244

Perspective

Cardiac biomarkers the old and the new: a review

Vikas Singh, Pedro Martinezclark, Mario Pascual, Eric Scot Shaw
and William W. ONeill
Biomarkers are biological parameters that can be
objectively measured and quantified as indicators of
normal biologic processes, pathogenic processes, or
responses to a therapeutic intervention. Typically thought
of as disease process screening, diagnosing, or monitoring
tools, biomarkers may also be used to determine disease
susceptibility and eligibility for specific therapies. Cardiac
biomarkers are protein components of cell structures that
are released into circulation when myocardial injury occurs.
They play a pivotal role in the diagnosis, risk stratification,
and treatment of patients with chest pain and suspected
acute coronary syndrome and those with acute
exacerbations of heart failure. Cardiac markers are central
to the new definition of acute myocardial infarction put
forward by the American College of Cardiology and the
European Society of Cardiology. Active investigation has

brought forward an increasingly large number of novel

candidate markers but few have withstood the test of time
and become integrated into contemporary clinical care
because of their readily apparent diagnostic, prognostic, or
c 2010
therapeutic utility. Coron Artery Dis 21:244256
Wolters Kluwer Health | Lippincott Williams & Wilkins.

Introduction

inflammation and infection and, in such cases, is

increased several hundred-fold. Extensive studies
beginning in the early 1990s showed elevated CRP levels
independently predicted adverse cardiac events at both
the primary and secondary prevention levels. More
than 15 prospectively conducted clinical studies have
shown CRP to be associated with short-term and longterm morality risk not only for patients with acute and
chronic ischemic heart disease but also for those at risk
for atherosclerosis [3].

Biomarkers are biological parameters that can be objectively measured and quantified as indicators of normal
biologic processes, pathogenic processes, or responses to
a therapeutic intervention. Typically thought of as disease
process screening, diagnosing, or monitoring tools, biomarkers may also be used to determine disease susceptibility
and eligibility for specific therapies.
Cardiac biomarkers are protein components of cell
structures that are released into circulation when
myocardial injury occurs. They play a pivotal role in the
diagnosis, risk stratification, and treatment of patients
with chest pain and suspected acute coronary syndrome
(ACS) as well as those with acute exacerbations of heart
failure. Cardiac markers are central to the new definition
of acute myocardial infarction (AMI) put forward by the
American College of Cardiology and the European Society
of Cardiology [1,2].
Active investigation has brought forward an increasingly
large number of novel candidate markers but few have
withstood the test of time and become integrated into
contemporary clinical care because of their readily
apparent diagnostic, prognostic, and/or therapeutic utility
(Table 1).
Markers for inflammation and plaque destabilization
C-reactive protein

C-reactive protein (CRP) is a protein found in serum or

plasma at elevated levels during an inflammatory process
(Fig. 1). It is a sensitive marker of acute and chronic
c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0954-6928

Coronary Artery Disease 2010, 21:244256

Keywords: acute, coronary, novel, protein, syndrome
University of Miami, Miller School of Medicine, Miami, Florida, USA
Correspondence to Dr Pedro Martinezclark, MD, University of Miami, Miller
School of Medicine, 1400 NW 12th Avenue, Suite 1179, Miami, FL, 33136, USA
Tel: + 1 305 243 5050; fax: + 1 305 243 5578;
e-mail: pmclark@med.miami.edu
Received 4 January 2010 Revised 31 January 2010
Accepted 2 February 2010

Increases in CRP levels detected by assays with

expanded sensitivity to very low levels of CRP, so-called
high-sensitivity CRP (hs-CRP), showed a strong correlation as an independent risk factor for future cardiac
events. New rapid tests for CRP at the ultrasensitive
level have also been developed. Guidelines published by
the Centers for Disease Control/AHA indicate that based
on results using standardized assays with precision to or
below 0.3 mg/l, cut points of low risk (< 1.0 mg/l), average
risk (13 mg/l), and high risk (> 3.0 mg/l) be assigned
to those patients with an intermediate 10-year CHD
risk (1020% Framingham Risk Score/Adult Treatment
Panel III guidelines) [4].
hs-CRP predicts new coronary events in patients with
ACS and unstable angina (UA), AMI, and risk of restenosis after revascularization procedures, independent of
troponin T [5]. The estimations that more than 30%
of patients with severe UA do not present with elevated
hs-CRP levels along with its nonspecific nature pose a
limitation to its use [6].
DOI: 10.1097/MCA.0b013e328338cd1f

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Cardiac biomarkers the old and the new Singh et al. 245

Table 1

Clinical utility-based classification of cardiac biomarkers

Inflammation and plaque

destabilization
C-reactive protein (CRP)
hs-CRP
Myeloperoxidase

Matrix metalloproteinases
Soluble CD-40L (sCD40L)
Pregnancy-associated plasma
protein A

Ischemia

Early necrosis

Intermediate/late necrosis

Heart failure

Ischemia-modified albumin

Myoglobin

CK-MB

Glycogen phosphorylase enzyme

BB (GPBB)

Creatinine kinase MB
isoforms-CKMB2

Cardiac troponins (cTn)

cTnT
cTnI

Brain natriuretic peptide

(BNP)
Terminal fragment of
prohormone of BNP

Free fatty acids

Fatty acid binding proteins
Phospholipase enzymes (AD)
Lipoprotein associated
phospholipase A2

Placenta growth factor

Interleukin-6

Fig. 1

Platelets:
sCD40L

Lipid core:
PAPP-A
IL-6

Macrophage:
MMPO
MMP-2

Ischemia:
FFA2
IMA
GPBB
FABP
LP-PLA2
Biomarkers for plaque destabilization and ischemia. FABP, fatty acid binding protein; FFA, free fatty acids; GPBB, glycogen phosphorylase enzyme
BB in brain; IL-6, interleukin-6; IMA, ischemia-modified albumin; LP-PLA2, lipoprotein-associated phospholipase A2; MMP, matrix metalloproteinase;
PAPP-A, pregnancy-associated plasma protein A; sCD40L, soluble CD40 ligand.

Myeloperoxidase

Released from activated neutrophils, myeloperoxidase

(MPO) is a leukocyte enzyme possessing powerful prooxidative and pro-inflammatory properties that play
important roles in the pathogenesis of destabilization of
coronary artery disease (CAD). MPO catalyzes the
conversion of chloride and hydrogen peroxide to hypochlorite. It has been implicated in the oxidation of lipids
contained within LDL cholesterol and consumption of
endothelial-derived nitrous oxide, thereby reducing
nitrous oxide bioavailability and impairing its vasodilating
and anti-inflammatory properties. The blood and leukocyte MPO activity is found to be higher in patients
with CAD than angiographically verified normal individuals [7]. A recent study has shown an association of
MPO levels with the risk of future CAD in an apparently
healthy population [8]. Thus, even in the absence of
myocardial necrosis and in negative cardiac troponin
patients, baseline measurements of MPO significantly
enhance the identification of patients at risk.

New rapid tests for MPO levels have been developed and
studies suggest that a value of more than 350 mg/l is
associated with a considerably increased risk of heart
attack [9]. MPO plays a role in the degradation of the
fibrous cap, making it both a marker of inflammation
(neutrophil activation) and plaque instability (that
precedes ACS). This property makes MPO a useful
marker for short-term risk stratification. Further validation
studies on MPO in the general emergency department
(ED) chest pain population are needed to determine its
sensitivity, specificity, positive predictive value, and
negative predictive value (NPV).

Matrix metalloproteinases

Matrix metalloproteinases (MMPs) are a family of

proteolytic enzymes that cleave the extracellular matrix
and have been shown to be regulated by a class of
proteins called tissue inhibitors of metalloproteinases.
The MMPs are found in most tissues and are regulated by

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Coronary Artery Disease 2010, Vol 21 No 4

transcription in response to growth factors, cytokines,

and hormones, and, extracellularly, in the form of prohormones, whose breakdown occurs mostly in response to
plasmin. They are sub-grouped based on substrate
specificity and structure, with MMP-2 and MMP-9,
(gelatinases) being of most current interest in inflammation and cardiac disease. Several studies have shown that
extracellular matrix degradation by MMPs, specifically
MMP-9, are involved in the pathogenesis of a wide
spectrum of cardiovascular disorders, including atherosclerosis, restenosis, cardiomyopathy, congestive heart
failure, MI, and aortic aneurysm [10,11]. Similar to
MPOs, the proteinases MMP-2 and MMP-9 are released
from macrophages within the atherosclerotic plaques and
have attracted attention as markers of plaque rupture. In
patients with ACS MMP-2 and MMP-9, levels at hospital
admission are found to be two to three-fold higher as
compared to that of patients with stable angina pectoris
[12,13]. Studies measuring MMP-9 have indicated it to
be another risk factor for assessing the severity of CAD
in patients with ST-elevation MI [14].

Pregnancy-associated plasma protein A and placenta

growth factor

Human pregnancy-associated plasma protein-A (PAPP-A)

is a 200 kDa metalloproteinase belonging to the metzincin superfamily of zinc peptidases originally identified in the serum of pregnant women before delivery
[1921]. The role of PAPP-A in tissue other than placenta
including fibroblasts, vascular smooth muscle cells,
and male and female reproductive tissues has been
explored [22,23]. PAPP-A, found equally in men and
women, is histologically abundant in eroded and ruptured
plaques but is not expressed in stable plaques [24].
Pregnancy-associated protein A is one of six different
proteases that degrades insulin-like growth factor binding
proteins. This proteolytic degradation of the insulinlike growth factor binding proteins is considered the
predominant mechanism for the release of bioactive
insulin growth factor-1 (IGF-1) [25]. A large study has
illustrated that decreases in IGF-1 appear to be cardio
protective, yet some research shows that increases in
PAPP-A, which should also increase the bioavailability
of IGF-1, may be a relevant marker for the presence and
extent of coronary atherosclerosis [26].

