International Journal of Cardiology 164 (2013) 282294

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Review

Cardiac biomarkers in acute myocardial infarction

Sally J. Aldous
Christchurch Hospital, Christchurch, New Zealand

a r t i c l e

i n f o

Article history:
Received 3 October 2011
Received in revised form 16 December 2011
Accepted 26 January 2012
Available online 17 February 2012
Keywords:
Troponin
High-sensitivity troponin
Myocardial infarction
Prognostic utility
cardiac biomarkers
Novel biomarkers

a b s t r a c t
Each year, a large number of patients are seen in the Emergency Department with presentations necessitating
investigation for possible acute myocardial infarction. Patients can be stratied by symptoms, risk factors and
electrocardiogram results but cardiac biomarkers also have a prime role both diagnostically and prognostically. This review summarizes both the history of cardiac biomarkers as well as currently available (established and novel) assays. Cardiac troponin, our current gold standard biomarker criterion for the diagnosis
of myocardial infarction has high sensitivity and specicity for this diagnosis and therapies instituted in
patients with elevated troponin have been shown to inuence outcomes. Other markers of myocardial necrosis,
inammation and neurohormonal activity have also been shown to have either diagnostic or prognostic utility,
but none have been shown to be superior to troponin. The measurement of multiple biomarkers and the use of
point of care markers may accelerate current diagnostic protocols for the assessment of such patients.
2012 Elsevier Ireland Ltd. All rights reserved.

1. The history of cardiac biomarkers

Biochemical markers of ischaemic cardiac damage, used to diagnose
AMI, have been used for over half a century. Aspartate transaminase
(AST) was found to be elevated in patients with AMI in 1954 and was
the rst cardiac biomarker to be used in clinical practice. AST catalyzes
the reversible transfer of an -amino group between aspartate and
glutamate and, as such, is an important enzyme in amino acid metabolism. AST is found in the heart, liver, skeletal muscle, kidneys and brain
and is currently used clinically as a marker for liver health [14]. In
1959, the world health organization (WHO) produced a denition for
AMI, dened as at least 2 out of; symptoms suggestive of cardiac ischaemia, ischaemic electrocardiogram (ECG) changes and elevated cardiac
biomarkers, with AST as the biomarker of choice [5]. As the use of AST
became more widely used, its lack of specicity for cardiac tissue injury
was appreciated [14].
Plasma creatine kinase (CK), an enzyme that catalyzes the transfer
of high-energy phosphate from creatine phosphate to adenosine triphosphate, is rapidly released during muscle damage. In 1959, it
was demonstrated that CK was an extremely sensitive index of skeletal
muscle disease and one year later, it was also seen in patients with AMI
[1,2,4]. In 1960, lactate dehydrogenase (LDH), an enzyme that catalyses
the reversible oxidation of lactate to pyruvate, was discovered. However,
LDH is found in all cells and, like AST, is very nonspecic. CK was found to

Cardiology department, Christchurch Hospital, Riccarton Road, Christchurch, New

Zealand. Fax: + 64 33641415.
E-mail address: sally.aldous@cdhb.govt.nz.
0167-5273/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2012.01.081

be more specic than either AST or LDH because low levels of CK in the
liver less confound results in those with hepatic dysfunction. In 1979,
WHO recommended CK, AST and LDH as the biomarker components
for diagnosis of AMI. Despite this, specicity remained a problem, especially in patients with muscle and hepatic diseases or injury [1,2,4].
Advances in electrophoresis allowed identication of more cardiospecic iso-enzymes of both CK and LDH. Cardiac muscle has higher
CKMB levels (2530%) compared with skeletal muscle (1%), which
is mostly CKMM. The measurement of CKMB, CKMB fraction or
CKMB/CKMM ratio was a more specic marker for AMI. Cardiac muscle is also particularly rich in LDH 1 (or HHHH) and 2 (or HHHM)
compared with skeletal muscle, which contains primarily LDH 4 and
5. In the well-oxygenated heart, H subunits are more prominent but
during infarction they become reduced, thus lowering relative ratios
of LDH 1 or H subunits. Unfortunately these CK and LDH isoenzyme
assays remained lacking in specicity [1,2,69].
Electrophoretic assays were rst developed in 1966 but lacked sensitivity. This improved with advances in chromatography in 1974 and the
production of quantitative assays by the close of the 1970s [1,6,7,911].
However, the detection and measurement of biomarkers was revolutionized by the development of immunoassays (initially congured
with polyclonal antibodies and then, in the 1980s, with monoclonal antibodies) as well as technical advances in automation [1,6,7,911].
Monoclonal antibodies allowed measurement of CKMB mass. This
enabled earlier and more rapid detection of myocardial damage and
was also more sensitive and specic than the original CKMB activity
assay. However, with further research it was realized that even CKMB
mass was elevated in a variety of situations as a result of skeletal muscle
injury as well as in non-ischaemic cardiac disease and certain malignancies [13,12,13].

S.J. Aldous / International Journal of Cardiology 164 (2013) 282294

Recognition of the lack of specicity of CKMB for AMI underpinned

the search for a test with superior performance. The contractile
proteins of the myobril include myosin, actin, tropomyosin and the
troponin complex. When cardiac myocytes are acutely damaged and
the integrity of the cell membrane is lost, myosin fragments are released into the circulation from a soluble cytoplasmic pool of myosin
light chains. Myosin light chain release was thought to be a potential
marker for AMI [14,15]. In itself, this discovery was disappointing, as
peak levels of myosin light chains did not signicantly vary between
patients presenting with AMI, unstable angina or non-cardiac chest
pain. However, this improved understanding lead on to a pivotal breakthrough, the discovery of troponin.
Troponin has three subunits. Troponin C (TnC) binds to calcium
ions to produce a conformational change in troponin I (TnI), troponin
T (TnT) binds to tropomyosin, interlocking them to form a troponin
tropomyosin complex and TnI binds to actin in thin myolaments to
hold the troponintropomyosin complex in place [1619]. Troponin
is found in both skeletal and cardiac muscle but cardiac TnI (cTnI)
and TnT (cTnT) isotypes have additional residues on the N-amino
terminal and can therefore be readily identied as cardiac type [20].
TnC cannot.
Troponin, as a constituent of the muscle myobril, was discovered in
the 1970s but sensitive radioimmunoassays for cardiac troponin (cTn)
were not developed until the late 1980s. cTn was proposed as a specic
marker of myocardial necrosis but the high sensitivity of cTn compared
with CK and CKMB had not been envisaged. Early studies showed that
cTn was raised in AMI (as diagnosed by WHO criteria) [7,2027] with
high sensitivities and specicities [7,12,17,22,24,25,2838] and had
the advantage over CKMB in differentiating cardiac from skeletal muscle injury [7,39]. Studies in the 1990s also showed that signicant numbers of patients classed as unstable angina (as opposed to AMI) by
conventional WHO criteria, had elevated cTn levels [25,26,36,3844].
Furthermore, cTn positive patients exhibited an increased risk of subsequent death [29,36,38,4550], AMI [21,38,43,44,47,5153], need for
revascularization [40,45,46,48,54] and readmission [36] than cTn negative patients, even though other baseline characteristics and symptoms
appeared matched [40,52]. Those with unstable angina and cTn elevation were thought to have unstable plaque with subsequent platelet
emboli leading to micro infarcts, as opposed to stable plaque in those
without elevations [21,27,33,39]. Subsequent studies showed that
various medical and interventional techniques already instituted into
practice or under investigation, were rened as the relationships with
cTn and outcomes became apparent. Such interventions included low
molecular weight heparin [18,5560], glycoprotein llbllla inhibitors in
patients with refractory angina and in patients undergoing PCI
[18,5658,60,61], antiplatelet therapy [62], 2448 h of telemetry [60],
angiography as the preferred investigation [56,57] and revascularization [46,49,57,63].
In 2000, guidelines for the diagnosis of AMI were changed with
the new denition suggesting cTn as the preferred biomarker [64].
Initial scepticism, due to a signicant increase in the positive rate,
a lack of assay standardization and a lack of conrmed correlation
between cTn and histopathology, was eventually replaced by widespread acceptance. Assay variability was acknowledged. This led to
recommendations for only cut-off values with a coefcient of
variation (CV) of b10% to be employed. The recommended cut-off
value was now suggested at the 99th percentile, much lower than
values previously used in practice. Many assays were not able to
meet precision guidelines at this level. This change in guidelines
had follow through effects. There was an increase in incidence of
diagnosed AMI [6570] although a small proportion of patients fullling WHO criteria for AMI were no longer considered AMI by the new
denition [69]. There was an increase in coronary care unit admissions [68], an increase in number of angiograms performed [68] and
a reduction in length of stay in patients without AMI [68]. Long
term, there have possibly been decreases in post-AMI mortality

