Biomarkers in Acute Coronary Syndromes

Biomarkers in acute coronary syndromes
Oxford Medicine Online
The ESC Textbook of Intensive and Acute

Cardiovascular Care (2 ed.)
Edited by Marco Tubaro, Pascal Vranckx, Susanna Price,
and Christiaan Vrints
Latest update
This online textbook has been comprehensively reviewed for the

February 2018 update, with revisions made to 28 chapters. Find
out more about the updates made.
Publisher: Oxford University Press Print Publication Date: Feb 2015

Print ISBN-13: 9780199687039 Published online: Feb 2018
DOI: 10.1093/med/ © European Society of Cardiology
9780199687039.001.0001
Chapter: Biomarkers in acute coronary syndromes
Author(s): Evangelos Giannitsis and Hugo A Katus
DOI: 10.1093/med/9780199687039.003.0036_update_002
Update:
Introduction of MINOCA to describe acute myocardial infarction in

the presence of non-obstructive coronary artery disease
Page 1 of 29
Modification of risk stratification and timing of invasive strategy

according to 2015 ESC guidelines on NSTE-ACS
Updated on 22 February 2018. The previous version of this

content can be found here.
Summary
Biomarker testing in the evaluation of a patient with acute chest pain

is best established for cardiac troponins that allow the diagnosis of
myocardial infarction, risk estimation of short- and long-term risk of
death and myocardial infarction, and guidance of pharmacological
therapy, as well as the need and timing of invasive strategy. Newer,
more sensitive troponin assays have become commercially available
and have the capability to detect myocardial infarction earlier and
more sensitively than standard assays, but they are hampered by a
lack of clinical specificity, i.e. the ability to discriminate myocardial
ischaemia from myocardial necrosis not related to ischaemia such as
myocarditis, pulmonary embolism, or decompensated heart failure.
Strategies to improve clinical specificity (including strict adherence to
the universal myocardial infarction definition and the need for serial
troponin measurements to detect an acute rise and/or fall of cardiac
troponin) will improve the interpretation of the increasing number of
positive results.
Other biomarkers of inflammation, activated coagulation/fibrinolysis,

and increased ventricular stress mirror different aspects of the
underlying disease activity and may help to improve our
understanding of the pathophysiological mechanisms of acute
coronary syndromes. Among the flood of new biomarkers, there are
several novel promising biomarkers, such as copeptin that allows an
earlier rule-out of myocardial infarction in combination with cardiac
troponin, whereas MR-proANP and MR-proADM appear to allow a
refinement of cardiovascular risk. GDF-15 might help to identify
patients at higher risk of bleeding
A multi-marker approach to biomarkers becomes more and more

attractive, as increasing evidence suggests that a combination of
several biomarkers may help to predict individual risk and treatment
benefits, particularly among subjects with normal troponin. Future
goals include the acceleration of rule-in and rule-out of patients with
suspected acute coronary syndrome, in order to shorten lengths of
stay in the emergency department, and to optimize patient
management and the use of health care resources. New algorithms
using high-sensitivity cardiac troponin assays at low cut-offs alone, or
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in combination with additional biomarkers or clinical scores, allow to

establish accelerated rule-out algorithms within 1 or 2 hours.
Contents
Summary [link]
Introduction: pathophysiology and classification of acute coronary
syndromes—the role of biomarkers [link]
Cardiac troponins [link]
High-sensitivity cardiac troponin assays [link]
Risk stratification and selection of invasive vs medical
treatment [link]
Point-of-care testing [link]
Cardiac troponin testing on point-of-care systems [link]
Other biomarkers [link]

Early markers of ischaemia [link]
Prognostic biomarkers [link]
Novel biomarkers: copeptin, MR-proatrial natriuretic peptide, and

MR-proadrenomedullin [link]
Copeptin [link]
Atrial natriuretic peptide (MR-proatrial natriuretic peptide)
[link]
MR-proadrenomedullin [link]
Biomarkers of renal function [link]

Biomarkers of haemostasis and fibrinolysis [link]
Combination of biomarkers—a multimarker approach [link]
Personal perspective [link]
Further reading [link]
Introduction: pathophysiology and classification of

acute coronary syndromes—the role of biomarkers
The aetiology of acute coronary syndromes (ACS) is complex and involves

multiple interrelated mechanisms, of which many have yet not been fully
understood (see Chapters 35, 43, and 46). Our current understanding
is that a plaque may rupture or erode, in response to inflammation,
leading to local occlusive or non-occlusive thrombosis [1]. Depending on
the degree and reversibility of this dynamic obstruction, the clinical
manifestations of ACS comprise a continuous spectrum of risk that
progresses from unstable angina (UA) to non-ST-segment elevation
myocardial infarction (NSTEMI) to ST-segment elevation myocardial
infarction (STEMI). NSTEMI is distinguished from UA by ischaemia
Page 3 of 29


sufficiently severe in intensity and duration to cause myocyte necrosis,

which is recognized by the detection of cTn, the most sensitive and
specific biomarker of myocardial injury [2, 3].
The most recent achievement with biomarker testing is the

