TROPONINAS/INTERPRETACION

INTRODUCTION — Cardiac injury occurs when there is disruption of normal cardiac myocyte
membrane integrity. This results in the loss into the extracellular space (including blood) of
intracellular constituents, including detectable levels of a variety of biologically active cytosolic
enzymes and structural proteins, referred to as biomarkers, such as troponin, creatine kinase,
myoglobin, heart-type fatty acid binding protein, and lactate dehydrogenase. When a sufficient
number of myocytes have died, be it due to necrosis, apoptosis, or some other mechanism,
troponin (and other biomarkers) is detectable in the blood [1]. (See "Troponin testing: Clinical
use", section on 'Diagnosis of acute MI'.)
Injury may be acute or chronic, and it is usually considered irreversible (cell death). The causes of
cardiac injury are numerous. Ischemia, consequent to an imbalance between the supply and
demand of oxygen (and nutrients), is one common cause. Other causes of myocardial injury are
included in a table (table 1).
This topic will provide a basis for understanding troponin and aspects of the troponin test. The
clinical use of troponin testing is discussed separately. (See "Troponin testing: Clinical use".)
Other relevant topics include:
●(See "Biomarkers of cardiac injury other than troponin".)
●(See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome".)
WHAT IS TROPONIN — Cardiac troponin I (cTnI) and T (cTnT) are cardiac regulatory proteins that
control the calcium-mediated interaction of actin and myosin [2]. Both have early releasable and
structural pools, with most troponin being present in the structural pool [3,4]. (See "Excitation-
contraction coupling in myocardium", section on 'Role of tropomyosin and troponins'.)
These proteins are products of specific genes and therefore have the potential to be unique to the
heart (ie, specific cardiac isoforms). Studies performed with cTnI have failed to find any cTnI
outside of the heart at any stage of neonatal development [5,6]. In contrast, cTnT is expressed to a
minor extent in skeletal muscle. Data indicate that there are at least some patients with chronic
skeletal muscle disease who have proteins that are detected by the antibodies in the cTnT and
high sensitivity cTnT assay. This implies that skeletal muscle can, in some patients, be the source
for elevations of cTnT detected in the blood [7]. Data suggest this may be more common than was
originally thought [8,9]. In most (but not all) of these patients, the typical rise and fall of cTnT with
myocardial infarction is not seen. In addition, chronic skeletal muscle disease should be suspected
if a cTnI is within the normal range or rejected if it is elevated.
For most clinical purposes, it appears that cTnT and cTnI have equal utility except in patients with
renal failure where there are more elevations of cTnT than of cTnI [10].
HOW IS TROPONIN MEASURED? — Cardiac troponin (cTn) assays differ substantially from each
other. Almost all assays for cTn are enzyme-linked immunosorbent assays in which there is an
antibody that captures the material and then a tag antibody that labels it. In most assays, the
capture antibodies are monoclonal antibodies that are specific for the cTn being measured, either
cardiac troponin I (cTnI) or cardiac troponin T (cTnT) [11,12]. Often, more than two antibodies are
used in order to increase the amount of protein captured and labelled. Each assay is different
because the antibodies used in the assays are different. For this reason, as well as differing
detection methods and calibration, the values from one assay are not harmonized with other
assays. One cannot substitute the value from one assay for another. This issue is particularly
evident for cTnI assays because of the large number of assays available commercially. In contrast,
because of patent protections, only a single fourth generation assay is available for cTnT.
However, there are some minor differences in reported cTnT concentrations at low values with
the fourth versus the fifth generation high-sensitivity cTnT assays [13,14].
The detailed analytical characteristics of all cTn assays can be found on the International
Federation of Clinical Chemistry web page at http://www.ifcc.org/executive-board-and-
council/eb-task-forces/task-force-on-clinical-applications-of-cardiac-bio-markers-tf-cb.
TERMINOLOGY — The following terms are used in discussions of the analytical aspects of troponin
testing:
●Co-efficient of variation is a measure of reproducibility (or precision) of the assay and is
calculated as the ratio of the standard deviation over the mean value for repeated testing of the
same sample. Ideally, this value should be measurable with a coefficient of variation of 10 percent
or less [15]. Importantly, good analytical precision allows for detection of a smaller magnitude of
changing values that enhance diagnostic specificity.
●Limit of detection is the lowest value that can be measured as one progressively dilutes a sample
with cardiac troponin (cTn). The limit of detection has been used in a variety of studies as a
threshold for ruling out myocardial infarction [16]. Stated another way, it is the lowest detectable
cTn concentration reliably distinguished in a sample containing low cTn concentration [17].
It should be understood that at this concentration value, there is substantial analytical variability,
ie, noise that makes it problematic to discriminate small differences or changes.
