CLINICIAN UPDATE
How to Interpret Elevated Cardiac Troponin Levels
Vinay S. Mahajan, MD, PhD; Petr Jarolim, MD, PhD
C ardiac troponin (cTn) testing is an
essential component of the diag-
nostic workup and management of
acute coronary syndromes (ACS). Al-
though over the past 15 years the
diagnostic performance of the previous
gold-standard assay, creatine kinase-
MB, has not changed appreciably, the
ever-increasing sensitivity of cTn as-
says has had a dramatic impact on the
use of cTn testing to diagnose ACS.1
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Here, we present 3 recent clinical cases
from the emergency department with
acute chest discomfort that exemplify
the challenges introduced by high-
sensitivity cTn assays: a 48-year-old
man who presented to the emergency
department with chest discomfort last-
ing 2 hours and a 3-day history of
flu-like symptoms whose ECG showed
diffuse ST-segment changes, a 60-
year-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 non-
diagnostic, 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 (TnI-
Ultra assay on the ADVIA Centaur XP
immunoanalyzer, both Siemens Health-
care Diagnostics) was ordered on all 3
patients. The laboratory results were re-
From the Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.
Correspondence to Petr Jarolim, MD, PhD, Brigham and Women’s 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
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 non–ST-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, al-
though 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 Women’s Hospital
Clinical Laboratories in early 2007 re-
sulted in a doubling of positive cTn
results in samples collected in the emer-
gency 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 tech-
nologies and the international adoption
DOI: 10.1161/CIRCULATIONAHA.111.023697
2350
of traceable troponin calibration stan-
dards 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 (Elec-
sys TnT-hs, Roche Diagnostics; ap-
proved 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. Be-
tween 1995 and 2007, the limit of
detection fell from 0.5 ng/mL for some
cTn assays to 0.006 ng/mL for TnI-
Ultra, an ⬇100-fold improvement in
analytic sensitivity (Figure 1).
Remarkably, the use of contempo-
rary 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-
 Mahajan and Jarolim Interpretation of Elevated Troponin Levels 2351
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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 con-
centration of cTn exceeding the 99th
percentile of values (with optimal pre-
cision 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 inter-
vention (Figure 2). However, while
improving clinical sensitivity for the
diagnosis of myocardial infarction, the
 2352 Circulation November 22, 2011

practice litigation forces many clini-

cians to order comprehensive panels of
laboratory tests, including cTn, for pa-
tients with a very low pretest probabil-
ity of ACS, which adversely affects the
positive predictive value of cTn assays
for diagnosing myocardial infarction.
Traditional wisdom, before the ad-
vent 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, circu-
lating 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 pulmo-
nary embolism, and even after strenu-
ous exercise in healthy individuals.8
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The Need for Serial

Troponin Testing
In addition to the absolute level of cTn
in plasma or serum above the decision
limit, a critical component of the diag-
nosis of ACS is cTn kinetics. This was
Figure 2. Cardiac troponin I (cTnI) levels in a healthy reference population and in an reiterated in the current universal def-
acute coronary syndrome (ACS) population. Top, Frequency histograms of real TnI lev- inition of myocardial infarction ad-
els (blue filled) in healthy reference controls are shown, along with the distribution of the opted in 2007.5 Although absolute cTn
same TnI levels as measured with a less precise cTnI (green) and the more precise TnI-
Ultra (blue) assay for comparison. In practice, the values below the assay detection
elevations are seen in multiple chronic
threshold (dashed portions of the histogram plots) cannot be distinguished from one cardiac and noncardiac conditions, a
another. Note how the 99th percentile decision limits decrease with increased assay rise or fall in serial cTn levels strongly
precision. Bottom, Hypothetical frequency histograms of cTnI concentrations in individ- supports an acutely evolving cardiac
uals 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 injury such as, most commonly, acute
on the 99th percentile in a healthy reference population. Note the impact of decreased myocardial infarction.
