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CLINICIAN UPDATE

How to Interpret Elevated Cardiac Troponin Levels


Vinay S. Mahajan, MD, PhD; Petr Jarolim, MD, PhD

ardiac troponin (cTn) testing is an


essential component of the diagnostic workup and management of
acute coronary syndromes (ACS). Although over the past 15 years the
diagnostic performance of the previous
gold-standard assay, creatine kinaseMB, has not changed appreciably, the
ever-increasing sensitivity of cTn assays has had a dramatic impact on the
use of cTn testing to diagnose ACS.1
Here, we present 3 recent clinical cases
from the emergency department with
acute chest discomfort that exemplify
the challenges introduced by highsensitivity cTn assays: a 48-year-old
man who presented to the emergency
department with chest discomfort lasting 2 hours and a 3-day history of
flu-like symptoms whose ECG showed
diffuse ST-segment changes, a 60year-old woman with a medical history
of heart failure who presented to the
emergency department with chest pain
lasting 1.5 hours whose ECG was nondiagnostic, and a 54-year-old man with
a medical history of diabetes mellitus
who presented with chest discomfort
lasting 1 hour whose ECG was normal.
Cardiac troponin I (cTnI) testing (TnIUltra assay on the ADVIA Centaur XP
immunoanalyzer, both Siemens Healthcare Diagnostics) was ordered on all 3
patients. The laboratory results were re-

ported as positive in all 3 cases, with the


reported values being 0.05, 0.06, and
0.06 ng/mL, respectively, all just above
the diagnostic limit of 0.04 ng/mL.
Assays for cTn, namely cTnI and
cardiac troponin T (cTnT), are the
preferred diagnostic tests for ACS, in
particular nonST-segment elevation
myocardial infarction, because of the
tissue-specific expression of cTnI and
cTnT in the myocardium. The results of
cTn testing often guide the decision for
coronary intervention. However, although the increasing sensitivity of cTn
assays lowers the number of potentially
missed ACS diagnoses, it presents a
diagnostic challenge because the gains in
diagnostic sensitivity have inevitably
come with a decrease in specificity. For
instance, the replacement of the cTn
assay (Siemens Healthcare Diagnostics)
by the more sensitive TnI-UItra assay in
the Brigham and Womens Hospital
Clinical Laboratories in early 2007 resulted in a doubling of positive cTn
results in samples collected in the emergency department2 even though there
was no change in the frequency of final
diagnoses of ACS.

What Is a High-Sensitivity
Troponin Test?
Rapid advances in immunoassay technologies and the international adoption

of traceable troponin calibration standards have allowed manufacturers to


develop and calibrate troponin assays
with unprecedented analytic sensitivity
and precision. Thus, a contemporary
cTnI assay such as TnI-Ultra detects
plasma cTn levels as low as 0.006
ng/mL with an assay range that spans 4
orders of magnitude (0.006 50 ng/
mL). Similarly, the limit of detection
of a contemporary cTnT assay (Elecsys TnT-hs, Roche Diagnostics; approved for clinical use in Europe but
not yet in the United States) is as low
as 0.005 ng/mL.3 Although cTnI and
cTnT concentrations correlate to some
extent, the numeric values can be quite
different in a given patient, with cTnT
readings generally being lower. Between 1995 and 2007, the limit of
detection fell from 0.5 ng/mL for some
cTn assays to 0.006 ng/mL for TnIUltra, an 100-fold improvement in
analytic sensitivity (Figure 1).
Remarkably, the use of contemporary high-sensitivity cTn assays makes
it possible to detect low levels of cTn
even in plasma from healthy subjects.
Indeed, high-sensitivity cTn assays are
designated as such on the basis of their
ability to detect cTns even in healthy
individuals. The latest generation of
high-sensitivity cTn assays can detect
cTn in 95% of a reference popula-

From the Brigham and Womens Hospital, Harvard Medical School, Boston, MA.
Correspondence to Petr Jarolim, MD, PhD, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. E-mail pjarolim@partners.org
(Circulation. 2011;124:2350-2354.)
2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.111.023697

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Mahajan and Jarolim

Interpretation of Elevated Troponin Levels

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Figure 1. Evolution of the cardiac troponin (cTn) assays and their diagnostic cutoffs. A hypothetical case of acute coronary syndrome is
depicted with the earliest times of potential diagnosis corresponding to the diagnostic cutoffs of more sensitive cTn assays. The years
correspond to the availability of the respective assays in the US market.

tion.4 The ability to detect cTns in


healthy individuals made it imperative
to define a clinical decision limit for
cTn concentration, ie, a positive cTn
result.