implementation of hscTn assays, instead of the conventional, less
sensitive troponin assays, in patients with suspected ACS [4]. The higher
analytical sensitivity and precision of the more sensitive assays have
facilitated an earlier and more accurate detection of NSTEMI [5–8].
Accordingly, recent European Society of Cardiology (ESC) guidelines [4]
recommend the implementation of hscTn assays with a second sample
after 3 hours, and if the diagnosis is still uncertain at later time points, in
order to rule out NSTEMI earlier than with standard cardiac troponin
(cTn) assays. As an alternative, a 1-hour diagnostic protocol can be used
if validated hsTn assays are available, a 2-hour accelerated diagnostic
protocol with cTn, or an instant rule-out using a single hsTn with a cutoff
at the detection limit, or a combination of a normal cTn or hsTn together
with a normal copeptin (see Chapter 46).
Other biomarkers representing inflammation, activation of coagulation,

myocyte necrosis, vascular damage, and haemodynamic stress—while less
helpful for diagnosis—may improve risk stratification and the selection of
invasive vs conservative treatment strategy, and allow insights into
individual components of the pathophysiological process of
atherosclerosis and the relative contribution at different stages of the
disease (see Figure 36.1).
Figure 36.1
Representative biomarkers involved in the process of atherosclerosis at
different stages of the disease
Page 4 of 29


Cardiac troponins
cTnT and cTnI are now considered as the preferred biomarkers

for the diagnosis of myocardial injury, as the cardiac isoforms of troponin
T or I are expressed exclusively in myocytes on the thin myofilament of
the contractile apparatus and, to a lower degree (3–6%), as unbound
proteins in the cytoplasm of myocytes [2, 3]. Thus, cTn constitute the
most sensitive and specific biochemical markers of myocardial damage
presently available. According to the criteria of the third updated version
of the Universal definition [9], an MI is diagnosed when cTn is rising and/
or falling, with at least one value in serial blood sampling above the 99th
percentile of a reference control group, and in the presence of signs or
symptoms of myocardial ischaemia (see Table 36.1). Myocardial
ischaemia is suspected in the presence of symptoms of ischaemia, typical
ECG changes indicative of ischaemia, new Q waves, imaging evidence of
new loss of viable myocardium, new regional wall motion abnormalities,
or the detection of intracoronary thrombus on coronary angiography.
Table 36.1 Joint ESC/ACCF/AHA/WHF Task Force definition of acute

myocardial infarction
Myocardial infarction should be diagnosed when there is evidence of

myocardial necrosis in a clinical setting consistent with myocardial
ischaemia. Under these conditions the following criteria meet the
diagnosis for myocardial infarction:
♦ Detection of rise and/or fall of cardiac biomarkers (preferably

troponin) with at least one value above the 99th percentile of the
upper reference limit (URL), together with evidence of myocardial
ischaemia with at least one of the following:
• Symptoms of ischaemia
• ECG changes indicative of new ischaemia(new ST-T changes
or new left bundle branch block [LBBB])
• Development of pathological Q waves in the
electrocardiogram (ECG)
• Imaging evidence of new loss of viable myocardium or new
regional wall motion abnormality
• Identification of an intracoronary thrombus on coronary
angiography or autopsy
The Universal myocardial infarction (MI) definition [9] further

differentiates five subtypes that are clearly defined (see Table 36.2). In
the third version of the Universal MI definition [9], the criteria for the
definition of post-procedural MI have been modified; after an elective
PCI, a post-procedural MI should only be diagnosed if cTn exceeds the
Page 5 of 29


upper limit of normal (99th percentile) by >5 times, together with

symptoms, ST-segment changes, new Q waves, or other signs of
myocardial ischaemia. An isolated increase of cTn of any magnitude, or
an increase to <5 times the upper limit of normal, without an indicator of
myocardial ischaemia, should not be labelled as MI but as myocardial
injury. Accordingly, a type 5 MI, following an elective CABG, requires a
rise of cTn of >10 times the upper limit of normal, along with additional
evidence of myocardial ischaemia. A great challenge is to discriminate a
type 1 MI, as a consequence of rupture, erosion, fissuring, or dissection
of a vulnerable plaque, from a type 2 MI that is caused by myocardial
ischaemia due to an imbalance between O2 demand and supply, without
the anatomical information from coronary angiography (see Figure
36.2 ). Although peak cTn values may be lower in type 2 MI [10, 11], a
discrimination of type 1 from type 2 MI can rarely be accomplished
prospectively without a coronary angiogram [12, 13]. Recently the term
“MINOCA” has been introduced particularly for patients with an acute
myocardial infarction based on the criteria of the universal acute
myocardial infarction (AMI) criteria (4) in the absence of obstructive
coronary artery disease (≥ 50% stenosis) on the coronary angiogram, and
no overt cause for the clinical presentation at the time of angiography
such as takotsubo cardiomyopathy. MINOCA should be considered as a
‘working diagnosis’, analogous to heart failure, and thus prompts further
evaluation regarding its underlying mechanism(s) (Agewall, 2017).
Cardiac magnetic resonance imaging is the key diagnostic tool to be
employed in MINOCA patients since late gadolinium enhancement (LGE),
when present, permits localization of the area of myocardial damage and
provides insight into mechanisms. Other suggested include
echocardiography to assess wall motion, intracoronary imaging at the
time of cardiac catheterization with intravascular ultrasound or optical
coherence tomography to identify atherosclerotic plaque disruption and
plaque erosion as well as coronary dissection or thrombosis, CT coronary
angiography to obtain further information regarding underlying
atherosclerosis, CT pulmonary angiography to exclude suspected
pulmonary embolism, The term MINOCA is not synonymous with type 2
MI, and the advocats of the term MINOCA indicate that type 2 MI is one
of the potential aetiologies for MINOCA (Agewall, 2017). A type 3 MI
should be diagnosed in patients who died suddenly with signs or
symptoms suggestive of myocardial ischaemia, with death occurring
before blood samples could be obtained, or who died before cTn appeared
in blood [9].
Table 36.2 Subtypes of MI
Type Spontaneous myocardial infarction related to ischemia due