Soluble CD40 ligand

The CD40 and CD40 ligand (CD40L) system is

expressed on a variety of cell types including activated
platelets, vascular endothelial cells, vascular smooth
muscle cells, monocytes, and macrophages. After expression on the cell surface, CD40L is partly cleaved by
proteases and subsequently released into the circulation
as soluble CD40L (sCD40L) that can be detected in
serum and plasma. The main source of circulating
sCD40L is platelets [15]. It also shows that the antiplatelet treatment using the glycoprotein IIb/IIIa receptor antagonist abciximab is beneficial to patients with
elevated sCD40L levels [16]. Several clinical studies
have consistently reported that sCD40L is elevated in
patients with ACS and that it provides prognostic
information with therapeutic implications independent
of established cardiac markers, for example cardiac
troponins [16]. Furthermore, patients with UA have
higher plasma concentrations of sCD40L than healthy
volunteers or those with stable angina, and elevation
of sCD40L in this setting indicates a higher risk for
recurrent events [16,17]. The current standard for
recurrent MI prediction by simultaneous assessment of
sCD40L and cardiac troponin I (cTnI) yields independent and complementary prognostic information, thus
enabling more powerful prediction of adverse cardiac
outcomes [18]. Increases in sCD40L have also been
shown in a number of different inflammatory processes,
so it is not specific for cardiac inflammation. No
commercially available kit has been approved by the
FDA to date and more studies using large cohorts will be
required to validate the clinical use of sCD40L independently or in combination with other markers in the
prediction of cardiovascular events after ACS.

It is believed that PAPP-A is released during plaque

destabilization and appears to be a valuable indicator
of UA and AMI in patients lacking other indicators
of necrosis [24]. In a study of patients with angiographically confirmed ACS, an elevated level of serum PAPP-A
was a strong independent predictor of nonfatal AMI
or death. Elevated PAPP-A levels were able to identify
patients at risk [27]. PAPP-A as a marker can detect
plaque rupture before markers that indicate onset of
MI and myocardial necrosis. This capability for early
determination of event risk makes PAPP-A a promising
novel cardiac biomarker with potential applications
for CAD risk assessment, diagnosis, and management.
Placental growth factor is a member of the vascular
endothelial growth factor family that stimulates vascular
smooth muscle cell growth, recruits macrophages into
atherosclerotic lesions, upregulates production of tumor
necrosis factor-a and monocyte chemotactic protein 1 by
macrophages, and stimulates pathological angiogenesis
[28]. It appears to be an initiator of the inflammatory
process and a promising biomarker of plaque formation
and plaque rupture. In one study, elevated placenta
growth factor (P1GF) levels not only identified patients
with acute chest pain who developed ACS, but also
those patients with an increased risk of recurrent
instability after hospital discharge [29]. In another
study comprising over 32 000 women, an elevated level
of PlGF was associated with an elevated risk for
cardiovascular disease and subsequent cardiovascular
events over a 14-year follow-up period [30]. The definite
value of PAPP-A and PlGF still needs to be proven in
larger studies.

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Cardiac biomarkers the old and the new Singh et al. 247

Interleukin-6

Interleukin-6 (IL-6) is a cytokine, a nonantibody protein,

and intercellular mediator. Cytokine IL-6 is produced by
a variety of cells in the body; plasma concentrations
reflect both the intensity of plaque vulnerability to
rupture and, following percutaneous coronary intervention, restenosis. Cytokine IL-6 is involved in the pathogenesis of ACS and has the following effects: stimulating
the linear production of fibrinogen and CRP, stimulating
the macrophage to produce tissue factor and MMPs,
platelet aggregation, adhesion molecules, tumor necrosis
factor, and vascular smooth muscle cell proliferation [31].
Cytokine IL-6 predicts future MIs in healthy men and
total mortality in the elderly [32]. Elevation of circulating
IL-6 is a strong and independent marker of increased
mortality in acute coronary events [33,34].
Current value of inflammation markers

Aforementioned markers for inflammation and plaque

destabilization are nonspecific to cardiac disease but
have, time and again, proved to be useful adjuncts as
diagnostic markers for ACS in the ED when used in
combination with TnI and brain natriuretic peptide
(BNP). hs-CRP is the most valuable among these and
predicts new coronary events in such cardiac patients
independent of troponin T. Elevated PAPP-A levels
identify patients with UA even in the absence of
elevations in cTn or hs-CRP levels; there are, unfortunately, no currently available tests in a point-of-care
testing (POCT) format. Although increased MPO has a
role superior to that of PAPP-A, CD40L, and cytokines, is
still inferior to CRP [35].
Markers for ischemia

The aim of diagnostic markers is to identify patients with

ACS even in the absence of myocyte necrosis evidence
(Fig. 1).
Ischemia-modified albumin

Albumin loses its ability to bind transitional metals like

copper, cobalt, nickel in its N terminus region as it
undergoes conformational change because of ischemia.
This alteration is most likely caused by hypoxia, acidosis,
free radical injury or energy-dependent membrane disruption [3638]. This decrease in binding capacity can be
measured by addition of a specified amount of cobalt to
the patients serum followed by a colorimetric assay that
determines the amount of unbound cobalt. This assay has
been reported to be positive within minutes of ischemia,
peaking within 6 h, and remains elevated for up to 12 h,
thus allowing detection before the development of myocardial necrosis [as evidenced by normal levels of creatinine kinase isoenzyme (CK-MB), troponin and, myoglobin]
[3942].
Studies have also shown that ischemia-modified albumin
(IMA) is a sensitive biomarker for the identification of

ACS in patients presenting to the ED with typical chest

pain at rest [43]. The albumin cobalt binding test has
been approved by the FDA for use as a rule-out marker
for acute myocardial ischemia. The optimum cut-off for
IMA, for ruling out ACS, is 85 kU/l and the higher values
of 100 kU/l or more can be used for risk stratification. A
meta-analysis of current data has shown that the finding
of a negative IMA result, negative cTnT measurements,
and a normal or nondiagnostic ECG, has a high NPV for
excluding ACS in the ED [44].
It is estimated that approximately 12% of the total
albumin concentration in the normal population is IMA
compared to 68% in patients experiencing ischemia and
it is also found to be elevated in most patients with
cirrhosis, bacterial and viral infections, advanced cancers,
stroke (brain ischemia), and end-stage renal disease.
Studies on the use of IMA in patients with chest pain in
the ED have found sensitivities that ranged from 71 to
98%, and specificities of 4565%, with a NPV of 9097%
for ACS. Thus, the main limitation of IMA at the present
time is its low specificity.
Glycogen phosphorylase isoenzyme BB

Glycogen phosphorylase (GP) plays an essential role in

the regulation of carbohydrate metabolism by mobilization of glycogen [45]. It catalyses the first step in
glycogenolysis in which glycogen is converted to glucose1-phosphate, utilizing inorganic phosphate. The physiological form of GP is a dimer, which is composed of two
identical subunits. Three different GP isoenzymes have
been described in human tissues: GPLL (liver), GPMM
(muscle), and GPBB (brain). Although isoenzymes BB
and MM are found in the heart, GPBB is predominant.
However, tissue concentrations of GPBB in the heart and
brain are comparable raising issues with specificity [46].
In cardiomyocytes, GP is associated with glycogen and
the sarcoplasmatic reticulum and forms a macromolecular
complex, the sarcoplasmatic reticulum glycogenolysis
complex [47,48]. The metabolic state of the myocardium
determines the degree of association of GP with this
complex. With the onset of tissue hypoxia, GP is thereby
converted from a particulate, structurally bound form
into a soluble, cytoplasmatic form [47,49]. A high GPBB
concentration gradient is immediately formed in the
perisarcoplasmatic reticulum compartment and GPBB is
released from cardiomyocytes upon an increase in the cell
membrane permeability. This makes GPBB an early
marker for detection of ischemic myocardial damage.
GPBB is not a heart-specific marker. However, its
increase is rather specific for ischemic myocardial injury
when damage to the brain and consequent disturbance
of the bloodbrain barrier can be excluded.
GPBB levels increase between 1 and 4 h from chest pain
onset and return to the reference interval within 12 days
after AMI onset [50,51]. Similar to other soluble markers,

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Coronary Artery Disease 2010, Vol 21 No 4

such as myoglobin and CK-MB, it can be shown that

GPBB time courses in AMI patients are markedly
influenced by the fact of whether early reperfusion of
the infarct-related coronary artery occurs. The accelerated GPBB release from cardiomyocytes after successful
thrombolysis leads to a more rapid increase in GPBB,
earlier and usually also higher peak values. GPBB thus
may be useful, along with other soluble myocardial
proteins, for assessing the effectiveness of thrombolytic
therapy noninvasively. GPBB also increases, early on, in
patients with UA and reversible ST-T alterations in the
resting ECG at hospital admission and could be useful
for early risk stratification in these patients [51,52].
GPBB is a promising marker for the early diagnosis of
ACSs and could probably act as a marker of ischemia.
However, further studies on specificity and development
of a fast, automated assay are necessary before GPBB can
be recommended as a routine diagnostic tool [53].
Free fatty acids

