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REVIEW
Frontiers in cardiovascular medicine
Troponin elevation in coronary vs. non-coronary
disease
S. Agewall1*, E. Giannitsis3, T. Jernberg2, and H. Katus 3
1
Department of Medicine, Oslo University Hospital and Oslo University, 0514 Oslo, Norway;
2
Department of Medicine Section of Cardiology, Hud dinge, Karolinska Institutet,
Karolinska University Hospital, Stockholm, Sweden; and
3
Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
Received 23 April 2010; revised 5 November 2010; accepted 18 November 2010; online publish-ahead-of-print 18 December 201 0
Acute myocardial infarction is defined as myocardial cell death due to prolonged myocardial ischaemia. Cardiac troponins (cTn) are the most
sensitive and specific biochemical markers of myocardial injury and with the new high-sensitivity troponin methods very minor damages on
the heart muscle can be detected. However, elevated cTn levels indicate cardiac injury, but do not define the cause of the injury. Thus, cTn
elevations are common in many disease states and do not necessarily indicate the presence of a thrombotic acute coronary syndrome (ACS).
In the clinical work it may be difficult to interpret dynamic changes of troponin in conditions such as stroke, pulmonary embolism, sepsis,
acute perimyocarditis, Tako-tsubo, acute heart failure, and tachycardia. There are no guidelines to treat patients with elevated cTn levels and
no coronary disease. The current strategy of treatment of patients with elevated troponin and non-acute coronary syndrome involves treat-
ing the underlying causes. The aim of this paper is to review data from studies of non-ACS patients with acutely elevated troponin who in
clinical practice may be difficult to discriminate from ACS patients.
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Keywords Troponin †Myocardial infarction
Introduction
Acute myocardial infarction (MI) is defined as myocardial cell death
due to prolonged myocardial ischaemia. The ESC/ACCF/AHA/WHF
task force
1
for the redefinition of MI agreed on the following defi-
nition of MI; Detection of rise and/or fall of cardiac biomarkers (pre-
ferably troponin) above the 99th percentile of the upper reference
limit together with evidence of ischaemia with at least one of the fol-
lowing: Ischaemic symptoms, electrocardiography (ECG) changes of
new ischaemia, development of pathologic Q-waves in the ECG or
imaging evidence of new loss of viable myocardium or new regional
wall motion abnormality. In the task force document clinical classifi-
cation of five different types of MI were defined (Table 1). Type 2 MI is
defined as MI secondary to ischaemia due to either increased oxygen
demand or decreased supply, e.g. coronary spasm, coronary embo-
lism, anaemia, arrhythmias, hypertension, or hypotension. In
addition, there are numerous causes of troponin release due to myo-
cardial damage not related to myocardial ischaemia. Discrimination
of Type 2 MI from troponin release due to non-coronary diseases
is challenging. However, discrimination is paramount in order to
provide timely and appropriate treatment.
The new high-sensitivity troponin methods allow detection of
very minor damages on the heart muscle increasing numbers of
patients with elevated troponin concentrations and thus hamper
interpretation of troponin results. In clinical practice it may be dif-
ficult to interpret dynamic changes of troponin in conditions such
as stroke, pulmonary embolism (PE), sepsis, acute perimyocarditis,
Tako-tsubo, acute heart failure (HF), and tachycardia (Table 2).
The aim of this paper is to review data from studies of non-ACS
patients with acutely elevated troponin who in clinical practice may
be difficult to discriminate from ACS patients.
Troponins for diagnosis of
myocardial injury
Cardiac troponin is composed of three subunits T, I, and C, which
are the products of different genes. The total mass of the troponin
complex is minuscule when compared with the protein mass of
other myofibrillar proteins like actin and myosin. However, both
*Corresponding author. Tel: +47 228 94655, Fax: +47228 94259, Email: stefan.agewall@medisin.uio.no
Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2010. For permissions please email: journals.permissions@oup.com.
European Heart Journal (2011) 32, 404–411
doi:10.1093/eurheartj/ehq456
troponin T and I are ideally suited for the detection of myocardial
damage as they are expressed as cardio-specific isoforms. There is
a distinct release kinetics following MI show a first peak resulting
from the loosely bound troponin pool and a second prolonged
elevation due to degradation of the contractile apparatus.
2
Patients
with large reperfused MI typically show such a biphasic time-release
pattern of cardiac troponin (cTn) T when compared with the
monophasic pattern seen with cTnI.
2
The release pattern of cTnT
is different in non-reperfused MI and may vary with small MIs.
Although the exact reason for this different release kinetics is still
illusive, cTnT differs from cTnI with respect to higher molecular
weight, higher fraction of unbound cTnT, less degradation,
whereas cTnI is more frequently found as binary or tertiary
complex in blood (Figure 1). There is evidence that the early appear-
ing pool may give information on the quality of micro-vascular
reperfusion, while the concentration of cTn on Day 3 or 4 reflects
myocardial infarct size.
3
Experimental data strongly suggest that tro-
ponin leaks out of the cell only after membrane disruption following
myocardial cell death.
4
The detection of brief rise and subsequent
fall of troponin concentration during marathon running
5
and rise
after inducible myocardial ischaemia
6
has cast some doubts on the
hypothesis that troponin is released only upon irreversible
damage. However, there are neither consistent experimental nor
clinical data providing proof of this concept, so far.
Troponin assays
The Joint ESC/ACCF/AHA/WHF Task Force has promoted the use
of the 99th percentile and state that a cTn imprecision ≤10% at
the 99th percentile is desirable.
1
During the time period when tro-
ponin assays were insufficiently precise at very low levels, some
institutions advocated the use of the lowest value at which the
assay achieved a 10%CV rather than the 99th percentile value.
As a consequence several diagnostic companies have improved
assay sensitivity to comply with these recommendations.
7
The cri-
teria defining a hsTn assay are still under debate. According to our
understanding hsTn assays—by virtue of their higher analytical sen-
sitivity—possess the capability to identify more patients with
hitherto undetectable cTn concentrations (with or without ACS)
and also allow detection of low cTn concentrations in many if
not all healthy subjects. These hsTn assays comprise hsTnI assays
from Singulex, Nanosphere, Beckman-Coulter (Access), Centaur
Troponin I Ultra and Vista (both Siemens), cTnI (Ortho Vitros),
and TnThs (Roche).
8,9
Additional criteria may serve for subclassifi-
cation such as the scorecard classification proposed by Apple.
9
Analytical issues
By definition, using the 99th percentile as the reference limit, an elev-
ated troponin value may be encountered in 1% of a healthy reference
population. A cTn elevation reflects acute or chronic myocardial
damage but is not exclusive for ACS thus causing some problems
with interpretation of results. Sometimes the term false-positive is
being used to describe a patient with suspected ACS and elevated
troponin but subsequently absence of significant coronary disease
on coronary angiogram. In this setting several differential diagnoses
have to be considered where troponin elevation may be related to
underlying cardiac but non-coronary pathology or extracardiac
disease, such as severe renal dysfunction.
10
Rarely, elevated troponin concentrations cannot be explained
despite thorough clinical examination. These rare instances are
referred to as truly false-positives, and are most frequently
related to heterophilic antibodies or other analytical issues.
