Molecular Biotechnology (2022) 64:758–772

https://doi.org/10.1007/s12033-022-00449-5

REVIEW

Research Progress of LncRNAs in Atrial Fibrillation

Wenhui Wang1 · Bei Tian2 · Zhongping Ning2 · Xinming Li3 

Received: 13 September 2021 / Accepted: 2 January 2022 / Published online: 2 February 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Abstract
Atrial fibrillation (AF) is one of the most common arrhythmias in adults, with high morbidity and increased mortality risk. In
recent years, the clinical diagnosis, treatment, and mechanistic research of AF have increased exponentially, and regulation
based on the potential molecular mechanism of AF is a research hotspot. Long noncoding RNAs (LncRNAs), usually refer to
noncoding RNA transcripts greater than 200 nucleotides in length, have been shown to play a role in cardiovascular diseases
such as coronary artery disease, heart failure, and myocardial fibrosis through various regulatory methods. An increasing
number of researchers have begun to pay attention to the identification and function of LncRNAs in AF. This article reviews
changes in the expression of related LncRNAs detected in AF and describes the LncRNAs that play a regulatory role in AF-
related processes, to explore the potential of LncRNAs as new biomarkers and therapeutic targets in AF.

Keywords  Atrial fibrillation · Long noncoding RNA · Differential expression · Biomarker · Therapeutic target

Introduction stroke, dementia, and congestive heart failure (CHF), lead-

Atrial fibrillation (AF) is one of the most common persistent
arrhythmias in adults. Among the Framingham Heart Study
population, 37% of people have a lifetime risk of develop-
ing AF for age 55, and men have a higher risk of AF than
women [1]. The mortality risk in patients with AF is 1.5–1.9
times that of those without AF [2], and AF can cause sig-
nificant morbidity and mortality in patients [3]. The global
prevalence of AF was 37.574 billion cases (0.51% of the
global population) by 2017, has increased by 33% in the past
20 years and will continue to increase in the next 30 years.
The global burden of AF in 2050 is expected to increase by
more than 60% [4]. The prevalence and incidence of AF
increase with age, and AF is related to a higher incidence of
* Xinming Li
xinming06@163.com
1
Tongji University School of Medicine, Shanghai 200082,
China
2
Department of Cardiology, Shanghai University of Medicine
& Health Sciences Affiliated Zhoupu Hospital, No. 1500 of
Zhouyuan Road, Pudong New District, Shanghai 201318,
China
3
Shanghai Pudong New Area Center for Disease Control
and Prevention, Shanghai 200136, China
ing to serious social and economic burdens [4, 5].
The current management of AF focuses on symptom
reduction and complication prevention [6]. Heart rate con-
trol and rhythm control are used to improve symptoms, and
anticoagulation is used to reduce the risk of stroke. However,
the above treatments are often not sufficiently efficacious and
are accompanied by potential adverse reactions [7], failing
to meet the therapeutic needs of AF patients.
Noncoding RNA (ncRNA) has become a hot topic in car-
diovascular system diseases in recent years. It participates in
the pathophysiological processes of myocardial infarction,
atherosclerosis, thrombosis, fibrosis, and inflammation and
is a new risk marker for cardiovascular disease [8]. Long
noncoding RNAs (LncRNAs), a group of ncRNAs with
a length greater than 200 nucleotides, have been found to
regulate a variety of diseases, including cancer, Alzheimer’s
disease, and cardiovascular disease [9]. However, fewer
studies have been found on LncRNA in AF than in other
diseases (such as heart failure and atherosclerosis).
We hypothesized that LncRNAs play a role in AF and,
therefore, conducted a comprehensive analysis of the current
experimental evidence supporting the involvement of LncR-
NAs in AF with a focus on clinical significance. Background
information related to AF and LncRNAs is first presented,
and the expression of LncRNAs in AF and experimental
evidence supporting LncRNAs as regulatory factors in AF

