Troponin Past and Present

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TroponinPast, Present, and Future

Allan S. Jaffe, MD

Abstract:Cardiac troponin is the analyte of choice for

the diagnosis of cardiac injury. It is highly specific for

the heart and much more sensitive than prior biomark-

ers. Because of this increased sensitivity, clinicians

have had to struggle with elevations in novel clinical

situations. We have developed new understandingsabout coronary artery disease but also have begun to

appreciate that many other entities as well can result in

cardiac injury. As assays have increased in sensitivity

over time, this trend has, if anything, accelerated. This

review attempts to put the past, the present, and the

future into a clinical perspective that will help

clinicians. (Curr Probl Cardiol 2012;37:209-228.)

Cardiac troponin has become the marker of choice for the evalua-

tion of patients with possible myocardial injury.1,2 Because our

understanding of cardiac troponin (cTn) is still evolving and

because old friends like the NB isoenzyme of creatine kinase (CKMB)

who have served us well often are hard to give up,3 it has taken a long

time for troponin to be used as efficiently as guidelines and experts have

suggested.4,5 Indeed, because of its improved sensitivity compared to

prior markers, clinicians have been very reluctant to use troponin at the

99th percentile of the upper reference limit (URL) because so many

patients had elevated values of troponin even with the first-generation

assays.3,5 This level of sensitivity has increased still further with modern

day assays.6 Thus, many clinicians and laboratories have used higher

cutoffs for cTn to reduce the frequency of elevations of troponin that

clinicians have a difficult time explaining.3,5 This of course simply makes

the literature and the field far more difficult for clinicians to understand

because the heterogeneity of cutoff values leads to tremendous confusion

in the literature and mixed messages about how clinicians should use

cTn.3,5 The present articulation attempts to resolve some of these issues

Curr Probl Cardiol 2012;37:209-228.0146-2806/$ see front matterdoi:10.1016/j.cpcardiol.2012.02.002

Curr Probl Cardiol, June 2012 209


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and provides a common sense way of dealing with cTn and cTn

elevations. As part of being able to accomplish this important task, certain

basic information about troponin is obligatory and a certain limited

understanding of the analytical constraints that come with measuringtroponin is also of importance. This article does not attempt to review in

detail all of these elements but instead identifies those that are critical and

provides appropriate references so that those who are interested in more

information can augment their understanding about these important

issues.

Cardiac Troponin Basics

The cTn complex consists of 3 separate proteins encoded by differentgenes. These include cardiac troponin T (cTnT), cardiac troponin I (cTnI),

and cardiac troponin C.7 Each protein plays an important role in

regulating the interaction of actin and myosin filaments and thus on

cardiac contraction. Troponin C is encoded by 2 genes, 1 specific for fast

twitch skeletal muscle and a second expressed in both slow-twitched

skeletal muscle and cardiac muscle.8 Thus, it might not be expected to

have cardiac specificity and, indeed, that is the case. Both cTnT and cTnI

come from unique genes.7

It appears that both cTnI and cTnT have highcardiac specificity. The history in regard to cTnI is fairly clear. As best we

can tell, it has never been expressed during neonatal development nor in

pathologic circumstances in any tissue outside of the heart.7 The situation

for cTnT is more complex. Fetal isoforms of the protein are expressed

during neonatal development and there were isoforms of cTnT that were

detected by the initial assay for cTnT many years ago. Part of this was

because there was some cross-reactivity between the antibodies used to

detect cTn and skeletal muscle troponin. However, it also appeared thatthere might be re-expressed isoforms of cTnT in diseased skeletal muscle,

particularly in renal failure patients. New antibodies were developed that

eliminated this problem such that the cross-reacting antibodies that were

found were eliminated.9-11 Recently, we described that some patients who

have skeletal muscle disease express proteins that are detected by the

antibodies used in the standard and high-sensitivity cTnT assay. Whether

these are re-expressed isoforms is unclear but they do appear capable of

causing a signal with the cTnT assay.