●Limit of quantitation is the concentration at which the coefficient of variation (a measure of
imprecision) for the assay is <20 percent. The more sensitive and precise an assay is, the lower the
limit of quantitation will be. However, for all high sensitivity cTn assays, it will be higher than the
limit of detection.
●Limit of the blank is an assessment of noise in the system. It is the lowest value that one can
distinguish from zero and is estimated as the upper 95th percentile of observed values from
repeated measurements of a blank sample. Stated another way, it is the highest apparent cTn
concentration expected when multiple tests of a sample that has no cTn are performed.
●The upper reference limit (URL) is the upper boundary of a normal population. For cTn, that is
defined as the 99th percentile of the normal distribution, which is roughly 3 standard deviations
from the mean value. Thus, 1 percent of normal subjects may have a value that is above the 99th
percentile URL (see below).
INTERPRETING TROPONIN RESULTS — The original cardiac troponin (cTn) assays were relatively
insensitive with regard to their ability to detect the presence of troponin. Typically, results were
reported in ng/mL or mcg/mL. As sensitivity was increased, the number of leading zeros that
would be necessary to report very low detectable values has increased substantially. Accordingly,
values are now reported in ng/L for high sensitivity (hs) assays (1000 ng/mL = 1 ng/L) [12].
Although in an ideal world, hs-cTn assays simply have the same cut-off values as standard assays
and provide similar values, this is not the case. For hs-cTnT, as an example, a value with the fourth
generation assay of 0.01 ng/mL corresponds to a value of 30 ng/L with the hs-cTnT assay, and a
value of 0.03 ng/mL to a value of 52 ng/L [13,14]. However, values above 100 ng/L with the hs-
cTnT assay are well correlated with values with the fourth generation except for the change in
units from ng/L with hs-cTnT compared with ng/mL for the standard assay. Thus, a value of 0.1
ng/ml is equivalent to a value of 100 ng/L with the hs-cTnT assays.
Defining a meaningful delta — Knowing whether one value is different from another depends on
the ability to be sure that the apparent change in values is not simply a consequence of analytic
and biologic variation. Biological variation can be assessed accurately only with high sensitivity
assays, and the assessment presumes normal physiology [18]. Abnormal physiology might
markedly influence the amount of change present. Conjoint analytic and biologic variation can be
measured and when done so, short-term (hours) biologic and analytic variability range somewhere
between 40 and 60 percent for hs-cTn assays. Longer-term analytical variation can be higher [19].
Thus, in order to know with certainty that an individual has had a true change in cTn values, a
difference exceeding 40 to 60 percent is necessary.
Clinically, the situation is more complex, particularly in relation to possible acute myocardial
infarction [20]. Use of such criteria for relative (percentage) change among patients with possible
acute myocardial infarction does not provide optimal sensitivity for detection of acute cardiac
injury. In that circumstance, fixed absolute thresholds for change criteria are preferable and
preserve sensitivity when baseline values are already elevated [20]. Once values are elevated, they
are not likely to increase by large percentages, and less marked changes are required to preserve
the sensitivity for diagnosis. Some have suggested lowering the percentage change to 20 percent.
Others note that when using a fixed absolute change, the relative change provides a continuous
correction. It is exactly in this situation that absolute values seem to be superior [20,21].
Taking these issues into account, we generally prefer to use a fixed absolute threshold that will
vary for each assay. Evidence-based, assay-specific values should be used when available. In most
cases, a delta value that is approximately 50 percent of the 99th percentile upper reference limit
(URL) has been shown to be a reasonable absolute delta criterion. For example, with the hs-cTnT
assay, this would yield an absolute delta criterion of 7 ng/L. Investigation of the optimal delta
thresholds remains intense and thus this approach may evolve with new data.
Normal range — With the use of hs-cTn assays, all healthy ("normal") individuals have small but
detectable levels of troponin in their blood [22]. (See 'Defining a high sensitivity assay' below.)
With conventional (older) assays, apparently healthy individuals with values above the 99th
percentile URL (see 'Terminology' above) are at increased cardiovascular risk; such individuals
have higher cardiovascular event rates than those with values <99th percentile. Aggregate studies
of "predictors" of troponin elevation in this population suggest that such individuals harbor cardiac
comorbid conditions (eg, left ventricular hypertrophy) that may or may not have been detected.
For example, it has been shown that having a detectable level of troponin with a conventional
assay defined a group of stable patients likely to have either significant coronary artery disease or
elevated filling pressures [23]. Even within the normal range of these hs assays, it appears that the
higher the value, the greater the risk [24-28]. This suggests that each individual has his/her own
normal baseline and that elevations above that baseline occur as cardiac disease ensues and thus
signify increased risk.
Conventional (older) assays are not capable of accurately defining such values below the 99th
percentile value due to significant imprecision. With hs-cTn assays, there will be more gradation in
risk as values rise, even within the normal range [27]. As with most risks, there will be a gradient
that integrates other characteristics of the individual (eg, age, diabetes mellitus, renal function,
ventricular hypertrophy).