What Is a Positive Troponin


Result? The 99th
Percentile Rule
The National Academy of Clinical
Biochemistry issued a guideline in

2007 that stated that in the presence


of a clinical history suggestive of ACS,
the following is considered indicative
of myocardial necrosis consistent with
myocardial infarction: maximal concentration of cTn exceeding the 99th
percentile of values (with optimal precision defined by total c.v. [coefficient
of variation] 10%) for a reference
control group on at least one occasion
during the first 24 hours after the
clinical event.5 This guideline pro-

vides the framework for determining


the decision limit or a positive
troponin result.
Based on the 99th percentile rule,
troponin decision limits of several
high-sensitivity cTn assays can be set
as low as 0.01 ng/mL.6 This makes it
possible to identify patients with ACS
earlier, enabling earlier coronary intervention (Figure 2). However, while
improving clinical sensitivity for the
diagnosis of myocardial infarction, the

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Circulation

November 22, 2011

practice litigation forces many clinicians to order comprehensive panels of


laboratory tests, including cTn, for patients with a very low pretest probability of ACS, which adversely affects the
positive predictive value of cTn assays
for diagnosing myocardial infarction.
Traditional wisdom, before the advent of high-sensitivity cTn assays,
held that troponins do not appear in the
circulation of individuals with a
healthy myocardium. These levels
used to be considered indicative of
myocardial necrosis. However, with
high-sensitivity troponin assays, circulating cTnT or cTnI can be found in
the plasma as a result of transient
ischemic or inflammatory myocardial
injury. Thus, elevated cTn may be
detected in conditions other than ACS
(the Table), including heart failure,
cardiomyopathies, myocarditis, renal
failure, tachyarrhythmias, and pulmonary embolism, and even after strenuous exercise in healthy individuals.8

The Need for Serial


Troponin Testing

Figure 2. Cardiac troponin I (cTnI) levels in a healthy reference population and in an


acute coronary syndrome (ACS) population. Top, Frequency histograms of real TnI levels (blue filled) in healthy reference controls are shown, along with the distribution of the
same TnI levels as measured with a less precise cTnI (green) and the more precise TnIUltra (blue) assay for comparison. In practice, the values below the assay detection
threshold (dashed portions of the histogram plots) cannot be distinguished from one
another. Note how the 99th percentile decision limits decrease with increased assay
precision. Bottom, Hypothetical frequency histograms of cTnI concentrations in individuals with ACS 2, 2 to 3, or 3 to 4 hours after the onset of symptoms. The decision
limits (dashed vertical lines) for the contemporary high-sensitivity cTnI assays are based
on the 99th percentile in a healthy reference population. Note the impact of decreased
diagnostic cutoffs of the newer cTnI assays on the fraction of acute myocardial infarctions diagnosed at earlier time intervals. (All frequency histograms in this figure are
hypothetical and for illustrative purposes only.)

increased analytic sensitivity has come


at the cost of reduced specificity, thus
presenting an additional diagnostic
challenge for clinicians.

The Specificity of a Troponin


Test for ACS
The use of the 99th percentile cutoff
for cTn positivity does not imply that
1% of the population suffers from
myocardial damage. Rather, this cutoff

is useful only when applied to patients


with a high pretest probability of ACS.
The clinician must interpret cTn results in the context of clinical history,
ECG findings, and possibly cardiac
imaging to establish the correct diagnosis. A positive troponin in the setting
of a low pretest probability for ACS
may be suggestive but clearly is not
indicative of a coronary event. Unfortunately, the pressure to avoid mal-