12

Because of the high sensitivity ofthe cTnT, it is impossible to know for sure that there is no concomitant

cardiac disease, but, at least in a few cases where extensive evaluations

have been done, that has not appeared to be the case. The frequency of

this phenomenon is unclear at present and it would be a mistake to think

that all elevations that are difficult to explain are false positives caused by

210 Curr Probl Cardiol, June 2012


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this mechanism.12 Nonetheless, it does appear that some patients with

skeletal muscle disease will have elevated values of cTnT but not cTnI

and that, unless clinicians are astute to this possibility, the possibility of

confusing such patients with those who have cardiovascular disease could

occur (Fig 1). Ongoing research is attempting to define the extent to

which this phenomenon occurs.

In addition, it is important to understand the way in which the troponinsare released. It appears, in contrast to some proteins, such as CK-MB,

which are only localized in the cytosol of myocytes, that troponin has

multiple localizations.13,14 The initial studies used gentle buffers and

defined a pool of troponin, which was called the cytosolic pool, which

was roughly of the same magnitude as that of CK-MB.15 In looking back

at these studies, it appears, given the way in which they were done, a

better term for this pool might be the early releasable pool because it is

not clear that all the protein is localized in the cytosol of cells.

7

Nonetheless, it is thought that this is the pool that is released early after

a cardiac insult and thus leads to early elevations of cTn. However,

because this pool is similar in size for both CK-MB and cTn, one could

be confused as to why troponin might be more sensitive. In fact, it is more

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

FIG 1. Detection of skeletal muscle proteins by the antibodies used in the cTnT assay. Westernblot of SMD from patients with myopathies in lanes 1-4, normal human heart muscle in lane 5,and normal human soleus muscle in lane 6. Note molecular weight designations on theordinate. The antibodies used in the standard cTnT assay (M7 and M11-7) and those used inthe high-sensitivity assay (M7 and 5D8) all tag a protein at a molecular weight of about 39 kDa.This suggests strongly that the 2 antibodies in each of these assays would detect these proteinsin blood, indicating that there is a good possibility that elevations in cTnT or the high sensitivitycardiac troponin T assay could occur because of diseased skeletal muscle. (Reproduced withpermission.12)



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released into the circulation over the amount that is depleted from heart,

is far greater for the cTn than it is for CK-MB, which is degraded

locally.16 Thus, greater amounts of protein are elaborated for any given

insult via this early releasable pool. This early increase of cTn is followedby a longer period when troponin is released from what is thought to be

from a more structurally bound pool that is released as the damaged area

is remodeled. This provides an explanation for why troponin elevations

persist for many days, perhaps even weeks, despite its short half-life in

the blood.15 These kinetics have been used to argue that perhaps troponin

could be released in the absence of necrosis. Specifically, what has been

suggested is that perhaps increases in the early release comes from the

early releasable pool and may not represent cell death but ratherreversible injury. It is then suggested that the more sustained release,

which represents the breakdown of the structural pool, is associated with

cell death. Thus, it has been argued that the presence of only early but not

late release would indicate reversible injury. Alternatively, it has been

argued that all the release is due to cell death. This is an intriguing

scientific argument and there is tremendous controversy over this partic-

ular issue.17 At present, there are inadequate data to adjudicate which of

these hypotheses are correct, in part because we have only recently begunto develop sensitive enough assays to be able to probe whether the values

we observe are elevated or normal after transient increases.17 Even if the

values go down totally, there probably will still be controversy about

whether the cells need to be irreversibly injured. When this issue first

became important in the biomarker field, it did not appear that the heart

could regenerate in any substantive way. We now know that that is not the

case and that cardiac regeneration can and does occur.18 Consequently,

perhaps now this is a less important issue. Nonetheless, because this has beendescribed in certain patients with exercise as well as in certain disease

entities, it has become an important area of controversy for clinicians. This

author would argue, given that most elevations of cTn, perhaps exercise

aside, are associated with an adverse prognosis, that from the clinical

perspective this distinction is not worth being concerned about17 and that

troponin should be considered a marker of cardiac damage or injury and that

such injury should be taken as a sign of underlying cardiovascular disease in

almost all instances

17

except perhaps exercise.

