i) symptoms suggestive ofiographic loss of patency of a major coronary artery or a side branch orloss of viable myocardium or new regional wall motion abnormality are

iography or autopsy in the setting of myocardial ischemia and with a risepercentile URL.

diac biomarker values �10 x 99th percentile URL in patients with normalal Q waves or new LBBB, or (ii) angiographic documented new graft or newyocardium or new regional wall motion abnormality.

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

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these procedures, since various insults may occur that canlead to myocardial injury with necrosis (29–32). It is likelythat limitation of such injury is beneficial to the patient:however, a threshold for a worsening prognosis, related toan asymptomatic increase of cardiac biomarker values in theabsence of procedural complications, is not well defined(33–35). Subcategories of PCI-related MI are connected tostent thrombosis and restenosis that may happen after theprimary procedure.

Electrocardiographicdetection of myocardial infarction

The ECG is an integral part of the diagnostic work-up ofpatients with suspected MI and should be acquired andinterpreted promptly (i.e. target within 10 min) after clinicalpresentation (2). Dynamic changes in the ECG waveformsduring acute myocardial ischemic episodes often requireacquisition of multiple ECGs, particularly if the ECG atinitial presentation is non-diagnostic. Serial recordings insymptomatic patients with an initial non-diagnostic ECGshould be performed at 15–30 min intervals or, if available,continuous computer-assisted 12-lead ECG recording. Re-currence of symptoms after an asymptomatic interval are anindication for a repeat tracing and, in patients with evolvingECG abnormalities, a pre-discharge ECG should be ac-quired as a baseline for future comparison. Acute or evolvingchanges in the ST-T waveforms and Q waves, whenpresent, potentially allow the clinician to time the event, toidentify the infarct-related artery, to estimate the amount ofmyocardium at risk as well as prognosis, and to determinetherapeutic strategy. More profound ST-segment shift or Twave inversion involving multiple leads/territories is associ-ated with a greater degree of myocardial ischemia and aworse prognosis. Other ECG signs associated with acutemyocardial ischemia include cardiac arrhythmias, intraven-tricular and atrioventricular conduction delays, and loss ofpre-cordial R wave amplitude. Coronary artery size anddistribution of arterial segments, collateral vessels, location,extent and severity of coronary stenosis, and prior myocar-dial necrosis can all impact ECG manifestations of myo-cardial ischemia (36). Therefore the ECG at presentationshould always be compared to prior ECG tracings, whenavailable. The ECG by itself is often insufficient to diagnoseacute myocardial ischemia or infarction, since ST deviationmay be observed in other conditions, such as acute pericar-ditis, left ventricular hypertrophy (LVH), left bundle branchblock (LBBB), Brugada syndrome, stress cardiomyopathy,and early repolarization patterns (37). Prolonged new ST-segment elevation (e.g. �20 min), particularly when asso-ciated with reciprocal ST-segment depression, usually re-flects acute coronary occlusion and results in myocardialinjury with necrosis. As in cardiomyopathy, Q waves may

also occur due to myocardial fibrosis in the absence of CAD. w

ECG abnormalities of myocardial ischemia or infarctionmay be inscribed in the PR segment, the QRS complex, theST-segment or the T wave. The earliest manifestations ofmyocardial ischemia are typically T wave and ST-segmentchanges. Increased hyperacute T wave amplitude, withprominent symmetrical T waves in at least two contiguousleads, is an early sign that may precede the elevation of theST-segment. Transient Q waves may be observed during anepisode of acute ischemia or (rarely) during acute MI withsuccessful reperfusion. Table 3 lists ST-T wave criteria forthe diagnosis of acute myocardial ischemia that may or maynot lead to MI. The J point is used to determine themagnitude of the ST-segment shift. New, or presumed new,J point elevation �0.1 mV is required in all leads other thanV2 and V3. In healthy men under age 40, J-point elevationcan be as much as 0.25 mV in leads V2 or V3, but it

ecreases with increasing age. Sex differences require differ-nt cut-points for women, since J point elevation in healthyomen in leads V2 and V3 is less than in men (38).

Contiguous leads’ refers to lead groups such as anterioreads (V1–V6), inferior leads (II, III, aVF) or lateral/apical

leads (I, aVL). Supplemental leads such as V3R and V4Rreflect the free wall of the right ventricle and V7–V9 theinferobasal wall.

