ORIGINAL ARTICLE

Original Article

Biomarkers of Cardiovascular Damage and

Dysfunction—An Overview
Paul O. Collinson, FRCPath, FACB, MD ∗ and David C. Gaze, FIBiol, AIBMS
Departments of Chemical Pathology, Cardiac Research and Cardiology, St George’s Hospital and Medical School,
Blackshaw Road, London SW17 0QT, United Kingdom

Acute coronary syndromes (ACS) are due to the rupture or erosion of atheromatous plaques. This produces, depending
on plaque size, vascular anatomy and degree of collateral circulation, progressive tissue ischaemia which may progress to
cardiomyocyte necrosis and subsequent cardiac remodelling. Cardiac biomarkers can be used for diagnosis and assess-
ment of all of these stages. Markers to detect myocardial ischaemia at the pre-infarction stage are potentially the most
interesting but also the most challenging. An ischaemia marker offers the opportunity to intervene to prevent progres-
sion to infarction. The challenges with potential ischaemia markers are specificity and the diagnostic reference standard
for assessment. To date, only one, ischaemia modified albumin, has reached the point where clinical studies can be per-
formed. The measurement of the cardiac troponins, cardiac troponin T and cardiac troponin I, has become the diagnostic
standard as the biomarker of myocardial necrosis. The sensitive nature of troponin measurement has also revealed that
myocardial necrosis is also found in a range of other clinical situations. This illustrates the need to use all clinical infor-
mation for diagnosis of acute myocardial infarction. The measurement of B type natriuretic peptides can be shown to
be diagnostic and prognostic for both acute ACS and detecting the sequelae of post infarction myocardial insufficiency.
The role of the B type natriuretic peptides in detection of cardiac failure, acute and chronic, is well defined. Their role in
ACS remains the subject of further studies.
(Heart, Lung and Circulation 2007;16:S71–S82)
© 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and
New Zealand. Published by Elsevier Inc. All rights reserved.
Keywords. Ischaemia; Acute coronary syndrome; Prognostic risk assessment; Chest pain; Myocardial infarction; Biomark-
ers; Ischaemia modified albumin; Troponin; Cardiac troponin T; Cardiac troponin I; N terminal B type natriuretic peptide;
B type natriuretic peptide

Biomarkers of Cardiovascular Damage duce myonecrosis. Downstream from the area of partial
occlusion there may be myocardium with supply/demand
T he pathophysiology of acute coronary syndromes
(ACS) is now accepted as the rupture or erosion of an
atherosclerotic plaque.1 This process may be self-limiting
mismatch. If this is the case, a reduction in the rate of blood
supply may tip an area of myocardium from ischaemia
to necrosis. This will be most likely at the watersheds
or progressive (Fig. 1) and may occur rapidly (minutes to
of different branches of the vascular supply. A second
hours) or over a longer period (over several days). Rup-
mechanism is the release of platelet micro-aggregates with
ture of a single plaque with all of the clinical effects due to
downstream micro-embolisation and infarction.3 Progres-
occlusion of a single downstream vessel has been shown
sion from white thrombus formation to activation of the
to be too simple a model of ACS. Intravascular imaging
clotting cascade will result in partial or total occlusion of
shows that plaque rupture is often multiple and often
the vessel. Partial occlusion will produce ischaemia and
affects arteries other than the culprit artery.2
necrosis if it compromises downstream tissue viability, as
Initial plaque rupture typically occurs at the shoulder
described above. Total occlusion will produce ischaemia
of the plaque and is followed by intra-plaque thrombo-
and progress to necrosis if occlusion is maintained and
sis. This can then spread to the vascular lumen by platelet
when there is inadequate or no collateral blood supply.
aggregation. If the degree of platelet aggregation is suffi-
The final phase will be organisation of the thrombus and
cient to cause vascular occlusion, cardiomyocyte damage
infarcted area with healing by fibrosis. This sequence of
will occur. Occlusion does not have to be total to pro-
events is illustrated in Fig. 2.
