Markers of Myocardial Injury
Also known as: CK MB, CPK
Formally known as: Creatine
We subscribe to the
HONcode principle of
the Health on the
Cardiac Markers: Cardiac
Markers Update Troponin I / Troponin T
of patients presenting with chest pain under suspicion of an
acute myocardial infarction (AMI) or minor myocardial damage
(MMD) is a major problem even today. Differentiation between
myocardial damage and non-cardiac syndromes with related
symptoms has a major impact on the treatment strategy for each
patient. Commonly used standard methods, such as ECG, and the
measurements of enzymes, such as CK and CK-MB, allow no clear
diagnosis in a high number of cases.
availability of troponin T assays for the specific detection
of cardiac troponin T has enhanced diagnostic specificity,
sensitivity and reliability in the diagnosis of myocardial
Troponin T is part of the troponin complex which, in addition,
comprises the subunit I and C (T for "tropomyosin
binding", I for "inhibitory", and C for
"calcium binding"). The complex is located on the
thin filament of the contractile muscle apparatus and
regulates the calcium mediated interaction of myosin and
actin. Apart from their synergisms in the complex, troponin T,
C and I are otherwise unrelated proteins.
Skeletal and cardiac troponin T isoforms differ from each
other in amino acid sequence. Following myocardial damage,
cardiac troponin T (cTnT) is released into blood within 2 to 6
hours after the event and can be detected with immunoassays
based on specific antibodies.
All available Roche troponin T assays
specifically detect the cardiac troponin T isoform by using
monoclonal antibodies specific for the cardiac troponin T
The highly specific detection of all cardiac troponin T
released into blood makes Roche troponin T assays a superior
diagnostic tool for diagnosing myocardial damage.
troponin I assays are not directly comparable. This is
due to the high variability of the analyte and the use
of different antibodies in various assays. The analyte
troponin I is not standardised!
Troponin T on the other hand is a stable analyte. cTnT
assays are not affected by biochemical variations. The
same antibodies are used in all assays to guarantee
the same results and clinical interpretation.
Troponin T is a standardised parameter and all
available troponin T assays are standardised and
Troponin T or troponin I?
There is a tendency to suggest that troponin T and
troponin I are the same biochemically and that results
can be used interchangeably. However, there are
significant differences in their biochemistry
which suggest that this is not true:
There are several biochemical
modifications of troponin I after its liberation.
Several complexes of troponin I with troponin C, I and
T have been identified in blood circulation. These
result in three different complex forms of troponin I
(I, II, IC, and ICT) (Lavigne et al. [ref 23],
Katrukha et al. [ref 17-21]). Troponin I can also be
phosphorylated and oxidised. Furthermore, there is
evidence of fragmentation of the troponin I molecule
by proteolytic enzymes.
Consequences of biochemical variation of troponin
All troponin assays use pairs of antibodies that
recognise two different epitopes on the analyte.
Different troponin I assays use different troponin I
antibody pairs. In terms of standardisation and
comparability of results, this causes a problem
for troponin I assays:
The available troponin I assays differently detect the
modified TnI molecules. For example, phosphorylation
of troponin I may interfere with recognition of the
epitope by different monoclonal TnI antibodies.
Different assays using different antibodies may not
identify some of the fragments, complexes or
phosphorylated troponin I isoforms. As a consequence,
results obtained with troponin I assays from different
companies cannot be compared directly.
A.H.B. Wu et al. (ref 39). It was published recently
in Clinical Chemistry that: "there are
differences in absolute cTnI results due to a lack of
mass standardisation and heterogeneity in the
cross-reactivities of antibodies to various TnI
In contrast, in cardiac troponin T assays, the
antibody pair is well characterised and standardised
across available measurement platforms (Point of Care
and Laboratory). Troponin T assays are not affected by
any biochemical variations after liberation into
Therefore, troponin T is a standardised parameter
whilst troponin I is not!
In addition, more shortcomings of troponin I have
of analyte: two different tests for troponin I may
show increasing or decreasing levels of troponin I if
a sample has been left at room temperature for some
hours. (Waskiewicz et al. [ref 38]; Morjana et al.
4) Azzazy et al. found elevated cardiac troponin I in
a patient with metastatic liver tumours without
myocardial necrosis (autopsy).
(ref 29) Missov et al. also described elevated TnI
levels in patients with various cancers not treated
with cardiotoxic substances, such as doxorubicin.
(ref 10) Recently a false
increase of cardiac troponin I with
heterophilic antibodies in the sample has been
described (Fitzmaurice et al. in Clin. Chem. 10/98).
| Testing for Troponin-T in Potential
Myocardial Infarction Patients
By Daryl Shaw, Medical Student
The following is a synopsis of an article in the May/June issue of RETTUNGSMAGAZIN.
I have condensed and translated it and will include additions re: muscle/cardiological physiology for easier understanding.:
More than 250,000 persons suffer an AMI per year in Germany. Approx. 20% of these expire within 2 hours of ischamic begin. For this reason, it was of great importance that an objective test be found to confirm or indicate AMI in the preclinical (EMS) theater.