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Molecular Biotechnology (2022) 64:758–772 759
are summarized. The goal of this work was to provide a
comprehensive overview of the research of lncRNA in AF to
determine the feasibility of LncRNA as potential biomarkers
and therapeutic targets in AF.
Pathophysiology of Atrial Fibrillation
The electrocardiogram has diagnostic value for AF and
reveals the disappearance of the P wave, which is replaced
by an irregular baseline fibrillation f wave, and demonstrates
an extremely irregular QRS complex [6]. AF can be divided
into three groups based on duration: paroxysmal AF (conver-
sion to sinus rhythm within 7 days), persistent AF (lasting
more than 7 days and needing drugs or electric shock to
convert to sinus rhythm), and permanent AF (unsuccess-
ful conversion to sinus rhythm or relapse within 24 h after
conversion). The pathogenesis of AF involves many factors,
including focal ectopic electrical activity, reentry mecha-
nisms, inflammatory mediators, abnormal C ­ a2+ ion chan-
nels, autonomic nervous system involvement, etc. [10]. The
specific mechanisms involved vary depending on the type
of AF.
The general hypothesis for the occurrence of AF is that
a rapid electric trigger forms reentrant propagation in the
fragile atrial matrix [11]. Haissaguerre et al. [12] first dis-
covered focal ectopic discharges in muscle sleeve cells along
the pulmonary vein (PV) of patients with paroxysmal AF;
the ablation of these ectopic lesions reduced the burden of
AF, demonstrating their role in the occurrence of AF. After
AF is triggered, a relatively fragile atrial matrix environ-
ment is formed through electrical remodeling and structural
remodeling of the atrium, and the stable reentry mechanism
promotes the persistence of AF [11]. For patients with long-
term persistent AF or permanent AF, atrial remodeling is
more extensive and serious, and the presence or absence of
an electric trigger is no longer a decisive factor [11, 13]. A
brief summary of the pathophysiology of AF is shown in
Fig. 1.
The prominent feature in AF-related electrical remode-
ling is the shortening of the atrial effective refractory period
(AERP), which is mainly due to the shortening of the action
potential duration (APD) [14], caused by the enhancement of
the inward ­K+ current (IK1) or the acetylcholine-dependent
­K+ current (IKACh) or the decrease in the inward L-type ­Ca2+
current (ICaL) [15]. The development of cardiac structural
remodeling, characterized by atrial enlargement and fibrosis,
is slower than electrical remodeling [15]. Atrial enlargement
helps maintain the complex mechanism of reentrant arrhyth-
mia, and atrial fibrosis contributes to the atrial matrix of
AF [16]. However, the mechanism of atrial fibrosis is not
fully understood. Multiple studies have shown that angio-
tensin-II (Ang-II), transforming growth factor β1 (TGF-β1),
platelet-derived growth factor (PDGF), and connective tis-
sue growth factor (CTGF) are effective profibrotic factors
[5]. Inflammation and noncoding RNAs are also involved
in the process of fibrosis [10]. Although the pathogenesis of
AF is controversial and may vary among individuals, elec-
trophysiological abnormalities and atrial structural changes
(including fibrosis) are the bases for the generation and
maintenance of AF [11].
Biology of LncRNAs
LncRNAs, noncoding RNAs larger than 200 nucleotides,
often regulate a variety of diseases, including cancer, Alz-
heimer's disease, and cardiovascular disease [9]. LncRNAs
can be divided into three types based on their positions in
the genome: intergenic LncRNAs (lincRNAs), antisense
LncRNAs, and intron region LncRNAs [17]. On the LNCi-
pedia website (an authoritative summary website of LncR-
NAs), 127,802 transcripts and 56,946 genes are presented.
Due to the complexity of the LncRNA population, the bio-
logical characteristics and mechanisms of most LncRNAs
are uncertain. Another question that remains unsolved is
whether many LncRNAs have biological functions [17]. It
will take many years to elucidate these questions, especially
because many LncRNAs have multiple forms of alternative
splicing. In an effort to accelerate the progress, researchers
are using bioinformatics strategies, such as high-throughput
sequencing, screening methods, RNA interference (such as
siRNA/shRNA), and target gene prediction, to study the
function and mechanism of candidate LncRNAs [18, 19].
The sequence of LncRNAs is less conserved in mam-
malian LncRNAs, which is similar to that of the intron
region of mRNA, but it shows strong conservation in func-
tion [20, 21]. The mechanism of LncRNAs is different from
that of microRNAs (miRNAs), which directly bind to target
mRNAs to reduce their translation and/or stability [22]. The
molecular mechanisms of LncRNA are mainly described as
(i) a bait for localizing transcription factors; (ii) a regulatory
signal for transcription; (iii) a scaffold for bridging different
proteins; (iv) a sponge for microRNA; (v) a direction for the
protein to reach its target; and (vi) possibly possessing short
open reading frames (ORFs) that can be translated, allowing
it to increase the function of protein [9].
Expression of LncRNA in AF Patients
There are two types of evidence for the pathophysiological
role of LncRNAs in AF. First, abnormal LncRNA expression
is often observed in the heart tissue and blood of AF patients
and animal models. The changes in heart tissue indicate a
potential role in AF-related cardiac remodeling, while the
13