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

expected that there will be problems at times with cTn assays. It is

important, particularly as we move toward more highly sensitive assays,6



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that we take these into account because, absent doing that, we run the risk

of being confounded because small changes with these highly sensitive

assays would be of importance. Some of these include the following:

1. Preanalytic factors. These include issues like hemolysis, which is

known to increase cTn values for some assays and reduce cTnT values

with that assay. It is suggested that even small amounts of hemolysis

may be important with the modern day highly sensitive assays19 (Fig

2). There also are other potential problems, the most common of which

is fibrin in the sample, which can stick to the well of the plate and

cause false-positive results for that reason. Therefore, clinicians shouldnot be uncomfortable about calling and challenging the laboratory in

regard to specific results.

2. Analytical factors. In addition, there are other analytical issues that

may need to be taken into account in some patients. The most common

are what is called cross-reacting or heterophilic antibodies. This

designation refers to a group of antibodies either made to the

antibodies that are used to make the cTn assay or which cross-react to

those 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 when

rheumatoid factor was shown to cross-react with one of the cTnI

assays, leading to confusion.20 This is no longer a problem, but

heterophilic antibodies still exist, although most companies have done

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



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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 clinical

picture. The situation where one might suspect such antibody inter-ference is in a patient who has high values that do not change over

time. In most situations, elevations of cTn do increase and then

decrease over time. There is an occasional renal failure patient who

may have high values that do not change but most other marked

elevations should either increase or decrease. If one finds a pattern like

this, there are several things that good laboratories can do.7 The first

is to add additional blocking antibodies to the sample and see if that

resolves the problem. These are widely available in what are calledheterophile blocking tubes and all good laboratories should have

access to them. A second approach is to dilute the sample. Samples

that have interferences of any kind will not change until the interfering

substance is eliminated. Thus, the failure of a sample to dilute linearly

should lead to a suspicion of some sort of interfering substance.

Sometimes these interfering substances can be more complex but the

vast 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

There are major initiatives going on in an attempt to standardize cTn

assays but they thus far have not been highly successful.22,23 Thus, it

should be clear that the numbers generated with any given assay cannot

and are not related in any way to the numbers generated with other assays.

This in part reflects the different ways of measuring used by various

companies but also differences in antibodies as well. All of this informa-

tion in greater detail can be found in recent reviews.24

Decision Limits and PrecisionThis is a critical issue of which clinicians often are not aware. The

decision limit suggested since 2000 has been the 99th percentile of a

normal reference population designated usually as URL.25 This is roughly

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

sense of that word of the sensitivity of cTn assays. Although initiated in

2000, because of the reluctance of many clinicians to use these low

cutoffs because of the difficulty in explaining more subtle increases, these

cutoffs often have not been used and this can cause confusion.4 Even



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more recently, high-level sophisticated studies using cTn have failed to

use the recommended cutoff values.26 Thus, this remains a problem that

clinicians need to be aware of both when seeing patients and when

reading the literature. Part of the reluctance in this area occurred with theconcern that imprecision at the low end might cause false-positive

elevations.27 This was a reasonable concern when there was no clue as to

where the normal values existed. Thus, some laboratories argued that one

should use a cutoff value where there was a high level of precision so that

one would not potentially overlap with normal values. This led to the

concept that the cutoff value might be the 10% coefficient of variation

(CV) value.27 However, over time, it has become clear clinically that

normal values are substantially far from anything measured today withthe exception of very high sensitivity troponin assays and thus the most

predictive clinical cutoff to use is the 99th percentile.7 A recent article

from the Global Task Force on the redefinition of myocardial infarction

was developed in part to clarify this previously confusing issue.5 This

issue was in part even more confounding for cTnT than for cTnI because

with that assay most normal values are undetectable and thus, to define a

rising pattern, one often had to go significantly above the 99th percentile

and frequently the value used was the 10% CV value, making itadditionally more difficult for clinicians who used that assay to under-