11
Table 1 Clinical classification of different types of
myocardial infarction
Type 1
Spontaneous myocardial infarction related to ischaemia due to a
primary coronary event such as plaque erosion and/or rupture,
fissuring, or dissection
Type 2
Myocardial infarction secondary to ischaemia due to either
increased oxygen demand or decreased supply, e.g. coronary
artery spasm, coronary embolism, anaemia, arrhythmias,
hypertension, or hypotension
Type 3
Sudden unexpected cardiac death, including cardiac arrest, often
with symptoms suggestive of myocardial ischaemia, accompanied
by presumably new STelevation, or new LBBB, or evidence of
fresh thrombus in a coronary artery by angiography and/or at
autopsy, but death occurring before blood samples could be
obtained, or at a time before the appearance of cardiac
biomarkers in the blood
Type 4a
Myocardial infarction associated with PCI
Type 4b
Myocardial infarction associated with stent thrombosis as
documented by angiography or at autopsy
Type 5
Myocardial infarction associated with CABG
Table 2 Reasons for acutely elevated troponins
Acute coronary syndrome
Acute heart failure
Pulmonary embolism
Stroke
Acute aortic dissection
Tachyarrhythmias
Hypotension / Shock
Sepsis
ARDS
Perimyocarditis
Endocarditis
Tako-tsubo cardiomyopathy
Radiofrequency catheter ablation
Cardiac contusion
Strenuous exercise
Sympathomimetic drugs
Chemotherapy
Troponin elevation in coronary vs. non-coronary disease 405
The development of three-site sandwich immunoassays needed for
the generation of some of more sensitive troponin assays involving
two capture and one detection antibody or two detection and one
capture antibody is associated with an increased susceptibility to
heterophile interference.
12
Conversely, interference of troponin
with cTnI- and less frequently cTnT-autoantibodies may result in
falsely negative results or lower concentrations of detectable
cTn.
13
Haemolysis may interfere with cTn and cause measurement
of higher or lower cTn concentrations. This issue is not relevant
with mild haemolysis
7,11
or high cTn concentrations but may be
relevant with more severe haemolysis (.100 mg/dL), particularly
at concentrations near the 99th percentile value, and in clinical set-
tings where haemolysis is more prevalent like in emergency
departments.
14,15
There are several other analytical issues that
may confound the result and need attention including non-specific
binding, effect of matrix selection, lot-to-lot variation.
Lowering the cut-off value in
patients with acute coronary
syndrome
Applying the 99th percentile cut-off using highly sensitive assays in ACS
patients has now been substantiated in several studies.
16 –18
It has been
demonstrated beyond doubt that lowering the decision cut-off allows
earlier detection of MI, increases numbers of cases with MI, and
decreases numbers of cases with unstable angina proportionately.
7
However, the ESC/ACCF/AHA/WHF infarct definition gives no
recommendations for use of the 99th percentile value for risk
assessment. Previous studies suggested that lowering the decision
cut-off from the 10%CV to the 99th percentile gradually improved
risk stratification, treatment, and selection of early invasive vs.
selective invasive strategy among patients with ACS in randomized
clinical trials.
19 –22
However, measurements were made with cTn assays with an
imprecision ≥20%. More recently, the MERLIN-TIMI-38 trial that
randomized 4513 ACS patients to ranolazine or placebo found
that using a hsTnI assay concentrations above the 99th percentile
value predicted an adverse prognosis.
23
The problem of diagnosing
myocardial injury in minor
elevations: the role of kinetic
changes
Given the lack of a clear definition of rise and fall of cTn, many clin-
icians have operated with a change in the cTn concentration of
≥20% as a practical cut-off. MacRae et al.
24
could demonstrate
the usefulness of a 20% delta change in a cohort of 258 patients
with suspected ACS. Recent studies suggest that this cut-off
value regarding significant rise of troponin level needs to be
higher in the lower cTn range.
25,26
Two strategies to determine the required delta change appear
promising. The first strategy requires that pre-specified or receiver-
operating characteristic (ROC)-optimal delta change values obtained
from ACS studies have to be validated with respect to their diagnostic
and prognostic performance. Apple et al.
25
tested the utility of a delta
Figure 1 Schematic representation of the cardiac myofibrillar thin filament. Cardiac troponins exist in a structural (bound) form and in a free
cytosolic pool. Cardiac troponins are released from myocytes as complexes or as free protein. Permission received from the authors and BMJ.
S. Agewall et al.406
change of cTnI of ≥10%, ≥20, and ≥30%, and found that ≥30%
change improved specificity and risk assessment. In another study,
concentration changes of hsTnT within 3 h were compared
between patients with a finaldiagnosis of non-STEMI who initially pre-
sented with a negative troponin and in patients with a final diagnosis of
unstable angina (Figure 2). In this study, ROC analysis demonstrated
that a delta change ≥117% from the baseline to the subsequent
sample within 3 h increased clinical specificity.
26
Forthcoming
studies should validate criteria for delta change and should address
interesting aspects such as the question for the minimal value for
change to allow a diagnosis of MI, or other criteria such as discrimi-
nation by absolute differences, or maximal concentrations (Figure 3).
The second strategy requires the measurement of normal biologi-
cal variability of troponin concentrations in order to calculate the
reference change value (RCV) from intraindividual and interassay
variability.
27
Due to biochemical differences of cTnI assays RCV has
to be established individually for each commercially available cTnI
assay. In addition, RCV values have to be calculated for different
automated analysers as technologies may differ substantially regarding
precision. Wu et al.
27
calculated the RCV and derived parameters of a
cTnI assay using a single molecule detection system and found a RCV
of 46% for an increasing cTn and 32% for a decreasing cTnI value.
More recently, Vasile et al.
28
reported a log-normal RCV of 85%,
and calculated a delta change of 58% for an increasing cTnT, and
57.5% for a decreasing cTnT using the hsTnT assay.
Troponin concentration changes
in patients with end-stage renal
disease
Only for the subset of patients with end-stage renal disease
(ESRD), the NACB guidelines
29
have recommended a change in
the cTn concentration of ≥20% for the diagnosis of MI in those
who present with elevated cTn, 6–9 h after presentation, as indica-
tive of a relevant concentration change because it represents a sig-
nificant (3 SD) change in cTn on the basis of a 5–7% analytical CV.
However, the NACB made recommendations utilizing less sensi-
tive troponin assays and it is not clear if those recommendations
still fit for the more sensitive assays. Recently, in a cohort of
asymptomatic patients with ESRD a troponin concentration
exceeding the 99th percentile value using the new hsTnT assay
was found in 100% of patients.
30
Tachycardias
In clinical practice, elevated troponin concentrations are some-
times observed after prolonged episodes of supraventricular
tacharrhythmias (SVT), even in presumably healthy individuals.
The most likely mechanism for troponin elevation following tachy-
cardia may be shortening of diastole with subsequent subendocar-
dial ischaemia.
31
In animal studies, myocardial stretch is believed to
represent a second possible mechanism for tachycardia-mediated
troponin elevation as there exists a direct association between a
parallel rise in natriuretic peptide and troponins concentrations
in patients with various tachycardias.
32
It has been hypothesized
that cTnI release from viable cardiomyocytes may be mediated
by stimulation of stretch-responsive integrins, mechanotransducer
molecules that link the extracellular matrix to the intracellular
cytoskeleton.
33
Bakshi et al.
34
reported on 21 patients with normal coronary
angiograms in whom tachycardia was believed to account for the
observed troponin elevation in 28% of patients. Bukkapatnam
et al.