The criteria in Table 3 require that the ST shift bepresent in two or more contiguous leads. For example, �0.2mV of ST elevation in lead V2, and �0.1 mV in lead V1,would meet the criteria of two abnormal contiguous leads ina man �40 years old. However, �0.1 mV and �0.2 mV of

T elevation, seen only in leads V2–V3 in men (or �0.15V in women), may represent a normal finding. It should

e noted that, occasionally, acute myocardial ischemia mayreate sufficient ST-segment shift to meet the criteria in oneead but have slightly less than the required ST shift in aontiguous lead. Lesser degrees of ST displacement or Tave inversion do not exclude acute myocardial ischemia or

volving MI, since a single static recording may miss theore dynamic ECG changes that might be detected with

erial recordings. ST elevation or diagnostic Q waves inontiguous lead groups are more specific than ST depressionn localizing the site of myocardial ischemia or necrosis39,40). Supplemental leads, as well as serial ECG record-ngs, should always be considered in patients that present

Table 3. ECG Manifestations of AcuteMyocardial Ischemia (in Absence of LVH and LBBB)

ST elevation

New ST elevation at the J point in two contiguous leads with the cut-points:�0.1 mV in all leads other than leads V2–V3 where the following cutpoints apply: �0.2 mV in men �40 years; �0.25 mV in men �40 years,or �0.15 mV in women.

ST depression and T wave changes

New horizontal or down-sloping ST depression �0.05 mV in two contiguousleads and/or T inversion �0.1 mV in two contiguous leads withprominent R wave or R/S ratio �1.

ith ischemic chest pain and a non-diagnostic initial ECG

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(41,42). Electrocardiographic evidence of myocardial isch-emia in the distribution of a left circumflex artery is oftenoverlooked and is best captured using posterior leads at thefifth intercostal space (V7 at the left posterior axillary line,

8 at the left mid-scapular line, and V9 at the left paraspinalborder). Recording of these leads is strongly recommendedin patients with high clinical suspicion for acute circumflexocclusion (for example, initial ECG non-diagnostic, orST-segment depression in leads V1–V3). A cut-point of0.05 mV ST elevation is recommended in leads V7–V9;specificity is increased at a cut-point �0.1 mV ST elevationand this cut-point should be used in men �40 years old. STdepression in leads V1–V3 may be suggestive of inferobasal

yocardial ischemia (posterior infarction), especially whenhe terminal T wave is positive (ST elevation equivalent),owever this is non-specific (41–43). In patients with

nferior and suspected right ventricular infarction, rightre-cordial leads V3R and V4R should be recorded, since ST

elevation �0.05 mV (�0.1 mV in men �30 years old)provides supportive criteria for the diagnosis (42).

During an episode of acute chest discomfort, pseudo-normalization of previously inverted T waves may indicateacute myocardial ischemia. Pulmonary embolism, intracra-nial processes, electrolyte abnormalities, hypothermia, orperi-/myocarditis may also result in ST-T abnormalities andshould be considered in the differential diagnosis. Thediagnosis of MI is more difficult in the presence of LBBB(44,45). However, concordant ST-segment elevation or aprevious ECG may be helpful to determine the presence ofacute MI in this setting. In patients with right bundlebranch block (RBBB), ST-T abnormalities in leads V1–V3are common, making it difficult to assess the presence ofischemia in these leads: however, when new ST elevation orQ waves are found, myocardial ischemia or infarctionshould be considered.

Prior myocardial infarction

As shown in Table 4, Q waves or QS complexes in thebsence of QRS confounders are pathognomonic of a prior

I in patients with ischemic heart disease, regardless ofymptoms (46,47). The specificity of the ECG diagnosis for

I is greatest when Q waves occur in several leads or leadroupings. When the Q waves are associated with STeviations or T wave changes in the same leads, the

Table 4. ECG ChangesAssociated With Prior Myocardial Infarction

Any Q wave in leads V2–V3 �0.02 sec or QS complex in leads V2 and Vr

Q wave �0.03 sec and �0.1 mV deep or QS complex in leads 1, II, aVL,aVF or V4–V6 in any two leads of a contiguous lead grouping(1, aVL; V1–V6; II, III, aVF).

a

R wave �0.04 sec in V1–V2 and R/S �1 with a concordant positive T wave inabsence of conduction defect.

aThe same criteria are used for supplemental leads V7–V9.

ikelihood of MI is increased; for example, minor Q waves

�0.02 sec and �0.03 sec that are �0.1 mV deep aresuggestive of prior MI if accompanied by inverted T wavesin the same lead group. Other validated MI codingalgorithms, such as the Minnesota Code and WHOMONICA, have been used in epidemiological studiesand clinical trials (3).

Silent myocardial infarction

Asymptomatic patients who develop new pathologic Qwave criteria for MI detected during routine ECG follow-up, or reveal evidence of MI by cardiac imaging, that cannotbe directly attributed to a coronary revascularization proce-dure, should be termed ‘silent MI’ (48–51). In studies, silentQ wave MI accounted for 9-37% of all non-fatal MI eventsand were associated with a significantly increased mortalityrisk (48,49). Improper lead placement or QRS confoundersmay result in what appear to be new Q waves or QScomplexes, as compared to a prior tracing. Thus, thediagnosis of a new silent Q wave MI should be confirmed bya repeat ECG with correct lead placement, or by an imagingstudy, and by focused questioning about potential interimischemic symptoms.

