Emerging Biomarkers of Acute Myocardial
Infarction, An Overview of the Newest
MicroRNAs
Venus Shahabi Raberi1, Elnaz Javanshir2, Mohsen Abbasnezhad2, Sina Mashayekhi2, Amirreza Abbasnezhad3, Ma-
sumeh Ahmadzadeh2, Akram Shariati4
1 Seyed-Al-Shohada Cardiology Hospital, Urmia University of Medical Sciences, Urmia, Iran
2 Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
3 Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
4 Department of Cardiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
GMJ.2023;12:e2909
www.gmj.ir
Correspondence to:
Akram Shariati, Department of Cardiology, School of
Medicine, Urmia University of Medical Sciences, Ur-
mia, Iran.
Telephone Number: +989144451534
Email Address: Shariatiakram2016@gmail.com
Received 2023-01-08
Revised 2023-01-18
Accepted 2023-01-21
Abstract
Globally, acute myocardial infarction (AMI) is the leading cause of death. Early and precise di-
agnosis is essential for medical care to enhance prognoses and reduce mortality. The diagnosis of
AMI relies primarily on conventional circulating biomarkers. However, these markers have many
drawbacks. Non-coding RNAs (ncRNAs) form a signicant fraction of the transcriptome and have
been shown to be essential for many biological processes, including the pathogenesis of the disease.
ncRNAs can be utilized as biomarkers due to their important role in the disease’s development.
The current manuscript describes recent progress on the role of ncRNAs as new AMI biomarkers.
[GMJ.2023;12:e2909] DOI:10.31661/gmj.v12i0.2909
Keywords: Myocardial; Biomarker; LcnRNA
Introduction
Myocardial Infarction (MI) and Its Markers
It is now widely recognized that cardiovas-
cular diseases (CVD) and circulatory dis-
eases are the main causes of mortality world-
wide [1, 2]. Cerebrovascular and ischemic
heart disease (IHD) accounted for most of
these CVD deaths [3, 4]. One of the primary
causes of hospital admission and mortality is
acute myocardial infarction (AMI).
It’s critical to correctly determine whether a
person with severe chest pain is undergoing an
AMI [5]. Suitable markers of AMI should rst
be quantitatively modied to be used to pre-
dict AMI and monitor its pathogenic process-
es [6]. Cardiac troponins (cTns) are the most
frequently used markers in clinical practice
for AMI diagnosis. The preferred biomark-
ers have been cTns T and I (cTnT and cTnI)
due to their sensitivity and cardiac selectivity.
However, acute myocardial infarction is only
one of the conditions that can result in elevat-
ed cardiac troponin levels. Therefore, nding
specic and sensitive biomarkers for incredi-
bly early AMI diagnosis is crucial [7, 8].
Non-coding RNAs
Non-coding RNAs (ncRNAs) are transcribed
from the genome but do not encode proteins.
ncRNAs have important activities including
regulation of gene expression [9]. ncRNAs,
including long ncRNAs (lncRNAs), recently
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Shahabi Raberi V, et al. Non-coding RNAs as MI Biomarkers
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identied circular RNAs (circRNAs), small
interfering RNAs (siRNAs), and microRNAs
(miRNAs), have been demonstrated to have
diagnostic and regulatory eects in cardio-
vascular disorders [10]. MicroRNAs are sin-
gle-stranded ncRNAs with 21–23 nucleotides
that regulate the post-transcriptional process
and RNA silencing [11]. NcRNA molecules
consisting of 200 or more nucleotides belong
to the lncRNAs group. Through interactions
with proteins and nucleic acids, lncRNAs con-
trol the expression of genes during post-trans-
lational, translational, RNA processing, and
transcriptional stages. They control lifespan
pathways by regulating senescence, apop-
tosis, dierentiation, and cell proliferation
[12]. Similar to miRNAs, siRNAs are dou-
ble-stranded ncRNAs that control genes. They
are typically 20–24 (commonly 21) base pairs
in length. This genome regulation occurs at
critical levels of genome function, including
translation, transcription, chromosome seg-
regation, RNA stability, chromatin structure,
and RNA processing [13]. CircRNAs have a
covalent loop structure and belong to a fami-
ly of endogenous RNAs. Circular RNAs are
less common than other types of RNA, but
are very stable due to their circular structure.
circRNAs also exhibit a high level of tissue
specicity [14].