1 to a primary coronary event such as plaque erosion or
rupture, fissuring or dissection
Page 6 of 29


Type Myocardial infarction secondary to ischemia due to

2 imbalance between oxygen demand and supply e.g. coronary
spasm, anemia, or hypotension
Type Sudden cardiac death with symptoms of ischemia,

3 accompanied by new ST elevation or left bundle branch
block (LBBB), or verified coronary thrombus by angiography
or autopsy, but death occurring before blood samples could
be obtained
Type Myocardial infarction associated with percutaneous

4a coronary intervention (PCI)
Type Myocardial infarction associated with verified stent

4b thrombosis
Type Myocardial infarction associated with coronary artery

5 bypass grafting (CABG)
Figure 36.2
Putative mechanisms related to the development of type 1 or type 2 MI
Elevated cTn values in patients with acute ischaemic presentations are

related to more extensive coronary artery disease (CAD), procoagulant
activity, and lower Thrombolysis in Myocardial Infarction (TIMI) flow
grades [14]. Angioscopic and angiographic evidence suggests a clear
relationship between the presence and concentration of cTn and the
presence and magnitude of intracoronary thrombus [15]. As such, an
elevated cTn indicates a higher risk for acute coronary events, due to the
increased prothrombotic activity and the development of cardiac events
during mid- and long-term follow-up, due to its relation to disease severity
and persistent inflammatory activity of the atherosclerotic plaque.
Consistently, benefits of more aggressive antithrombotic or antiplatelet
therapies with dalteparin [16], and antiplatelet therapies with abciximab
Page 7 of 29


[17], tirofiban [18], lamifiban [19], or triple antiplatelet therapy, followed

by early coronary intervention [20], were almost restricted to patients
with cTn elevations.
The diagnosis of an AMI requires a relevant rise and/or fall of cTn, with at
least one cTn value exceeding the 99th percentile [9]. Therefore, cTn has
to be measured serially to distinguish an acute from a chronic cTn
elevation. According to current ESC guideline recommendations [4], cTn
must be measured on presentation and at 6–9 hours after admission,
unless a hscTn assay is being used [4, 21]. In patients with an
intermediate or high clinical index of suspicion, who remain troponin-
normal, and after recurrence of typical symptoms, a later measurement at
12–24 hours should be considered, in order not to miss a late rise in cTn.
Clinical indicators, other than cTn, also provide an estimate of the acute
thrombotic risk such as dynamic ST-segment deviations, refractory
angina, diabetes mellitus, renal failure, older age, and an intermediate or
high GRACE or TIMI risk score [4]. Current ESC guidelines therefore
advocate that the decision and timing of an early invasive treatment
strategy should be based on individual risk stratification. Patients at
higher risk were found to benefit from an early invasive strategy within
72 hours. Patients with a high GRACE score exceeding 140 points,
dynamic ST-segment changes, or a relevant rise and/or fall of cTn qualify
for an invasive strategy within 24 hours (see Table 36.3). An
immediate invasive strategy within 2 hours is recommended in patients
with very high-risk features.
Table 36.3 Need and timing of invasive strategy according to 2015

ESC guidelines for NSTE-ACS (4)
Risk category Timing of coronary

angiography
Very high risk Immediate

invasive(<120 min)
Hemodynamic instability or
cardiogenic shock
Recurrent or ongoing chest pain
refractory to medical therapy
Life-threatening arrhythmias or
cardiac arrest
Mechanical complications of MI
Acute heart Failzre
Recurrent dynamic ST-T wave
changes, particularly with intermittent
ST elevation
Page 8 of 29


