Things ain’t what they used to be: Impact of a newdefinition of myocardial infarctionHarvey D. White, DSc Auckland, New Zealand

See related articles on pages 957 and 981.

In September 2000 a new definition of myocardialinfarction (MI) was promulgated by the Joint EuropeanSociety of Cardiology/American College of Cardiology(ESC/ACC) Committee.1 The definition is based largelyon rising and falling levels of the cardio-specific bi-omarkers, troponin T and troponin I, in the appropri-ate clinical context.

The ESC/ACC Committee has been criticized forchanging the definition of MI, and some commentatorshave said there is little justification for adopting theirrecommendations at face value.2-6 The criticisms havelargely focused on 2 issues. The first is the impact onepidemiology caused by difficulties in making compari-sons with previous populations classified according toa different definition. With the change in definition,the number of patients receiving a diagnosis of MI willrise and the case fatality rates will fall, thus it will bedifficult to compare prevalence trends over time. Thismeans that audits of the prevalence of MI and patientoutcomes will need to continue using previous defini-tions for a transition period in order to obtain compar-ative data. Notwithstanding the value of epidemiologi-cal studies such as the Monitoring Trends andDeterminants in Cardiovascular Disease (MONICA)Project,7 new epidemiological studies using the newdefinition of MI are needed to provide comparativedata for research in future years.

The second major criticism is the lack of attentiongiven in the recommendations to the diagnosis of MIin situations where troponin levels cannot be deter-mined. The release of troponins from the myocardialcontractile apparatus in response to prolonged isch-emia occurs slowly, and thus troponin levels in theblood do not rise for at least 3 to 4 hours after theonset of ischemia. The new definition of MI does notcater for patients who present very early, before theirtroponin levels have had time to rise, or who die be-fore signs of myocardial necrosis have developed suffi-

ciently to be detected at autopsy. Thus there is still aplace for definitions of MI not based entirely on tro-ponins. The diagnosis of MI should always take intoaccount information obtained clinically and from imag-ing modalities such as angiography, echocardiography,radionuclide scanning or magnetic resonance imaging,which may show regional wall motion abnormalitieswith thinning of the myocardium.1

In this issue of the Journal, Newby et al8 describethe discussions and recommendations from a meetingheld in January 2001 to consider the implications ofthe new definition. Three recommendations weremade.

1. Any elevation of creatine kinase-MB (CK-MB) or tropo-nin is associated with a worse prognosis and should beconsidered an event whether it occurs in the context ofan acute coronary syndrome, percutaneous coronaryintervention (PCI), or coronary artery bypass grafting(CABG).

2. Continuous measures of myocardial necrosis, ratherthan dichotomous measures, should be used.

3. The troponin assays currently available do not meet therecommendations defined by the ESC/ACC Committee,and need to be improved.

To these important and cogent recommendations Iwould add 4 further comments. First, although Europeand the United States are prominent on the interna-tional stage, they are not the whole world. The ESC/ACC recommendations have worldwide ramifications(including cost implications), which should have beenconsidered, and the change in definition to a largelytroponin-based one may not be possible to implementin Africa, Asia, South America, and many parts of East-ern Europe.

Second, the emphasis on troponins at a time whennone of the available troponin assays had been shownto fulfil the Committee’s recommendations of 10% pre-cision and a 99th percentile coefficient of variation (ie,the detection limit) has been problematic. Many labo-ratories worldwide have not yet performed formal lo-cal reference range studies to determine whether theyfulfil the recommended criteria for precision at thedetection limit. They should do so as a matter of ur-gency, and should provide clinicians with supportingdata for the particular assay they use. It is almost 2years since the new definition was promulgated. Teststhat are used for diagnosis and management of seriousmedical conditions must be accurate, and it wouldseem reasonable to set a time limit of 3 years after

From the Cardiology Department, Green Lane Hospital, Auckland, New Zealand.Reprint requests: Harvey White, DSc, Cardiology Department, Green Lane Hospital,Private Bag 92-189, Auckland 1030, New Zealand.E-mail: harveyw@adhb.govt.nzAm Heart J 2002;144:933-7.Copyright 2002, Mosby, Inc. All rights reserved.0002-8703/2002/$35.00 � 0 4/4/129780doi:10.1067/mhj.2002.129780

Editorial

publication of the ESC/ACC recommendations for as-says to achieve the recommended level of precision.Any assays that don’t measure up should be with-drawn in the interests of patient care.