Free fatty acids (FFAs) play several essential roles in

physiologic homeostasis. Plasma long-chain fatty acids
are either esterified to glycerol or nonesterified (or FFAs),
most of which are bound to albumin. Under aerobic
conditions, nonesterified long-chain FFAs represent the
primary metabolic sources for the myocardium, accounting for almost two-thirds of the ATP generated [54]. The
mechanism for uptake of FFAs into myocytes remains
unclear but involves passive diffusion and/or active
carrier-mediated transport. In the cytoplasm, long-chain
FFAs are bound to fatty acid binding proteins (FABPs),
which presumably facilitates their transport to the
outer mitochondrial membrane where they become
esterified/activated by long-chain acyl-CoA synthetase.
Once activated, acyl-CoA esters are directed mainly to
b-oxidation, but some may be stored as triglycerides or
converted into membrane phospholipids. During hypoxia
and ischemia, nonesterified fatty acids/FFAs have damaging effects on heart tissue and have been associated with
an increased incidence of ventricular dysrhythmias and
death in patients with AMI [55,56]. Although most of the
FFAs in serum are bound to albumin, a small amount is
unbound; this is frequently referred to as the free
fraction. Serum FFAu concentrations are determined
from the ratio of total serum FFAs to total serum albumin
[57]. Several studies suggest that increased unbound FFA
concentration (FFAu), which is determined from the ratio
of total serum FFAs to total serum albumin, may provide
an early indicator of myocardial ischemia [58]. Although
the exact mechanism is not clear, it has been suggested
that increased unbound FFAs result from catecholamine
stimulated lipolysis in conjunction with a reduction of
FFA utilization in myocardial ischemia. A POCT method
for the determination of unbound FFA has already been
developed (FFA Sciences) and has turned out to be quick
(turnaround-time < 1 min) and precise (coefficient of

variation 7%) while requiring as little as 15 ml of plasma

[59,60]. This method uses a recombinant fatty acid
binding protein labeled with a fluorescent probe of
FFAu termed acrylodated intestinal fatty acid binding
protein. When FFA binds to acrylodated intestinal fatty
acidbinding protein, the fluorescent tag is displaced,
thus producing a spectral shift that can be measured with
a hand-held reader.
Current data, although limited, suggest that monitoring
of FFAu concentrations in patients presenting with
ischemic symptoms may provide an early indication of
cardiac ischemia.

Fatty acid binding proteins

FABPs are relatively small (15 kDa) intracellular proteins

that are abundantly produced in tissues having active
fatty acid metabolism, including the heart, liver, and
intestine [61]. FABPs bind long-chain fatty acids reversibly and noncovalently. Currently, nine distinct FABP
types have been identified, with each type showing a
characteristic pattern of tissue distribution and a stable
intracellular half-life of 23 days [61]. Several studies
investigated H-FABPs application as a biochemical marker
of myocardial injury after it was first shown to be released
from injured myocardium in 1988. The H-FABP isoform
is produced not only in cardiomyocytes but also, to a
lesser extent, in skeletal muscle, distal tubular cells of
the kidney, specific parts of the brain, lactating mammary
glands, and placenta [6264]. H-FABP is not found in
the circulation (plasma concentration <5 mg/l) under
nonpathological conditions and is rapidly released after
AMI. H-FABP secretion into the interstitial space may be
mediated by increased permeability of the myocardial cell
membrane associated with severe ischemia [65]. It has
been shown that sequential H-FABP monitoring by
only two samples, at admission and 1 h after admission,
can reliably diagnose AMI within 1 h with a 0.995 area
under the curve value in receiver operating characteristic
curve analysis. In addition, 100% of non-AMI can be
excluded with no false-negative results [66]. Therefore,
H-FABP has been touted as an alternative to myoglobin
but its limitations include a lack of complete cardiac
specificity, a relatively small diagnostic window of 2430 h
after the acute event, and the probability of falsely
increased values in patients with renal insufficiency
cardiac specificity. H-FABP and myoglobin ratios have
similar predictive accuracies for early detection of
successful coronary reperfusion [67]. Serial plasma HFABP or myoglobin concentrations may be used for infarct
sizing within the first 24 h after symptom onset only in
AMI patients with normal renal function [68].
Several immunosensors have been developed using
enzyme amperometric, immuno-optical, or immunoassay
technologies, as reviewed by Chan et al. [66]. At present
there is only one immunochromatographic POCT assay

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Cardiac biomarkers the old and the new Singh et al. 249

Phospholipase enzymes and choline

The idea of a marker of plaque destabilization for the

very early diagnosis of patients with MI is very attractive.
Here, the marker is effectively a surrogate for direct
detection of ischemia. Plaque rupture/erosion is the
underlying pathophysiological event, which will lead to
ischemia then to infarction. A plaque rupture marker does
not have the problems of need for a gold standard to
diagnose ischemia as hard outcomes such as death,
AMI, and major adverse cardiac events (death, AMI,
readmission with UA, and need for urgent revascularization) can be used as endpoints. A plaque rupture marker
may still have the problem of cardiospecificity. There is a
significant interest in the possibility that choline and
phospholipase A2 and D may be good markers of plaque
instability. Phospholipases are enzymes subgrouped
into four major categories (AD) that catalyze phospholipids into fatty acids and another lipophilic substance.
Lipoprotein-associated phospholipase A2, also known as
platelet-activating factor acetylhydrolase, is regulated by
mediators of inflammation. It circulates bound mainly to
LDL and HDL and has been found to correlate with the
levels of LDL, another indicator of CAD [69]. In one study
lipoprotein-associated phospholipase A2 was associated
with an almost two-fold increase in stroke in the selected
population coupled with a six-fold increase in hypertensive individuals, leading to interest in its assay [70].
Phospholipase D catalyzes membrane-bound phospholipids producing phosphatidic acid and choline. It is also
involved with the promotion of fibrinogen binding to
platelets [71]. Several experimental studies support the
concept that phospholipase D activation is a key event in
early ischemic membrane damage and in coronary plaque
destabilization. Choline has been identified as a promising marker for ACS by metabolic screening of human
blood [72]. Choline appears to be useful for risk
stratifications in patients with angina pectoris, particularly if tests for troponins are negative on admission.
Increased levels of plasma and whole blood choline
concentrations are observed in tissue ischemia in patients
with negative troponin values. Choline is not a marker for
myocardial necrosis but indicated high-risk UA in patients
without AMI (sensitivity 86.4%, specificity 86.2%) [73].
Assessment of both increased levels of plasma and whole
blood choline may prove to be useful in patients
suspected of ACS.
At present, reliable choline assays are based on highperformance liquid chromatographymass spectrometry,
but development of rapid central laboratory assays and
POCT for choline is expected to help to identify such
high-risk patients in the emergency room as well.

Current value of ischemia markers

Although markers for ischemia are not specific to

cardiovascular disease, further clinical studies are warranted so that this exciting tool may be used to routinely
detect MI before myocardial necrosis. At present, IMAs
role is limited to ruling out ischemia rather than as a
diagnostic test for the occurrence of ischemia because
of its lack of specificity. Increased GPBB is specific for
ischemic myocardial injury and has shown potential in
assessing the effectiveness of thrombolytic therapy and in
early diagnosis of ACS; however, a quick automated assay
is not yet widely available. POCT has been developed
both for FFA and H-FABP. FFA promises to be an early
indicator of myocardial ischemia and H-FABPs role in
diagnosing AMI has been found to be comparable with
myoglobin.
Early markers for cardiac tissue necrosis
Myoglobin

Myoglobin is a heme protein that is found in all striated

muscle fibers, which accounts for about 2% of both
skeletal and cardiac tissue mass (Fig. 2). The small
molecular weight of myoglobin allows it to be rapidly
released during skeletal muscle injury and cardiac tissue
necrosis [74]. This is unlike creatine kinase and its
isoform CK-MB, which are larger molecules and are
released more slowly after an AMI [75]. Myoglobin
typically rises 24 h after onset of infarction, peaks at
612 h, and returns to normal within 2436 h (Fig. 2). In
one study measurement of myoglobin levels in blood
samples obtained 2 h after the patient came to the ED
with chest pain had a sensitivity of 100% for detecting
AMI [76]. Myoglobin is released in a pulsatile manner, so
serial testing with early presentation may be needed
[77]. Myoglobin has an excellent NPV (99.9 vs. 95% for
CK-MB) if determined early enough to onset of
symptoms, generally within the first hour [78]. Rapid
Fig. 2

1000

Relative marker increase

for H-FABP (rennesens CardioDetect) available commercially. The use of H-FABP in ruling out MI in patients
with ACS is promising but needs further study.

Myoglobin
MB isoforms

CK-MB
Troponin T

Troponin I

100

10

Upper reference interval

0.1
0

12

48
24
36
Hours after chest pain

60

72

Early, intermediate, and late cardiac markers for necrosis.

