General cardiology

DIFFERENTIAL DIAGNOSIS OF
ELEVATED TROPONINS
Susanne Korff, Hugo A Katus, Evangelos Giannitsis 987

Heart 2006; 92:987–993. doi: 10.1136/hrt.2005.071282

I
Take the online multiple choice n the year 2000, the European Society of Cardiology and the American College of Cardiology
questions associated with this Committee jointly redefined myocardial infarction (MI) by an elevation of cardiac troponin T
article (see page 1000)
(cTnT) or I (cTnI) in conjunction with clinical evidence of myocardial ischaemia.1 Since then,
cTnT and cTnI have replaced creatine kinase-MB (CK-MB) as the preferred biochemical markers
for the diagnosis of MI. The decision for including cardiac troponins (cTn) in the diagnostic
pathway was made because of the high sensitivity of cTn for detection of even small amounts of
myocardial necrosis. An elevation of cTn indicates the presence of, but not the underlying reason
for, myocardial injury. Hence, besides acute myocardial infarction (AMI), there is a myriad of
potential diseases with troponin release, including acute pulmonary embolism, heart failure,
myocarditis, and end stage renal disease. But regardless of what the release mechanism into the
blood from cardiac myocytes is, elevated cTnT and cTnI almost always imply a poor prognosis.
This article attempts to highlight the differential diagnosis of elevated cTn according to the
various aetiologies of myocyte damage (table 1).

c WHAT ARE CARDIAC TROPONINS?

The troponin complex consists of three subunits—troponin C, troponin I, and troponin T—and is
located on the myofibrillar thin (actin) filament of striated (skeletal and cardiac) muscle (fig 1).
The cardiac isoforms troponin T and I are only expressed in cardiac muscle. Hence, cardiac
troponin T (cTnT) and I (cTnI) are more specific than creatine kinase (CK) values for myocardial
injury and, because of their high sensitivity, they may even be elevated when CK-MB
concentrations are not. The cTn complex regulates excitation–contraction coupling in the heart.
Cardiac troponin C (cTnC), a calcium (Ca2+) binding 18-kD-protein, regulates the activation of
the actin filaments. cTnI (,23 kD) inhibits contraction in the absence of Ca2+ binding to cTnC,
and cTnT, the greatest subunit (,35 kD), attaches the whole troponin complex to tropomyosin
and to the actin filaments.2 cTn are found as structural (bound) proteins and as a small free pool
that exists in the cytosol, which is about 6–8% for cTnT and 3.5% for cTnI. In some diseases, and
supposedly in the case of pulmonary embolism or after ultra-endurance physical exercise, a
transient leakage of the cytosolic pool of cTn, although never proven, cannot be excluded.
Following myocardial damage, cTn egress rapidly from the myocyte and will appear in blood after
2–4 hours and persist long enough (up to 10–21 days) for convenient diagnosis. Furthermore,
detection of cTn with immunoassays is easy, inexpensive, and the results are readily available,
making them ideal biomarkers in most emergency facilities.

CARDIAC TROPONINS IN ACUTE CORONARY SYNDROME (ACS)

Spontaneous acute myocardial infarction
In their current guidelines from 2000, the Joint European Society of Cardiology/American College
of Cardiology committee redefined AMI as an elevation of cTn in blood above the 99th centile of a
healthy reference population in conjunction with signs or symptoms of ischaemia.1 This did
expand the diagnostic capacity to detect micro-MI which was not evident by CK-MB
measurements. cTn do not only allow for more sensitive diagnosis of AMI but are also the
See end of article for authors’ most important predictor for acute thrombotic risk. Multiple randomised studies and several
affiliations
_________________________ meta-analyses have substantiated the adverse prognostic risk associated with elevated cTn.3 w1
For example, the meta-analysis by Ottani et al found that the odds ratio for death and MI was
Correspondence to:
Dr P D Evangelos Giannitsis, 3.44-fold at 30 days in the cTnT-positive group compared to patients with unstable angina.3
Abteilung Innere Medi-zin III, Further lowering of the cTn cut-off has been shown to improve risk stratification as pointed out in
Medizinische Klinik, several randomised trials and registries.4 In addition, the implementation of a lower troponin cut-
Universitätsklinikum
Heidelberg, Im Neuenheimer off as proposed by the guidelines led to a substantial increase in the frequency of MI diagnosis.w2
Feld 410, 69120 Heidelberg, Several angiographic and angioscopic studies have demonstrated that the presence and
Germany; magnitude of intracoronary thrombus is directly related to the concentration of cTn.w3 Therefore,
evangelos.giannitsis@med.
uni-heidelberg.de cTn is regarded as a surrogate marker for active plaque and intracoronary thrombus. As an
_________________________ indirect finding, numerous randomised trials have found that patients with a positive troponin