It was discovered that the cardial enzyme Troponin-T, a deciding factor in the Actin-Myosin contractile system typical to all muscles, especially striped muscle and, histologically related, cardial myocardial muscle. The component Troponin-T of the Actin strand is responsible, along with Tropomyosin, for the contraction in the individual muscle strand, in that they interact with calcium to allow or block the contraction cycle.
It has been determined that ischemia results in the release of Troponin-T from the damaged area of the myocard, whereby concentrations above 0.2 ng/ml blood are pathological and can be illustrated with the test.
The best situation for the use of the test is AMI suspect patients where ECG conformation is not definite or the symptomatic picture is "unappropriate". Dr. Motschwiller from Boehringer Mannheim stresses the fallicy of sole usage for AMI diagnosis, "The Tropt-Test should not be overestimated...(it) is primarily for the conformation of a suspected (AMI) diagnosis"(Due to individual cardiovascular kinetics and release rate, enzyme conformation may take up to 30 mins. after ischemia beginning.).
The test is composed of documentation card, test stick and syringe. 150 microliter anti-coagulated blood (i.e. from blood lab tube/Vacutainer) is put in window of test stick and covered with included flap. The stick is attached to the documentation card and the necessary information including start time is included. After "a few" (5) minutes a result can be visually registered; 1 stripe (control): negative , 2 stripes: positive. When negative, a waiting period of 20 minutes is advisable (kinetics). This test is only of qualitative value; a quantitive evaluation must be done in the treating facility. Due to the kinetics of release, a negative test result can occur up to 12 hours post ischemia.
Finally, there is the problem of storage; the test must be kept between 2 and 8 degrees celsius and only is good for a week at room temperature, hence the need for a cool storage area, i.e. a refridgerator.
The tests cost DM 179,98 for 10 sets or DM 100,40 for 5 Sets.
Dr. E. Motschwiller
Sandhofer Strasse 116
68298 Mannheim GERMANY
room triage of patients with acute chest pain by
means of rapid testing for cardiac troponin T or
C, Goldmann B, Heeschen C, Kreymann G, Berger J,
England Journal of Medicine. 337:1648-53.
December 4, 1997.
Hospital Eppendorf, Hamburg, Germany
injury, commonly assessed by CPK-MB levels, can
be detected with greater sensitivity by assaying
blood levels of the cardiac contractile proteins
troponin T and I. These have been shown to have
prognostic significance in the setting of acute
ischemic syndromes, such as unstable angina.
With the development of rapid bedside assays for
these proteins, their use in the evaluation of
chest pain in the emergency room becomes
feasible. This study was designed to investigate
the diagnostic and prognostic value of rapid
bedside troponin testing in emergency room
patients with chest pain and without ST-segment
elevation on EKG.
were eligible if they presented to the emergency
room of the University Hospital with less than
12 hours of anterior or left-sided chest pain,
not explained by trauma or obvious abnormality
on chest x-ray.
with ST-segment elevation or recent MI were
obtained for troponin T and I assays within 15
minutes of arrival at the ER and again four
hours later. For those patients who had arrived
less than two hours after the onset of pain, a
third sample was drawn 6 hours after the onset
of pain (so that all patients had one sample
drawn at least 6 hours after the onset of pain).
qualitative bedside assay for troponin T was
performed on all samples and the results were
immediately available to the treating
centrifuged and frozen for quantitative troponin
T measurement as well as for rapid qualitative
and quantitative troponin I measurements.
also had EKG's performed, blood drawn for CPK
and MB fractions and history and physical
examination recorded according to a protocol.
excluding patients with ST-segment elevation,
the admission EKG was classified as:
segment depression (with or without T-wave
(paced or bundle branch block)
MI at the
time of admission was judged to be present if
the CPK within 24 hours of admission was greater
than twice the upper limits of normal with an
elevated MB fraction.
were followed during hospitalization and for 30
days after discharge. Endpoints were death from
cardiac causes and nonfatal MI (more than 24
hours after admission).
and clinical diagnoses
eligible patients were screened between June,
1994 and March, 1996. There were 97 with
ST-segment elevation, which left 773 study
patients with chest pain but no ST-segment
were admitted to the hospital (63%), 224 to the
MI (by CPK): 47 patients
specific cardiovascular diagnosis: 258
and quantitative troponin tests
good correspondence between the rapid bedside
assays and the quantitative assays -- 94.8% for
troponin T and 98.7% for troponin I. There was
only one false negative for troponin T and 5 for
and clinical diagnoses
773 patients, 16% had at least one positive
troponin T result; 22% had at least one positive
troponin I. Approximately 40% of patients with a
positive test had a negative first sample.
within the first 24 hours (47 patients):
(315 patients): 22% had at least one positive
troponin T; 36% had at least one positive
troponin I; 5% had elevation of CPK-MB
(presumably the total CPK did not rise enough to
qualify for acute MI).