Available online 6 July 2007 The sequential phases that follow plaque formation
and destabilisation are therefore ischaemia, infarction and
∗ Corresponding author at: Department of Chemical Pathology, repair/remodelling. This is illustrated schematically in
2nd Floor Jenner Wing, St George’s Hospital, Blackshaw Road,
London SW17 0QT, United Kingdom. Tel.: +44 208 725 5934; Fig. 3. Cardiac biomarkers for the assessment of all three
fax: +44 208 682 0744. phases are available. This article will provide an overview
E-mail address: paul.collinson@stgeorges.nhs.uk (P.O. Collinson). of current markers of myocardial ischaemia, necrosis and

© 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of 1443-9506/04/$30.00
Australia and New Zealand. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.hlc.2007.05.006
 S72 Collinson and Gaze
ORIGINAL ARTICLE
Biomarkers of cardiovascular damage and dysfunction
Figure 1. Plaque rupture—the balance between thrombosis and thrombolysis.
Figure 2. Plaque formation and progression.
Figure 3. Progression of vascular occlusion to ischaemia and infarction.
Heart, Lung and Circulation
2007;16:S71–S82
dysfunction. The role of candidate and actual biomarkers
plaque destabilisation will not be covered. There is, as yet,
no consensus on these markers and they currently have
no role to play in patient management.4
The assessment of the diagnostic performance of
biomarkers is typically examined by the construction of
a receiver operating characteristic curve, an ROC curve.
This is a graphical representation of sensitivity of the test
plotted against 1—specificity. The area under the curve
(AUC) is determined mathematically. AUC is used as the
measure of test performance.5 The AUC should be bet-
ter than 0.7 to be diagnostically useful but values greater
than 0.85 would normally be expected. An AUC of 0.9 or
greater shows excellent test performance and a value of
1.0 indicates perfection.
Heart, Lung and Circulation Collinson and Gaze S73

ORIGINAL ARTICLE
2007;16:S71–S82 Biomarkers of cardiovascular damage and dysfunction

Biomarkers of Ischaemia tulated mechanism is degradation of the N terminus of

albumin, sequence analysis reveals that samples contain-
The detection of ischaemia prior to infarction is an
ing IMA do not show evidence of this change.11 The
attractive concept. If ischaemia can be detected prior to
mechanism of IMA generation therefore remains unex-
myocardial damage, early intervention by mechanical or
plained at this time.
therapeutic means might abort myonecrosis. Three mark-
Three initial studies focussed on proof of concept for
ers of ischaemia have been studied, choline, unbound free
IMA and concentrated on ability of early measurement
fatty acids and ischaemia modified albumin.
to predict a final diagnosis of AMI defined by cardiac
Choline is released by cleavage of membrane phos-
troponin. The first evaluation utilised sampling on admis-
pholipids by phospholipase D to yield plasma choline
sion and with two subsequent samples and studied ACS
(PCHO). Phospholipase activation occurs in plaque
patients.12 Sensitivity for a final diagnosis of AMI was
destabilisation. Ischaemic membrane damage produces
23.9% for cTnI alone (n = 296), 39.1% for the ACB test
phospholipid breakdown, choline release and uptake into
(n = 299) and 55.9% for the two combined (n = 293).22 In
red blood cells via a choline transporter. Initial stud-
samples taken 1–6 h and >6–12 h from presentation, the
ies utilising proton magnetic resonance spectroscopy
ACB test improved diagnostic sensitivity over troponin
demonstrated increased whole blood choline (WBCHO) in
measurement alone but this failed to reach statistical
ACS. Subsequently, HPLC–mass spectrometry was used
significance. The second study examined samples taken
to prospectively measure WBCHO on admission in 327
on admission and 6–24 h later and enrolled 256 ACS
patients.6 This study used cTnT and cTnI for diagnosis of
patients at four centres.13 The AUC of the ROC curve
myocardial infarction and 30 day outcome as an endpoint.
was 0.78 with sensitivity 83% and specificity 69% at the
WBCHO was not a good marker for a subsequent diagno-
optimised decision threshold for a final diagnosis of AMI.
sis of acute myocardial infarction (AMI). When used alone
The third study utilised an in-house ACB test.11 75 ED
or in combination with cardiac troponins it was a good
patients with ischaemia and 92 non-ischaemic patients
indicator of major adverse cardiac events (MACE) and
were examined.21 In this study, the ACB test had poor pre-
did distinguish between high risk and low risk patients
dictive power in discriminating between a final diagnosis
without AMI. Choline measurement is a promising new
of AMI or not in patients with underlying ischaemic heart
marker but the measurement methodology is not suit-
disease (AUC of 0.66). However, the test gave good dis-
able for routine clinical application. Currently, the method
crimination between patients with or without ischaemia.
is being developed for routine clinical use on a high
The AUC for the ROC curve for diagnosis of ischaemia was
throughput analyser. When this becomes available it will
0.95 with sensitivity of 94% and specificity of 88%.
be possible to evaluate this test further.