NcRNAs are expressed in many human tis-
sues, and their expression is particularly tis-
sue-specic in certain circumstances. Due to
their unique characteristics, they can be em-
ployed as potential biomarkers for the diagno-
sis of various pathologic diseases, including
cancer, myocardial infarction (MI), and other
cardiovascular problems [10].
None-coding RNAs and Cardiovascular Dis-
orders
NcRNAs perform a variety of cell- or tis-
sue-specic biological and pathological func-
tions. Additionally, ncRNAs can be used as
biomarkers for the detection of cardiovascular
disorders due to the presence of ncRNAs in
circulatory systems [15]. Researchers have
suggested that ncRNAs, especially lncRNAs
and microRNAs, play an important role in
regulating cardiovascular aging and heart
development. MicroRNAs have received the
most attention among them due to their role
in MI and cardiovascular disorders. Addition-
ally, many lncRNAs were found to be regu-
lated during AMI in cardiac tissue [16]. In the
current manuscript, we discussed the most re-
cent advances regarding ncRNAs’ role as new
AMI biomarkers.
Search Strategy
Data were collected using the keywords “mi-
croRNA” or “miR” or “myocardial infarction”
or “biomarker” or “LncRNA” or “ncRNAs”
or “Heart” or “MI” or “ncRNA” in the Web of
Science, Scopus, and PubMed databases. The
title and abstract of all articles were reviewed,
and papers related to the objective of our in-
vestigation were selected.
MiR-499
The heart contains over 200 miRNAs, and
miR-499 is one of the most extensively re-
searched. Exosomes from infarcted mouse
hearts were found to release miR-499 into
circulation, and their circulating levels were
all elevated [17]. MiR-499 level can be uti-
lized to diagnose AMI earlier than traditional
markers. While creatine phosphokinase-MB
(CK-MB) and cTnI are detectable 2 hours af-
ter the onset of chest pain, miR-499 is present
in the plasma only 1 hour after the AMI and
continues to rise 9 hours later [18]. Accord-
ing to previous studies, the concentration of
circulating miR-499 in a cohort of healthy
controls was hardly detectable and extremely
close to the assay’s detection limit. However,
there was an increase in troponin-negative pa-
tients in certain patients with non-AMI heart
disease including angina pectoris and myocar-
ditis. These ndings imply that miR-499 can
be used as a possible biomarker to identify
early-stage myocarditis and angina pectoris
in other diseases [18, 19]. In another study,
miR-499 showed an increase in patients with
acute non-ST-elevation myocardial infarction
(NSTEMI) compared to controls in 92 elderly
people with NSTEMI, 81 non-AMI patients
with chronic heart failure (CHF), and 99 con-
trols. Findings demonstrated that circulat-
ing miR-499 is a reliable biomarker of acute
NSTEMI, with a diagnostic accuracy greater
than cTnT in elderly patients [20].
Before using miR-499 as a reliable biomark-
er of AMI diagnosis, several issues including
Non-coding RNAs as MI Biomarkers Shahabi Raberi V, et al.
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3
the inability to quickly identify miR-499 must
be resolved. However, miR-499 has distinct
advantages over cTnT and other tradition-
al markers, such as the fact that it has a high
level of in vitro stability and is unaected by
renal function. Additionally, giant troponin,
troponin antibodies, and other specimen vari-
ables can interfere with currently used immu-
nological approaches to detect cTnT and CK-
MB. As a result, miR-499 remains a reliable
indicator of myocardial damage [18].
