Universal Deﬁnition of Myocardial Infarction · Universal Deﬁnition of Myocardial Infarction Kristian Thygesen,* Joseph S. Alpert, ... Ernst E. Van Der Wall (The Netherlands)

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Journal of the American College of Cardiology© 2007 by the European Society of Cardiology, the American College of Cardiology Foundation,tP

Vol. 50, No. 22, 2007

ESC/ACCF/AHA/WHF EXPERT CONSENSUS DOCUMENT

Universal Definition of Myocardial Infarction

Kristian Thygesen,* Joseph S. Alpert, and Harvey D. White,on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction

he American Heart Association, and the World Heart Federationublished by Elsevier Inc.

ISSN 0735-1097/07/$32.00doi:10.1016/j.jacc.2007.09.011

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Task ForceMembers

he party authorized to handleDisclaimer: The document

hairpersons: Kristian Thygesen (Denmark)*, Jo-eph S. Alpert (USA)*, Harvey D. White (Newealand)*

iomarker Group: Allan S. Jaffe, CoordinatorUSA), Fred S. Apple (USA), Marcello GalvaniItaly), Hugo A. Katus (Germany), L. Kristinewby (USA), Jan Ravkilde (Denmark)

CG Group: Bernard Chaitman, CoordinatorUSA), Peter M. Clemmensen (Denmark), Mi-ael Dellborg (Sweden), Hanoch Hod (Israel),ekka Porela (Finland)

maging Group: Richard Underwood, CoordinatorUK), Jeroen J. Bax (The Netherlands), George A.eller (USA), Robert Bonow (USA), Ernst E.an Der Wall (The Netherlands)

ntervention Group: Jean-Pierre Bassand, Coordi-

such permissions on behalf of the ESC.represents the views of the ESC, which were arrived at

dial infarctionPermissions

ium), T. Bruce Ferguson (USA), Philippe G.teg (France), Barry F. Uretsky (USA), David O.illiams (USA)

linical Investigation Group: Paul W. Armstrong,oordinator (Canada), Elliott M. Antman

USA), Keith A. Fox (UK), Christian W. HammGermany), E. Magnus Ohman (USA), Maarten. Simoons (The Netherlands)

lobal Perspective Group: Philip A. Poole-Wilson,oordinator (UK), Enrique P. Gurfinkel (Argen-

ina), Jose-Luis Lopez-Sendon (Spain), Prem PaisIndia), Shanti Mendis† (Switzerland), Jun-Renhu (China)

mplementation Group: Lars C. Wallentin Coordi-ator (Sweden), Francisco Fernandez-AvilesSpain), Kim M. Fox (UK), Alexander N. Park-omenko (Ukraine), Silvia G. Priori (Italy),ichal Tendera (Poland), Liisa-Maria Voipio-

nator (France), William Wijns, Coordinator (Bel- Pulkki (Finland)

he recommendations set forth in this report are those of the Task Force Membersnd do not necessarily reflect the official position of the American College ofardiology.*Corresponding authors/co-chairpersons: Professor Kristian Thygesen, Depart-ent of Medicine and Cardiology, Aarhus University Hospital, Tage Hansens, Gade

, DK-8000 Aarhus C, Denmark. Tel: �45 89 49 76 14; fax: �45 89 49 76 19.-mail: [email protected]. Professor Joseph Alpert, Department ofedicine, University of Arizona College of Medicine, 1501 N. Campbell Ave,

O Box 245017, Tucson, AZ 85724-5017, USA. Tel: �1 520 626 6138; fax: �120 626 6604. E-mail: [email protected]. Professor Harvey White, Greenane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, 1030uckland, New Zealand. Tel: �64 96309992; fax: �64 96309915. E-mail:[email protected].†Dr Shanti Mendis of the WHO participated in the task force in her personal capacity,

ut this does not represent WHO approval of this document at the present time.The content of this European Society of Cardiology (ESC) document has been

ublished for personal and educational use only. No commercial use is authorized. Noart of the document may be translatedorreproducedinany form without writtenermission from the ESC. Permission can be obtained upon submission of a writtenequest to Oxford University Press, the publisher of the European Heart Journal and

after careful consideration of the available evidence at the time they were written.Health professionals are encouraged totake them fully into account when exercisingtheir clinical judgement. The document does not, however, override the individualresponsibility of health professionals to make appropriate decisions in the circum-stances of the individual patients, in consultation with that patient, and whereappropriate and necessary the patient’s guardian or carer. It is also the healthprofessional’s responsibility to verify the rules and regulations applicable to drugs anddevices at the time of prescription.

This article has been copublished in the October II (Vol. 28 no. 20), 2007, issue ofthe European Heart Journal (also available on the Web site of the European Society ofCardiology at www.escardio.org) and the November 27, 2007, issue of Circulation(also available on the Web site of the American Heart Association at my.americanheart.org).

This document was approved by the European Society of Cardiology in April 2007,the World Heart Federation in April 2007, and by the American Heart AssociationScience Advisory and Coordinating Committee on May 9, 2007. The EuropeanSociety of Cardiology, the American College of Cardiology, the American HeartAssociation, and the World Heart Federation request that this document be cited asfollows: Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF TaskForce for the Redefinition of Myocardial Infarction. Universal definition of myocar-

. J Am Coll Cardiol 2007;50:2173–95.: Please e-mail: [email protected].

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2174 Thygesen et al. JACC Vol. 50, No. 22, 2007ESC/ACCF/AHA/WHF Expert Consensus Document November 27, 2007:2173–95

ESCCommitteefor PracticeGuidelines

Alec Vahanian, Chair (France), A. John Camm(UK), Raffaele De Caterina (Italy), VeronicaDean (France), Kenneth Dickstein (Norway),Gerasimos Filippatos (Greece), Christian Funck-Brentano (France), Irene Hellemans (The Neth-

erlands), Steen Dalby Kristensen (Denmark),Keith McGregor (France), Udo Sechtem (Ger-many), Sigmund Silber (Germany), Michal Ten-dera (Poland), Petr Widimsky (Czech Republic),Jose Luis Zamorano (Spain)

DocumentReviewers

Joao Morais, Review Coordinator (Portugal),Sorin Brener (USA), Robert Harrington (USA),David Morrow (USA), Udo Sechtem (Germany),Michael Lim (Singapore), Marco A. Martinez-

Rios (Mexico), Steve Steinhubl (USA), Glen N.Levine (USA), W. Brian Gibler (USA), DavidGoff (USA), Marco Tubaro (Italy), Darek Dudek(Poland), Nawwar Al-Attar (France)

TABLE OF CONTENTS

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ntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2175

Clinical Features of Ischaemia . . . . . . . . . . . . . . . . . . . . . . . . . .2176

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2176

Clinical Classification of Myocardial Infarction. . . . . . . .2177

iomarker Evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2177

Reinfarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2178

lectrocardiographic Detection of MyocardialInfarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2178

ECG Abnormalities of Myocardial Ischaemia ThatMay Evolve to Myocardial Infarction . . . . . . . . . . . . . . .2179

Prior Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2179

Conditions That Confound the ECG Diagnosis ofMyocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2180

Reinfarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2180

Coronary Revascularization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2180

maging Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2180

Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2180

Radionuclide Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2181

Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . .2181

X-Ray Computed Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . .2181

Application in the Acute Phase of MyocardialInfarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2181

Application in the Healing or Healed Phase ofMyocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2181

yocardial Infarction Associated WithRevascularization Procedures. . . . . . . . . . . . . . . . . . . . . . . . .2181

Diagnostic Criteria for Myocardial InfarctionWith PCI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2182

Diagnostic Criteria for Myocardial InfarctionWith CABG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2182

efinition of Myocardial Infarction inClinical Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2182

ublic Policy Implications of Redefinition ofMyocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2184

lobal Perspectives of the Redefinition ofMyocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2184

onflicts of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2185

cknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2185

eferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2185

ppendix 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2188

ppendix 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2192

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2175JACC Vol. 50, No. 22, 2007 Thygesen et al.November 27, 2007:2173–95 ESC/ACCF/AHA/WHF Expert Consensus Document

efinition of Myocardial Infarction

Criteria for Acute Myocardial InfarctionThe term myocardial infarction should be used when there is evidence of myocardial necrosis in a clinical settingconsistent with myocardial ischaemia. Under these conditions any one of the following criteria meets the diagnosis formyocardial infarction:

• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99thpercentile of the upper reference limit (URL) together with evidence of myocardial ischaemia with at least one ofthe following:

• Symptoms of ischaemia;• ECG changes indicative of new ischaemia (new ST-T changes or new left bundle branch block [LBBB]);• Development of pathological Q waves in the ECG;• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

• Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms suggestive of myocardial ischaemia,and accompanied by presumably new ST elevation, or new LBBB, and/or evidence of fresh thrombus by coronaryangiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before theappearance of cardiac biomarkers in the blood.

• For percutaneous coronary interventions (PCI) in patients with normal baseline troponin values, elevations of cardiacbiomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By convention,increases of biomarkers greater than 3 � 99th percentile URL have been designated as defining PCI-relatedmyocardial infarction. A subtype related to a documented stent thrombosis is recognized.