stand the concept of the 99th percentile. Nonetheless, values above the

99th percentile URL should be taken seriously as they imply cardiovas-

cular disease and in almost all instances patient risk.7

A recent article provides a good example of the need to use lower rather

than higher cutoff values. In the study, the investigators first evaluated the

outcomes of 1038 individuals presenting with chest discomfort evaluated

with a contemporary but fairly sensitive cTnI assay using a high cutoffvalue. They then compared those outcomes to those of 1054 individuals

evaluated with the same assay using a lower cutoff value (the 10% CV

cutoff). Each group was stratified into 3 subgroupsclearly normal,

clearly abnormal, and a middle group that was initially called normal and

subsequently called abnormal. The primary outcome was the combination

of recurrent myocardial infarction and death at 1 year. They found that the

rates of the use of statins and dual antiplatelet therapy at discharge, were

similar in the clearly normal and clearly abnormal groups but improvedsignificantly in the middle group, as might be expected. Importantly, these

changes in treatment translated into improved outcomes. In the first

cohort, the primary outcome occurred in 39% of patients in this middle

(identified as normal) group compared to 7% in the clearly normal group

and 24% in the clearly abnormal group. During the second part of the



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study, the event rates were similar for those 2 groups but improvedsignificantly in the group newly called abnormal. The outcomes in this

group improved from 39% to 21% and were statistically similar to those

in the clearly elevated group (Fig 3).

As acknowledged by the authors, these results might have been even

better had the 99th percentile URL value been used.28

Interpretation of Troponin Results

It is now clear with more sensitive cTn assays that the development ofstructural heart disease over time causes values of cTn to rise slowly.29,30

It appears that they do not rise acutely but are chronically elevated. Thus,

minor elevations of cTn will be seen more and more frequently as assay

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

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

FIG 3. Better treatment associated with using lower cutoff values of cTn. Effect of altering thecutoff value deemed as abnormal in patients with acute coronary syndromes. The top curves inbold and dashed lines represent patients with very low clearly normal values, and they did well.Two of the curves in the middle designate patients with marked elevations (solid line and smalldashed line) and they did not do as well as those who were normal. Because this value was

clearly abnormal during both phases of the study, the patients did comparably. The lower curverepresents those patients considered normal during the initial (validation) phase of the study andthey did poorly. When they were included as being abnormal in the subsequent (implementa-tion) phase of the study as indicated by the third curve in the middle (larger dashes and dots),they received treatment and improved their prognosis to be similar to those treated previously(the groups with clearly abnormal values). These data confirm the advantage of using lowerrather than higher cutoff values for cTn. (Reproduced with permission.26)



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danger. If the value is markedly elevated, because most of these structural

abnormalities are associated with only minor degrees of elevation (with

the possible exception of a rare patient with renal failure), then this may

still be a useful concept.31 However, one cannot and should not believethat a solitary cutoff will work for all assays. For that reason, one of the

important issues now that people are attempting to resolve is how to

define best a changing pattern of values, which might distinguish those

individuals with acute disease from those with more chronic elevations.32

This is a highly complex topic, in particular, with high-sensitivity cTn

assays. With non-high-sensitivity assays, the best that can be done is to

use a metric, asking the question whether the value is different from

analytical variability. It is known for any 2 values that they aresignificantly different analytically if they are roughly 3 SDs of the

variance around the values from each other. Thus, by knowing the metrics

of a given assay, laboratorians can provide an estimate as to whether these

values are above the variation given the imprecision of that assay. This is

more complex than it appears because at very low values assay variability

goes up substantially. Thus, although this value is probably close to 20%

once elevations have occurred, when one is dealing with values near the

normal range or perhaps slightly below it, these values could besubstantially higher even with some assays as high as 100 or 200%.33