MiR-1
MiR-1 is a highly expressed conserved miR-
NA in the heart and has important implica-
tions for cardiac tissue development. MiR-1
has been found to target the transcription
factor Heart, and Neural Crest Derivatives
Expressed 2 (HAND2), which promotes the
development of ventricular cardiomyocytes
[21]. Several studies have reported changes in
miR-1 during myocardial disorders. In a recent
study, the potential of using miR-1 as a substi-
tute for cardiac steatosis biomarkers was ex-
plored. Regardless of confounding variables,
circulating miR-1 levels were strongly asso-
ciated with myocardial steatosis. It has been
proposed that circulating miR-1 can predict
myocardial steatosis on its own. This result
highlights the signicance of circulating miR-
1 as asymptomatic diabetic cardiomyopathy
diagnostic tool [22].
Several other studies have reported the di-
agnostic value of miR-1 in MI. According to
research by Enrica Pinchi et al., a reduction
in the miR-1 level in blood samples from pa-
tients with AMI can be utilized as a biomark-
er to identify sudden cardiac death (SCD)
caused by AMI. Along with miR-499, the
miR-1 demonstrated signicant accuracy in
separating SCD from AMI. Overexpression of
miR-1 has been reported as a potential marker
for AMI by downregulating the urothelial car-
cinoma-associated 1 (UCA1) [23].
UCA1
A lncRNA known as urothelial carcinoma-as-
sociated 1 (UCA1) may be useful as a MI di-
agnostic marker. UCA1 may be used as AMI
because it is only expressed in the spleen and
heart after birth [24]. In a study, the level of
UCA1 in the plasma of patients with AMI
and healthy controls was measured to veri-
fy this hypothesis. Because it is thought that
miR-1 controls the expression of UCA1, they
also checked the amount of miR-1. The UCA1
was dropped early but elevated after MI.
These results suggest that UCA1 may serve as
a possible new marker for AMI detection [25].
The miR-1 gene controls the amount of
UCA1. In bladder cancer cells, miR-1 was
found to have an Ago2-slicer-dependent eect
on decreasing UCA1 expression. The eec-
tor RNA-induced silencing complex (RISC),
which comprises an Argonaute protein (AGOs
1–4 in humans), mediates small RNA silenc-
ing. Plasma from rats or patients with AMI has
been reported to have signicantly increased
amounts of miR-1. The research also revealed
a negative correlation between the expression
of miR-1 and the UCA1. The results suggest
that miR-1/UCA1 axis in circulation may be a
more useful predictive and diagnostic marker
for AMI compared to miR-1 levels alone [26].
H19
LncRNA H19 (H19), located on chromosome
11p15.5 and encoded by the H19 gene, was
one of the rst discovered lncRNAs. After
transcription and polyadenylation, it is trans-
ported from the nucleus to the cytoplasm. This
LncRNA is typically expressed in fetal tis-
sues, and after delivery, its expression is sig-
nicantly diminished. Recently, it was discov-
ered that H19 participates in several patholog-
ical processes, including brosis progression,
neurogenesis, angiogenesis, and inammato-
ry responses [27]. It is not surprising that the
alteration in LncRNA H19 expression occurrs
preferentially in heart tissue and is associated
with CVD [28, 29]. Additionally, cardiac cells
become leaky during cardiac muscle injury
and release their contents into the bloodstream
[30]. A signicant increase in circulating H19
transcript levels has been reported in patients
with AMI. There was also a direct association
between the plasma homocystine and relative
H19 expression. To dierentiate MI patients
from controls, the relative expression of H19
demonstrated 70% sensitivity and 94% spec-
icity. This study also found that the H19
level could be used as a marker for MI; how-
ever, more research is required to apply this
nding more broadly [31]. In a recent study,
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Shahabi Raberi V, et al. Non-coding RNAs as MI Biomarkers
the lncRNA H19 change was associated with
cardiovascular risk variables including cardi-
ac ejection fraction, lipoprotein A, high-den-
sity lipoprotein (HDL), and white blood cell
counts and negatively correlated with several
cardiovascular protective factors. There was
a strong correlation between lncRNA H19
and the cardiac biomarkers CK-MB, CK, and
cTnT. Consequently, increased expression of
H19 can be considered a potential AMI mark-
er [15].