• For coronary artery bypass grafting (CABG) in patients with normal baseline troponin values, elevations of cardiacbiomarkers above the 99th percentile URL are indicative of peri-procedural myocardial necrosis. By convention,increases of biomarkers greater than 5 � 99th percentile URL plus either new pathological Q waves or new LBBB,or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss ofviable myocardium have been designated as defining CABG-related myocardial infarction.

• Pathological findings of an acute myocardial infarction.

Criteria for Prior Myocardial InfarctionAny one of the following criteria meets the diagnosis for prior myocardial infarction:

• Development of new pathological Q waves with or without symptoms.• Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a

non-ischaemic cause.• Pathological findings of a healed or healing myocardial infarction.

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ntroduction

yocardial infarction is a major cause of death and disabil-ty worldwide. Coronary atherosclerosis is a chronic diseaseith stable and unstable periods. During unstable periodsith activated inflammation in the vascular wall, patientsay develop a myocardial infarction. Myocardial infarctionay be a minor event in a lifelong chronic disease, it may

ven go undetected, but it may also be a major catastrophicvent leading to sudden death or severe haemodynamiceterioration. A myocardial infarction may be the firstanifestation of coronary artery disease, or it may occur,

epeatedly, in patients with established disease. Informationn myocardial infarction attack rates can provide useful dataegarding the burden of coronary artery disease within and
cross populations, especially if standardized data are col- (
ected in a manner that demonstrates the distinction be-ween incident and recurrent events. From the epidemio-ogical point of view, the incidence of myocardial infarctionn a population can be used as a proxy for the prevalence oforonary artery disease in that population. Furthermore, theerm myocardial infarction has major psychological andegal implications for the individual and society. It is anndicator of one of the leading health problems in the world,nd it is an outcome measure in clinical trials and observa-ional studies. With these perspectives, myocardial infarc-ion may be defined from a number of different clinical,lectrocardiographic, biochemical, imaging, and pathologi-al characteristics.

In the past, a general consensus existed for the clinicalyndrome designated as myocardial infarction. In studies ofisease prevalence, the World Health Organization
WHO) defined myocardial infarction from symptoms,

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CG abnormalities, and enzymes. However, the develop-ent of more sensitive and specific serological biomarkers

nd precise imaging techniques allows detection of evermaller amounts of myocardial necrosis. Accordingly, cur-ent clinical practice, health care delivery systems, as well aspidemiology and clinical trials all require a more preciseefinition of myocardial infarction and a re-evaluation ofrevious definitions of this condition.It should be appreciated that over the years, while more

pecific biomarkers of myocardial necrosis became available,he accuracy of detecting myocardial infarction has changed.uch changes occurred when glutamine-oxaloacetic

ransaminase (GOT) was replaced by lactate dehydrogenaseLDH) and later by creatine kinase (CK) and the MBraction of CK, i.e. CKMB activity and CKMB mass.urrent, more specific, and sensitive biomarkers and imag-

ng methods to detect myocardial infarction are furtherefinements in this evolution.

In response to the issues posed by an alteration in ourbility to identify myocardial infarction, the Europeanociety of Cardiology (ESC) and the American College ofardiology (ACC) convened a consensus conference in999 in order to re-examine jointly the definition ofyocardial infarction (published in the year 2000 in theuropean Heart Journal and Journal of the Americanollege of Cardiology [1]). The scientific and societal

mplications of an altered definition for myocardial infarc-ion were examined from seven points of view: pathological,iochemical, electrocardiographic, imaging, clinical trials,pidemiological, and public policy. It became apparent fromhe deliberations of the former consensus committee thathe term myocardial infarction should not be used withouturther qualifications, whether in clinical practice, in theescription of patient cohorts, or in population studies.uch qualifications should refer to the amount of myocardialell loss (infarct size), to the circumstances leading to thenfarct (e.g. spontaneous or procedure related), and to theiming of the myocardial necrosis relative to the time of thebservation (evolving, healing, or healed myocardial infarc-ion) (1).

Following the 1999 ESC/ACC consensus conference, aroup of cardiovascular epidemiologists met to address thepecific needs of population surveillance. This internationaleeting, representing several national and international

rganizations, published recommendations in Circulation003 (2). These recommendations addressed the needs ofesearchers engaged in long-term population trend analysisn the context of changing diagnostic tools using retrospec-ive medical record abstraction. Also considered was surveil-ance in developing countries and out-of-hospital death,oth situations with limited and/or missing data. Theseecommendations continue to form the basis for epidemio-ogical research.

Given the considerable advances in the diagnosis andanagement of myocardial infarction since the original

ocument was published, the leadership of the ESC, the t

CC, and the American Heart Association (AHA) con-ened, together with the World Heart Federation (WHF),Global Task Force to update the 2000 consensus docu-ent (1). As with the previous consensus committee, thelobal Task Force was composed of a number of working

roups in order to refine the ESC/ACC criteria for theiagnosis of myocardial infarction from various perspectives.

ith this goal in mind, the working groups were composedf experts within the field of biomarkers, ECG, imaging,nterventions, clinical investigations, global perspectives,nd implications. During several Task Force meetings, theecommendations of the working groups were coordinated,esulting in the present updated consensus document.

The Task Force recognizes that the definition of myocar-ial infarction will be subject to a variety of changes in theuture as a result of scientific advance. Therefore, thisocument is not the final word on this issue for all time.urther refinement of the present definition will doubtlessccur in the future.

linical Features of Ischaemia

he term myocardial infarction reflects cell death of cardiacyocytes caused by ischaemia, which is the result of a

erfusion imbalance between supply and demand. Isch-emia in a clinical setting most often can be identified fromhe patient’s history and from the ECG. Possible ischaemicymptoms include various combinations of chest, upperxtremity, jaw, or epigastric discomfort with exertion or atest. The discomfort associated with acute myocardial in-arction usually lasts at least 20 min. Often, the discomforts diffuse, not localized, not positional, not affected by

ovement of the region, and it may be accompanied byyspnoea, diaphoresis, nausea, or syncope.These symptoms are not specific to myocardial ischaemia

nd can be misdiagnosed and thus attributed to gastroin-estinal, neurological, pulmonary, or musculoskeletal disor-ers. Myocardial infarction may occur with atypical symp-oms, or even without symptoms, being detected only byCG, biomarker elevations, or cardiac imaging.

athology

yocardial infarction is defined by pathology as myocardialell death due to prolonged ischaemia. Cell death is cate-orized pathologically as coagulation and/or contractionand necrosis, which usually evolves through oncosis, butan result to a lesser degree from apoptosis. Careful analysisf histological sections by an experienced observer is essen-ial to distinguish these entities (1).

After the onset of myocardial ischaemia, cell death is notmmediate but takes a finite period to develop (as little as 20

in or less in some animal models). It takes several hoursefore myocardial necrosis can be identified by macroscopicr microscopic post-mortem examination. Complete necro-is of all myocardial cells at risk requires at least 2–4 h oronger depending on the presence of collateral circulation to
he ischaemic zone, persistent or intermittent coronary

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rterial occlusion, the sensitivity of the myocytes to isch-emia, pre-conditioning, and/or, finally, individual demandor myocardial oxygen and nutrients. Myocardial infarctionsre usually classified by size: microscopic (focal necrosis),mall (�10% of the left ventricular [LV] myocardium),oderate (10–30% of the LV myocardium), and large

�30% of the LV myocardium), and by location. Theathological identification of myocardial necrosis is madeithout reference to morphological changes in the coronary

rterial tree or to the clinical history (1).Myocardial infarction can be defined pathologically as

cute, healing, or healed. Acute myocardial infarction isharacterized by the presence of polymorphonuclear leuko-ytes. If the time interval between the onset of the infarctionnd death is quite brief, e.g. 6 h, minimal or no polymor-honuclear leukocytes may be seen. The presence of mono-uclear cells and fibroblasts, and the absence of polymor-honuclear leukocytes characterize healing infarction.ealed infarction is manifested as scar tissue without

ellular infiltration. The entire process leading to a healednfarction usually takes at least 5–6 weeks. Reperfusion maylter the macroscopic and microscopic appearance of theecrotic zone by producing myocytes with contractionands and large quantities of extravasated erythrocytes.yocardial infarctions can be classified temporally from

linical and other features, as well as according to theathological appearance, as evolving (�6 h), acute (6 h–7ays), healing (7–28 days), and healed (29 days and be-ond). It should be emphasized that the clinical andlectrocardiographic timing of the onset of an acute infarc-ion may not correspond exactly with the pathologicaliming. For example, the ECG may still demonstratevolving ST-T changes and cardiac biomarkers may still belevated (implying a recent infarct) at a time when patho-ogically the infarction is in the healing phase (1).