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Coronary Artery Disease 2010, Vol 21 No 4

myoglobin assays are available, but overall they suffer

from lack of cardiospecificity as many noncardiac-related
factors, such as skeletal muscle or neuromuscular
disorders, strenuous exercise, renal failure, intramuscular
injections, and cardiac bypass surgery, can elevate serum
levels of myoglobin [74]. A controversy also exists about
the level at which myoglobin becomes indicative of an
AMI, with the reported reference ranges varying from 50
to 120 mg/ml [74,76]. Because of these variables, the
sensitivity and specificity of myoglobin tests vary,
depending on the criteria defined for diagnosis of AMI.
The specificity of myoglobin tests in the diagnosis of AMI
can be increased by monitoring an additional marker,
carbonic anhydrase III (CA-III). CA-III is found primarily
in skeletal muscle and occurs in trace amounts in the
myocardium. Because damage to skeletal muscle results in
the release of both myoglobin and CA-III, and damage to
cardiac tissue results primarily in release of myoglobin, the
ratio of myoglobin to CA-III can be used to determine if
infarction has occurred [79]. The normal range for CA-III is
1329 mg/l. A serum myoglobin concentration greater than
110 mg/l together with a myoglobin/CA-III ratio of 3.21 or
higher is considered abnormal and indicative of AMI [80].
Although myoglobin is not the perfect cardiac marker for
diagnosing AMI, it is the earliest significant indicator of
breakdown of myocardial cells [74]. Myoglobin may be
most helpful when used in conjunction with other cardiac
markers in the rapid determination of AMI, especially
in patients with atypical chest pain or nonspecific ECG
changes.
Creatinine kinase MB isoforms

Conventional assays for creatine kinase and its MB

isoenzyme (CK-MB) are of limited utility in the initial
hours after symptom onset because of the enzymes
release kinetics [81,82]. As small amounts of CK-MB are
released from myocardium into the blood soon after
coronary occlusion, carboxypeptidase cleaves the terminal
amino acid from CK-MBs M monomer, resulting in two
distinct serum isoforms. In the initial hours of infarction,
levels of the unmodified tissue isoform (CK-MB2) rapidly
rise and the CK-MB2/CK-MB1 ratio increases before the
total CK-MB level exceeds the normal range [83].
Normally, the tissue CK-MB1 isoform predominates;
thus, the ratio is characteristically less than 1. A result
is positive if CK-MB2 is elevated and the ratio is more
than 1.7. CK-MB2 is detected in serum within 24 h
after onset of MI and peaks at 69 h. The ratio of
cleaved to uncleaved CK-MB subforms returns to normal
within 1830 h. Among chest pain patients, CK-MB
isoform measurement is able to diagnose MI with 95.7%
sensitivity and 93.9% specificity within 6 h of symptom
onset [84]. The CK-MB isoforms may be analyzed using
high-voltage electrophoresis with relatively long turnaround time (approximately 25 min); however, automated
analyzers with rapid turnaround times are now available.

Intermediate/late markers of cardiac tissue necrosis

CK-MB

CK-MB is an enzyme catalyzing the transfer of highenergy phosphate from ATP to creatine (Fig. 2). CK is a
dimeric molecule composed of two subunits (M or B)
with a molecular mass of 42 000 Da thus forming three
isoenzymes, namely CK-MM, CK-MB, and CK-BB. Increased plasma CK activity is an extremely sensitive index
of skeletal muscle disease but is not myocardial-specific
[85]. However, the MB isoenzyme (also called CK-2)
comprises about 40% of the CK activity in cardiac muscle
and 2% or less of the activity in most muscle groups and
other tissues and therefore serves as a more sensitive and
specific marker for MI [86,87]. MB levels usually increase
46 h after an MI, peak in 1024 h, and return to normal
within 72 h. Measurement of CK-MB may be performed
through electrophoresis or immunoassays; the latter shows
better analytical sensitivity and better precision.
The relative index calculated by the ratio of CK-MB
(mass)/total CK  100 can assist the clinician in differentiating false-positive elevations of CK-MB arising from
skeletal muscle (such as in muscular dystrophy or a
crush injury) and renal failure. The relative index is only
useful when both the total CK and the CK-MB levels
are increased. A ratio less than 3 is consistent with a
skeletal muscle source. Ratios greater than 5 are
indicative of a cardiac source. Ratios between 3 and 5
represent a gray zone. No definitive diagnosis can be
established without serial determinations to detect a rise.
The Thrombolysis in MI IIIB trial showed that CK-MB
levels were not predictive of adverse cardiac events and
had no prognostic value. However, data from the Platelet
Glycoprotein IIb/IIIa in UA: Receptor Suppression Using
Integrilin Therapy and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded
Coronary Arteries IIb trial suggested that an elevated
CK-MB correlated with an increased mortality rate. Therefore, the utility of CK-MB in risk stratification and
therapeutic decision-making in patients with ACS remains
unclear.
Cardiac troponins

Troponin is a complex of three regulatory proteins, namely

TnC (18 kD), TnI (26 kD), and TnT (39 kD), that form
the thin filaments of muscle fibers and regulate the
movement of contractile proteins in muscle tissue [88].
The genes that code for the skeletal and cardiac isoforms
of TnC are identical; thus, no structural difference exists
between them. However, the skeletal and cardiac subforms for TnI and TnT are distinct, and immunoassays
have been designed to differentiate between them with
no cross-reactivity.
cTnT and cTnI assays can detect heart muscle injury
with great sensitivity and specificity. They appear in
serum within 48 h after symptom onset but unlike

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Cardiac biomarkers the old and the new Singh et al. 251

CK-MB, remain elevated for as long as 710 days post-MI

but a much lower increase and elevation duration in
cases of microinfarction [89]. Assays for cTnT have a
sensitivity of up to 100% for myocardial damage within 4
6 h after an AMI, and assays for cTnI have a sensitivity of
up to 100% by 6 h after an AMI [90]. The antibodies used
in the current generation of cTnT and cTnI assays are
highly specific for their respective cardiac isoforms for
each of the troponin proteins unlike CK-MB, which is
released from a number of noncardiac muscles. However,
it should be noted that interferences because of increased
levels of fibrinogen and the presence of autoantibodies
to cTnI have been reported [91].
The assays for cTnT are commercially available from
only one manufacturer (Cardiac T by Roche, Indianapolis,
Indiana, USA) but there are multiple manufacturers for
cTnI using different antibodies and hence differing in
their normal values and sensitivities [92]. This lack of
standardization between cTnI assays means test results
from different assays are not comparable, leading to a
debate regarding the application of cut-off points and their
subsequent interpretation. Upper reference levels generally accepted as indicative of AMI are a serum level of
cTnT of at least 0.10.2 mg/l or a serum level of cTnI of at
least 1.53.1 mg/l [9395]. Another factor that contributes
to the discrepancy in standardized reference levels is that
several forms and subunits of cTnT and I are found in
the blood after AMI. For example, a small percentage of
the cardiac troponins (68% of cTnT and 34% of cTnI) is
found in the cytoplasm; the rest is structurally bound.
The cTn together with clinical information from the
patient history and the electrocardiogram are the gold
standard for diagnosing AMI [96]. Troponin is the
preferred biomarker but others, such as the MB fraction
of creatinine kinase (CK-MB), suffice when troponin
testing is unavailable. Both cTnT and cTnI provide
independent prognostic information with regard to
cardiac death and AMI [97].
Serum levels of cardiac troponins may also be used as
noninvasive indicators of the effectiveness of reperfusion
therapy after AMI. Levels of cTnT can indicate the
success of reperfusion as early as 90 min after thrombolytic therapy has been started [98]. An early, sharp
increase in the serum level of cTnT results from the
washout of cytoplasmic cTnT after reperfusion occurs.
Because myocardial damage is limited by reperfusion, the
amount of structurally bound cTnT released will be
decreased. Reperfusion can be assessed by monitoring
and calculating these changes in the levels of cTnT [99].
The cTnI has also shown promise as a clinical indicator
of reperfusion.
Current value of necrosis markers

Markers of myocardial necrosis have been used for

decades and have withstood the test of time. Troponins

remain the gold standard for diagnosing AMI but CK-MB

suffices in its absence. Myoglobin is the earliest (< 1 h)
indicator of myocardial necrosis and has excellent NPV.
CK-MB isoforms are useful in detecting early AMI (24 h),
and rapid assays are now available.
Markers for heart failure
Brain natriuretic peptide and terminal fragment
of its prohormone

BNP and the terminal fragment of its prohormone (NTpro BNP) are hormones released from cardiac tissue in
response to ventricular wall stress in the absence of
necrosis and preceding angina and ST-segment changes
[100,101]. These natriuretic peptides have filled a
strongly perceived need in clinical practice as an aid to
the often challenging diagnosis of heart failure in patients
presenting to the clinic or ED with shortness of breath.
Recent evidence suggests that the use of either marker
may contribute to both the diagnosis and prognostic
outcome in patients with a MI [102].
Elevations in the natriuretic proteins are merely an
indication of hemodynamic stress, and fluid overload
states, and are not specific for heart disease. Their levels
rise, not only in the edematous conditions associated
with kidney, lung (e.g. cor pulmonale, pulmonary hypertension, acute pulmonary embolism) and liver disease,
but also in situations where there is a triggering of the
reninangiotensin system. Nevertheless, measurement of
the natriuretic peptides has consistently been shown to
improve upon the clinicians initial diagnostic impression,
and to correlate with prognosis across the variety of
pathologic conditions in which increased concentrations
may be detected.
In patients with ACS, more than 10 studies have shown a
strong association between BNP or NT-proBNP and
outcome [103]. The higher concentrations of BNP and
NT-proBNP are associated with a higher risk of death or
heart failure independently of other prognostic variables, including the left ventricular ejection fraction. The
plasma concentration of BNP rises quickly, peaking at
about 24 h after infarction and its level and duration of
elevation corresponds to the likelihood of future adverse
cardiac events [104]. NT-proBNP has a longer biological
half-life (B1 to 2 h) than that of the biologically active
BNP (B20 min). Similar to the troponin assays, quality
specifications for BNP and NT-proBNP assays are not
universally adopted, and hence any cut-off values applied
for determining clinical significance needs to reflect the
biases associated with the analytical aspects of the assay
employed.
BNP and NT-proBNP are equally useful when indicating
increased intracardiac pressure and the presence of
cardiac structural disease in asymptomatic patients
having systemic arterial hypertension, regardless of the
underlying pathology [105].