760
changes in blood suggest that LncRNAs may have diagnostic
and prognostic value. Second, experiments have confirmed
that LncRNAs have a direct causal relationship with AF by
manipulating LncRNA expression, suggesting the therapeu-
tic potential of LncRNAs in AF.
The Expression of LncRNAs in the Blood of AF
Patients
Researchers [23–30] collected blood samples from patients
with AF and control groups with sinus rhythm and per-
formed RNA sequencing, microarray, and/or polymerase
chain reaction (PCR) methods to screen out the differen-
tially expressed LncRNAs (DElncRNAs) in AF patients. The
results showed an abundant expression profile change. Some
studies further explored the clinical and practical values of
DELncRNAs for AF patients through clinical follow-up. The
experimental designs and results of these studies are shown
in Table 1.
Qian et al. [31] recommended LncRNA GAS5 as a new
biomarker in atrial tissue for AF by constructing an AF-
related LncRNA-mRNA network (AFLMN) via microar-
ray analysis, which shows powerful diagnostic ability for
AF. Functional module analysis shows that GAS5 is closely
related to 52 mRNAs and is enriched in many AF-related
pathways involved in inflammation, ion channels, and meta-
bolic regulation. Another study [32] also confirmed the sig-
nificant difference in the expression of GAS5 in the atrial
tissue of AF patients and emphasized its inhibitory effect
on proliferation. Shi et al. [23] tested the level of LncRNA
GAS5 in the blood of AF patients and found that its expres-
sion was significantly downregulated. This change occurs
before the left atrial volume enlarges and is closely related
to the progression of AF, indicating the potential role of
GAS5 as an early biomarker for AF. In the group of patients
with persistent AF without a history of hypertension, blood
GAS5 was further downregulated, indicating that GAS5 can
be used for the prognosis of AF progression. Of the 70 AF
patients who underwent radiofrequency catheter ablation
(RFCA), 22 (31.4%) experienced recurrence at the 1-year
follow-up. K-M analysis (log-rank test, P = 0.031) and mul-
tivariate Cox analysis (HR = 0.127, 95% CI 0.026–0.616;
P = 0.01) showed that GAS5 may predict the recurrence of
atrial arrhythmia after RFCA.
Wang et al. [27] studied the blood LINC00472 levels in
125 AF patients and 168 control patients and found that the
expression was decreased in AF patients, while the DNA
methylation level of LINC00472 was increased. Yao et al.
[25] evaluated the differential expression of LncRNA MIAT
in the white blood cells of 35 AF patients and 30 healthy
controls and found that the expression of MIAT was sig-
nificantly upregulated in AF patients. Ruan et al. [26] and
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Molecular Biotechnology (2022) 64:758–772
Xu et al. [30] also found some DELncRNAs in smaller AF
populations.
Su et al. [28] found that LncRNA RP11-519G16.3 was
upregulated in 31 paroxysmal AF patients compared to
controls, and AK000451 was downregulated. This sug-
gests that these two LncRNAs may contribute to predict-
ing the occurrence of paroxysmal AF. Yu et al. [29] found
49 upregulated and 45 downregulated LncRNAs in 6 per-
sistent AF patients and 6 controls. The study shows that
higher levels of TCONS_00024161, TCONS_00194688,
and TCONS_00076385 may be useful to predict persistent
AF. A bioinformatics analysis was conducted on the dif-
ferentially expressed mRNAs and LncRNAs and identified
enriched signaling pathways, such as the TNF signaling
pathway, NF-κB signaling pathway, Toll-like receptor path-
way, and NOD-like receptor pathway. These pathways are
related to apoptosis, immunity, inflammation, and oxidative
stress, suggesting that these signal transduction pathways
may play an important role in the initiation and development
of AF [29].
In prognostic studies of AF patients, Zeng et al. [24]
followed patients for 2–4 years and found that AF patients
without ischemic stroke had lower serum LncRNA ANRIL
levels. The sensitivity and specificity of LncRNA ANRIL
for recognizing ischemic stroke with AF were 76.6% and
81.4%, respectively.
Overall, these results show that circulating LncRNA
changes in AF patients, but inconsistent results indicate that
LncRNAs are not currently strong biomarkers for AF. Part of
the problem may be the heterogeneity of the AF population,
and more specific subgroups (such as isolated AF patients,
AF patients with congestive HF, or AF patients only with
hypertension) may need to be studied. Another problem is
that the blood samples in these studies were different, and
the presence or absence blood cells will cause great differ-
ences in results. In the future, LncRNAs could be identified
as reliable biomarkers in AF. These results can be useful for
risk stratification, individualized treatment based on patho-
physiology, evaluation of AF progression, and assessment
of response to treatment.
The Expression of LncRNAs in Heart Tissue of AF
Patients
Currently, RNA sequencing and microarray analysis, as out-
standing disease mining technologies, have been applied to
identify DELncRNAs in AF patients and healthy people.
Researchers [32–43] collected heart tissue samples from
patients with AF and control groups with sinus rhythm and
performed the same methods as above to screen out the
DElncRNAs in heart tissue of AF patients. The heart tis-
sue samples included atrial tissue, epicardial adipose tissue,
and pericardial fluid of AF patients. As expected, the initial
 Table 1  The expression of LncRNAs in the blood of AF patients
Studies Patients
Shi et al. [23] (screening) AF (n = 20) and control (n = 20);
(validation) AF (n = 85) and control (n = 43);
1-year follow-up of patients with AF underwent radio
frequency catheter ablation (RFCA) (n = 70)
Zeng and Jin [24] 2–4 years follow-up of patients with AF: AF with
ischemic stroke (n = 132) and AF without ischemic
stroke (n = 254)
Yao et al. [25] AF (n = 35) and control (n = 30)
Ruan et al. [26] AF (n = 20) and control (n = 20)
Wang et al. [27] AF (n = 125) and control (n = 168)
Su et al. [28] Paroxysmal AF (n = 3) and control (n = 3);
(validation) paroxysmal AF (n = 31) and control (n = 31)
13
Samples Methods Results
Plasma qRT-PCR (screening): Reduced level of blood LncRNA GAS5
was observed in patients with AF. Other three candi-
dates (LncRNA NEAT1, UCA1 and TUG1) had not
been observed significant difference
(validation): Reduced level of circulating LncRNA GAS5
was observed in patients with AF
1-year follow-up of patients with AF underwent RFCA:
K-M analysis showed that the low GAS5 group had a
higher risk of recurrence after RFCA. Multivariate anal-
ysis showed that GAS5 and left ventricular end diastolic
Molecular Biotechnology (2022) 64:758–772
diameter were independent predictors of recurrence
Serum qRT-PCR Reduced level of blood LncRNA ANRIL was observed in
AF patients without ischemic stroke compared with the
patients that have AF and ischemic stroke
Peripheral leukocyte qRT-PCR LncRNA MIAT was upregulated in peripheral leukocytes
of AF patients
Peripheral monocyte Microarray analysis, Upregulated: HNRNPU-AS1*, LINC00926,
qRT-PCR LINC00861*, AC005786.7, (AC005786.7),
XLOC_099061
Downregulated: GS1-115G20.1, LINC00877,
ENSG00000239794, LINC00476, CTD-2616J11.3,
CTD-2616J11.2*, RP11-443B7.3*, CTD-2006K23.1,
(CTD-2616J11.14), LINC00936, RP11-810P12.7,
XLOC_060065, XLOC_109634
Plasma qRT-PCR The expression level of LINC00472 was decreased in
patients with AF, while the DNA methylation level of
LINC00472 was increased
Peripheral leukocyte Microarray analysis, qRT-PCR Upregulated: HBBP1, RP11-119D9.1, RP11-519G16.3*,
LOC100130275, XLOC_006934, (DQ583499),
AC139099.4, XLOC_005160, RPL29P30, RP11-
40A13.1, AC073135.3, RP5-981L23.1, LOC283761,
RP11-64I17.1, XLOC_002560, RP11-328K4.1,
BC040700, AC131097.3, RP11-16,217.1
Downregulated: (RP11-605F22.2), XLOC_007697,
RP11-1060J15.4, PI4KAP2, AK000451*, CTD-
2574D22.4, TTTY6, RP1-251I12.1, XLOC_005775,
XLOC_010596, AY927499, chr12:53,675,775–
53,689,275, BC160930, RNF157-AS1, XLOC_007777,
LOC375196, PRSS21
Validation: RP11-519G16.3 and AK000451 may be help-
ful in predicting paroxysmal AF
761