High risk Early invasive (<24

hours)
Rise or fall in cardiac troponin

compatible with MI
Dynamic ST- or T-wave changes
(symptomatic or silent)
GRACE score > 140
Intermediate risk Invasive (<72 hours)
Diabetes
Renal insufficiency (eGFR <60 ml/min/
1.73m2
LVEF < 40% or congestive heart
failure
Early postinfarct angina
Prior PCI
Prior CABG
GRACE score > 109 and < 140
Low risk Non-invasive testing if

appropriate
Any characteristics not mentioned above
An early invasive strategy (<24 h) is recommended in patients with high

risk features, i.e. a GRACE score >140 or a rise or fall of cardiac troponin
compatible with an MI (level of recommendation IA). Patients at
intermediate risk should undergo an invasive strategy within 72 hours. A
selective invasdive strategy can be followed in patients with low risk who
remain asymptomatic following optimal medical therapy and do not
disclosae myocardial ischemia on stress testing, preferably stress
imaging.
Other biomarkers of myocardial necrosis, including total creatine kinase

(CK), lactate dehydrogenase (LDH), and aspartate aminotransferase
(AST), have historical significance and should not be used for the
diagnosis of MI, because they have low specificity for cardiac injury. In
the rare instance that cTn is not available, the next best alternative is CK-
MB (measured by mass assay). A still useful application of CK-MB is in the
detection of reinfarction in the very early phase following an MI when cTn
is less useful, due to its more prolonged elevation. In other instances,
serial measurements of cTn provide the same degree of evidence for
reinfarction as CK or CK-MB.
Page 9 of 29


High-sensitivity cardiac troponin assays
Several years ago, manufacturers started to develop novel high-sensitivity

generations of cTn assays, in order to comply with the precision criteria
of the ESC/ACC [22]. It has been proposed that a cardiac troponin (cTn)
assay should be designated as ‘high-sensitivity’ assay if cTn can be
measured in at least 50% of healthy individuals, in order to ensure a high
clinical sensitivity [23]. These high-sensitivity assays are characterized by
a substantially higher analytical sensitivity than conventional sensitive
assays, allowing the measurement of cTn in ng/L, rather than microgram/
L [24]. The more sensitive hscTn assays differ regarding their analytical
characteristics. In direct comparison, 19 cTn assays were found to show
very heterogenous analytical characteristics regarding the 99th
percentile value and their analytical sensitivity, as reflected by the
proportion of detectable cTn concentrations in a healthy reference
population [25]. Whether the clinical performance of the different hscTn
assays is similar is unsettled as yet only a few studies have directly
compared hscTn assays head to head for the detection of reversible
ischaemia [26], diagnosis, and prognosis [8, 27, 28].
The key differentiating feature of hscTn assays, when compared to the

conventional sensitive cTn assays, is not apparent at higher values but is
restricted to the area around the 99th percentile cut-off. The clinical
interpretation of hscTn concentrations in this range is challenging, but
important, as most of the increased sensitivity for the detection of
myocardial injury is at the low concentration level.
In clinical routine, there is substantial evidence that the use of more

sensitive cTn assays enables more accurate and earlier detection of
myocardial infarction (MI) [5–8]. Numerous trials [7, 8, 29] and a recent
meta-analysis [30] now provide substantial evidence that high-sensitivity
assays, using the 99th percentile as the threshold for positivity, can
achieve sensitivity at presentation of 90% or more. A higher analytical
sensitivity changes the spectrum of ACS, as hscTn assays used at lower
thresholds increase the incidence of non-ST-segment elevation myocardial
infarction (NSTEMI), particularly small MI, that would have been
mislabelled as unstable angina (UA) [31, 32]. Maximizing early sensitivity
results in some loss of clinical specificity [33]. Thus, lowering the
diagnostic cut-off increases the number of patients with analytically true
cTn elevations that are related to myocardial injury, but not to MI (see
Figure 36.3). Compared to conventional sensitive assays, the
prevalence of detectable and elevated cTn values increases with the use
of hscTn assays in various study populations, including patients with
acute [34] or chronic heart failure [35, 36, 37], stable coronary artery
disease (CAD) [38], and in general populations of middle-aged individuals
[39–41], and patients with structural heart disease are identified at
earlier clinical stages [35, 42]. Not uncommonly, patients with suspected
ACS may present with symptoms other than typical chest pain (CP).
Therefore, the diagnosis may be uncertain in many patients who require
Page 10 of 29


strategies to overcome the loss of clinical specificity. Such strategies to

increase the clinical specificity without a loss of sensitivity include a strict
adherence to the Universal MI definition, the use of recommended cut-
offs, and relevant concentration change in serial testing. A working group
of the ESC [43] recommends, by consensus, an increase of >50% of the
99th percentile value if the baseline value lies below the 99th percentile
and the second value exceeds the 99th percentile. In cases where the
initial cTn value is already above the 99th percentile value, an increase of
only 20% on the second sample is necessary to diagnose NSTEMI [43].
Figure 36.3
Increasing numbers of differential diagnoses with the use of more
sensitive and highly sensitive cardiac troponin assays.
Patients with a rising pattern of hscTn to high peak values most likely
have an acute aetiology such as NSTEMI, acute heart failure (AHF),
stress cardiomyopathy, myocarditis, or PE [44]. On the other hand, if the
pattern of the hscTn values is not changing, chronic structural heart
disease should be suspected. Irrespective of the cause of myocardial
injury, elevations of hscTn are associated with an adverse clinical
outcome in most clinical conditions [45]. The higher the cTn
concentrations on admission, the less likely a differential diagnosis other
than an AMI is [46], particularly among those who present with AHF [47].
Risk stratification and selection of invasive vs medical treatment
In the era of previously less sensitive assay generations, a positive cTn