diagnostic cutoffs of the newer cTnI assays on the fraction of acute myocardial infarc- Serial cTn testing helped establish
tions diagnosed at earlier time intervals. (All frequency histograms in this figure are
hypothetical and for illustrative purposes only.) final diagnoses in our 3 patients. Pa-
tient 1 (Figure 3, top) had a steady but
increased analytic sensitivity has come is useful only when applied to patients relatively slow increase in cTnI with a
at the cost of reduced specificity, thus with a high pretest probability of ACS. peak value of 0.9 ng/mL. The findings
presenting an additional diagnostic The clinician must interpret cTn re- of acute dilated cardiomyopathy and
challenge for clinicians. sults in the context of clinical history, global ventricular dysfunction on
ECG findings, and possibly cardiac echocardiography were consistent with
The Specificity of a Troponin imaging to establish the correct diag- a diagnosis of acute myocarditis.
Test for ACS nosis. A positive troponin in the setting Patient 2 (Figure 3, middle) had
The use of the 99th percentile cutoff of a low pretest probability for ACS modest cTn elevations fluctuating just
for cTn positivity does not imply that may be suggestive but clearly is not above the decision limit in the 0.05 to
1% of the population suffers from indicative of a coronary event. Unfor- 0.09 ng/mL range. She was diagnosed
myocardial damage. Rather, this cutoff tunately, the pressure to avoid mal- with acutely decompensated heart fail-
 Mahajan and Jarolim Interpretation of Elevated Troponin Levels 2353

Table. Causes of Elevated Plasma Cardiac Troponin Other Than Acute ure. Additional TnI testing did not
Coronary Syndromes provide evidence of ACS.
Cardiac Causes Noncardiac Causes TnI levels in patient 3 (Figure 3,
bottom) rose to a peak of 53 ng/mL
Cardiac contusion resulting from trauma Pulmonary embolism
within 24 hours. He was diagnosed
Cardiac surgery Severe pulmonary hypertension
with non–ST-segment– elevation myo-
Cardioversion Renal failure cardial infarction when the second cTn
Endomyocardial biopsy Stroke, subarachnoid hemorrhage result of 6.3 ng/mL was obtained after
Acute and chronic heart failure Infiltrative diseases, eg, amyloidosis 6 hours. The rapid, steep increase from
Aortic dissection Cardiotoxic drugs the initial barely positive value of 0.06
Aortic valve disease Critical illness ng/mL to the 6-hour value of 6.3
Hypertrophic cardiomyopathy Sepsis ng/mL illustrates that more frequent
Tachyarrhythmia Extensive burns
testing during the first several hours
may be sufficient to detect a diagnostic
Bradyarrhythmia, heart block Extreme exertion
rise in cTn levels that is eventually
Apical ballooning syndrome
destined to increase by a few orders of
Post–percutaneous coronary intervention magnitude such as the peak of 53
Rhabdomyolysis with myocyte necrosis ng/mL in this patient.
Myocarditis or endocarditis/pericarditis Fortunately, simultaneous improve-
Adapted from Jaffe et al7 with permission of the publisher. Copyright © 2006, Elsevier. ments in contemporary assay sensitiv-
ity and precision allow 2 cTn values
with a difference as small as a few
hundredths of 1 ng/mL to be distin-
guished reliably. This has significant
implications for serial cTn testing.
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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 tro-
ponin measurement, but today’s high-
sensitivity 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 appropri-
ate emergency intervention, as well as
the ease of performing this relatively
inexpensive assay, clinicians do not
need to wait 6 to 8 hours before order-
ing a second troponin test to rule in
ACS. We recommend collecting a sec-
ond 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
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 it’s
becoming a great assay, it’s getting to
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 be a lousy test.”9 However, frequent
dashed horizontal line. See the text for detailed description. monitoring of cTn kinetics, along with
 2354 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 belong—among
the greatest, most useful assays in
clinical chemistry laboratories.