Conditions that confound theECG diagnosis of myocardial infarction

A QS complex in lead V1 is normal. A Q wave �0.03 secand �25% of the R wave amplitude in lead III is normal ifthe frontal QRS axis is between �30° and 0°. A Q wave mayalso be normal in aVL if the frontal QRS axis is between 60°and 90°. Septal Q waves are small, non-pathological Qwaves �0.03 sec and �25% of the R-wave amplitude inleads I, aVL, aVF, and V4–V6. Pre-excitation, obstructive,

ilated or stress cardiomyopathy, cardiac amyloidosis,BBB, left anterior hemiblock, LVH, right ventricularypertrophy, myocarditis, acute cor pulmonale, or hyperka-

emia may be associated with Q waves or QS complexes inhe absence of MI. ECG abnormalities that mimic myo-ardial ischemia or MI are presented in Table 5.

Imaging techniques

Non-invasive imaging plays many roles in patients withknown or suspected MI, but this section concerns only itsrole in the diagnosis and characterization of MI. Theunderlying rationale is that regional myocardial hypoperfu-sion and ischemia lead to a cascade of events, includingmyocardial dysfunction, cell death and healing by fibrosis.Important imaging parameters are therefore perfusion,myocyte viability, myocardial thickness, thickening andmotion, and the effects of fibrosis on the kinetics ofparamagnetic or radio-opaque contrast agents.

Commonly used imaging techniques in acute and chronic

infarction are echocardiography, radionuclide ventriculog-


raphy, myocardial perfusion scintigraphy (MPS) using sin-gle photon emission computed tomography (SPECT), andmagnetic resonance imaging (MRI). Positron emissiontomography (PET) and X-ray computed tomography (CT)are less common (52). There is considerable overlap in theircapabilities and each of the techniques can, to a greater orlesser extent, assess myocardial viability, perfusion, andfunction. Only the radionuclide techniques provide a directassessment of myocyte viability, because of the inherentproperties of the tracers used. Other techniques provideindirect assessments of myocardial viability, such as contrac-tile response to dobutamine by echocardiography or myo-cardial fibrosis by MR.

Echocardiography

The strength of echocardiography is the assessment ofcardiac structure and function, in particular myocardialthickness, thickening and motion. Echocardiographic con-trast agents can improve visualization of the endocardialborder and can be used to assess myocardial perfusion andmicrovascular obstruction. Tissue Doppler and strain imag-ing permit quantification of global and regional function(53). Intravascular echocardiographic contrast agents havebeen developed that target specific molecular processes, butthese techniques have not yet been applied in the setting ofMI (54).

Radionuclide imaging

Several radionuclide tracers allow viable myocytes to beimaged directly, including the SPECT tracers thallium-201,technetium-99m MIBI and tetrofosmin, and the PETtracers F-2-fluorodeoxyglucose (FDG) and rubidium-82(18,52). The strength of the SPECT techniques is thatthese are the only commonly available direct methods ofassessing viability, although the relatively low resolutionof the images leaves them at a disadvantage for detecting

Table 5. Common ECG Pitfallsin Diagnosing Myocardial Infarction

False positives

● Early repolarization● LBBB● Pre-excitation● J point elevation syndromes, e.g. Brugada syndrome● Peri-/myocarditis● Pulmonary embolism● Subarachnoid hemorrhage● Metabolic disturbances such as hyperkalemia● Cardiomyopathy● Lead transposition● Cholecystitis● Persistent juvenile pattern● Malposition of precordial ECG electrodes● Tricyclic antidepressants or phenothiazines

False negatives

● Prior Ml with Q-waves and/or persistent ST elevation● Right ventricular pacing● LBBB

small areas of MI. The common SPECT radiopharma-

ceuticals are also tracers of myocardial perfusion and thetechniques thereby readily detect areas of MI and induc-ible perfusion abnormalities. ECG-gated imaging pro-vides a reliable assessment of myocardial motion, thick-ening and global function. Evolving radionuclidetechniques that are relevant to the assessment of MIinclude imaging of sympathetic innervation using iodine-123-labelled meta-iodo-benzylguanidine (mIBG) (55),imaging of matrix metalloproteinase activation in ven-tricular remodeling (56,57), and refined assessment ofmyocardial metabolism (58).

Magnetic resonance imaging

The high tissue contrast of cardiovascular MRI provides anaccurate assessment of myocardial function and it hassimilar capability to echocardiography in suspected acuteMI. Paramagnetic contrast agents can be used to assessmyocardial perfusion and the increase in extracellular spacethat is associated with the fibrosis of prior MI. Thesetechniques have been used in the setting of acute MI(59,60), and imaging of myocardial fibrosis by delayedcontrast enhancement is able to detect even small areas ofsubendocardial MI. It is also of value in detectingmyocardial disease states that can mimic MI, such asmyocarditis (61).