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 EDUCATION IN HEART

Table 1 Causes of elevated troponins, prevalence, and underlying mechanism

Prevalence of troponins
Troponin elevation (disease) (cut-offs) Key references Mechanism of troponin release

ACS related
AMI 100% per definition Alpert JS. J Am Coll Cardiol 2000;36:959–69. Thrombotic occlusion of coronary artery
(STEMI), microembolisation (NSTEMI)
988 Post-PCI 31% (cTnI) – 40% (cTnI); Nageh T. Heart 2005; 91:1181–5. Okmen E. Side branch occlusion, coronary
24% (cTnT) J Invasive Cardiol 2005;17:63–7. dissection, bulky devices causing
transient ischaemia and microembolisms
Open heart surgery 100% (cTnT) Lehrke S. Clin Chem 2004;50:1560–7. Myocardial infarction, incomplete
cardioprotection, reperfusion injury,
direct surgical trauma
Non-ACS related
Acute pulmonary embolism Variable, depending on Giannitsis E. Circulation 2000;102:211–7. Right ventricular strain
cut-off; 32% at cTnT .0.1 ng/ml Pruszczyk P. Chest 2003;123:1947–52.
– 50% at cTnT .0.01 ng/ml
Asymptomatic patients with Variable, depending on cut-off; Apple FS. Circulation 2002;106:2941–5. Several possible reasons including
ESRD 99th centile/10% CV/ROC: coronary and non-coronary cardiac
82%/53%/20% for cTnT and origin; prolonged renal elimination;
6%/1%/0.4% for cTnI non-dialysable, intact cTnT; differences
to cTnI may be related to higher affinity
to dialysis membrane, unstable molecule
(fragments), smaller protein
Pericarditis/myocarditis 32–49% (cTnI) Smith SC. Circulation 1997;95:163–8. Direct damage of myocytes
Imazio M. J Am Coll Cardiol 2003;42:
2144–8.
Bonnefoy E. Eur Heart J 2000;21:832–6.
Aortic dissection Stanford A 24% (cTnI .1.5 ng/ml) Bonnefoy E. Acta Cardiol 2005;60:165–70. Dissection of coronary artery
Chronic HF 15% (cTnT .0.1 ng/ml) –23% Missov E. Am Heart J 1999;138:95–9. Global wall stretch, degradation of
(stable and unstable) (cTnI La Vecchia L. Am J Cardiol 1997;80:88–90. contractile protein and cellular injury
.0.3 ng/ml) due to oxidative stress and
neurohumoral factors
Acute HF 52% (cTnT >0.02 ng/ml) –55% Setsuda K. Am J Cardiol 1999; 84: 608–11. Global wall stretch, hypoxaemia,
(cTnT >0.1 ng/ml) Perna ER. Am Heart J 2002;143:814–20. systemic hypoperfusion, coronary
malperfusion
Strenuous exercise/ultra- 26% (cTnT), 9% (cTnI); Rifai N. Am J Cardiol 1999;83:1085–9. Ventricular stretch, release of soluble
endurance athletes 23% (cTnT), 32% (cTnI) Urhausen A. Am J Cardiol 2004;94:696–8. troponin, underlying cardiac disease
Cardiotoxic chemotherapy Unknown Yeh ET. Circulation 2004;109:3122–31. Direct toxic effect on myocytes
High frequency ablation/ 90% (cTnI) Madrid AH. Am Heart J 1998;136:948–55. Direct myocardial damage
current cardioversion-
defibrillator shocks
Cardiac infiltrative disorders Unknown Dispenzieri A. Lancet 2003;361:1787–9. Myocyte compression
(amyloidosis)
Heart transplant 100% (up to 3 months) Zimmermann R. Br Heart J 1993;69:395–8. Inflammatory/immune mediated
variable after 3 months Labarrere CA. JAMA 2000;284:457–64.
Cardiac contusion after blunt 12% (cTnI) – 15% (cTnT) Edouard AR. Anesthesiology 2004;101:1262–8. Direct myocardial damage
chest wall trauma Collins JN. Am J Surg 2001;67:821–5.
Sepsis/critical ill patients 36% (cTnT >0.1 ng/ml) – 85% ver Elst KM. Clin Chem 2000;46:650–7. Oxygen supply/demand mismatch,
(cTnT .0.1 ng/ml) Ammann P. Intensive Care Med 2001;27:965–9 cytokine/endotoxin mediated toxicity,
heterophilic antibodies (false positive)
Rhabdomyolysis Unknown Lavoinne A. Clinical Chemistry 1998;44:667–8. Cross-reactivity between skeletal and
cardiac muscle isoforms of troponins in
first and second generation troponin
assays