One of the major issues with hs-cTn assays is how to best determine the 99th percent URL.
Manufacturers often do not perform studies under ideal circumstances. For example, the hs-cTnT
assay was initially reported to detect values in roughly 80 percent of normal subjects [13].
However, in a study based on a population including abnormal subjects where one might
anticipate fewer undetectable values [27], only 25 percent of the population had detectable
values and in one study, only 34 percent were detected [22]. These differences in the proportion
of patients with measurable cTn likely reflect differences in the age of the samples, the specific
equipment used for the analysis, and the populations studied [29]. Some studies screen only with
questionnaires, some with additional biomarker testing, and some with imaging. The more
extensive the screening, the lower the 99th percent URL [30,31].
Studies have confirmed the early diagnostic and therapeutic value of using the 99th percentile URL
for cTn, as well as the diagnostic value of using high sensitivity assays [32-35]. (See "Coronary
angiography and revascularization for unstable angina or non-ST elevation acute myocardial
infarction" and "Initial evaluation and management of suspected acute coronary syndrome
(myocardial infarction, unstable angina) in the emergency department" and "Acute ST elevation
myocardial infarction: Selecting a reperfusion strategy".)
In 1999, a decision was made that the 99th percentile of normal values would be used to define an
abnormal cTn value [36]. This 99th percentile URL is higher than the 97.5th percentile that is used
for most laboratory tests. However, given the greater sensitivity of cTn assays than their
predecessor, creatine kinase MB, there was concern about including 2.5 percent of the population
as abnormal, which would have been the case with a URL at the 97.5th percentile. Eventually, with
hs-cTn assays, it has become clear that very few of the values detected by most standard assays
are in the normal range when established in apparently healthy individuals using an hs-cTn assay.
Accordingly, for most non-high sensitivity cTn assays, the finding of any detectable value is
abnormal [22].
Determination of the 99th percentile has become more complicated with the availability of hs-cTn
assays. It turns out that when one asks what a normal value is, the answer depends upon how
hard one attempts to define normality. This issue is not simply semantic but a real concern for
clinical implementation. The more rigorously that the reference population is tested for
cardiovascular diseases or risk factors, the lower the determined 99th percentile values [30,31].
This observation appears to be due to the comorbidities that many individuals harbor that subtly
increase the 99th percentile. Thus, if one simply uses a convenience sample of individuals to
determine the 99th percentile, the value is substantially higher than if one uses a variety of other
screening tools such as history; physical examination; and assessment of hemodynamic status
such as N-terminal pro-brain natriuretic peptide, hemoglobin A1c, and estimated glomerular
filtration rate to exclude individuals with possible cardiovascular disease. When one performs such
rigorous screening, the 99th percentile values decrease substantially, provoking arguments about
how low those values should be to be truly normal. For example, the determined 99th percentile
value is even lower if cardiovascular imaging is added to the screening evaluation to exclude
patients with previously undetected cardiovascular abnormalities [30,31]. However, diagnostic
companies, in performing their reference limit determinations, may not include imaging as part of
the screening evaluation because it is too expensive. Thus, the manufacturer-determined 99th
percentiles for hs-cTn assays may be slightly higher than a true upper limit of normal value. These
issues have led to controversy over how normal range studies ought to be done, how many
samples are necessary, and the appropriate statistics to use [12,37,38]. The caveat for clinicians is
that with hs assays, one needs to be circumspect not to routinely dismiss a rising pattern of values
that falls just below the 99th percentile URL because of the ambiguity we have described in
developing this metric.
It is also now clear that there are significant differences in the 99th percentiles between men and
women. It has been hypothesized that this difference is explained by a lower cardiac mass in
women; however, the reason for this difference is not yet clear. In addition, there is debate as to
whether sex-specific cut-offs improve clinical performance [39]. Most studies of this issue have
focused on diagnosis of acute myocardial infarction. In that setting with hs-cTnT, it has been
difficult to see a clear signal of superiority using sex-specific cut-offs [40]. In other studies with hs-
cTnI with a focus on this issue, use of sex-specific cut-offs improved the identification of women
with disease [41]. In addition, when one begins to consider the use of cTn for chronic indications,
which is one of the potential benefits of hs assays, sex-specific cut-offs are important. For that
reason, and because of anticipation of additional data from better designed studies in this area,
most guidelines recommend the use of sex-specific cut-offs for the 99th percentile URL for cTn
assays [12,39].
Defining a high sensitivity assay — We prefer highly sensitive (newer) to sensitive (older) tests in
most clinical situations (see "Troponin testing: Clinical use"). This section will provide the
background for that recommendation.