Therefore, the task of defining that when a significant change occurs that

should be taken care of and developed by the laboratory community, who

should report these data to help clinicians with this.7

For high-sensitivity assays, the issues are more complex. With high-

sensitivity assays, one can measure results in normals repetitively and

define what is known has biological variation.34 Unfortunately, biological

variation may be higher than what may be clinically significant and thisis a tension in the field.33 However, the theory of biological variation

would argue that if one is using a change that is below the level of

biological variation, one at least has the risk of including patients who are

in that category because of changes related solely to biological and

analytical issues. Thus, it should be clear and is the case that the use of

any paradigm looking at a changing pattern is very likely to increase

specificity for acute change but may reduce sensitivity.35 At present,

many people using high-sensitivity assays are attempting to argue foreither percentage changes or absolute changes as the best metrics to

define a changing pattern.33 These data will play out over time. It is this

authors opinion that absolute values as recently reported36 may turn out

to be somewhat better only because, as values increase, the percentage

values will cause changes to be mandated that are unlikely to occur except



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with very large infarctions, making the use of percentages less efficient.

By contrast, as values rise, the use of absolute values will impinge on the

biological variation discussed above and likely lead to the exclusion of

some patients who have significant disease. This issue is presently veryconflicting and needs further investigation.33

Although the distinction between chronic and acute elevations is

important, it is also important to understand that, whereas previously

assays, because of their relative insensitivity, detected mostly patients

with acute ischemic heart disease, cTn, given its improved sensitivity,

detects many other pathophysiologies. This can include tachycardia or

hyper-/hypotension-induced supply-demand abnormalities and therefore

ischemia as well as a variety of other acute and chronic cardiac stressors

diseases. Reviews on these topics can be found elsewhere.37 Conse-

quently, an elevated troponin or even a changing pattern should not be

taken as indicative of acute myocardial infarction (AMI) but solely of

cardiac injury. It is true that very high values of cTn are seen rarely with

the exception of an occasional renal failure patient and with either

myocarditis or AMI.31 Thus, high values (these are assay specific) can be

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

be due to unstable coronary heart disease. In point of fact, not only could

elevations be due to a variety of other acute etiologies (Table 1) but in

addition they could be due to coronary artery disease that is stable. Recent

data suggest that elevations occur in patients with stable coronary disease

but that that group probably is the higher risk subset of those with stable

coronary disease38 and the frequency of these elevations is increasing as

assay sensitivity increases.39,40

It could turn out eventually that we willfind that cTn elevations identify those with chronic stable disease who are

at risk and there are some data to suggest that, the worse the disease, the

higher the cTn value,40 and the worse the prognosis.38,39 It is also of

interest that women have lower values for any given extent of coronary

artery disease than men.40 However, chronic stable disease, like hypo-

tension or hypertension without coronary artery disease, does not imply

that there was necessarily acute plaque rupture and a myocardial

infarction in need of intervention. Thus, what is necessary is a clinicalstory highly suggestive of ischemic heart disease coupled with a rising

pattern of cTn. It should be noted that if one sees patients with elevated

cTn (but not a rising pattern) and then relies only on cardiac catheteriza-

tion, one might presume that many of them have myocardial infarctions

because they have coronary artery disease. However, again, a solitary



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elevation of cTn does not infer that coronary artery disease is unstable

because this could occur with stable coronary artery disease as well.

Another area that is interesting and difficult to deal with in regard to cTnis congestive heart failure. cTn elevations are quite common in this

situation, particularly with acute heart failure,41 and can occur with

chronic heart failure as well.42 These occur with or without the presence

of coronary artery disease so they likely represent acute left ventricular

dilation,43 supply-demand imbalance, and endothelial dysfunction.44

Again, whether these patients should be called AMIs is an issue now

being discussed for the new guidelines.