admission, troponin T was positive in 51%,
troponin I in 66%, CPK-MB was elevated in
hours later, troponin T was positive in 94%,
troponin I in 100%, CPK-MB in 91%
- CHF: 1
positive troponin T, 5 positive troponin I
- PE: 1
positive troponin T, 2 positive troponin I
1 positive troponin T, 2 positive troponin I
chest pain: 1 positive troponin I
patients had an elevated troponin T but normal
troponin I; these were considered to be false
positives. Six of these patients also had renal
and events during follow-up
was present in 331 patients (43%). At least
one positive troponin test (both T and I)
was present in 10% of these. One of the 47
myocardial infarctions on admission was in
(paced or bundle branch block) was present
in 87 patients (11%). The percentage of
positive troponin T and I tests in this
group was 32% and 47%, respectively. Of the
47 myocardial infarctions, 23 were in this
was present in 158 patients (20%). The
percentage of positive troponin T and I
tests was 32% and 56%. There were 8
myocardial infarctions in this group.
only were present in 197 patients (25%).
Positive troponin T and I tests were present
in 6% and 5%. There were 15 myocardial
infarctions in this group.
were 20 deaths from cardiac causes during
the follow-up period (11 in hospital and 9 after
discharge). The troponin T test was positive in
16 out of these 20 patients; troponin I was
positive in all but one.
after admission occurred in 14 patients (9 in
hospital, 5 after discharge). Troponin T was
positive in 11 and negative in 3. Troponin I was
positive in 13 and negative in 1.
For the 34
total events, troponin I was positive in 32
and negative in 2. Troponin T was positive in 27
and negative in 7. The EKG was normal in 5 and
abnormal or nondiagnostic in 29.
331 patients with a normal EKG, there were 5
events. Four of these had an abnormal troponin
T, all 5 had an abnormal troponin I.
overall event rate for patients with negative
troponin T was 1.1%, and for negative troponin I
0.3%. Troponin T and troponin I provided
additional prognostic information, after EKG
status and CPK-MB were taken into account.
state that "the primary aim of this study
was to demonstrate that two negative test
results on admission and four hours later (or at
least six hours from the onset of chest pain)
allow safe early discharge". Patients with
two normal troponin measurements had a low rate
of cardiac events within 30 days (1.1% for
troponin T; 0.3% for troponin I).
that patients with one positive result should be
admitted and evaluated further, and that a
single test on admission is not sufficient. They
feel that the slightly higher sensitivity of the
troponin I test "may be related to
different release kinetics and different limits
of detection of the versions of the test that
are currently available". They also feel
that the six false positives seen in patients
with renal failure may reflect a true difference
between the troponin T and I assays.
accompanying editorial, Dr. Mark Hlatky from
Stanford University reviews the problem of the
evaluation of chest pain in the emergency room.
He makes several important points about this
with a positive troponin test who were
classified as unstable angina could also be
classified as "small myocardial
no details about the clinical history were
given, it is not possible to determine the
risk of events in clinically high-risk
subsets with negative troponin tests.
results obtained here only apply when at
least two samples are obtained, with one
sample at least 6 hours after the onset of
patients with ST-segment depression, the
event rates with negative troponin T and I
were 2.8% and 1.4%, not negligeable numbers.
This was a study of
773 patients evaluated in an emergency room for chest
pain without ST-segment evaluation. Patients underwent
troponin T and I determination; the troponin T results
were immediately available and all patients with a
positive test were admitted. Patients with negative
troponin tests had a good prognosis -- the event rate
(cardiac MI or death) within 30 days was 1.1% for
patients with a negative troponin T test and 0.3% for
patients with a negative troponin I test.
In addition to
the limitations noted in Dr. Hlatky's editorial, there
is another problem with the study that greatly limits
its applicability, in my opinion. Of the 773 patients,
487 were admitted to the hospital, the vast majority
with a diagnosis of unstable or stable angina. Overall,
123 patients had at least one positive troponin T test
and 171 had a positive troponin I test. This means that
at least 364 patients were admitted to the hospital with
negative troponin T tests and at least 316 with negative
troponin I tests.
Thus, a large
number of patients with negative troponin tests were
admitted to the hospital, mainly with the diagnoses of
unstable and stable angina, and presumably received
treatment for this. Their good prognosis could be in
part related to in-hospital therapy (such as heparin),
not only to their negative troponin tests.
Although we can
conclude that patients who are appropriately treated
(including hospitalization) have a good prognosis with
negative troponins, we cannot conclude from this study
that it is safe to discharge patients from the emergency
room, even with normal EKG's and negative troponin
tests, since so many patients in this study were, in
fact, hospitalized. We do not know how they would have
fared had they been discharged from the emergency room.
The objective of
this study, according to the authors, was to demonstrate
that "two negative test results on admission and
four hours later (or at least six hours from the onset
of chest pain) allow safe early discharge". This
has not yet been persuasively accomplished, in my
December 20, 1997