The potential major role of the ACB test is in the exclu-
Ischaemia is associated with the release of free fatty
sion of patients with ischaemic heart disease. The most
acids (FFA) from cardiac muscle. Albumin binds the
logical place for its use is therefore patients presenting
majority but some remain unbound and can be detected
to the Emergency Department (ED) with suspected ACS.
in the serum (unbound free fatty acids, FFAu). Follow-
A study of ED presentations examined 208 patients.14
ing angioplasty induced ischaemia, a significant rise in
In samples taken within the first three hours the diag-
FFAu was demonstrated in 22 patients following balloon
nostic sensitivity of IMA measurement alone was 82% at
inflation comparing measurements performed 5 min pre-
46% specificity. The combination of ECG, cTnT and IMA
procedure with those performed 30 min post-procedure.7
showed 95% sensitivity for diagnosis of ACS at presen-
The highest FFAu values were found in 11 patients where
tation. A subsequent study of 538 patients admitted to
there were accompanying ST segment changes in the
a chest pain evaluation unit found admission measure-
electrocardiogram (ECG). FFAu were studied in samples
ment of IMA plus cTnT had 100% sensitivity for prediction
taken as part of the Thrombolysis in Myocardial Infarc-
of a final diagnosis of AMI.15 The presence of an ele-
tion (TIMI) II study. Sensitivity was 91% on admission and
vated IMA and an elevated cTnT on admission predicted
98% at 50 min from admission to predict a final diagnosis
21% risk of MACE compared to patients where both were
of AMI.4 This study enrolled patients with ST segment ele-
not elevated, even in patients where the final diagnosis
vation myocardial infarction (STEMI), where biochemical
excluded AMI by troponin based criteria. In a recently
diagnosis is not required and where the prior probability
published meta-analysis, the role of IMA as a rule out test
of AMI is 100%.8 Although interesting, the measurement
has been demonstrated.16 A prospective multicentre ran-
technology is not yet suitable for routine use and validation
domised controlled trial of IMA for diagnosis is currently
is required in more representative patient groups.
being undertaken (the IMAGINE study). This will provide
a definitive answer.
Ischaemia Modified Albumin Problems remain to be resolved with IMA. The mech-
The N terminus of albumin is known to bind transition anism remains unexplained. Very low albumin level
metals such as cobalt II, nickel II and copper II ions and co-incident lactic acidosis affect assay performance
and also to be susceptible to biochemical degradation.9 and samples need to be analysed rapidly. Despite this,
It was noted that myocardial ischaemia resulted in reduc- IMA currently remains the only ischaemia assay to have
tion of the ability of albumin to bind cobalt. This is the reached the clinical validation stage.
basis of the albumin cobalt-binding test (ACB® test) for Clinical studies of ischaemia markers are challenging.
ischaemia modified albumin (IMA® ).10 Although the pos- An appropriate population for study must be selected. It
 S74 Collinson and Gaze
ORIGINAL ARTICLE
Biomarkers of cardiovascular damage and dysfunction
is the in the nature of initial validation studies that sam-
ple banks are used. The best documented sample banks
are those arising from clinical trials. The exclusion crite-
ria for trial entry results in elimination of patients with
potentially confounding clinical conditions as well as rais-
ing the probability of pre-existing cardiac disease, often
to 100%. In addition, there is no reference diagnostic test
for myocardial ischaemia. An analogy is the initial evalu-
ation of troponin testing when specificity was apparently
poor. This was not due to the test but that measurement of
creatine kinase MB isoenzyme (CK-MB), used as the refer-
ence ‘Gold standard’, was insufficiently sensitive. The use
of outcome measures as an independent reference stan-
dard is one way of solving this problem (as was shown for
cTn). It is interesting to note that an elevated IMA appears
also to be an outcome predictor.
Biomarkers of Necrosis
Cardiac troponin measurement has become the ‘Gold
standard’ test for the detection of myocardial necrosis
leading to the redefinition document produced by the
European Society of Cardiology (ECS) and the American
College of Cardiology (ACC).17 The paradigm shift to tro-
ponin measurement as biomarker is due to the sensitivity
and specificity of the test and the evidence base for out-
come prediction.