Criteria for deciding which assays are high sensitivity and which ones are not were proposed some
years ago [12,37]. There are very few, if any, well-done comparative studies between assays. For
that reason, it is almost impossible to compare values from one assay with another. In addition to
the fact that the assays are not harmonized, the calibrations of the assays vary as well. One
reasonable approach is to label an assay as high sensitivity if it can detect values, ie, values above
the level of detection (see 'Terminology' above) in at least 50 percent of normal individuals (see
'Normal range' above) [42]. There are some controversies about which assays are high sensitivity
assays and which ones are not, based on the number of normal subjects in whom values are
detected. Some assays, like hs-cTnT, have been on the margin of the 50 percent benchmark, and
have, in most studies, not detected more than 50 percent [43]. Finally, it is not at all clear that the
designation of high sensitivity based on these consensus metrics is a totally accurate reflection of
clinical sensitivity. For example, hs-cTnT often detects more elevations in cTn than many of the hs-
cTnI assays [44,45].
In addition, how "normal" is defined is of some debate. It is clear that all comorbidities associated
with cardiovascular disease such as hypertension, hyperlipidemia, and diabetes raise high
sensitivity values at least modestly [46]. There is a variety of mechanisms that have been proposed
for these effects [47], such as the extrusion of troponin in the absence of cell death, but it is also
clear that some physiologic increases of troponin can be due to cell death and release due to
apoptosis, and that this can be part of normal physiology [1,48]. Thus, rapid atrial pacing
elaborates minor amounts of troponin, even in normal subjects [49]. Infusion of dobutamine also
can lead to release of cTn [50]. This finding could be due to one of these alternative mechanisms
for cardiac release or due to apoptotic cell death. This later mechanism was not proposed as a
possibility in the past because it was thought that cardiac myocytes could not replenish
themselves, and therefore if cells died, one would end up eventually running out of
cardiomyocytes. We now know this is not true and that like skeletal muscle, there are reparative
processes [51].
Nonetheless, this does not mean that we can with certainty make the claim that all of the hs-cTn
increases are due to apoptosis, cell death, and replenishment. They could also be related to these
multiple alternative mechanisms of release. Interestingly, alcohol is associated with lower values,
as is smoking [46].
Asssay false positives and false negatives — There are a variety of reasons for false-positive and
false-negative cTn results.
The most common way to develop a false-positive increase is due to cross-reacting or heterophilic
antibodies (see "Infectious mononucleosis", section on 'Pathogenesis') [52]. Heterophilic
antibodies are antibodies to the immunoglobulin G material from which the antibody comes.
These antibodies are rare, occurring in <0.5 percent of individuals. Heterophilic antibodies are
slightly more common with cTnI assays and appear to be reduced with high sensitivity assays. In
addition, there are macrokinases that are immunoglobulin, troponin complexes that are a rare
cause of elevations [52]. When one suspects an elevated value due to an interfering substance,
the laboratory can employ a variety of approaches to address the issue. The first is the use of
additional blocking antibodies that block the cross-reacting antibodies. This approach will not rule
out a macrokinase. Exclusion of a macrokinase requires column separation to remove the complex
immunoglobulins and troponin. However, both are usually unmasked by dilution studies. When
one has an interferent, the reported concentration from the sample does not dilute until the
interferent is gone, at which point in time the values fall precipitously. This approach can be taken
by all laboratories. In addition, there is a rare skeletal muscle false-positive with cTnT [7,9,52] that
likely occurs due to the re-expression of fetal isoforms in response to skeletal muscle disease. The
frequency of false-positive results due to skeletal muscle disease is controversial but usually
should not confound the diagnosis of myocardial infarction because the values are stable rather
than dynamic. Additional studies are necessary to determine whether the differences between
normal value studies where hs-cTnT detects far fewer normal individuals than hs-cTnI assays, and
clinical studies where there are more elevations of hs-cTnT, are due to this particular cross-
reactivity. Alternatively, it could be due to high values for the 99th percentile of hs-cTnI assays or
cross-reacting antibodies that reduce values, so-called anti-TnI antibodies [52,53].
It should also be appreciated that since many antibody-based troponin assays use biotinylation,
the ingestion of large amounts of biotin can interfere with the assays themselves [54,55]. In
general, troponin values are reduced, but there have been instances in which they were elevated.
Biotin is cleared rapidly from blood and is usually not detectable for six to eight hours in the
absence of renal failure. Biotin is increasingly being consumed by patients for a variety of reasons
and has become part of an increasing number of vitamins and dietary supplements (see "Overview
of water-soluble vitamins", section on 'Biotin'). Often, patients are unaware of how much biotin
they may be taking.
One published systematic evaluation of the effects of biotin on troponin levels used Roche assays,
which are effected variably by biotin [56]. The frequency of biotin elevations and their impact on
high sensitivity troponin assays is being explored in ongoing studies. The clinical impact of these
observations is discussed separately. (See "Troponin testing: Clinical use", section on
'Unanticipated results'.)