result strongly predicted the acute thrombotic risk within 30 days after
the index event, but also the long-term outcomes for several years [48,
49]. As a proof of principle that cTn was also a surrogate for
intracoronary thrombus and platelet reactivity, following the rupture of a
vulnerable plaque, a positive cTn result was found to be associated with
treatment benefits from more potent anticoagulants, antiplatelet
therapies, or an early invasive strategy [16–20]. In line with the
observation that risk stratification improves as cTn cut-offs of the same
assay are lowered [50], new hscTn assays used at the 99th percentile
Page 11 of 29


demonstrated an excellent prediction of the risk for death or MI [50–53],

even in patients with cTn levels below the lower limit of detection of
conventional sensitive assays [28, 51]. However, the question of whether
very low decision cut-offs using hscTn assays warrant the selection of an
invasive strategy vs that of medical treatment is still unresolved. The
GUSTO IV trial reported an excess of death/MI among patients who
underwent an early invasive treatment, compared to a conservative
approach, if patients were stratified as low-risk patients, as suggested by
undetectable cTnT levels and low NT-proBNP values [54]. On the other
hand, the TACTICS TIMI 18 trial found that rates of death and MI were
significantly reduced in patients who received tirofiban and underwent an
early invasive treatment within 48 hours if conventional cTnT values were
elevated [55]. At present, there is some evidence that hscTn assays may
be useful to improve in-hospital management and outcomes, particularly
in the intermediate range of cTn elevation [56]. In addition, a biomarker
substudy from the Platelet Inhibition and Patient Outcomes (PLATO) trial
investigated the relationship between hscTnT status and the benefits of
ticagrelor, a more potent P2Y12 inhibitor, compared to clopidogrel, across
the entire spectrum of ACS. Patients with hscTnT values above the 99th
percentile and a diagnosis of NSTEMI derived benefits from ticagrelor by
reducing cardiac endpoints, regardless of whether they underwent an
invasive or a conservative treatment [57]. Conversely, patients with a
normal hscTnT result (UA) did not derive the same amount of benefit
from ticagrelor, compared to clopidogrel. If treated invasively during
index hospitalization, there was an increase of the primary endpoint,
driven by higher rates of procedure-related MIs and significant excess of
major bleedings, particularly procedural non-CABG-related major
bleeding [58]. Thus, it appears that patients with UA represent a low-risk
cohort that may not benefit from treatment strategies outlined for the
NSTEMI cohorts. In agreement, the current ESC guidelines recommend
not to perform an early routine coronary angiography in normal-cTn
patients, but to base the decision on the recurrence of CP or on a positive
stress test [4].
Point-of-care testing
Cardiac troponin testing on point-of-care systems
The National Academy of Clinical Biochemistry (NACB) recommends the

use of point-of-care testing (POCT) when central laboratory testing is not
available, or when turnaround times exceed 60 min [21]. The use of POCT
has been shown to reduce turnaround times and can lead to reduced time
to anti-ischaemic treatment and need for hospital admission [59], but
effects on admission and length of stay were inconsistent and varied
between centres [60, 61]. There are two major shortcomings that limit the
usefulness of POCT of cTn in acute cardiac care. First, several POCT do
not achieve a comparable level of analytical sensitivity, compared to cTn
assays measured in a central laboratory [23, 25]. In addition, there is an
issue, both with standardization between different cTnI assays and
between point-of-care and central laboratories, even with the use of a
Page 12 of 29


cTnI or cTnT assay from the same manufacturer. Strategies on how to

improve the analytical sensitivity of cTn on point-of-care systems or how
to implement current point-of-care systems for an accurate and safe rule-
out of NSTEMI are under investigation. Recently, four different POCT cTn
assays were compared to a contemporary sensitive central laboratory
assay [62]. On the one hand, this study demonstrates the continuous
improvement of point-of-care systems and assays, as two point-of-care
assays, using of a cut-off at the 99th percentile, yielded a diagnostic
accuracy on admission that was comparable to that of the central
laboratory test. On the other hand, this study also underscores the issue
regarding the clinical and analytical variability of point-of-care assays,
particularly the lack of standardization and harmonization of point-of-care
assays. However, in this study, the conventional central laboratory assay
had a sensitivity on admission of only 68%, which is inferior to
sensitivities on admission of 90% or higher reported for hscTn central
laboratory assays [7, 8, 29, 30]. Thus, it becomes clear that the role of
point of care in the era of hscTn assays is even more challenging and will
remain a matter of debate until point-of-care assays have been optimized
to a hscTn standard.
Modern hscTn assays appear to have a superior early sensitivity to