Patients who suffer sudden cardiac death with or withoutCG changes suggestive of ischaemia represent a challeng-

ng diagnostic group. Since these individuals die beforeathological changes can develop in the myocardium, it isifficult to say with certainty whether these patients suc-umbed to a myocardial infarction or to an ischaemic eventhat led to a fatal arrhythmia. The mode of death in theseases is sudden, but the aetiology remains uncertain unlesshe individual reported previous symptoms of ischaemiceart disease prior to the cardiac arrest. Some patients withr without a history of coronary disease may develop clinicalvidence of ischaemia, including prolonged and profoundhest pain, diaphoresis and/or shortness of breath, andudden collapse. These individuals may die before bloodamples for biomarkers can be obtained, or these individualsay be in the lag phase before cardiac biomarkers can be

dentified in the blood. These patients may have suffered anvolving, fatal, acute myocardial infarction. If these patientsresent with presumably new ECG changes, for exampleT elevation, and often with symptoms of ischaemia, they
hould be classified as having had a fatal myocardial infarc- n
ion even if cardiac biomarker evidence of infarction isacking. Also, patients with evidence of fresh thrombus byoronary angiography (if performed) and/or at autopsyhould be classified as having undergone sudden death as aesult of myocardial infarction.

linical Classification of Myocardial Infarction

linically the various types of myocardial infarction can belassified as shown in Table 1.

On occasion, patients may manifest more than one typef myocardial infarction simultaneously or sequentially. Ithould also be noted that the term myocardial infarctionoes not include myocardial cell death associated withechanical injury from coronary artery bypass grafting

CABG), for example ventricular venting, or manipulationf the heart; nor does it include myocardial necrosis due toiscellaneous causes, e.g. renal failure, heart failure, cardio-

ersion, electrophysiological ablation, sepsis, myocarditis,ardiac toxins, or infiltrative diseases.

iomarker Evaluation

yocardial cell death can be recognized by the appearancen the blood of different proteins released into the circula-ion from the damaged myocytes: myoglobin, cardiac tro-onin T and I, CK, LDH, as well as many others (3).yocardial infarction is diagnosed when blood levels of

ensitive and specific biomarkers such as cardiac troponin orKMB are increased in the clinical setting of acute myo-

ardial ischaemia (1). Although elevations in these biomar-ers reflect myocardial necrosis, they do not indicate itsechanism (3,4). Thus, an elevated value of cardiac tropo-

able 1. Clinical Classification of Different Types ofyocardial Infarction

ype 1

Spontaneous myocardial infarction related to ischaemia due to a primarycoronary event such as plaque erosion and/or rupture, fissuring, ordissection

ype 2

Myocardial infarction secondary to ischaemia due to either increased oxygendemand or decreased supply, e.g. coronary artery spasm, coronaryembolism, anaemia, arrhythmias, hypertension, or hypotension

ype 3

Sudden unexpected cardiac death, including cardiac arrest, often withsymptoms suggestive of myocardial ischaemia, accompanied bypresumably new STelevation, or new LBBB, or evidence of fresh thrombusin a coronary artery by angiography and/or at autopsy, but deathoccurring before blood samples could be obtained, or at a time before theappearance of cardiac biomarkers in the blood

ype 4a

Myocardial infarction associated with PCI

ype 4b

Myocardial infarction associated with stent thrombosis as documented byangiography or at autopsy

ype 5

Myocardial infarction associated with CABG

in in the absence of clinical evidence of ischaemia should

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rompt a search for other aetiologies of myocardial necrosis,uch as myocarditis, aortic dissection, pulmonary embolism,ongestive heart failure, renal failure, and other examplesndicated in Table 2.

The preferred biomarker for myocardial necrosis is car-iac troponin (I or T), which has nearly absolute myocardialissue specificity as well as high clinical sensitivity, therebyeflecting even microscopic zones of myocardial necrosis (3).n increased value for cardiac troponin is defined as aeasurement exceeding the 99th percentile of a normal

eference population (URL � upper reference limit). De-ection of a rise and/or fall of the measurements is essentialo the diagnosis of acute myocardial infarction (6). Thebove-mentioned discriminatory percentile is designated ashe decision level for the diagnosis of myocardial infarction,nd must be determined for each specific assay with appro-riate quality control (7–9) Optimal precision (coefficient ofariation [CV]) at the 99th percentile URL for each assayhould be defined as �10%. Better precision (CV �10%)llows for more sensitive assays (10,11). The use of assayshat do not have independent validation of optimal preci-ion (CV �10%) is not recommended. The values for the9th percentile can be found on the International Federa-ion for Clinical Chemistry website http://www.ifcc.org/ndex.php?option�com_remository&Itemid�120&func�leinfo&id�7.Blood samples for the measurement of troponin should

e drawn on first assessment (often some hours after thenset of symptoms) and 6–9 h later (12). An occasionalatient may require an additional sample between 12 and4 h if the earlier measurements were not elevated and thelinical suspicion of myocardial infarction is high (12). Tostablish the diagnosis of myocardial infarction, one ele-

able 2. Elevations of Troponin in the Absence of Overtschemic Heart Disease

ardiac contusion, or other trauma including surgery, ablation, pacing, etc.

ongestive heart failure—acute and chronic

ortic dissection

ortic valve disease

ypertrophic cardiomyopathy

achy- or bradyarrhythmias, or heart block

pical ballooning syndrome

habdomyolysis with cardiac injury

ulmonary embolism, severe pulmonary hypertension

enal failure

cute neurological disease, including stroke or subarachnoid haemorrhage

nfiltrative diseases, e.g. amyloidosis, haemochromatosis, sarcoidosis, andscleroderma Inflammatory diseases, e.g. myocarditis or myocardialextension of endo-/pericarditis

rug toxicity or toxins

ritically ill patients, especially with respiratory failure or sepsis

urns, especially if affecting �30% of body surface area

xtreme exertion

odified from Jaffe et al. (4) and French and White (5).

ated value above the decision level is required. The dem- d

nstration of a rising and/or falling pattern is needed toistinguish background elevated troponin levels, e.g. pa-ients with chronic renal failure (Table 2), from elevations inhe same patients which are indicative of myocardial infarc-ion (6). However, this pattern is not absolutely required toake the diagnosis of myocardial infarction if the patient

resents �24 h after the onset of symptoms. Troponinalues may remain elevated for 7–14 days following thenset of infarction (4).If troponin assays are not available, the best alternative is

KMB (measured by mass assay). As with troponin, anncreased CKMB value is defined as a measurement abovehe 99th percentile URL, which is designated as theecision level for the diagnosis of myocardial infarction (9).ender-specific values should be employed (9). TheKMB measurements should be recorded at the time of therst assessment of the patient and 6–9 h later in order toemonstrate the rise and/or fall exceeding the 99th percen-ile URL for the diagnosis of myocardial infarction. Anccasional patient may require an additional diagnosticample between 12 and 24 h if the earlier CKMB measure-ents were not elevated and the clinical suspicion ofyocardial infarction is high.Measurement of total CK is not recommended for the

iagnosis of myocardial infarction, because of the largekeletal muscle distribution and the lack of specificity of thisnzyme.

einfarction

raditionally, CKMB has been used to detect reinfarction.owever, recent data suggest that troponin values provide

imilar information (13). In patients where recurrent myo-ardial infarction is suspected from clinical signs or symp-oms following the initial infarction, an immediate measure-ent of the employed cardiac marker is recommended. A

econd sample should be obtained 3–6 h later. Recurrentnfarction is diagnosed if there is a �20% increase of thealue in the second sample. Analytical values are consideredo be different if they are different by �3 SDs of the variancef the measures (14). For troponin, this value is 5–7% forost assays at the levels involved with reinfarction. Thus, a

0% change should be considered significant, i.e. over thatxpected from analytical variability itself. This value shouldlso exceed the 99th percentile URL.

lectrocardiographic Detection ofyocardial Infarction

he ECG is an integral part of the diagnostic work-up ofatients with suspected myocardial infarction (1,2,15,16).he acute or evolving changes in the ST-T waveforms and

he Q-waves when present potentially allow the clinician toate the event, to suggest the infarct-related artery, and tostimate the amount of myocardium at risk. Coronary artery
ominance, size and distribution of arterial segments, col-
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ateral vessels, and location, extent, and severity of coronarytenoses can also impact ECG manifestations of myocardialschaemia (17). The ECG by itself is often insufficient toiagnose acute myocardial ischaemia or infarction since STeviation may be observed in other conditions such as acuteericarditis, LV hypertrophy, LBBB, Brugada syndrome,nd early repolarization patterns (18). Also Q-waves mayccur due to myocardial fibrosis in the absence of coronaryrtery disease, as in, for example, cardiomyopathy.

CG Abnormalities of Myocardial Ischaemia Thatay Evolve to Myocardial Infarction

CG abnormalities of myocardial ischaemia or infarctionay be inscribed in the PR segment, the QRS complex, and

he ST segment or T-waves. The earliest manifestations ofyocardial ischaemia are typical T-waves and ST segment

hanges (19,20). Increased hyper-acute T-wave amplitudeith prominent symmetrical T-waves in at least two con-

iguous leads is an early sign that may precede the elevationf the ST segment. Increased R-wave amplitude and widthgiant R-wave with S-wave diminution) are often seen ineads exhibiting ST elevation, and tall T-waves reflectingonduction delay in the ischaemic myocardium (21). Tran-ient Q-waves may be observed during an episode of acuteschaemia or rarely during acute myocardial infarction withuccessful reperfusion (22).