Computed tomography

Infarcted myocardium is initially visible as a focal area ofdecreased left ventricle (LV) enhancement, but later imag-ing shows hyper-enhancement, as with late gadoliniumimaging by MRI (62). This finding is clinically relevantbecause contrast-enhanced CT may be performed for sus-pected pulmonary embolism and aortic dissection—conditions with clinical features that overlap with those ofacute MI—but the technique is not used routinely. Simi-larly, CT assessment of myocardial perfusion is technicallyfeasible but not yet fully validated.

Applying imaging in acute myocardial infarction

Imaging techniques can be useful in the diagnosis of acuteMI because of their ability to detect wall motion abnormal-ities or loss of viable myocardium in the presence of elevatedcardiac biomarker values. If, for some reason, biomarkershave not been measured or may have normalized, demon-stration of new loss of myocardial viability in the absence ofnon-ischemic causes meets the criteria for MI. Normalfunction and viability have a very high negative predictivevalue and practically exclude acute MI (63). Thus, imagingtechniques are useful for early triage and discharge ofpatients with suspected MI. However, if biomarkers havebeen measured at appropriate times and are normal, thisexcludes an acute MI and takes precedence over the imagingcriteria.

Abnormal regional myocardial motion and thickeningmay be caused by acute MI or by one or more of several

other conditions, including prior MI, acute ischemia, stun-

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ning or hibernation. Non-ischemic conditions, such ascardiomyopathy and inflammatory or infiltrative diseases,can also lead to regional loss of viable myocardium orfunctional abnormality. Therefore, the positive predictivevalue of imaging for acute MI is not high unless theseconditions can be excluded, and unless a new abnormality isdetected or can be presumed to have arisen in the setting ofother features of acute MI.

Echocardiography provides an assessment of many non-ischemic causes of acute chest pain, such as peri-myocarditis, valvular heart disease, cardiomyopathy, pulmo-nary embolism or aortic dissection (53). It is the imagingtechnique of choice for detecting complications of acute MI,including myocardial free wall rupture, acute ventricularseptal defect, and mitral regurgitation secondary to papillarymuscle rupture or ischemia.

Radionuclide imaging can be used to assess the amount ofmyocardium that is salvaged by acute revascularization (64).Tracer is injected at the time of presentation, with imagingdeferred until after revascularization, providing a measure ofmyocardium at risk. Before discharge, a second restinginjection provides a measure of final infarct size, and thedifference between the two corresponds to the myocardiumthat has been salvaged.

Applying imaging in latepresentation of myocardial infarction

In case of late presentation after suspected MI, the presenceof regional wall motion abnormality, thinning or scar in theabsence of non- ischemic causes, provides evidence of pastMI. The high resolution and specificity of late gadoliniumenhancement MRI for the detection of myocardial fibrosishas made this a very valuable technique. In particular, theability to distinguish between subendocardial and otherpatterns of fibrosis provides a differentiation between isch-emic heart disease and other myocardial abnormalities.Imaging techniques are also useful for risk stratification aftera definitive diagnosis of MI. The detection of residual orremote ischemia and/or ventricular dysfunction providespowerful indicators of later outcome.

Diagnostic criteria formyocardial infarction with PCI (MI type 4)

Balloon inflation during PCI often causes transient isch-emia, whether or not it is accompanied by chest pain orST-T changes. Myocardial injury with necrosis may resultfrom recognizable peri-procedural events—alone or in com-bination—such as coronary dissection, occlusion of a majorcoronary artery or a side-branch, disruption of collateralflow, slow flow or no-reflow, distal embolization, andmicrovascular plugging. Embolization of intracoronarythrombus or atherosclerotic particulate debris may not bepreventable, despite current anticoagulant and antiplate-

let adjunctive therapy, aspiration or protection devices. c

Such events induce inflammation of the myocardiumsurrounding islets of myocardial necrosis (65). New areasof myocardial necrosis have been demonstrated by MRIfollowing PCI (66).

The occurrence of procedure-related myocardial cell in-jury with necrosis can be detected by measurement ofcardiac biomarkers before the procedure, repeated 3–6 hlater and, optionally, further re-measurement 12 h thereaf-ter. Increasing levels can only be interpreted as procedure-related myocardial injury if the pre-procedural cTn value isnormal (�99th percentile URL) or if levels are stable orfalling (67,68). In patients with normal pre-proceduralvalues, elevation of cardiac biomarker values above the 99thpercentile URL following PCI are indicative of procedure-related myocardial injury. In earlier studies, increased valuesof post-procedural cardiac biomarkers, especially CKMB,were associated with impaired outcome (69,70). However,when cTn concentrations are normal before PCI andbecome abnormal after the procedure, the threshold abovethe 99th percentile URL—whereby an adverse prognosis isevident—is not well defined (71) and it is debatable whethersuch a threshold even exists (72). If a single baseline cTnvalue is elevated, it is impossible to determine whetherfurther increases are due to the procedure or to the initialprocess causing the elevation. In this situation, it appearsthat the prognosis is largely determined by the pre-procedural cTn level (71). These relationships will probablybecome even more complex for the new high-sensitivitytroponin assays (70).

