GRAND ROUNDS

CLINICIANS CORNER

AT THE UNIVERSITY OF TEXAS

SOUTHWESTERN MEDICAL CENTER

Increasingly Sensitive Assays

for Cardiac Troponins
A Review
James A. de Lemos, MD
CASE PRESENTATION
A 62-year-old man presented to the
emergency department following a
3-hour plane flight from Guatemala
with symptoms of intermittent chest
discomfort and shortness of breath.
He described pressure in his chest and
shoulders that was not worsened by
exertion and had no obvious precipitating cause. The patient had a history
of diabetes, hypertension, stage 2
chronic kidney disease (CKD), gastroesophageal reflux disease, chronic
heart failure with a left ventricular
ejection fraction of 30%, and paroxysmal atrial flutter. The results of coronary angiography, performed 3 years
previously at an outside hospital,
were reported by the patient to have
been normal.
On examination, his heart rate was
60 beats/min; his blood pressure was
118/70 mm Hg. Pulses were equal in
all extremities and no edema, ascites,
or jugular venous distension was
noted. His 12-lead electrocardiogram
(ECG) showed sinus rhythm with low
limb-lead voltages and nonspecific
ST-segment and T-wave abnormalities
and was unchanged from his previous
ECG. His cardiac troponin T (cTnT)
level at presentation was 20 ng/L
CME available online at
www.jamanetworkcme.com
and questions on p 2276.
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JAMA, June 5, 2013Vol 309, No. 21

Cardiac troponins are the preferred biomarkers for diagnosis of myocardial

infarction because of their high sensitivity and specificity for myocardial injury. However, acute and chronic conditions distinct from acute coronary syndromes (ACS) commonly lead to small elevations in troponin levels, with
few data available regarding management of care for patients with such conditions. Recently developed highly sensitive troponin assays will likely lead
to a substantial increase in the proportion of detectable troponin levels attributable to non-ACS conditions. Novel algorithms with highly sensitive assays, incorporating baseline troponin values and changes in values over 1
to 2 hours, may allow rapid exclusion of myocardial infarction and help to
address specificity concerns but must be validated in appropriate target populations. Enhanced detection of very low troponin levels with highly sensitive assays has made feasible several potential new indications for troponin
testing, including in the ambulatory setting, where assessment for lowlevel chronic myocardial injury may enhance risk stratification for heart failure and cardiac death.
www.jama.com

JAMA. 2013;309(21):2262-2269

(upper limit of normal, 10 ng/L);

during an admission 6 months
previously, his cTnT level was
less than 10 ng/L.
The patient was admitted with a diagnosis of nonST-segment elevation
myocardial infarction (MI). His warfarin was temporarily discontinued, and
he received aspirin, clopidogrel, enoxaparin, simvastatin, lisinopril, and
carvedilol. Cardiac catheterization was
deferred because of an elevated international normalized ratio, but when serial measurements of cTnT levels demonstrated unchanged levels of 20 ng/L
over the subsequent 2 days, noninvasive risk stratification was pursued. A
vasodilator perfusion scan revealed

a left ventricular ejection fraction

of 32% and mild, fixed inferior
and inferolateral perfusion defects described as patchy and more consistent with nonischemic cardiomyopathy than prior infarction.
This case highlights challenges in interpreting small elevations of troponin levels in patients with clinical
presentations that are not specific for
Author Affiliation: Division of Cardiology, Department of Medicine, University of Texas Southwestern
Medical Center, Dallas.
Corresponding Author: James A. de Lemos, MD, University of Texas Southwestern Medical Center, 5323
Harry Hines Blvd, Dallas, TX 75390-8830 (james
.delemos@utsouthwestern.edu).
Grand Rounds Section Editor: Mary McGrae
McDermott, MD, Contributing Editor, JAMA.