35
studied 104 patients with a diagnosis of SVT of whom
48% had elevated cTn. However, no difference in the diagnosis
Figure 2 Box and whiskers plot showing delta change between presentation and subsequent blood sample obtained within 3 h in patients
with a diagnosis of unstable angina (left, n¼25) and evolving non-STEMI (right, n¼12). Diagnosis of myocardial infarction was based on fourth
generation cTnT (≥0.03 ng/mL). hsTnT concentration increased significantly (P¼0.0024) from a mean of 10.66% (SEM 10.8, median 0%, range
284.6 to 192.8%) to a mean of 1176.9% (SEM 520.9, Median 358.4%, range: 296.6 to 5503.6%).
Troponin elevation in coronary vs. non-coronary disease 407
of CAD was found between those with when compared with
those without CAD. However, several shortcomings limit the
value of these observations as the diagnostic work-up including
coronary angiography, stress testing, and haemodynamic measure-
ments was not routinely performed in all patients, and serial tropo-
nin results to support an acute and reversible concentration
change were not available. Therefore, it is still illusive if tachycardia
alone may cause a troponin release in the absence of underlying
structural heart disease, significant CAD, myodepressive factors,
and inflammatory mediators or whether troponin release is due
to an imbalance between oxygen demand and supply (Type 2 MI)
in patients with subclinical heart disease. Recently, the GISSI-Atrial
Fibrillation (AF) investigators found that higher concentrations of
myocardial strain or injury markers like hsTnT, MR-proANP,
NT-proBNP, and endothelin predicted higher risk of a first recur-
rence of AF in 382 patients having sinus rhythm but with a history
of recent AF.
36
These data suggest that presence of underlying struc-
tural heart disease is closely related to recurrence of AF. No data are
presently available to address whether AF itself has any effect on the
concentration change over time.
Acute heart failure
The ADHERE Registry
37
examined 67 924 acutely decompensated
HF patients and explored the relationship between elevated tropo-
nin concentrations and adverse events. Using less sensitive formu-
lation of the cTnT assay or cTnI assays, 4240 patients (6.2%) were
positive for troponin. These patients had lower systolic blood
pressure on admission, a lower ejection fraction, and higher
in-hospital mortality (8.0 vs. 2.7%, P,0.001) than those who
were negative for troponin. The adjusted odds ratio (OR) for
death in the group of patients with a positive troponin test was
more than two-fold (OR 2.55) higher, independent of other pre-
dictive variables. These findings on the important prognostic role
of troponins in patients with acutely decompensated HF were
confirmed in another international pooled analysis of 1256 acute
destabilized HF patients.
38
Reasons for higher prevalence of
cTnT in acute HF are still unsettled. It has been speculated that
increased ventricular preload causing myocardial strain may
cause troponin release.
39
It is tempting to speculate that a detectable baseline level of
cTnT is the result of physiological loss of myocardium by necrosis
and apoptosis. About 1 g of myocardial mass, corresponding to
64 million cells, is being lost per year in the human heart.
40
However, the relative contribution of necrosis and apoptosis is dif-
ficult to ascertain. In a study that included 40 patients with acute
HF, Miller et al.
41
could demonstrate that baseline concentrations
of cTn were significantly lower in those with dilated cardiomyopa-
thies than in those with ischaemic cardiomyopathies. No data are
currently available to clarify whether prevalence of elevated
troponin and magnitude of rise and/or fall are higher in acute vs.
chronic HF.
Pericarditis and myocarditis
Despite the fact that troponins are not present in the pericardium,
cTn has been reported to be elevated in 32 –49% of cases of acute
pericarditis, as a consequence of the involvement of the epicar-
dium in the inflammatory process.
42
Troponin elevations reflect
myocardial lesion, thus an acute pericarditis with signs of myocar-
ditis (evidenced by global or regional myocardial dysfunction or
elevated cTn) is called myopericarditis. Clinical studies in patients
with myopericarditis are sparse. Imazio et al.
43
have reported
data on 274 consecutive cases of idiopathic or viral acute pericar-
ditis. At presentation, when patients with pericarditis and myoper-
icarditis were compared, patients with myopericarditis were
younger, they were more often male, they had more often had
recent febrile syndrome with gastrointestinal symptoms and/or
skeletal muscle myalgia and ST-segment elevation at presentation
was more common. They had also more often a deteriorated
Figure 3 Relation between troponin level and possible causes.
S. Agewall et al.408
ejection fraction and arrhythmias, but less frequently pericardial
effusion compared with those with pericarditis.
Limited data have been published on the natural history of myo-
pericarditis. Seroepidemiologic studies suggest that the majority of
cases of Coxsackie B virus infection are subclinical and have a
benign course. In the majority of patients, the inflammatory
process is apparently self-limited without short-term, overt seque-
lae. Troponin increase is roughly related to the extent of myocar-
dial inflammatory involvement, but unlike acute coronary
syndromes it does not seem to carry an adverse prognosis in
patients with myopericarditis. Remes et al.
44
have reported a
good clinical outcome in a long-term follow-up of 18 patients
with Coxsackievirus myopericarditis. Also in the larger study by
Imazio et al.
43
the prognosis was good. After 12 months the fre-
quency of complications was similar in acute pericarditis and myo-
pericarditis, with normalization of echocardiography, ECG, and
treadmill testing in the majority of cases.
The pathophysiology of myocarditis is poorly understood and
cTn levels may vary from normal levels up to high levels.
Primary myocarditis is presumed to be caused by an acute viral
infection or a post-viral autoimmune response. An increased
prevalence of coronary vasospasm has been demonstrated in
patients with myocarditis.
45
Thus, myocardial inflammation or
virus persistence, or both, may cause a coronary vasomotility dis-
order enabling the occurrence of coronary vasospasm. This vasos-
pasm may be the reason for atypical chest pain in subjects with
myocarditis, which in turn may lead to some confusion in
whether or not the aetiology of a given troponin elevation is
due to myocarditis or due to an ischaemic aetiology.
Magnetic resonance imaging (MRI) is a powerful diagnostic tool
for acute myocarditis, based on delayed enhancement imaging find-
ings. Delayed enhancement usually involves the subendocardial
layer in MI, whereas it usually spares the subendocardial layer in
myocarditis.
46,47
Acute pulmonary embolism
Despite that most patients with acute PE have an uncomplicated
clinical course, this condition has a wide spectrum of clinical
outcome varying from an early recovery of symptoms to sudden
death. Patients with PE and signs of shock or hypotension have
high mortality rates. It is generally accepted that these high-risk
patients should be considered for thrombolytic therapy.
48
In
patients with absolute contraindications to thrombolysis and in
those in whom thrombolysis has failed to improve haemodynamic
status, surgical embolectomy is the preferred therapy. If this is not
immediately available, catheter embolectomy or thrombus frag-
mentation may be considered.
48
Routine use of thrombolysis in non-high-risk patients is not rec-
ommended, but it may be considered in selected patients with
intermediate-risk PE and after thorough consideration of con-
ditions increasing the risk of bleeding.
48
Patients with
intermediate-risk PE are characterized as patients with a stable cir-
culation but with right ventricular dysfunction or elevated tropo-
nins. Kucher et al.
49
concluded that a normal echocardiogram
combined with a negative cTnI level was most useful to identify
patients at lowest risk for early death.
Among patients with stable circulation at admission, right ventri-
cular dysfunction at echocardiography identifies patients with elev-
ated risk for in-hospital mortality.