In an article accompanying the paper by Newby etal,8 Apple et al9 make further comments about imple-mentation of the ESC/ACC recommendations. Theymake a number of recommendations, including using acut-off value of �10% imprecision (which was abovethe 99th percentile of the reference range for all as-says) until assays improve. This idea has considerablemerit. They also make recommendations regarding thedefinition of MI associated with PCI, namely that anincrease above the cut-off value determined at 10%imprecision should be considered an MI, and that anincrease of �25% in cases where the troponin levelwas already increased should be defined as recurrentinjury associated with PCI.

There are now several troponin assays available (eg,the Roche Diagnostics troponin T assay) that fulfil theESC/ACC recommendations (personal communication).Several troponin I assays come close to fulfilling therecommendations. Apart from the precision of the as-says themselves, it will be important for individual lab-oratories to show that they can achieve the requiredstandards routinely.10

Another issue is that some laboratories may assaytroponins only once a day or just several times a week.The ACC/American Heart Association (AHA) guidelinesrecommend that laboratories should provide cardiacbiomarker results within 30 to 60 minutes,11 and theUS National Academy of Clinical Biochemistry recom-mends bedside or point-of-care testing if laboratoriescannot provide cardiac biomarker results consistentlywithin 1 hour.12

Third, the ESC/ACC Committee did not give any rec-ommendations for an implementation strategy. Manyhospitals worldwide still do not perform troponin test-ing. For example, in a recent survey, only 70% of hos-pitals in Scotland had troponin testing available.13 Hap-hazard introduction of the new definition has alreadyled to hospitals in the same community using differentcriteria for the diagnosis of MI. The transition mighthave been smoother if the introduction of the newdefinitions had been coordinated by national cardiacsocieties, the World Heart Federation and the WorldHealth Organization. Major educational efforts are re-quired to educate doctors and the public that there isnow a new definition of what constitutes a heart at-tack, and national heart foundations should take a lead-ing role in such initiatives. Many patients will now betold that they have had a heart attack who would nothave been diagnosed as such previously. It is impor-tant that they are told that for most patients the futureafter a heart attack is excellent.

As the ESC/ACC Committee indicated, the new defi-nition has had wide implications for patients and clini-cal practice. The Committee’s recommendations affectdriving and rehabilitation guidelines; sick leave anddisability entitlements; employers’ perceptions aboutemployability; advice as to when patients can return towork or fly; pilot licensing; life, health and travel insur-ance; coding of diagnostic groups; epidemiology; clini-cal trials; and health funding and public policy.

In New Zealand the new definitions have alreadybeen accepted by the Land Transport Safety Authority,which governs driver licencing. Thus patients whohave a positive troponin test (without elevation ofother myocardial proteins) after PCI or in connectionwith a non-ST-elevation acute coronary syndrome areclassified in the same way and must not drive a privatevehicle for 2 weeks, and must not drive a commercialvehicle for 4 weeks.

The psychological impact of the diagnosis of MI onindividuals and their families should not be underesti-mated, and the response—whether conscious or sub-conscious—will vary enormously. Of course, tellingpatients that they have had a heart attack should notbe the only information given. Not all MIs are thesame,14 and the implications for social activities, em-ployment, and patients’ prognoses will vary widelyaccording to the extent of myocardial necrosis, evi-dence of inducible ischemia, predisposition to ventric-ular arrhythmias, the severity of coronary artery dis-ease, whether revascularization has been performed,and the degree of impairment of left ventricular func-tion. This information should be conveyed and dis-cussed with patients and their families.