283

[70,71] and heart failure admissions as the primary diagnosis [71].

The use of cTn as the biomarker of choice in AMI was further
endorsed in 2007, by the World Heart Federation Task Force for the
Redenition of Myocardial Infarction [72].
There was and is only one manufacturer for cTnT (Boehringer
Mannheim, acquired by Roche Diagnostics the late 1990s, and test
platform Elecsys) and therefore the assay is standardized [7375].
There are many manufacturers of cTnI assays which vary from each
other by assay format, antibodies used, specicity to different
epitopes of complexed, free and modied cTn, types of indicator
molecule and detection technique (spectrophotometric, uorescent,
chemiluminescent or electrochemical) [76]. They may also have varying interference from pre-analytical variables such as haemolysis,
icterus, lipaemia, anticoagulant, ascorbic acid levels, biotin levels,
the use of streptokinase or ruthenium, heterophile antibodies and
autoantibodies, which can lead to both false negatives and false positives [7678]. This leads to differences in analytical sensitivity
between assays and therefore different levels at which there is a
b10% coefcient of variation and different limits of detection (LOD)
[7678]. The lack of standardization has lead to discrepancies in
cut-point values [74,75,79,80] with over a 3040 fold differences
documented [81,82] and in the past have been notorious for poor
performance at the lower end of the reference range. However, later
generation assays are much improved and now many meet or are
near to meeting, precision guidelines [81,8385]. The early cTnT
assay had slightly limited specicity in patients with skeletal muscle
disease because of cross reactivity of the signal antibody with skeletal
muscle and re-expression of foetal forms of cTnT (cTnI isoforms are
not present in foetal skeletal muscle) in conditions such as rhabdomyolysis and chronic skeletal muscle diseases such as muscular dystrophy and myositis. These isoforms are not detected by the assay
used today [73,74,79,80,86,87].
There have been many studies comparing troponin assays
[74,75,79,86,8892] demonstrating that correlation and concordance
is variable [44,74,9093], however, all have been shown to be sensitive
and specic tests for the diagnosis of AMI.
2. Current cardiac biomarkers
2.1. Biomarkers of myocardial necrosis
2.1.1. Troponin
Because of the recommendations to use only cTn assays which are
reliable (b10% coefcient of variation) at the decision limit (99th percentile), there has been development of high-sensitivity troponin
assays (hs-cTn) to increase the analytical, and thus clinical, sensitivity
for detection of myocardial injury. Such an approach may identify
more patients at risk and permit earlier diagnosis [83,94101]. This
may allow more rapid triage to intensive and invasive treatment
strategies in those with elevations in hs-cTn and possibly earlier
stress testing or even discharge without such testing in those without
elevations [97,102]. In the FRISC II subgroup analysis, comparing the
results of several cTnT and cTnI assays, 1012% of patients with a
poor prognosis at 1-year follow-up were identied only by the cTn
assay that had the highest analytical sensitivity [103]. The use of
lower troponin cutoff concentrations also better separated the rate
of clinical events at 1 year between groups receiving invasive versus
non-invasive treatment. Other studies conrm this prognostic utility
[85,104106].
The hs-cTn assays also allow detection of circulating cTn in
healthy individuals, and therefore denition of a true normal range
[99,100]. However, although hs-cTn assays will allow rened denition of the upper limit of normal, their clinical application will also
require revisiting specicity as the upper 1% of the normal range
and non-coronary causes of cardiac injury may now more frequently
confound the effort to rule out AMI [100].

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S.J. Aldous / International Journal of Cardiology 164 (2013) 282294