50
Several observational studies
have reported elevated cardiac troponin levels in PE, even in hae-
modynamically stable patients. The reason for cTn release in PE is
still unclear. The acute right ventricular strains secondary to
increase in pulmonary artery resistance may cause a troponin
elevation in PE. In the study by Meyer et al.
51
63% of those with
right ventricular dilation had an increased cTnI level whereas
29% of positive cTnI levels had a normal right ventricular end-
diastolic diameter. Also significant was the finding that a positive
cTnI level correlated with having more segmental defects on ven-
tilation–perfusion scintigraphy. However, another explanation to
an elevated troponin in PE patients might be hypoxaemia due to
perfusion–ventilation mismatch, hypoperfusion as a consequence
of low output and reduced coronary blood flow, as well as para-
doxical embolism from systemic veins to the coronary arteries,
usually via a patent foramen ovale. Transmural right ventricle
infarction despite patent coronary arteries has been found in
autopsies of patients who died of massive PE.
52
Studies investi-
gating the release of kinetics of cTnT in patients with PE showed
that the peak cTnT was lower and persisted for a shorter period
of time compared with cTnT values in acute MI.
53
Thus, the mech-
anism of myocardial damage and cTnT release in patients with sig-
nificant PE is different from that in patients with ACS. Whether
cTnT in PE patients originates from the cytosolic pool or from a
different readily accessible cell pool or whether troponin release
in PE is attributable to severe reversible or irreversible myocardial
ischaemia is unknown.
Several studies have reported an association between elevated
troponin levels and a poor prognosis in patients with PE. Becattini
et al.
54
has performed a meta-analysis of 20 studies in 1985 patients
with PE. Elevated cTn levels were significantly associated with
short-term mortality, death resulting from PE and other adverse
events. Increased cTn values were also associated with a higher
mortality in the subgroup of haemodynamically stable patients.
Another more recent metanalysis focused on normotensive
patients with acute symptomatic PE.
55
In this analysis, consisting
of 1366 patients, elevated troponin level resulted in a four-fold
increased risk of short-term death.
Tako-tsubo
Tako-tsubo cardiomyopathy has been called stress-induced cardi-
omyopathy, broken heart syndrome or transient left ventricular
apical ballooning syndrome. The Prevalence is reported to be
0.7–2.5% in patients presenting with acute coronary syndromes.
56
The typical Tako-tsubo cardiomyopathy patient has been charac-
terized as an older woman with an acute emotional or physiologic
stress commonly preceding the clinical presentation of Tako-tsubo
cardiomyopathy. However, the clinical profile of Tako-tsubo cardi-
omyopathy is broader including both younger patients and men
57
and emotional or physically stressful events immediately before
hospitalization can not be identified in all patients with Tako-tsubo
cardiomyopathy.
57
The pathophysiology of Tako-tsubo cardiomyopathy is not
well understood. Several mechanisms for the reversible
Troponin elevation in coronary vs. non-coronary disease 409
cardiomyopathy have been proposed, including catecholamine-
induced myocardial stunning, ischaemia-mediated stunning due to
multivessel epicardial or microvascular spasm, aborted acute myo-
cardial infarction (AMI), and focal myocarditis. The reason of selec-
tive involvement of apical and/or midportion of the left ventricle
with relative sparing of basal segments is unknown and might be
partly explained by the evidence that apical myocardium has
increased responsiveness to sympathetic stimulation.
These patients frequently present with symptoms consistent
with ischaemic chest pain or dyspnoea. Electrocardiography
often shows minimal ST elevation in the precordial leads and
most patients exhibit a small elevation of troponin.
58
Studies eval-
uating the ability of the ECG to differentiate Tako-tsubo cardio-
myopathy and ACS have been unsuccessful in identifying reliable
differences between the two groups to diagnose Tako-tsubo cardi-
omyopathy based on the ECG alone.
58
In most reports of
Tako-tsubo cardiomyopathy, echocardiography during the acute
phase (within 72 h of admission) demonstrates findings with dyski-
netic or akinetic apical and midventricular wall motion abnormal-
ities and basal hyperkinesis.
Magnetic resonance imaging examination may also be used to
identifying the typical regional wall motion abnormalities. It also
allows a precise quantification of right and left ventricular function
enables the assessment of myocardial perfusion and can be used to
exclude other disease processes. Late gadolinium enhancement
(LGE) on MRI is considered as indicative of myocarditis or
embolic infarction, depending on the mural distribution of
enhancement. Most reports suggest that LGE rules out Tako-tsubo
cardiomyopathy, but there are studies reporting LGE in patients
with Tako-tsubo cardiomyopathy.
59
Most patients with Tako-tsubo cardiomyopathy have a modest
rise in cTn that peaks within 24 h.
58,60
The magnitude of increase
in the biomarkers is less than that observed with a STEMI and dis-
proportionately low for the extensive acute regional wall motion
abnormalities that characterize Tako-tsubo cardiomyopathy.
58
One prospective study evaluated the magnitude of troponin T
and I elevation in differentiating between Tako-tsubo cardiomyopa-
thy and ACS. In this analysis, those with troponin T .6 ng/mL or
troponin I .15 ng/mL were unlikely to have Tako-tsubo
cardiomyopathy.
60
The optimal management of Tako-tsubo cardiomyopathy has
not been established, but supportive therapy invariably leads to
spontaneous recovery. The systolic dysfunction and the regional
wall motion abnormalities are transient and often resolve comple-
tely within a matter of days to a few weeks.
57
Sepsis
Approximately 50% of patients with severe sepsis and septic shock
may develop impairment of ventricular performance. Elevations in
cTn correlate with the presence of left ventricular systolic
dysfunction.
61,62
Among patients who are treated in intensive care units for sepsis
or systemic inflammatory response syndrome, elevated cTn have
been detected in 12 –85%, with a median frequency of 43%
according to a recent meta-analysis of 3278 patients in 20
studies.
63
This wide range of prevalence is probably due to the
different underlying causes of sepsis, the different troponin assays
used, and the different cut-off values that were applied. Several
studies have demonstrated that an elevated cTn predicts mortality
in sepsis patients.
63
The high prevalence of elevated serum levels of cTn in septic
patients raises the question of what mechanism results in troponin
release in septic shock. One theory of myocardial dysfunction in
sepsis has been based on the hypothesis of global myocardial
ischaemia. The release of cTn from damaged myocardial cells
might be an oxygen supply –demand mismatch of the myocardium.
As a consequence of fever and tachycardia the oxygen demand of
the myocardium is increased. Simultaneously, oxygen supply of the
myocardium is reduced due to systemic hypoxaemia from respir-
atory failure, microcirculatory dysfunction, hypotension, and some-
times anaemia. Thus, there are reasons for a Type II MI. However,
studies using thermodilution catheters placed in the coronary sinus
in patients with septic shock allowing measurement of coronary
flow and myocardial metabolism report preservation of myocardial
blood flow, net myocardial lactate extraction, and diminished cor-
onary artery–coronary sinus oxygen difference compared with
controls.
64
Thus, these observations argue against global ischaemia
as a cause of septic myocardial depression. Apart from ischaemia,
several factors may contribute to microinjury and minimal myocar-
dial cell damage in setting of septic shock. A possible direct cardiac
injury and myocytotoxic effect of endotoxins,
65
cytokines,
66
or
reactive oxygen radicals induced by infectious process and pro-
duced by activated neutrophils, macrophages, and endothelial
cells have been postulated.