For any testing modality, sensitivity is dependant on the
discrimination that can be achieved between the normal
and abnormal state. This is determined by the background
level of signal in the normal state, the background noise,
and the change of level in the signal in the abnormal state.
This is referred to as the signal-to-noise ratio. Currently
with cardiac troponins, the background level in the cir-
culation appears to be determined by the detection limit
of the assay. Although there may be a background level
of cTn in the circulation, this is currently undetectable by
the commercially available assays. Cardiac troponins are
found only in cardiac tissue with detectable levels only
Figure 4. Relationship between WHO and European Society of Cardiology/American College of Cardiology definition of myocardial infarction.
Heart, Lung and Circulation
2007;16:S71–S82
when there is myocardial damage. A low background plus
cardiospecificity means that the signal-to-noise ratio is
much higher. In mass terms, the amount of cTn released
is less than that of CK-MB but the ability to detect it
is much greater. Elevations of cardiac troponin do not
occur where there is pure skeletal muscle trauma.18,19
Initial reports that cTnT might be re-expressed in skele-
tal muscle have been demonstrated to be an artefact of
the techniques originally used and in particular due to
problems of nonspecificity of the antibodies selected for
immunostaining.20,21
Troponin biochemistry and measurement methodology
has been reviewed in detail elsewhere.18 Although initial
clinical studies examined the diagnostic utility, it is the
prognostic ability of cardiac troponin measurement that
has resulted in its widespread adoption. Initial studies of
cTnT demonstrated that an elevated troponin was asso-
ciated with an increased MACE rate in both short term
and long term follow up. The measurement methodology
for cTnT is supplied by only one manufacturer. Mea-
surement of cTnI is available on a range of platforms,
from different suppliers, which do not produce numeri-
cally similar results. Despite numerical differences in the
values obtained, measurement of either detectable cTnT
or cTnI in patients classified as having unstable angina
by conventional diagnostic criteria predicts an increased
MACE rate both in individual studies and in subsequent
meta-analyses.22,23 The superiority of cTnT and cTnI mea-
surement over the other markers currently in use has
led to their being proposed as the ‘Gold standard’ test
for detection of myocardial infarction. Cardiac troponin
measurement extends the diagnostic threshold into the
unstable angina group but there is a significant overlap
between the original WHO and the current clinical classi-
fication as is indicated schematically in Fig. 4. The advent
of troponin measurement can be considered simply as an
extension of the existing biomarker technology into a more
sensitive and specific phase. The analogy would be the
replacement of CK by CK-MB.
Heart, Lung and Circulation
2007;16:S71–S82
The mechanisms by which troponin release can occur
in ACS were discussed earlier, necrosis from partial
or total vascular occlusion and platelet emboli. Tro-
ponin released into the circulation appears to be stable
although there is loss of some N terminal and C termi-
nal immunoreactivity.18 Whilst intracellular degradation
does occur during infarction,24,25 the majority of troponin
released following myocyte necrosis appears as the intact
troponin molecule. Work to define if there are degradation
products present in significant amounts in the circulation
is still ongoing.
The clinical role of cTn measurement can be divided
according to clinical presentation: patients presenting
with ST elevation on the ECG; patients with ACS at high
risk of non ST elevation myocardial infarction and patients
presenting with a low risk of ACS.
Patients with ST elevation have a presumptive diagnosis
of ST elevation myocardial infarction (STEMI). Manage-
ment is by re-establishing blood flow in the acutely
occluded vessel by primary percutaneous intervention
(PCI) or thrombolysis. There is no role for cTn measure-
ment in the initial management of this group. An elevated
cTn at first presentation identifies a higher risk group26 but
there is no evidence for a different management strategy in
these patients. In patients presenting with a presumptive
diagnosis of STEMI the role of cardiac troponin measure-
ment is to audit the final diagnosis. There may be a role in
Figure 5. Strategy for rapid rule out of AMI in low risk chest pain patients.
Collinson and Gaze S75
ORIGINAL ARTICLE
Biomarkers of cardiovascular damage and dysfunction
quantification of the extent of infarction as it can be shown
that cTn measurements allow prediction of a decreased
ejection fraction.27,28
In patients presenting at high risk of ACS and devel-
oping non-ST segment elevation myocardial infarction
(NSTEMI) the objective is diagnostic confirmation and
risk stratification. Patients can be categorised into tro-
ponin positive on admission, positive 12–24 hours from
admission or negative at 12–24 hours from admission.