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INCREASINGLY SENSITIVE ASSAYS FOR CARDIAC TROPONINS

acute coronary syndromes (ACS). This

patient had multiple potential nonACS etiologies for his elevated troponin levels. Application of ACS treatment guidelines 1,2 to patients with
elevated troponin levels not attributable to ACS may expose such patients
to unnecessary testing and risk.
Current Status of Troponin
Measurement to Rule Out MI

Evaluation for chest pain accounts for

more than 5 million emergency
department visits each year in the
United States.3 Troponins T and I are
currently the preferred biochemical
markers of myocardial necrosis in
patients with suspected ACS, because
of these markers high sensitivity and
almost complete cardiac specificity.4
The regulatory troponin complex is
composed of 3 protein subunits, troponins T, I, and C. Troponins T and I
have unique cardiac isoforms,
whereas cardiac and skeletal muscle
share troponin C isoforms, rendering
this protein unsuitable for diagnostic
use. Cardiac troponins are complexed
with actin in cardiac myofibrils, with
a smaller fraction (3%-6%) soluble in
the cytoplasm.5 Ischemia is thought to
alter cell membrane integrity, causing
rapid depletion of the soluble cytoplasmic pool, followed by larger and
more sustained release of troponin
into the circulation as the contractile
apparatus breaks down (FIGURE 1).6
Cardiac troponins T and I provide
largely identical information, and selection between them is typically influenced by equipment and vendor selection in the central laboratory. The
cTnT assay is produced by a single
manufacturer. However, multiple
manufacturers make cardiac troponin
I (cTnI) assays and each manufacturer
uses different antibody pairs, so assays are not interchangeable. Medicare reimbursement for measurement
of troponin levels is approximately $13
to $18.
It is important to recognize that troponin is a laboratory measure of myocardial necrosis, whereas MI is a clinical diagnosis. The Universal Definition

of MI, a consensus document representing multiple international cardiology societies, requires an elevated troponin level combined with symptoms
or signs of ischemia for the diagnosis
of MI (BOX 1).4 In addition to requiring at least 1 troponin value above the
MI diagnostic threshold, an increase or
decrease in troponin levels over serial
measurement is necessary to meet the
MI definition. The decision limit for MI
is set by consensus at the 99th percentile value of a healthy normal population and varies with each troponin
assay.
The universal definition recognizes
the distinction between classic (type
1) MI, caused by ACS with atherosclerotic plaque rupture or erosion and

coronary thrombus, and secondary

(type 2) MI, in which a condition
other than coronary artery disease
(CAD) contributes to increased myocardial oxygen demand or decreased
oxygen supply, resulting in myocardial necrosis. Plaque disruption is not
the cause of type 2 MI, but underlying
CAD may be present. Myocardial
infarction in the setting of atrial
arrhythmia, hypertensive emergency,
and critical medical or surgical illness
may represent type 2 MI.
With conventional clinical assays, serial measurements of troponin levels are
needed to exclude MI, because a single
measurement has only approximately
70% to 85% sensitivity.7,8 Although the
period of monitoring is typically 6 to

Figure 1. Release of Cardiac Troponins Following Ischemic Cardiac Injury

A Structure of cardiac troponins

Myofibrillar troponins
Myosin

Cardiomyocytes

TnC
cTnT

cTnI

Actin

Tropomyosin

Cytosolic troponins
cTnI
cTnT

B Ischemia-induced cardiomyocyte damage

Ischemic cardiomyocytes

Release of
cardiac troponins into
the bloodstream

BLOOD
VESSEL

TnC indicates troponin C; cTnI, cardiac troponin I; cTnT, cardiac troponin T.

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JAMA, June 5, 2013Vol 309, No. 21 2263

INCREASINGLY SENSITIVE ASSAYS FOR CARDIAC TROPONINS

Box 1. Third Universal

Definition of Myocardial
Infarction a
Detection of increase, decrease, or
both of levels of cardiac biomarkers
(preferably cardiac troponin) with at
least 1 value above the 99th percentile of the upper reference limit and
with at least 1 of the following:
Symptoms of ischemia
New significant ST-segment and
T-wave changes or new left bundlebranch block
Development of pathological
Q waves
Cardiac imaging findings consistent with ischemia or infarction
(ie, new wall motion abnormality)
Identification of an intracoronary
thrombus by angiography
aAdapted

