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Diagnosis

Biochemical Markers for Diagnosis of Myocardial Infarction

Cardiac Troponin
a report by

Robert H Christenson, PhD

Professor of Pathology and Medical and Research Technology, University of Maryland School of Medicine

Accurate and timely biochemical marker testing for aiding the diagnosis of
myocardial infarction (MI) has been important for the appropriate disposition
and treatment of patients for the past several decades. Creatine kinase (CK)
muscle and brain (CK-MB) mass and myoglobin measurements were the
standard up to the mid-1990s, when assays for the cardiac-specific isoforms
of troponin I and troponin Thereafter referred to collectively as cardiac
troponins (cTn)became available. The data for cTn were so compelling that
in 2000 a global task force comprising representatives from the European
Society of Cardiology (ESC) and the American College of Cardiology (ACC)
was convened to redefine the diagnosis of MI based on cTn measurements.1
Recently, the National Academy of Clinical Biochemistry (NACB) has published
updated guidelines for clinical utilization of biochemical markers in the
context of acute coronary syndrome (ACS) and MI diagnosis.2,3 Also, this
NACB committee developed guidelines for logistics, measurement
specifications, and point-of-care testing of these biochemical markers.4 The
recommendations and strength of scientific data supporting each NACB
guideline statement were rated using scoring criteria adopted from the
American Heart Association (AHA)/American College of Cardiology (ACC),
which are summarized in Table 1. For each recommendation, the designations
I, IIa, IIb, and III describe the indications, and the upper-case letters A to C
describe the weight of evidence.5
Who Should Be Tested with Biochemical Markers?
It is well known that the clinical signs and symptoms of patients presenting
with suspected ACS are frequently vague and non-specific, and mimic a
number of other conditions. For this reason, measurement of biomarkers
should be obtained in all patients presenting with ACS symptoms, as indicated
in Recommendation 1 in Table 2. Although quantitative measurement of
biochemical markers is important for objectifying the diagnostic process of the
MI work-up, Recommendation 2 in Table 2 is a reminder that the patients
clinical presentation (history, physical examination) and electrocardiogram
(ECG) must be used in conjunction with biomarkers in the diagnostic
evaluation of suspected MI.

Robert H Christenson, PhD, is a Professor of Pathology and

Medical and Research Technology at the University of Maryland
School of Medicine in Baltimore. He is Director of the Clinical
Chemistry, Toxicology, and Rapid Response Laboratories at the
University of Maryland Medical Center, where he is also Director
of Point-of-Care Services. Dr Christenson is Vice Chair of the
National Academy of Clinical Biochemists practice guidelines in
the area of emerging markers of long-term risk assessment for
coronary artery disease.
E: rchristenson@umm.edu

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Which Biochemical Markers and When?