The major role of troponin measurement is for the exclu-
sion of myocardial damage by a negative test result. Such
patients are at low risk and can be considered for hos-
pital discharge. It must always be remembered that a
negative troponin result does not rule out a flow lim-
iting stenosis. Subsequent investigation by either stress
testing29 or perfusion scanning is required.30 The com-
bination of a negative exercise stress test plus a negative
troponin has an excellent negative predictive value and
identifies a very low risk population. A detectable cTnT
and cTnI in patients with ACS identifies a high risk group
who will benefit from interventions such as low molecu-
lar weight heparin,31 glycoprotein IIb/IIIa antagonists32
and revascularisation.33 This has led to the incorpora-
tion of troponin measurement into management guide-
lines.34
Patients with chest pain who on clinical assessment
are considered to be at low risk of NSTEMI can be
 S76 Collinson and Gaze
ORIGINAL ARTICLE
Biomarkers of cardiovascular damage and dysfunction
investigated by an accelerated chest pain protocol incor-
porating a cytoplasmic marker such as CK-MB and a
troponin. An example of such protocol is illustrated in
Fig. 5. Patients who test negative proceed to stress test-
ing. The utilisation of such a chest pain protocol, ideally
within a chest pain evaluation unit is both clinically and
cost effective.35 Although a multi-marker approach util-
ising either myoglobin or CK-MB is currently favoured,
the utilisation of a sensitive troponin method allows a tro-
ponin only based strategy to be implemented success-
fully.36
Myocardial infarction is not the only cause of cardiac
damage. There are some obvious causes, such as direct
myocardial trauma from stabbing, where troponin eleva-
tion would be expected to occur and ACS is not involved.
However, there is a large, and increasing, number of condi-
tions where elevation of cTn has been reported and which
are not associated with ACS. In many cases, there is a high
probability of associated atherosclerotic disease which
may contribute to the pathophysiological process, but not
in all. Studies which have demonstrated elevated cTn in
non-ACS populations which have also examined outcome
have found that elevations of troponin in these non-ACS
populations are of prognostic significance. Two clinical
scenarios associated with troponin elevation deserve spe-
cial comment, renal failure and PCI.
Troponin elevation in renal failure was first described
only for cTnT and was considered to be an analytical
false positive.37 Subsequent studies have clarified this
original report. It has been shown that both cTnT and
cTnI are elevated in patients with renal failure38 and that
such elevations are prognostic.39 This has been confirmed
by meta-analysis.40 The precise mechanism remains to
be clarified. A detailed study of 121 patients with end
stage renal disease selected for a renal transplantation
performed a detailed anatomical and functional cardiac
assessment by coronary angiography, echocardiography
and dobutamine stress echocardiography. All patients had
a detailed biochemical profile and were followed up for a
minimum of one year. It was found that an elevated cTnT
did not predict the presence of coronary artery disease
but did predict survival. An abnormal dobutamine stress
echo indicative of global dysfunction was associated with
increased cTnT and an adverse outcome.41 In patients
with end stage renal failure undergoing haemodialysis,
troponin elevation is prognostic and related not to coro-
nary artery disease but to evidence of global cardiac
damage.
