BIOMEDICAL REPORTS 3: 743-748, 2015

Diagnostic markers of acute myocardial infarction (Review)

SABESAN MYTHILI* and NARASIMHAN MALATHI*
Department of Oral Pathology and Microbiology, Faculty of Dental Sciences,
Sri Ramachandra University, Chennai, Tamil Nadu 600116, India
Received July 1, 2015; Accepted July 15, 2015
DOI: 10.3892/br.2015.500
Abstract. Acute myocardial infarction (AMI) is a major cause
of morbidity and mortality worldwide. The highest risk of
fatality occurs within the initial hours of onset of AMI. Thus,
early diagnosis of cardiac ischemia is critical for the effective management of patients with AMI. Improper diagnosis of
patients with chest pain often leads to inappropriate admission
of patients without AMI and vice versa. In addition to clinical
history, physical examination, accurate electrocardiogram
findings and assessment of cardiac biomarkers have an important role in the early diagnosis of acute ischemia. The present
review discusses in detail the various cardiac biomarkers
released during the event of an AMI.
Contents
1. Introduction
2. Biomarkers of myocardial infarction
3. Inflammatory markers
4. Plaque destabilization markers
5. Myocardial necrosis markers
6. Salivary biomarkers associated with myocardial necrosis
7. Conclusion

Correspondence to: Dr Sabesan Mythili, Department of

Oral Pathology and Microbiology, Faculty of Dental Sciences,

SriRamachandra University, 1Ramachandra Nagar, Chennai, Tamil
Nadu 600116, India
Email: sabesanm@hotmail.com
*

Contributed equally

Abbreviations: AMI, acute myocardial infarction; AST, aspartate

aminotransferase; CK, creatine kinase; LDH, lactate dehydrogenase;

CRP, Creactive protein; PTX3, pentraxin 3; MPO, myeloperoxidase;
PAPPA, pregnancy-associated plasma proteinA; TNF, tumor
necrosis factor; CK-MB, creatine kinase myocardial band; HFABP,
heart fatty acidbinding protein; BNP, Btype natriuretic peptide;
IMA, ischemiamodified albumin; GDF15, growthdifferentiation
factor15; ACS, acute coronary syndrome; MYO, myoglobin; MMP9,
matrix metalloproteinase9

Key words: acute myocardial infarction, electrocardiogram,

atherosclerosis, biomarkers

1. Introduction
In the early 1970s, the World Health Organization (WHO) had
defined the term myocardial infarction by the presence of2
of the 3following characteristics(1,2): i)Symptoms of acute
ischemia (chest pain), ii)development of Qwaves in electrocardiogram (ECG) and iii)increase of enzymes in the blood
[combination of total creatine kinase (CK), CKmyocardial
band (MB), aspartate aminotransferase (AST) and lactate
dehydrogenase (LDH)]. However, in1999, the Joint European
Society of Cardiology and the American College of Cardiology
Committee jointly proposed the new definition for myocardial infarction, emphasizing the importance of sensitive and
serological biomarkers for the diagnosis of acute myocardial
infarction (AMI), and introduced cardiac troponins (cTn) as
the gold standard(3) (Fig.1).
2. Biomarkers of myocardial infarction
Myocardial infarction is defined as myocardial cell death due
to prolonged ischemia(4). Myocardial cell death does not occur
immediately following the onset of myocardial ischemia, but
occurs 6h. Atherosclerosis is by far the most common cause
of myocardial infarction. The major risk factors of atherosclerosis are hyperlipidemia, diabetes, smoking, hypertension,
gender and age. Endothelial dysfunction and inflammation
have a major role in the initiation of the atherosclerotic plaque
formation(5,6). Atherosclerosis is characterized by lipid
accumulation in the vessel walls leading to the formation of
an atherosclerotic plaque consisting of a central lipid core
surrounded by foamy macrophages and smooth muscle cells
covered by a fibrous cap(7). Rupture of the fibrous cap leads to
communication between the lipid content of the plaque and the
blood flowing through the arterial lumen(8). The tissue factor
expressed by the macrophages activates the platelets eventually
leading to the formation of intraluminal thrombus(9,10). Finally
occlusion of the coronary artery by the thrombus reduces the
blood supply to the myocardial tissues leading to ischemia and
necrosis, eventually causing myocardial infarction(11) (Fig.2).
Rapid identification of AMI is mandatory to initiate effective treatment for better prognosis. The newer concept of
diagnosis of AMI emphasizes the importance of the 12lead
ECG and the assessment of early cardiac biomarkers since
ECG by itself is often inadequate to diagnose AMI (TableI).
In the year1954, AST was the first cardiac biomarker to be
used. AST is found in the liver, heart, skeletal muscles, brain