Falsely low values can also occur with hemolysis with hs-cTnT and with some non-high sensitivity
cTnI assays [57], and is a major problem if one does not have good sample quality. In addition,
there are anti-troponin antibodies that were initially thought to be specific for cTnI. It is now clear
that they bind to a complex composed of troponin T, troponin I, and troponin C, which is one of
the multiple fragments of troponin that is released [53]. Therefore, it is likely that they modestly
reduce cTnI as well as cTnT. It is usually the case that they do not change diagnostic signals
because the complex of troponin T, troponin I, and troponin C is only one of a series of proteins
that are released in response to cardiac injury.
SUMMARY AND RECOMMENDATIONS
●Troponin values within the normal range likely come from a mixture of truly normal individuals
(with detectable values) and individuals with comorbidities reflected by low but detectable values.
(See 'Normal range' above.)
●Troponin elevations (above the 99th percentile) can be due to structural heart disease in the
absence of any acute process. (See "Troponin testing: Clinical use", section on 'Diagnosis of acute
MI'.)
●For most clinical purposes, it appears that cardiac troponin T and I have equal utility. (See 'What
is troponin' above.)
●The sensitivity of present day assays varies markedly from very insensitive assays (many of the
point-of-care assays) to very sensitive, which are referred to as high sensitivity cardiac troponin
(hs-cTn) assays. (See 'Defining a high sensitivity assay' above.)
●With the use of hs-cTn assays, all healthy ("normal") individuals have small but detectable levels
of troponin in their blood (See 'Normal range' above.

OTROS BIOMARCADORES CARDIACOS

INTRODUCTION — Cardiac injury can be defined as the disruption of normal cardiac myocyte
membrane integrity resulting in the loss into the extracellular space (including blood) of
intracellular constituents including detectable levels of a variety of biologically active cytosolic and
structural proteins such as troponin, creatine kinase, myoglobin, heart-type fatty acid binding
protein, and lactate dehydrogenase. Injury is usually considered irreversible (cell death), but
definitive proof that cell death is an inevitable consequence of the process is not available.
Causes of cardiac injury include trauma, toxins, and viral infection, but ischemia or infarction
consequent to an imbalance between the supply and demand of oxygen (and nutrients) is the
most common cause.
When a sufficient number of myocytes have died (myocyte necrosis) or lost function, acute clinical
disease is apparent; examples include myocardial infarction (MI) or myocarditis. (See "Diagnosis of
acute myocardial infarction" and "Clinical manifestations and diagnosis of myocarditis in adults".)
The biochemical characteristics and utility of myoglobin, fatty acid binding protein, lactate
dehydrogenase, and creatine kinase for the diagnosis of and prognosis after acute MI will be
reviewed here. Troponins, which are the preferred biomarkers for diagnosis and prognosis, are
discussed separately. (See "Troponin testing: Clinical use".)
CREATINE KINASE AND CK-MB — Creatine kinase (CK) and its MB isoenzyme (CK-MB) were the
most commonly used serologic tests for the diagnosis of myocardial infarction prior to the
widespread adoption of troponin. Their use has markedly diminished over time. They are
discussed here predominantly for those areas of the world where cardiac troponin assays are not
yet in use. (See "Troponin testing: Clinical use".)
It is difficult to find any situation in which CK-MB adds anything other than cost to the clinical
utility of cardiac troponin (cTn) if that marker is used properly [1]. Thus, many recommend it no
longer be used [1]. However, some experts continue to advocate for measurement of CK-MB in
the setting of assessment of periprocedural (percutaneous coronary intervention [PCI] or coronary
artery bypass graft surgery [CABG]) myocardial infarction (MI) for epidemiological reasons. Also,
some clinicians prefer the use of CK-MB for the detection of early reinfarction, although this is not
guideline recommended. Nonetheless, there are data to support the usefulness of cTn for each of
these applications. Some have even argued that using it at all will reduce the ability of clinicians to
use cTn properly.
CK basics — The enzyme CK (formerly referred to as creatine phosphokinase) exists as isoenzymes,
which are dimers of M and B chains and exist in three combinations: MM, MB, and BB [2]. These
isoenzymes reside in the cytosol and facilitate the egress of high-energy phosphates into and out
of mitochondria. CK isoenzyme activity is distributed in many tissues, including skeletal muscle,
but there is more of the CK-MB fraction in the heart [3]. Most muscles have more CK per gram
than heart tissue [4,5]. Thus, skeletal muscle breakdown can lead to absolute increases in CK-MB
in the plasma. In addition, in response to organ damage, including vigorous exercise [6], there is
regeneration of skeletal muscle fibers and re-expression of proteins that existed during ontogeny,
resulting in increased production of B chain CK protein [5,7,8]. A large percentage of the CK that is
released is degraded locally or in lymph [9]. Reperfusion truncates this process and increases the
rapidity and magnitude of egress of CK into plasma [10].