Table 3 lists ECG criteria for the diagnosis of acuteyocardial ischaemia that may lead to infarction. The

-point is used to determine the magnitude of the STlevation. J-point elevation in men decreases with increasingge; however, that is not observed in women, in whom-point elevation is less than in men (23).

Contiguous leads means lead groups such as anterioreads (V1–V6), inferior leads (II, III, and aVF), or lateral/pical leads (I and aVL). More accurate spatial contiguity inhe frontal plane can be established by the Cabrera display:VL, I, aVR, II, aVF, and III (24). Supplemental leads suchs V3R and V4R reflect the free wall of the right ventricle.

Although the criteria in Table 3 require that the ST shifte present in two or more contiguous leads, it should beoted that occasionally acute myocardial ischaemia mayreate sufficient ST segment shift to meet the criteria in oneead but have slightly less than the required ST shift in andjacent contiguous lead. Lesser degrees of ST displacement

able 3. ECG Manifestations of Acute Myocardial Ischaemiain Absence of LVH and LBBB)

T elevation

New ST elevation at the J-point in two contiguous leads with the cut-offpoints: �0.2 mV in men or �0.15 mV in women in leads V2–V3 and/or�0.1 mV in other leads

T depression and T-wave changes

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

r T-wave inversion in leads without prominent R-wave*g

mplitude do not exclude acute myocardial ischaemia orvolving myocardial infarction.

ST elevation or diagnostic Q-waves in regional leadroups are more specific than ST depression in localizinghe site of myocardial ischaemia or necrosis (25,26). How-ver, ST depression in leads V1–V3 suggests myocardialschaemia, especially when the terminal T-wave is positiveST elevation equivalent), and may be confirmed by con-omitant ST elevation �0.1 mV recorded in leads V7-V927,28). The term ‘posterior’ to reflect the basal part of theV wall that lies on the diaphragm is no longer recom-ended. It is preferable to refer to this territory as infero-

asal (29). In patients with inferior myocardial infarction its advisable to record right precordial leads (V3R and V4R)eeking ST elevation in order to identify concomitant rightentricular infarction (30).

During an acute episode of chest discomfort, pseudo-ormalization of previously inverted T-waves may indicatecute myocardial ischaemia. Pulmonary embolism, intracra-ial processes, or peri-/myocarditis may also result in ST-Tbnormalities and should be considered (false positives) inhe differential diagnosis.

The diagnosis of myocardial infarction is difficult in theresence of LBBB even when marked ST-T abnormalitiesr ST elevation are present that exceed standard criteria31,32). A previous ECG may be helpful to determine theresence of acute myocardial infarction in this setting. Inatients with right bundle branch block (RBBB), ST-Tbnormalities in leads V1–V3 are common, making itifficult to assess the presence of ischaemia in these leads;owever, when ST elevation or Q-waves are found, myo-ardial ischaemia or infarction should be considered. Someatients present with ST elevation or new LBBB, and sufferudden cardiac death before cardiac biomarkers becomebnormal or pathological signs of myocardial necrosis be-ome evident at autopsy. These patients should be classifieds having had a fatal myocardial infarction.

rior Myocardial Infarction

s shown in Table 4, Q-waves or QS complexes in thebsence of QRS confounders are usually pathognomonic ofprior myocardial infarction (33–35). The specificity of theCG diagnosis for myocardial infarction is greatest when-waves occur in several leads or lead groupings. ST

eviations or T-waves alone are non-specific findings for

able 4. ECG Changes Associated With Prior Myocardialnfarction

ny Q-wave in leads V2–V3 �0.02 s or QS complex in leads V2 and V3

-wave �0.03 s and �0.1 mV deep or QS complex in leads I, II, aVL, aVF, orV4–V6 in any two leads of a contiguous lead grouping (I, aVL,V6; V4–V6; II, III,and aVF)*

-wave �0.04 s in V1–V2 and R/S �1 with a concordant positive T-wave in theabsence of a conduction defect

The same criteria are used for supplemental leads V7–V9, and for the Cabrera frontal plane leadrouping.

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yocardial necrosis. However, when these abnormalitiesccur in the same leads as the Q-waves, the likelihood ofyocardial infarction is increased. For example, minor-waves �0.02 and �0.03 s that are �0.1 mV deep are

uggestive of prior infarction if accompanied by inverted-waves in the same lead group.Other validated myocardial infarction-coding algorithms,

uch as the Minnesota code, Novacode, and WHOONICA, define Q-wave depth on the basis of depth,

idth, and ratio of R-wave amplitude, such as Q-waveepth at least one-third or one-fifth of R-wave amplitude,nd have been used extensively in epidemiological studiesnd clinical trials (36,37).

onditions That Confound the ECG Diagnosis ofyocardial Infarction

QS complex in lead V1 is normal. A Q-wave �0.03 s and1/4 of the R-wave amplitude in lead III is normal if the

rontal QRS axis is between 30 and 0°. The Q-wave maylso be normal in aVL if the frontal QRS axis is between 60nd 90°. Septal Q-waves are small non-pathological-waves �0.03 s and �1/4 of the R-wave amplitude in

eads I, aVL, aVF, and V4–V6. Pre-excitation, obstructive orilated cardiomyopathy, LBBB, RBBB, left anterior hemi-lock, left and right ventricular hypertrophy, myocarditis,cute cor pulmonale, or hyperkalaemia may be associatedith Q/QS complexes in the absence of myocardial infarc-

ion. ECG abnormalities that simulate myocardial isch-emia or infarction are presented in Table 5.

einfarction

he ECG diagnosis of reinfarction following the initialnfarction may be confounded by the initial evolutionaryCG changes. Reinfarction should be considered when ST

levation �0.1 mV reoccurs in a patient having a lesseregree of ST elevation or new pathognomonic Q waves, int least two contiguous leads, particularly when associated

able 5. Common ECG Pitfalls in Diagnosingyocardial Infarction

alse positives

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LBBB

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Brugada syndrome

Peri-/myocarditis

Pulmonary embolism

Subarachnoid haemorrhage

Metabolic disturbances such as hyperkalaemia

Failure to recognize normal limits for J-point displacement

Lead transposition or use of modified Mason–Likar configuration (24)

Cholecystitis

alse negatives

Prior myocardial infarction with Q-waves and/or persistent ST elevation

Paced rhythm

LBBB

a

ith ischaemic symptoms for 20 min or longer. Thee-elevation of the ST segment can, however, also be seen inhreatening myocardial rupture and should lead to addi-ional diagnostic work-up. ST depression or LBBB on theirwn should not be considered valid criteria for myocardialnfarction.

oronary Revascularization

CG abnormalities during or after percutaneous coronaryntervention (PCI) are similar to those seen during sponta-eous myocardial infarction. In patients who have under-one CABG, new ST-T abnormalities are common but notecessarily diagnostic of myocardial ischaemia (38). How-ver, when new pathological Q waves (Table 4) appear inerritories other than those identified before surgery, myo-ardial infarction should be considered, particularly if asso-iated with elevated biomarkers, new wall motion abnor-alities, or haemodynamic instability.

maging Techniques

on-invasive imaging plays many roles in patients withnown or suspected myocardial infarction, but this sectiononcerns only its role in the diagnosis and characterizationf infarction. The underlying rationale is that regionalyocardial hypoperfusion and ischaemia lead to a cascade of

vents including myocardial dysfunction, cell death, andealing by fibrosis. Important imaging parameters are there-ore perfusion, myocyte viability, myocardial thickness,hickening, and motion, and the effects of fibrosis on theinetics of radiolabelled and paramagnetic contrast agents.Commonly used imaging techniques in acute and chronic

nfarction are echocardiography, radionuclide ventriculog-aphy, myocardial perfusion scintigraphy (MPS), and mag-etic resonance imaging (MRI). Positron emission tomog-aphy (PET) and X-ray computed tomography (CT) areess common. There is considerable overlap in their capa-ilities, but only the radionuclide techniques provide a directssessment of myocardial viability because of the propertiesf the tracers used. Other techniques provide indirectssessments of myocardial viability, such as myocardialunction from echocardiography or myocardial fibrosis from

RI.

chocardiography

chocardiography is an excellent real-time imaging tech-ique with moderate spatial and temporal resolution. Itstrength is the assessment of myocardial thickness, thicken-ng, and motion at rest. This can be aided by tissue Dopplermaging. Echocardiographic contrast agents can improvendocardial visualization, but contrast studies are not yetully validated for the detection of myocardial necrosis,
lthough early work is encouraging (39).