Biomarker release following PCI was first described in
1985 and has been the subject of continuing investiga-
tion (and considerable controversy because of its role in
defining post-PCI endpoints in clinical trials). Publica-
tions from over 60 studies have reported the incidence
of elevated biomarkers to range from 0 to 69% depend-
ing on biomarker measured and cut-off utilised. For cTnT
the range is 7–69% and for cTnI 5–53%.42 Visualisation
of myocardial tissue by magnetic resonance imaging has
shown that elevations of both CK-MB43 and cTnI44 can
be correlated with evidence of myocardial damage. The
relationship between biomarker elevation and outcome is
Heart, Lung and Circulation
2007;16:S71–S82
contentious45,46 The literature on CK-MB elevation is not
consistent. Meta-analysis has shown incremental increase
in risk of long term mortality according to degree of
CK-MB elevation.47 Conversely, a large study comparing
patients undergoing PCI with those having medical man-
agement alone found that an elevated CK-MB post-PCI
had the same relative risk of death as spontaneous CK-
MB elevation in the non PCI group. However, the absolute
risk of death was lower in the post-PCI group.48 The data
for cTn is even less certain. Elevations of cTnT and cTnI,
like CK-MB, do occur after PCI but are not major predic-
tors of adverse outcomes. Where there is CK-MB elevation
post-PCI, troponin elevation may not be predictive.49 One
recent study specifically evaluated the role of post-PCI
troponin elevation, comparing pre-PCI with post-PCI tro-
ponin values. The authors concluded that an elevation of
troponin following PCI was only significant in predict-
ing an adverse outcome when the baseline pre-procedural
troponin was elevated.50
It is likely that a range of other factors including acute
plaque destabilisation, lesion complexity, aspirin resis-
tance and co-incident therapy are the major determinants
of subsequent events.42 Two patterns of myocardial dam-
age associated with post-PCI troponin elevation have
been described, type 1 and type 2. The type 1 pattern
shows damage in proximity to the target lesion, prob-
ably due to side branch occlusion or damage to small
vessels at the site of balloon inflation. With the type 2
pattern, damage occurs to the distal perfusion territory of
the treated artery. There are a range of potential causes
including micro particles, plaque debris and thrombus
dislodged by the procedure causing micro vascular plug-
ging, platelet and neutrophil activation. In addition there
is the neurohormonal systemic effects of the procedure.42
The type of damage is therefore not the same as that
seen in AMI but represent a distinct type of secondary
ischaemic cardiac injury, peri-procedural injury. Recent
discussions on the revision of the original redefinition
(World Congress of Cardiology 2006) have suggested that
PCI induced biomarker elevation be classified as a sub-
type of AMI. It is debatable if this is the most appropriate
grouping.
A pragmatic approach to troponin release due to
myocardial damage is to divide it into three categories.51
Troponin release occurs due to primary ischaemic car-
diac injury (PICI) with troponin release in the context of
an acutely ruptured plaque as part of a clinical presen-
tation with ACS. Troponin release can also occur due to
secondary ischaemic cardiac injury (SICI). In this case,
ischaemia is the underlying cause but primary plaque
rupture is not the underlying pathophysiology. Finally,
there can be non-ischaemic cardiac injury (NICI) with the
cause due to direct cardiac damage. The mechanism of
troponin release in SICI will be a combination of direct
vascular occlusion and supply/demand mismatch, with
the balance between the two components dependant on
the underlying cause. Direct damage from the underlying
disease process to either the myocardial vasculature or the
myocardium itself will produce the troponin elevations of
NICI. Examples are given in Table 1.
Heart, Lung and Circulation Collinson and Gaze S77

ORIGINAL ARTICLE
2007;16:S71–S82 Biomarkers of cardiovascular damage and dysfunction

Table 1. Secondary Ischaemic and non-Ischaemic Causes of Cardiac Injury

Primary ischaemic cardiac injury (PICI)
Thrombotic coronary artery occlusion due ST elevation MI
to platelets/fibrin
Non-ST elevation MI (non Q wave MI plus cTn-positive unstable angina)
Secondary ischaemic cardiac injury (SICI)
Coronary intervention Primary PTCA Distal embolisation from atheroma or debris
Side branch occlusion
Elective PTCA Distal embolisation or debris
Side branch occlusion
CABG Global ischaemia form inadequate perfusion,
myocardial cell production of anoxia
Sympathomimetics Cocaine abuse
Catecholamine storm Head injury, stroke, intracerebral bleeding
Pulmonary embolus Presumed right heart strain or hypoxia
Coronary artery spasm In Japan—up to 10% of admissions for chest pain
Coronary artery embolisation Clot
Air
CABG
Coronary artery inflammation with Vasculitidies
microvascular occlusion
Connective tissue damage (e.g. Pompe’s disease)
Systemic lupus erythematosus (SLE)
End-stage renal failure More severe coronary artery disease, but 50% ESRD patients have normal coronaries