It has become evident that although elevations in cTn reect myocardial damage, they do not indicate its mechanism. In addition to
spontaneous AMI secondary to plaque rupture and acute coronary
occlusion, AMI can be secondary to the ischaemia produced either
by increased oxygen demand or decreased supply, e.g. coronary
artery spasm, coronary embolism, anaemia, arrhythmias, hypertension or hypotension. Therefore cTn may be raised in coronary, noncoronary cardiac as well as non-cardiac conditions such as sepsis
[72,82,96,107]. cTn has also been shown to be raised in patients
with renal failure without symptoms of ACS. These patients have
been shown to have increased cardiac risk and it has been suggested
that the marker may represent subclinical myocardial ischaemia
especially when raised acutely. However, cTn can be raised chronically
in these patients. Obialo et al found that 50% of patients with elevated
cTn and end-stage renal disease had coronary arteries free from ow
limiting stenoses on angiography [96]. Other associations such as uraemic myo/pericarditis, congestive cardiac failure, left ventricular hypertrophy and diabetes suggest cTn release in these patients is not always
AMI related [51,74,75,86,108].
Patients with raised cTn may have normal coronary angiography
even in a setting of apparent spontaneous AMI. Whether these represent false positives or whether unstable plaque/plaque rupture with
attendant microscopic myocyte ischaemia and injury has been
successfully treated by intensive antithrombotic/antiplatelet therapy
prior to angiography is unclear. Nevertheless, cTn positive patients
with normal angiograms still have increased future risk compared
with cTn negative patients (although lower risk than cTn positive
patients with abnormal angiograms).
Because of these facts, troponin results must be interpreted within
the clinical context in which they are measured [108]. An elevated
value of cTn in the absence of clinical evidence of ischaemia should
prompt consideration of aetiologies other than spontaneous AMI or
plaque rupture [72,99], especially as cTn positive patients are treated
more aggressively with potent antiplatelet therapies and early angiography i.e. procedures and treatments which carry risks.
In order to aid differentiation between AMI and other conditions
(in particular chronic from acute elevations), it has been suggested
that observing the pattern of cTn using serial measurements can
increase specicity as increasing values may signifying new onset
infarction and decreasing values may signifying resolving infarction.
The National Academy for Clinical Biochemistry has recommended
changes in cTn of 20% (i.e. greater than imprecision levels assuming
up to a 10% CV when levels are around the 99th percentile) from
elevated baseline values (i.e. those with pathological levels of cTn).
They make no recommendation on a threshold change from normal initial levels [109]. If this dynamic change is not present, other diagnoses
should be considered [84,97,100,110,111]. However, other acute illnesses such as myocarditis, takotsubo syndrome, pulmonary embolism
and sepsis have also been associated with acute cardiac injury. Recent
studies have shown that absolute rather than delta values in cTn [112]
and absolute changes rather than relative changes [113] perform better
in this setting. Also, those with increasing or decreasing cTn have been
shown to have higher incidence of short-term adverse events compared
to patients with stable cTn [96,110].
Other emerging concerns with these new hs-cTn assays include
contributions from nonspecic binding at very low cTn concentrations [94], contribution of biological variation in cTn over time [94]
as well as the other pre-analytical factors listed previously [82].
2.1.2. Myoglobin
Myoglobin, is a low molecular weight, cytoplasmic haem protein.
It has been the most sensitive conventionally assayed early marker
of AMI and can be raised as early as 1 h from onset of infarction.
Unfortunately, its specicity for AMI is low, being raised in other conditions such as skeletal muscle disease or injury, which need only be
minor, and renal impairment [1,3,7,8,12,27,114116]. Nevertheless,

use of myoglobin on presentation, can aid provisional diagnosis and

risk stratication in the early hours after symptom onset. Myoglobin
has also been shown to predict mortality and still plays a role in the
clinical assessment of patients with cardiac symptoms in many clinical centres [1,3,7,8,12,27,114116].
2.1.3. Heart fatty acid binding protein (hFABP)
hFABP is a small, 132 amino acid, soluble protein, with general
characteristics resembling myoglobin. It is a cytosolic protein that is
abundant in the heart and is involved in myocardial lipid homeostasis. Because of its low molecular weight and cytoplasmic location, it
is readily released into the circulation after myocardial injury and
maybe helpful in the diagnosis of AMI in patients presenting early
[118120]. It is highly but not uniquely cardiac-specic, also being
expressed at low levels in extra-cardiac tissues including skeletal
muscle and the kidneys [117]. It is unsuitable as a test for patients
presenting >6 h from onset of symptoms due to rapid renal clearance
[120122]. hFABP has also been shown to independently predict
mortality in patients with ACS [123]. The use of this marker has
never become main stream although investigations are ongoing.
2.1.4. Ischaemia modied albumin
During acute ischaemia the N-terminal site of albumin is altered, reducing its binding capacity; the modied protein is termed ischaemiamodied albumin (IMA). Although, levels of IMA are much higher in
those with ischaemia than without, the sensitivity of IMA for AMI is
insufcient to compete with other current markers and specicity is
low. Overall, studies do not support its use as an effective diagnostic
or prognostic marker [119,124127].
2.2. Biomarkers of Inammation
Coronary artery disease is an inammatory process. Atherosclerotic
plaque formation begins with endothelial cell injury thought to be triggered by a range of factors including smoking, diabetes, hypertension
and dyslipidaemia. Dyslipoproteinaemias such as elevated low density
lipoprotein (LDL)-cholesterol, play a central role in atherosclerosis. An
elevated LDL concentration is pro-atherogenic because LDL is intimately
linked to oxidative and inammatory processes in the arterial wall. Impaired endothelial cells respond by activating adhesion molecules and
secreting pro-inammatory chemokines [128,129]. These attract monocytes (which then multiply and mature into active macrophages) and T
lymphocytes. Eventually a plaque is formed consisting of a large lipid
core, a thin brous cap, and an active inammatory cell inltrate. AMI
results from plaque rupture or supercial erosion, stimulating the
secretion of pro-inammatory and pro-coagulant substances which
may trigger formation of occlusive thrombus [128,129]. Inammatory
processes therefore not only promote initiation and progression of atheromas but also contribute to the precipitation of thrombotic complications.
Consequently, it has been speculated that markers of inammation are
raised in patients with AMI.
2.2.1. C-reactive protein
C-reactive protein (CRP), an acute-phase reactant produced by
hepatocytes in response to stimulation by inammatory cytokines,
primarily IL-6, is the most widely used inammatory marker. In the
absence of transient acute disturbances in CRP in response to certain
stimuli such as infections, injuries etc, CRP levels in individuals otherwise
remain relatively constant. CRP, in itself, also has a pro-inammatory
effect by inducing the expression of adhesion molecules and other
inammatory cells. CRP has been implicated in vascular dysfunction
and in the progression of atherosclerosis, and subsequently has been
shown to predict future cardiovascular events, including rst-ever AMI,
stroke and development of peripheral arterial disease [129].
It has also been shown that CRP is raised in patients with unstable
coronary syndromes, but specicity and sensitivity are not sufcient