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adionuclide Imaging

everal radionuclide tracers allow viable myocytes to bemaged directly, including thallium-201, technetium-99m

IBI, tetrofosmin, and (18F)2-fluorodeoxyglucose (FDG)40–42). The strength of the techniques are that they arehe only commonly available direct methods of assessingiability, although the relatively low resolution of the imagesisadvantages them for detecting small areas of infarction (43).he common single photon-emitting radio-pharmaceuticals

re also tracers of myocardial perfusion and so the tech-iques readily detect areas of infarction and inducibleer-fusion abnormalities. ECG-gated imaging provides aeliable assessment of myocardial motion, thickening, andlobal function (44,45).

agnetic Resonance Imaging

ardiovascular MRI has high spatial resolution and mod-rate temporal resolution. It is a well-validated standard forhe assessment of myocardial function and has, in theory,imilar capability to echocardiography in suspected acutenfarction. It is, however, more cumbersome in an acuteetting and is not commonly used. Paramagnetic contrastgents can be used to assess myocardial perfusion and thencrease in extracellular space associated with the fibrosis ofhronic infarction. The former is not yet fully validated inlinical practice, but the latter is well validated and can playn important role in the detection of infarction (46,47).

-Ray Computed Tomography

nfarcted myocardium is initially visible to CT as a focal area ofecreased LV enhancement, but later imaging shows hyper-nhancement as with late gadolinium imaging by MRI48,49). This finding is clinically relevant because contrast-nhanced CT may be performed for suspected embolism andortic dissection, conditions with clinical features that overlapith those of acute myocardial infarction.

pplication in the Acute Phase ofyocardial Infarction

maging techniques can be useful in the diagnosis ofyocardial infarction because of the ability to detect wallotion abnormalities in the presence of elevated cardiac

io-markers. If for some reason biomarkers have not beeneasured or may have normalized, demonstration of new

oss of myocardial viability alone in the absence of non-schaemic causes meets the criteria for myocardial infarc-ion. However, if biomarkers have been measured at appro-riate times and are normal, the determinations of theseake precedence over the imaging criteria.

Echocardiography provides assessment of many non-schaemic causes of acute chest pain such as peri-

yocarditis, valvular heart disease, cardiomyopathy, pulmo-ary embolism, or aortic dissection. Echocardiography ishe imaging technique of choice for detecting complicationsf acute infarction including myocardial free wall rupture,
cute ventricular septal defect, and mitral regurgitation w
econdary to papillary muscle rupture or ischaemia. How-ver, echocardiography cannot distinguish regional wallotion abnormalities due to myocardial ischaemia from

nfarction.Radionuclide assessment of perfusion at the time of

atient presentation can be performed with immediateracer injection and imaging that can be delayed for up toeveral hours. The technique is interpreter dependent,lthough objective quantitative analysis is available. ECGating provides simultaneous information on LV function.

An important role of acute echocardiography or radio-uclide imaging is in patients with suspected myocardial

nfarction and a non-diagnostic ECG. A normal echocar-iogram or resting ECG-gated scintigram has a 95–98%egative predictive value for excluding acute infarction50–54). Thus, imaging techniques are useful for earlyriage and discharge of patients with suspected myocardialnfarction (55,56).

A regional myocardial wall motion abnormality or loss oformal thickening may be caused by acute myocardial

nfarction or by one or more of several other ischaemiconditions including old infarction, acute ischaemia, stun-ing, or hibernation. Non-ischaemic conditions such asardiomyopathy and inflammatory or infiltrative diseasesan also lead to regional loss of viable myocardium orunctional abnormality, and so the positive predictive valuef imaging techniques is not high unless these conditionsan be excluded and unless a new abnormality is detected oran be presumed to have arisen in the setting of othereatures of acute myocardial infarction.

pplication in the Healing or Healed Phase ofyocardial Infarction

maging techniques are useful in myocardial infarction fornalysis of LV function, both at rest and during dynamicxercise or pharmacological stress, to provide an assessmentf remote inducible ischaemia. Echocardiography andadio-nuclide techniques, in conjunction with exercise orharmacological stress, can identify ischaemia and myocar-ial viability. Non-invasive imaging techniques can diag-ose healing or healed infarction by demonstrating regionalall motion, thinning, or scar in the absence of other causes.The high resolution of contrast-enhanced MRI means that

reas of late enhancement correlate well with areas of fibrosisnd thereby enable differentiation between transmural andubendocardial scarring (57). The technique is therefore po-entially valuable in assessing LV function and areas of viablend hence potentially hibernating myocardium.

yocardial Infarction Associated Withevascularization Procedures

eri-procedural myocardial infarction is different frompontaneous infarction, because the former is associated
ith the instrumentation of the heart that is required during

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echanical revascularization procedures by either PCI orABG. Multiple events that can lead to myocardial necrosis

re taking place, often in combination, during both types ofntervention (58–61). While some loss of myocardial tissue

ay be unavoidable during procedures, it is likely thatimitation of such damage is beneficial to the patient andheir prognosis (62).

During PCI, myocardial necrosis may result from recog-izable peri-procedural events, alone or in combination,uch as side-branch occlusion, disruption of collateral flow,istal embolization, coronary dissection, slow flow or no-eflow phenomenon, and microvascular plugging. Emboli-ation of intracoronary thrombus or atherosclerotic partic-late debris cannot be entirely prevented despite currentntithrombotic and antiplatelet adjunctive therapy or pro-ection devices. Such events induce extensive inflammationf non-infarcted myocardium surrounding small islets ofyocardium necrosis (63–67). New areas of myocardial

ecrosis have been demonstrated by MRI following PCI68). A separate subcategory of myocardial infarction iselated to stent thrombosis as documented by angiographynd/or autopsy.

During CABG, numerous additional factors can lead toeri-procedural necrosis. These include direct myocardialrauma from sewing needles or manipulation of the heart,oronary dissection, global or regional ischaemia related tonadequate cardiac protection, microvascular events relatedo reperfusion, myocardial damage induced by oxygen freeadical generation, or failure to reperfuse areas of theyocardium that are not subtended by graftable vessels

69–71). MRI studies suggest that most necrosis in thisetting is not focal, but diffuse and localized to the sub-ndocardium (72) Some clinicians and clinical investigatorsave preferred using CKMB for the diagnosis of peri-rocedural infarction because of a substantial amount ofata relating CKMB elevations to prognosis (73,74). How-ver, an increasing number of studies using troponins in thatespect have emerged (59,75).

iagnostic Criteria for Myocardial Infarctionith PCI

n the setting of PCI, the balloon inflation during arocedure almost always results in ischaemia whether or notccompanied by ST-T changes. The occurrence ofrocedure-related cell necrosis can be detected by measure-ent of cardiac biomarkers before or immediately after the

rocedure, and again at 6–12 and 18–24 h (76,77). Eleva-ions of biomarkers above the 99th percentile URL afterCI, assuming a normal baseline troponin value, are indic-tive of post-procedural myocardial necrosis. There is cur-ently no solid scientific basis for defining a biomarkerhreshold for the diagnosis of peri-procedural myocardialnfarction. Pending further data, and by arbitrary conven-ion, it is suggested to designate increases more than threeimes the 99th percentile URL as PCI-related myocardial
nfarction (type 4a). t
If cardiac troponin is elevated before the procedure andot stable for at least two samples 6 h apart, there are

nsufficient data to recommend biomarker criteria for theiagnosis of peri-procedural myocardial infarction (77). Ifhe values are stable or falling, criteria for reinfarction byurther measurement of biomarkers together with the fea-ures of the ECG or imaging can be applied.

A separate subcategory of myocardial infarction (type 4b)s related to stent thrombosis as documented by angiographynd/or autopsy. Although iatrogenic, myocardial infarctionype 4b with verified stent thrombosis must meet the criteriaor spontaneous myocardial infarction as well.

iagnostic Criteria for Myocardial Infarctionith CABG

ny increase of cardiac biomarkers after CABG indicatesyocyte necrosis, implying that an increasing magnitude of

iomarker is likely to be related to an impaired outcome.his has been demonstrated in clinical studies employingKMB where elevations five, 10 and 20 times the upper

imit of normal after CABG were associated with worsenedrognosis (73,78,79). Likewise, the increase of troponin

evels after CABG indicates necrosis of myocardial cells,hich predicts a poor outcome, in particular when elevated

o the highest quartile or quintile of the troponin measure-ents (59,75).Unlike the prognosis, scant literature exists concerning

he use of biomarkers for defining myocardial infarction inhe setting of CABG. Therefore, biomarkers cannot standlone in diagnosing myocardial infarction (type 5). In viewf the adverse impact on survival observed in patients withignificant biomarker elevations, this Task Force suggests,y arbitrary convention, that biomarker values more thanve times the 99th percentile of the normal reference rangeuring the first 72 h following CABG, when associatedith the appearance of new pathological Q-waves or newBBB, or angiographically documented new graft or nativeoronary artery occlusion, or imaging evidence of new lossf viable myocardium, should be considered as diagnostic ofCABG-related myocardial infarction (type 5 myocardial

nfarction).

efinition of Myocardial Infarction inlinical Investigations

universal definition for myocardial infarction would bef great benefit to future clinical studies in this area sincet will allow for trial-to-trial comparisons as well asccurate meta-analyses involving multiple investigations.n clinical trials, myocardial infarction may be an entryriterion or an end-point. The definition of myocardialnfarction employed in these trials will thus determinehe characteristics of patients entering the studies as wells the number of outcome events. In recent investiga-
ions, different infarct definitions have been employed,

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hereby hampering comparison and generalization amonghese trials.