Total CK measurements for the detection of cardiac damage — Elevations in total serum CK lack
specificity for cardiac damage, which improves with measurement of the MB fraction. The normal
range of CK also varies considerably; a twofold or greater increase in the CK concentration is
required for diagnosis. This criterion can be problematic in older individuals who, because of their
lower muscle mass, may have low baseline serum total CK and, during MI, may have elevated
serum CK-MB with values of total CK that rise but remain within the normal range [11-13]. For
these reasons, total CK has not been used in the diagnosis of myocardial damage for years.
CK-MB fraction for diagnosis of acute MI — When cTn is available, CK-MB should not be used for
the initial diagnosis of acute MI. If it is the only assay available, it can be used but is far less
sensitive and specific.
Most assays measure CK-MB mass because they are more sensitive than activity assays. In
addition, mass assays avoid, for the most part, detection of macrokinases (CK linked to IgG and
dimers of mitochondrial CK) that can confound diagnosis with activity assays. The presence of
macrokinases should be considered as one possibility when CK-MB is a very high percentage (>20
percent) of total CK [14]. However, patients with chronic skeletal muscle disease often have falsely
positive CK-MB results when percentage criteria are used [8,15-17]. The proportion of CK that is
CK-MB can be as high as 50 percent with chronic skeletal muscle injury, such as
dermatomyositis/polymyositis, due to increased production of B chain CK protein [5,8,15].
Specificity and sensitivity — CK-MB has high specificity for cardiac tissue and was the preferred
marker of cardiac injury for many years [14]. CK-MB typically begins to rise four to six hours after
the onset of infarction but is not elevated in all patients until about 12 hours (figure 1) [18,19].
An elevated CK-MB is relatively specific for myocardial injury, particularly in patients with ischemic
symptoms, when skeletal muscle damage is not present. Elevations return to baseline within 36 to
48 hours, in contrast to elevations in troponin, which can persist for as long as 10 to 14 days [20].
This means that CK-MB, unlike troponins, cannot be used for the late diagnosis of an acute MI but
can be used to suggest infarct extension if levels rise again after declining. (See "Diagnosis of acute
myocardial infarction".)
Gender specific values are essential for diagnostic use [21].
Because CK-MB can be released from skeletal muscle, its diagnostic use is impaired when skeletal
muscle injury is present [22]. Some have suggested using a ratio of CK-MB to total CK to improve
specificity, but that approach markedly reDuces the sensitivity.
CK-MB fraction for prognosis — There is a relationship between infarct size, which can be
estimated by CK-MB and prognosis. Peak values are less precise, but if adequate numbers of
samples are obtained, they can provide a reasonable estimate. Comparisons with cTn suggest that
cTn provides better estimates [23-27].
CK and coronary reperfusion — The time to peak CK-MB levels and the slope of CK-MB release can
be used to assess whether reperfusion has occurred after fibrinolysis and, when used in
conjunction with clinical variables, can predict whether TIMI 0 or 1 and TIMI 2 or 3 grade flow is
present [28]. However, CK-MB criteria cannot identify the presence of TIMI 3 flow, which is the
only level of perfusion associated with improved survival after fibrinolysis and this approach is not
necessary at all with primary PCI.
Reinfarction and late diagnosis — Since CK-MB levels return to baseline 36 to 48 hours after
infarction, resampling can be used to detect very early reinfarction. Since cTn does not normalize
that rapidly, it has been suggested that CK-MB might be of value in this area. It is now clear that
cTn increases rapidly, albeit from an abnormal baseline in patients with reinfarction.
After myocardial revascularization — CK-MB still has advocates for its use to define MI after
myocardial revascularization with either PCI or CABG. As it detects larger infarcts, CK-MB holds
more “weight” with some clinicians and trialists.
Why troponin is preferred
Diagnosis — Because of their increased sensitivity and specificity compared with CK-MB and other
markers, troponins are preferred for the diagnosis of MI in most settings. (See "Troponin testing:
Clinical use", section on 'Diagnosis of acute MI'.)
The basis for the consistent observation that troponin is more sensitive than CK-MB relates to the
fact that more troponin is found in the heart per gram of myocardium and that a greater
percentage depleted from the heart by cardiac injury arrives in the blood [1].
With regard to specificity, troponin elevations are almost always specific for cardiac injury, except
for the infrequent analytical false positives caused by fibrin interference and/or cross-reacting
antibodies [1]. As mentioned above, CK-MB is not specific for cardiac injury, as a small amount is
found in skeletal muscle. (See 'CK basics' above.)