In patients undergoing PCI with normal (�99th percen-tile URL) baseline cTn concentrations, elevations of cTn�5 � 99th percentile URL occurring within 48 h of theprocedure—plus either (i) evidence of prolonged ischemia(�20 min) as demonstrated by prolonged chest pain, or(ii) ischemic ST changes or new pathological Q waves, or(iii) angiographic evidence of a flow limiting complication,such as of loss of patency of a side branch, persistentslow-flow or no-reflow, embolization, or (iv) imaging evi-dence of new loss of viable myocardium or new regional wallmotion abnormality—is defined as PCI-related MI (type4a). This threshold of cTn values �5 � 99th percentile

RL is arbitrarily chosen, based on clinical judgment andocietal implications of the label of peri-procedural MI.

hen a cTn value is �5 � 99th percentile URL after PCInd the cTn value was normal before the PCI—or when theTn value is �5 � 99th percentile URL in the absence ofschemic, angiographic or imaging findings—the termmyocardial injury’ should be used.

If the baseline cTn values are elevated and are stable oralling, then a rise of �20% is required for the diagnosis oftype 4a MI, as with reinfarction. Recent data suggest that,hen PCI is delayed after MI until biomarker concentra-

ions are falling or have normalized, and elevation of cardiaciomarker values then reoccurs, this may have some long-erm significance. However, additional data are needed to

onfirm this finding (73).

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A subcategory of PCI-related MI is stent thrombosis, asdocumented by angiography and/or at autopsy and a riseand/or fall of cTn values �99th percentile URL (identifiedas MI type 4b). In order to stratify the occurrence of stentthrombosis in relation to the timing of the PCI procedure,the Academic Research Consortium recommends temporalcategories of ‘early’ (0 to 30 days), ‘late’ (31 days to 1 year),and ‘very late’ (�1 year) to distinguish likely differences inthe contribution of the various pathophysiological processesduring each of these intervals (74). Occasionally, MI occursin the clinical setting of what appears to be a stentthrombosis: however, at angiography, restenosis is observedwithout evidence of thrombus (see section on clinical trials).

Diagnostic criteria for myocardialinfarction with CABG (MI type 5)

During CABG, numerous factors can lead to periproceduralmyocardial injury with necrosis. These include direct myo-cardial trauma from (i) suture placement or manipulation ofthe heart, (ii) coronary dissection, (iii) global or regionalischemia related to inadequate intra-operative cardiacprotection, (iv) microvascular events related to reperfu-sion, (v) myocardial injury induced by oxygen free radicaleneration, or (vi) failure to reperfuse areas of the myocar-ium that are not subtended by graftable vessels (75–77).RI studies suggest that most necrosis in this setting is not

ocal but diffuse and localized in the subendocardium (78).In patients with normal values before surgery, any in-

crease of cardiac biomarker values after CABG indicatesmyocardial necrosis, implying that an increasing magnitudeof biomarker concentrations is likely to be related to animpaired outcome. This has been demonstrated in clinicalstudies employing CKMB, where elevations 5, 10 and 20times the URL after CABG were associated with worsenedprognosis; similarly, impaired outcome has been reportedwhen cTn values were elevated to the highest quartile orquintile of the measurements (79–83). Unlike prognosis,scant literature exists concerning the use of biomarkers fordefining an MI related to a primary vascular event in a graftor native vessel in the setting of CABG. In addition, whenthe baseline cTn value is elevated (�99th percentile URL),higher levels of biomarker values are seen post-CABG.Therefore, biomarkers cannot stand alone in diagnosing MIin this setting. In view of the adverse impact on survivalobserved in patients with significant elevation of bio-marker concentrations, this Task Force suggests, byarbitrary convention, that cTn values �10 x 99th percen-tile URL during the first 48 h following CABG, occur-ring from a normal baseline cTn value (�99th percentileURL). In addition, either (i) new pathological Q waves ornew LBBB, or (ii) angiographically documented new graftor new native coronary artery occlusion, or (iii) imagingevidence of new loss of viable myocardium or new regional

wall motion abnormality, should be considered as diagnostic

of a CABG-related MI (type 5). Cardiac biomarker releaseis considerably higher after valve replacement with CABGthan with bypass surgery alone, and with on-pump CABGcompared to off-pump CABG (84). The threshold de-scribed above is more robust for isolated on-pump CABG.As for PCI, the existing principles from the universaldefinition of MI should be applied for the definition of MI�48 h after surgery.

Assessment of MI in patientsundergoing other cardiac procedures

New ST-T abnormalities are common in patients whoundergo cardiac surgery. When new pathological Q wavesappear in different territories than those identified beforesurgery, MI (types 1 or 2) should be considered, particularlyif associated with elevated cardiac biomarker values, newwall motion abnormalities or hemodynamic instability.