Michael H. Crawford: The complexities and difficulties with the troponinassay that Dr Jaffe expertly enumerates have been a source of greatfrustration for clinicians. Few blood-based laboratory tests are as difficult tointerpret as troponin, yet our less knowledgeable colleagues often think thatthe reported value is as definitive as a serum sodium level. Add to this the

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

Damage related to secondary myocardial ischemia (MI type 2)

Tachy- or bradyarrhythmias

Hypo- or hypertension, eg, hemorrhagic shock, hypertensive emergency

Acute and chronic heart failure without significant concomitant coronary artery disease

(CAD)

Hypertrophic cardiomyopathy

Coronary vasculitis, eg, systemic lupus erythematosus, Kawasaki syndrome

Coronary endothelial dysfunction without significant CAD, eg, cocaine abuse

Damage not related to myocardial ischemia

Cardiac contusion

Cardiac incisions with surgery

Radiofrequency or cryoablation therapy

Rhabdomyolysis with cardiac involvement

MyocarditisCardiotoxic agents, eg, anthracyclines, Herceptin, carbon monoxide poisoning

Severe burns affecting 30% of body surface

Indeterminant or multifactorial group

Apical ballooning syndrome

Severe pulmonary embolism or pulmonary hypertension

Peripartum cardiomyopathy

Renal failure

Severe acute neurological diseases, eg, stroke, trauma

Infiltrative diseases, eg, amyloidosis, sarcoidosis

Extreme exertion

Sepsis

Acute respiratory failure

Frequent defibrillator shocks

Reproduced with permission.7



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progressive increase in the sensitivity of the assays and you have a recipe foroverutilization of health care resources. The latest insult to clinicians is thepoint-of-care assay, which can be done by minimally trained individuals atthe bedside. Although it is highly variable and uses a markedly different

normal range, it is being touted as the first arbiter of hospital admission.Fortunately, at my institution, the results were so inaccurate that we wereable to discontinue it after a couple of weeks. As Dr Jaffe points out, thenewer high-sensitivity troponin assays have not caught on yet in the USA,mainly because of poor reproducibility, but this problem will be overcome.Emergency Department doctors will embrace this assay because it willreduce the false negatives that result in lawsuits. Also, it may permit theearlier detection of myocardial infarction, resulting in a faster turnover in theEmergency Department, which is desirable for patient care as well. However,false positives will abound. The bottom line is that things will worsen before

they improve.

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

the clinical situation. Thus, the situation must be a circumstance where

the clinical situation and/or signs and symptoms of the patient lead to a

strong suspicion of AMI before measuring cTn.45 This could be at times

the clinical circumstance that exists because diabetics may have relativelyunrecognized AMIs or, in surgery patients who are not doing well, even

if they do not complain of chest pain. In the postoperative circumstance,

symptoms may not be present and electrocardiography (ECG) changes

can be frequent and nonspecific.46 Thus, one needs to have an open mind

and not insist on the classic presentation. By contrast, the idea that simply

because a cTn is elevated that acute coronary event has occurred is also

not an appropriate stance. Thus, the first issue of importance in the

diagnosis of AMI is the clinical circumstances around the presentation ofany given patient. The second circumstance is, assuming appropriate of

the presentation, is a rising and/or falling pattern of troponin values.1

AMI, being an acute event, should show an increasing pattern of values

and then a decreasing pattern of values. This can be problematic if the

time of onset of symptoms is unclear because the persistence of elevations

of cTn; one lead is to find relatively slowly changing values of cTn on the

tail end of the curve. This can be a problem for clinicians to sort out but

the only way to deal with this issue is clinically. There are no biochemicaldeterminants that can answer that question.

One also needs to be aware that there are variants of AMI that can

occur. For example, there are subsets of patients, more often women, who

can have AMI without overt coronary artery disease47,48 (Fig 4). Whether

this is due to endothelial dysfunction or the fact that an inciting event,



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such as a thrombus or a small dissection, may have resolved before

angiography is unclear at present but such cases clearly exist. They appear

to be associated with a better prognosis than certain other circumstances

but that does not mean that AMI should not be diagnosed.49 Several series

have examined this type of presentation and found that magnetic

resonance imaging often is often helpful in these individuals. It may well

be that identifying these groups, whether it is the females with endothelial

dysfunction or the broader group who do not have fixed coronary disease,may be clinically helpful. In fact, it may be that, as the sensitivity of

cTn assays increase, the percentage of such patients, because it is

thought that their cTn values are somewhat lower, may increase.