from Thygesen et al.4

9 hours, shorter intervals are appropriate among individuals with a low probability of MI who are also at low risk
for death or ischemic complications. An
innovative approach proposed by Than
et al9 incorporated assessment of pretest probability for MI and risk for complications using the Thrombolysis in
Myocardial Infarction (TIMI) risk score,
together with ECG findings and serial
measurement of cTnI levels at 0 and 2
hours. Among 1975 patients presenting with suspected ACS, 20% were classified as at low risk, defined prospectively as a TIMI risk score of 0, the
absence of ischemic ECG changes, and
cTnI level below the MI detection
threshold at both time points. The negative predictive value (NPV) was greater
than 99% in the low-risk group, suggesting that this expedited algorithm,
or a similar one, may allow rapid discharge of low-risk individuals without additional testing.
Risk Stratification and Therapeutic
Decision Making in Suspected ACS

In patients with suspected ACS, even

minimally elevated troponin levels iden2264

JAMA, June 5, 2013Vol 309, No. 21

tify patients at increased risk for death

and recurrent ischemic events.10 Patients with suspected ACS and elevated troponin levels have more severe and complex CAD, with a larger
thrombus burden and greater microvascular injury than similar patients
with normal troponin levels.11,12 These
pathophysiological observations also
have implications for therapeutic decision making, because clinical trials
have generally demonstrated significant benefit from intensive antiplatelet and antithrombotic regimens, as well
as percutaneous coronary interventions, in patients with ACS and elevated troponin levels, with less favorable risk-benefit and cost-benefit ratios
for these therapies among patients with
normal troponin levels.13-17
The Specificity Problem

Although troponins are generally

specific for myocardial injury, they
are not specific for a particular
mechanism of myocardial injury.
Any conditionacute or chronic
that injures cardiomyocytes may lead
to measurable increases in levels of
circulating troponins. Acute conditions that can elevate troponin levels
include heart failure, sepsis, and pulmonary embolism, although multiple
other potential etiologies exist
(BOX 2).18,19 When sensitive assays are
used, elevated troponin levels are common after endurance athletics, such as
marathon running, but these elevations are transient and are not associated with cardiac abnormalities or
risk.20,21
Persistent low-level elevations in levels of cardiac troponins are commonly
seen in patients with chronic cardiac
conditions, including patients stabilized months after an ACS event and
those with chronic ambulatory heart
failure.22,23 Less frequently, elevated
cTnT or cTnI levels are seen among individuals from the general population, in whom chronic structural heart
disease, or major determinants of structural heart disease such as diabetes and
CKD, rather than coronary atherosclerosis, appear to explain most cases.24-26

Alcalai et al,27 adjudicating all elevated troponin levels measured in their

hospital over a 1-year period, determined that only about half of the elevated levels were attributable to ACS.
In older patients with CKD, the proportion of elevated levels attributable to ACS
decreased to 37%. Of note, among patients with elevated troponin levels,
2-year mortality was more than double
in the non-ACS group compared with the
ACS group.27 Thus, although clinicians
frequently trivialize elevated troponin
levels not attributable to ACS using terms
such as troponinemia or troponinosis, these elevations are of important
prognostic significance.
Approach to the Patient With
Non-ACS Elevated Troponin Levels
Not Attributable to ACS

Few data are available to guide evaluation and management when

elevated troponin levels are not
attributable to ACS. Because elevated
troponin levels (identified using
assays in current clinical use in the
United States) are uncommon in the
absence of underlying cardiovascular
or renal disease and are associated
with a poor prognosis, an attempt
should be made to explain the cause
of all elevated troponin levels. However, care must be taken to implement a prudent strategy that minimizes unnecessary treatment and
resource utilization. Evaluation
should include a detailed history,
physical examination, assessment of
renal function, and an ECG. Given
the strong association between
elevated troponin levels and cardiac
structural and functional abnormalities, echocardiography should be
considered for most unexplained
elevations in troponin levels. However, there is no evidence that performing echocardiography in all
patients with elevated levels
improves outcomes. Using the information gathered, elevated levels
should be classified as attributable to
type 1 or type 2 MI, to a non-ACS
acute condition, or to a non-ACS
chronic condition (FIGURE 2).19,28