S.J. Aldous / International Journal of Cardiology 164 (2013) 282294

for use as a reliable diagnostic marker. It is, however, a signicant

predictor of poor outcome. Studies including the TIMI 11B sub-study
in 1998 and GUSTO IV analysis in 2003 conrmed the short-term prognostic value of CRP in acute coronary syndromes even in patients with
negative cTn results [129131]. Treatment of healthy individuals with
Rosuvastatin (Justication for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study) in response to elevations
in high-sensitivity CRP, even in those without hyperlipidaemia, signicantly reduced the incidence of major cardiovascular events [132].
However, in assessing outcome in patients with ACS studies
showed that cTn out-performed CRP for mortality prediction. In addition to this, it was found that CRP has no relationship with the early or
late occurrence of AMI, unlike cTn, and more importantly, only cTn
but not CRP is helpful in therapeutic triage of such patients by identifying those who will benet from an invasive over a conservative
strategy or antithrombotic treatment [129,133,134].
Nevertheless, in 2003, the American Heart Association (AHA) and
the Centres for Disease Control and Prevention issued a scientic
statement that suggested the use of high-sensitivity CRP as an optional
risk factor measurement in patients with ACS [128]. With this interest in
inammation and ACS, attention turned to other candidate inammatory biomarkers.
2.2.2. Pro-inammatory markers
The major pro-inammatory markers include IL-6 and TNF-. The
immuno-inammatory response to injury resulting from ischaemia
and reperfusion of infarcted myocardium is associated with the induction of many cytokines including IL-6 and TNF-. IL-6 is involved
in inammatory cell recruitment and activation, stimulates the liver
to produce acute-phase proteins such as CRP and may also have a
negative inotropic effect mediated through myocardial nitric oxide
synthase [135,136]. TNF- is a cytokine found in endothelial cells,
smooth muscle cells and macrophages. TNF- is a cardio-inhibitory cytokine that depresses cardiac contractility either directly or through
induction of nitric oxide synthase [137].
2.2.3. Markers of plaque destabilization
Cell adhesion molecules (CAM) are produced by the arterial wall
and include inter-cellular adhesion molecules (ICAM), endothelial
adhesion molecules (ELAM) and vascular adhesion molecules
(VCAM). Myocardial necrosis induces complement activation and
free radical generation, triggering a cytokine cascade. Interleukins
are activated and recruit neutrophils in the ischaemic myocardium.
Neutrophil inltration is regulated through a complex sequence of
molecular steps involving the selectins and the integrins, which
mediate leukocyte adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic
enzymes and adhere to ICAM expressing cardiomyocytes. Also,
atherosclerosis in itself appears to be modulated by soluble forms of
adhesion molecules. CAMs are therefore involved both in the acute
phase of AMI and chronic process of atherosclerosis [15,138,139].
Metalloproteinases are also markers of plaque destabilization.
Myeloperoxidase, (MPO) is the most abundant metalloproteinase
and is an enzyme produced by polymorphonuclear neutrophils and
macrophages. It catalyzes the conversion of chloride and hydrogen
peroxide to hypochlorite and is involved in the oxidation of lipids
contained within LDL particles. It generates an array of reactive oxidants
and radical species that contribute to the development of atheroma and
subsequent plaque rupture [140143]. Myeloperoxidase is not specic
to cardiac diseases, as activation of neutrophils and macrophages can
occur in infectious, inammatory and inltrative disease processes.
Studies have shown that myeloperoxidase is inferior to current biomarkers for diagnostic purposes but elevated levels independently
predict future risk of coronary artery disease in both healthy individuals
and those with ACS [143].

285

Pregnancy associated plasma protein A (PAPPA) is another metalloproteinase, originally discovered as a glycoprotein in pregnant
women, produced by the syncytiotrophoblasts of the placenta. However, it is also produced by non-placental cell types, including broblasts, vascular endothelial cells, and vascular smooth muscle cells.
It is responsible for the cleavage of insulin-like growth factor binding
protein-4. The insulin-like growth factors are important regulatory
proteins involved in cell proliferation and metabolism and have
been implicated in atherosclerotic plaque progression and instability
[144147].
Matrix metalloproteinases, in particular matrix metalloproteinases
2 and 9, play an important role in the collagen breakdown and structural changes associated with ventricular remodeling after AMI. MMPs
have been shown to correlate with Nt-proBNP levels [148,149].
2.2.4. Markers of myocyte rupture
CD40L is a cytokine belonging to the TNF- family and CD40 is its
receptor. CD40L is up-regulated on platelets within fresh thrombus.
Delivery into the peripheral circulation is thought to occur when activated platelets are released from the intracoronary thrombus that has
formed at the site of the unstable/ruptured plaque [135,150]. In addition
to the cell-associated form, CD40L is also present in plasma as the biologically active fragment, soluble CD40L, which is pro-inammatory and
promotes coagulation [151153].
Platelet derived growth factor (PDGF) is a glycoprotein found in
platelets, macrophages, smooth muscle cells and endothelial cells.
Its main function involves wound repair by causing mitosis of smooth
muscle cells and broblasts and attracting other cells such as monocytes, neutrophils and platelets [154,155].
Placental growth factor (PGF) is a member of the vascular endothelial growth factor family and acts as a specic ligand for vascular
endothelial growth factor receptor-1. It has been implicated in neovascularization in ischaemic myocardium and promoting atherosclerosis. The major site of augmented expression of PGF has been found to be
the endothelium of vessels within an infarcted region [156,157].
Many of these biomarkers sparked interest and evidence was
obtained from both large scale trial sub studies such as the Optimal
Trial in Myocardial Infarction with the Angiotensin II Antagonist
Losartan (OPTIMAAL) and Cholesterol and Recurrent Events (CARE)
trials (TNF-), the CAPTURE trial (PGF, CD40L, myeloperoxidase),
the FRISC ll sub-study (CD40L) and the Fast ASsessment of Thoracic
pain by nEuRal networks (FASTER Imyeloperoxidase) study as well
as smaller targeted studies. Although these biomarkers are raised in
patients with AMI, the spread of values limits their use for diagnosis.
Many also are related to risk of adverse events, particularly of death
and heart failure, rather than ischaemic events, but there is no consistent evidence to show any of these markers are independently predictive variables or convey additional information to cTn which may
therefore inuence treatment. Hence they have not evolved to become
mainstream markers in ACS [137,138,142,143,153,158,159].
2.3. Neuro-endocrine biomarkers
2.3.1. BNP/NT-proBNP
The predominant site of BNP gene expression is the heart and is
translated to a parent peptide, preproBNP. This peptide is translocated across the lumen of the cellular endoplasmic reticulum where
it is cleaved to form proBNP and BNP-signal peptide. proBNP is
cleaved into an amino-terminal product (NT-proBNP) and the physiologically active BNP. NT-proBNP has a longer half life (70 to 120 min)
than BNP (20 min) in part due to the fact it is actively degraded by
circulating endopeptidases as well as cleared by cellular binding receptors. Due to the clearance of BNP and NT-proBNP partially by renal
excretion, either may accumulate in patients with renal insufciency
creating false positive results.

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BNP has a constitutive release with a background homeostatic and