Table 1  (continued)
762

Studies Patients Samples Methods Results

13
Yu et al. [29] Persistent AF (n = 6) and control (n = 6) Peripheral lymphocyte RNA sequencing, qRT-PCR Upregulated: TCONS_00039400, TCONS_00008957,
TCONS_00024161*, TCONS_00194688*,
TCONS_00024160, TCONS_00045457,
TCONS_00164108, TCONS_00064672,
TCONS_00076385*, TCONS_00128364 and etc
Downregulated: TCONS_00202959, TCONS_00065233,
TCONS_00049962, TCONS_00134390,
TCONS_00095749, TCONS_00147447,
TCONS_00028780, TCONS_00065235,
TCONS_00010002, TCONS_00132941 and etc
Xu et al. [30] AF (n = 3) and control (n = 3); Whole blood Microarray analysis, Upregulated: NONHSAT098586, NONHSAG007503*,
(validation) AF (n = 20) and control (n = 10) qRT-PCR NONHSAT076398, NONHSAT053927,
NONHSAT098582, NONHSAT017667,
NONHSAT090718, NONHSAT098591,
NONHSAT076870, NONHSAT076401,
NONHSAT055019
Downregulated: NONHSAT040387*, NONHSAT040421,
TCONS_l2_00030433, NONHSAT039492,
NONHSAG053956, NONHSAT136136,
XR_245045.1, NONHSAT141981, NONHSAT142052,
NONHSAT040390, ENST00000460164,
ENST00000456563, NONHSAT040540,
NONHSAT136135

