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 1. Introduction

of morbidity and mortality worldwide. The highest risk of
fatality occurs within the initial hours of onset of AMI. Thus, In the early 1970s, the World Health Organization (WHO) had
early diagnosis of cardiac ischemia is critical for the effec- defined the term myocardial infarction by the presence of 2
tive management of patients with AMI. Improper diagnosis of of the 3 following characteristics (1,2): i) Symptoms of acute
patients with chest pain often leads to inappropriate admission ischemia (chest pain), ii) development of Q waves in electro-
of patients without AMI and vice versa. In addition to clinical cardiogram (ECG) and iii) increase of enzymes in the blood
history, physical examination, accurate electrocardiogram [combination of total creatine kinase (CK), CK‑myocardial
findings and assessment of cardiac biomarkers have an impor- band (MB), aspartate aminotransferase (AST) and lactate
tant role in the early diagnosis of acute ischemia. The present dehydrogenase (LDH)]. However, in 1999, the Joint European
review discusses in detail the various cardiac biomarkers Society of Cardiology and the American College of Cardiology
released during the event of an AMI. Committee jointly proposed the new definition for myocar-
dial infarction, emphasizing the importance of sensitive and
serological biomarkers for the diagnosis of acute myocardial
Contents infarction (AMI), and introduced cardiac troponins (cTn) as
the gold standard (3) (Fig. 1).
1. Introduction
2. Biomarkers of myocardial infarction 2. Biomarkers of myocardial infarction
3. Inflammatory markers
4. Plaque destabilization markers Myocardial infarction is defined as myocardial cell death due
5. Myocardial necrosis markers to prolonged ischemia (4). Myocardial cell death does not occur
6. Salivary biomarkers associated with myocardial necrosis immediately following the onset of myocardial ischemia, but
7. Conclusion occurs ≥6 h. Atherosclerosis is by far the most common cause
of myocardial infarction. The major risk factors of atheroscle-
rosis are hyperlipidemia, diabetes, smoking, hypertension,
gender and age. Endothelial dysfunction and inflammation
have a major role in the initiation of the atherosclerotic plaque
Correspondence to: Dr Sabesan Mythili, Department of
formation (5,6). Atherosclerosis is characterized by lipid
Oral Pathology and Microbiology, Faculty of Dental Sciences,
Sri Ramachandra University, 1 Ramachandra Nagar, Chennai, Tamil accumulation in the vessel walls leading to the formation of
Nadu 600116, India an atherosclerotic plaque consisting of a central lipid core
E‑mail: sabesanm@hotmail.com surrounded by foamy macrophages and smooth muscle cells
covered by a fibrous cap (7). Rupture of the fibrous cap leads to
*
Contributed equally communication between the lipid content of the plaque and the
blood flowing through the arterial lumen (8). The tissue factor
Abbreviations: AMI, acute myocardial infarction; AST, aspartate expressed by the macrophages activates the platelets eventually
aminotransferase; CK, creatine kinase; LDH, lactate dehydrogenase; leading to the formation of intraluminal thrombus (9,10). Finally
CRP, C‑reactive protein; PTX‑3, pentraxin 3; MPO, myeloperoxidase; occlusion of the coronary artery by the thrombus reduces the
PAPPA, pregnancy-associated plasma protein A; TNF‑α, tumor blood supply to the myocardial tissues leading to ischemia and
necrosis factor‑α; CK-MB, creatine kinase myocardial band; H‑FABP,
necrosis, eventually causing myocardial infarction (11) (Fig. 2).
heart fatty acid‑binding protein; BNP, B‑type natriuretic peptide;
IMA, ischemia‑modified albumin; GDF‑15, growth‑differentiation Rapid identification of AMI is mandatory to initiate effec-
factor‑15; ACS, acute coronary syndrome; MYO, myoglobin; MMP‑9, tive treatment for better prognosis. The newer concept of
matrix metalloproteinase‑9 diagnosis of AMI emphasizes the importance of the 12‑lead
ECG and the assessment of early cardiac biomarkers since
Key words: acute myocardial infarction, electrocardiogram, ECG by itself is often inadequate to diagnose AMI (Table I).
atherosclerosis, biomarkers In the year 1954, AST was the first cardiac biomarker to be
used. AST is found in the liver, heart, skeletal muscles, brain
744 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 CRP is increased in patients with unstable angina; however,
it is no longer used for the diagnosis of AMI (12,13). In the owing to lack of sensitivity and specificity, it cannot be used as
year 1959, the total CK level was assessed for AMI, as it was a diagnostic marker (19). As a prognostic indicator, high CRP
a good indicator of skeletal muscle injury (14). Following this, levels have also been associated with poor outcome (20).
in the year 1960, LDH was used for diagnosis of AMI (15).
Finally in the year 1979, WHO recommended the panel of CK, Pentraxin 3 (PTX‑3). PTX‑3 of the PTX family is a specific
AST and LDH for the diagnosis of AMI (2). marker of vascular inflammation produced by the vascular
However, the assessment of the cardiac biomarkers was endothelial cells, vascular smooth muscle cells, macrophages,
revolutionized in the year 1980 after the development of and neutrophils in response to an inflammatory stimulus (21).
immunoassays (16). The PTX‑3 level has been proposed as a prognostic biomarker
of adverse outcome in patients with unstable angina pectoris,
3. Inflammatory markers myocardial infarction and heart failure (22,23). However, as
opposed to CRP, PTX‑3 predicts advanced atherosclerosis and
C‑reactive protein (CRP). CRP is an acute phase protein is more specific for vessel wall inflammation (24).
secreted by the hepatocytes during an inflammatory stim-
ulus (17). In addition to being an inflammatory marker, CRP Interleukin (IL)‑6. Another marker of early atherosclerosis is
has a pro‑inflammatory effect causing expression of adhesion IL‑6, which has a major role in the recruitment and activa-
molecules and inflammatory cells (18). It has been shown that tion of inflammatory cells in response to ischemia and further
 BIOMEDICAL REPORTS 3: 743-748, 2015 745