It is not clear whether higher cTn represents reversible or irre-
versible myocardial injury in septic shock. ver Elst et al.
62
did not
find evidence of irreversible myocyte necrosis in autopsy cases
of septic shock where there was a positive premortem cTn.
These authors suggested the possibility of cTn release as reversible
injury in these patients.
There is no consensus on the appropriate approach and man-
agement of an elevated cTn level in the intensive care unit (ICU)
setting. A plaque rupture MI (Type I) and a MI secondary to ischae-
mia due to either increased oxygen demand or decreased supply
(Type II) must always be considered. A history of coronary
artery disease with typical ischaemic ECG changes may indicate a
Type I MI. Patients at ICU can rarely communicate classic ischaemic
symptoms because of endotracheal intubation, sedation, or analge-
sia, underscoring how difficult it might be to decide whether an
increased cTn is caused by cardiac ischaemia or not.
Stroke
Increases in cTn have been reported in all types of stroke [ischaemic,
intracerebral haemorrhage, and subarachnoid haemorrhage
(SAH)].
67
In a recent meta-analysis of 15 studies including 2901
patients with acute stroke, 18% of the patient had a positive cTn.
The prevalence varied from 0 to 35% most likely due to different
exclusion criteria and different cTn cut-offs.
68
Also contractile dys-
function and ECG changes such as ST-segment depression and
T-wave inversion (ST– T changes) are common in stroke patients.
69
The majority of studies relating cTn and stroke (including SAH)
demonstrate an association between raised cTn level and adverse
S. Agewall et al.410
outcomes. In the meta-analyses made by Kerr et al.,
68
acute stroke
patients with a positive troponin level were more likely to have fea-
tures suggestive of myocardial ischaemia on the ECG and had a
greater risk of death than those without a troponin rise. Even
when adjusted for potential confounding factors, a positive cTn
level was associated with an overall increased mortality. A strong
positive correlation between the rise in cTn and the severity of
the stroke has also been observed in several studies,
70,71
and
increased cTn levels may therefore represent a surrogate marker
for the severity of a stroke.
Although the aetiology of increased cTn in the setting of stroke
has not been entirely elucidated, there are a number of possible
causes of raised cTn after stroke. After AMI, stroke incidence is
markedly increased, particular early after the cardiac event.
72
Cer-
tainly the extent of the ischaemic penumbra of the brain and the
location of the stroke affects the prognosis, however, in patients
surviving a stroke, other manifestations of cardiovascular disease,
particularly coronary artery disease, are the main causes of long-
term mortality.
73
Thus, patients with ischaemic stroke may have
had antecedent MI perhaps complicated by AF.
69
However, it is
clear that this could not be the whole explanation. In a recent
study of 244 patients with acute ischaemic stroke but without
overt ischaemic heart disease, perfusion abnormalities on myocar-
dial perfusion scintigraphy were not more frequent or pronounced
in acute stroke patients with elevated cTn compared with acute
stroke patients with normal cTn.
74
The authors suggested that
heart and renal failure rather than MI are the most likely causes
to elevated cTn levels in patients with acute stroke.
Left-ventricular systolic dysfunction has been observed in all
three kinds of strokes. In patients with SAH and wall motion
abnormalities no perfusion defects were observed at myocardial
scintigraphy
75
and in another study no abnormalities were found
during coronary angiography.
76
The observed wall motion
abnormalities were reversible.
76
It has also been proposed that the observed cardiac abnormal-
ities are secondary to increased/disturbed sympathetic activity pro-
voked by acute stroke. An exaggerated catecholamine release may
lead to excessive release of intracellular calcium ions and sub-
sequent reversible myocyte dysfunction. An alternate explanation
is that the catecholamine surge acts as an uncontrolled severe
myocardial stress test, which essentially reveals stable coronary
plaques or induces a Tako-tsubo disease. Animal studies have
documented that acute stroke trigger an acute release of catechol-
amines, which is followed by a severe decrease in cardiac function
accompanied by a significant increase in cTn.
77
Similar findings
have been found in patients with SAH.
78
Banki et al.
75
reported
that LV systolic dysfunction in humans with SAH was associated
with normal myocardial perfusion and abnormal sympathetic
innervation.
Strenuous exercise
cTn can be elevated immediately after strenuous exercise, a
phenomenon that has been studied mainly in the setting of pro-
longed running.
79 –81
Troponin elevation has been found to
occur mainly in participants with less training and in those with a
lack of prior endurance racing.
81,82
Prolonged exercise induces a
state of muscular fatigue. Involvement of cardiac muscle in this
process is manifested as transiently decreased systolic and diastolic
function, so-called cardiac fatigue.
83
Interestingly, runners with
increased levels of troponin post-race have also been reported
to exhibit more pronounced signs of right and left ventricular dys-
function including regional wall motion abnormalities.
82
The proportion of individuals with increased troponin concen-
tration has varied widely between studies. In a meta-analysis
using a third-generation troponin assay, 47% of individuals had
elevated troponin T after endurance exercise.
84
However, in a
recent study using high-sensitivity troponin methods almost all
(80–86%) marathon runners had increased levels after racing.
85
Data obtained using high-sensitivity troponin methods have
shown that even a brief bout of exercise may lead to troponin
elevation if the intensity is high. In a study by Shave et al.,
86
30 min of high-intensity exercise resulted in small troponin I
elevations in six out of eight participants.
Several authors have shown that the kinetics of exertional tro-
ponin release do not necessarily indicate true cardiac damage
since the increase is typically transient and levels usually normalize
within 24–48 h, at least when non-high sensitive troponin methods
have been used.
79
Therefore, it has been hypothesized that tropo-
nin is released due to degradation of ‘cytosolic’ troponin or
increased permeability of the cell membranes of myocytes under
stress. Indeed, data from a murine model of forced physical
stress support the notion that troponin is depleted from the cyto-
solic pool as serum levels rise.
87
Exertional symptoms are relatively common in long-distance
runners and troponin elevation in the setting of dizziness, chest
pain or collapse may therefore constitute a considerable diagnostic
challenge.
88
Currently, there is no data suggesting that endurance
exercise should be discouraged in individuals with elevated post-
exercise troponins.
Cardiac contusion
Troponins may be elevated after thoracic trauma. No significant
complications occurred in patients in whom ECG findings were
normal and serial measurements of cTn were within reference
intervals.
89
Thus, a patient with chest trauma and an absence of
other injuries or haemodynamic instability, with normal ECG and
cTn can be discharged, whereas increased cTn may serve to ident-
ify patients at increased risk of mortality.
90
Conflict of interest: none declared.
References
1. Thygesen Kristian, Alpert Joseph S, Harvey D. White on behalf of the Joint ESC/
ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Uni-
versal definition of myocardial infarction. Eur Heart J 2007;28:2525 – 2538.
2. Thygesen K, Mair J, Katus H, Plebani M, Venge P, Collinson P, Lind ahl B,
Giannitsis E, Hasin Y, Galvani M, Tubaro M, Alpert JS, Biasucci LM, Koenig W,
Mueller C, Huber K, Hamm C, Jaffe AS; Study Group on Biomarkers in Cardiol-
ogy of the ESC Working Group on Acute Cardiac Care. Recommendations for
the use of cardiac troponin measurement in acute cardiac care. Eur Heart J
2010;31:2197–2204.