Novel procedures such as transcatheter aortic valve im-plantation (TAVI) or mitral clip may cause myocardialinjury with necrosis, both by direct trauma to the myocar-dium and by creating regional ischemia from coronaryobstruction or embolization. It is likely that, similarly toCABG, the more marked the elevation of the biomarkervalues, the worse the prognosis—but data on that are notavailable.

Modified criteria have been proposed for the diagnosis ofperiprocedural MI �72 h after aortic valve implantation(85). However, given that there is too little evidence, itappears reasonable to apply the same criteria for procedure-related MI as stated above for CABG.

Ablation of arrhythmias involves controlled myocardialinjury with necrosis, by application of warming or cooling ofthe tissue. The extent of the injury with necrosis can beassessed by cTn measurement: however, an elevation of cTnvalues in this context should not be labeled as MI.

Myocardial infarctionassociated with non-cardiac procedures

Perioperative MI is the most common major perioperativevascular complication in major non-cardiac surgery, and isassociated with a poor prognosis (86,87). Most patients whohave a perioperative MI will not experience ischemic symp-toms. Nevertheless, asymptomatic perioperative MI is asstrongly associated with 30-day mortality, as is symptomaticMI (86). Routine monitoring of cardiac biomarkers inhigh-risk patients, both prior to and 48–72 h after majorsurgery, is therefore recommended. Measurement of high-sensitivity cTn in post-operative samples reveals that 45% ofpatients have levels above the 99th percentile URL and 22%have an elevation and a rising pattern of values indicative ofevolving myocardial necrosis (88). Studies of patients un-dergoing major non-cardiac surgery strongly support the

idea that many of the infarctions diagnosed in this context


are caused by a prolonged imbalance between myocardialoxygen supply and demand, against a background of CAD(89,90). Together with a rise and/or fall of cTn values, thisindicates MI type 2. However, one pathological study offatal perioperative MI patients showed plaque rupture andplatelet aggregation, leading to thrombus formation, inapproximately half of such events (91), that is to say, MItype 1. Given the differences that probably exist in thetherapeutic approaches to each, close clinical scrutiny andjudgment is needed.

Myocardial infarctionin the intensive care unit

Elevations of cTn values are common in patients in theintensive care unit and are associated with adverse progno-sis, regardless of the underlying disease state (92,93). Someelevations may reflect MI type 2 due to underlying CADand increased myocardial oxygen demand (94). Other pa-tients may have elevated values of cardiac biomarkers, due tomyocardial injury with necrosis induced by catecholamine ordirect toxic effect from circulating toxins. Moreover, insome patients, MI type 1 may occur. It is often a challengefor the clinician, caring for a critically ill patient with severesingle organ or multi-organ pathology, to decide on a planof action when the patient has elevated cTn values. If andwhen the patient recovers from the critical illness, clinicaljudgment should be employed to decide whether—and towhat extent—further evaluation for CAD or structural heartdisease is indicated (95).

Recurrent myocardial infarction

‘Incident MI’ is defined as the individual’s first MI. Whenfeatures of MI occur in the first 28 days after an incidentevent, this is not counted as a new event for epidemiologicalpurposes. If characteristics of MI occur after 28 daysfollowing an incident MI, it is considered to be a recurrentMI (3).

Reinfarction

The term ‘reinfarction’ is used for an acute MI that occurswithin 28 days of an incident or recurrent MI (3). The ECGdiagnosis of suspected reinfarction following the initial MImay be confounded by the initial evolutionary ECGchanges. Reinfarction should be considered when ST ele-vation �0.1 mV recurs, or new pathognomonic Q wavesappear, in at least two contiguous leads, particularly whenassociated with ischemic symptoms for 20 min or longer.Re-elevation of the ST-segment can, however, also be seenin threatened myocardial rupture and should lead to addi-tional diagnostic workup. ST depression or LBBB alone arenon-specific findings and should not be used to diagnose

reinfarction.

In patients in whom reinfarction is suspected fromclinical signs or symptoms following the initial MI, animmediate measurement of cTn is recommended. A secondsample should be obtained 3–6 h later. If the cTn concen-tration is elevated, but stable or decreasing at the time ofsuspected reinfarction, the diagnosis of reinfarction requiresa 20% or greater increase of the cTn value in the secondsample. If the initial cTn concentration is normal, thecriteria for new acute MI apply.

Myocardial injury or infarctionassociated with heart failure

Depending on the assay used, detectable-to-clearly elevatedcTn values, indicative of myocardial injury with necrosis,may be seen in patients with HF syndrome (96). Usinghigh-sensitivity cTn assays, measurable cTn concentrationsmay be present in nearly all patients with HF, with asignificant percentage exceeding the 99th percentile URL,particularly in those with more severe HF syndrome, such asin acutely decompensated HF (97).