In brief, cTn is the cornerstone of biochemical marker testing for evaluation
of MI in the suspected ACS patient. The data for cTn have been so
convincing that it has emerged as the preferred biomarker for use in the
diagnosis of MI (see Table 2, Recommendation 3). Given the high prevalence
and increased risk profile of MI, cTn should be available in virtually every
urgent care venue. However, if for some reason cTn testing is not available,
CK-MB by mass assay is an acceptable alternative (see Table 2). cTn is a
structural protein and several hours are usually required for its release into
the blood after myocardial necrosis. It is therefore not an early biomarker of
myocardial damage. For this reason the recommended sampling strategy
includes collection at hospital presentation followed by serial sampling, with
timing based on the clinical circumstances. Ideally, the temporal sampling
sequence would begin at the time of the acute onset. However, patients and
bystanders are frequently unable to provide an accurate account of precisely
when the suspected cardiac event occurred. For this reason, in routine clinical
practice blood collections should be referenced relative to the time of
presentation and, if available, the reported time of symptom onset should be
noted as well (see Recommendation 4, Table 2). Serial sampling up to six to
nine hours after presentation is necessary to evaluate the MI diagnosis with
high clinical sensitivity and specificity (see Recommendation 5, Table 2).
However, testing should continue for up to 1224 hours if earlier samples are
negative and the clinical index of suspicion remains intermediate or high.2
Given the relatively late release profile for cTn, an early marker of necrosis
such as myoglobin may be useful in addition to a cTn for patients who
present within the first hours after symptom onset. Also, a rapid rule-in
protocol with frequent early sampling of markers of myocardial necrosis may
be appropriate if tied to therapeutic strategies. Note that Recommendations
6 and 7 in Table 2 are both considered Class IIb, because their
usefulness/efficacy is less well established by evidence/opinion.
What Is the Cardiac Troponin Decision Point (Cut-off) to Use?
There has been no shortage of controversy and confusion regarding what
cut-off should be used for indicating the diagnosis of MI. Outcomes show that
even a small release of cTn confers a high risk profile in the setting for ACS.
This evidence justifies a low cTn cut-off.2 It is of interest that both clinicians and
the laboratory prefer quantitative rather than qualitative results (see
Recommendation 8, Table 2). The ESC/ACC global task force was the first to
designate a low cTn decision point, specified as the 99th percentile of a
reference control population.1 The NACB guidelines are confluent with the
notion of a low cut-off. They state that, in the context of ACS, a maximal
concentration of cTn exceeding the 99th percentile for a reference control
group on at least one occasion during the first 24 hours after the clinical event
is indicative of myocardial necrosis consistent with MI. In the event that CK-MB

TOUCH BRIEFINGS 2007

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Biochemical Markers for Diagnosis of Myocardial InfarctionCardiac Troponin

Table 1: American College of Cardiology/American Heart

Association ClassificationsCriteria Used for Rating Evidence
Summary of Indications
I
Conditions for which there is evidence and/or general agreement that a given
procedure or treatment is useful and effective.
II
Conditions for which there is conflicting evidence and/or a divergence of opinion
about the usefulness/efficacy of a procedure or treatment.
IIa
Weight of evidence/opinion is in favor of usefulness/efficacy.
IIb
Usefulness/efficacy is less well-established by evidence/opinion.
III
Conditions for which there is evidence and/or general agreement that the
procedure/treatment is not useful/effective and in some cases may be harmful.
Weight of Evidence
A
Data derived from multiple randomized clinical trials that involved large numbers
of patients.
B
Data derived from a limited number of randomized trials that involved small
numbers of patients or from careful analyses of non-randomized studies or
observational registries.
C
Expert consensus was the primary basis for the recommendation.

Table 2: Recommendations for the Use of Biochemical Markers for

the Diagnosis of Myocardial Infarction
All Class I
1
Biomarkers of myocardial necrosis should be measured in all patients who present
with symptoms consistent with acute coronary syndrome. (Level of Evidence: C)
2
The patients clinical presentation (history, physical exam) and ECG should be used
in conjunction with biomarkers in the diagnostic evaluation of suspected
myocardial infarction. (Level of Evidence: C)
3
Cardiac troponin is the preferred marker for the diagnosis of myocardial infarction.
CK-MB by mass assay is an acceptable alternative when cardiac troponin is not
available. (Level of Evidence: A)
4
For routine clinical practice, blood collections should be referenced relative to the
time of presentation to the emergency department and (when available) the
reported time of chest pain onset. (Level of Evidence: C)
5
Blood should be obtained for testing at hospital presentation followed by serial
sampling with timing of sampling based on the clinical circumstances. For most
patients, blood should be obtained for testing at hospital presentation and at six
to nine hours. (Level of Evidence: C)
Class IIb
6
For patients who present within six hours of the onset of symptoms, an early
marker of myocardial necrosis may be considered in addition to a cardiac troponin.
Myoglobin is the most extensively studied marker for this purpose. (Level of
Evidence: B)
7
A rapid rule-in protocol with frequent early sampling of markers of myocardial
necrosis may be appropriate if tied to therapeutic strategies. (Level of Evidence: C)
8
While it is recognized that qualitative systems do provide useful information, it is
recommended that point-of-care systems provide quantitative results. (Level of
Evidence: C)
Class I
9
In the presence of a clinical history suggestive of acute coronary syndrome, the
following are considered indicative of myocardial necrosis consistent with
myocardial infarction (Level of Evidence: C)
a. Maximal concentration of cardiac troponin exceeding the 99th percentile of
values (with optimal precision defined by total CV 10%) for a reference control
group on at least one occasion during the first 24 hours after the clinical event.