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MYTHILI and MALATHI: DIAGNOSTIC MARKERS OF ACUTE MYOCARDIAL INFARCTION

Figure 1. Characteristics of an ideal cardiac biomarker.

Figure 2. Schematic representation of the pathogenesis of myocardial infarction.

and kidneys. Due to its lack of specificity to the cardiac tissue

it is no longer used for the diagnosis of AMI(12,13). In the
year1959, the total CK level was assessed for AMI, as it was
a good indicator of skeletal muscle injury(14). Following this,
in the year1960, LDH was used for diagnosis of AMI(15).
Finally in the year1979, WHO recommended the panel of CK,
AST and LDH for the diagnosis of AMI(2).
However, the assessment of the cardiac biomarkers was
revolutionized in the year1980 after the development of
immunoassays(16).
3. Inflammatory markers
Creactive protein (CRP). CRP is an acute phase protein
secreted by the hepatocytes during an inflammatory stimulus(17). In addition to being an inflammatory marker, CRP
has a proinflammatory effect causing expression of adhesion
molecules and inflammatory cells(18). It has been shown that

CRP is increased in patients with unstable angina; however,

owing to lack of sensitivity and specificity, it cannot be used as
a diagnostic marker(19). As a prognostic indicator, high CRP
levels have also been associated with poor outcome(20).
Pentraxin 3 (PTX3). PTX3 of the PTX family is a specific
marker of vascular inflammation produced by the vascular
endothelial cells, vascular smooth muscle cells, macrophages,
and neutrophils in response to an inflammatory stimulus(21).
The PTX3 level has been proposed as a prognostic biomarker
of adverse outcome in patients with unstable angina pectoris,
myocardial infarction and heart failure(22,23). However, as
opposed to CRP, PTX3 predicts advanced atherosclerosis and
is more specific for vessel wall inflammation(24).
Interleukin (IL)6. Another marker of early atherosclerosis is
IL6, which has a major role in the recruitment and activation of inflammatory cells in response to ischemia and further

BIOMEDICAL REPORTS 3: 743-748, 2015

Table I. Biomarkers of myocardial infarction.

Type Marker
Obsolete
Aspartate aminotransferase

Total CK

Lactate dehydrogenase
Established
Troponin T

Troponin I

Myocardial fraction of CK
Myoglobin
Emerging
Heart fatty acidbinding protein

B-type natriuretic peptide

Ischemiamodified albumin

Pregnancy-associated plasma proteinA
Copeptin

Growth differentiation factor-15
CK, creatine kinase.

during the reperfusion of the infarcted myocardium(25). In

addition, it stimulates the liver to produce the acute phase
protein, CRP(26). Thus, an elevated serum level of IL6 and
CRP are associated with the development of atherosclerosis
and additionally to the development of typeII diabetes in
insulinresistant individuals(27).
4. Plaque destabilization markers
Myeloperoxidase (MPO). MPO is a metalloproteinase
produced by the polymorphonuclear leukocytes and macrophages. It initiates the production of reactive oxygen species
that are important for the development of atheroma and plaque
rupture(28). Thus, an increased level of MPO is a marker of
plaque instability(29). Furthermore, it serves as a predictive
marker for future cardiovascular adverse events(30).
Pregnancyassociated plasma proteinA (PAPPA). PAPPA
is also a metalloproteinase that has an active role during
the rupture of an atherosclerotic plaque(31). It is primarily
produced by the syncytiotrophoblasts of the placenta,
aswellas by the fibroblasts, vascular endothelial cells and
vascular smooth muscle cells. In atherosclerosis, it has been
associated with plaque progression and instability(32).
Soluble cluster of differentiation40 ligand (sCD40L). sCD40L
of the tumor necrosis factor (TNF) family is upregulated
on the platelets located in the intraluminal thrombus. The
activation of the inflammatory and coagulant pathways during
thrombogenesis causes the release of CD40L into the circulation, thus indicating plaque rupture and subsequent myocardial
infarction(33).
TNF . TNF is a pleiotropic cytokine produced by the endothelial cells, smooth muscle cells and macrophages. TNF
levels are markedly elevated in advanced heart failure(34).
The role of TNF in atherosclerosis is the production of

