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Troponin—Past, Present, and Future

Allan S. Jaffe, MD

Abstract:Cardiac troponin is the analyte of choice forthe diagnosis of cardiac injury. It is highly specific forthe heart and much more sensitive than prior biomark-ers. Because of this increased sensitivity, clinicianshave had to struggle with elevations in novel clinicalsituations. We have developed new understandingsabout coronary artery disease but also have begun toappreciate that many other entities as well can result incardiac injury. As assays have increased in sensitivityover time, this trend has, if anything, accelerated. Thisreview attempts to put the past, the present, and thefuture into a clinical perspective that will help
clinicians. (Curr Probl Cardiol 2012;37:209-228.)
C ardiac troponin has become the marker of choice for the evalua-tion of patients with possible myocardial injury.1,2 Because ourunderstanding of cardiac troponin (cTn) is still evolving and

ecause old friends like the NB isoenzyme of creatine kinase (CKMB)ho have served us well often are hard to give up,3 it has taken a long

ime for troponin to be used as efficiently as guidelines and experts haveuggested.4,5 Indeed, because of its improved sensitivity compared torior markers, clinicians have been very reluctant to use troponin at the9th percentile of the upper reference limit (URL) because so manyatients had elevated values of troponin even with the first-generationssays.3,5 This level of sensitivity has increased still further with modernay assays.6 Thus, many clinicians and laboratories have used higherutoffs for cTn to reduce the frequency of elevations of troponin thatlinicians have a difficult time explaining.3,5 This of course simply makeshe literature and the field far more difficult for clinicians to understandecause the heterogeneity of cutoff values leads to tremendous confusionn the literature and mixed messages about how clinicians should useTn.3,5 The present articulation attempts to resolve some of these issuesurr Probl Cardiol 2012;37:209-228.
146-2806/$ – see front matteroi:10.1016/j.cpcardiol.2012.02.002
urr Probl Cardiol, June 2012 209

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nd provides a common sense way of dealing with cTn and cTnlevations. As part of being able to accomplish this important task, certainasic information about troponin is obligatory and a certain limitednderstanding of the analytical constraints that come with measuringroponin is also of importance. This article does not attempt to review inetail all of these elements but instead identifies those that are critical androvides appropriate references so that those who are interested in morenformation can augment their understanding about these importantssues.

ardiac Troponin BasicsThe cTn complex consists of 3 separate proteins encoded by differentenes. These include cardiac troponin T (cTnT), cardiac troponin I (cTnI),nd cardiac troponin C.7 Each protein plays an important role inegulating the interaction of actin and myosin filaments and thus onardiac contraction. Troponin C is encoded by 2 genes, 1 specific for fastwitch skeletal muscle and a second expressed in both slow-twitchedkeletal muscle and cardiac muscle.8 Thus, it might not be expected toave cardiac specificity and, indeed, that is the case. Both cTnT and cTnIome from unique genes.7 It appears that both cTnI and cTnT have highardiac specificity. The history in regard to cTnI is fairly clear. As best wean tell, it has never been expressed during neonatal development nor inathologic circumstances in any tissue outside of the heart.7 The situationor cTnT is more complex. Fetal isoforms of the protein are expresseduring neonatal development and there were isoforms of cTnT that wereetected by the initial assay for cTnT many years ago. Part of this wasecause there was some cross-reactivity between the antibodies used toetect cTn and skeletal muscle troponin. However, it also appeared thathere might be re-expressed isoforms of cTnT in diseased skeletal muscle,articularly in renal failure patients. New antibodies were developed thatliminated this problem such that the cross-reacting antibodies that wereound were eliminated.9-11 Recently, we described that some patients whoave skeletal muscle disease express proteins that are detected by thentibodies used in the standard and high-sensitivity cTnT assay. Whetherhese are re-expressed isoforms is unclear but they do appear capable ofausing a signal with the cTnT assay.12 Because of the high sensitivity ofhe cTnT, it is impossible to know for sure that there is no concomitantardiac disease, but, at least in a few cases where extensive evaluationsave been done, that has not appeared to be the case. The frequency ofhis phenomenon is unclear at present and it would be a mistake to think
hat all elevations that are difficult to explain are false positives caused by
10 Curr Probl Cardiol, June 2012