1.
2.

Alpert JS, et al., J Am Coll Cardiol, 2000;36:95969.

Morrow DA, Cannon CP, Jesse RL, et al., Circulation,
2007;115:e35675.

US CARDIOVASCULAR DISEASE 2007

3.
4.

10

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b. Observation of a rise and/or fall in values is useful in discriminating the timing

of injury. Maximal concentration of CK-MB exceeding the 99th percentile of
values for a sex-specific reference control group on two successive samples
(values for CK-MB should rise and/or fall).
The laboratory should perform cardiac marker testing with a turnaround time of
one hour, optimally 30 minutes, or less. The turnaround time is defined as the time
from blood collection to the reporting of results. (Level of Evidence: B)
The specimen of choice for analysis of biochemical markers of cardiac injury is
plasma or anticoagulated whole blood to facilitate a more rapid turnaround time
for testing. (Level of Evidence: C)

Class IIa
12
Institutions that cannot consistently deliver cardiac marker turnaround times of
approximately one hour should implement point-of-care testing devices. (Level of
Evidence: B)
Class I
13
Members of emergency departments, divisions of cardiology, primary care
physicians, hospital administrations, and clinical laboratories should work
collectively to develop an accelerated protocol for the use of biochemical markers
in the evaluation of patients with possible ACS. (Level of Evidence: C)
From the National Academy of Clinical Biochemistry (NACB) guideline documents.2,3,4 See Table 1
for interpretation of recommendation class and level of scientific data supporting each NACB
guideline statement.
ECG = electrocardiogram; CV = cardiovascular; CK-MB = creatine kinase muscle and brain;
ACS = acute coronary syndromes.

must be utilized, the guidelines state that the maximal concentration must
exceed the 99th percentile of values for a sex-specific reference control group
on two successive samples (see Recommendation 9, Table 2).
What Is the Need for Speed?
The consensus among cardiology and emergency medicine (EM) physicians is
that cardiac markers should be available within one hour of specimen
collection, and optimally within 30 minutes or less (see Recommendation 10,
Table 2). To meet this stringent requirement, several measures are necessary.
First, the specimen for analysis should be either anticoagulated whole blood,
so that centrifugation and handling is not necessary, or plasma, to avoid a delay
due to the clotting process (see Recommendation 11, Table 3). Second,
institutions that cannot consistently deliver cardiac marker turnaround times of
approximately one hour should implement point-of-care testing devices (see
Recommendation 12, Table 2). Although it should go without saying, the
guidelines remind us that members of EM, cardiology, primary care, hospital
administrations, and laboratory medicine should work to develop an
accelerated protocol for the use of biochemical markers in the evaluation of
patients with possible ACS (see Table 2).
Summary and Path Forward
cTn measurements are an essential part of the MI evaluation and should be
measured in all patients with signs and symptoms of ACS. Sampling is
necessary at presentation and at six to nine hours, and in some cases again at
1224 hours. The troponin cut-off that should be used is the 99th percentile
of a reference control population. cTn results should be available within one
hour after specimen collection, and optimally in 30 minutes or less. Use of
anticoagulated whole blood or plasma facilitates shorter turnaround times,
and point-of-care testing is an attractive alternative when turnaround
times are suboptimal.

Apple FS, Jesse RL, Newby LK, et al., Clin Chem, 2007;53:54751.
Storrow AB, Apple FS, Wu AHB, et al., National Academy of Clinical
Biochemistry laboratory medicine practice guidelines for point of care

5.

testing, oversight and administration of cardiac biomarkers for acute

coronary syndromes, Acad Emer Med, in press.
Christenson RH, Clin Chem, 2007;53:5456.

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