Disclosures
Dr Jarolim has research grants from Roche
Diagnostics, Siemens Healthcare Diagnos-
tics, Ortho Clinical Diagnostics, Beckman
Coulter, Inc, and Amgen, as well as hono-
raria from Ortho Clinical Diagnostics and
Roche Diagnostics. Dr Mahajan reports no
conflicts.
References
1. Melanson SEF, Morrow DA, Jarolim P.
Earlier detection of myocardial injury in a
preliminary evaluation using a new troponin I
assay with improved sensitivity. Am J Clin
Pathol. 2007;128:282–286.
2. Melanson SEF, Conrad MJ, Mosammaparast
N, Jarolim P. Implementation of a highly sen-
Downloaded from http://ahajournals.org by on March 6, 2023
sitive cardiac troponin I assay: test volumes,
positivity rates and interpretation of results.
Clin Chim Acta. 2008;395:57– 61.
3. Saenger AK, Beyrau R, Braun S, Cooray R,
Dolci A, Freidank H, Giannitsis E, Gustafson
S, Handy B, Katus H, Melanson SE,
Panteghini M, Venge P, Zorn M, Jarolim P,
Bruton D, Jarausch J, Jaffe AS. Multicenter
analytical evaluation of a high-sensitivity
troponin T assay. Clin Chim Acta. 2011;412:
748 –754.
4. Apple FS. A new season for cardiac troponin
assays: it’s time to keep a scorecard. Clin
Chem. 2009;55:1303–1306.
5. Thygesen K, Alpert JS, White HD, Jaffe AS,
Apple FS, Galvani M, Katus HA, Newby LK,
Ravkilde J, Chaitman B, Clemmensen PM,
Dellborg M, Hod H, Porela P, Underwood R,
Bax JJ, Beller GA, Bonow R, Van der Wall
EE, Bassand JP, Wijns W, Ferguson TB, Steg
PG, Uretsky BF, Williams DO, Armstrong
PW, Antman EM, Fox KA, Hamm CW,
Ohman EM, Simoons ML, Poole-Wilson PA,
Gurfinkel EP, Lopez-Sendon JL, Pais P,
Mendis S, Zhu JR, Wallentin LC, Fernández-
Avilés F, Fox KM, Parkhomenko AN, Priori
SG, Tendera M, Voipio-Pulkki LM, Vahanian
A, Camm AJ, De Caterina R, Dean V,
Dickstein K, Filippatos G, Funck-Brentano C,
Hellemans I, Kristensen SD, McGregor K,
Sechtem U, Silber S, Tendera M, Widimsky
P, Zamorano JL, Morais J, Brener S, Har-
rington R, Morrow D, Lim M, Martinez-Rios
MA, Steinhubl S, Levine GN, Gibler WB,
Goff D, Tubaro M, Dudek D, Al-Attar N.
Universal definition of myocardial infarction.
Circulation. 2007;116:2634 –2653.
6. Apple FS, Parvin CA, Buechler KF, Chris-
tenson RH, Wu AHB, Jaffe AS. Validation of
the 99th percentile cutoff independent of
assay imprecision (CV) for cardiac troponin
monitoring for ruling out myocardial
infarction. Clin Chem. 2005;51:2198 –2200.
7. Jaffe AS, Babuin L, Apple FS. Biomarkers in
acute cardiac disease: the present and the
future. J Am Coll Cardiol. 2006;48:1–11.
8. Mingels AMA, Jacobs LHJ, Kleijnen VW,
Laufer EM, Winkens B, Hofstra L, Wodzig
WK, van Dieijen-Visser MP. Cardiac troponin
T elevations, using highly sensitive assay, in
recreational running depend on running
distance. Clin Res Cardiol. 2010;99:385–391.
9. Jesse RL. On the relative value of an assay
versus that of a test: a history of troponin for
the diagnosis of myocardial infarction. J Am
Coll Cardiol. 2010;55:2125–2128.