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his mechanism.12 Nonetheless, it does appear that some patients withkeletal muscle disease will have elevated values of cTnT but not cTnInd that, unless clinicians are astute to this possibility, the possibility ofonfusing such patients with those who have cardiovascular disease couldccur (Fig 1). Ongoing research is attempting to define the extent tohich this phenomenon occurs.In addition, it is important to understand the way in which the troponins

re released. It appears, in contrast to some proteins, such as CK-MB,hich are only localized in the cytosol of myocytes, that troponin hasultiple localizations.13,14 The initial studies used gentle buffers and

efined a pool of troponin, which was called the “cytosolic pool,” whichas roughly of the same magnitude as that of CK-MB.15 In looking back

t these studies, it appears, given the way in which they were done, aetter term for this pool might be the “early releasable pool” because it isot clear that all the protein is localized in the cytosol of cells.7

onetheless, it is thought that this is the pool that is released early aftercardiac insult and thus leads to early elevations of cTn. However,

ecause this pool is similar in size for both CK-MB and cTn, one coulde confused as to why troponin might be more sensitive. In fact, it is more

IG 1. Detection of skeletal muscle proteins by the antibodies used in the cTnT assay. Westernlot of SMD from patients with myopathies in lanes 1-4, normal human heart muscle in lane 5,nd normal human soleus muscle in lane 6. Note molecular weight designations on therdinate. The antibodies used in the standard cTnT assay (M7 and M11-7) and those used in

he high-sensitivity assay (M7 and 5D8) all tag a protein at a molecular weight of about 39 kDa.his suggests strongly that the 2 antibodies in each of these assays would detect these proteinsn blood, indicating that there is a good possibility that elevations in cTnT or the high sensitivityardiac troponin T assay could occur because of diseased skeletal muscle. (Reproduced withermission.12)

ensitive because the so-called release ratio, ie, the amount of protein


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eleased into the circulation over the amount that is depleted from heart,s far greater for the cTn than it is for CK-MB, which is degradedocally.16 Thus, greater amounts of protein are elaborated for any givennsult via this early releasable pool. This early increase of cTn is followedy a longer period when troponin is released from what is thought to berom a more structurally bound pool that is released as the damaged areas remodeled. This provides an explanation for why troponin elevationsersist for many days, perhaps even weeks, despite its short half-life inhe blood.15 These kinetics have been used to argue that perhaps troponinould be released in the absence of necrosis. Specifically, what has beenuggested is that perhaps increases in the early release comes from thearly releasable pool and may not represent cell death but rathereversible injury. It is then suggested that the more sustained release,hich represents the breakdown of the structural pool, is associated with

ell death. Thus, it has been argued that the presence of only early but notate release would indicate reversible injury. Alternatively, it has beenrgued that all the release is due to cell death. This is an intriguingcientific argument and there is tremendous controversy over this partic-lar issue.17 At present, there are inadequate data to adjudicate which ofhese hypotheses are correct, in part because we have only recently beguno develop sensitive enough assays to be able to probe whether the valuese observe are elevated or normal after transient increases.17 Even if thealues go down totally, there probably will still be controversy abouthether the cells need to be irreversibly injured. When this issue firstecame important in the biomarker field, it did not appear that the heartould regenerate in any substantive way. We now know that that is not thease and that cardiac regeneration can and does occur.18 Consequently,erhaps now this is a less important issue. Nonetheless, because this has beenescribed in certain patients with exercise as well as in certain diseasentities, it has become an important area of controversy for clinicians. Thisuthor would argue, given that most elevations of cTn, perhaps exerciseside, are associated with an adverse prognosis, that from the clinicalerspective this distinction is not worth being concerned about17 and thatroponin should be considered a marker of cardiac damage or injury and thatuch injury should be taken as a sign of underlying cardiovascular disease inlmost all instances17 except perhaps exercise.

mportant Preanalytic and Analytical FactorsNo assays are perfect. No antibodies are perfect. Therefore, it should be

xpected that there will be problems at times with cTn assays. It is
mportant, particularly as we move toward more highly sensitive assays,6

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hat we take these into account because, absent doing that, we run the riskf being confounded because small changes with these highly sensitivessays would be of importance. Some of these include the following:

. Preanalytic factors. These include issues like hemolysis, which isknown to increase cTn values for some assays and reduce cTnT valueswith that assay. It is suggested that even small amounts of hemolysismay be important with the modern day highly sensitive assays19 (Fig2). There also are other potential problems, the most common of whichis fibrin in the sample, which can stick to the well of the plate andcause false-positive results for that reason. Therefore, clinicians shouldnot be uncomfortable about calling and challenging the laboratory inregard to specific results.