ACS, acute coronary syndrome; AMI; acute myocardial infarction, ESRD; end stage renal disease; HF; heart failure; NSTEMI, non-ST elevation myocardial
infarction; PCI; percutaneous coronary intervention; STEMI, ST elevation myocardial infarction.

result benefit from a more intense antithrombin or anti- side branch occlusion, coronary dissection, bulky devices
platelet treatment and also from an early invasive strategy.w4 causing transient ischaemia, and microembolisms. Regardless
of the exact mechanism, contrast-enhanced magnetic reso-
AMI after percutaneous coronary intervention or open nance imaging has demonstrated beyond doubt that post-
heart surgery procedural increases in cTn are related to myocardial
Percutaneous coronary intervention necrosis.w7 In direct comparison, cTn were more sensitive for
In addition to spontaneous AMI, the current guidelines have detection of minor injury and hence were detectable more
also labelled post-procedural elevations of troponins after frequently than CK or CK-MB after elective PCI. However, the
elective percutaneous coronary intervention (PCI) or coronary relationship between the magnitude of CK-MB and future
artery bypass graft surgery as AMI. However, minor elevations prognosis is seemingly more robust and consistent than the
of cTn are frequently observed after elective PCI and are always relationship of cTn with outcomes.w8 In a recent study
found after open heart surgery. While there is no doubt as to involving 316 patients with stable symptoms, cTnI elevation
the cardiac origin of troponins in these settings, neither the following PCI correlated significantly with an increased risk of
exact pathological mechanism nor the prognostic impact of adverse events at 18 months.w5 In a study by Ricciardi et al, a
these minor elevations are currently determined. threefold elevation of cTnI after successful elective PCI was
An elevation of cTn has been reported in 24–40% of patients predictive for future cardiac events, especially for early repeat
after successful PCI in stable and unstable coronary artery vascularisation.5 In contrast, Cavallini et al showed that a cTnI
disease.w5 w6 Possible reasons for the appearance of cTn include elevation following coronary intervention was detected in

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EDUCATION IN HEART

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 as indicated on the right.
989

44.2% of the cases, but was not associated with a significant suspicion of ACS is improper and misleading, possibly
increase in long-term mortality.w8 causing inadequate secondary prevention.

Open heart surgery CARDIAC TROPONIN RELEASE UNRELATED TO ACS

Cardiac troponins are always increased in small amounts and Sepsis/septic shock and systemic inflammatory
for an average time of five days following open heart surgery, response syndrome
even when no coronary artery bypass is effected.w9 Figure 2 Among patients who are treated in intensive care units for
shows the release curves of cardiac markers cTnT, myoglobin sepsis or systemic inflammatory response syndrome (SIRS),
and CK-MB in 204 patients after open heart surgery. These elevated cTn have been detected in 36% (cTnT > 0.1 ng/ml)
troponin elevations do not necessarily reflect perioperative to 85% (cTnI . 0.1 ng/ml) of cases.8 w11 This wide range of
MI, but are more often attributable to myocardial cell injury prevalence is mainly due to the different underlying causes of
resulting from incomplete cardioprotection, reperfusion sepsis, the different troponin assays used, and the different
injury, and direct surgical trauma. Hence, it is difficult to cut-off values that were applied. In the majority of cases,
distinguish perioperative MI from these ‘‘normal’’ elevations significant coronary artery disease has been ruled out,
of cTn, especially as no accepted cut-offs have yet been indicating that other mechanisms underlie these troponin
defined. Nevertheless, recent trials have established a elevations. One reason for the release of cTn from damaged
significant association between elevated postoperative tropo- myocardial cells might be an oxygen supply–demand
nin values and increased mortality and morbidity.w10 Lehrke mismatch of the myocardium. As a consequence of fever
et al defined a cTnT concentration > 0.46 ng/ml 48 hours and tachycardia the oxygen demand of the myocardium is
after open heart surgery as being predictive for long term increased. Simultaneously, oxygen supply of the myocardium
mortality.6 is reduced due to systemic hypoxaemia from respiratory
failure, microcirculatory dysfunction, hypotension and some-
Elevated troponin in suspected ACS without times anaemia. In addition, local and circulating inflamma-
significant coronary artery disease tory markers including tumour necrosis factor a, interleukin
In symptomatic patients with suspected acute coronary 6 and reactive oxygen species, as well as bacterial endotoxins,
syndrome (ACS) and even in those with elevated cTn, it is may lead to direct myocardial injury by cytotoxic effects.w11
not uncommon that a significant culprit lesion is not detected Moreover, elevated cTn values provide prognostic informa-
by coronary angiography. It is tempting to speculate that a tion and the extent of cTn elevation seems to correlate with
platelet-rich thrombus superimposed on the ruptured plaque the severity of the disease process. Ver Elst et al demonstrated
has dissolved spontaneously or after antithrombotic treat- that cTnI-positivity was strongly associated with LV-dysfunc-
ment, or has dislodged leaving an insignificant atherosclero- tion (78% v 9% in cTnI-negative patients; p , 0.001). cTnI
tic lesion at the time of angiography. Nevertheless, the values were found to correlate significantly with the degree of
presence of a troponin elevation implies a higher risk for hypotensionw12 and APACHE II score.w11 Finally, in a study
death or AMI in these patients.7 Labelling of a positive by Spies and colleagues on 26 patients with sepsis, the group
troponin result as false positive in patients with a high of patients with cTnT values > 0.2 m/l had an increased