myoglobin and CK-MB [7, 8, 29, 30]. However, at present, there are only
few, if any at all, commercially available point-of-care systems that meet
the criteria of a hscTn assay, and small NSTEMIs may escape detection,
due to the lower diagnostic sensitivity.
Thus, for most point-of-care systems, the potential for reduced times to
decision making needs to be weighed against a loss of sensitivity, when
compared to hscTn assays in central laboratories.
Other biomarkers
A variety of different biomarkers have been studied to

investigate their potential role in diagnosis and prognosis. Elevation of
representative biomarkers mirror components of the pathophysiological
process of atherosclerosis such as inflammation, myocardial stress,
haemostasis and fibrinolysis, or myocardial ischaemia.
Early markers of ischaemia
Several markers, including heart-type fatty acid-binding protein (h-FABP),

ischaemia-modified albumin (IMA), and myoglobin, have been proposed to
detect myocardial necrosis, before cTn becomes measurable in blood.
Myoglobin and h-FABP are among the biomarkers that have been studied
extensively in the past for this purpose. A recent meta-analysis [30]
demonstrates a pooled sensitivity of myoglobin of only 62%, disqualifying
myoglobin measurement as a stand-alone strategy. For h-FABP assays, a
pooled sensitivity of 81% for quantitative, but only 68% for qualitative,
assays has been reported [30]. Due to an inadequate tissue specificity of
most additional biomarkers, their use has only been advocated in
Page 13 of 29


combination with cTn [63]. Combination of cTn with h-FABP, copeptin,

IMA, and myoglobin improved sensitivity for MI at presentation, but at
the expense of a loss of specificity [30]. In recent guidelines [4], a
strategy combining a normal copeptin on admission with a normal cTn or
hsTn on admission received a recommendation for instant rule-out of MI.
With the use of hscTn assays, the usefulness of earlier ischaemia

biomarkers has been challenged, as a similar diagnostic accuracy can be
achieved with cTn as a single test by using a high-sensitivity assay [7, 8,
29, 30].
Prognostic biomarkers
From carefully conducted meta-analyses [30], there was some evidence

that BNP, NT-proBNP, MPO, and h-FABP can provide additional prognostic
value beyond cTn, whereas CRP, PAPP-A, and h-FABP can predict major
adverse cardiac events (MACEs) in normal-troponin patients. Regarding
CRP, results from studies on the prognostic value are conflicting. For
some other biomarkers, such as GDF-15 [64, 65] or copeptin [66–70],
there is increasing supporting evidence for a prognostic value,
particularly among normal-cTn patients. However, the number of studies
is still too small to draw definite conclusions.
In summary, findings on a large variety of biomarkers are based on small

numbers of heterogeneous studies, and the utility of the prognostic value
of most biomarkers is unclear. In particular, little is known about the
added value of representative biomarkers of inflammation, myocardial
stress, or ischaemia listed when hscTn is used, instead of conventional
cTn. Recently, the utility of 14 novel biomarkers for prognostic
assessment in ACS patients with undetectable conventional cTn levels
was investigated [65]. Along with hscTn, independent prognostic
information was conferred only by GDF-15 and MR-proADM. In another
study, copeptin not only improved rapid rule-out of an emerging NSTEMI
when cTn was low, but also helped to identify patients at higher risk for
adverse outcomes, if copeptin levels were high [70].
Novel biomarkers: copeptin, MR-proatrial

natriuretic peptide, and MR-proadrenomedullin
Copeptin
There is accumulating evidence indicating that copeptin, the stable

fragment of vasopressin, can improve rapid rule-out of MI when
measured together with a conventional [66, 67], or with a hscTn, assay
[68]. Following an index event, such as a small infarct, copeptin is rapidly
released from the pituitary gland and appears rapidly in the blood in
patients with an evolving MI, while cTn is still normal [66]. Copeptin
concentrations decline fast to normal as cTn levels rise above the 99th
percentile. Copeptin levels do not increase in patients with uncomplicated
UA. Accordingly, patients who are measured normal for copeptin and cTn
on presentation are unlikely to develop an NSTEMI at serial testing [66–
Page 14 of 29


68]. The performance of copeptin is excellent, in combination with a

conventional cTnT or cTnI assay, with NPVs of about 99% when using
copeptin cut-off levels of 10 pmol/L, for example [66, 67]. The added
benefit of copeptin, combined with a hscTn assay, is smaller, but still
significant [68]. In a randomized interventional trial, discharge of patients
with suspected ACS at low-to-moderate risk using copeptin and troponin
in combination was earlier and at least as safe as the standard protocol
using serial cTn or hsTn [69]. In addition, copeptin not only improved a
rapid rule-out of an emerging NSTEMI, but also helped to identify
patients at higher risk for adverse outcomes, if copeptin levels were high
[70].
Atrial natriuretic peptide (MR-proatrial natriuretic peptide)
ANP is derived from the cleavage of its precursor proatrial natriuretic

peptide (proANP) [71]. MR-proatrial natriuretic peptide (MR-proANP) has
so far been shown to offer comparable diagnostic and prognostic
performance to other natriuretic peptides in heart failure [72]. More
recently, there is some evidence for a prognostic role for ANP in different
settings of ACS [73–75].
The LAMP study (Leicester AMI Peptide study) reported that, post-MI,
MR-proANP added prognostic information, independently of established
conventional risk factors [73]. As a shortcoming, STEMI was over-
represented, and results of MR-proANP were not evaluated against a
hscTn assay.
In another study, Meune et al. [74] investigated the diagnostic and