3. Giannitsis E, Steen H, Kurz K, Ivandic B, Simon AC, Futterer S, Schild C, Isfort P,
Jaffe AS, Katus HA. Cardiac magnetic resonance imaging study for quantification
of infarct size comparing directly serial versus single time-po int measurements of
cardiac troponin T. J Am Coll Cardiol 2008;51:307 –314.
Troponin elevation in coronary vs. non-coronary disease 411
4. Fishbein MC, Wang T, Matijasevic M, Hong L, Apple FS. Myocardial tissue tropo-
nins T and I. An immunohistochemical study in experimental models of myocar-
dial ischemia. Cardiovasc Pathol 2003;12:65 –71.
5. Giannitsis E, Roth HJ, Leitha¨user RM, Scherhag J, Beneke R, Katus HA. New highly
sensitivity assay used to measure cardiac troponin T concentration changes
during a continuous 216-km marathon. Clin Chem 2009;55:590– 592.
6. Sabatine MS, Morrow DA, de Lemos JA, Jarolim P, Braunwald E. Detection of
acute changes in circulating troponin in the setting of transient stress test-induced
myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart
J2009;30:162–169.
7. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe A, Katus HA. Analytical vali-
dation of a high sensitivity cardiac troponin T assay. Clin Chem 2010;56:254 – 261.
8. http://www.ifcc.org/pdf/scientificactivities/committees/ccd/ctn_assay_table_v091209.
pdf.
9. Apple FS. A new season for cardiac troponin assays: it’s time to keep a scorecard.
Clin Chem 2009;55:1303 –1306.
10. Hamm CW, Giannitsis E, Katus HA. Cardiac troponin elevations in patients
without acute coronary syndrome. Circulation 2002;106:2871 –2872.
11. Panteghini M. Assay-related issues in the measurement of cardiac troponins. Clin
Chim Acta 2009;402:88 –93.
12. Zhu Y, Jenkins MM, Brass DA, Ravago PG, Horne BD, Dean SB, Drayton N. Het-
erophilic antibody interference in an ultra-sensitive 3-site sandwich troponin I
immunoassay. Clin Chim Acta 2008;395:181 –182.
13. Go¨ser S, Andrassy M, Buss SJ, Leuschner F, Volz CH, Ottl R, Zittrich S,
Blaudeck N, Hardt SE, Pfitzer G, Rose NR, Katus HA, Kaya Z. Cardiac troponin
I but not cardiac troponin T induces severe autoimmune inflammation in the
myocardium. Circulation 2006;114:1693– 1702.
14. Bais R. The effect of sample hemolysis on cardiac troponin I and T assays. Clin
Chem 2010;56:1357–1359.
15. Florkowski C, Wallace J, Walmsley T, George P. The effect of hemolysis on
current troponin assays—a confounding preanalytical variable? Clin Chem 2010;
56:1195–1197.
16. Melanson SE, 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.
17. Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, Bickel C, Baldus S,
Warnholtz A, Fro¨hlich M, Sinning CR, Eleftheriadis MS, Wild PS, Schnabel RB,
Lubos E, Jachmann N, Genth-Zotz S, Post F, Nicaud V, Tiret L, Lackner KJ,
Mu¨nzel TF, Blankenberg S. Sensitive troponin I assay in early diagnosis of acute
myocardial infarction. N Engl J Med 2009;361:868 –877.
18. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, Biedert S,
Schaub N, Buerge C, Potocki M, Noveanu M, Breidthardt T, Twerenbold R,
Winkler K, Bingisser R, Mueller C. Early diagnosis of myocardial infarction with
sensitive cardiac troponin assays. N Engl J Med 2009;361:858 –867.
19. James S, Armstrong P, Califf R, Simoons ML, Venge P, Wallentin L, Lindahl B. Tro-
ponin T levels and risk of 30-day outcomes in patients with the acute coronary
syndrome: prospective verification in the GUSTO-IV trial. Am J Med 2003;115:
178– 184.
20. Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH,
Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub WS,
Braunwald E; TACTICS-TIMI 18 Investigators. Ability of minor elevations of tro-
ponins I and T to predict benefit from an early invasive strategy in patients with
unstable angina and non-ST-elevation myocardial infarction. Results from a ran-
domized trial. J Am Med Assoc 2001;286:2405 –2412.
21. Morrow DA, Rifai N, Sabatine MS, Ayanian S, Murphy SA, de Lemos JA,
Braunwald E, Cannon CP. Evaluation of the AccuTnI cardiac troponin I assay
for risk assessment in acute coronary syndromes. Clin Chem 2003;49:1396– 1398.
22. Venge P, Lagerqvist B, Diderholm E, Lindahl B, Wallentin L. Clinical performance
of three cardiac troponin assays in patients with unstable coronary artery disease
(a FRISC II substudy). Am J Cardiol 2002;89:1035 –1041.
23. Bonaca M, Scirica B, Sabatine M, Dalby A, Spinar J, Murphy SA, Jarolim P,
Braunwald E, Morrow DA. Prospective evaluation of the prognostic implications
of improved assay performance with a sensitive assay for cardiac troponin I. JAm
Coll Cardiol 2010;55:2118 –2124.
24. Macrae AR, Kavsak PA, Lustig V, Bhargava R, Vandersluis R, Palomaki GE,
Yerna MJ, Jaffe AS. Assessing the requirement for the 6-hour interval between
specimens in the American Heart Association Classification of Myocardial Infarc-
tion in Epidemiology and Clinical Research Studies. Clin Chem 2006;52:812 – 818.
25. Apple FS, Pearce LA, Smith SW, Kaczmarek JM, Murakami MM. Role of monitor-
ing changes in sensitive cardiac troponin I assay results for early diagnosis of myo-
cardial infarction and prediction of risk of adverse events. Clin Chem 2009;55:
930– 937.
26. Giannitsis E, Becker M, Kurz K, Hess G, Zdunek D, Katus HA. High-sensitivity
cardiac troponin T for early prediction of evolving non-ST-segment elevation
myocardial infarction in patients with suspected acute coronary syndrome and
negative troponin results on admission. Clin Chem 2010;56:642 –650.
27. Wu AHB, Lu QA, Todd J, Moecks J, Wians F. Short- and long-term biological vari-
ation in cardiac troponin I measured with a high-sensitivity assay: implications for
clinical practice. Clin Chem 2009;55:52 –58.
28. Vasile VC, Saenger AK, Kroning JM, Jaffe AS. Biological and analytical variability of
a novel high-sensitivity cardiac troponin T assay. Clin Chem 2010;56:1086– 1090.
29. Wu AH, Jaffe AS, Apple FS, Jesse RL, Francis GL, Morrow DA, Newby LK,
Ravkilde J, Tang WH, Christenson RHNACB CommitteeCannon CP,
Storrow AB. National Academy of Clinical Biochemistry labo ratory medicine
practice guidelines: use of cardiac troponin and B-type natriuretic peptide or N-
terminal proB-type natriuretic peptide for etiologies other than acute coronary
syndromes and heart failure. Clin Chem 2007;53:2086 –2096.
30. Jacobs LH, van de Kerkhof J, Mingels AM, Kleijnen VW, van der Sande FM,
Wodzig WK, Kooman JP, van Dieijen-Visser MP. Haemodialysis patients longitud-
inally assessed by highly sensitive cardiac troponin T and commercial cardiac tro-
ponin T and cardiac troponin I assays. Ann Clin Biochem 2009;46:283 –290.