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 EDUCATION IN HEART

Figure 2 Release curves of cardiac

markers cTnT, myoglobin and CK-MB in
204 patients following open heart
surgery. Concentrations are displayed
as multiples of normal (mon). Cardiac
markers are elevated up to seven days
after open heart surgery.
990

mortality rate (83% v 38%, p = 0.02) compared to the group data) and values above 0.07 ng/ml predict all-cause mortality
with cTnT values below this value.8 (3.7%).w15 Conversely, normal troponin values are associated
with a good outcome. In several studies, the negative
Pulmonary embolism predictive value of normal troponins was determined at
In acute pulmonary embolism (PE) elevated cTn are found in up between 97–100%.9 w13 Especially in patients with moderate
to 50% of cases. For cTnT, rates of 32% and 50% were reported PE, defined by haemodynamic stability and right ventricular
depending on the cut-off used (0.1 ng/ml v 0.01 ng/ml, dysfunction, elevated cTn may help in guiding therapeutic
respectively).9 w13 Among 38 patients with PE, elevated cTnI management. It has been shown that patients with right
values (. 0.4 ng/ml) were seen in 47%.w14 Unfortunately, the ventricular dysfunction determined by echocardiography are
reasons why cTn appear in blood after PE remain unclear. It is at increased risk of adverse clinical outcome.w16 This risk is
believed that cTn are released from injured right ventricular 10-fold higher in the presence of elevated cTn (. 0.04 ng/ml)
myocardial cells due to the acute dilatation of the right ventricle justifying a more aggressive treatment approach such as
as a consequence of the abrupt increase of pulmonary artery thrombolysis or embolectomy.w17
pressure. Other possible reasons include reduced coronary
perfusion, hypoxaemia from perfusion–ventilation mismatch, Acute and chronic heart failure
systemic hypoperfusion, or a combination of these factors. Briefly, elevated cTn in heart failure (HF) are associated with
Studies investigating the release kinetics of cTnT in patients decreased left ventricular ejection fraction and correlate with
with PE showed that the peak cTnT was lower and persisted for severity of heart failure and prognosis. The aggravation of HF,
a shorter time compared to cTnT values in AMI.10 Hence, in ischaemic or non-ischemic, results from progressive myocyte
contrast to ACS, where cTn are released only after irreversible loss caused by necrosis and apoptosis.w18 Additional factors,
myocardial damage,11 in patients with PE, the brief appearance including the activation of renin–angiotensin–aldosterone and
of small amounts of cTn suggests that troponin elevation may sympathic nervous systems as well as inflammatory mediators,
be caused by the efflux of the free cytosolic pool of cTnT due to may contribute to myocardial injury. Lost myocytes are
transient membrane leakage.10 Figure 3 shows the differences in replaced by fibrotic tissue leading to progressive cardiac
the kinetics of cTnT and N-terminal pro-B type natriuretic dysfunction. cTn elevations in patients with HF reflect
peptide (NT-proBNP) in two patients with acute pulmonary myocardial injury. In the setting of decompensated HF, the
embolism who received thrombolysis or conservative treatment release of cTn is thought to be caused by excessive myocardial
with standard heparin to resolve pulmonary hypertension. wall tension from acute volume and pressure overload. In
Recently, cTn have emerged as important prognostic tools addition, increased wall strain leads to subendocardial
for risk stratification of patients with PE. Giannitsis et al ischaemia. In patients with chronic stable HF, elevated cTnI
showed that troponin-positive patients (> 0.1 ng/ml) were at values were found in 15–23% of cases (. 0.1 ng/ml).w19 w20
increased risk for a complicated in-hospital course including For cTnT, values above 0.1 ng/ml were reported in 10–15% of
death, prolonged hypotension, cardiogenic shock, and need cases.12 w21 There was no difference between the ischaemic and
for resuscitation.9 Elevated admission cTnT values correlate non-ischaemic group.12 w19 Of the patients admitted to hospital
significantly with severity of PE according to the grading because of acute HF, 52–55% had elevated cTnT values.w21 w22
system of Goldhaber (p = 0.003, r = 0.502, unpublished The presence of cTn in HF predicts a poorer short and long term