cardio-protective role. However, at times of wall stress/dysfunction of
the ventricles, it is produced in higher levels in response to neurohormonal signals from the adrenergic and reninangiotensinaldosterone
(RAA) systems. BNP production has also been shown to be stimulated
by hypoxia suggesting that ischaemia can directly induce BNP release
in addition to the effects infarction has on regional left ventricular
function [160163]. The function of BNP includes vasodilatation, natriuresis and inhibition of the RAA and sympathetic nervous systems
[160165]. BNP levels trend upward to a peak between 14 and 40 h
after an ischaemic event. Some patients have a biphasic release with
second peak at 73120 h thought to reect the long term adverse effect
of left ventricular remodelling and has been shown to be prognostically
adverse compared with the monophasic response [160163,166169].
BNP/NT-proBNP are higher in patients with more severe coronary
artery disease, greater extent of ischaemic territory, left ventricular
dysfunction (systolic and diastolic), regional wall motion abnormalities
and heart failure/cardiogenic shock [116,159,166,169175].
Although BNP/NT-proBNP are increased in those with ACS, they
are not useful diagnostic markers with levels being raised in other
conditions with similar symptoms such as heart failure and pulmonary embolus. They can aid diagnosis of heart failure in patients
with cardiac ischaemia [116,166,168]. Their usefulness, however,
lies in risk stratication, shown in large trials such as Orboban in
Patients with Unstable coronary Syndromes (OPUS)-TIMI 16 and TACTICS TIMI 18 as well as smaller trials. BNP/NT-proBNP are independent
predictors of death [116,160,164,167,168,170181] and heart failure
[116,159161,166,174,179,182] independent of left ventricular ejection
fraction and this risk is graduated. They predict those who incur adverse
left ventricular remodelling (progressive dilatation and cardiac dysfunction) [161,172,183], with a correlation better than for cTn [165].
BNP/NT-proBNP have been found to predict recurrent ischaemia in
some but not all trials [116,160,161,166,173,174,181,182,184] and
particularly in subjects with impaired left ventricular function [160].
Once BNP/NT-proBNP were identied as risk stratication tools,
analyses directed at assessing their potential in guiding treatment
were undertaken. Studies have tested the benets of ACE inhibitors,
ARBs and renin inhibitors in patients with and without raised BNP/
NT-proBNP. They have been shown to be of benet to patients with
AMI and heart failure and/or left ventricular dysfunction but evidence
in patients without heart failure and with normal left ventricular
function is less strong [160162]. One sub-study analysis suggested
that those with high but not low levels of NT-proBNP benet from
treatment with tiroban but this association was lost after correction
for cTn levels [185]. Some studies have also shown that early revascularization in patients with high but not low levels of BNP/NT proBNP
signicantly reduce rates of mortality and heart failure [131,133] but
others did not [186,187].
In conclusion, both BNP and NT-proBNP are excellent markers of
adverse events post-AMI, (death, heart failure and less strongly for
recurrent cardiac ischaemia) but, in contrast to their proven role in
the diagnosis and management of acute and chronic heart failure, as
yet there is no consensus they can be used to guide early treatment
in AMI in order to improve outcomes.
2.3.2. ANP
ANP is a peptide, stored and released by cardiac myocytes in the
atria. It is released in response to atrial stretch and a variety of
other signals induced by hypervolaemia, exercise or caloric restriction. ANP is constitutively expressed in the ventricle and is released
in response to stress induced by increased afterload or injury (e.g.
AMI). ANP stimulates a reduction in blood volume via extravasation
of uid into the extracellular space and therefore a reduction in cardiac
output and systemic blood pressure. It also directly vasodilates,
suppresses pressor hormones including the RAA system and reduces
sympathetic trafc. Lipolysis is increased and renal sodium reabsorption

is decreased. The overall effect of ANP is to counter increases in blood

pressure and volume caused by the RAA system. ANP and NT-ANP
have been shown to be increased in patients with AMI and heart failure
and in those with adverse outcomes, although not particularly reinfarction. However, although levels of ANP and BNP correlate, it is only BNP
that consistently provides additional prognostic information beyond
left ventricular function [159,181,182].
2.3.3. Adrenomedullin
Adrenomedullin was originally isolated from human pheochromocytoma tissue and subsequently found in the adrenal medulla,
kidney, lung, peripheral vascular bed, and the cardiac ventricles. It is
a cardiovascular regulatory peptide with vasodilatory, diuretic and
natriuretic functions and also inhibits aldosterone secretion, broblast proliferation and cardiomyocyte hypertrophy. Levels of adrenomedullin increase in parallel to the progression of cardiovascular
disease, including hypertension, renal failure, heart failure and
pulmonary hypertension. It can also attenuate infarct development
during acute ischaemia-reperfusion injury. It is suggested that rapid
up-regulation of adrenomedullin in the coronary circulation may
exert a cardio-protective effect via autocrine/paracrine mechanisms
after the onset of AMI [188,189]. Elevated adrenomedullin levels are
indicative of cardiac remodelling. However, patients with a variety
of cardiomyopathies with elevated indices of left ventricular mass
and diastolic dysfunction also have higher adrenomedullin levels
compared with patients with non-remodelled hearts. Adrenomedullin
has the potential to inuence the pathological process in both the
acute phase of AMI and the subsequent remodelling and haemodynamic features associated with chronic heart failure. Adrenomedullin
may also augment BNP-induced natriuresis [189].
2.3.4. Reninangiotensinaldosterone system
After AMI, the increasing preload (volume) and afterload (vasoconstriction) stimulates the RAA system [190]. Renin catalyses the
conversion of angiotensinogen to angiotensin l followed by conversion to angiotensin II by angiotensin converting enzyme. Angiotensin
ll stimulates the sympathetic nervous system and aldosterone production, acts as a vasoconstrictor, is involved in sodium retention,
activates smooth muscle cell growth and migration, promotes cardiac
brosis, promotes oxidative stress, activates monocyte/macrophage
migration, activates release of adhesion and inammatory molecules
and is prothrombotic [191,192]. Aldosterone is responsible for sodium
and water retention. During AMI, aldosterone promotes a broad spectrum of detrimental cardiovascular effects, including acute endothelial
dysfunction, inhibition of nitric oxide activity, increased endothelial
oxidative stress, increased vascular tone, rapid occurrence of vascular
smooth muscle cell and cardiac myocyte necrosis, collagen deposition
in blood vessels, and myocardial hypertrophy and brosis. Aldosterone
rises and decreases rapidly within hours of infarction [193].
Levels of these neuro-endocrine markers are often raised in AMI
which may be due to pain (catecholamines), or due to the complications of AMI including heart failure, shock and arrhythmias. Despite
the salutary contribution these analyte investigations have made to
our understanding of the pathophysiology of ACS (and other forms
of acute and chronic cardiac injury), with the exception of BNP, they
have not entered clinical practice in the form of widely applied diagnostic/prognostic tests. Nevertheless, treatment of patients with AMI
(and heart failure) with inhibitors of the neuro-endocrine system
reduces morbidity and mortality. Large trials have demonstrated
reduction in mortality, left ventricular dysfunction, reinfarction and
stroke with the use of -blockers [194197], reduction in mortality,
reinfarction and heart failure with the use of ACE inhibitors
[198203], reduction in death and heart failure with the use of ARBs
(or equivalence to ACE inhibitors) [204,205] and reduction in mortality
and heart failure in those with reduced left ventricular function with the
use of aldosterone inhibitors [206].

S.J. Aldous / International Journal of Cardiology 164 (2013) 282294

A summary of established biomarkers can be seen in Table 1.