Therefore, the prior data, developed with less sensitive cTn assays,

that an elevated cTn in patients with chest discomfort makes them

good candidates for an aggressive therapeutic approach, including

aggressive anticoagulation IIB/IIIA agents and an early invasive

strategy, may no longer be the case.Possible Nonacute Myocardial Infarction Etiologiesfor Elevations of Troponin

One of the most common reasons for marked elevations of cTn that has

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

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



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myocarditis could be a mimicker,50 but a recent article examining patients

who present with what appears to be acute infarction but have normal

coronary arteries angiographically found a small percentage of individuals

who have the pattern associated with AMI but a larger percentage ofindividuals who had what appears to be acute myocarditis.51 The therapeutic

significance of such a diagnosis is not clear yet but it is now well established

that this is a diagnosis that should be considered a possible mimicker of AMI.

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

is more common than myocarditis. Usually, it is characterized by apicalballooning that resolves after several days, but some patients may havepersistent heart failure, shock, or death. Rarely, the wall motion abnormalityinvolves mainly the mid-left ventricular wall. In subarachnoid hemorrhagepatients, the basal walls are preferentially involved (Zaroff JG, Rordorf GA,Ogilvy CS, et al. Regional patterns of left ventricular systolic dysfunction aftersubarachnoid hemorrhage: evidence for neurally mediated cardiac injury.J Am Soc Echocardiogr 2000;13:774-9). The common theme is that the wallsinvolved do not follow a single coronary artery distribution. Aside from theunusual wall motion distribution, these patients presentation is similar to AMIwith the major exception that it occurs much more commonly in women. You

have to have a high index of suspicion in postsurgical patients who are notdoing well hemodynamically and have elevated troponin levels, for stresscardiomyopathy, because these patients are often sedated and do notcomplain of chest pain. The ECG resembles a typical stent thrombosiselevation MI, which is why the diagnosis is usually made at cardiac cathe-terization. In the right clinical setting with the characteristic echocardio-graphic findings, coronary angiography can often be reserved for those whodo not do well.

As assay sensitivity increases, there also are likely to be an increasedpercentage in what are thought to be AMIs related to supply-demand

imbalance.1 These could be due to hypotension or hypertension, or

tachycardia with or without hypotension, but more likely than not they

reflect some underlying cardiovascular pathology. However, because they

may be related more to the supply-demand imbalance than to acute plaque

rupture, these individuals may be far less in need of aggressive therapy

and an invasive strategy. There is presently ongoing discussion as to

whether this group should be culled out separately or should be subsumedunder the rubric of AMI. The dilemma of this issue is clear. Should young

individuals with Wolf-Parkinson-White syndrome who have severe

tachycardia and elevated cTn who often have peculiar chest symptoms

and even ECG changes be considered to have AMI? How this evolves in

the guidelines remains to be determined.



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Patients who are critically ill often have elevated cTn values.52 Whether

they are due to supply-demand imbalance and therefore may meet the

definition of AMI or whether such elevations are due to direct toxic

effects of catecholamines, sepsis, and other drugs is unclear. Theimportant concept, however, is they are all associated with an adverse

prognosis both short and longer term.52 What to do acutely is unclear

other than to treat the underlying disease optimally but these patients

continue to be at risk even if they survive to discharge.52 However, often,

the concept of the elevated cTn is out of sight and out of mind at a point

when perhaps intervention would be helpful. For that reason, these

patients should be at least evaluated clinically and, if they have structural

heart disease as is likely, that it be addressed. At present, there are noguidelines for subsequent management and this is an area of need that will

likely be helped with time. A similar circumstance occurs in patients with

elevated cTn values who are postoperative.46 It appears that some of the

morbidity, perhaps a great deal associated with postsurgical problems, has

to do with cardiovascular abnormalities, perhaps mostly a supply-demand

imbalance but perhaps some plaque rupture as well.46 If indeed these

events are due to a supply-demand imbalance, careful scrutiny of patients

potentially at risk may be necessary to intervene when they this occurswith the idea of reducing the morbidity of cardiovascular disease in this