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INCREASINGLY SENSITIVE ASSAYS FOR CARDIAC TROPONINS

17. Bavry AA, Kumbhani DJ, Quiroz R, Ramchandani
SR, Kenchaiah S, Antman EM. Invasive therapy along
with glycoprotein IIb/IIIa inhibitors and intracoronary stents improves survival in nonST-segment elevation acute coronary syndromes: a meta-analysis and
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(7):830-835.
18. Jeremias A, Gibson CM. Narrative review: alternative causes for elevated cardiac troponin levels when
acute coronary syndromes are excluded. Ann Intern
Med. 2005;142(9):786-791.
19. Newby LK, Jesse RL, Babb JD, et al. ACCF 2012
expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology
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20. Mingels A, Jacobs L, Michielsen E, Swaanenburg
J, Wodzig W, van Dieijen-Visser M. Reference population and marathon runner sera assessed by highly
sensitive cardiac troponin T and commercial cardiac
troponin T and I assays. Clin Chem. 2009;55(1):
101-108.
21. Baker P, Davies SL, Larkin J, et al. Changes to
the cardiac biomarkers of non-elite athletes completing the 2009 London Marathon [published online
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22. Eggers KM, Lagerqvist B, Oldgren J, Venge P,
Wallentin L, Lindahl B. Pathophysiologic mechanisms of persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary
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23. Sato Y, Yamada T, Taniguchi R, et al. Persistently increased serum concentrations of cardiac troponin T in patients with idiopathic dilated cardiomyopathy are predictive of adverse outcomes. Circulation.
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24. Wallace TW, Abdullah SM, Drazner MH, et al.
Prevalence and determinants of troponin T elevation
in the general population. Circulation. 2006;113
(16):1958-1965.
25. Eggers KM, Lind L, Ahlstro m H, et al. Prevalence
and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of
elderly subjects. Eur Heart J. 2008;29(18):22522258.
26. Leistner DM, Klotsche J, Pieper L, et al; DETECT
Study Group. Circulating troponin as measured by a
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A, Lotan C. Acute coronary syndrome vs nonspecific
troponin elevation: clinical predictors and survival
analysis. Arch Intern Med. 2007;167(3):276-281.
28. Korley FK, Jaffe AS. Preparing the United States
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29. Peacock WF IV, De Marco T, Fonarow GC, et al;
ADHERE Investigators. Cardiac troponin and out-

come in acute heart failure. N Engl J Med. 2008;

358(20):2117-2126.
30. Giannitsis E, Mu ller-Bardorff M, Kurowski V, et al.
Independent prognostic value of cardiac troponin T
in patients with confirmed pulmonary embolism.
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31. Ammann P, Maggiorini M, Bertel O, et al. Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes. J Am Coll
Cardiol. 2003;41(11):2004-2009.
32. Apple FS, Murakami MM, Pearce LA, Herzog CA.
Predictive value of cardiac troponin I and T for subsequent death in end-stage renal disease. Circulation.
2002;106(23):2941-2945.
33. Keller T, Zeller T, Ojeda F, et al. Serial changes in
highly sensitive troponin I assay and early diagnosis
of myocardial infarction. JAMA. 2011;306(24):
2684-2693.
34. Napoli AM, Arrighi JA, Siket MS, Gibbs FJ. Physician discretion is safe and may lower stress test utilization in emergency department chest pain unit
patients. Crit Pathw Cardiol. 2012;11(1):26-31.
35. Mahler SA, Hiestand BC, Goff DC Jr, Hoekstra
JW, Miller CD. Can the HEART score safely reduce
stress testing and cardiac imaging in patients at low
risk for major adverse cardiac events? Crit Pathw
Cardiol. 2011;10(3):128-133.
36. de Lemos JA, Morrow DA, deFilippi CR. Highly
sensitive troponin assays and the cardiology community: a love/hate relationship? Clin Chem. 2011;
57(6):826-829.
37. Januzzi JL Jr, Bamberg F, Lee H, et al. Highsensitivity troponin T concentrations in acute chest pain
patients evaluated with cardiac computed tomography.
Circulation. 2010;121(10):1227-1234.
38. deFilippi CR, de Lemos JA, Christenson RH, et al.
Association of serial measures of cardiac troponin T
using a sensitive assay with incident heart failure and
cardiovascular mortality in older adults. JAMA. 2010;
304(22):2494-2502.
39. Saunders JT, Nambi V, de Lemos JA, et al. Cardiac troponin T measured by a highly sensitive assay
predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study.
Circulation. 2011;123(13):1367-1376.
40. Apple FS, Ler R, Murakami MM. Determination
of 19 cardiac troponin I and T assay 99th percentile
values from a common presumably healthy population.
Clin Chem. 2012;58(11):1574-1581.
41. Morrow DA, Cannon CP, Jesse RL, et al; National Academy of Clinical Biochemistry. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: clinical characteristics and utilization
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Clin Chem. 2007;53(4):552-574.
42. Turer AT, Addo TA, Martin JL, et al. Myocardial
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43. Sabatine MS, Morrow DA, de Lemos JA, Jarolim
P, Braunwald E. Detection of acute changes in circu-