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EDUCATION IN HEART

heart disease in presumably healthy athletes.w26 w27 Hence,

elevated cTn could result from underlying subclinical heart
disease being unmasked by strenuous exercise. In a recent
study on 10 well-trained healthy athletes, who participated in
an ultra-marathon of 216 km in Death Valley at extreme
environmental conditions, we found that cTnT values
remained below detection limits during and after the run, 991
even in one athlete who developed severe exercise-induced
rhabdomyolysis with a CK value of . 27 000 U/l (unpublished
data). Further information is needed to clarify some
inconsistencies in this field.

Acute pericarditis/myocarditis
In addition to AMI and acute pulmonary embolism, acute
pericarditis/myocarditis is commonly diagnosed in patients
with elevated troponins presenting to the emergency room
with acute chest pain. Although troponins are not present in
the pericardium, cTnI was reported to be elevated in 32–49%
of cases of pericarditis,w28 w29 as a consequence of the
involvement of the epicardium in the inflammatory process.
In patients with acute myocarditis cTnI concentrations have
been found to be increased in 34% of patients.w30
Usually in patients with suspected pericarditis, coronary
angiography is performed to rule out MI. In the absence of
significant coronary disease, endomyocardial biopsies (EMB)
are taken to establish the diagnosis. However, in only 10–25%
of patients with clinically suspected myocarditis have EMB
shown the typical myocytolysis and lymphocytic infil-
trates.w31 Elevated cTnT values are seemingly more sensitive
than EBM and may confirm the clinical suspicion of
myocarditis, even in the absence of histological signs of
Figure 3 Time course of cardiac troponin T (cTnT) and N-terminal pro-
myocarditis.w30 w31
brain natriuretic peptide (NT-proBNP) in two patients with acute
pulmonary embolism. Patient A was treated successfully with
thrombolysis and exhibited a rapid decrease of both biomarkers (cTnT: Cardiotoxic chemotherapy
blue open circles; NT-proBNP: red solid circles) to normal values within Most chemotherapeutic agents, including anthracyclines,
48 hours. Patient B received conservative treatment with standard alkylating agents, anti-metabolites or anti-microtubules,
heparin and showed an uncomplicated in-hospital course. Note the can have cardiotoxic side effects. Observed adverse cardiac
slower decline of both biomarkers. events following chemotherapy are ischaemia (anti-metabo-
lites, alkylating agents), endomyocardial fibrosis and cardio-
outcome. Patients with increased troponin values have myopathy (alkylating agents—for example, anthracyclines),
significantly lower ejection fractions, higher clinical grading pericarditis (alkylating agents—for example, cyclophospha-
of HF (New York Heart Association functional class), and mide), and different types of arrhythmias (anti-micro-
greater mortality (hazard ratio 6.86).13 w23 Moreover, serial tubules—for example, paclitaxel).w32 Routinely, cardiac
measurements of cTn could provide additional prognostic toxicity is detected by echocardiography, ECG, or endomyo-
information.w21 A decrease of cTn is associated with an cardial biopsies. Recent data suggest that biochemical
improvement of left ventricular function while persistently markers such as troponins and natriuretic peptides could be
elevated or rising troponin values were observed in patients useful in identifying patients at risk for myocardial damage
who eventually died.w23 and in monitoring the development of cardiac damage.w33
w34
However, their role in predicting clinical and subclinical
Strenuous exercise myocardial damage and in influencing therapeutic strategies
Several studies have reported the appearance of cTnT or cTnI remains to be evaluated by future clinical trials.
after strenuous ultra-endurance exercise.14 w24 w25 However,
neither the mechanisms nor the prognostic significance of High frequency ablation/external current
elevated cTn are clear. Interestingly, following prolonged cardioversion/defibrillator shocks
endurance exercise, only transient elevations of small Following radiofrequency catheter ablation, an elevation of
amounts of cTn that decreased or normalised within 24 cTn has been reported in more than 90% of patients and is
hours after the race have been detected.14 These changes in related to direct traumatic myocardial injury,w35 but these
plasma concentrations are very different from those found in elevations have no prognostic significance. External current
MI. This led to the assumption that elevated cTn could result cardioversion (ECV) of atrial fibrillation or flutter caused no
from a transient release of the cytoplasmatic pool of cTnT and or only small increases of cTnIw36 and no increases of
cTnI and not from continuous release of structurally bound cTnT,w37 especially when biphasic modus was used.w36
troponin after myocardial necrosis. On the other hand, Repetitive defibrillator shocks because of ventricular tachy-
autopsy findings and extensive cardiac examinations have cardia or fibrillation or mechanical cardiac resuscitation are
revealed critical coronary heart disease or significant structural known to release cTn. These elevations seem to indicate the

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 EDUCATION IN HEART

diagnosis of AMI presenting with life-threatening arrhyth- Unfortunately, there are no approved protocols on the
mias rather than myocardial damage caused by ECV.w38 frequency and intervals of blood sampling.