Fourth, the ESC/ACC Committee gave no recommen-dations as to the definition of MI in patients undergo-ing CABG, although a consensus conference in 1998recommended that the CK-MB threshold should be 5times the upper limit of normal.15 (The same confer-ence recommended that the CK-MB threshold for PCIshould be 3 times the upper limit of normal). Definingthe troponin levels that correlate with increased riskafter CABG is a different concept than defining thelevel at which to label an event “MI” based on an isch-emic cause. In the setting of CABG, a positive tropo-nin test signifies that myocyte necrosis has occurred,and patients should be risk-stratified according to theirtroponin level and other risk factors. There is clearevidence that patients with increased cardiac proteinlevels after CABG have worse outcomes. In the ArterialRevascularization Therapy (ARTS) Study,16 which com-pared multivessel stenting with CABG, elevated CK-MBlevels were detected in 30.5% of patients treated withPCI and 62% of those treated with CABG. The 12-month mortality rate in the latter group increased sig-nificantly when CK-MB levels rose above 5 times nor-mal (7% vs 0% in the 38% of patients without elevated

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CK-MB levels), and there was a trend towards a highermortality rate in those with CK-MB levels above 3times normal (5.4%). I believe that, as with periproce-dural events associated with PCI, events associatedwith CABG should be reported separately in clinicaltrials.

A rise in troponin levels in patients with non-ST-ele-vation acute coronary syndromes clearly signifies anincreased risk of death or MI. Meta-analysis has shownthat elevated troponin levels are associated with a9-fold increased risk of death or MI within the subse-quent 30 days.17 Elevated troponin levels in patientswith acute coronary syndromes have a prognosticvalue that is out of proportion to the extent of myo-cyte necrosis and left ventricular impairment, andprobably indicate the occurrence of microinfarctionsdue to platelet microemboli from ulcerated, complexand unstable atheromatous coronary artery plaques(Figure 1).

Various different populations of patients developelevated troponin levels (eg, after an acute coronarysyndrome, PCI, or CABG). It is possible that similardegrees of troponin elevation are associated with simi-lar outcomes irrespective of the etiology of myocardialnecrosis. Another possibility is that these populationswill have differing prognoses even though they havethe same magnitude of troponin elevation (Figure 2).For example, a patient with an occluded branch arteryafter PCI, such as a small diagonal or obtuse marginal

branch, may have an excellent prognosis based on fac-tors other than those associated with myocyte necro-sis, whereas a patient presenting with a non-ST-eleva-tion acute coronary syndrome with a thrombus-rich,

Figure 2

Increasing risk in different clinical scenarios with the same tropo-nin level. ACS, Acute coronary syndrome; CABG, coronary arterybypass grafting; LAD, left anterior descending coronary artery; LV,left ventricular; PCI, percutaneous coronary intervention.

Figure 1

Microvascular obstruction after plaque rupture. Despite recurrent micro emboli, the levels of CK-MB do not reach the diagnostic threshold,whereas because of the long half life and higher sensitivity of the assays, the diagnostic threshold for troponin is reached. CK-MB, Creatinekinase-MB. Adapted with permission from: Goldman BU, Christenson RH, Hamm CW, et al. Implications of troponin testing in clinical medi-cine. Curr Control Trials Cardiovasc Med 2001;2:75-84.

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fissured and unstable plaque in the left anterior de-scending coronary artery is likely to have an unstableclinical course and a poor prognosis even though therise in troponin levels may be no greater.