. Analytical factors. In addition, there are other analytical issues thatmay need to be taken into account in some patients. The most commonare what is called cross-reacting or heterophilic antibodies. Thisdesignation refers to a group of antibodies either made to theantibodies that are used to make the cTn assay or which cross-react tothose antibodies and come from some sort of human disease processthat can cause the assay to be falsely elevated. The most well-publicized situation occurred during the early assay days whenrheumatoid factor was shown to cross-react with one of the cTnIassays, leading to confusion.20 This is no longer a problem, but

IG 2. Hemolysis and cardiac troponin. Influence of hemolysis on the values obtained with 2ifferent troponin assays, the cTnI assay from Ortho and the high sensitivity cardiac troponin Tssay from Roche. With very sensitive assays, these problems become more crucial. (Repro-uced with permission.19)

heterophilic antibodies still exist, although most companies have done


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a good job of eliminating them. With very highly sensitive assays,however, even small amounts of these could be problematic.6 Thus,clinicians must question values that do not appear to fit the clinicalpicture. The situation where one might suspect such antibody inter-ference is in a patient who has high values that do not change overtime. In most situations, elevations of cTn do increase and thendecrease over time. There is an occasional renal failure patient whomay have high values that do not change but most other markedelevations should either increase or decrease. If one finds a pattern likethis, there are several things that good laboratories can do.7 The firstis to add additional blocking antibodies to the sample and see if thatresolves the problem. These are widely available in what are called“heterophile blocking tubes” and all good laboratories should haveaccess to them. A second approach is to dilute the sample. Samplesthat have interferences of any kind will not change until the interferingsubstance is eliminated. Thus, the failure of a sample to dilute linearlyshould lead to a suspicion of some sort of interfering substance.Sometimes these interfering substances can be more complex but thevast majority can be diagnosed easily if one remembers the sugges-tions made above. There are a variety of other relatively less frequentproblems, including macrotroponemias (troponin linked to immuno-globulins), which have recently been described.21

here are major initiatives going on in an attempt to standardize cTnssays but they thus far have not been highly successful.22,23 Thus, ithould be clear that the numbers generated with any given assay cannotnd are not related in any way to the numbers generated with other assays.his in part reflects the different ways of measuring used by variousompanies but also differences in antibodies as well. All of this informa-ion in greater detail can be found in recent reviews.24

ecision Limits and PrecisionThis is a critical issue of which clinicians often are not aware. Theecision limit suggested since 2000 has been the 99th percentile of aormal reference population designated usually as URL.25 This is roughly

SDs from the mean of a normal population and was selected toinimize the frequency of false positives and to take advantage in a good

ense of that word of the sensitivity of cTn assays. Although initiated in000, because of the reluctance of many clinicians to use these lowutoffs because of the difficulty in explaining more subtle increases, these
utoffs often have not been used and this can cause confusion.4 Even

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ore recently, high-level sophisticated studies using cTn have failed tose the recommended cutoff values.26 Thus, this remains a problem thatlinicians need to be aware of both when seeing patients and wheneading the literature. Part of the reluctance in this area occurred with theoncern that imprecision at the low end might cause false-positivelevations.27 This was a reasonable concern when there was no clue as tohere the normal values existed. Thus, some laboratories argued that one

hould use a cutoff value where there was a high level of precision so thatne would not potentially overlap with normal values. This led to theoncept that the cutoff value might be the 10% coefficient of variationCV) value.27 However, over time, it has become clear clinically thatormal values are substantially far from anything measured today withhe exception of very high sensitivity troponin assays and thus the mostredictive clinical cutoff to use is the 99th percentile.7 A recent articlerom the Global Task Force on the redefinition of myocardial infarctionas developed in part to clarify this previously confusing issue.5 This

ssue was in part even more confounding for cTnT than for cTnI becauseith that assay most normal values are undetectable and thus, to define a

ising pattern, one often had to go significantly above the 99th percentilend frequently the value used was the 10% CV value, making itdditionally more difficult for clinicians who used that assay to under-tand the concept of the 99th percentile. Nonetheless, values above the9th percentile URL should be taken seriously as they imply cardiovas-ular disease and in almost all instances patient risk.7