AF atrial fibrillation, qRT-PCR quantitative real-time polymerase chain reaction

*LncRNA indicates dysregulated LncRNA that has statistically significant changes on subsequent qRT-PCR measurement. Bracketed LncRNA antisense
Molecular Biotechnology (2022) 64:758–772
Molecular Biotechnology (2022) 64:758–772 763
research data indicate that the number of DELncRNAs in the
heart tissue of AF patients is significantly greater than that in
blood. The differential expression of LncRNAs in the heart
tissues of AF patients (see Table 2 for details) suggests that
the DELncRNAs may be related to AF.
Many researchers have conducted differential expres-
sion studies in the atria, epicardial adipose tissue, and
pericardial fluid of AF patients and have reported exciting
results. LncRNA GAS5 was also found to be downregu-
lated in the atrial tissue of AF patients [32], making it an
LncRNA that has been described in both the circulation and
heart tissues of AF patients. At the same time, NEAT1 was
found to be upregulated in the right atrial appendage tis-
sue of AF patients [35], but no significant difference was
observed in blood samples [23], suggesting that there is dif-
ferential expression of LncRNA in tissues and blood in AF
patients. The details of different studies warrant attention.
LINC00636 was found to be downregulated in the human
pericardial fluid of AF patients [33], but no studies have
identified it in other tissues of AF patients.
Ke et al. [38] conducted a sequencing screen on the paired
left and right atrial appendages of 5 AF patients and 5 non-
AF patients and analyzed several related LncRNAs. NPPA-
AS1 may participate in the pathogenesis of AF by regulating
muscle contraction. RP11-99E15.2 interacts with the protein
ITGB3 and participates in ECM-receptor interaction and the
intracellular activation of TGF-β signal transduction. The
combination of RP3-523K23.2 and the protein HSF2 may
enhance the transcriptional activity of HSF2, thereby reshap-
ing ion channels by regulating the transcription of HSF2
target genes.
Tissue-specific gene expression programs are carefully
controlled during heart development [44]. Yeh et al. [45]
reported that there are 391 differentially expressed genes
between left atrium (LA)-PV and left atrial appendage
(LAA) in patients with persistent AF, which are related to
arrhythmia, cell death, inflammation and hypertrophy. Chen
et al. [42] further found 94 DELncRNAs between LA-PV
and LAA in AF patients by microarray analysis. Among
these LncRNAs, AK055347 was selected for further verifi-
cation in H9C2 cardiomyocytes. LncRNAs may deregulate
mitochondrial energy production by regulating Cyp450, ATP
synthase, and MSS51, thereby promoting the pathogenesis
of AF. Knockdown of AK055347 significantly inhibited the
viability of H9C2 cardiomyocytes. Therefore, AK055347
upregulates and regulates mitochondrial energy production
in cardiomyocytes in AF patients. It is well known that the
LA-PV area is an important area where electrophysiological
abnormalities of AF originate. Electrical triggering remains
an important initiating factor for patients who have not yet
reached the permanent AF stage [11, 13]. This means that
intervention of the origin of electrophysiological abnormali-
ties can greatly reduce the electrical load of AF and improve
the electrical and structural remodeling of AF [46]. Further
exploration of gene expression and regulatory mechanisms
in the heart will help reveal new treatments for AF. In the
next section, we summarize the LncRNAs that are kown to
play regulatory roles in AF.
Mechanisms of LncRNAs in AF
To date, LncRNAs have been used as new biomarkers in
many areas, such as tumors, neurological diseases, and
cardiovascular diseases (CVDs) [47]. Various studies have
shown that the dysregulation of LncRNA expression is rel-
evant to AF. Some LncRNAs and mRNAs share the same
miRNA. Therefore, LncRNAs act as "sponges" of miRNAs
and can regulate mRNA transcription [48], which suggests
that LncRNAs may play a role in signal transduction in the
pathogenesis of AF. The AF-associated LncRNAs that act
as "sponges" of miRNAs are shown in Fig. 2.
The common experimental design to explore the mecha-
nism of LncRNAs in AF is to select a target LncRNA that
was differentially expressed in the AF patient or AF animal
model and then to observe the effect by inhibiting or upregu-
lating the expression of the LncRNA in an animal model
(in vivo) or in a cell model (in vitro). Electrical remodeling
and structural remodeling are commonly observed. Even the
relatively rare LncRNAs that can affect autonomic nerve
remodeling are ultimately involved in atrial electrical remod-
eling by affecting AERP [49].
As mentioned above, the increase in IK1 and the decrease
in ICaL are the two most significant changes in ionic channels
in AF-associated electrical remodeling. Table 3 shows the
LncRNAs related to AF electrical remodeling. Atrial fibro-
sis is a sign of AF structural remodeling. Table 4 shows the
LncRNAs related to the atrial structural remodeling in AF.
One study [50] found that TCONS_00075467 was down-
regulated in the AF rabbit model and could sponge miR-
328 as an endogenous competitive RNA (ceRNA). Over-
expression of miR-328 increased susceptibility to AF [51]
by reducing the voltage-dependent L-type calcium channel
current (ICaL), reducing the expression of the L-type cal-
cium channel α subunit and β subunit, and shortening APD.
This shows that downregulation of TCONS_00075467 has
arrhythmogenic effects.
The LncRNA KCNQ1OT1 was found to be upregulated
in the AF mouse model [52]. The mechanism of KCN-
Q1OT1 in AF is to regulate the expression of CACNA1C
by sponging miR-384 [52]. Silencing KCNQ1OT1 can pro-
long AERP, shorten interatrial conduction time (IACT),
and improve atrial electrical remodeling, which produces a
therapeutic effect on AF.
The expression of TCONS-00106987 was upreg-
ulated in the AF group [53]. Overexpression of
13

Table 2  The expression of LncRNAs in heart tissue of AF patients
Studies Patients
13
Liu et al. [33] AF (n = 12) and control (n = 12)
Sun et al. [34] Persistent AF (n = 3), paroxysmal AF (n = 3) and
control (n = 3)
Dai et al. [35] AF (n = 15) and control (n = 15)
Lu et al. [24] AF (n = 40) and control (n = 30)
Wu et al. [36] Patients with valvular heart disease and AF
(n = 7) and patients with valvular heart disease
but no AF (n = 7);
(validation): Patients with valvular heart disease
and AF (n = 35) and patients with valvular heart
disease but no AF (n = 35)
Zhao et al. [37] Non-valvular persistent AF (n = 6) and control
(n = 6)
Ke et al. [38] AF (n = 5) and control (n = 5)
Wu et al. [39] Patients with rheumatic valvular heart disease and LAA, RAA​
AF (n = 7) and patients with rheumatic valvular
heart disease but no AF (n = 10)
Wang et al. [40] AF (n = 34) and control (n = 20) Atrial tissue
764
Samples Methods Results
Exosomes in human pericardial fluid qRT-PCR Compared with control group, reduced level of
LINC00636 was observed in exosomes of AF
patients’ pericardial fluid
LAA RNA sequencing, qRT-PCR Compared with control group, reduced level of
RP11-442H21.2 was observed in LAA of parox-
ysmal AF patients, while reduced level of CTA-
134P22.2 was observed in persistent AF patients
RAA​ qRT-PCR LncRNA NEAT1 was upregulated in RAA of AF
patients
RAA​ qRT-PCR LncRNA GAS5 was downregulated in RAA of AF
patients
RAA​ RNA sequencing, qRT-PCR Upregulated: LOC105370977, LOC105371928,
LOC105376344, BANCR, SEC1P,
LOC105369818, LOC440568, LOC105377983,
VWFP1, LINC01479, etc
Downregulated: IMMTP1, LOC105374598,
LGALS17A, KRT88P, LOC105373923,
LOC105375472, LOC105372145,
LOC101928989, LOC105377227,
LOC105372685, etc
(validation): VDAC2P2* was found to have signifi-
cantly difference among three selected LncRNAs
EAT Microarray analysis, qRT-PCR Upregulated: TPRG1, PDLIM1*, AC015802.6,
ANKRD12, SUB1, NOS3, AHCTF1, LAMC1,
FAM208B, MRPL43, TTC3, MSANTD2,
MAP3K7CL, TBRG1, ENST00000489394*,
ENST00000557365*, etc
Downregulated: CTSB, FXYD6, LGALS3*, PI16,
GPX3, ICAM2, ANAPC5, WNT11, RASSF4,
GPAA1, LOXL3, DNM1, FCGR2C*, PRMT7,
NUBP1, ENST00000491449*, etc
LAA, RAA​ RNA sequencing The biological changes of AF between LAA and
RAA were similar
Microarray analysis LncRNA-n336928 was the most significantly
upregulated LncRNA in AF patients
qRT-PCR LncRNA NRON was downregulated in the atria of
AF patients
Molecular Biotechnology (2022) 64:758–772
 Table 2  (continued)
Studies Patients Samples Methods Results