Cardiac infiltrative disorders Troponins in asymptomatic patients without suspicion

In systemic amyloidosis, the extent of cardiac involvement is of ACS
tightly linked to the clinical outcome. In one retrospective In asymptomatic patients with ESRD interpretation of
992 analysis on 261 patients with systemic amyloidosis, elevated troponin values is much more difficult.
Dispenzieri and colleagues showed that the median survival Cardiovascular disease is by far the leading cause of death
of patients with detectable cTnI and cTnT was significantly in patients with ESRD, hence a clinically silent cardiac
reduced (six and eight months, respectively) compared to pathology can always underlie these troponin elevations.
that of patients with normal values (22 and 21 months, Most studies on prevalence and prognostic impact of cTn in
respectively).w39 It is believed that extracellular amyloid patients with ESRD were conducted in patients with
deposition causes compression of myocytes with subsequent haemodialysis as renal replacement therapy. Only sparse
release of cTn. In many patients, the diagnosis of cardiac information exists for peritoneal dialysis patients. Both cTnT
involvement is made incidentally by a positive troponin result and cTnI are commonly increased in asymptomatic patients
in the absence of signs or symptoms of ACS. Therefore, it is with ESRD, even when there is no suspected myocardial
tempting to speculate that at least in patients with a systemic ischaemia. Using third generation assay for cTnT, up to 53%
disease with potential involvement of the heart, routine (10% coefficient of variation, . 0.03 ng/ml) of haemodialysis
measurement of cardiac troponin could allow earlier detec- patients had elevated cTnT values,16 w45 w46 while elevation of
tion of prognostically adverse cardiac involvement. cTnI was less frequently observed (up to 19%).w47–49 This
finding led to the assumption that cTnI would be a more
Post-heart transplantation specific marker for myocardial ischaemia in patients with
Since the early 1990s it has been known that cTn can be ESRD than cTnT. This is not true, however, and there are
elevated in nearly all heart transplant recipients for up to three some possible explanations for the different prevalence of the
months after successful transplantation.w40 w41 In the following two troponins. First, as mentioned above, the cytosolic
years, cTn were found to be related to allograft rejection. In 1998 unbound fraction of cTnI is half of that of cTnT (approxi-
Dengler and colleagues found that cTnT values increased in mately 3.5% v 7%). Secondly, the cTnI molecule is more
parallel with the severity of graft rejection according to the positively loaded than cTnT and has a higher affinity for the
ISHLT (International Society of Heart and Lung negative loaded dialysis membrane.17 Thirdly, cTnI is only
Transplantation) grading system. In the group with severe released in complex with cTnC, so that epitopes necessary for
rejection (ISHLT grade 3 and 4), nearly all patients had elevated the antibody binding in the immunoassay could be covered.w50
cTnT values; if cTnT was negative, significant rejection could be Finally, the cTnI protein is more unstable than cTnT and might
excluded with a probability of 96.2%.15 Moreover, in a study on therefore undergo fragmentation, oxidation and phosphoryla-
110 heart transplant recipients, Labarrere et al showed that cTnI tion which might influence epitope binding.w51
was elevated in all patients during the first month following
heart transplantation; however, only those with persistently Why do cTn appear in blood in patients with ESRD?
elevated cTnI values during the follow-up period of 12 months The answer to this question has been sought but no satisfying
were at increased risk for subsequent development of coronary explanation has been found yet. Several hypotheses have been
artery disease and graft failure.w41 Today, endomyocardial discussed. First, a re-expression of cTn in uraemic myopathic
biopsies are the gold standard for diagnosis of allograft skeletal muscle was assumed. In 1997, McLaurin and colleagues
rejection. Cardiac troponins can provide additional information, reported expression of cTnT, but not cTnI, in four of five skeletal
especially if they are negative. muscle biopsies of haemodialysis patients.w52 In several
subsequent studies, re-expression of cardiac isoforms in skeletal
Myocardial contusion muscle could be convincingly excluded.18 w53
In the setting of severe blunt chest trauma, cardiac contusion Secondly, reduced renal clearance of cTn in ESRD patients
occurs in 3–56% of cases. Because cardiac contusion may was widely believed to contribute to elevated cTn values.
cause lethal arrhythmias and heart failure, diagnosis is of In addition, increased cTn values can be caused by
great importance. Cardiac troponins have been reported to be concomitant diseases known to be associated with cTn
elevated in 15–45% of patients with cardiac contusion.w42 w43 release such as severe HF, left ventricular hypertrophy
Their high negative predictive value (between 21–94%) helps leading to a subendocardial ischaemiaw54 or renal anaemia
in precluding cardiac injury after severe chest traumaw44 in with consecutive oxygen supply–demand mismatch.
conjunction with standard echocardiography. Recent evidence suggests that cTnI is fragmented into
pieces of 8–25 kD that are normally released in very small
RENAL FAILURE/END STAGE RENAL DISEASE quantities in the blood and are sufficiently small enough to
Troponins in symptomatic patients with suspected ACS be cleared by the healthy kidney.w55 In patients with ESRD,
In symptomatic patients with suspected ACS, elevation of cTn these microfragments cannot be cleared from blood and are
is associated with adverse outcomes regardless of the degree detectable by immunoassays.
of renal insufficiency.4 However, in patients with advanced
renal failure, cTn concentrations develop higher peaks and Are troponin-positive patients with ESRD at increased
troponin remains detectable for longer periods. Given that risk for death?
patients with end stage renal disease (ESRD) already have Several large observational studies have clearly shown that
elevated troponin values before the acute cardiac event, elevated concentrations of cTnT in patients with ESRD are
repeated early measurements are needed to detect a valuable, independent, short and long term predictors of
pronounced rise indicating an acute ischaemia. cardiac death.16 19 w45 In a prospective study by Apple et al on