Whilst MI type 1 is an important cause of acutelydecompensated HF—and should always be considered inthe context of an acute presentation—elevated cTn valuesalone, in a patient with HF syndrome, do not establish thediagnosis of MI type 1 and may, indeed, be seen in thosewith non-ischemic HF. Beyond MI type 1, multiple mech-anisms have been invoked to explain measurable-to-pathologically elevated cTn concentrations in patients withHF (96,97). For example, MI type 2 may result fromincreased transmural pressure, small-vessel coronary ob-struction, endothelial dysfunction, anemia or hypotension.Besides MI type 1 or 2, cardiomyocyte apoptosis andautophagy due to wall stretch has been experimentallydemonstrated. Direct cellular toxicity related to inflamma-tion, circulating neurohormones, infiltrative processes, aswell as myocarditis and stress cardiomyopathy, may presentwith HF and abnormal cTn measurement (97).

Whilst prevalent and complicating the diagnosis of MI,the presence, magnitude and persistence of cTn elevation inHF is increasingly accepted to be an independent predictorof adverse outcomes in both acute and chronic HF syn-drome, irrespective of mechanism, and should not bediscarded as ‘false positive’ (97,98).

In the context of an acutely decompensated HF presen-tation, cTn I or T should always be promptly measured andECG recorded, with the goal of identifying or excluding MItype 1 as the precipitant. In this setting, elevated cTn valuesshould be interpreted with a high level of suspicion for MItype 1 if a significant rise and/or fall of the marker are seen,or if it is accompanied by ischemic symptoms, new ischemicECG changes or loss of myocardial function on non-invasive testing. Coronary artery anatomy may often bewell-known; such knowledge may be used to interpret

abnormal troponin results. If normal coronary arteries are

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present, either a type 2 MI or a non-coronary mechanismfor troponin release may be invoked (97).

On the other hand, when coronary anatomy is notestablished, the recognition of a cTn value in excess of the99th percentile URL alone is not sufficient to make adiagnosis of acute MI due to CAD, nor is it able to identifythe mechanism for the abnormal cTn value. In this setting,further information, such as myocardial perfusion studies,coronary angiography, or MRI is often required to betterunderstand the cause of the abnormal cTn measurement.However, it may be difficult to establish the reason for cTnabnormalities, even after such investigations (96,97).

Application of MI in clinical trialsand quality assurance programs

In clinical trials, MI may be an entry criterion or anend-point. A universal definition for MI is of great benefitfor clinical studies, since it will allow a standardized ap-proach for interpretation and comparison across differenttrials. The definition of MI as an entry criterion, e.g. MItype 1 and not MI type 2, will determine patient character-istics in the trial. Occasionally MI occurs and, at angiogra-phy, restenosis is the only angiographic explanation(99,100). This PCI-related MI type might be designated asan ‘MI type 4c’, defined as �50% stenosis at coronaryangiography or a complex lesion associated with a riseand/or fall of cTn values �99th percentile URL and no otherignificant obstructive CAD of greater severity following:i) initially successful stent deployment or (ii) dilatation of aoronary artery stenosis with balloon angioplasty (�50%).

In recent investigations, different MI definitions haveeen employed as trial outcomes, thereby hampering com-arison and generalization between these trials. Consistencymong investigators and regulatory authorities, with regardo the definition of MI used as an endpoint in clinicalnvestigations, is of substantial value. Adaptation of theefinition to an individual clinical study may be appropriate

n some circumstances and should have a well-articulatedationale. No matter what, investigators should ensure thattrial provides comprehensive data for the various types of

Table 6. Tabulation in Clinical Trials of MI Types According toof the Applied Cardiac Biomarker

Multiples � 99%Ml type 1

SpontaneousMl type 2Secondary

Ml type 3*Death

1–3

3–5

5–10

�10

Total

MI � myocardial infarction; PCI � percutaneous coronary intervention; CABG � coronary artery*Biomarker values are unavailable because of death before blood samples are obtained (bluRed areas indicate arbitrarily defined cTn values below the MI decision limit whether PCI or CA

†Restenosis is defined as �50% stenosis at coronary angiography or a complex lesion associated witf greater severity following: (i) initially successful stent deployment or (ii) dilatation of a coronary arte

I and includes the 99th percentile URL decision limits ofTn or other biomarkers employed. Multiples of the 99thercentiles URL may be indicated as shown in Table 6. Thisill facilitate comparison of trials and meta-analyses.Because different assays may be used, including newer,

igher-sensitivity cTn assays in large multicenter clinicalrials, it is advisable to consistently apply the 99th percentileRL. This will not totally harmonize troponin values acrossifferent assays, but will improve the consistency of theesults. In patients undergoing cardiac procedures, thencidence of MI may be used as a measure of quality,rovided that a consistent definition is applied by all centersarticipating in the quality assurance program. To beffective and to avoid bias, this type of assessment will needo develop a paradigm to harmonize the different cTn assayesults across sites.