A recent article provides a good example of the need to use lower ratherhan higher cutoff values. In the study, the investigators first evaluated theutcomes of 1038 individuals presenting with chest discomfort evaluatedith a contemporary but fairly sensitive cTnI assay using a high cutoffalue. They then compared those outcomes to those of 1054 individualsvaluated with the same assay using a lower cutoff value (the 10% CVutoff). Each group was stratified into 3 subgroups—clearly normal,learly abnormal, and a middle group that was initially called normal andubsequently called abnormal. The primary outcome was the combinationf recurrent myocardial infarction and death at 1 year. They found that theates of the use of statins and dual antiplatelet therapy at discharge, wereimilar in the clearly normal and clearly abnormal groups but improvedignificantly in the middle group, as might be expected. Importantly, thesehanges in treatment translated into improved outcomes. In the firstohort, the primary outcome occurred in 39% of patients in this middleidentified as normal) group compared to 7% in the clearly normal group
nd 24% in the clearly abnormal group. During the second part of the

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tudy, the event rates were similar for those 2 groups but improvedignificantly in the group newly called abnormal. The outcomes in thisroup improved from 39% to 21% and were statistically similar to thosen the clearly elevated group (Fig 3).As acknowledged by the authors, these results might have been evenetter had the 99th percentile URL value been used.28

nterpretation of Troponin ResultsIt is now clear with more sensitive cTn assays that the development of

tructural heart disease over time causes values of cTn to rise slowly.29,30

t appears that they do not rise acutely but are chronically elevated. Thus,inor elevations of cTn will be seen more and more frequently as assay

ensitivity increases. Therefore, the concept of using a solitary cutoff

IG 3. Better treatment associated with using lower cutoff values of cTn. Effect of altering theutoff value deemed as abnormal in patients with acute coronary syndromes. The top curves inold and dashed lines represent patients with very low clearly normal values, and they did well.wo of the curves in the middle designate patients with marked elevations (solid line and smallashed line) and they did not do as well as those who were normal. Because this value waslearly abnormal during both phases of the study, the patients did comparably. The lower curveepresents those patients considered normal during the initial (validation) phase of the study andhey did poorly. When they were included as being abnormal in the subsequent (implementa-ion) phase of the study as indicated by the third curve in the middle (larger dashes and dots),hey received treatment and improved their prognosis to be similar to those treated previouslythe groups with clearly abnormal values). These data confirm the advantage of using lowerather than higher cutoff values for cTn. (Reproduced with permission.26)

alue for cTn as abnormal and indicative of an acute event is fraught with


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anger. If the value is markedly elevated, because most of these structuralbnormalities are associated with only minor degrees of elevation (withhe possible exception of a rare patient with renal failure), then this maytill be a useful concept.31 However, one cannot and should not believehat a solitary cutoff will work for all assays. For that reason, one of themportant issues now that people are attempting to resolve is how toefine best a changing pattern of values, which might distinguish thosendividuals with acute disease from those with more chronic elevations.32

his is a highly complex topic, in particular, with high-sensitivity cTnssays. With non-high-sensitivity assays, the best that can be done is tose a metric, asking the question whether the value is different fromnalytical variability. It is known for any 2 values that they areignificantly different analytically if they are roughly 3 SDs of theariance around the values from each other. Thus, by knowing the metricsf a given assay, laboratorians can provide an estimate as to whether thesealues are above the variation given the imprecision of that assay. This isore complex than it appears because at very low values assay variability

oes up substantially. Thus, although this value is probably close to 20%nce elevations have occurred, when one is dealing with values near theormal range or perhaps slightly below it, these values could beubstantially higher even with some assays as high as 100 or 200%.33

herefore, the task of defining that when a significant change occurs thathould be taken care of and developed by the laboratory community, whohould report these data to help clinicians with this.7