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lating troponin in the setting of transient stress

testinduced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart J. 2009;
30(2):162-169.
44. Reichlin T, Irfan A, Twerenbold R, et al. Utility of
absolute and relative changes in cardiac troponin concentrations in the early diagnosis of acute myocardial
infarction. Circulation. 2011;124(2):136-145.
45. Body R, Carley S, McDowell G, et al. Rapid exclusion of acute myocardial infarction in patients with
undetectable troponin using a high-sensitivity assay.
J Am Coll Cardiol. 2011;58(13):1332-1339.
46. Reichlin T, Schindler C, Drexler B, et al. Onehour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med. 2012;172(16):1211-1218.
47. Latini R, Masson S, Anand IS, et al; Val-HeFT
Investigators. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic
heart failure. Circulation. 2007;116(11):12421249.
48. Omland T, de Lemos JA, Sabatine MS, et al; Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery
disease. N Engl J Med. 2009;361(26):2538-2547.
49. Omland T, Pfeffer MA, Solomon SD, et al; PEACE
Investigators. Prognostic value of cardiac troponin I
measured with a highly sensitive assay in patients with
stable coronary artery disease. J Am Coll Cardiol. 2013;
61(12):1240-1249.
50. de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in
the general population. JAMA. 2010;304(22):
2503-2512.
51. Neeland IJ, Drazner MH, Berry JD, et al. Biomarkers of chronic cardiac injury and hemodynamic stress
identify a malignant phenotype of left ventricular hypertrophy in the general population. J Am Coll Cardiol.
2013;61(2):187-195.
52. Wang TJ, Wollert KC, Larson MG, et al. Prognostic utility of novel biomarkers of cardiovascular
stress: the Framingham Heart Study. Circulation. 2012;
126(13):1596-1604.
53. deFilippi CR, de Lemos JA, Tkaczuk AT, et al. Physical activity, change in biomarkers of myocardial
stress and injury, and subsequent heart failure risk in
older adults. J Am Coll Cardiol. 2012;60(24):25392547.
54. Rubin J, Matsushita K, Ballantyne CM, Hoogeveen
R, Coresh J, Selvin E. Chronic hyperglycemia and subclinical myocardial injury. J Am Coll Cardiol. 2012;
59(5):484-489.
55. Hlatky MA, Greenland P, Arnett DK, et al; American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and
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from the American Heart Association [published correction appears in Circulation. 2009;119(25):e606].
Circulation. 2009;119(17):2408-2416.

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INCREASINGLY SENSITIVE ASSAYS FOR CARDIAC TROPONINS

Figure 2. Proposed Algorithm for Classifying Elevated Troponin Levels

Cardiac injury present
Troponin level >99th percentile

Acute troponin elevation

Rise and/or fall in troponin
level over serial measurements

Ischemic mechanisim present?

Are the patient history, ECG,
or cardiac imaging consistent
with myocardial ischemia?