It is difficult today to find any situation in which CK-MB adds anything other than cost to the
clinical utility of cTn if that marker is used properly [1]. Some have even argued that using it at all
will reduce the ability of clinicians to use cTn properly [1]. However, some experts continue to
advocate for measurement of CK-MB in the setting of assessment of periprocedural (PCI or CABG)
MI for epidemiological reasons. Also, some clinicians prefer the use of CK-MB for the detection of
early reinfarction. Nonetheless, there are data to support the usefulness of cTn for each of these
applications.
Prognosis — A number of well-done studies have shown that troponin measurements have
enhanced prognostic value compared with CK-MB measurements in patients with a non-ST
elevation acute coronary syndrome (ACS) [29-32]. This was illustrated in a review of almost 30,000
such patients from the multicenter CRUSADE initiative in the United States [30]. The following
findings were noted:
●The results were discordant in 28 percent of patients. Troponin was more sensitive, as 18
percent had elevated troponin but normal CK-MB values. In addition, 10 percent had false positive
CK-MB elevations, as defined by normal troponin values.
●Compared with patients who were negative for both biomarkers, in-hospital mortality was not
increased in patients who were troponin-negative and CK-MB-positive (ie, false positives; 3.0
versus 2.7 percent, adjusted odds ratio 1.02, 95 percent CI 0.75-1.38).
●Compared with patients who were negative for both biomarkers, there was a nonsignificant
trend toward increased mortality in patients who were troponin-positive/CK-MB-negative (4.5
versus 2.7 percent, adjusted odds ratio 1.15, 95% CI 0.86-1.54) and a significant increase in
mortality in patients who were positive for both biomarkers (5.9 versus 2.7 percent, adjusted odds
ratio 1.53, 95% CI 1.18-1.98).
These differences in outcomes could not be explained by differences in therapy since the two
discordant groups were treated similarly with antithrombotic agents and PCI. Thus, an isolated CK-
MB elevation has limited prognostic value in patients with a non-ST elevation ACS, while an
isolated troponin elevation was associated with increased risk.
Similar findings have been noted in other studies [29,31,32]. In a report of over 10,000 patients
with an ACS from the multicenter GRACE registry, 1110 (10.4 percent) were troponin-positive/CK-
MB-negative and 822 (7.7 percent) were troponin-negative/CK-MB-positive (false positives) [32].
In-hospital mortality was highest when both troponin and CK-MB were positive (7.7 percent),
intermediate in troponin-positive/CK-MB-negative patients (3.9 percent), and lowest in patients in
whom both markers were negative and those who were troponin-negative/CK-MB-positive (1.7
and 2.3 percent, respectively).
MYOGLOBIN — Myoglobin is a ubiquitous heme protein that is rapidly released from damaged
tissue because of its small size [33]. Its half-life in plasma is in the range of nine minutes [34]. Due
to its early appearance in the serum, myoglobin was postulated to be a useful adjunct to either
troponin or creatine kinase MB (CK-MB) for the early diagnosis of myocardial infarction (MI) [35].
(See "Initial evaluation and management of suspected acute coronary syndrome (myocardial
infarction, unstable angina) in the emergency department".)
With contemporary, highly sensitive cardiac troponin (cTn) assays and the use of the 99th
percentile or 10 percent coefficient of variation cut-off, cTn is elevated prior to elevations in
myoglobin [36-38]. Thus, there is little advantage for the use of myoglobin as a marker of early
injury unless an insensitive cTn assay is being employed. (See "Troponin testing: Clinical use".) In
addition, the prior use of myoglobin and/or biomarkers in general for the detection of reperfusion
is no longer used. Thus, this marker no longer should be used.
COPEPTIN — The role of copeptin, the C-terminal portion of the arginine vasopressin precursor
peptide that is secreted from the pituitary gland early in the course of acute myocardial infarction
(MI), in the evaluation of patients with suspected MI There are mixed data concerning its use. (See
"Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction,
unstable angina) in the emergency department", section on 'Cardiac biomarkers'.)
The CHOPIN study investigated the potential value of adding a copeptin level to the early
evaluation of patients suspected of an acute coronary syndrome. In CHOPIN, 1967 patients with
chest pain presenting to an emergency department within six hours of pain onset underwent
evaluation with clinical examination, serial sensitive troponin, measurements, and
electrocardiograms [39]. Copeptin was measured simultaneously with each troponin. A negative
copeptin and cardiac troponin (cTn) I at baseline ruled out acute MI for 58 percent of patients,
with a negative predictive value of 99.2 percent. It was estimated that the average time-to-
decision could be reduced by 43 percent by the simultaneous use of these two biomarkers. We
have some concerns regarding the way in which the gold standard diagnosis was achieved and
specifically what cut-off values were used for cTn. Data from this trial have suggested that second
values may also be of help [40].