For high-sensitivity assays, the issues are more complex. With high-ensitivity assays, one can measure results in normals repetitively andefine what is known has biological variation.34 Unfortunately, biologicalariation may be higher than what may be clinically significant and thiss a tension in the field.33 However, the theory of biological variationould argue that if one is using a change that is below the level ofiological variation, one at least has the risk of including patients who aren that category because of changes related solely to biological andnalytical issues. Thus, it should be clear and is the case that the use ofny paradigm looking at a changing pattern is very likely to increasepecificity for acute change but may reduce sensitivity.35 At present,any people using high-sensitivity assays are attempting to argue for

ither percentage changes or absolute changes as the best metrics toefine a changing pattern.33 These data will play out over time. It is thisuthor’s opinion that absolute values as recently reported36 may turn outo be somewhat better only because, as values increase, the percentage
alues will cause changes to be mandated that are unlikely to occur except

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ith very large infarctions, making the use of percentages less efficient.y contrast, as values rise, the use of absolute values will impinge on theiological variation discussed above and likely lead to the exclusion ofome patients who have significant disease. This issue is presently veryonflicting and needs further investigation.33

Although the distinction between chronic and acute elevations ismportant, it is also important to understand that, whereas previouslyssays, because of their relative insensitivity, detected mostly patientsith acute ischemic heart disease, cTn, given its improved sensitivity,etects many other pathophysiologies. This can include tachycardia oryper-/hypotension-induced supply-demand abnormalities and thereforeischemia” as well as a variety of other acute and chronic cardiac stressorsiseases. Reviews on these topics can be found elsewhere.37 Conse-uently, an elevated troponin or even a changing pattern should not beaken as indicative of acute myocardial infarction (AMI) but solely ofardiac injury. It is true that very high values of cTn are seen rarely withhe exception of an occasional renal failure patient and with eitheryocarditis or AMI.31 Thus, high values (these are assay specific) can be

ntuited to be due to myocardial infarction or myocarditis. However,odest elevations need to be triaged clinically and cannot be assumed to

e due to unstable coronary heart disease. In point of fact, not only couldlevations be due to a variety of other acute etiologies (Table 1) but inddition they could be due to coronary artery disease that is stable. Recentata suggest that elevations occur in patients with stable coronary diseaseut that that group probably is the higher risk subset of those with “stable”oronary disease38 and the frequency of these elevations is increasing asssay sensitivity increases.39,40 It could turn out eventually that we willnd that cTn elevations identify those with chronic stable disease who aret risk and there are some data to suggest that, the worse the disease, theigher the cTn value,40 and the worse the prognosis.38,39 It is also ofnterest that women have lower values for any given extent of coronaryrtery disease than men.40 However, chronic stable disease, like hypo-ension or hypertension without coronary artery disease, does not implyhat there was necessarily acute plaque rupture and a myocardialnfarction in need of intervention. Thus, what is necessary is a clinicaltory highly suggestive of ischemic heart disease coupled with a risingattern of cTn. It should be noted that if one sees patients with elevatedTn (but not a rising pattern) and then relies only on cardiac catheteriza-ion, one might presume that many of them have myocardial infarctions
ecause they have coronary artery disease. However, again, a solitary

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levation of cTn does not infer that coronary artery disease is unstableecause this could occur with stable coronary artery disease as well.Another area that is interesting and difficult to deal with in regard to cTn

s congestive heart failure. cTn elevations are quite common in thisituation, particularly with acute heart failure,41 and can occur withhronic heart failure as well.42 These occur with or without the presencef coronary artery disease so they likely represent acute left ventricularilation,43 supply-demand imbalance, and endothelial dysfunction.44

gain, whether these patients should be called AMIs is an issue noweing discussed for the new guidelines.

ichael H. Crawford: The complexities and difficulties with the troponinssay that Dr Jaffe expertly enumerates have been a source of greatrustration for clinicians. Few blood-based laboratory tests are as difficult tonterpret as troponin, yet our less knowledgeable colleagues often think that

ABLE 1. Causes of cTn elevations in the absence of overt acute ischemic heart disease

amage related to secondary myocardial ischemia (MI type 2)Tachy- or bradyarrhythmiasHypo- or hypertension, eg, hemorrhagic shock, hypertensive emergencyAcute and chronic heart failure without significant concomitant coronary artery disease