Consistency among investigators and regulatory au-horities with regard to the definition of myocardialnfarction used in clinical investigations is essential. Theask Force strongly encourages trialists to employ theefinition described in this document. Furthermore, in-estigators should ensure that a trial provides compre-ensive data for the various types of myocardial infarctione.g. spontaneous, peri-procedural) and includes the em-loyed decision limits for myocardial infarction of theardiac biomarkers in question. All data should be madevailable to interested individuals in published format orn a website. Data concerning infarctions should bevailable in a form consistent with the current revisedefinitions of myocardial infarction. This does not nec-ssarily restrict trialists to a narrow end-point definition,ut rather ensures that across all future trials access toomparable data exists, thereby facilitating cross-studynalyses. The recommendations put forward in thisection are not detailed and should be supplemented byareful protocol planning and implementation in anylinical trial.

The Task Force strongly endorses the concept of theame decision limit for each biomarker employed for myo-ardial infarction types 1 and 2, and, likewise, the sameigher three- and five-fold decision limits in the setting ofyocardial infarction types 4a and 5, respectively (78–80)

Tables 6 and 7). In clinical trials, as in clinical practice,easurement of cardiac troponin T or I is preferred over

able 6. Classification of the Different Types of Myocardial Infapplied Cardiac Biomarker

Multiples � 99%MI type 1

(spontaneous)MI type 2

(secondary)MI type 3*

(sudden death)

–2 �

–3 �

–5 �

–10 �

10 �

otal number

Biomarkers are not available for this type of myocardial infarction since the patients expired beff biomarker values should be reported. The dark grey areas represent biomarker elevations beloefinition chosen in a clinical trial, all data should be provided. All boxes in the table should be

able 7. Sample Clinical Trial Tabulation of Randomizedatients by Types of Myocardial Infarction

Treatment A Treatment B

Types of MI Number of patients Number of patients

I type 1

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otal number

easurement of CKMB or other biomarkers for the diag-osis of myocardial infarction. Assessment of the quantityf myocardial damage (infarct size) is also an important trialnd-point. Although the specific measurements vary de-ending on the assay and whether cardiac troponin T or I issed, in most studies troponin values correlate better withadionuclide- and MRI-determined infarct size than do CKnd CKMB (81–83).

The use of cardiac troponins will undoubtedly increasehe number of events recorded in a particular investigationecause of increased sensitivity for detecting infarction84–87). Ideally, data should be presented so that futurelinical investigations or registries can translate the myocar-ial infarction end-point chosen in one study into thend-point of another study. Thus, measurements should beresented in a uniform manner to allow independent judge-ent and comparison of the clinical end-points. Further-ore, this Task Force suggests that data be reported asultiples of the 99th percentile URL of the applied biomar-

er, enabling comparisons between various classes andeverity of the different types of myocardial infarction asndicated in Tables 6 and 7.

It is recommended that within a clinical trial allnvestigators whenever possible should employ the samessay in order to reduce the inter-assay variability, and,ven better, the latter could be reduced to zero bypplication of a core laboratory using the same assay forll measurements.

In the design of a study, investigators should specify thexpected effect of the new treatment under investigation.actors that should be considered include:

Assessment of the incidence of spontaneous myocardialinfarction (type 1) and infarction related to myocardialoxygen supplies and demand (type 2) in treated patientsvs. control subjects.Assessment of the incidence of sudden death related tomyocardial infarction when applying the suggested cri-teria (type 3).Assessment of the incidence of procedure-related myo-cardial infarctions and biomarker elevations (PCI, types

n According to Multiples of the 99th Percentile URL of the

I type 4a†(PCI)

MI type 4b(stent thrombosis)

MI type 5†(CABG)

Totalnumber

marker determination could be performed. †For the sake of completeness, the total distributionecision limit used for these types of myocardial infarction. Irrespective of the specific end-point

eted, including the shaded areas.

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ublic Policy Implications of Redefinition ofyocardial Infarction

volution of the definition of a specific diagnosis such asyocardial infarction has a number of implications for

ndividual citizens as well as for society at large. The processf assigning a specific diagnosis to a patient should bessociated with a specific value for the patient. The re-ources spent on recording and tracking a particular diag-osis must also have a specific value to society in order to

ustify the effort. A tentative or final diagnosis is the basis fordvice about further diagnostic testing, treatment, lifestylehanges, and prognosis for the patient. The aggregate ofatients with a particular diagnosis is the basis for healthare planning and policy, and resource allocation.

One of the goals of good clinical practice is to reach aefinitive and specific diagnosis, which is supported byurrent scientific knowledge. The approach to the definitionf myocardial infarction outlined in this document meetshis goal. In general, the conceptual meaning of the termyocardial infarction has not changed, although new sen-

itive diagnostic methods have been developed to diagnosehis entity. Thus, the current diagnosis of acute myocardialnfarction is a clinical diagnosis based on patient symptoms,CG changes, and highly sensitive biochemical markers, asell as information gleaned from various imaging tech-iques. However, it is important to characterize the extentf the infarct as well as residual LV function and the severityf coronary artery disease, rather than merely making aiagnosis of myocardial infarction. The information con-eyed about the patient’s prognosis and ability to workequires more than just the mere statement that the patientas suffered an infarct. The multiple other factors justentioned are also required so that appropriate social,

amily, and employment decisions can be made. A numberf risk scores have been developed predicting post-infarctionrognosis. The classification of the various other prognosticntities associated with myocardial necrosis should lead to aeconsideration of the clinical coding entities currentlymployed for patients with the myriad conditions that canead to myocardial necrosis with consequent elevation ofiomarkers.Many patients with myocardial infarction die suddenly.ifficulties in definition of sudden and out-of-hospital

eath make attribution of the cause of death variable amonghysicians, regions, and countries. For example, out-of-ospital death is generally ascribed to ischaemic heartisease in the USA but to stroke in Japan. These arbitrarynd cultural criteria need re-examination.

It is important that any revised criteria for the definitionf myocardial infarction involve comparability of this defi-ition over time so that adequate trend data can bebtained. Furthermore, it is essential to ensure widespreadvailability and standard application of the measures in
rder to ensure comparability of data from various geo- m
raphic regions. Shift in criteria resulting in a substantialncrease or decrease in case identification will have signifi-ant health resource and cost implications (86,87). More-ver, an increase in sensitivity of the criteria for myocardialnfarction might entail negative consequences for someatients who are not currently labelled as having had annfarction. On the other hand, increasing diagnostic sensi-ivity for myocardial infarction can have a positive impactor a society:

Increasing the sensitivity of diagnostic criteria for myo-cardial infarction will result in more cases identified in asociety, thereby allowing appropriate secondary preven-tion.Increasing the specificity of diagnostic criteria for myo-cardial infarction will result in more accurate diagnosisbut will not exclude the presence of coronary arterydisease, the cases of which may benefit from secondaryprevention.

It should be appreciated that the agreed modification ofhe definition of myocardial infarction may be associatedith consequences for the patients and their families with

espect to psychological status, life insurance, professionalareer, as well as driving and pilot licences. Also theiagnosis is associated with societal implications as toiagnosis-related coding, hospital reimbursement, mortalitytatistics, sick leave, and disability attestation.

In order to meet this challenge, physicians must bedequately informed of the altered diagnostic criteria. Ed-cational materials will need to be created and treatmentuidelines must be appropriately adapted. Professional so-ieties should take steps to facilitate the rapid disseminationf the revised definition to physicians, other health carerofessionals, administrators, and the general public.

lobal Perspectives of the Redefinition ofyocardial Infarction

ardiovascular disease is a global health problem. Approx-mately one-third of persons in the world die of cardiovas-ular disease, largely coronary artery disease and stroke, and0% of these deaths from cardiovascular disease occur ineveloping countries. The greater proportion of deaths isue to heart disease and specifically coronary heart disease,f which myocardial infarction is a major manifestation.ince it is difficult to measure the prevalence of coronaryrtery disease in a population, the incidence of myocardialnfarction may be used as a proxy, provided that a consistentefinition is used when different populations, countries, orontinents are being compared.

The changes in the definition of myocardial infarctionave critical consequences for less developed and developingountries. In many countries, the resources to apply the newefinition may not be available in all hospitals. However,
any developing countries already do have medical facilities

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1


apable of or currently employing the proposed definition ofyocardial infarction. In the context of the overall cost forpatient with myocardial infarction, the expense associatedith a troponin assay would not be excessive and should be

conomically affordable in many hospitals in developingountries, particularly those where infarcts are frequentvents. The necessary equipment, staff training, and runningosts may be lacking in some regions, but certainly not inthers. In less advantaged hospitals, the diagnosis of myo-ardial infarction may depend mostly on clinical signs andymptoms coupled with less sophisticated biomarker anal-ses. Some of these institutions may only have access to CKnd its isoenzymes at the present time. The redefinitionrises from and is compatible with the latest scientificnowledge and with advances in technology, particularlyith regard to the use of biomarkers, high quality electro-

ardiography, and imaging techniques. The definition cannd should be used by developed countries immediately, andy developing countries as quickly as resources becomevailable.