Rhythm disorders Prolonged tachycardia or bradycardia with IHD
Acute heart failure Only if due to IHD
Direct coronary trauma
Extreme endurance exercise Extreme marathons Wall motion abnormalities
Extreme training cTn positive deaths presumed due to extreme
oxygen debt producing ischaemia
Non-ischaemic cardiac injury (NICI)
Known causes of myocarditis Infection Bacterial or Viral
Rheumatic myocarditis
Septic shock
Acute pericarditis
Inflammation
Autoimmune Polymyositis
Scleroderma
Sarcoidosis
Drug-induced Alcohol
Cocaine abuse
Chemotherapy
Toxins Snake, puffer fish envenomation
Cardiac Trauma Direct Road traffic accident
Stabbing
Cardiac surgery
Metabolic/toxic Renal failure
Multiple organ failure (MOF)

Biomarkers of Cardiac Dysfunction—Natriuretic
Peptides
There are three natriuretic peptides of current clinical
interest; atrial natriuretic peptide (ANP), B type natri-
uretic peptide (BNP) and C type natriuretic peptide. Only
measurement of BNP is in routine clinical use. BNP was
originally described in the porcine ventricle where it
was thought to be a neurotransmitter. Hence the origi-
nal nomenclature of brain type natriuretic peptide. It was
subsequently found in large quantities in the ventricles of
the heart hence has been renamed B type natriuretic pep-
tide. It is secreted predominantly by the ventricular wall
myocytes in response to increased ventricular stretch. It is
an unusual hormone as it is not stored to any major extent
but is under constant transcription and translation. Trans-
lation of mRNA produces a prohormone which is then
cleaved either intracellularly by furin or during transmem-
brane secretion by corin (Fig. 6) to yield the active portion
of the molecule, B type natriuretic peptide (BNP) and the N
terminal portion of the hormone, NTproBNP. This model
has recently been challenged by the finding that there is a
significant amount of the intact prohormone circulating.52
In addition, recent papers have suggested that it is the
prohormone that is present in cardiac failure and not the
cleavage products.53,54 Although this is of great analyti-
cal and pathophysiological interest, it does not affect the
results of clinical studies performed to date.
 S78 Collinson and Gaze
ORIGINAL ARTICLE
Biomarkers of cardiovascular damage and dysfunction
Figure 6. Secretion of B type natriuretic peptide.
The measurement of BNP and NTproBNP was origi-
nally described 10 years ago.55 The recent interest has
come about as these assays are now routinely available
on high throughput automated platforms from the labora-
tory or by a point of care testing. The only major difference
between measurement of BNP and NTproBNP is the supe-
rior sample stability of NTproBNP.56 This makes it a more
suitable test for primary care applications where there
may be a delay in sample transport and processing. Cur-
rent interest in BNP and NTproBNP measurement as a
diagnostic test has also been stimulated by the awareness
of cardiac failure as an increasing public health problem.
Incidence is noted to be rising and prognosis is poor with
median survival from time of diagnosis as little as 3.2
years.57
Detection of Chronic Ventricular Dysfunction in
Primary Care Patients
The diagnosis of cardiac failure in primary care is noto-
riously difficult and it has been estimated that between
30 and 60% of referrals of ‘cardiac failure’ from primary
to secondary care are inappropriate. The measurement
of BNP/NTproBNP allows systolic dysfunction in primary
care to be excluded with a high degree of certainty. Sys-
tematic evaluation of test performance by ROC curve
analysis report AUC’s in the range 0.75–0.94 depending
on the population studied with negative predictive values
of 95–100%.58 BNP/NTproBNP measurement also pre-
dicts risk. In one primary-care based study, NTproBNP
values above the study median predicted a high risk
of hospital admission with cardiac failure and risk of
death.59 Measurement of NTproBNP in 1205 asymp-
tomatic patients in primary care allowed exclusion of
a range of cardiac pathologies including systolic and
diastolic dysfunction and valve disease.58 It has been sug-
Heart, Lung and Circulation
2007;16:S71–S82
gested that BNP/NTproBNP measurement should be used
as the ‘Gold standard’ test for ventricular dysfunction.
Perspective and observational studies suggest that
BNP/NTproBNP measurement, like cTnT and cTnI in
ACS, can be used for selection and monitoring of ther-
apy. Response to the beta blocker carvedilol is predicated
by pre-treatment BNP/NTproBNP levels.60 In a prospec-
tive randomised controlled trial of Valsartan versus
placebo (VAL-HeFT, n = 4284 patients), initial and follow-
up BNP/NTproBNP values during treatment predicted
outcome.61–63 In a prospective randomised controlled
trial 69 patients were allocated to a structured treatment
protocol with the objective of reducing NTproBNP to
<200 pmol/L or achieving a Framingham Heart Failure
score of <2. Those allocated will to BNP based manage-
ment had significantly less cardiovascular events, heart
failure or death.64 Further trials are underway and are due
to report.