(CAD)Hypertrophic cardiomyopathyCoronary vasculitis, eg, systemic lupus erythematosus, Kawasaki syndromeCoronary endothelial dysfunction without significant CAD, eg, cocaine abuse

amage not related to myocardial ischemiaCardiac contusionCardiac incisions with surgeryRadiofrequency or cryoablation therapyRhabdomyolysis with cardiac involvementMyocarditisCardiotoxic agents, eg, anthracyclines, Herceptin, carbon monoxide poisoningSevere burns affecting �30% of body surface

ndeterminant or multifactorial groupApical ballooning syndromeSevere pulmonary embolism or pulmonary hypertensionPeripartum cardiomyopathyRenal failureSevere acute neurological diseases, eg, stroke, traumaInfiltrative diseases, eg, amyloidosis, sarcoidosisExtreme exertionSepsisAcute respiratory failureFrequent defibrillator shocks

eproduced with permission.7

he reported value is as definitive as a serum sodium level. Add to this the


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rogressive increase in the sensitivity of the assays and you have a recipe forverutilization of health care resources. The latest insult to clinicians is theoint-of-care assay, which can be done by minimally trained individuals athe bedside. Although it is highly variable and uses a markedly differentnormal range,” it is being touted as the first arbiter of hospital admission.ortunately, at my institution, the results were so inaccurate that we wereble to discontinue it after a couple of weeks. As Dr Jaffe points out, theewer high-sensitivity troponin assays have not caught on yet in the USA,ainly because of poor reproducibility, but this problem will be overcome.mergency Department doctors will embrace this assay because it willeduce the false negatives that result in lawsuits. Also, it may permit thearlier detection of myocardial infarction, resulting in a faster turnover in themergency Department, which is desirable for patient care as well. However,

alse positives will abound. The bottom line is that things will worsen beforehey improve.

iagnosis of Acute Myocardial InfarctionAs should be apparent, the diagnosis of AMI is heavily determined by

he clinical situation. Thus, the situation must be a circumstance wherehe clinical situation and/or signs and symptoms of the patient lead to atrong suspicion of AMI before measuring cTn.45 This could be at timeshe clinical circumstance that exists because diabetics may have relativelynrecognized AMIs or, in surgery patients who are not doing well, evenf they do not complain of chest pain. In the postoperative circumstance,ymptoms may not be present and electrocardiography (ECG) changesan be frequent and nonspecific.46 Thus, one needs to have an open mindnd not insist on the classic presentation. By contrast, the idea that simplyecause a cTn is elevated that acute coronary event has occurred is alsoot an appropriate stance. Thus, the first issue of importance in theiagnosis of AMI is the clinical circumstances around the presentation ofny given patient. The second circumstance is, assuming appropriate ofhe presentation, is a rising and/or falling pattern of troponin values.1

MI, being an acute event, should show an increasing pattern of valuesnd then a decreasing pattern of values. This can be problematic if theime of onset of symptoms is unclear because the persistence of elevationsf cTn; one lead is to find relatively slowly changing values of cTn on thetail end” of the curve. This can be a problem for clinicians to sort out buthe only way to deal with this issue is clinically. There are no biochemicaleterminants that can answer that question.One also needs to be aware that there are variants of AMI that canccur. For example, there are subsets of patients, more often women, whoan have AMI without overt coronary artery disease47,48 (Fig 4). Whether
his is due to endothelial dysfunction or the fact that an inciting event,

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uch as a thrombus or a small dissection, may have resolved beforengiography is unclear at present but such cases clearly exist. They appearo be associated with a better prognosis than certain other circumstancesut that does not mean that AMI should not be diagnosed.49 Several seriesave examined this type of presentation and found that magneticesonance imaging often is often helpful in these individuals. It may welle that identifying these groups, whether it is the females with endothelialysfunction or the broader group who do not have fixed coronary disease,ay be clinically helpful. In fact, it may be that, as the sensitivity of

Tn assays increase, the percentage of such patients, because it ishought that their cTn values are somewhat lower, may increase.herefore, the prior data, developed with less sensitive cTn assays,

hat an elevated cTn in patients with chest discomfort makes themood candidates for an aggressive therapeutic approach, includingggressive anticoagulation IIB/IIIA agents and an early invasivetrategy, may no longer be the case.