Table I. Biomarkers of myocardial infarction. tissue inhibitors of metalloproteinases by the fibroblasts.

Thus, the production of excess amounts of metalloproteinases
Type Marker causes rupture of the atheromatous plaque (35). Additionally,
it can stimulate the synthesis of IL‑6 by the smooth muscle
Obsolete Aspartate aminotransferase cells. This confirms the role of TNF‑ α in the regulation of
Total CK the inflammatory cascade. Thus, elevated levels of TNF‑α are
Lactate dehydrogenase indicative of recurrent non‑fatal myocardial infarction or a
Established Troponin T fatal cardiovascular event (36).
Troponin I
Myocardial fraction of CK 5. Myocardial necrosis markers
Myoglobin
Troponins. The troponins are a complex of 3 protein subunits,
Emerging Heart fatty acid‑binding protein namely troponin C, troponin T and troponin I, located on
B-type natriuretic peptide the thin filaments of the skeletal and cardiac muscle fibers.
Ischemia‑modified albumin Troponin C is the calcium‑binding component, troponin T
Pregnancy-associated plasma protein A is the tropomyosin‑binding component and troponin I is
Copeptin the inhibitory component. As the isoforms of troponin C is
Growth differentiation factor-15 identical in the skeletal and cardiac muscle, troponin C is not
extremely specific for myocardial injury (37,38). The isoforms
CK, creatine kinase. of troponin T and troponin I differ in the skeletal and the
cardiac muscle, and thus are extremely specific for cardiac
tissue necrosis (39). Troponin T is present chiefly in the bound
form to the contractile elements of the myocardial cells;
during the reperfusion of the infarcted myocardium (25). In however, it is also present free in the cytoplasm. Troponin T
addition, it stimulates the liver to produce the acute phase exhibits a dual release initially of the cytoplasmic component
protein, CRP (26). Thus, an elevated serum level of IL‑6 and and later of the bound component (40). Troponin I is extremely
CRP are associated with the development of atherosclerosis specific for the cardiac muscle and has not been isolated from
and additionally to the development of type II diabetes in the skeletal muscle. This absolute specificity makes it an ideal
insulin‑resistant individuals (27). marker of myocardial injury (41). They are released into the
circulation 6‑8 h after myocardial injury, peak at 12‑24 h and
4. Plaque destabilization markers remain elevated for 7‑10 days (42). The only disadvantage of
cTn is the late clearance that makes it difficult to identify a
Myeloperoxidase (MPO). MPO is a metalloproteinase recurrent myocardial infarction.
produced by the polymorphonuclear leukocytes and macro-
phages. It initiates the production of reactive oxygen species Myoglobin (MYO). MYO is a small cytoplasmic oxygen‑binding
that are important for the development of atheroma and plaque protein found in the skeletal as well as the cardiac muscle. It
rupture (28). Thus, an increased level of MPO is a marker of is released extremely early into the serum, 1 h after the onset
plaque instability (29). Furthermore, it serves as a predictive of myocardial injury, peaks at 4‑12 h and returns to baseline
marker for future cardiovascular adverse events (30). values immediately (43,44). The major disadvantage of MYO
is the lack of specificity to the cardiac tissue due to the pres-
Pregnancy‑associated plasma protein A (PAPPA). PAPPA ence of large amounts of MYO in the skeletal muscle (45). The
is also a metalloproteinase that has an active role during levels of MYO can therefore not be used as a single diagnostic
the rupture of an atherosclerotic plaque (31). It is primarily marker, but in conjunction with the troponins or CK‑MB.
produced by the syncytiotrophoblasts of the placenta, Thus, serum levels of MYO can be used to rule out, rather
as well as by the fibroblasts, vascular endothelial cells and than diagnose, myocardial infarction (46).
vascular smooth muscle cells. In atherosclerosis, it has been
associated with plaque progression and instability (32). CK and CK‑MB. CK was first indicated as a cardiac biomarker
in the year 1979. CK is an enzyme that is found primarily in the
Soluble cluster of differentiation 40 ligand (sCD40L). sCD40L cardiac muscle and skeletal muscle. This enzyme has 3 isoen-
of the tumor necrosis factor‑α (TNF‑α) family is upregulated zymes: MM, MB and BB. CK‑MM is the skeletal muscle
on the platelets located in the intraluminal thrombus. The fraction, CK‑MB is the cardiac muscle fraction and CK‑BB is
activation of the inflammatory and coagulant pathways during the brain fraction of the total CK (47). Previously, the total CK
thrombogenesis causes the release of CD40L into the circula- was assessed for myocardial infarction. However, as the total
tion, thus indicating plaque rupture and subsequent myocardial CK contains 95% of the CK‑MM fraction, recent concepts have
infarction (33). proposed the use of the relative index score (RI) as follows (48).