The prognostic importance of troponin elevationsafter PCI was shown in the Sibrafiban versus aspirin toYield Maximum Protection from ischemic Heart eventspost-acute corONary sYndromes (SYMPHONY) trial, inwhich 82% of patients underwent PCI with stenting.Forty-eight percent had elevated troponin I levels,whereas only 29% had elevated CK-MB levels.18 Twen-ty-six percent of patients who tested negative for tro-ponins before the procedure tested positive after theprocedure, and these patients had a combined hazardratio (HR) for death or MI within 90 days of 4.3 (95%CI 1.4-13.5) versus those without elevated troponinlevels. Multivariate analysis including baseline charac-teristics and procedural variables showed that troponinI (entered as a continuous variable) was an indepen-dent predictor of the time to death or MI (P � .0001).In a recent meta-analysis of 2605 patients who werefollowed up for 1.5 to 77 months after PCI, those withelevated troponin levels (measured using a variety oftroponin assays and a variety of cutpoints) after theprocedure were found to have double the rates ofmortality (HR 2.09, CI 1.42-3.08) and MI (HR 2.27, CI1.62-3.16).19 Troponin elevations occur more fre-quently after stenting and are higher than after PCIwithout stenting, but because stenting produces betteroutcomes, the risk gradient may not be so pronouncedand may be concentrated in patients with the greatesttroponin elevations.20

The mechanism for the increase in adverse eventsassociated with troponin elevations after PCI is un-clear. Small myocardial scars resulting from plaque orplatelet emboli may act as a focus for arrhythmogen-esis and sudden death. The impaired prognosis couldalso be due to an underlying unifying factor, such asinflammation.15 Alternatively, it is possible that thetroponin elevation is not the cause of a poor progno-sis, but rather the result of diffuse coronary diseasewith an increased plaque burden.

Elevated troponin levels are found in most patientsafter CABG, but some patients may have only smallincreases (eg, those undergoing off-pump CABG).21

Troponin levels have been shown to be superior toCK-MB levels as a predictor of inhospital death or MIafter CABG.21 As with PCI, it is likely that outcomeswill vary according to the etiology of the troponinrise—but whatever the cause, such a rise signifies thatmyocyte necrosis has occurred, and the prognosis willbe worse than if it had not occurred. There are a num-ber of reasons why cardiac protein levels may rise af-ter CABG, such as ischemic causes, anesthetic factors,atrial cannulation, aortic cross-clamping, handling ofthe heart,22 suturing of heart muscle, inadequate myo-

cardial protection, and factors related to graft patency,including plaque and platelet embolism, spasm andthrombosis.

Where the resources are available, troponin testingshould be considered mandatory for prognostic evalua-tion of patients with non-ST-elevation acute coronarysyndromes, diagnosis of MI, and treatment selection(also taking into account other clinical information andtests).23-26 Use of the new definitions of MI may actu-ally reduce costs because the greater precision of tro-ponin testing for risk assessment should mean that un-necessary hospitalization and drug usage can bereduced in low-risk patients, while those with elevatedtroponin levels should be more likely to receive appro-priate antithrombotic therapy, revascularization,27,28

and secondary preventative measures such as aspirinand statins.

A heart attack in 2002 is not the same as a heart at-tack in previous years. I believe that the new defini-tion will lead to improved patient care and conse-quently better patient outcomes. There is much workto be done to ensure that assays are of an appropriatestandard and to educate the public that, as the old TedParsons song says, “Things ain’t what they used to be.”

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2. Dargie H. Myocardial infarction: redefined or reinvented? [editori-al]. Heart 2002;88:1-3.

3. Birkhead JS. Defining myocardial infarction: not too late for com-mon sense or consistency? Hospital Medicine 2001;62:260-1.

4. Richards AM, Lainchbury JG, Nicholls MG. Unsatisfactory redefini-tion of myocardial infarction [commentary]. Lancet2001;357:1635-6.

5. Tormey W. Redefinition of myocardial infarction [letter]. Lancet2001;358:764.

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8. Newby LK, Alpert JS, Ohman EM, et al. Changing the diagnosisof acute myocardial infarction: implications for practice and clini-cal investigations. Am Heart J 2002;144:957-80.

9. Apple FS, Wu AHB, Jaffe AS. European Society of Cardiologyand American College of Cardiology guidelines for redefinition ofmyocardial infarction: how to use existing assays clinically and forclinical trials. Am Heart J 2002;144:981-6.