Yes

Clinical presentation consistent

with atherosclerotic plaque rupture

Precipitant other than

coronary artery disease
Anemia, tachyarrhythmia,
severe hypertension, etca

Type 1 MI

Type 2 MI

Follow treatment guidelines

for acute MI

Chronic troponin elevation

Troponin level elevated but no rise
and/or fall over serial measurements

No

Nonischemic acute
myocardial injury
Pulmonary embolism,
acute heart failure, etca

Possible structural heart

disease, chronic renal disease

Consider echocardiogram

Correct precipitant

Treat underlying disease

Consider aspirin and -blocker

treatment

Recognize elevated troponin

level as poor prognostic marker

This algorithm is based on available literature19,28 but has not been separately validated. ECG indicates electrocardiogram; MI, myocardial infarction.
a See Box 2 for more detail.

Table. Comparison of Test Performance Characteristics for Detection of Myocardial Infarction

Between Standard and High-Sensitivity Assays for Troponins T and I at the Time of Presentation a
cTnT a
Characteristic
AUC
99th Percentile
cut point, ng/L
10% CV threshold,
ng/L
Sensitivity, %

Fourth-Generation
0.90 (0.86-0.94)
10

cTnI b
Highly
Sensitive
0.96 (0.94-0.98)
14

Contemporary
Sensitive
0.92 (0.90-0.94)
32

Highly
Sensitive
0.96 (0.95-0.97)
30

35

13

32

5.2

83 (76-90)

95 (90-98)

79 (75-84)

82 (77-87)

Specificity, %
Positive predictive
value, %

93 (91-95)
72 (64-79)

80 (77-83)
50 (43-56)

95 (93-96)
81 (76-85)

92 (90-94)
75 (70-80)

Negative predictive
value, %

97 (95-98)

99 (97-100)

94 (92-95)

95 (93-96)

Abbreviations: AUC, area under the receiver operating characteristic curve; cTnI, cardiac troponin I; cTnT, cardiac troponin
T; CV, coefficient of variation.
a Data for the comparisons of the Roche fourth-generation cTnT assay vs Roche highly sensitive cTnT assay are abstracted from Reichlin et al.7
b Data for comparisons of the contemporary sensitive (Abbott Architect STAT cTnI) assay vs highly sensitive (Abbott Architect hs-cTnI) assay are abstracted from Keller et al.33

and anxiety for patients and clinicians, are likely to be greater with the
highly sensitive assays.
2266

JAMA, June 5, 2013Vol 309, No. 21

It is also important to consider the

resource implications of troponin levels that are measurable but below the

MI detection threshold. Based on recent population-based studies, 50% or

more of patients in a typical chest pain
observation unit would be expected to
have a low but detectable cTnT level
with the highly sensitive assay,38,39 with
similar or even higher proportions detectable with emerging highly sensitive cTnI assays.40 If such individuals
are routinely referred for cardiology
consultation, additional testing, or both,
the indirect costs and potential harms
from excess testing may be substantial.
Serial Troponin Measurements
to Improve Specificity

Although the Universal Definition of MI

requires dynamic changes in troponin
concentrations to meet the MI definition, it does not provide guidance regarding the magnitude of change required.4 Existing recommendations
from the National Academy of Clinical Biochemistry suggest that relative

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INCREASINGLY SENSITIVE ASSAYS FOR CARDIAC TROPONINS

changes 20% greater than baseline over

serial follow-up are sufficient to document rising troponin levels.41 The 20%
change value was selected empirically
as a value that would exceed analytical variation alone. However, with
highly sensitive assays, substantial relative increases in troponin levels are
common even among individuals without evidence of ischemia or infarction,42,43 and a large relative change in
troponin level may occur despite a very
small absolute increase.44 Such small absolute changes do not demonstrate
specificity for MI.
The APACE (Advantageous Predictors of Acute Coronary Syndrome Evaluation) investigators recently compared
absolute and relative changes over serial measurements at 1 and 2 hours with
highly sensitive troponin assays. Using
receiver operating characteristic curve
optimized cut points for changes over
2 hours, they reported a PPV of only 35%
for a relative change in cTnT level of 30%
or greater compared with a PPV of 64%
for an absolute change of 7 ng/L or
greater.44 This observation was supported by a study of a highly sensitive
cTnI assay in a similar population, which
identified a large relative change of 250%
or greater over 3 hours as the optimal
threshold, yielding a PPV of 65%.33 Exclusive focus on such large change values, however, would reduce sensitivity
for MI detection, because MIs can occur with much smaller changes in troponin levels. Thus, optimized thresholds for these assays may differ in the
emergency department, where sensitivity and high NPV are critical, compared with the inpatient floor, where
specificity and high PPV are needed to
guide decision making.28
Rapid MI Diagnostic Protocols
With Highly Sensitive Assays