Mei et al. [41] Patients with rheumatic valvular heart disease and RAA​
AF (n = 3) and patients with rheumatic valvular
heart disease but no AF (n = 3);
(validation): patients with rheumatic valvular
heart disease and AF (n = 15) and patients with
rheumatic valvular heart disease but no AF
(n = 15)
Chen et al. [42] Persistent AF (n = 16)
Microarray analysis, qRT-PCR Upregulated: uc010vaf.1, DQ596229,
TCONS_00023347, DQ589437, SNORD115-
22*, SNORD115-38, SNORD115-32,
SNORD115-42, CR608741, SNORD115-6, etc
Downregulated: uc001eiy.2, uc001ejh.1,
DQ590126, DQ579288, BC041938*,
DQ576791, DQ576039, uc010yty.1, DQ595787,
TCONS_00005387, etc
Pulmonary veins and the surround- Microarray analysis, qRT-PCR The top 10 LncRNAs with most significant differ-
ing left atrium area (LA-PV), LAA ential expression between LA-PV and LAA in AF
Molecular Biotechnology (2022) 64:758–772

patients: AK055347*, AK310040, AK026494,

BC010527, AK027294, AB007979, AK091573,
UC003qev.1, AK125186, U9981
Ruan et al. [43] Patients with rheumatic valvular heart disease and LAA Microarray analysis, qRT-PCR Upregulated: ENST00000575612*, uc001eqh.1*,
AF (n = 3) and patients with rheumatic valvular BC064139*, ENST00000425309*,(E
heart disease but no AF (n = 3) NST00000500112)
Downregulated: TCONS_00006371*, Z74666*,
X85157*,(X72487), NR_033661*

AF atrial fibrillation, qRT-PCR quantitative real-time polymerase chain reaction, LAA left atrial appendage, RAA​right atrial appendage, EAT epicardial adipose tissue
*LncRNA indicates dysregulated LncRNA that has statistically significant changes on subsequent qRT-PCR measurement. Bracketed LncRNA antisense

13
765


Table 3  LncRNA associated with electrical remodeling of AF

766

LncRNA Model Pathway Results

13
HOTAIR Chronic AF patients; miR-613/ Cx43 HOTAIR was downregulated in chronic AF patients,
HL-1 cardiomyocytes and the level of connexin 43 (Cx43) mRNA and
Cx43 protein were also downregulated
In vitro, HOTAIR positively regulated Cx43 by spong-
ing miR-613, and the decrease of Cx43 was related to
atrial electrical remodeling [55]
KCNQ1OT1 AF mouse model; miR-384/ CACNA1C In AF mouse model, four LncRNAs were signifi-
Ang-II-induced mouse cantly upregulated: KCNQ1OT1, LOC102723321,
KCNQ1-AS1, KCNJ2-AS1
Among them, only KCNQ1OT1 was upregulated in
both AF mouse model and Ang-II- induced mouse
heart [52]
In vivo, silencing KCNQ1OT1 prolonged AERP,
shorten IACT, and reduced the AF induction rate and
AF duration that was caused by Ang-II. Inhibiting
KCNQ1OT1 could improve atrial electrical remod-
eling
TCONS-00106987 AF rabbit model of atrial rapid pacing miR-26/ KCNJ2 TCONS-00106987 was upregulated in the AF rab-
bit model Overexpression of TCONS-00106987
significantly shortened AERP and increased the AF
induction rate, while inhibition leaded to the opposite
effect
In vivo, TCONS-00106987 induced the transcription
of KCNJ2 by sponging miR-26, thereby increas-
ing the inward rectifier K channel current ­(IK1) and
promoting electrical remodeling [53]
MIAT AF patients; miR-133a-3p MIAT was upregulated in the blood leukocytes of AF
AF rat model of atrial rapid pacing patients
In vivo, the expression of MIAT increased significantly
after AF induction, and showed a gradual downward
trend over time
MIAT could sponge miR-133a-3p to play a regulatory
role Inhibition of MIAT increased AERP, shortened
the duration of AF, and reduced AF-induced cardio-
myocyte apoptosis and atrial fibrosis [25]
LncRNA TCONS_00202959 AF rat model of Ach-CaCl2 Unclear TCONS_00202959 was downregulated in the AF rat
model
Overexpression of TCONS_00202959 prolonged
AERP, reduced the AF induction rate, and improved
electrical remodeling in rats [56]
Molecular Biotechnology (2022) 64:758–772
 Molecular Biotechnology (2022) 64:758–772 767