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252 Coronary Artery Disease 2010, Vol 21 No 4

Table 2

Evidence based table (2009): latest research in cardiac biomarkers

Authors
Bhagavan et al.
[106]
Demir et al.
[107]
Kazanis et al.
[108]

Chen et al.
[109]

Title

Result/conclusion

Utility of serum fatty acid concentrations as a marker for AMI and

their potential role in the formation of IMA: a pilot study
IMA elevation after percutaneous coronary intervention reflects
albumin concentration rather than ischemia

A plausible but not a causal relationship between FFA and IMA, and a
potential role for measurement of total FFA and specific FFAs in ACS
IMA results reflect albumin concentrations rather than myocardial ischemia
also in PCI. This situation and lack of standard reference materials for the
albumin cobalt binding assay can lessen the diagnostic performance of IMA
For CAD diagnosis the best cut-off point for IMA was 101.5 kU/l with a
sensitivity and a specificity of 87.7% and a NPV of 83.3%. IMA was
associated with an increased risk for CAD (OR = 1.23, 95% CI: 1.161.31,
P < 0.001)
The mean absorbance in AMI group was higher than that in the control
group (1.195 0.320 vs. 0.855 0.068, P < 0.001). The area under the
receiver of ROC curve was 0.947, and at the cut-off value of 0.906 ABSU,
the sensitivity and specificity of the assay were 93.0 and 82.9%,
respectively
For early diagnosis, H-FABP has superior sensitivity but inferior
specificity for acute MI compared to initial cTnT for patients presenting
within 4 h from pain onset
The measurement of H-FABP and NT-proBNP at the time of hospital
admission for patients with ischemic-type chest pain adds useful prognostic
information to that provided by the measurement of baseline and 12-h cTnT
In ST-elevation MI, a larger release of cardiac necrosis markers soon after
reperfusion therapy relates to abnormal perfusion. Troponin appears as the
most reliable necrosis marker for an early detection of cardiovascular
magnetic resonance-derived abnormal microvascular reperfusion
The carboxylated magnetic microbead-assisted protocol could be utilized to
semi-quantitatively detect both myoglobin and H-FABP
IMA is a marker of cardiac ischemia with rapid clearance and a narrow
diagnostic time window that may decrease NPV and clinical usefulness due
to its dependency of short symptoms duration. Sensitivity of the assay was
low compared with other markers
This method is novel in offering higher accuracy of measuring true CK-MB
contents in human serum as compared to the conventional method. The
possibility of accurately estimating CK-MB activity by this method which can
inhibit mitochondrial CKs in healthy person and patient serum is likely to
bring a break-through in clinical diagnostics
Prognostic significance of borderline increased TnI values varied greatly by
assay, with borderline Beckman Access AccuTnI increases being predictive
of adverse 30-day outcomes (OR = 4.0, 95% CI: 1.4610.97, P = 0.007),
but not with the other two assays
In adults presenting to the ED, sCD40L is not useful as a diagnostic marker
for acute cardiac, cerebrovascular ischemic, or thromboembolic events
Lp-PLA2 mass levels decrease modestly, whereas hsCRP and Lp-PLA2
activity appear stable over time. Acutely after stroke and MI, hsCRP
increases whereas Lp-PLA2 mass and activity levels decrease. These
changes imply that measurements made soon after stroke and MI are not
reflective of prestroke levels and may be less reliable for long-term risk
stratification
Early measurement of PAPP-A may identify chest pain patients at higher risk
for long-term death. Additional prospective ACS studies are required to fully
elucidate PAPP-As role
PAPP-A levels are elevated in > 90% of patients presenting with STEMIs if
measured < 6 h after the onset of symptoms or < 2 h of primary
percutaneous coronary intervention. In the early stages of STEMI, PAPP-A
seems to be a more sensitive marker of MI than CK-MB and TnT
Simultaneous measurement of cardiac TnI, B-type natriuretic peptide, and
CRP improves the risk assessment of long-term adverse cardiac outcome
after cardiac surgery
A co-peptin level < 14 pmol/l in combination with a troponin T r 0.01 mg/l
correctly ruled out AMI with a sensitivity of 98.8% and a NPV of 99.7%
In patients presenting within 3 h after chest-pain onset, a single sensitive TnI
assay had a NPV of 84.1% and a PPV of 86.7%. A TnI level of more than
0.04 ng/ml was independently associated with an increased risk of an
adverse outcome at 30 days
Among patients who presented within 3 h after the onset of chest pain, the
AUCs were 0.93 (95% CI: 0.880.99), 0.92 (95% CI: 0.870.97), 0.92
(95% CI: 0.860.99), and 0.94 (95% CI: 0.900.98) for the sensitive
assays, respectively, and 0.76 (95% CI: 0.640.88) for the standard assay

Ischemia modified albumin, hsCRP and natriuretic peptide in

patients with coronary atherosclerosis

Clinical value of an improved IMA assay in the diagnosis of early

AMI

McCann et al.
[110]

Investigation of a multimarker approach to the initial

assessment of patients with acute chest pain

McCann et al.
[111]

Prognostic value of a multimarker approach for patients presenting

to hospital with acute chest pain

Husser et al.
[112]

Release of necrosis markers and cardiovascular magnetic

resonance-derived microvascular perfusion in reperfused STelevation MI

Wang et al.
[113]
Hjortshj et al.
[114]

Carboxylated magnetic microbead-assisted fluoroimmunoassay for

early biomarkers of AMI
Kinetics of ischemia modified albumin during ongoing severe
myocardial ischemia

Hoshino et al.
[115]

Development and performance of an enzyme immunoassay to

detect creatine kinase isoenzyme MB activity using antimitochondrial creatine kinase monoclonal antibodies

Zahid et al.
[116]

Clinical significance of borderline elevated TnI levels across

different assays in patients with suspected ACS

Plaikner et al.
[117]
Elkind et al.
[118]

Lack of association of soluble CD40 ligand with the presence of

AMI or ischemic stroke in the ED
hsCRP and Lp-PLA2 stability before and after stroke and MI

Kavsak et al.
[119]

PAPP-A as a marker of increased long-term risk in patients with

chest pain

Iversen et al.
[120]

Pregnancy-associated plasma protein A, a novel, quick, and

sensitive marker in ST-elevation MI

Fellahi et al.
[121]

Simultaneous measurement of cardiac TnI, B-type natriuretic

peptide, and CRP for the prediction of long-term cardiac outcome
after cardiac surgery
Incremental value of co-peptin for rapid rule out of AMI

Reichlin et al.
[122]
Keller et al.
[123]

Reichlin et al.
[124]

Sensitive TnI assay in early diagnosis of AMI

Early diagnosis of MI with sensitive cardiac troponin assays

ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAD, coronary artery disease; CI, confidence interval; ED, emergency department; FFAs, free fatty
acids; FABP, fatty acid binding protein; hsCRP, high-sensitivity C-reactive protein; IMA, ischemia-modified albumin; LP-PLA2, lipoprotein-associated phospholipase A2;
MI, myocardial infarction; NPV, negative predictive value; NT-pro-BNP, brain natriuretic peptide and the terminal fragment of its prohormone; OR, odds ratio; PAPP-A,
pregnancy-associated plasma protein A; PPV, positive predictive value; ROC, receiver operating characteristic; STEMI, ST-segment elevation myocardial infarction;
tnI, troponin.

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Cardiac biomarkers the old and the new Singh et al. 253

Current value of heart failure markers

Despite consistent data showing a robust relationship

between BNP and NT-proBNP on the one hand, and
the risk of death and worsening heart failure in patients
presenting with ACS on the other, the predominant
clinical application of these natriuretic peptides is as a
diagnostic tool to identify heart failure in the patient with
undifferentiated chest symptoms.

9
10
11

Conclusion

Cardiac biomarkers have proved extremely valuable for

diagnosis, risk stratification, and treatment of patients
in the emergency setting. Novel studies are currently
underway using biomarkers to predict long-term outcomes and mortality in patients with stable coronary
heart disease. There is also much interest in the use of
cardiac biomarkers to provide further risk stratification,
especially in those patients who are at an intermediate
risk per Framingham score.

12
13

14

15

Each of the markers discussed in this review has limitations. To be clinically useful, a biomarker must provide
incremental information that both adds to existing
clinical findings and is useful in the clinical care of the
patient. The guidelines-based application of cTn for
therapeutic decision-making serves as a standard against
which newer biomarkers have informally and formally
been assessed. An ideal marker is one in which there is a
specific, easily measurable increase that clearly aligns
with a predictable outcome be it evidence of ischemia,
inflammation, myocardial necrosis, plaque rupture, plaque destabilization, or heart failure. It remains a major
challenge for researchers and clinicians to show whether
newer and future biomarkers are useful for guiding
specific treatment algorithms (Table 2).