The change in the definition of myocardial infarction willave a substantial impact on the identification, prevention,nd treatment of cardiovascular disease throughout theorld. The new definition will impact epidemiological data

rom developing countries relating to prevalence and inci-ence. The simultaneous and continuing use of the older

HO definition for some years would allow a comparisonetween data obtained in the past and data to be acquired inhe future employing the newer biomarker approach. Cul-ural, financial, structural, and organizational problems inhe different countries of the world in diagnosis and therapyf acute myocardial infarction will require ongoing investi-ation. It is essential that the gap between therapeutic andiagnostic advances be addressed in this expanding area ofardiovascular disease.

onflicts of Interest

he members of the Task Force established by the ESC,he ACCF, AHA and the WHF have participated inde-endently in the preparation of this document, drawing onheir academic and clinical experience and applying anbjective and critical examination of all available literature.ost have undertaken and are undertaking work in collab-

ration with industry and governmental or private healthroviders (research studies, teaching conferences, consulta-ion), but all believe such activities have not influenced theirudgement. The best guarantee of their independence is inhe quality of their past and current scientific work. How-ver, to ensure openness, their relations with industry,overnment and private health providers are reported inppendixes 1 and 2. Expenses for the Task Force/Writingommittee and preparation of this document were provided

ntirely by the above mentioned joint associations.

cknowledgementse are indebted to Professor Erling Falk MD for reviewing

he section on ‘Pathology.’ Furthermore, we are very gratefulo the dedicated staff of the Guidelines Department of theSC. We would also like to thank and to acknowledge the

ontribution of the following companies through unre-tricted educational grants, none of whom were involved inhe development of this publication and in no way influ-nced its contents. Premium observer: GlaxoSmithKline.bserver: AstraZeneca, Beckman-Coulter, Dade Behring,oche Diagnostics, Sanofi-Aventis, Servier.

EFERENCES

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9. Mahnken AH, Koos R, Katoh M, et al. Assessment of myocardialviability in reperfused acute myocardial infarction using 16-slicecomputed tomography in comparison to magnetic resonance imaging.J Am Coll Cardiol 2005;45:2042–7.

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2. Sabia P, Abbott RD, Afrookteh A, Keller MW, Touchstone DA, KaulS. Importance to two-dimensional echocardiographic assessment ofleft ventricular systolic function in patients presenting to the emer-gency room with cardiac-related symptoms. Circulation 1991;84:1615–24.

3. Saeian K, Rhyne TL, Sagar KB. Ultrasonic tissue characterization fordiagnosis of acute myocardial infarction in the coronary care unit. Am J
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5. Udelson JE, Beshansky JR, Ballin DS, et al. Myocardial perfusionimaging for evaluation and triage of patients with suspected acutecardiac ischemia: a randomized controlled trial. JAMA 2002;288:2693–700.

6. Stowers SA, Eisenstein EL, Wackers FJT, et al. An economic analysisof an aggressive diagnostic strategy with single photon emissioncomputed tomography myocardial perfusion imaging and early exer-cise stress testing in emergency department patients who present withchest pain but non-diagnostic electrocardiograms: results from arandomized trial. Ann Emerg Med 2000;35:17–25.

7. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayedcontrast enhancement to irreversible necrosis, infarct age, and contrac-tile function. Circulation 1999;100:1992–2002.

8. Harris BM, Nageh T, Marsden JT, Thomas MR, Sherwood RA.Comparison of cardiac troponin Tand I and CK-MB for the detectionof minor myocardial damage during interventional cardiac procedures.Ann Clin Biochem 2000;37:764–9.

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2. Anderson KM, Califf RM, Stone GW, et al. Long-term mortalitybenefit with abciximab in patients undergoing percutaneous coronaryintervention. J Am Coll Cardiol 2001;37:2059–65.

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6. Ricciardi MJ, Davidson CJ, Gubermikoff G, et al. Troponin Ielevation and cardiac events after percutaneous coronary intervention.Am Heart J 2003;145:522–8.

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PPENDIX 1. RELATIONSHIPS WITH INDUSTRY—JOINT ESC/ACCF/ACA/WHF TASK FORCE FOR THEEDEFINITION OF MYOCARDIAL INFARCTION

NameResearch Contracts

(Such as Grants, etc.) Consulting/AdvisingEmployment in

Industry

Stockholderof a

HealthcareCompany

Owner of aHealthcareCompany

(or Partnership) Others

riters

oseph S. Alpert None ● Exeter ContinuingMedical EducationCompany

● Novartis● Sanofi-Aventis

None None None None

lliott M.Antman

● Eli Lilly (via TIMI StudyGroup)

● Sanofi-Aventis (via TIMIStudy Group)

● Sanofi-Aventis None None None None

red S. Apple ● Abbott● Bayer● Beckman● BioMerieux● Biosite● Clinical Diagnostics● DPC● Medical KnowledgeInstitute

● Ortho● Roche

● Abbott● ClinicalDiagnostics

● Ortho● Sensera

None None None None

aul W.Armstrong

● Boerhringer Ingelheim● Hoffman LaRocheCanada

● Procter &Gamble/Alexion

● Sanofi-Aventis● Schering-PloughResearch Institute

● AbbottLaboratories

● Medicure● TaregGen

None None None None

ean-PierreBassand

None None None None None None

eroen J. Bax ● Bristol-Myers Squibb● General Electric● Guidant● Medtronic

None None None None None

eorge A. Beller None None None None None None

obert Bonow None None None None None None

ernardChaitman

● CV Therapeutics● Pfizer

● CV Therapeutics● Merck● Pfizer● Sanofi-Aventis

None None None None

eter M.Clemmensen

● Medtronic ● Medtronic None None None None

ikael Dellborg None None None None None None

. BruceFerguson, Jr.


ranciscoFernandez-Avilés

None None None

eith A. Fox ● Bristol-Myers Squibb● GlaxoSmithKline● Sanofi

● Bristol-MyersSquibb

● GlaxoSmithKline● Sanofi

None None None None

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PPENDIX 1. CONTINUED



Industry

Stockholderof a

HealthcareCompany



im M. Fox ● Servier Labs ● Servier Labs None None None None

arcelloGalvani


nrique P.Gurfinkel

● Sanofi-Aventis● Schering-Plough

● Sanofi-Aventis None None None None

hristian W.Hamm

● Abbott● Roche

● Abbott None None None None

anoch Hod None None None None None None

llan S. Jaffe ● Dade-Behring ● Bayer● Beckman-Coulter● Dade-Behring● GlaxoSmithKline● Ortho Diagnostics● Pfizer

None None None None

ugo A. Katus None None None None None • I have inventedthe troponin Tassay and hold apatent jointlywith RocheDiagnostics

ose-Luis Lopez-Sendon

● Amgen● AstraZeneca● Bayer● Bristol-Myers Squibb● CV Therapeutics● Eli Lilly● Merck● Novartis● Schering-Plough● Servier● Solvay

● Medtronic None None None None

hanthi Mendls None None None None None None

. Kristin Newby ● BG Medicine● Bristol-Myers Squibb-Sanofi

● Inverness Medical, Inc.● Roche Diagnostics● Schering-Plough

● Adolor● Atherogenics● Biosite● Johnson &Johnson/Scios

● Procter & Gamble● Tethys

None None None None

. MagnusOhman

● Berlex*● Bristol-Myers Squibb*● Eli Lilly*● MillenniumPharmaceuticals*

● Sanofi-Aventis*● Schering-Plough*

● Abiomed● Dataxcope● Invoise*● Liposcience● ResponseBiomedical

● Savacor*● The MedicinesCompany

● Invoise*● Medtronic*● Savacor*

Speaker’s bureau:● CV Therapeutics*● Schering-Plough*

rem Pais ● AstraZeneca● Boehringer Ingelheim● Cadila Limited

None None None None None

lexander N.Parkhomenko

● GlaxoSmithKline● Sanofi-Aventis● Servier

● GlaxoSmithKline None None None None

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(Such as Grants, etc.) Consulting/Advising

hilip A. Poole-Wilson

● Roche None

ekka Porela None None

ilvia G. Priori ● Guidant● Medtronic

● Lundbeck

an Ravkilde ● Abbott Diagnostics● Dade-Behring Diagnostics● Roche Diagnostics

None

aarten L.Simoons

● Servier ● Servier

hilippe GabrielSteg

● Sanofi-Aventis ● Nycomed● Sanofi-Aventis● Servier● Takeda● The MedicinesCompany

ichal Tendera ● Amgen● Bayer● Servier

● Amgen● Bayer● Servier

ristianThygesen

None None

ichardUnderwood

None ● CV Therapeutics● GE Healthcare

arry F. Uretsky None None

rnst E. Van DerWall

None None

iisa-MariaVoipio-Pulkki

None None

ars C.Wallentin

● AstraZeneca● Bristol-Myers Squibb● Boerhringer Ingelheim● Eli Lilly● GlaxoSmithKline● Sanofi● Schering-Plough