One strategy to maximize advantages

of the lower detection range of the
highly sensitive assays is to focus not
on high-end values above the MI diagnosis threshold but rather on the low
end of the assay range, at the limit of
detection. In one study of 703 patients, 28% had a cTnT value at pre-

sentation below the 3 ng/L detection

threshold. Although MI occurred in
19% of the cohort, none of the individuals with undetectable cTnT at presentation subsequently ruled in (NPV,
100%).45 In the study by Keller et al,33
which used a highly sensitive cTnI assay, a similar proportion of individuals had cTnI levels below the detection limit of 3.4 ng/L at presentation
(27%), and the NPV was also 100%.
These preliminary findings suggest that
serial monitoring of troponin levels may
not be necessary among patients with
troponin levels undetectable using a
highly sensitive assay, with the likely
exception of those presenting very early
(1-2 hours) after symptom onset.
Reichlin et al 46 derived an algorithm incorporating baseline values and
1-hour absolute changes in cTnT levels among 436 randomly selected patients with chest pain from the APACE
study and validated the algorithm in the
remaining 436 patients. The algorithm assigned individuals with both a
baseline cTnT level lower than 12 ng/L
and a change of less than 3 ng/L over
the first hour to the rule-out group
(n = 259 [60%]), those with a baseline
cTnT level of 52 ng/L or greater or a
1-hour change of 5 ng/L or greater to
the rule-in group (n=76 [17%]), and
the remaining 101 patients (23%) to an
observational zone group. Prevalence of MI in the observational zone
was 8%. Sensitivity and NPV were both
100% in the rule-out group, with a 30day mortality of only 0.2%. In the
rule-in group, specificity was 97% and
PPV was 84%. If validated in additional data sets, this algorithm, which
allowed safe rule out or relatively accurate rule in for more than threefourths of patients within 1 hour, may
help to address some of the important
challenges limiting application and interpretation of the highly sensitive troponin assays in the United States.
Clearly, the transition to increasingly
sensitive troponin assays for MI diagnosis will require clinicians to move
from largely qualitative interpretation
to a more quantitative assessment of troponin levels.

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Risk Assessment in the Outpatient

Setting: A Better Use of the Highly
Sensitive Assays?

The development of highly sensitive assays has expanded the possible applications of troponin testing, including
potentially to the outpatient office visit.
With the highly sensitive assay, cTnT
can be detected at very low concentrations in more than 90% of outpatients
with stable chronic heart failure47 or
chronic CAD.48 In these chronic conditions, dose-dependent associations
have been observed between both cTnT
and cTnI and the subsequent risk for
death and heart failure, at levels well
below the detection threshold of standard assays.47-49
More recently, population screening with highly sensitive cTnT assays
was assessed in 3 large epidemiologic
cohorts totaling more than 17 500 individuals. The prevalence of detectable cTnT (3 ng/L) with the highly
sensitive assay ranged from 25% in the
Dallas Heart Study (ages 30-65 years)50
to 66.5% in the ARIC (Atherosclerosis
Risk in Communities) study (ages
54-74 years)39 and 66.2% in the CHS
(Cardiovascular Health Study) (ages
65 years).38 Concentrations of cTnT
increased with age and were higher in
men, African Americans, and individuals with CKD. Cardiac troponin T demonstrated strong associations with
pathological cardiac remodeling, in that
levels increased in parallel with the
presence and severity of left ventricular hypertrophy and left ventricular systolic dysfunction.50 Of interest is that
prior MI, angina, and coronary calcium were not associated with detectable levels of cTnT.
In each population-based study,
higher cTnT level was associated with
all-cause and cardiovascular mortality
and with incident heart failure,38,39,50,51
findings that remained significant after adjustment for traditional risk factors, renal function, and concentrations of N-terminal pro-brain natriuretic
peptide (NT-proBNP) and highsensitivity C-reactive protein (CRP).
When added to traditional risk assessment models, cTnT improved metrics
JAMA, June 5, 2013Vol 309, No. 21 2267