MiR-133a
MiR-133 and miR-1 share the same chromo-
somal locations for transcription [32]. In par-
ticular, miR-133a has an important impact on
several malignancies, including hepatocellu-
lar carcinoma and breast cancer, as well as
heart development and dysfunction [33]. Fur-
thermore, miR-1 and miR-133a are essential
for promoting cardiogenesis, heart health, and
pathology. By controlling the cardiac action
potential, miR-133a and miR-1 also regulate
cardiac automaticity and conductance in the
heart [32]. High expression of miR-133 en-
hances cardiac function by increasing the
fractional shortening (FS) and left ventricular
ejection fraction (LVEF) [34].
According to a study by Liu Peng1 et al., miR-
133 levels were signicantly increased in pa-
tients with AMI compared to non-MI controls.
The miR-133 specicity and sensitivity were
91.2% and 81.1%, respectively [35].
In a study, patients with unstable angina pec-
toris or acute myocardial infarction have sig-
nicantly higher serum levels of miR-133a
than healthy individuals [36]. MiR-133a se-
rum levels had a strong correlation with all-
cause mortality in ACS patients [37]. Kimura
et al. showed that when cTnT and CPK se-
rum levels are normal, circulating levels of
miR-133a and miR-1 increased shortly after
AMI. The blood miR-133 level was more sen-
sitive to myocardial damage than the miR-1
level. In addition to traditional markers, miR-
133a may also provide prognostic informa-
tion, possibly much former [38, 36].
Other Important ncRNAs
Many ncRNAs have been shown to be asso-
ciated with MI. MiR-208a, miR-1, miR-133,
and miR-499 were the rst miRNAs discov-
ered as markers for MI patients [39]. Several
genes are dierentially expressed in patients
with AMI, including potassium voltage-gated
channel, KQT-like subfamily, member one
opposite strand/antisense transcript 1 (KCN-
Q1OT1), metastasis-associated lung adeno-
carcinoma transcript 1 (MALAT1), cyclin-de-
pendent kinase inhibitor 2B antisense RNA
1 (ANRIL), and hypoxia-inducible factor 1A
antisense RNA 2 (aHIF). More importantly,
ST-elevation myocardial infarction (STEMI)
from NSTEMI could be distinguished by
KCNQ1OT1, ANRIL, and MALAT1 [40].
Two miRNAs essential for vascular biolo-
gy, miR-126, and miR-155, were reduced in
serum from patients after o-pump coronary
artery bypass graft, pointing to a possible con-
trolling role for miR-126 and miR-155 in car-
diac surgery [41]. Following a prior study that
suggested serum miR-191 and serum miR-26a
were reduced in patients with AMI, a subse-
quent microarray-based investigation also
found the same results [42, 43]. Microarray
assays revealed that miR-320b and miR-125b
levels were lower in the patients with AMI,
and this decrease was subsequently conrmed
in a cohort of 178 Chinese patients with AMI
[44]. Some studies have discovered that heart
failure, STEMI, and NSTEMI patients’ plas-
ma miR-145 levels were decreased [45]. Stud-
ies showed that miRNA-208b, miRNA-34a,
miRNA-328, and miRNA-134 were also linked
to heart failure development and increased
risk of mortality after AMI [46].
Limitations
The application of ncRNA screening tech-
niques in clinical practice is currently limited
by cost and time requirements. Material se-
lection, sample separation, detection, process-
ing methods, and normalization strategies are
among the operational criteria yet to be estab-
lished. Particularly, ncRNA levels can range
signicantly between various material selec-
tions and various isolation techniques. Anoth-
er restriction is the ncRNA’s lack of specic-
ity as biomarkers. Since the majority of the
sample sizes considered in these studies were
small, long-term and follow-up investigations
are still required for further conrmation of
the clinical application of ncRNAs for AMI
diagnosis [47].
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5
Non-coding RNAs as MI Biomarkers Shahabi Raberi V, et al.
Conclusion
In conclusion, ncRNAs, particularly miRNAs,
showed many advantages as biomarkers of
AMI. Such biomarkers are arguably required
to aid healthcare decisions in the diagnosis
and prognosis of AMI and facilitate the transi-
tion from conventional diagnostic markers to
new methods. However, there are still many
challenges to overcome before these ncRNAs
can be used therapeutically.
Conict of Interest
None.
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