16

References

22

Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction

redefineda consensus document of the Joint European Society of
Cardiology/American College of Cardiology Committee for the redefinition
of myocardial infarction. J Am Coll Cardiol 2000; 36:959969.
Joint European Society of Cardiology/American College of Cardiology
Committee for the redefinition of myocardial infarction. A consensus
document myocardial infarction redefined. Eur Heart J 2002;
21:15021513.
Scirica BM, Morrow DA, Cannon CP, de Lemos JA, Murphy S,
Sabatine MS, et al. Clinical application of C-reactive protein across
the spectrum of acute coronary syndromes. Clin Chem 2007;
53:18001807.
Pearson T, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui
M, et al. Markers of inflammation and cardiovascular disease: application to
clinical and public health practice: a statement for healthcare professionals
from the Centers for Disease Control and Prevention and the American
Heart Association. Circulation 2003; 107:499511.
Heeschen C, Hamm CW, Bruemmer J, Simoons ML; The Chimeric c7E3
Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment
(CAPTURE) Investigators. Predictive value of C-reactive protein and
troponin T in patients with unstable angina: a comparative analysis.
J Am Coll Cardiol 2000; 35:15351542.
Riker PM, Cook N. Clinical usefulness of very high and very low levels of
C-reactive protein across the full range of Framingham risk scores.
Circulation 2004; 109:19551959.

17

18

19

20

21

23

24

25

26

27

28

Zhang R, Brennan M-L, Fu X, Aviles RJ, Pearce GL, Penn MS, et al.
Association between myeloperoxidase levels and risk of coronary artery
disease. J Am Med Assoc 2001; 286:21362142.
Meuwese MC, Stroes ESG, Hazen SL, van Miert JN, Kuivenhoven JA,
Schaub RG, et al. Serum myeloperoxidase levels are associated with the
future risk of coronary artery disease in apparently healthy individuals.
The EPIC-Norfolk prospective population study. J Am Coll Cardiol 2007;
50:159165.
Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease.
Arterioscler Thromb Vasc Biol 2005; 25:11021111.
Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and
cardiovascular disease. Circ Res 1995; 77:863868.
Lindsay MM, Maxwell P, Dunn FG. TIMP-1: a marker of left ventricular
diastolic dysfunction and fibrosis in hypertension. Hypertension 2002;
40:136141.
Fingleton B. Matrix metalloproteinases as valid clinical targets. Curr Pharm
Des 2007; 13:333346.
Kai H, Ikeda H, Yasukawa H, Kai M, Seki Y, Kuwahara F, et al. Peripheral
blood levels of matrix metalloproteases-2 and -9 are elevated in patients
with acute coronary syndromes. J Am Coll Cardiol 1998; 32:368.
Squire IB, Evans J, Ng LL, Loftus IM, Thompson MM. Plasma MMP-9 and
MMP-2 following acute myocardial infarction in man: correlation with
echocardiographic and neurohormonal parameters of left ventricular
dysfunction. J Card Fail 2004; 10:328333.
Henn V, Steinbach S, Buchner K, Presek P, Kroczek RA. The inflammatory
action of CD40 ligand (CD154) expressed on activated human platelets is
temporally limited by coexpressed CD40. Blood 2001; 98:10471054.
Heeschen C, Dimmeler S, Hamm CW, van den Brand MJ, Boersma E,
Zeiher AM, Simoons ML. Soluble CD40 ligand in acute coronary
syndromes. N Engl J Med 2003; 348:11041111.
Aukrust P, Muller F, Ueland T, Berget T, Aaser E, Brunsvig A, et al.
Enhanced levels of soluble and membrane-bound CD40 ligand in patients
with unstable angina: possible reflection of T lymphocyte and platelet
involvement in the pathogenesis of acute coronary syndromes. Circulation
1999; 100:614620.
Varo N, de Lemos JA, Libby P, Morrow DA, Murphy SA, Nuzzo R, et al.
Soluble CD40L risk prediction after acute coronary syndromes. Circulation
2003; 108:r43r46.
Oxvig C, Sand O, Kristensen T, Gleich GJ, Sottrup-Jensen L. Circulating
human pregnancy-associated plasma protein-A is disulfide bridge to
proform of eosinophil major basic protein. J Biol Chem 1993; 268:
1224312246.
Overgaard MT, Haaning J, Boldt HB, Olsen IM, Laursen LS, Christiansen M,
et al. Expression of recombinant human pregnancy-associated plasma
protein- A and identification of the proform of eosinophil major basic protein
as its physiological inhibitor. J Biol Chem 2000; 275:3112831133.
Lin TM, Halbert SP, Kiefer D, Spellacy WN, Call S. Characterization of four
human pregnancy-associated plasma proteins. Am J Obstet Gynecol
1974; 118:223236.
Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ,
Hays LG, et al. The insulin-like growth factor (IGF)-dependent IGF binding
protein-4 protease secreted by human fibroblasts is pregnancy-associated
plasma protein-A. Proc Natl Acad Sci U S A 1999;
96:31493153.
Overgaard MT, Oxvig C, Christiansen M, Lawrence JB, Conover CA,
Gleich GJ, et al. Messenger ribonucleic acid levels of pregnancyassociated plasma protein-A and the proform of eosinophil major basic
protein: expression in human reproductive and nonreproductive tissues.
Biol Reprod 1999; 61:10831089.
Bayes-Genis A, Conover CA, Overgaard MT, Bailey KR, Christiansen M,
Holmes DR Jr, et al. Pregnancy-associated plasma protein A as a marker of
acute coronary syndromes. N Engl J Med 2001; 345:10221029.
Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Zuppi C, Andreotti F.
Insulin-like growth factor-1 as a vascular protective factor. Circulation
2004; 110:22602265.
Cosin-Sales J, Kaski JC, Christiansen M, Kaminski P, Oxvig C,
Overgaard MT, et al. Relationship among pregnancy associated plasma
protein-A levels, clinical characteristics and coronary artery disease extent
in patients with chronic stable angina. Eur Heart 2005; 26:20932098.
Heeschen C, Dimmeler S, Hamm CW, Fichtlscherer S, Simoons ML,
Zeiher AM. Pregnancy-associated plasma protein-A levels in patients with
acute coronary syndromes: comparison with markers of systemic
inflammation, platelet activation, and myocardial necrosis. J Am Coll
Cardiol 2005; 45:229.
Autiero M, Luttun A, Tjwa M, Carmeliet P. Placental growth factor and its
receptor, vascular endothelial growth factor receptor-1: novel targets for

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

254

29

30

31
32

33
34

35

36
37
38

39

40

41

42

43

44

45

46

47

48

49

50

51

Coronary Artery Disease 2010, Vol 21 No 4

stimulation of ischemic tissue revascularization and inhibition of angiogenic

and inflammatory disorders. J Thromb Haemost 2003; 1:13561370.
Heeschen D, Dimmeler S, Fichtlscherer S, Hamm CW, Berger J,
Simoons ML, et al. Prognostic value of placental growth factor in patients
with acute chest pain. JAMA 2004; 291:435441.
Cassidy A, Chiuve SE, Manson JE, Rexrode KM, Girman CJ, Rimm EB.
Potential role for plasma placental growth factor in predicting coronary
heart disease risk in women. Arterioscler Thromb Vasc Biol 2009; 29:
134139.
Futterman LG, Lemberg L. Novel markers in the acute coronary syndrome:
BNP, IL-6, PAPP-A. Am J Crit Care 2002; 11:168172.
Harris TB, Ferricco L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr,
et al. Associations of elevated interleukin- 6 and c-reactive protein levels
with mortality in the elderly. Am J Med 1999; 106:506512.
Vorchheimer DA, Fuster V. Inflammatory markers in coronary artery disease:
let prevention douse the flames. JAMA 2001; 286:21542155.
Lindmark E, Diderhom E, Wallentin L, Siegbahn A. Relationship between
interleukin 6 and mortality in patients with unstable coronary artery disease.
JAMA 2001; 286:21072113.
Loria V, Dato I, Graziani F, Luigi M. Review article Myeloperoxidase: A New
Biomarker of Inflammation in Ischemic Heart Disease and Acute Coronary
Syndromes. 21 January 2008.
McCord JM. Oxygen-derived free radicals in post-ischemic tissue injury
[review]. N Engl J Med 1985; 312:159163.
Cobbe SM, Poole-Wilson PA. The time of onset and severity of acidosis in
myocardial ischaemia. J Mol Cell Cardiol 1980; 12:745760.
Berenshtein E, Mayer B, Goldberg C, Kitrossky N, Chevion M.
Patterns of mobilization of copper and iron following myocardial ischemia:
possible predictive criteria for tissue injury. J Mol Cell Cardiol 1997;
29:30253034.
Bar-Or D, Winkler JV, Vanbenthuysen K, Harris L, Lau E, Hetzel FW.
Reduced albumincobalt binding with transient myocardial ischemia after
elective percutaneous transluminal coronary angioplasty: a preliminary
comparison to creatine kinaseMB, myoglobin, and troponin I. Am Heart J
2001; 141:985991.
Bar-Or D, Curtis G, Rao N, Bampos N, Lau E. Characterization of the
Co2 + and Ni2 + binding amino-acid residues of the N-terminus of human
albumin: an insight into the mechanism of a new assay for myocardial
ischemia. Eur J Biochem 2001; 268:4247.
Christenson RH, Duh SH, Sanhai WR, Wu AH, Holtman V, Painter P, et al.
Characteristics of an albumin cobalt binding test for assessment of acute
coronary syndrome patients: a multicenter study. Clin Chem 2001;
47:464470.
Immanuel S, Sanjaya AI. Albumin cobalt binding (ACB) test: its role as a
novel marker of acute coronary syndrome. Acta Med Indones 2006;
38:9296.
Sinha MK, Roy D, Gaze D, Collinson PO, Kaski JC. Role of ischemia
modified albumin, a new biochemical marker of myocardial ischaemia, in
the early diagnosis of acute coronary syndromes. Emerg Med J 2004;
21:2934.
Peacock F, Morris D, Anwaruddin S, Christenson R, Collinson P, Goodacre
SW, et al. Meta-analysis of ischemia modified albumin to rule out acute
coronary syndromes in the emergency department. Am Heart J 2006;
152:253262.
Newgard CB, Hwang PK, Fletterick RJ. The family of glycogen
phosphorylases: structure and function. Crit Rev Biochem Mol Biol 1989;
24:6999.
Kato A, Shimizu A, Kurobe N, Takashi M, Koshikawa T. Human brain-type
glycogen phosphorylase: quantitative localization in human tissues
determined with an immunoassay system. J Neurochem 1989;
52:14251432.
Meyer F, Heilmeyer LMG Jr, Haschke RH, Fischer EH. Control of
phosphorylase activity in a muscle glycogen particle: isolation and
characterization of the proteinglycogen complex. J Biol Chem 1970;
245:66426648.
Entman ML, Kaniike K, Goldstein MA, Nelson TE, Bornet EP, Futch TW,
Schwartz A. Association of glycogenolysis with cardiac sarcoplasmic
reticulum. J Biol Chem 1976; 251:31403146.
Krause EG, Rabitzsch G, Noll F, Mair J, Puschendorf B. Glycogen
phosphorylase isoenzyme BB in diagnosis of myocardial ischaemic injury
and infarction. Mol Cell Biochem 1996; 160161:289295.
Rabitzsch G, Mair J, Lechleitner P, Noll F, Hofmann V, Krause EG, et al.
Isoenzyme BB of glycogen phosphorylase b and myocardial infarction
(letter). Lancet 1993; 341:10321033.
Rabitzsch G, Mair J, Lechleitner P, Noll F, Hofmann U, Krause EG, et al.
Immunoenzymometric assay of human glycogen phosphorylase isoenzyme