TCONS-00106987 significantly shortens AERP and

AF atrial fibrillation, AERP atrial effective refractory period, IACT​ interatrial conduction time, APD action potential duration, ceRNA competing endogenous RNAs, Ang-II angiotensin-II, ICaL
were screened out to be possibly related to autonomic
1220 DELncRNAs were identified by RNA sequencing

Silencing TCONS_00075467 shortened AERP in vivo,

In vitro and in vivo, TCONS_00075467 could regulate

the expression of CACNA1C by sponging miR-328
in AF rabbit model, and the expression of LncRNA

In vivo, knockdown of TCONS_00032546 shortened

increases the AF induction rate, while inhibition leads

prolonged AERP. Both of them participate in atrial

were identified by sequencing in AF canine model
TCONS_00032546, TCONS_00026102 AF canine model of atrial rapid pacing The former may activate the MAPK pathway through 410 upregulated and 166 downregulated LncRNAs

Through target gene prediction, the two LncRNAs

to the opposite effect. An in vivo study has shown that

AERP, and knockdown of TCONS_00026102

TCONS_00075467 was downregulated [50]
TCONS-00106987 forms endogenous competition by

electrical remodeling in different ways [49]

sponging miR-26, and previous studies have confirmed

and regulate atrial electrical remodeling

that KCNJ2 (a gene encoding the Kir2.1α subunit of the
and decreased ICaL and APD in vitro
inward rectifier potassium channel) is the target gene of
miR-26 [54]. Upregulated TCONS-00106987 induces
the transcription of KCNJ2 by sponging miR-26, thereby
increasing the inward rectifier K channel current ­(IK1) and

neural remodeling
promoting electrical remodeling [53].
LncRNA HOTAIR was downregulated in chronic AF
patients, and it was confirmed in cardiomyocytes that
HOTAIR can positively regulate Cx43 by sponging miR-
Results

613 [55], indicating that dysregulated HOTAIR contributes

to the pathogenesis of AF. However, further in vivo experi-
ments are essential to establish direct causality.
and the latter may increase SLC25A4 through the

Zhao et  al. [56] found that the DELncRNA

the CCND1-FGF19-FGF4-FGF3 gene cluster,

TCONS_00202959 is related to electrical remodeling in an

AF rat model, which has been observed to be consistent
with circulating lymphocytes in AF patients [29]. Overex-
pression of TCONS_00202959 prolonged the AERP in rats.
Wang et al. [49] screened two LncRNAs related to elec-
trical remodeling in the AF canine model and confirmed
the effects on electrical remodeling by knocking down the
miR-328/ CACNA1C

LncRNAs, which has shown potential for further clinical

NF-κB pathway

transformation.
Yao et al. [25] found that inhibiting MIAT increased
AERP and improved cardiac electrical remodeling, while
Pathway

reducing AF-induced cardiomyocyte apoptosis and atrial

fibrosis, but they did not further investigate the mechanism.
MIAT can bind with miR-133a-3p to inhibit its expression,
AF rabbit model of atrial rapid pacing

but the role of miR-133a in cardiac electrical remodeling is

not yet clear. Some studies have found that miR-133a inhibits
the expression of the IKr channel (a repolarization potassium
current channel) encoded by ether-a-go-go-related genes
(ERGs), leading to pathological prolongation of the QT
interval [57]. Therefore, we predict that MIAT may increase
AF sensitivity by affecting the inward potassium current dur-
ing repolarization. On the other hand, MIAT upregulation
Model

increases atrial fibrosis in AF animals by sponging miR-

133a-3p. Inhibiting it can improve atrial fibrosis and AF
structural remodeling. The signal pathways are intricately
related [58]. A literature review found that miR-133 can
directly downregulate the expression of TGF-β1 [59] and
L-type calcium channel current

can also bind to the 3' untranslated region of CTGF mRNA

to reduce the expression of CTGF, a downstream molecule
of the TGF-β/Smad pathway [60]. Liu et al. [61] constructed
Table 3  (continued)

TCONS_00075467

an LncRNA/mRNA gene coexpression network based on the

RNA sequencing results of 235 left atrial appendage samples
and identified MIAT and LINC00964 as key LncRNAs that
LncRNA

participate in multiple pathways of cardiac remodeling in

AF patients.

13

768 Molecular Biotechnology (2022) 64:758–772

Table 4  LncRNA associated with structural remodeling of AF

LncRNA Model Pathway Results

NEAT1 Persistent AF patients; miR-320/NPAS2 The expression of NEAT1 was upregulated in