31. Jeremias A, Gibson M. Alternative causes for elevated cardiac troponin levels
when acute coronary syndromes are excluded. Ann Intern Med 2005;142:
786– 791.
32. Qi W, Kjekshus H, Klinge R, Kjekshus JK, Hall C. Cardiac natriuretic peptides and
continuously monitored atrial pressures during chronic rapid pacing in pigs. Acta
Physiol Scand 2000;169:95 –102.
33. Hessel MH, Atsma DE, van der Valk EJ, Bax WH, Schalij MJ, van der Laarse A.
Release of cardiac troponin I from viable cardiomyocytes is mediated by integrin
stimulation. Pflugers Arch 2008;455:979 –986.
34. Bakshi TK, Choo MK, Edwards CC, Scott AG, Hart HH, Armstrong GP. Causes of
elevated troponin I with a normal coronary angiogram. Intern Med J 2002;32:
520– 525.
35. Bukkapatnam RN, Robinson M, Turnipseed S, Tancredi D, Amsterdam E,
Srivatsa UN. Relationship of myocardial ischemia and injury to coronary artery
disease in patients with supraventricular tachycardia. Am J Cardiol 2010;106:
374– 377.
36. Latini R, Masson S, Pirelli S, Barlera S, Pulitano G, Carbonieri E, Gulizia M, Vago T,
Favero C, Zdunek D, Struck J, Staszewsky L, Maggioni AP, Franzosi MG,
Disertori M; on the behalf of the GISSI-AF Investigators. Circulating cardiovascu-
lar biomarkers in recurrent atrial fibrillation: data from the GISSI-Atrial Fibrillation
Trial. J Intern Med 2010; doi: 10.1111/j.1365-2796.2010.02287.x. Published online
ahead of print 17 September 2010.
37. Peacock WF 4th, De Marco T, Fonarow GC, Diercks D, Wynne J, Apple FS,
Wu AH; ADHERE Investigators. Cardiac troponin and outcome in acute heart
failure. N Engl J Med 2008;358:2117 –2126.
38. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J,
Santalo-Bel M, Pinto YM, Richards M. NT-proBNP testing for diagnosis and short-
term prognosis in acute destabilized heart failure: an international pooled analysis
of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J
2006;27:330–337.
39. Feng J, Schaus BJ, Fallavollita JA, Lee TC, Canty JM Jr. Preload induces troponin I
degradation independently of myocardial ischemia. Circulation 2001;103:
2035–2037.
40. Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR,
Anversa P. Gender differences and aging: effects on the human heart. J Am Coll
Cardiol 1995;26:1068–1079.
41. Miller WL, Hartman KA, Burritt MF, Burnett JC Jr, Jaffe AS. Troponin, B-type
natriuretic peptides and outcomes in severe heart failure: differences between
ischemic and dilated cardiomyopathies. Clin Cardiol 2007;30:245 – 250.
42. Brandt RR, Filzmaier K, Hanrath P. Circulating cardiac troponin I in acute pericar-
ditis. Am J Cardiol 2001;87:1326 –1328.
43. Imazio M, Cecchi E, Demichelis B, Chinaglia A, Ierna S, Demarie D, Ghisio A,
Pomari F, Belli R, Trinchero R. Myopericarditis vs. viral or idiopathic acute peri-
carditis. Frequency, clinical clues to diagnosis, and prognosis. Heart 2008;94:
498– 501.
44. Remes J, Helin M, Vaino P, Rautio P. Clinical outcome and left ventricular function
23 years after acute Coxsackie virus myopericarditis. Eur Heart J 1990;11:
182– 188.
45. Yilmaz A, Mahrholdt H, Athanasiadis A, Vogelsberg H, Meinhardt G,
Voehringer M, Kispert EM, Deluigi C, Baccouche H, Spodarev E, Klingel K,
Kandolf R, Sechtem U. Coronary vasospasm as the underlying cause for chest
pain in patients with PVB19 myocarditis. Heart 2008;94:1456 – 1463.
46. Mahrholdt H, Wagner A, Judd RM, Sechtem U, Kim RJ. Delayed enhancement car-
diovascular magnetic resonance assessment of nonischemic cardiomyopathies.
Eur Heart J 2005;26:1461 –1474.
47. Skouri HN, Dec GW, Friedrich MG, Cooper LT. Noninvasive imaging in myocar-
ditis. J Am Coll Cardiol 2006;48:2085 –2093.
S. Agewall et al.411a
48. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie
`N, Pruszczyk P, Bengel F,
Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M,
Bassand JP, Vahanian A, Camm J, 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, Zamorano JL,
Andreotti F, Ascherman M, Athanassopoulos G, De Sutter J, Fitzmaurice D,
Forster T, Heras M, Jondeau G, Kjeldsen K, Knuuti J, Lang I, Lenzen M,
Lopez-Sendon J, Nihoyannopoulos P, Perez Isla L, Schwehr U, Torraca L,
Vachiery JL; Task Force for the Diagnosis and Management of Acute Pulmonary
Embolism of the European Society of Cardiology. Guidelines on the diagnosis
and management of acute pulmonary embolism: the Task Force for the Diagnosis
and Management of Acute Pulmonary Embolism of the European Society of Car-
diology (ESC). Eur Heart J 2008;18:2276 –2315.
49. Kucher N, Wallmann D, Carone A, Windecker S, Meier B, Hess OM. Incremental
prognostic value of troponin and echocardiography in patients with acute pul-
monary embolism. Eur Heart J 2003;24:1651 –1656.
50. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiogra-
phy among patients with acute pulmonary embolism and a systolic arterial
pressure of 90 mm Hg or higher. Arch Intern Med 2005;165:1777– 1781.
51. Meyer T, Binder L, Hruska N, Luthe H, Buchwald AB. Cardiac troponin I elevation
in acute pulmonary embolism is associated with right ventricular dysfunction. JAm
Coll Cardiol 2000;36:1632 –1636.
52. Coma-Canella I, Gamallo C, Martinez OP, Lopez-Sendon J. Acute right ventricular
infarction secondary to massive pulmonary embolism. Eur Heart J 1988;9:
534– 540.
53. Muller-Bardorff M, Weidtmann B, Giannitsis E, Kurowski V, Katus HA. Release
kinetics of cardiac troponin T in survivors of confirmed severe pulmonary embo-
lism. Clin Chem 2002;48:673 –675.
54. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pul-
monary embolism: a meta-analysis. Circulation 2007;116:427 –433.
55. Jime
´nez D, Uresandi F, Otero R, Lobo JL, Monreal M, Martı
´D, Zamora J, Muriel A,
Aujesky D, Yusen RD. Troponin-based risk stratification of patients with acute
nonmassive pulmonary embolism: systematic review and metaanalysis. Chest
2009;136:974–982.
56. Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular
apical ballooning syndrome: a systematic review. Int J Cardiol 2008;124:283 –292.
57. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN,
Haas TS, Hodges JS, Maron BJ. Natural history and expansive clinical profile of
stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol 2010;55:333 –341.
58. Ramaraj R, Sorrell VL, Movahed MR. Levels of troponin release can aid in the
early exclusion of stress-induced (takotsubo) cardiomyopathy. Exp Clin Cardiol
2009;14:6– 8.
59. Rolf A, Nef HM, Mo¨ llmann H, Troidl C, Voss S, Conradi G, Rixe J, Steiger H,
Beiring K, Hamm CW, Dill T. Immunohistological basis of the late gadolinium
enhancement phenomenon in tako-tsubo cardiomyopathy. Eur Heart J 2009;30:
1635– 1642.