52

53

54
55

56

57
58

59

60

61

62

63

64

65

66

67

68

69

70

71
72

73

74

BB in diagnosis of ischemic myocardial injury. Clin Chem 1995;

41:966978.
Mair J, Puschendorf B, Smidt J, Lechleitner P, Dienstl F, Noll F, et al. Early
release of glycogen phosphorylase in patients with unstable angina and
transient ST-T alterations. Br Heart J 1994; 72:125127.
Peetz D, Post F, Schinzel H, Schweigert R, Schollmayer C, Steinbach K,
et al. Glycogen phosphorylase BB in acute coronary syndromes. Clin
Chem Lab Med 2005; 43:13511358.
Liedtke AJ. Alterations of carbohydrate and lipid metabolism in the acutely
ischemic heart. Prog Cardiovasc Dis 1981; 23:321336.
Oliver MF, Kurien VA, Greenwood TW. Relation between serumfree
fatty acids and arrhythmias and death after acute myocardial infarction.
Lancet 1968; 1:710714.
Gupta DK, Jewitt DE, Young R, Hartog M, Opie LH. Increased plasma-freefatty-acid concentrations and their significance in patients with acute
myocardial infarction. Lancet 1969; 2:12091213.
Spector AA. Fatty acid binding to plasma albumin. J Lipid Res 1975;
16:165179.
Kleinfeld AM, Prothro D, Brown DL, Davis RC, Richieri GV, DeMaria A.
Increases in serum unbound free fatty acid levels following coronary
angioplasty. Am J Cardiol 1996; 78:13501354.
Huber AH, Kampf JP, Kwan T, Zhu B, Kleinfeld AM. Fatty acid-specific
fluorescent probes and their use in resolving mixtures of unbound
free fatty acids in equilibrium with albumin. Biochemistry 2006;
45:14263.
Azzazy HM, Pelsers MM, Christenson RH. Unbound free fatty acids and
heart-type fatty acid-binding protein: diagnostic assays and clinical
applications. Clin Chem 2006; 52:19.
Glatz JF, van der Vusse GJ. Cellular fatty acid-binding proteins: their
function and physiological significance. Prog Lipid Res 1996;
35:243282.
Zschiesche W, Kleine AH, Spitzer E, Veerkamp JH, Glatz JF. Histochemical
localization of heart-type fatty acid-binding protein in human and murine
tissues. Histochem Cell Biol 1995; 103:147156.
Maatman RG, van de Westerlo EM, van Kuppevelt TH, Veerkamp JH.
Molecular identification of the liver- and the heart-type fatty acid-binding
proteins in human and rat kidney. Use of the reverse transcriptase
polymerase chain reaction. Biochem J 1992; 288:285290.
Pelsers MM, Hanhoff T, Van der Voort D, Arts B, Peters M, Ponds R,
et al. Brain- and heart-type fatty acid-binding proteins in the brain: tissue
distribution and clinical utility. Clin Chem 2004; 50:15681575.
Tambara K, Fujita M, Miyamoto S, Doi K, Nishimura K, Komeda M.
Pericardial fluid level of heart-type cytoplasmic fatty acid-binding protein
(H-FABP) is an indicator of severe myocardial ischemia. Int J Cardiol 2004;
93:281284.
Chan CP, Wan TS, Watkins KL, Pelsers MM, Vand V, Tang FP, et al.
Rapid analysis of fatty acid-binding proteins with immunosensors and
immunotests for early monitoring of tissue injury. Biosens Bioelectron
2005; 20:2566.
Ishii J, Nagamura Y, Nomura M, Wang JH, Taga S, Kinoshita M, et al. Early
detection of successful coronary reperfusion based on serum
concentration of human heart-type cytoplasmic fatty acid binding protein.
Clin Chim Acta 1997; 262:1327.
Wodzig KW, Kragten JA, Hermens WT, Glatz JF, van Dieijen-Visser MP.
Estimation of myocardial infarct size from plasma myoglobin or fatty acidbinding protein. Influence of renal function. Eur J Clin Chem Clin Biochem
1997; 35:191198.
Packard CJ, OReilly DSJ, Caslake MJ, McMahon AD, Ford I, Cooney J,
et al. Lipoprotein-associated phospholipase A2 as an independent
predictor of coronary heart disease. N Engl J Med 2000;
343:11481155.
Chambless LE, Folson AR, Davis V, Sharrett R, Heiss G, Sorlie P, et al. Risk
factors for progression of common carotid atheroclerosis; the
atherosclerosis risk in communities study, 19871998. Am J Epidemiol
2002; 155:3847.
Wu AH. Markers for early detection of cardiac diseases. Scand J Clin Lab
Invest 2005; 65 (Suppl 240):112121.
Nicholson JK, Foxall PJ, Spraul M, Farrant RD, Lindon JC. 750 MHz 1H and
1H-13C NMR spectroscopy of human blood plasma. Anal Chem 1995;
67:793.
Danne O, Mockel M, Leuders C, Mugge C, Zschunke GA, Lufft H, et al.
Prognostic implications of elevated whole blood choline levels in acute
coronary syndrome. Am J Cardiol 2003; 91:10601067.
Bhayana V, Henderson AR. Biochemical markers of myocardial damage.
Clin Biochem 1995; 28:129.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Cardiac biomarkers the old and the new Singh et al. 255