INCREASINGLY SENSITIVE ASSAYS FOR CARDIAC TROPONINS

of discrimination and risk classification, performing at least as well as NTproBNP and outperforming highsensitivity CRP.38,39,50 Although cTnT
was associated with coronary heart disease events in the ARIC study, the magnitude of association was weaker than
for death and heart failure events.39
In a recent analysis from the Framingham Offspring Study incorporating a
novel highly sensitive cTnI assay, the proportion of adults with detectable cTnI
levels was 81%; in that study, higher cTnI
levels were associated with higher rates
death and heart failure but not MI,52 findings similar to those reported above for
highly sensitive cTnT assays.
In the CHS, approximately twothirds of individuals underwent a follow-up cTnT measurement 2 to 3 years
after the baseline measurement. In
analyses adjusting for baseline cTnT
levels as well as other risk predictors,
increases in cTnT level of 50% or more
during follow-up identified individuals at increased subsequent risk for
death and heart failure, with decreases in cTnT level associated with
lower risk. 38 This observation suggests that risk reflected by higher troponin concentrations may be modifiable. However, to date, only limited data
are available regarding the factors that
might favorably influence troponin levels in the population. An exploratory
analysis from the CHS demonstrated
that higher levels of baseline physical
activity were associated with a lower
probability of increased cTnT levels
over follow-up.53 In the ARIC study,
higher hemoglobin A1c levels (even
those below the diagnostic range for
diabetes) were associated with higher
cTnT levels measured years later.54
Much work still needs to be done before highly sensitive troponin assays can
be considered in the outpatient setting. Additional research is needed to
identify treatments that prevent additional cardiac injury and modify risk associated with elevated troponin levels. Although structural heart disease
and CKD explain some of the variation in troponin levels, many other
known and unknown factors contrib2268

JAMA, June 5, 2013Vol 309, No. 21

ute as well. Troponins are agnostic

markers of cardiac damage that may reflect multiple different sources of injury. The effects and costs of noninvasive cardiovascular imaging to identify
the source of chronic cardiac injury and
identify targets of therapy must be delineated prior to implementation of any
screening strategy.55
CONCLUSIONS
The new highly sensitive troponin assays will present myriad challenges for
clinicians evaluating patients with chest
pain. The adoption of highly sensitive
assays for MI detection should be accompanied by implementation of algorithms to enhance specificity and PPV
and to shorten the period of observation. In addition, recommendations for
additional testing and referral for patients with increased cardiac troponin
levels and a low clinical suspicion for
ACS need to be developed.
The application of highly sensitive
troponin assays for risk assessment in
the ambulatory setting is a potentially
attractive approach to maximize the advantages of increased assay sensitivity. In this setting, the detection of very
low troponin concentrations identifies risk not captured with other tools.
Future studies should clarify the clinical value and identify the best approach to incorporating these assays for
population screening.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure
of Potential Conflicts of Interest and reported serving
as a consultant for Janssen Pharmaceuticals, Diadexus Inc, AstraZeneca, Bristol-Myers Squibbsanofiaventis, Tethys Bioscience, St Jude Medical, and Daiichi Sankyo; receiving grants or grants pending from
Roche Diagnostics and Abbott Diagnostics; and receiving payment for lectures from Bristol-Myers
Squibbsanofi-aventis and AstraZeneca.
Funding/Support: Dr de Lemos has received grant support as the principal investigator for investigatorinitiated grants from Roche Diagnostics and Abbott
Diagnostics.
Role of the Sponsors: Roche Diagnostics and Abbott
Diagnostics had no role in the preparation, review, or
approval of the manuscript or the decision to submit
the manuscript for publication.
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