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EDUCATION IN HEART

In compliance with EBAC/EACCME guidelines, all authors participating

Table 2 Analytical causes of false-positive troponins in Education in Heart have disclosed potential conflicts of interest that
might cause a bias in the article
c Rhabdomyolysis in first and second generation troponin assays
c Heterophilic antibodies
c Rheumatoid factor
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consensus document of the Joint European Society of Cardiology/American
c Microparticles
c Analyser or analyte malfunction
College of Cardiology committee for the redefinition of myocardial infarction.
J Am Coll Cardiol 2000;36:959–69.
993
c This paper is of great importance because it completely changed our
definition of MI. Since the year 2000, MI is defined by an elevation of
cardiac troponin I or T in the clinical setting of ischaemia.
2 Parmacek MS, Solaro RJ. Biology of the troponin complex in cardiac
myocytes. Prog Cardiovasc Dis 2004;47:159–76.
733 patients with chronic intermittent haemodialysis, the two 3 Ottani F, Galvani M, Nicolini FA, et al. Elevated cardiac troponin levels
year mortality rate rose with increasing cTnT, reaching 47% for predict the risk of adverse outcome in patients with acute coronary syndromes.
Am Heart J 2000;140:917–27.
cTnT > 0.1 ng/ml. The adjusted relative risk of death for 4 Aviles RJ, Askari AT, Lindahl B, et al. Troponin T levels in patients with acute
elevated cTnT (. 99th centile) was 3.9 (confidence interval 1.9 coronary syndromes, with or without renal dysfunction. N Engl J Med
2002;346:2047–52.
to 7.9; p , 0.001). In direct comparison, the prevalence of a c This large prospective study on 7033 patients with acute coronary
positive troponin I result across all cut points was much lower syndrome and concomitant renal impairment clearly demonstrated that
than the prevalence of cTnT. In addition, cTnI failed to predict elevated cardiac troponin T predicts short term prognosis regardless of
the creatinine clearance.
outcomes in patients with ESRD. Accordingly, the US Food and 5 Ricciardi MJ, Davidson CJ, Gubernikoff G, et al. Troponin I elevation and
Drug Administration has only recommended the use of cTnT for cardiac events after percutaneous coronary intervention. Am Heart J
2003;145:522–8.
risk stratification in ESRD patients. c In their prospective study on 286 patients the authors showed that
elevated cardiac troponins following PCI are equally predictive for
Do false-positive troponin results exist? major adverse cardiac event, especially for early repeat
vascularisation, as CK-MB.
By definition, 1% of healthy volunteers with minor elevation 6 Lehrke S, Steen H, Sievers HH, et al. Cardiac troponin T for prediction of short-
of cTnT must be labelled false positive because only 99% of and long-term morbidity and mortality after elective open heart surgery. Clin
Chem 2004;50:1560–7.
tested healthy volunteers had cTnT values below the lower 7 Dokainish H, Pillai M, Murphy SA, et al. Prognostic implications of elevated
limit of detection (99th centile). In clinical practice, an troponin in patients with suspected acute coronary syndrome but no critical
epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol
elevation of cTn is more often misinterpreted as false-positive 2005;45:19–24.
when significant coronary artery disease has been ruled out 8 Spies C, Haude V, Fitzner R, et al. Serum cardiac troponin T as a prognostic
marker in early sepsis. Chest 1998;113:1055–63.
by coronary angiography in a symptomatic or asymptomatic 9 Giannitsis E, Muller-Bardorff M, Kurowski V, et al. Independent prognostic
patient. This labelling is inappropriate and frequently leads to value of cardiac troponin T in patients with confirmed pulmonary embolism.
cessation of further diagnostic work-up or adequate treat- Circulation 2000;102:211–7.
c In this study conducted by our group, elevated cTnT values in acute
ment. Usually, cTn confirms and supports a clinical suspicion pulmonary embolism were identified as a prognostic risk factor of in-