60. Sharkey SW, Lesser JR, Menon M, Parpart M, Maron MS, Maron BJ. Spectrum and
significance of electrocardiographic patterns, troponin levels, and thrombolysis in
myocardial infarction frame count in patients with stress (tako-tsubo) cardiomyo-
pathy and comparison to those in patients with ST-elevation anterior wall myo-
cardial infarction. Am J Cardiol 2008;101:1723
–1728.
61. Mehta NJ, Khan IA, Gupta V, Jani K, Gowda RM, Smith PR. Cardiac troponin I pre-
dicts myocardial dysfunction and adverse outcome in septic shock. Int J Cardiol
2004;95:13–17.
62. ver Elst KM, Spapen HD, Nguyen DN, Garbar C, Huyghens LP, Gorus FK. Cardiac
troponins I and T are biological markers of left ventricular dysfunction in septic
shock. Clin Chem 2000;46:650 –657.
63. Lim W, Qushmaq I, Devereaux PJ, Heels-Ansdell D, Lauzier F, Ismaila AS,
Crowther MA, Cook DJ. Elevated cardiac troponin measurements in critically
ill patients. Arch Intern Med 2006;166:2446 –2254.
64. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE. The coronary circu-
lation in human septic shock. Circulation 1986;73:637 –644.
65. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA,
Parrillo JE. The cardiovascular response of normal humans to the administration
of endotoxin. N Engl J Med 1989;321:280 –287.
66. Natanson C, Eichenholz PW, Danner RL, Eichacker PQ, Hoffman WD, Kuo GC,
Banks SM, MacVittie TJ, Parrillo JE. Endotoxin and tumor necrosis factor chal-
lenges in dogs simulate the cardiovascular profile of human septic shock. J Exp
Med 1989;169:823–832.
67. Sandhu R, Aronow WS, Rajdev A, Sukhija R, Amin H, D’aquila K, Sangha A.
Relation of cardiac troponin I levels with in-hospital mortality in patients with
ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Am J
Cardiol 2008;102:632 –634.
68. Kerr G, Ray G, Wu O, Stott DJ, Langhor ne P. Elevated troponin after stroke: a
systematic review. Cerebrovasc Dis 2009;28:220– 226.
69. Fure B, Bruun Wyller T, Thommessen B. Electrocardiographic and troponin T
changes in acute ischaemic stroke. J Intern Med 2006;259:592– 597.
70. Chalea JA, Ezzeddine MA, Davis L, Warach S. Myocardial injury in acute stroke. A
troponin I study. Neurocrit Care 2004;3:343 –346.
71. Ay H, Koroshetz WJ, Benner T, Vangel MG, Melinosky C, Arsava EM, Ayata C,
Zhu M, Schwamm LH, Sorensen AG. Neuroanatomic correlates of stroke-related
myocardial injury. Neurology 2006;66:1325 –1329.
72. James P, Ellis CJ, Whitlock RM, McNeil AR, Henley J, Anderson NE. Relation
between troponin T concentration and mortality in patients presenting with an
acute stroke: observational study. Br Med J 2000;320:1502– 1504.
73. Dixit S, Castle M, Velu RP, Swisher L, Hodge C, Jaffe AS. Cardiac involvement in
patients with acute neurologic disease: confirmation with cardiac troponin I. Arch
Intern Med 2000;160:3153 –3158.
74. Jensen JK, Atar D, Mickley H. Mechanism of troponin elevations in patients with
acute ischemic stroke. Am J Cardiol 2007;99:108 –112.
75. Banki NM, Kopelnik A, Dae MW, Miss J, Tung P, Lawton MT, Drew BJ, Foster E,
Smith W, Parmley WW, Zaroff JG. Acute neurocardiogenic injury after subarach-
noid hemorrhage. Circulation 2005;112:3314 –3319.
76. Kono T, Morita H, Kuroiwa T, Onaka H, Takatsuka H, Fujiwara A. Left ventricular
wall motion abnormalities in patients with subarachnoid hemorrhage: neurogenic
stunned myocardium. J Am Coll Cardiol 1994;24:636 –640.
77. Masuda T, Sato K, Yamamoto S. Sympathetic nervous activity and myocardial
damage immediately after subarachnoid hemorrhage in a unique animal model.
Stroke 2002;33:1671–1676.
78. Naredi S, Lambert G, Ede
´nE,Za¨ll S, Runnerstam M, Rydenhag B, Friberg P.
Increased sympathetic nervous activity in patients with nontraumatic subarach-
noid hemorrhage. Stroke 2000;31:901 –906.
79. Scharhag J, Herrmann M, Urhausen A, Haschke M, Herrmann W, Kindermann W.
Independent elevations of N-terminal pro-brain natriuretic peptide and cardiac
troponins in endurance athletes after prolonged strenuous exercise. Am Heart J
2005;150:1128–1134.
80. Saenz AJ, Lee-Lewandrowski E, Wood MJ, Neilan TG, Siegel AJ, Januzzi JL,
Lewandrowski KB. Measurement of a plasma stroke biomarker panel and
cardiac troponin T in marathon runners before and after the 2005 Boston mara-
thon. Am J Clin Pathol 2006;126:185 –189.
81. Sahlen A, Gustafsson TP, Svensson JE, Marklund T, Winter R, Linde C,
Braunschweig F. Predisposing factors and consequences of elevated biomarker
levels in long-distance runners aged .or ¼55 years. Am J Cardiol 2009;104:
1434–1440.
82. Neilan TG, Januzzi JL, Lee-Lewandrowski E, Ton-Nu TT, Yoerger DM, Jassal DS,
Lewandrowski KB, Siegel AJ, Marshall JE, Douglas PS, Lawlor D, Picard MH,
Wood MJ. Myocardial injury and ventricular dysfunction related to training
levels among nonelite participants in the Boston marathon. Circulation 2006;
114:2325 –2333.
83. Douglas PS, O’Toole ML, Hiller WD, Hackney K, Reichek N. Cardiac fatigue after
prolonged exercise. Circulation 1987;76:1206– 1213.
84. Shave R, George KP, Atkinson G, Hart E, Middleton N, Whyte G, Gaze D,
Collinson PO. Exercise-induced cardiac troponin T release: a meta-analysis.
Med Sci Sports Exerc 2007;39:2099 – 2106.
85. 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;55:101–108.
86. Shave R, Ross P, Low D, George K, Gaze D. Cardiac troponin I is released
following high-intensity short-duration exercise in healthy humans. Int J Cardiol.
Published online ahead of print 13 January 2010.
87. Chen Y, Serfass RC, Mackey-Bojack SM, Kelly KL, Titus JL, Apple FS. Cardiac tro-
ponin T alterations in myocardium and serum of rats after stressful, prolonged
intense exercise. J Appl Physiol 2000;88:1749 –1755.
88. Shave RE, Whyte GP, George K, Gaze DC, Collinson PO. Prolonged exercise
should be considered alongside typical symptoms of acute myocardial infarction
when evaluating increases in cardiac troponin T. Heart 2005;91:1219– 1220.
89. Schultz JM, Trunkey DD. Blunt cardiac injury. Crit Care Clin 2004;20:57 –70.
90. Elie M. Blunt cardiac injury. Mt Sinai J Med 2006;73:542 – 552.
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