2.4. Novel cardiac biomarkers
2.4.1. Choline
Choline is an enzymatic product of phospholipase D. Phospholipase D, is involved in endothelial dysfunction, and is considered a
marker of plaque instability, as well as a marker of severe myocardial
ischaemia, and has been associated with elements of the metabolic
syndrome. Isomers of choline are emerging as important components
in the cellular signal transduction pathways also involved in coronary
plaque inammation and destabilization [207,208]. Studies have
shown that choline offers no obvious improvement of an early
biochemical diagnosis of AMI. However it has been found to predict
adverse events including cardiac death, non-fatal cardiac arrest,
non-fatal myocardial infarction, development of heart failure, revascularization, life-threatening arrhythmias and heart failure either
alone or within a composite end-point [207,208].
2.4.2. F2 isoprostanes
F2 isoprostanes are a biologically active product of arachidonic
acid metabolism. The biosynthesis of F2 isoprostanes is thought to
occur in many different cells involved in the formation of atherosclerosis, including monocytes. This has been supported by studies showing elevated F2-isoprostane levels in those who smoke and have
dyslipidaemia and in the urine of those with unstable angina [207].
Studies have shown increased levels of free F2 isoprostane in those
with ACS compared to those without. Increased free F2 isoprostane
has also been shown to be predictive of a composite end-point of
non-fatal myocardial infarction, development of heart failure, revascularization, and death [207].
2.4.3. Growth-differentiation factor-15
Growth-differentiation factor-15 (GDF-15) is a stress-responsive
member of the transforming growth factor-b cytokine superfamily
and is involved in regulating inammatory and apoptotic pathways

287

needed for development, differentiation, and tissue repair in various

organs. Under normal physiologic conditions, the placenta is the
only tissue that expresses signicant amounts of GDF-15 but has
been shown to up-regulate in a wide range of cancers and in many
tissues following injury, ischaemia, and other forms of stress. Animal
models show that GDF-15 is induced in the heart in response to
ischaemia-reperfusion injury, pressure overload, and heart failure,
possibly via pro-inammatory cytokine and oxidative stress dependent signalling pathways [143,209211]. Studies have found that
circulating levels of GDF-15 are elevated in patients with AMI/ACS
but not statistically signicantly different from those with other cardiac
diagnoses or different chest pain aetiologies [209,210] and higher than
healthy controls [211].
GDF-15 has been shown to independently predict mortality or a
composite of death and non-fatal AMI and that risk is graded. The
association with non-fatal AMI alone is less strong. cTnT and NTproBNP appear to be prognostically superior than GDF-15 but risk
stratication can be improved by measuring both cTnT/NT-proBNP
and GDP-15 [210]. In a sub-study of the FRISC II trial randomizing
patients with non ST elevation ACS to an invasive compared with a
conservative strategy, patients with an elevated cTn but normal
GDF-15 did not have a detectable benet from the invasive strategy
whilst patients with elevated cTn and elevated GDF-15 levels, did
[212].

2.4.4. Copeptin
Preprovasopressin is the precursor peptide for anti-diuretic hormone,
copeptin and neurophysin ll. Anti-diuretic hormone is involved in the
regulation of the endogenous stress response via the hypothalamopituitary-adrenal axis and promotes renal water conservation and
hence inuences osmoregulation and cardiovascular homeostasis.
Copeptin, the C-terminal portion of provasopressin, is a 39-amino acid
glycopeptide of unknown function in the circulation. Anti-diuretic
hormone has been shown to be elevated in heart failure and in different
states of shock but is unstable with a short half life of only 5 to 15 min,

Table 1
Summary of current cardiac biomarkers.
Biomarker
Necrosis
Cardiac troponin

AST

CK/CKMB

LDH
Myoglobin
hFABP
Ischaemia modied albumin

Performance in diagnosis

Performance in prognosis

Highly sensitive and specic for

myocardial necrosis. Current gold
standard biochemical criterion for AMI
First biochemical marker of AMI but
lacks specicity. No longer used for this
purpose.
Second line biomarker for the
diagnosis of AMI, not as sensitive or
specic as cTn
Lacks specicity. No longer used for
this purpose.
Marker of AMI early after symptom
onset, lacks specicity
Marker of AMI early after symptom
onset, lacks specicity
Less sensitive than cTn and lacks
specicity

Highly predictive of adverse cardiac events including death

further ischaemia and need for revascularization. Treatments
instigated in response to cTn results improves outcomes
No data

Inammation
Not sensitive or specic for AMI
Inammatory markers
(CRP, TNF, IL6, cell adhesion molecules, myeloperoxidase,
PAPPA, matrix metalloproteinases, CD40L, PDGF, PGF)
Neurohormonal
BNP/NT-proBNP

Other
(ANP, adrenomedullin, RAA hormones)

Not sensitive or specic for AMI

Not sensitive or specic for AMI

Not consistently predictive of future events

No data
Predictive of mortality. No data to suggest
myoglobin guided treatment inuences outcomes
Predictive of mortality. No data to suggest hFABP guided
treatment inuences outcomes
No convincing data

CRP in particular and some of the other markers are predictive

of mortality (and heart failure) but not recurrent ischaemia.
Inammatory marker guided treatment does not inuence outcomes

Highly predictive of mortality and heart failure. BNP/NT-proBNP

can guide need for neurohormonal medical therapies (ACE
inhibitors etc) but not invasive therapies
Possibly predictive of adverse events in univariate analyses.
Cannot be used to guide treatment

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S.J. Aldous / International Journal of Cardiology 164 (2013) 282294

but copeptin is more stable and therefore more readily amenable to measurement [143,213216].
Copeptin levels have been found to be signicantly higher in
patients with AMI as compared with patients having other diagnoses
but only in those presenting early [213]. Studies have shown that the
diagnostic accuracy of cTn on presentation for the diagnosis of AMI
was improved by combination with copeptin [213216], however
this benet was less striking when hs-cTn assays were used. In
patients with AMI, copeptin was also shown to predict left ventricular
dysfunction and remodelling as well as clinical heart failure distant
from the infarct period [215]. In addition, copeptin has been shown
to be a marker of death and improves risk stratication when used
in conjunction with NT-proBNP. It has not been shown to be a predictor
of recurrent ischaemia. [209].
2.4.5. Adiponectin
Adiponectin is an adipocytokine, a regulator secreted by mature
adipocytes. It belongs to the collagen super family and shares homologies with collagens, complement factors, and TNF-. Adiponectin has insulin sensitizing, anti-inammatory, lipid metabolism, anti-atherogenic,
and antiangiogenic effects [217220]. It appears to be an endogenous
modulator ameliorating obesity linked complications and is inversely
correlated with cardiovascular risk factors such as type 2 diabetes,
hypertension and coronary artery disease. In particular, adiponectin
has been shown to accumulate in the vascular subendothelial space
after damage of the endothelial barrier, where it inhibits monocyte
adhesion to endothelial cells and inhibits the migration and proliferation
of vascular smooth muscle (i.e. it is directly anti-atherogenic).
Adiponectin levels have been found to be lower in females, the obese,
those with type 2 diabetes/insulin resistance, those with dyslipidaemia
involving high triglyceride levels and low high density lipoprotein
levels and thus the development of vascular pathology [217220].
The Health Professionals Follow-up Study has shown a correlation
between low baseline plasma adiponectin and increased risk of AMI
over a 6-year follow-up in subjects with no prior cardiovascular
disease [217220]. Plasma adiponectin concentrations have been
shown to be low in patients with AMI and in men with subsequent
adverse events (cardiac-related death, recurrent AMI, unstable angina,
and heart failure) and to fall during admission in women with adverse
events [217,220,221]. This was independent of other traditional metabolic and cardiovascular risk factors [220].
However, in contradistinction to these reports, others have found
either an increased risk of all-cause mortality but not non-fatal AMI
[222] or a trend to the composite of the two [218] in patients with
ACS and increased adiponectin levels. It has been suggested that
higher baseline levels of adiponectin may in fact be benecial under
normal and non-inammatory conditions but in those with active
vascular or myocardial remodelling (including ACS or heart failure),
there may be a counter-regulatory or compensatory increase in
adiponectin levels. Other hypotheses include the possibility of adiponectin resistance and that total adiponectin is a less useful measurement than the relative proportions of the biologically active or high
molecular weight adiponectin to inert forms, trimeric or hexameric
adiponectin [219].
2.4.6. ST2
ST2 is a peptide with a structural sequence of the interleukin (IL)-1
receptor family and has 2 isoforms, a membrane bound form, ST2L, as
well as a truncated soluble form, which lacks transmembrane and intracellular domains [223229]. ST2L binds free IL-33. This interface was
originally described to play a role in the inammatory process via the
induction of T helper cells. Soluble ST2, secreted in response to inammatory signals, inhibits the binding of IL-33 to ST2L by acting as a soluble decoy receptor and the local ratio of IL-33 and soluble ST2 could
regulate IL-33-mediated signalling. It binds to macrophages leading to