Public policy implicationsof the adjustment of the MI definition

Revision of the definition of MI has a number of implica-tions for individuals as well as for society at large. Atentative or final diagnosis is the basis for advice aboutfurther diagnostic testing, lifestyle changes, treatment andprognosis for the patient. The aggregate of patients with aparticular diagnosis is the basis for health care planning andpolicy and resource allocation.

One of the goals of good clinical practice is to reach adefinitive and specific diagnosis, which is supported bycurrent scientific knowledge. The approach to the definitionof MI outlined in this document meets this goal. In general,the conceptual meaning of the term ‘myocardial infarction’has not changed, although new, sensitive diagnostic meth-ods have been developed to diagnose this entity. Thus, thediagnosis of acute MI is a clinical diagnosis based on patientsymptoms, ECG changes, and highly sensitive biochemicalmarkers, as well as information gleaned from various imag-ing techniques. It is important to characterize the type ofMI as well as the extent of the infarct, residual LV function,and the severity of CAD and other risk factors, rather thanmerely making a diagnosis of MI. The information con-

iples of the 99th Percentile Upper Reference Limit

Ml type 4aPCI

Ml type 4bStent-Thrombus

Ml type 4c†

RestenosisMl type 5

CABG

grafting..

Mult

bypasse area)BG.

h a rise and/or fall of cTn values �99th percentile URL and no other significant obstructive CADry stenosis with balloon angioplasty (�50%).


veyed about the patient’s prognosis and ability to workrequires more than just the mere statement that the patienthas suffered an MI. The many additional factors justmentioned are also required so that appropriate social,family, and employment decisions can be made. A numberof risk scores have been developed to predict the prognosisafter MI. The classification of the various other prognosticentities associated with MI should lead to a reconsiderationof the clinical coding entities currently employed for pa-tients with the myriad conditions that can lead to myocar-dial necrosis, with consequent elevation of biomarker values.

It should be appreciated that the current modification ofthe definition of MI may be associated with consequencesfor the patients and their families in respect of psychologicalstatus, life insurance, professional career, as well as driving-and pilots’ licenses. The diagnosis is associated also withsocietal implications as to diagnosis-related coding, hospitalreimbursement, public health statistics, sick leave, anddisability attestation. In order to meet this challenge,physicians must be adequately informed of the altereddiagnostic criteria. Educational materials will need to becreated and treatment guidelines must be appropriatelyadapted. Professional societies and healthcare plannersshould take steps to facilitate the rapid dissemination of therevised definition to physicians, other health care profes-sionals, administrators, and the general public.

Global perspectives of thedefinition of myocardial infarction

Cardiovascular disease is a global health problem. Under-standing the burden and effects of CAD in populations is ofcritical importance. Changing clinical definitions, criteriaand biomarkers add challenges to our understanding andability to improve the health of the public. The definition ofMI for clinicians has important and immediate therapeuticimplications. For epidemiologists, the data are usually ret-rospective, so consistent case definitions are critical forcomparisons and trend analysis. The standards described inthis report are suitable for epidemiology studies. However,to analyze trends over time, it is important to have consis-tent definitions and to quantify adjustments when biomark-ers or other diagnostic criteria change (101). For example,the advent of cTn dramatically increased the number ofdiagnosable MIs for epidemiologists (3,102).

In countries with limited economic resources, cardiacbiomarkers and imaging techniques may not be availableexcept in a few centers, and even the option of ECGrecordings may be lacking. In these surroundings, theWHO states that biomarker tests or other high-cost diag-nostic testing are unfit for use as compulsory diagnosticcriteria (3). The WHO recommends the use of the ESC/ACCF/AHA/WHF Universal MI Definition in settingswithout resource constraints, but recommends more flexible

standards in resource-constrained locations (3).

Cultural, financial, structural and organizational prob-lems in the different countries of the world in the diagnosisand therapy of acute MI will require ongoing investigation.It is essential that the gap between therapeutic and diag-nostic advances be addressed in this expanding area ofcardiovascular disease.

Conflicts of interest

The members of the Task Force of the ESC, the ACCF,the AHA and the WHF have participated independentlyin the preparation of this document, drawing on theiracademic and clinical experience and applying an objectiveand clinical examination of all available literature. Mosthave undertaken—and are undertaking—work in collabo-ration with industry and governmental or private healthproviders (research studies, teaching conferences, consulta-tion), but all believe such activities have not influenced theirjudgment. The best guarantee of their independence is inthe quality of their past and current scientific work. How-ever, to ensure openness, their relationships with industry,government and private health providers are reported on theESC website (www.escardio.org/guidelines). Expenses forthe Task Force/Writing Committee and preparation of thisdocument were provided entirely by the above-mentionedjoint associations.

AcknowledgmentsWe are very grateful to the dedicated staff of the PracticeGuidelines Department of the ESC.

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