745

tissue inhibitors of metalloproteinases by the fibroblasts.

Thus, the production of excess amounts of metalloproteinases
causes rupture of the atheromatous plaque(35). Additionally,
it can stimulate the synthesis of IL6 by the smooth muscle
cells. This confirms the role of TNF in the regulation of
the inflammatory cascade. Thus, elevated levels of TNF are
indicative of recurrent nonfatal myocardial infarction or a
fatal cardiovascular event(36).
5. Myocardial necrosis markers
Troponins. The troponins are a complex of 3protein subunits,
namely troponinC, troponinT and troponinI, located on
the thin filaments of the skeletal and cardiac muscle fibers.
TroponinC is the calciumbinding component, troponinT
is the tropomyosinbinding component and troponinI is
the inhibitory component. As the isoforms of troponinC is
identical in the skeletal and cardiac muscle, troponinC is not
extremely specific for myocardial injury(37,38). The isoforms
of troponinT and troponinI differ in the skeletal and the
cardiac muscle, and thus are extremely specific for cardiac
tissue necrosis(39). TroponinT is present chiefly in the bound
form to the contractile elements of the myocardial cells;
however, it is also present free in the cytoplasm. TroponinT
exhibits a dual release initially of the cytoplasmic component
and later of the bound component(40). TroponinI is extremely
specific for the cardiac muscle and has not been isolated from
the skeletal muscle. This absolute specificity makes it an ideal
marker of myocardial injury(41). They are released into the
circulation 68h after myocardial injury, peak at 1224h and
remain elevated for 710days(42). The only disadvantage of
cTn is the late clearance that makes it difficult to identify a
recurrent myocardial infarction.
Myoglobin (MYO). MYO is a small cytoplasmic oxygenbinding
protein found in the skeletal aswellas the cardiac muscle. It
is released extremely early into the serum, 1h after the onset
of myocardial injury, peaks at 412h and returns to baseline
values immediately(43,44). The major disadvantage of MYO
is the lack of specificity to the cardiac tissue due to the presence of large amounts of MYO in the skeletal muscle(45). The
levels of MYO can therefore not be used as a single diagnostic
marker, but in conjunction with the troponins or CKMB.
Thus, serum levels of MYO can be used to rule out, rather
than diagnose, myocardial infarction(46).
CK and CKMB. CK was first indicated as a cardiac biomarker
in the year1979. CK is an enzyme that is found primarily in the
cardiac muscle and skeletal muscle. This enzyme has 3isoenzymes: MM, MB and BB. CKMM is the skeletal muscle
fraction, CKMB is the cardiac muscle fraction and CKBB is
the brain fraction of the total CK(47). Previously, the total CK
was assessed for myocardial infarction. However, as the total
CK contains 95% of the CKMM fraction, recent concepts have
proposed the use of the relative index score (RI) as follows (48).
CKMB RI=[CKMB (ng/ml)/Total CK (U/l)]x100
The CKMB rises in the serum at 49h after the onset
of chest pain, peaks ~24h and returns to baseline values at

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MYTHILI and MALATHI: DIAGNOSTIC MARKERS OF ACUTE MYOCARDIAL INFARCTION