down-regulation of pro-inammatory cytokines and may serve to

prevent uncontrolled inammatory reactions [223,226,227,229,230].
ST2L via its binding of IL33 also has been shown to be induced in
conditions of myocardial overload such as myocardial infarction and
acute heart failure and other causes of myocardial stretch (left
ventricular pressure and volume overload). The resulting negative
consequences of these conditions including myocardial hypertrophy,
dilation of ventricular chambers, and reduction in ejection fraction
(remodelling), are reduced by ST2 blocking angiotensin II and
phenylephrine-induced hypertrophy, in a possible cardio-protective
role [224,227,228,230232]. ST2 is associated with cardiac structural
abnormalities such as dilated and dysfunctional left and right ventricles, reduced left ventricular ejection fraction, elevated lling pressures and diastolic dysfunction, and volume and site of infarcted
myocardium [223,225227,230,231]. Previous studies have reported
elevated ST2 in patients with acute coronary syndromes (as well as
pulmonary diseases, acute heart failure, acutely dyspnoeic patients
with and without decompensated acute heart failure and chronic
heart failure) but would not be a reliable diagnostic marker. ST2 has
been shown to predict mortality and heart failure in such patients
[225231].
2.4.7. Other
Other novel markers have been tested only in smaller targeted
studies comparing those with AMI with healthy controls or other
patients groups rather than generalized Emergency Department
populations undergoing evaluation for ACS. These include:
i) Angiogenic factors: Angiogenesis (the formation of new capillaries) is essential for the repair of wounds and tissue damaged
by ischaemia, and therefore angiogenic factors in the heart are
up-regulated in myocardial ischaemia. Angiogenic factors include
Vascular Endothelial Growth Factor (VEGF) and the angiopoietins.
VEGF is a glycoprotein that induces early endothelial cell migration, proliferation and blood vessel formation. Angiopoietins are
the ligands of the endothelium-specic receptor tyrosine kinase.
Angiopoetin-2 destabilizes the vessel to make it responsive to
VEGF (and others) and angiopoietin 1 promotes vascular stabilization and counteracts VEGF induced angiogenesis [233,234].
ii) Apelin: This is the endogenous ligand for angiotensin-like 1
receptor, is inotropic, diuretic (nitric oxide-dependent), vasodilatory and antagonizes the effects of angiotensin II [235,236].
iii) Platelet glycoprotein VI: This is a platelet membrane glycoprotein that plays a crucial role in the collagen-induced activation
and aggregation of platelets [237].
iv) Procalcitonin: This is a 116 amino acid hormone involved in
calcium metabolism but has also been shown to be induced
in inammatory conditions. It is the prohormone of calcitonin
and is produced in the medullary C cells of the thyroid gland
but may be produced in other tissues [238,239].
v) Micro-ribonucleaic acid (RNA): These are 1925-nucleotide
non-coding RNAs that have been implicated in regulating cell
proliferation, differentiation, development and apoptosis. The
expression prole of micro RNAs is tissue/cell-specic. Some
cardio-specic micro RNAs are thought to play important
roles in cardiac/vascular development, hypertrophy, arrhythmia
and ischaemia [240242].
vii) Asymmetric dimethylarginine (ADMA): The methylarginines including ADMA, N-monomethylarginine and symmetric dimethylarginine, are generated by the post-translational methylation of
arginine residues in proteins. ADMA inhibits endothelial nitric
oxide synthase which leads to endothelial dysfunction due to
increased vasoconstrictor responses, adhesion of platelets and
monocytes, and proliferation of vascular smooth muscle cells
[243,244].

S.J. Aldous / International Journal of Cardiology 164 (2013) 282294

These studies have shown that concentrations of VEGF [233,234],

angiopoietin 2 [233,234], platelet glycoprotein VI [237], procalcitonin
[245,246], Micro RNA-1 [240,242], micro RNA-133a, micro RNA-208a
[240], micro RNA-499 [247], micro RNA-1291, micro RNA-663b [241]
and ADMA [243,248] but not angiopoietin 1 [233,234] or tyrosine
kinase [233,234] were signicantly higher and that concentrations
of apelin [235,236] were signicantly lower, in AMI cases compared
with the other groups. Apelin [235,236], platelet glycoprotein V1
[237] and procalcitonin [238,239] have also shown prognostic utility
for death and/or other ischaemic events, however, where adjustment
for clinical factors was made, prognostic utility was less robust.
A summary of novel markers is shown in Table 2.

3. Point of care cardiac markers

There are many commercial point of care (POC) kits for measurement
of biomarkers including cTn, CKMB, myoglobin and BNP/NT-proBNP
both individually as well as in multi-marker panels. POC devices have
been shown to reduce turn-around times compared with standard testing due to elimination of sample transfer time, no or minimal sample
preparation (analysers customarily use whole blood), and immediate
availability of results. It has been recommended that if standard laboratory testing exceeds a maximum 60-minute turn-around time (the average being 65128 min) or 25% of decision time, then a POC device (with
an average turn-around time of 1526.5 min) should be implemented
[249253]. POC testing has also been shown to reduce length of stay in
the Emergency Department [249,251,253]. Other potential advantages
include economic savings, assisting adherence to treatment, reduction
in complications and patient satisfaction [249,253255]. Although
more expensive than laboratory tests, money is potentially saved by
accelerating management decisions in the Emergency Department and
preventing unnecessary admissions, however economic benets have
not been proven.
The major disadvantage of POC tests is their inferiority compared
with standard testing. This is mainly due to reduced precision with
many not achieving recommended levels, and lack of standardization
[249,250,256] leading to poor correlation and concordance between
assays. Despite this, studies with POC biomarkers have shown diagnostic
and prognostic utility akin to standard testing [249,250]. Nevertheless, POC devices should remain compliant with quality requirements in order to be employed in routine practice and the core

289

laboratories and hospitals must be responsible for maintaining that

quality [250,251,255,257,258].