or diagnosis. The usefulness of troponin largely depends on hospital mortality.
10 Muller-Bardorff M, Weidtmann B, Giannitsis E, et al. Release kinetics of
the quality of the clinical judgement and the level of clinical cardiac troponin T in survivors of confirmed severe pulmonary embolism. Clin
probability. Chem 2002;48:673–5.
11 Katus HA, Remppis A, Neumann FJ, et al. Diagnostic efficiency of troponin T
In patients with a high probability of ACS, absence of a measurements in acute myocardial infarction. Circulation 1991;83:902–12.
significant lesion does not contradict the presence of an c This study conducted in the early 1990s is of major importance because
unstable plaque. In patients with low or intermediate it showed the outstanding role of cTnT for the diagnosis of AMI.
12 Missov E, Mair J. A novel biochemical approach to congestive heart failure:
probability of ACS other differential diagnoses should be cardiac troponin T. Am Heart J 1999;138:95–9.
considered. Thus, frequently cTn is the only indicator of c In a study on 80 patients with congestive heart failure, Missov and
colleagues found that the cTnT level represents the severity of the
cardiac pathology in numerous cardiac diseases or systemic disease and that cTnT could be a molecular marker for non-invasive
diseases with cardiac involvement. Elevated troponins could monitoring of congestive heart failure from a structural perspective.
13 La Vecchia L, Mezzena G, Zanolla L, et al. Cardiac troponin I as diagnostic
therefore open an avenue for more precise or specific and prognostic marker in severe heart failure. J Heart Lung Transplant
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14 Neumayr G, Gaenzer H, Pfister R, et al. Plasma levels of cardiac troponin I
The term false positive troponin should be restricted to after prolonged strenuous endurance exercise. Am J Cardiol
analytical issues. A summary of potential reasons is given in 2001;87:369–71, A10.
table 2. The continuous improvement of assay performance 15 Dengler TJ, Zimmermann R, Braun K, et al. Elevated serum concentrations of
cardiac troponin T in acute allograft rejection after human heart
has reduced rates of analyte-related false positive results over transplantation. J Am Coll Cardiol 1998;32:405–12.
the years by eliminating heparin interference, or cross- 16 Apple FS, Murakami MM, Pearce LA, et al. Predictive value of cardiac
troponin I and T for subsequent death in end-stage renal disease. Circulation
reactivity with skeletal muscle. For example, first and second 2002;106:2941–5.
generation troponin assays often yielded positive results in 17 Wu AH, Feng YJ. Biochemical differences between cTnT and cTnI and their
significance for diagnosis of acute coronary syndromes. Eur Heart J
patients with severe skeletal muscle injury because of an 1998;19:N25–9.
unspecific binding of skeletal muscle troponin T to the test 18 Haller C, Zehelein J, Remppis A, et al. Cardiac troponin T in patients with end-
tube.20 Using a third generation cTnT assay, in a recent study stage renal disease: absence of expression in truncal skeletal muscle. Clin
Chem 1998;44:930–8.
on 10 ultra-marathon athletes, we found no cross-reactivity 19 Dierkes J, Domrose U, Westphal S, et al. Cardiac troponin T predicts mortality
between cTnT and CK, neither in exercise-induced skeletal in patients with end-stage renal disease. Circulation 2000;102:1964–9.
20 Lavoinne A, Hue G. Serum cardiac troponins I and T in early posttraumatic
muscle trauma nor after rhabdomyolysis (unpublished data). rhabdomyolysis. Clin Chem 1998;44:667–8.
Additional references appear on the Heart website—http://
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Additional references appear on the Heart
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Authors’ affiliations
S Korff, H A Katus, E Giannitsis, Department of Medicine III, University
of Heidelberg, Germany

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