75

76
77

78

79

80

81

82

83

84

85

86

87

88

89
90
91

92
93

94

95

96

97

98

Ryan TJ, Anderson JL, Antman EM, Braniff BA, Brooks NH, Califf RM, et al.
Management of acute myocardial infarction. J Am Coll Cardiol 1996;
28:13281428.
Montague C, Kircher T. Myoglobin in early evaluation of acute chest pain.
Am J Clin Pathol 1995; 104:472476.
Mockel M, Gerhardt W, Heller G Jr, Klefisch F, Danne O, Maske J, et al.
Validation of NACB and IFCC guidelines for the use of cardiac markers for
early diagnosis and risk assessment inpatients with acute coronary
syndromes. Clin Chim Acta 2001; 303:167179.
Brogan GX Jr, Friedman S, McCuskey C, Cooling DS, Berrutti L,
Thode HC Jr, Bock JL. Evaluation of a new rapid quantitative immunoassay
for serum myoglobin versus CK-MB for ruling out acute myocardial
infarction in the emergency department. Ann Emerg Med 1994;
24:665671.
Vaananen HK, Syrjala H, Rahkila P, Vuori J, Melamies LM, Myllyla V,
Takala TE. Serum carbonic anhydrase III and myoglobin concentrations in
acute myocardial infarction. Clin Chem 1990; 36:635638.
Brogan GX Jr, Vuori J, Friedman S, McCuskey CF, Thode HC Jr,
Vaananen HK, et al. Improved specificity of myoglobin plus carbonic
anhydrase assay versus that of creatine kinase-MB for early diagnosis of
acute myocardial infarction. Ann Emerg Med 1996; 27:2228.
Adams JE, Abendschein DR, Jaffe AS. Biochemical markers of myocardial
injury; is MB creatine kinase the Choice for the 1990s? Circulation 1993;
88:750763.
Lee TH, Juarez G, Cook EF, Weisberg MC, Rouan GW, Brand DA,
Goldman L. Ruling out acute myocardial infarction: a prospective multicenter validation of a 12 h strategy for patients at low risk. N Engl J Med
1991; 324:12391246.
Puleo PR, Guadagno PA, Roberts R, Perryman MB. Sensitive, rapid
assay of subforms of creatine kinase MB in plasma. Clin Chem 1989;
35:14521455.
Puleo PR, Meyer D, Wathen C, Tawa CB, Wheeler S, Hamburg RJ,
et al. Use of a rapid assay of subforms of creatine kinase MB to
diagnose or rule out acute myocardial infarction. N Engl J Med 1994;
331:561566.
Ebashi S, Toyokura Y, Momoi H, Sugita H. High creatine phosphokinase
activity of sera of progressive muscular dystrophy. J Biochem 1959;
46:103106.
van der Veen KJ, Willebrands AF. Isoenzymes of creatine phosphokinase in
tissue extracts and in normal and pathological sera. Clin Chim Acta 1966;
13:312317.
Roberts R, Gowda KS, Ludbrook PA, Sobel BE. Specificity of elevated
serum MB creatine phosphokinase activity in the diagnosis of acute
myocardial infarction. Am J Cardiol 1975; 36:433438.
Frey N, Muller-Bardorff M, Katus HA. Myocardial damage: the role of
troponin T. In: Kaski JC, Holt DW, editors. Myocardial damage. Early
detection by novel biochemical markers. Location: Kluwer Academic
Publishers; 1998. pp. 2740.
Antman E. Decision making with cardiac troponin tests. N Engl J Med
2002; 346:20792082.
Wong SS. Strategic utilization of cardiac markers for the diagnosis of acute
myocardial infarction. Ann Clin Lab Sci 1996; 26:301312.
Eriksson S, Halenius H, Pulkki I, Hellman J, Pettersson K. Negative
interference in cardiac troponin I immunoassays by circulating troponin
autoantibodies. Clin Chem 2005; 51:839847.
Panteghini M. Standardization of cardiac troponin I measurements: the way
forward? Clin Chem 2005; 51:15941597.
Antman EM, Grudzien C, Sacks DB. Evaluation of a rapid bedside
assay for detection of serum cardiac troponin T. JAMA 1995;
273:12791282.
Martins JT, Li DJ, Baskin LB, Jialal I, Keffer JH. Comparison of cardiac
troponin I and lactate dehydrogenase isoenzymes for the late diagnosis of
myocardial injury. Clin Chem 1996; 106:705708.
Jaffe AS, Landt Y, Parvin CA, Abendschein DR, Geltman EM, Ladenson JH.
Comparative sensitivity of cardiac troponin I and lactate dehydrogenase
isoenzymes for diagnosing acute myocardial infarction. Clin Chem 1996;
42:17701776.
Thygesen K, Alpert JS, White HD, Jaffe AS, Apple FS, Galvani M, et al. Joint
ESC/ACCF/AHA/WHF task force for the redefinition of myocardial
infarction, universal definition of myocardial infarction. Circulation 2007;
116:26342653.
Luscher MS, Thygesen K, Ravkilde J, Heickendorff L. Applicability of
cardiac troponin T and I for early risk stratification in unstable coronary
artery disease. Circulation 1997; 96:25782585.
Apple FS, Voss E, Lund L, Preese L, Berger CR, Henry TD. Cardiac
troponin, CK-MB and myoglobin for the early detection of acute myocardial

99

100
101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

infarction and monitoring of reperfusion following thrombolytic therapy. Clin

Chim Acta 1995; 237:5966.
Gerhardt W, Ljungdahl L. Detection of myocardial damage by serial
measurements of cardiac troponin T, CK-MB mass, and TROPT rapid test.
Cardiovasc Drug Ther 1997; 11 (Suppl 1):227240.
De Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in
cardiovascular diseases. Lancet 2003; 362:316322.
De Lemos JA, Morrow DA. Brain natriuretic peptide measurement in acute
coronary syndromes: ready for clinical application? Circulation 2002;
106:28682870.
Omland T, Aakvaag A, Bonarjee VV, Caidahl K, Lie RT, Nilsen DW, et al.
Plasma brain natriuretic peptide as an indicator of ventricular systolic
function and long-term survival after acute myocardial infarction.
Comparison with plasma atrial natriuretic peptide and N-terminal proatrial
natriuretic peptide. Circulation 1996; 93:19631969.
Morrow DA, Cannon CP, Jesse RL, Newby LK, Ravkilde J, Storrow AB,
et al. National Academy of Clinical Biochemistry Laboratory Medicine
Practice Guidelines: clinical characteristics and utilization of
biochemical markers in acute coronary syndromes. Clin Chem 2007;
53:552574.
Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, et al.
Plasma natriuretic peptide levels and the risk of cardiovascular events and
death. N Engl J Med 2004; 350:655663.
Mueller T, Gegenhuber A, Dieplinger B, Poelz W, Haltmayer M. Capability
of B-type natriuretic peptide (BNP) and amino-terminal proBNP as
indicators of cardiac structural disease in asymptomatic patients with
systemic arterial hypertension. Clin Chem 2005; 51:22452251.
Bhagavan NV, Ha JS, Park JH, Honda SA, Rios CN, Sugiyama C, et al.
Utility of serum fatty acid concentrations as a marker for acute myocardial
infarction and their potential role in the formation of ischemia-modified
albumin: a pilot study. Clin Chem 2009; 55:15881590. [Epub 2009
June 4]
Demir H, Topkaya BC, Erbay AR, Dogan M, Yucel D. Ischaemia-modified
albumin elevation after percutaneous coronary intervention reflects albumin
concentration rather than ischaemia. Ann Clin Biochem 2009; 46 (Pt 4):
327331. [Epub 2009 June 1]
Kazanis K, Dalamaga M, Nounopoulos C, Manolis AS, Sakellaris N, Jullien
G, Dionyssiou-Asteriou A. Ischemia modified albumin, high-sensitivity
c-reactive protein and natriuretic peptide in patients with coronary
atherosclerosis. Clin Chim Acta 2009; 408:6569.
Chen ZX, Wang Q, Zheng L, Bao J. Clinical value of an improved ischemiamodified albumin assay in the diagnosis of early acute myocardial
infarction. Nan Fang Yi Ke Da Xue Xue Bao 2009; 29:13781380.
McCann CJ, Glover BM, Menown IB, Moore MJ, McEneny J, Owens CG,
et al. Investigation of a multimarker approach to the initial assessment of
patients with acute chest pain. Adv Ther 2009; 26:531534.
McCann CJ, Glover BM, Menown IB, Moore MJ, McEneny J, Owens CG,
et al. Prognostic value of a multimarker approach for patients
presenting to hospital with acute chest pain. Am J Cardiol 2009;
103:2228.
Husser O, Bodi V, Sanchis J, Nunez J, Mainar L, Rumiz E, et al. Release of
necrosis markers and cardiovascular magnetic resonance-derived
microvascular perfusion in reperfused ST-elevation myocardial infarction.
Thromb Res 2009; 124:592600.
Wang J, Wang Q, Ren L, Wang X, Wan Z, Liu W, et al. Carboxylated
magnetic microbead-assisted fluoroimmunoassay for early biomarkers of
acute myocardial infarction. Colloids Surf B Biointerfaces 2009;
72:112120.
Hjortshj S, Dethlefsen C, Kristensen SR, Ravkilde J. Kinetics of ischaemia
modified albumin during ongoing severe myocardial ischaemia. Clin Chim
Acta 2009; 403:114120.
Hoshino T, Sakai Y, Yamashita K, Shirahase Y, Sakaguchi K, Asaeda A,
et al. Development and performance of an enzyme immunoassay to
detect creatine kinase isoenzyme MB activity using anti-mitochondrial
creatine kinase monoclonal antibodies. Scand J Clin Lab Invest 2009;
29:19.
Zahid M, Good CB, Singla I, Sonel AF. Clinical significance of
borderline elevated troponin I levels across different assays in patients
with suspected acute coronary syndrome. Am J Cardiol 2009;
104:164168.
Plaikner M, Peer A, Falkensammer G, Schmidauer C, Pechlaner C,
Griesmacher A, et al. Lack of association of soluble CD40 ligand with the
presence of acute myocardial infarction or ischemic stroke in the
emergency department. Clin Chem 2009; 55:175178.
Elkind MS, Leon V, Moon YP, Paik MC, Sacco RL. High-sensitivity
C-reactive protein and lipoprotein-associated phospholipase A2 stability

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

256

Coronary Artery Disease 2010, Vol 21 No 4

before and after stroke and myocardial infarction. Stroke 2009;

40:32333237.
119 Kavsak PA, Wang X, Henderson M, Ko DT, MacRae AR, Jaffe AS. PAPP-A
as a marker of increased long-term risk in patients with chest pain.
Clin Biochem 2009; 42:10121018.
120 Iversen KK, Teisner AS, Teisner B, Kliem A, Thanning P, Grande P,
Clemmensen P. Pregnancy associated plasma protein A, a novel, quick,
and sensitive marker in ST-elevation myocardial infarction. Am J Cardiol
2008; 101:13891394.
121 Fellahi JL, Hanouz JL, Manach YL, Gue X, Monier E, Guillou L, Riou B.
Simultaneous measurement of cardiac troponin I, B-type natriuretic
peptide, and C-reactive protein for the prediction of long-term cardiac

122

123

124

outcome after cardiac surgery. Anesthesiology 2009. [Epub ahead of

print] PMID: 19568166
Reichlin T, Hochholzer W, Stelzig C, Laule K, Freidank H,
Morgenthaler NG, et al. Incremental value of copeptin for rapid
rule out of acute myocardial infarction. J Am Coll Cardiol 2009;
54:6068.
Keller T, Zeller T, Peetz D, Tzikas S, Roth A, Czyz E, et al. Sensitive troponin
I assay in early diagnosis of acute myocardial infarction. N Engl J Med
2009; 361:868877.
Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S,
et al. Early diagnosis of myocardial infarction with sensitive cardiac
troponin assays. N Engl J Med 2009; 361:858867.

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