None

Employment inIndustry

Stockholderof a

HealthcareCompany



None None None ● Bayer● Menarini● Merck Sharp &Dohme

None None None None

None None None Speaker’s bureau:● Guidant● Medtronic

None None None None

None None None None

None None None Speaker’s bureau:● Boehringer-Ingelheim


● GlaxoSmithKline● Nycomed● Sanofi-Aventis● Servier● ZLB-Behring

None None None None

None None None None

None None None None

None None None None

None None None None

None None None None

None None None None

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Tc ot necessarily reflect relationships with industry at the time of publication.





arvey D. White ● Alexion● Eli Lilly● Fournier Laboratories● GlaxoSmithKline● Janssen Cilag● Johnson & Johnson● Merck Sharp & Dohme● National Institutes ofHealth

● Neuren Pharmaceuticals● Pfizer● Procter & Gamble● Roche● Sanofi-Aventis● Schering-Plough● The Medicines Company

● GlaxoSmithKline● Medicure● NeurenPharmaceuticals

● The MedicinesCompany

illiam Wijns ● Abbott● Biotronic● Biotronik● Conor Medsystems● Cordis● Cordis, a Johnson &Johnson Company

● GlaxoSmithKline● Medtronic● Terumo● Therabel Pharma

avid O.Williams

● Abbott Vascular● Cordis, a Johnson &Johnson Company

● Abbott Vascular● Cordis, a Johnson& JohnsonCompany

un-Ren Zhu None None

he table represents the relationships of committee members with industry that were reported inonference calls of the writing committee during the document development process. It does n*Indicates significant relationship (More than $10,000)


Stockholderof a

HealthcareCompany



Speaker’shonorarium:

● Sanofi-Aventis● The MedicinesCompany

None None None None

None None None None

writing prior to the initial writing committee meeting and updated in conjunction with all meetings and

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PPENDIX 2. RELATIONSHIPS WITH INDUSTRY—EXTERNAL PEER REVIEW FOR THE EXPERT CONSENSUSOCUMENT ON THE UNIVERSAL DEFINITION OF MYOCARDIAL INFARCTION



Industry

Stockholderof a

HealthcareCompany



awwar Al-Attar None None None None None None

orin Brener None None None None None None

arek Dudek ● Balton● Biotronic● Boehringer Ingelheim● Eli Lilly● Eurocor● Nycomed● Pfizer● Sanofi● Schering● Volcano

● Abbott● Boston● Cordis● Invatec● Medtronic

. Brian Gibler ● Abbott POC● i-STAT

None None None None Education grantsto EMCREG-International:

● Biosite● Sanofi-Aventis● Schering-Plough

avid Goff None ● GlaxoSmithKline None None None None

obertHarrington*

● Abbott Vasc-Devices● Acorn Cardiovascular● Actelion● Acusphere, Inc. AdvancedCV Syst

● Advanced Stent Technologies,Inc.

● Agilent● Ajinomoto● Alexion†● Alsius● Allergan● Amgen● Amylin Pharmaceuticals, Inc.● Anadys● ANGES MG, Inc.● Arginox Pharmaceuticals†● Angiometrx, Inc.● Ark Therapeutics, Ltd.● Astellas Pharma US, Inc.● Astra Hassle● AstraZeneca†● Atritech● Aventis†● Avion Flumist● Baxter● Bayer AG● Bayer Corp.● Berlex● Biocompatibles, Ltd.● Biogen● Bioheart● Biomarin● Biosense Webster, Inc.● Biosite● Bio Technology General● Biotronik● Boehringer Ingelheim


None None None Educationalactivitiesgenerateactivity for DukeUniv.:

● Merck/Schering-Plough Venture*

● PortolaPharmaceutical*

● Sanofi-Aventis● Schering-Plough

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Industry

Stockholderof a

HealthcareCompany



obertHarrington*(continued)

● Boston MedTech Advisors● Boston Scientific● Bracco Diagnostics● Bristol-Myers Squibb†● CanAm Bioresearch†● Cardiac Science, Inc.● Cardio Thoracic Systems● CardioDynamics International● CardioKinetix, Inc.● Celsion Corp.● Centocor● Chugai Pharmaceuticals● Cierra, Inc.● Coley Pharma Group● Conor Medsystems, Inc.● Corautus Genetics, Inc.● Cordis● Corgentech● Corvalent Group● Critical Therapeutics, Inc.● CryoVascular System, Inc.● Cubist Pharmaceuticals● CV Therapeutics, Inc.● Cytokinetics, Inc.● Dade Behring● Daiichi● Decide Genetics● Dyax● Echosens, Inc.● Elipse Surg Tech● Edwards Lifesciences● Eisai● Enzon Pharmaceutical● EPI-Q, Inc.● Ev3, Inc.● Evalve, Inc.● First Circle Medical, Inc.● First Horizon● Flow Cardia, Inc.● Fox Hollow Pharmaceutical● Fujisawa● Genentech● General Electric Healthcare● General Electric MedicalSystems

● Genzyme Corporation● Getz Bros., Co., Inc.● Gilead● GlaxoSmithKline● Guidant● Guilford Pharmaceuticals● Heartscape Technologies, Inc.● Hoffman-LaRoche● Human Genome Sciences● Humana● IDB Medical● Idenix Pharmaceuticals, Inc.● Idun Pharmaceutical, Inc.● Immunex● Idenix Pharmaceutical● INFORMD, Inc.● InfraReDx● Inhibitex● INO Therapeutics, Inc.

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Industry

Stockholderof a

HealthcareCompany




● Inspire Pharm● Integrated TherapeuticsGroup

● InterMune Pharmaceuticals● Inverness MedicalInnovations

● ISIS Pharmaceuticals● Johnson & Johnson● Jomed, Inc.● KAI Pharmaceuticals†● Kerberos Proximal, Inc.● King Pharmaceuticals● Kuhera Chemical Co.● Lilly● Lumen Biomedical● Medacoustics● Medicure†● Medi-Flex, Inc.● Med Immune● Medtronic, Inc.● Merck● Merck/Schering-PloughVenture†

● MicroMed Tech, Inc.● Microphage, Inc.● Millenium Pharmaceutical†● Mitsubishi● Momenta Pharmaceuticals● Mycosol, Inc.● Myogen● NABI● Neuron Pharmaceuticals● NitroMed● NovaCardia, Inc.● Novartis*● Organon International● Ortho Biotech● Osiris Therapeutics, Inc.● Otsuka AmericaPharmaceutical, Inc.

● Pathway Medical Tech● PDL bioPharma● Pfizer● Pharmanetics● Pfizer● Portola Pharmaceutical†● Proctor and Gamble● Prometheus● Radiant● Recom Managed Systems● Regado Biosciences, Inc.†● Reliant Pharma● Roche Diagnostic Corp.● Salix Pharmaceuticals● Sanofi Pasteur● Sanofi-Aventis†● Sanofi-Synthelabo● Schering-Plough†● SciClone Pharmaceuticals● Scios● Searle● Sicel Technologies● Siemens

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M

M

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S

M

Ttot esearch contract with this company. Payments for the work performed for these contracts are made tot ject, has been supported by these funds in the past year.






● Social Scientific Systems, Inc.Spectranetics

● Summit● Suneis● TAP PharmaceuticalProducts, Inc.

● Terumo Corporation● The Medicines Company● Theravance● TherOx, Inc.● Titan Pharmaceuticals, Inc.● Valeant Pharmaceuticals● Valentis, Inc.● Vascular Solutions, Inc.● Velocimed● Veridex● Vertex Pharmaceuticals● Viasys Healthcare, Inc.● Vicuron Pharma● Wyeth● Wyeth-Ayerst● Xoma● Xsira Pharmaceuticals● XTL Biopharmaceuticals● Yamanouchi

len N. Levine None None

ichael Lim None None

arco A.Martınez-Rios

None None

oao Morals None ● AstraZeneca

avid Morrow ● Bayer Diagnostics● Beckman Coulter● Biosite Inc.● Dade-Behring● Roche Diagnostics

● Beckman Coulter

do Sechtem ● Bosch ● Novartis● Pfizer

teve Steinhubl ● Eli Lily● The Medicines Company

● AstraZeneca● Eli Lilly● Sanofi-Aventis● The MedicinesCompany

arco A. Tubaro None None

his table represents the relationships of peer reviewers with industry that were disclosed at thime of publication. *As Director of the Duke Clinical Research Institute (DCRI), I benefit indirectr completed within the past 3 years. †In addition to oversight role as DCRI Director, funding ishe Chairman, Co-Chairman, Executive or Steering Committee member. I am involved in such a rhe University. A portion of my salary as a faculty member, representative of % effort on the pro


Stockholderof a

HealthcareCompany



None None None None

None ● SingaporeHeart, Strokeand CancerCentre

None None

None None None None

None None None None

None None None Honoraria foreducationalpresentations:● BayerDiagnostics

None None None None

None None None None

e time of peer review of this guideline. It does not necessarily reflect relationships with industry at thely from DCRI’s institutional grants and contracts. Projects conducted with this entity are either currentprovided for my effort in research grants or contracts for multi-center projects in which I serve as either

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