10. Venge P, Lindahl B, Wallentin L. New generation cardiac troponinI assay for the access immunoassay system. Clin Chem 2001;47:959-61.

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11. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guide-lines for the management of patients with unstable angina andnon-ST-segment elevation myocardial infarction: executive sum-mary and recommendations: a report of the American College ofCardiology/American Heart Association Task Force on PracticeGuidelines (Committee on the Management of Patients with Unsta-ble Angina). Circulation 2000;102:1193-209.

12. Wu AH, Apple FS, Gibler WB, et al. National Academy of Clini-cal Biochemistry Standards of Laboratory Practice: recommenda-tions for the use of cardiac markers in coronary artery diseases.Clin Chem 1999;45:1104-21.

13. Pell ACH, Pell JP. Was it a heart attack? variations in access toand interpretation of troponin assays are wide [letter]. Br Med J2002;324:1216.

14. Pfeffer MA, McMurray JJ. Myocardial infarct: no one size fits all.Circulation 2002;105:2577-9.

15. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis afterrevascularization procedures. J Am Coll Cardiol 1998;31:241-51.

16. Costa MA, Carere RG, Lichtenstein SV, et al. Incidence, predictors,and significance of abnormal cardiac enzyme rise in patientstreated with bypass surgery in the Arterial Revascularization Ther-apies Study (ARTS). Circulation 2001;104:2689-93.

17. Ottani F, Galvani M, Nicolini FA, et al. Elevated cardiac troponinlevels predict the risk of adverse outcome in patients with acutecoronary syndromes. Am Heart J 2000;140:917-27.

18. Cantor WJ, Newby LK, Christenson RH, et al. Prognostic signifi-cance of elevated troponin I after percutaneous coronary interven-tion. J Am Coll Cardiol 2002;39:1738-44.

19. Wu AH, Boden WE, McKay RG. Long-term follow-up of patientswith increased cardiac troponin concentrations following percuta-neous coronary intervention. Am J Cardiol 2002;89:1300-2.

20. Brener SJ, Ellis SG, Schneider J, et al. Frequency and long-term

impact of myonecrosis after coronary stenting. Eur Heart J 2002;23:869-76.

21. Januzzi JL, Lewandrowski K, MacGillivray TE, et al. A comparisonof cardiac troponin T and creatine kinase-MB for patient evalua-tion after cardiac surgery. J Am Coll Cardiol 2002;39:1518-23.

22. Lee ME, Sethna DH, Conklin CM, et al. CK-MB release followingcoronary artery bypass grafting in the absence of myocardial in-farction. Ann Thorac Surg 1983;35:277-9.

23. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients withunstable coronary artery disease who benefit from long-term anti-thrombotic protection. Fragmin in Unstable Coronary Artery Dis-ease (FRISC) Study Group. J Am Coll Cardiol 1997;29:43-8.

24. Heeschen C, Hamm CW, Goldmann B, et al. Troponin concentra-tions for stratification of patients with acute coronary syndromes inrelation to therapeutic efficacy of tirofiban. Lancet1999;354:1757-62.

25. Morrow DA, Antman EM, Tanasijevic M, et al. Cardiac troponin Ifor stratification of early outcomes and the efficacy of enoxaparinin unstable angina: a TIMI-11B substudy. J Am Coll Cardiol 2000;36:1812-7.

26. Antman EM. Troponin measurements in ischemic heart disease:more than just a black and white picture [editorial]. J Am CollCardiol 2001;38:987-90.

27. Fragmin and Fast Revascularisation During Instability in CoronaryArtery Disease (FRISC II) Investigators. Invasive compared withnon-invasive treatment in unstable coronary-artery disease: FRISCII Prospective Randomised Multicentre Study. Lancet 1999;354:708-15.

28. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison ofearly invasive and conservative strategies in patients with unstablecoronary syndromes treated with the glycoprotein IIb/IIIa inhibitortirofiban. N Engl J Med 2001;344:1879-87.

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