A randomized emergency department (ED) trial using this marker was also reported (BIC-8) [41]. In
this trial, 902 patients with possible acute MI were evaluated for possible early discharge using a
troponin assay and a new, more sensitive copeptin assay. Event rates at 30 days were similar (5.17
percent in the standard group and 5.19 percent in the copeptin group). However, those with a
normal copeptin value (<10 pmol/L) had an event rate of 3.01 percent. Half of the patients with
events in the copeptin arm had normal values but were kept in the ED by physicians who were
concerned that the results were inaccurate. However, in the copeptin group, 80 percent of
patients were discharged compared to only 11 percent in the standard group. These data were
argued to indicate the ability of copeptin to identify a low-risk group to discharge. Some would
argue that astute ED physicians are key to avoiding morbidity from this approach. It also could be
argued that many of the patients in the standard group should have been discharged early as well
had that been part of the approach being studied.
An evaluation from a large data set from the APACE trial failed to find benefit with the use of
copeptin as an adjunct to high sensitivity (hs) cTnT in the evaluation of patients with possible
acute MI [42].
In summary, the cautious use of copeptin in association with close physician scrutiny may be
helpful when using contemporary cTn assays to allow some patients to be sent home earlier from
the ED. With hs-cTn assays, this is unlikely to be the case, even when one does not employ the
facile rule out protocols that are being developed [43].
HEART-TYPE FATTY ACID BINDING PROTEIN — Heart-type fatty acid binding protein (H-FABP) is a
low molecular weight protein that behaves similarly to myoglobin in its kinetics and release.
However, in contrast to myoglobin, there is more fatty acid binding protein in heart compared to
skeletal muscle, making this a potentially more specific test [44].
The possible efficacy of H-FABP for the early diagnosis of acute myocardial infarction (MI) was
illustrated in a study of 371 patients with acute chest pain and suspected MI [45]. There were 68
patients who presented within two hours of symptoms, 37 of whom had a final diagnosis of MI.
The sensitivity for MI at two-hour measurement was significantly higher with serum H-FABP
compared to cardiac troponin T or myoglobin (89 versus 22 and 38 percent, respectively).
However, cardiac troponin T had a significantly higher specificity (94 versus 52 percent). In a study,
H-FABP performed much better with respect to detection of acute coronary syndrome (ACS), but
an insensitive troponin assay was used as the comparator [46].
In addition to a possible role in diagnosis, H-FABP has been touted to help predict prognosis in
patients with an ACS. However, its benefit appears often to be in patients without troponin
elevations [47]. Thus, it may signal the presence of non-cardiovascular co-morbidities that exist in
specific patient subsets [48]. In these same studies, prognosis is worse with higher peak values
even in those with elevated troponin values but this effect may be due to differences in the extent
of the injury, which might also be evaluated easily by peak troponin values had they been
obtained [47,48] (see "Risk factors for adverse outcomes after non-ST elevation acute coronary
syndromes", section on 'Heart-type fatty acid binding protein').
Numerous studies have compared H-FABP to troponin for diagnosis or prognosis. However, they
used high cut-off values for troponin or insensitive assays. Good comparison studies using
contemporary troponin assays that are sensitive with the recommended cut-off values are needed
to confirm these claims.
Measurement of H-FABP has not been widely evaluated or adopted as a biomarker of cardiac
injury and is not approved for clinical use in the United States.
LACTATE DEHYDROGENASE — Lactate dehydrogenase (LD, formerly abbreviated LDH) was
commonly used in the past in combination with aspartate aminotransferase (AST or SGOT) and
creatine kinase MB (CK-MB) to diagnose an acute myocardial infarction (MI).
LD consists of M (muscle) and H (heart) subunits that give rise to five isoenzymes [49]. The heart
primarily contains LD1 and some LD2. Red cells, kidney, stomach, and pancreas are other
important sources of LD1. In contrast, LD5 predominates in skeletal muscle and liver [50].
LD activity rises to abnormal levels approximately 10 hours after the onset of MI, peaks at 24 to 48
hours, and remains elevated for six to eight days [47]. However, since troponins are more specific
than LD and remain elevated for 5 to 10 days, current recommendations suggest that LD no longer
has a role in the diagnosis of MI [51].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links:
Non-ST elevation acute coronary syndromes (non-ST elevation myocardial infarction)" and
"Society guideline links: ST elevation myocardial infarction (STEMI)".)
SUMMARY
●We recommend using cardiac troponins in preference to creatine kinase MB for diagnostic and
prognostic purposes. For most settings, it is unnecessary to obtain both values. (See "Troponin
testing: Clinical use".)
●Myoglobin and lactate dehydrogenase should no longer be used for the evaluation of patients
with acute coronary syndrome and/or possible acute myocardial infarction. While there are
theoretical advantages of other cardiac biomarkers, such heart-type fatty acid binding protein and
copeptin, available data suggest that cardiac troponin outperforms each of them in almost every
specific way. Their use is not encouraged.