ossible Nonacute Myocardial Infarction Etiologiesor Elevations of TroponinOne of the most common reasons for marked elevations of cTn that has

IG 4. MRI proof of AMI in a patient with chest pain but near normal coronary arteries. Delayednhancement sequence from magnetic resonance imaging of a woman with chest pain,levated and rising cTn values, but what appeared to be normal angiographic coronaryrteries. The area of abnormality shows an area of delayed hyperenhancement due toadolinium in the subendocardium. This pattern is highly suggestive of myocardial infarction.Reproduced with permission.47)

ecently emerged is that of acute myocarditis. Early on, it was clear that


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yocarditis could be a mimicker,50 but a recent article examining patientsho present with what appears to be acute infarction but have normal

oronary arteries angiographically found a small percentage of individualsho have the pattern associated with AMI but a larger percentage of

ndividuals who had what appears to be acute myocarditis.51 The therapeuticignificance of such a diagnosis is not clear yet but it is now well establishedhat this is a diagnosis that should be considered a possible mimicker of AMI.

ichael H. Crawford: Another cause of AMI mimic with normal coronaryrteries is stress cardiomyopathy. In our tertiary care hospital, this diagnosis

s more common than myocarditis. Usually, it is characterized by apicalallooning that resolves after several days, but some patients may haveersistent heart failure, shock, or death. Rarely, the wall motion abnormality

nvolves mainly the mid-left ventricular wall. In subarachnoid hemorrhageatients, the basal walls are preferentially involved (Zaroff JG, Rordorf GA,gilvy CS, et al. Regional patterns of left ventricular systolic dysfunction afterubarachnoid hemorrhage: evidence for neurally mediated cardiac injury.Am Soc Echocardiogr 2000;13:774-9). The common theme is that the walls

nvolved do not follow a single coronary artery distribution. Aside from thenusual wall motion distribution, these patients’ presentation is similar to AMIith the major exception that it occurs much more commonly in women. Youave to have a high index of suspicion in postsurgical patients who are notoing well hemodynamically and have elevated troponin levels, for stressardiomyopathy, because these patients are often sedated and do notomplain of chest pain. The ECG resembles a typical stent thrombosislevation MI, which is why the diagnosis is usually made at cardiac cathe-erization. In the right clinical setting with the characteristic echocardio-raphic findings, coronary angiography can often be reserved for those whoo not do well.

As assay sensitivity increases, there also are likely to be an increasedercentage in what are thought to be AMIs related to supply-demandmbalance.1 These could be due to hypotension or hypertension, orachycardia with or without hypotension, but more likely than not theyeflect some underlying cardiovascular pathology. However, because theyay be related more to the supply-demand imbalance than to acute plaque

upture, these individuals may be far less in need of aggressive therapynd an invasive strategy. There is presently ongoing discussion as tohether this group should be culled out separately or should be subsumednder the rubric of AMI. The dilemma of this issue is clear. Should youngndividuals with Wolf-Parkinson-White syndrome who have severeachycardia and elevated cTn who often have peculiar chest symptomsnd even ECG changes be considered to have AMI? How this evolves in
he guidelines remains to be determined.

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Patients who are critically ill often have elevated cTn values.52 Whetherhey are due to supply-demand imbalance and therefore may meet theefinition of AMI or whether such elevations are due to direct toxicffects of catecholamines, sepsis, and other drugs is unclear. Themportant concept, however, is they are all associated with an adverserognosis both short and longer term.52 What to do acutely is unclearther than to treat the underlying disease optimally but these patientsontinue to be at risk even if they survive to discharge.52 However, often,he concept of the elevated cTn is out of sight and out of mind at a pointhen perhaps intervention would be helpful. For that reason, theseatients should be at least evaluated clinically and, if they have structuraleart disease as is likely, that it be addressed. At present, there are nouidelines for subsequent management and this is an area of need that willikely be helped with time. A similar circumstance occurs in patients withlevated cTn values who are postoperative.46 It appears that some of theorbidity, perhaps a great deal associated with postsurgical problems, has