circumstance. There is a large ongoing trial attempting to define the

frequency of these acute cardiovascular problems and the preliminary

results with a high sensitivity assay suggest that it s quite high.53

Michael H. Crawford: Critically ill or postsurgical patients who are not doingwell hemodynamically often have troponin measured to screen for ischemic

heart disease. Whether this is an appropriate use of troponin measurement isdebatable, but it frequently occurs and cardiology is almost always subse-quently involved in the patients care. Most such cases have no history orECG findings consistent with a typical AMI. Thus, most are probably coronarysupply-demand mismatch situations with so-called demand ischemia.Many have no underlying heart disease, but you do not want to miss thosewho do have coronary artery disease. Consequently, I usually advise thosetaking care of the patient to obtain a cardiac stress test with imaging whenthe patient has recovered enough to tolerate testing. Rarely, we do cardiaccatheterization as a first step in such patients unless they are not doing well.

ExerciseThere is tremendous controversy about whether exercise acutely dam-

ages the heart because of the elevations seen in cTn.17,54 This is not a new

issue. It has been around for years because elevations of CK-MB were



16/20

also observed with exercise and found not to indicate cardiovascular

disease.17 Nonetheless, given the high specificity of cTn for the heart, this

has become a major question again. At present it is clear that there does

not appear to be an acute hazard associated with the mild to modestelevations in cTn seen in patients who have undergone extreme exercise,

such as a marathon.17 However, those elevations should resolve promptly

and should not be marked. If they are marked or do not resolve within a

day or so with present-day cTn assays, they should not be considered

because of the extreme exercise. In addition, it is not at all clear whether

in the long run we will find that there may be some detrimental effects

because of exercise.55 There are suggestions in several situations that

perhaps there are long-term negative consequences. This remains to bebetter defined.

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

sensitivity assays. These assays are starting to be used around the world

with the exception of the USA. They will detect still more patients at

risk.33 They will detect more minor elevations and with them new disease

entities to be considered.33

However, they also will increase the rapiditywith which AMI is diagnosed,56 increase the number of patients identi-

fied,57 and in the long run allow us to monitor things, such as drug

toxicity,58 that may be subtle and hard to do. It is worth noting that even

with present-day assays there are some preliminary data in this area in

particular developed around Adriamycin cardiotoxicity58 and carbon

monoxide poisoning.59

This is an exciting time. We will in the long run have many more

questions and many more answers. For now, following these relativelystraightforward guidelines will help clinicians begin to capture the great

promise of cTn assays.

Michael H. Crawford: Dr Jaffe, one of the worlds experts on myocardialbiomarkers, has contributed an excellent review of the laboratory and clinicalissues surrounding cTn measurements. Despite considerable issues with thetechnical aspects of the various assays available, cTn has become the pivotaldiagnostic step in the diagnosis of AMI. Current efforts are improving the

sensitivity of the assays in the hopes that a more sensitive assay will allow forearlier diagnosis of AMI, which will lead to earlier treatment and betteroutcomes. This attractive concept has yet to be proven and the only thingapparent to clinicians is the increase in false positives. It is clear that cTncomes from the heart, so these false positives clinically represent conditionsthat are not AMI, but release cTn into the blood. It seems that myocardialischemia because of an imbalance between myocardial oxygen supply and



17/20

demand can under certain circumstances release cTn. This fits with currentthinking about ischemia and heightens awareness that many ill hospitalizedpatients may have underlying coronary artery disease. Thus, it is notsurprising that cTn detection indicates a poor prognosis. What is moredifficult to understand is why apparently normal individuals can have elevatedcTn levels, such as after vigorous exercise. We still have a great deal to learnabout cTn, but it has quickly become a key test in our evaluation of suspectedmyocardial infarction or ischemia. Its detection is necessary to diagnose AMInow and elevated levels in other clinical situations suggest a poor prognosis,probably because of underlying heart disease.

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

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Troponin Past and Present