prognostic value of admission MR-proANP in a cohort of 675 patients
with CP and compared it with conventional and hscTn. MR-proANP was
an independent predictor for the composite of death or MI at 360 days of
follow-up and conferred additive discriminatory effects for prognosis to
fourth-generation cTnT and hscTn. However, MR-pro ANP failed to
improve diagnosis, in combination with a conventional sensitive cTn
assay. In another cohort of 1386 consecutive patients with suspected ACS,
Tzikas et al. [75] reported that an increment of the log-transformed MR-
proANP by 1 SD was associated with an adjusted 2.55-fold risk of death
or non-fatal MI. MR-proANP appeared in blood earlier than BNP and MR-
proADM, and it delivered robust predictive values on admission. However,
further serial measurements did not add any relevant prognostic
information.
MR-proadrenomedullin
Khan et al. [76] used a combined primary endpoint of death or heart

failure to evaluate the prognostic value of MR-proadrenomedullin (MR-
proADM) in a large cohort of patients after AMI. Investigators in the
LAMP II study [77] provided additional evidence on the prognostic utility
of MR-proADM in a large cohort of NSTEMI patients, even beyond that of
the GRACE score. In another study by Tzikas et al. [75], MR-proADM was
Page 15 of 29


measured in 1386 consecutive patients with suspected ACS. Adjusted risk

for risk of death and non-fatal MI was 1.91-fold per 1 SD increment of
MR-proADM, and resulted in a significant reclassification of patients
when added to the GRACE risk score.
In summary, novel biomarkers, such as copeptin, MR-proANP, and MR-

proADM, provide promising results for the diagnostic and prognostic
assessment in suspected ACS. Copeptin may facilitate a rapid rule-out of
NSTEMI on presentation, when combined with cTn or hscTn assays. In
addition, elevated copeptin levels indicate higher mortality rates at 1
year, in the absence of an elevated cTn using a hscTn assay. Likewise,
measurements of MR-proANP and MR-proADM improved the prognostic
assessment in suspected ACS, independent of, and additive to, the GRACE
score [75].
Biomarkers of renal function
An impaired renal function is associated with higher mortality

in patients with ACS (see Chapters 17 and 39) [78].
It is believed that the renal function indicates the cumulative extent of

vascular damage caused by hypertension, dyslipidaemia, and diabetes.
Knowledge of the renal function is important for risk assessment and for
dose adjustment of anticoagulation and antiplatelet therapies, as patients
with renal failure are prone to excess bleeding, due to overdosing. GFR
estimates, based on creatinine levels, are the accepted standard for
quantifying the renal function in most clinical settings, but this has
limitations, as serum creatinine concentrations may be affected by
tubular secretion, age, sex, muscle mass, physical activity, and diet.
There is accumulating evidence that plasma cystatin C level is an

accurate marker of renal function and an independent predictor of
mortality in patients with CAD, but only few studies have evaluated the
prognostic role of cystatin C specifically in patients with ACS [79]. In a
study on 726 patients with suspected ACS, cystatin C had better
discrimination power than creatinine clearance or creatinine, and this
suggests that its measurement can improve early risk stratification [79].
Renal function became the strongest predictor for 1-year mortality, in

combination with NT-proBNP [80].
Biomarkers of haemostasis and fibrinolysis
Markers of activated thrombosis contain useful information,

with regard to the ongoing thrombotic process in ACS (see Chapter
38) [81]. Previous studies have shown an association between the risk of
MI and the concentrations of fibrinogen, soluble fibrin, and markers of
the fibrinolytic pathway, including plasminogen activator inhibitor-1 [82,
83]. In addition, many of the novel markers are also associated with the
inflammatory atherosclerotic process. However, for several reasons, none
Page 16 of 29


of these markers appear to possess enough clinical information to be

included in the present recommendations for the management of ACS
[81].
Combination of biomarkers—a multimarker

approach
The pathophysiology of ACS is complex and cannot be reflected by a

single marker (see Chapter 37). There is growing evidence that
combining a biomarker of haemodynamic stress (BNP or NT-proBNP) or a
biomarker of inflammation (high-sensitivity CRP) with a biomarker of
necrosis (cTn) enhances the risk assessment in patients with ACS [80,
84].
Personal perspective
cTn are anticipated to remain the preferred biomarker for ACS
diagnosis and classification, due to its cardiospecificity and superior
sensitivity to other cardiac constituents. In addition, it appears that
an elevated cTn accurately indicates myocardial injury and thus
predicts a higher risk for cardiovascular events, regardless of the
underlying aetiology. Thus, elevated hscTn should be viewed as an
important tool for risk stratification in ACS and non-ACS conditions,
and not as a confounder of ACS diagnosis. Moreover, it is tempting to
speculate that cTn levels may be influenced by various forms of
intervention (physical activity, lifestyle modification, statin therapy,
potent antiplatelet therapies) and thus may be used for the
monitoring of disease progression or therapeutic effects.
Another interesting topic is the acceleration of rule-in and rule-out of