Natriuretic Peptide Measurements in Acute
Cardiac Care
Measurement of BNP/NTproBNP has been studied for
the acute assessment of dyspnoea in the ED. Mea-
surements made at first presentation are diagnostically
efficient compared to an adjudicated final diagnosis of
cardiac failure. The Breathing Not Properly study exam-
ined 1586 ED presentations and found by ROC curve
analysis BNP measurement had an AUC of 0.91.65 A
similar study with NTproBNP performed a pooled anal-
ysis of 1256 patients and demonstrated similar results
for diagnostic accuracy with the AUC from 0.86 to 0.99
depending on the age of the patient.66 BNP measurement
may in itself improve management in acute dyspnoea.
A prospective randomised trial compared diagnosis based
on BNP with conventional clinical diagnosis in 452 patients
Heart, Lung and Circulation
2007;16:S71–S82
admitted with acute dyspnoea. In the patient group allo-
cated to the diagnostic pathway including BNP there was
reduction in both hospital and intensive care stay but
with lower cost although with equivalent mortality in both
patient groups.67
Measurement of BNP/NTproBNP has been studied in
patients presenting with ACS. Measurement of both pep-
tides in selected and unselected ACS patients can be
used to predict outcome. In 2525 patients enrolled in
a clinical trial (OPUS-TIMI 16) with a mixed popula-
tion of STEMI, NSTEMI and unstable angina pectoris
(UAP), measurement of BNP showed that mortality at
10 months was dependent on the magnitude of BNP
elevation.68 Those with values in the lowest quartile had
1% mortality compared with 9% for those in the high-
est quartile. When the population was split into those
above or below 80 pg/L, an elevated BNP showed a signif-
icantly greater risk of death, heart failure or AMI both at
30 days or 10 months. An unselected prospective obser-
vational study of 755 patients with suspected NSTEMI
ACS demonstrated that admission NTproBNP measure-
ment predicted an adverse outcome with a relative risk
of 26.6 in the highest quartile compared to those with a
normal value.69 666 patients admitted with AMI had BNP
and NTproBNP measured 24–96 hours from symptom
onset. Subsequent death or heart failure was predicted
by BNP/NTproBNP levels even when ejection fraction
exceeded 40%.70 BNP/NTproBNP measurements have
been combined with other biomarkers including CRP and
cTn71 or cTn alone.69 Measurements of NTproBNP/BNP
provide additive information under these circumstances
with the worst prognosis seen when the greatest num-
ber of biomarkers are elevated. However, a large study of
6809 patients enrolled in a large clinical trial (GUSTO IV)
demonstrates that different biomarkers predict different
outcomes.72 Elevation of cTnT predicted subsequent AMI
whereas NTproBNP did not but NTproBNP was the best
outcome predictor for subsequent death. CRP was not a
particularly good predictor of either subsequent AMI or
death. Evaluation of a population of patients with stable
angina also showed that NTproBNP was the best marker
of outcome even when adjusted conventional risk factors.
This study found NTproBNP measurement to be superior
to measurement of CRP.73
The measurement of NTproBNP/BNP in ACS patients
cannot be currently recommended for inclusion into
routine clinical assessment. There are no data, obser-
vational or trial based, that show how knowledge of
NTproBNP/BNP value can be used to alter management
or outcome. Further studies are required to define the role
of NTproBNP/BNP in ACS.
In conclusion, the roles of cTnT and cTnI measure-
ment for the diagnosis and management of patients with
ACS are well established. They provide the definitive bio-
chemical test to confirm or exclude myocardial necrosis.
Laboratory testing, no matter how good, is not a substi-
tute for clinical assessment of the patient. The clinician
must remember that although both sensitive and specific
for cardiomyocyte damage, AMI remains a clinical diag-
nosis to which cTnT and cTnI measurements contribute
Collinson and Gaze S79
ORIGINAL ARTICLE
Biomarkers of cardiovascular damage and dysfunction
but are not the only feature. Elevation of cTnT and cTnI
occurs in a number of other clinical conditions, with and
without a background of underlying atheromatous dis-
ease. Ischaemia markers are promising but further work is
required because of the problems of specificity (which may
be a problem for all ischaemia tests) and the problem of an
appropriate reference diagnostic standard for ischaemia.
Measurement of NTproBNP/BNP has a well defined place
in the detection of acute or chronic cardiac dysfunction.
Measurement in patients with suspected ACS requires
demonstration that a management change will occur.
There is increasing evidence that BNP/NTproBNP mea-
surement is one of the best mortality predictors and is
superior to CRP in the presence of established vascular
disease.
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