In addition to the absolute level of cTn


in plasma or serum above the decision
limit, a critical component of the diagnosis of ACS is cTn kinetics. This was
reiterated in the current universal definition of myocardial infarction adopted in 2007.5 Although absolute cTn
elevations are seen in multiple chronic
cardiac and noncardiac conditions, a
rise or fall in serial cTn levels strongly
supports an acutely evolving cardiac
injury such as, most commonly, acute
myocardial infarction.
Serial cTn testing helped establish
final diagnoses in our 3 patients. Patient 1 (Figure 3, top) had a steady but
relatively slow increase in cTnI with a
peak value of 0.9 ng/mL. The findings
of acute dilated cardiomyopathy and
global ventricular dysfunction on
echocardiography were consistent with
a diagnosis of acute myocarditis.
Patient 2 (Figure 3, middle) had
modest cTn elevations fluctuating just
above the decision limit in the 0.05 to
0.09 ng/mL range. She was diagnosed
with acutely decompensated heart fail-

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Mahajan and Jarolim

Interpretation of Elevated Troponin Levels

Table. Causes of Elevated Plasma Cardiac Troponin Other Than Acute


Coronary Syndromes
Cardiac Causes

Noncardiac Causes

Cardiac contusion resulting from trauma


Cardiac surgery

Pulmonary embolism
Severe pulmonary hypertension

Cardioversion

Renal failure

Endomyocardial biopsy

Stroke, subarachnoid hemorrhage

Acute and chronic heart failure

Infiltrative diseases, eg, amyloidosis

Aortic dissection

Cardiotoxic drugs

Aortic valve disease

Critical illness

Hypertrophic cardiomyopathy

Sepsis

Tachyarrhythmia

Extensive burns

Bradyarrhythmia, heart block

Extreme exertion

Apical ballooning syndrome


Postpercutaneous coronary intervention
Rhabdomyolysis with myocyte necrosis
Myocarditis or endocarditis/pericarditis
Adapted from Jaffe et al7 with permission of the publisher. Copyright 2006, Elsevier.

2353

ure. Additional TnI testing did not


provide evidence of ACS.
TnI levels in patient 3 (Figure 3,
bottom) rose to a peak of 53 ng/mL
within 24 hours. He was diagnosed
with nonST-segment elevation myocardial infarction when the second cTn
result of 6.3 ng/mL was obtained after
6 hours. The rapid, steep increase from
the initial barely positive value of 0.06
ng/mL to the 6-hour value of 6.3
ng/mL illustrates that more frequent
testing during the first several hours
may be sufficient to detect a diagnostic
rise in cTn levels that is eventually
destined to increase by a few orders of
magnitude such as the peak of 53
ng/mL in this patient.
Fortunately, simultaneous improvements in contemporary assay sensitivity and precision allow 2 cTn values
with a difference as small as a few
hundredths of 1 ng/mL to be distinguished reliably. This has significant
implications for serial cTn testing.
Previously, clinicians often had to
wait an average of 6 hours with the
lower-sensitivity, lower-precision cTn
assays to see a conclusive increase in
plasma cTn levels after the first troponin measurement, but todays highsensitivity cTn tests that are separated
by a mere 2 to 3 hours can be highly
informative. Given the urgent need for
early diagnosis of ACS and appropriate emergency intervention, as well as
the ease of performing this relatively
inexpensive assay, clinicians do not
need to wait 6 to 8 hours before ordering a second troponin test to rule in
ACS. We recommend collecting a second specimen for cTn testing within 2
to 3 hours from the collection of the
blood sample at presentation to help
confirm the diagnosis of MI.

Conclusions

Figure 3. Troponin kinetics in the index cases. Plasma cardiac troponin I (cTnI) values
in the 3 index cases. The cutoff for the TnI assay (0.04 ng/mL) is indicated with a
dashed horizontal line. See the text for detailed description.

Commenting on the ever-increasing


sensitivity and decreasing specificity
of cTn assays, Robert Jesse quipped,
When troponin was a lousy assay it
was a great test, but now that its
becoming a great assay, its getting to
be a lousy test.9 However, frequent
monitoring of cTn kinetics, along with

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Circulation

November 22, 2011

careful attention to the noncoronary


causes of cTn elevations, will keep the
high-sensitivity cTn assays in the class
where they rightfully belongamong
the greatest, most useful assays in
clinical chemistry laboratories.

Disclosures
Dr Jarolim has research grants from Roche
Diagnostics, Siemens Healthcare Diagnostics, Ortho Clinical Diagnostics, Beckman
Coulter, Inc, and Amgen, as well as honoraria from Ortho Clinical Diagnostics and
Roche Diagnostics. Dr Mahajan reports no
conflicts.

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