o do with cardiovascular abnormalities, perhaps mostly a supply-demandmbalance but perhaps some plaque rupture as well.46 If indeed thesevents are due to a supply-demand imbalance, careful scrutiny of patientsotentially at risk may be necessary to intervene when they this occursith the idea of reducing the morbidity of cardiovascular disease in this

ircumstance. There is a large ongoing trial attempting to define therequency of these acute cardiovascular problems and the preliminaryesults with a high sensitivity assay suggest that it s quite high.53

ichael H. Crawford: Critically ill or postsurgical patients who are not doingell hemodynamically often have troponin measured to screen for ischemiceart disease. Whether this is an appropriate use of troponin measurement isebatable, but it frequently occurs and cardiology is almost always subse-uently involved in the patient’s care. Most such cases have no history orCG findings consistent with a typical AMI. Thus, most are probably coronaryupply-demand mismatch situations with so-called “demand ischemia.”any have no underlying heart disease, but you do not want to miss thoseho do have coronary artery disease. Consequently, I usually advise those

aking care of the patient to obtain a cardiac stress test with imaging whenhe patient has recovered enough to tolerate testing. Rarely, we do cardiacatheterization as a first step in such patients unless they are not doing well.

xerciseThere is tremendous controversy about whether exercise acutely dam-

ges the heart because of the elevations seen in cTn.17,54 This is not a new
ssue. It has been around for years because elevations of CK-MB were

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lso observed with exercise and found not to indicate cardiovascularisease.17 Nonetheless, given the high specificity of cTn for the heart, thisas become a major question again. At present it is clear that there doesot appear to be an acute hazard associated with the mild to modestlevations in cTn seen in patients who have undergone extreme exercise,uch as a marathon.17 However, those elevations should resolve promptlynd should not be marked. If they are marked or do not resolve within aay or so with present-day cTn assays, they should not be consideredecause of the extreme exercise. In addition, it is not at all clear whethern the long run we will find that there may be some detrimental effectsecause of exercise.55 There are suggestions in several situations thaterhaps there are long-term negative consequences. This remains to beetter defined.

he FutureAll of these problems will become much more difficult with high-

ensitivity assays. These assays are starting to be used around the worldith the exception of the USA. They will detect still more patients at

isk.33 They will detect more minor elevations and with them new diseasentities to be considered.33 However, they also will increase the rapidityith which AMI is diagnosed,56 increase the number of patients identi-ed,57 and in the long run allow us to monitor things, such as drug

oxicity,58 that may be subtle and hard to do. It is worth noting that evenith present-day assays there are some preliminary data in this area inarticular developed around Adriamycin cardiotoxicity58 and carbononoxide poisoning.59

This is an exciting time. We will in the long run have many moreuestions and many more answers. For now, following these relativelytraightforward guidelines will help clinicians begin to capture the greatromise of cTn assays.

ichael H. Crawford: Dr Jaffe, one of the world’s experts on myocardialiomarkers, has contributed an excellent review of the laboratory and clinical

ssues surrounding cTn measurements. Despite considerable issues with theechnical aspects of the various assays available, cTn has become the pivotaliagnostic step in the diagnosis of AMI. Current efforts are improving theensitivity of the assays in the hopes that a more sensitive assay will allow forarlier diagnosis of AMI, which will lead to earlier treatment and betterutcomes. This attractive concept has yet to be proven and the only thingpparent to clinicians is the increase in false positives. It is clear that cTnomes from the heart, so these false positives clinically represent conditionshat are not AMI, but release cTn into the blood. It seems that myocardial
schemia because of an imbalance between myocardial oxygen supply and

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emand can under certain circumstances release cTn. This fits with currenthinking about ischemia and heightens awareness that many ill hospitalizedatients may have underlying coronary artery disease. Thus, it is noturprising that cTn detection indicates a poor prognosis. What is moreifficult to understand is why apparently normal individuals can have elevatedTn levels, such as after vigorous exercise. We still have a great deal to learnbout cTn, but it has quickly become a key test in our evaluation of suspectedyocardial infarction or ischemia. Its detection is necessary to diagnose AMI

ow and elevated levels in other clinical situations suggest a poor prognosis,robably because of underlying heart disease.

Acknowledgment: The author appreciates the expert secretarial assistancef Michelle Small.

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