patients with suspected ACS, in order to shorten the lengths of stay in
ED, and to optimize patient management and health care resources.
New algorithms using hscTn assays at low cut-offs alone [85–87], or
in combination with additional biomarkers such as copeptin [66–68],
may allow the rapid exclusion of an evolving NSTEMI within 1–2
hours and the subsequent safe discharge of patients with suspected
ACS who are at low risk for subsequent death or MI.
Further reading
1. Apple FS. A new season for cardiac troponin assays: it’s time to keep a
scorecard. Clin Chem 2009;55:1303–6.
2. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA.

Analytical validation of a high sensitivity cardiac troponin T assay. Clin
Chem 2010;56:254–61.
Page 17 of 29


3. Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the
management of acute coronary syndromes in patients presenting without
persistent ST-segment elevation: the Task Force for the management of
acute coronary syndromes (ACS) in patients presenting without persistent
ST-segment elevation of the European Society of Cardiology (ESC). Eur
Heart J 2011;32:2999–3054.
4. Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early

diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868–77.
5. Latini R, Masson S, Anand I, et al; for the Val-HeFT Investigators.

Prognostic value of very low plasma concentrations of troponin T in
patients with stable chronic heart failure. Circulation 2007;116:1242–9.
6. Omland T, de Lemos JA, Sabatine MS, et al; Prevention of Events with

Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A
sensitive cardiac troponin T assay in stable coronary artery disease. N
Engl J Med 2009;361:2538–47.
7. Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of

myocardial infarction with sensitive cardiac troponin assays. N Engl J
Med 2009;361:858–67.
8. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD;
Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of
Myocardial Infarction, Katus HA, Lindahl B, Morrow DA, et al. Third
universal definition of myocardial infarction. Circulation 2012;126:
2020-35.
9. Thygesen K, Mair J, Giannitsis E, et al; Consensus Study Group on

Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care.
How to use high-sensitivity cardiac troponins in acute cardiac care. Eur
Heart J 2012;33:2252–7.
10. Thygesen K, Mair J, Katus H, et al; Study Group on Biomarkers in

Cardiology of the ESC Working Group on Acute Cardiac Care.
Recommendations for the use of cardiac troponin measurement in acute
cardiac care. Eur Heart J 2010;31:2197–204.
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Biomarkers in Acute Coronary Syndromes

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Biomarkers in acute coronary syndromes

Oxford Medicine Online

The ESC Textbook of Intensive and Acute

This online textbook has been comprehensively reviewed for the

Publisher: Oxford University Press Print Publication Date: Feb 2015

Biomarkers in acute coronary syndromes

Chapter: Biomarkers in acute coronary syndromes

Author(s): Evangelos Giannitsis and Hugo A Katus

Introduction of MINOCA to describe acute myocardial infarction in

Modification of risk stratification and timing of invasive strategy

Updated on 22 February 2018. The previous version of this

Biomarker testing in the evaluation of a patient with acute chest pain

Other biomarkers of inflammation, activated coagulation/fibrinolysis,

A multi-marker approach to biomarkers becomes more and more

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in combination with additional biomarkers or clinical scores, allow to

Other biomarkers [link]

Novel biomarkers: copeptin, MR-proatrial natriuretic peptide, and

Biomarkers of renal function [link]

Introduction: pathophysiology and classification of

The aetiology of acute coronary syndromes (ACS) is complex and involves

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sufficiently severe in intensity and duration to cause myocyte necrosis,

The most recent achievement with biomarker testing is the

Other biomarkers representing inflammation, activation of coagulation,

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cTnT and cTnI are now considered as the preferred biomarkers

Table 36.1 Joint ESC/ACCF/AHA/WHF Task Force definition of acute

Myocardial infarction should be diagnosed when there is evidence of

♦ Detection of rise and/or fall of cardiac biomarkers (preferably

The Universal myocardial infarction (MI) definition [9] further

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upper limit of normal (99th percentile) by >5 times, together with

Table 36.2 Subtypes of MI

Type Spontaneous myocardial infarction related to ischemia due

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Type Myocardial infarction secondary to ischemia due to

Type Sudden cardiac death with symptoms of ischemia,

Type Myocardial infarction associated with percutaneous

Type Myocardial infarction associated with verified stent

Type Myocardial infarction associated with coronary artery

Elevated cTn values in patients with acute ischaemic presentations are

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[17], tirofiban [18], lamifiban [19], or triple antiplatelet therapy, followed

Table 36.3 Need and timing of invasive strategy according to 2015

Risk category Timing of coronary

Very high risk Immediate

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High risk Early invasive (<24

Rise or fall in cardiac troponin

Intermediate risk Invasive (<72 hours)

Low risk Non-invasive testing if

Any characteristics not mentioned above

An early invasive strategy (<24 h) is recommended in patients with high

Other biomarkers of myocardial necrosis, including total creatine kinase

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