TNF‑ α. TNF‑α is a pleiotropic cytokine produced by the endo- CK‑MB RI = [CK‑MB (ng/ml)/Total CK (U/l)] x 100
thelial cells, smooth muscle cells and macrophages. TNF‑α
levels are markedly elevated in advanced heart failure (34). The CK‑MB rises in the serum at 4‑9 h after the onset
The role of TNF‑ α in atherosclerosis is the production of of chest pain, peaks ~24 h and returns to baseline values at
746 MYTHILI and MALATHI: DIAGNOSTIC MARKERS OF ACUTE MYOCARDIAL INFARCTION

48‑72 h. The one advantage of CK‑MB over the troponins is 6. Salivary biomarkers associated with myocardial necrosis
the early clearance that helps in the detection of reinfarction.
Thus, the serum level of troponin along with the level of the Saliva offers an easy, simple and non‑invasive screening
CK‑MB fraction is assessed for the diagnosis of myocardial procedure for various systemic diseases. Whole saliva
infarction (49). contains constituents from serum, gingival crevicular fluid
and oral mucosal transudate making it a valuable diagnostic
Heart fatty acid‑binding protein (H‑FABP). H‑FABP is a tool. Salivary markers of acute myocardial infarction include
small cytosolic low molecular weight protein found in the MYO, CRP, MPO, CK‑MB and cTn, which when used in
cardiac tissues that are responsible for the transport of fatty combination with an ECG, shows a positive correlation in
acids from the plasma membrane to sites of β ‑oxidation in patients when compared to healthy controls (63). The salivary
mitochondria and peroxisomes, and to the endoplasmic MYO levels were found to be significantly higher within 48 h
reticulum for lipid synthesis (50). It is chiefly present in the of onset of chest pain in AMI patients and correlated positively
myocardium and, to a lesser extent, in the brain, kidney and with its serum concentration (64). In a study performed by
skeletal muscle. H‑FABP is released extremely early into Miller et al (65), the salivary concentrations of CRP, TNF‑α,
the serum following myocyte rupture (51). An increased matrix metalloproteinase‑9 (MMP‑9) and MPO were signifi-
concentration of H‑FABP appears as early as 30 min after cantly higher in patients with AMI and correlated positively
myocardial injury, peaks at 6‑8 h and returns to baseline with the serum concentrations. Studies reveal that salivary
levels at ~24 h (52). Additionally, H‑FABP can be used as a soluble intracellular adhesion molecule 1 is significantly
predictive biomarker of mortality following acute coronary elevated in AMI patients; however, levels of salivary sCD40L
syndrome (ACS) (53). were significantly lowered in AMI patients. In a study
performed by Foley et al (66), salivary levels of troponin I
B‑type natriuretic peptide (BNP). BNP is a neurohormone and CRP correlated with the serum levels in patients with
released from the cardiac cells. Studies have shown that myocardial injury. Additionally, levels of MMP‑9 and MPO in
elevated BNP is a predictive marker of death and heart failure. saliva correlated with its serum levels (67). Thus, these studies
However, they are not useful for the diagnosis of AMI (54). suggest that saliva can be used as an alternative to serum in the
diagnosis of myocardial infarction (68).
Ischemia‑modified albumin (IMA). Under ischemic conditions,
the level of IMA in the blood is significantly increased, thus 7. Conclusion
aiding in the diagnosis of acute ischemia prior to the onset of
myocardial necrosis (55). The measurement of IMA is enabled The analysis of cardiac biomarkers has become the frontline
by the binding of the cobalt to the damaged N‑terminus of the diagnostic tools for AMI, and has greatly enabled the clini-
albumin. The increase in IMA levels occurs immediately after cians in the rapid diagnosis and prompt treatment planning,
the onset of ischemia and returns to baseline values within thereby reducing the mortality rate to a great extent. However,
6‑12 h, thus enabling early identification of ischemia (56). the future of cardiac biomarkers will follow the analysis of a
panel of markers for the diagnosis and prognosis of myocar-
Growth‑differentiation factor‑15 (GDF‑15). GDF‑15 is a dial infarction.
member of the transforming growth factor‑β family of cyto-
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