4872h. The one advantage of CKMB over the troponins is

the early clearance that helps in the detection of reinfarction.
Thus, the serum level of troponin along with the level of the
CKMB fraction is assessed for the diagnosis of myocardial
infarction(49).
Heart fatty acidbinding protein (HFABP). HFABP is a
small cytosolic low molecular weight protein found in the
cardiac tissues that are responsible for the transport of fatty
acids from the plasma membrane to sites of oxidation in
mitochondria and peroxisomes, and to the endoplasmic
reticulum for lipid synthesis(50). It is chiefly present in the
myocardium and, to a lesser extent, in the brain, kidney and
skeletal muscle. HFABP is released extremely early into
the serum following myocyte rupture(51). An increased
concentration of HFABP appears as early as 30min after
myocardial injury, peaks at 68h and returns to baseline
levels at ~24h(52). Additionally, HFABP can be used as a
predictive biomarker of mortality following acute coronary
syndrome (ACS)(53).
Btype natriuretic peptide (BNP). BNP is a neurohormone
released from the cardiac cells. Studies have shown that
elevated BNP is a predictive marker of death and heart failure.
However, they are not useful for the diagnosis of AMI(54).
Ischemiamodified albumin (IMA). Under ischemic conditions,
the level of IMA in the blood is significantly increased, thus
aiding in the diagnosis of acute ischemia prior to the onset of
myocardial necrosis(55). The measurement of IMA is enabled
by the binding of the cobalt to the damaged Nterminus of the
albumin. The increase in IMA levels occurs immediately after
the onset of ischemia and returns to baseline values within
612h, thus enabling early identification of ischemia(56).
Growthdifferentiation factor15 (GDF15). GDF15 is a
member of the transforming growth factor family of cytokines that is primarily expressed by the placenta; however,
under abnormal conditions, it can be expressed by various
tissues(57). During cardiac ischemia, the level of GDF15 is
increased favoring diagnosis of ACS(58). However, owing
to its lack of specificity, it can be used as a predictive marker
of mortality rather than a diagnostic marker following
ACS(59).
Copeptin. Copeptin, the Cterminal portion of provasopressin
is cosecreted with vasopressin. Copeptin is secreted extremely
early in the course of an AMI from the pituitary(60). Copeptin
levels are significantly increased within minutes in patients
with AMI. Thus, copeptin can be used as a diagnostic and
prognostic marker of myocardial injury(61).
F2 isoprostanes. F2 isoprostanes are products of arachidonic
acid metabolism. During atherosclerosis, the F2 isoprostanes
are secreted by a variety of cells including the monocytes.
Studies have shown that the F2 isoprostane level is increased
in the urine of patients with unstable angina. Additionally,
it can be used as a predictive marker of complications in
nonfatal myocardial infarction, development of heart failure
and fatality(62).

6. Salivary biomarkers associated with myocardial necrosis

Saliva offers an easy, simple and noninvasive screening
procedure for various systemic diseases. Whole saliva
contains constituents from serum, gingival crevicular fluid
and oral mucosal transudate making it a valuable diagnostic
tool. Salivary markers of acute myocardial infarction include
MYO, CRP, MPO, CKMB and cTn, which when used in
combination with an ECG, shows a positive correlation in
patients when compared to healthy controls(63). The salivary
MYO levels were found to be significantly higher within 48h
of onset of chest pain in AMI patients and correlated positively
with its serum concentration(64). In a study performed by
Milleretal(65), the salivary concentrations of CRP, TNF,
matrix metalloproteinase9 (MMP9) and MPO were significantly higher in patients with AMI and correlated positively
with the serum concentrations. Studies reveal that salivary
soluble intracellular adhesion molecule1 is significantly
elevated in AMI patients; however, levels of salivary sCD40L
were significantly lowered in AMI patients. In a study
performed by Foleyetal(66), salivary levels of troponinI
and CRP correlated with the serum levels in patients with
myocardial injury. Additionally, levels of MMP9 and MPO in
saliva correlated with its serum levels(67). Thus, these studies
suggest that saliva can be used as an alternative to serum in the
diagnosis of myocardial infarction(68).
7. Conclusion
The analysis of cardiac biomarkers has become the frontline
diagnostic tools for AMI, and has greatly enabled the clinicians in the rapid diagnosis and prompt treatment planning,
thereby reducing the mortality rate to a great extent. However,
the future of cardiac biomarkers will follow the analysis of a
panel of markers for the diagnosis and prognosis of myocardial infarction.
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