4. Multi-marker testing
A single cTn test can be insensitive for the diagnosis of AMI when
only early results post-symptom onset are taken, even when highsensitivity assays are used. Current AHA guidelines for cTn measurement, recommend testing on presentation and again at 812 h postsymptom onset [259] and National Academy of Clinical Biochemistry
recommends an early marker at 06 h and a denitive marker at
69 h post-presentation [109]. With current international guidelines
recommending disposition of 95% of Emergency Department patients
at 46 h, the requirement for follow-up cTn measurement at these
time points means patient admission to in-patient hospital care or
observation units. Multiple markers analysed on presentation and/or
repeated within a shorter time interval to comply with Emergency
Department guidelines, may be sufcient for appropriate risk stratication [252].
Studies have shown sensitivities for AMI of 80100% for CKMB/
myoglobin up to 4 h post-presentation [252,260], 9496.7% for cTnI/
myoglobin up to 1.5 h post-presentation [252,261], 92.6% for cTnI/
CKMB up to 8 h post-presentation [262] and 100% for cTnI/CKMB/
myoglobin up to 2 h post-presentation [261,263] compared with sensitivities for cTn alone of 8692.3% [252,262,263]. These studies used
the original WHO criteria/CKMB as the gold standard for the diagnosis
of AMI which may over-estimate test performance. Subsequently, the
CHECKMATE study has demonstrated that myoglobin/CKMB/cTnI
panel identied AMI patients earlier and provided better risk stratication for mortality compared with standard laboratory practice,
myoglobin/cTnI panel and CKMB/cTnI panel [251,252]. Goodacre et
al. showed that the use of a multi-marker panel in the Emergency
Department signicantly increased successful discharge, dened as
discharge within 4 h and no adverse events including death, nonfatal AMI, emergency revascularization, life-threatening arrhythmia
or hospitalization due to myocardial ischaemia within 3 months
[254]. Other studies have shown that low risk patients identied by
negative early cTnI/CKMB/myoglobin had low (03%) death or AMI/
ACS rates by 30 days to 6 months [261,264,265]. However, despite
these studies suggesting incremental benet of multiple biomarkers,
these studies have been criticized for using, in particular, cTn assays

Table 2
Summary of novel cardiac biomarkers.
Biomarker

Performance in diagnosis

Performance in prognosis

Choline

Raised but not sensitive or specic for AMI

F2 isoprostanes

Raised but not sensitive or specic for AMI

GDF-15

Raised but not sensitive or specic for AMI

Copeptin
Adiponectin

Marker of AMI early after symptom onset,

may improve sensitivity of early cTn
Not sensitive or specic for AMI

Predictive of mortality, ischaemia and heart failure. No data to suggest choline guided
treatment inuences outcomes
Predictive of mortality, ischaemia and heart failure. No data to suggest F2 isoprostane
guided treatment inuences outcomes
Predictive of mortality and ischaemia. Single study suggests GDF-15 can guide need
for invasive treatment to inuence outcomes
Predictive of mortality. No data to suggest copeptin guided treatment inuences outcomes

ST2

Not sensitive or specic for AMI

Angiogenic factors
Apelin

Raised in AMI but insufcient data

Lowered in AMI but insufcient data

Platelet glycoprotein VI

Raised in AMI but insufcient data

Procalcitonin

Raised in AMI but insufcient data

Micro-RNA
ADMA

Raised in AMI but insufcient data

Raised in AMI but insufcient data

Conicting results regarding whether low or high levels are predictive of events. No data
to suggest adiponectin guided treatment inuences outcomes
Predictive of mortality and heart failure. No data to suggest ST2 guided treatment
inuences outcomes
No data
Predictive of adverse events in univariate analyses. No data to suggest apelin guided
treatment inuences outcomes
Predictive of adverse events in univariate analyses. No data to suggest Platelet glycoprotein
VI guided treatment inuences outcomes
Predictive of adverse events in univariate analyses. No data to suggest apelin guided
treatment inuences outcomes
No data
No data

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S.J. Aldous / International Journal of Cardiology 164 (2013) 282294

with low analytical sensitivity; negating the advantages that cTn

alone may offer [100].
Other combinations using newer markers have also been proposed. Panels consisting of hFABP/cTn appear to have improved
early diagnostic utility [266,267] compared with cTn alone but
this combination has not been compared with newer hs-cTn assays. Panels consisting of cTnT/IL-10/myeloperoxidase/PGF [268],
brinogen/NT-proBNP [269], hFABP/NT-proBNP [266], hFABP/NTproBNP/cTnT [270] and cTn/copeptin [213,216] have been proposed as prognostic aids but require further prospective randomized testing. Other have found no additional prognostic
information beyond conventionally used stratication tools for
combinations of NT-proBNP, high-sensitivity CRP, matrix
metaloproteinase-9, PAPPA, myeloperoxidase, CD40L, IL 6/10/18,
P- and E-selectin, cystatin C, glycogen phosphorylase-BB, ddimer, brinogen [266,270272].
Conversely, multi-marker assessment has been shown to be
associated with higher Emergency Department, coronary care and
cardiac intervention costs but lower general in-patient costs and has
not been shown to reduce overall costs despite reducing admissions
[273].
5. Summary
With the advent and development of cTn assays, cTn has been
shown to be a highly sensitive and specic marker for the diagnosis
of AMI, ultimately resulting in a major change in the denition of
AMI. This was because studies demonstrated the relevance of cTn
status in guiding the effective application of invasive therapies with
benet on outcomes. Newer hs-cTn assays identify more patients at
risk and earlier than standard assays which may accelerate current
diagnostic protocols and improve outcomes, however, reduced specicity may lead to increased referrals and unnecessary investigations.
Other clinically valuable cardiac markers for the use in patients with
AMI comprise BNP/NT-proBNP, and to a lesser extent, CRP, which are independent predictors of adverse events including death, heart failure
and possibly recurrent ischaemia. Despite this, their ability to inuence
outcomes is much less established than that of cTn. Multiple markers
may accelerate the rule out of AMI and prevent unnecessary admissions.
Despite the multitude of cardiac biomarkers in production and
under investigation, none have convincingly demonstrated their incremental utility beyond that of cTn. Therefore, markers which (a) add
specicity or sensitivity to late generation troponin assays in detection
of AMI and (b) which provide objective evidence of unstable angina
or (c) provide prognostic utility with the ability to inuence outcomes
remain unmet needs.
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