Ang-II-induced atrial fibrosis mouse model
NRON AF patients;
Human atrial fibroblasts treated with Ang-II;
Ang-II-induced atrial fibrosis mouse model
NRON Atrial myocytes of mouse
NRON Fibroblasts and atrial myocytes of mouse
LICPAR Human atrial fibroblasts from patients with AF
and SR
PVT1 Human atrial muscle tissue from patients with
AF and SR;
Ang-II-induced atrial fibrosis mouse model
MEG3 AF canine model of atrial rapid pacing
(1 week);
AF canine model of atrial rapid pac-
ing + AVB + ventricular pacing (1 week)
MIAT AF patients and healthy individuals;
AF rat model of atrial rapid pacing
patients with AF, and was positively correlated
with the level of collagen I and collagen III
In vivo, silencing NEAT1 inhibited atrial fibrosis
caused by Ang-II
NEAT1 positively regulated the expression of
NPAS2 (neuronal PAS domain protein 2) by
sponging miR-320 [35], which is related to
atrial fibrosis
NFATc3 NRON was downregulated in atrial tissues of AF
patients
In vitro, overexpression of NRON inhibited the
proliferation of human atrial fibroblasts
In vivo, overexpression of NRON promoted
NFATc3 phosphorylation in Ang-II-induced
mice and inhibited cardiac fibrosis [40]
NFATc3 /IL-12 In vitro, NRON inhibited activation of M1 mac-
rophages from atrial myocytes, and alleviated
atrial fibrosis [62]
miR-23a In vitro, NRON inhibited miR-23a, which is
derived from atrial myocytes, stimulated M2
macrophages polarization, and alleviated atrial
fibrosis [63]
TGF-β/Smad signaling pathway In vitro, Ang-II treatment increased the levels
of cell LIPCAR, Smad2/3 phosphorylation,
and α-smooth muscle actin (α-SMA) Overex-
pression of LIPCAR promoted the levels of
collagen I, collagen II, α-SMA, and Smad2/3
phosphorylation, promoted cell viability, and
atrial fibroblast proliferation, while silencing
LIPCAR leaded to the opposite effect [69]
miR-128-3p/SP1/TGF-β1/Smad PVT1 was upregulated in the atrial tissue of AF
patients [65]
In vivo, PVT1-knockdown attenuated Ang-II-
induced atrial fibrosis in mice. In mechanism,
PVT1 activated the TGF-β/Smad signaling
pathway by sponging miR-128-3p and promot-
ing Sp1 expression [65]. Inhibition of PVT1 can
reduce atrial fibrosis
DLK1-DIO3 locus Through the gene sequencing of the AF dog
model, LncRNA MEG3 was found to be dys-
regulated at the DLK1-DIO3 locus [66]
Previous studies have shown that MEG3 can
inhibit TGF-β genes and alleviate the fibrotic
response [67]
miR-133a-3p MIAT was upregulated in the blood leukocytes of
AF patients
In vivo, the expression of MIAT increased signifi-
cantly after AF induction and showed a gradual
downward trend over time
MIAT could sponge miR-133a-3p to play a
regulatory role. Inhibition of MIAT increased
AERP, shortened the duration of AF, and
reduced AF-induced cardiomyocyte apoptosis
and atrial fibrosis [25]

AF atrial fibrillation, SR sinus rhythm, Ang-II angiotensin-II, α-SMA α-smooth muscle actin, AVB atrial ventricular block, AERP atrial effective
refractory period

13
Molecular Biotechnology (2022) 64:758–772 769

Fig. 1  The pathophysiology of AF

Fig. 2  A brief summary of AF-associated LncRNAs

Studies have found that the expression of LncRNA 63]. It can inhibit the activation of atrial macrophages
NRON is decreased in the atrial tissues of AF patients and reduce atrial fibrosis through inflammatory path-
[40]. Overexpression of NRON can reduce atrial fibrosis ways [62, 63]. It can also promote the phosphorylation of
in AF mouse models through different pathways [40, 62, NFATc3 (nuclear factor 3 of activated T cells) and inhibit

13

770
the activity of activated T cell factor (NFAT) to reduce
atrial fibrosis [40]. Further studies found that NRON is
abnormally expressed in the serum of patients with heart
failure [64], suggesting that LncRNAs can also be used
as circulating biomarkers and have excellent prospects in
the cardiovascular field.
LncRNA PVT1 activates the downstream TGF-β/
Smad pathway to promote atrial fibrosis by regulating
miR-128-3p-SP1 in patients with AF [65]. Inhibition of
PVT1 can alleviate atrial fibrosis; silencing of LncRNA
LICPAR also has a therapeutic effect on AF by affecting
the TGF-β/Smad pathway. Through gene sequencing of
the AF dog model, it was found that the DLK1-DIO3
locus was transcriptionally activated after 1 week of con-
tinuous arrhythmia, and the LncRNA MEG3 was found
to be dysregulated at this locus [66]. MEG3 can inhibit
TGF-β genes and alleviate the fibrotic response [67]. The
previous work of this laboratory in the AF canine model
showed that maintaining AF stimulation for 1 week acti-
vated fibroblasts, collagen gene expression, and changes
in ion channels in cardiomyocytes by rapid atrial pacing
but has not yet caused fibrosis [68]. Continued stimula-
tion for 3 weeks promoted fibrosis. Although no obvi-
ous atrial fibrosis was observed in the 1-week AF animal
model, there were disorders of fibrosis-related genes; we
can infer that if the gene regulation of the myocardial
fibrosis pathway is carried out in the early stage of AF, it
may have an early intervention effect on AF.
Although the potential therapeutic value of LncRNAs
has been proven in vivo and in animal studies, their long-
term efficacy, safety and pharmacokinetics in humans are
still largely unknown. Therefore, more research is needed
to develop clinically approved therapies for LncRNAs.
Research Limitations and Perspectives
One limitation is that research on LncRNAs is still in
the early stage. Most LncRNAs do not yet have clearly
defined functions, and even the naming methods of LncR-
NAs have not been fully unified. With further research,
some genes originally classified as LncRNAs may be
found to have protein coding functions and exit the clas-
sification. However, the studies described in this article
were all published after 2015, cover a short time span
and exhibit more consistent results. Another limitation is
that more DELncRNAs described in this article have not
undergone further experimental validation because of rap-
idly increased data. In this article, the verified LncRNAs
were annotated, and other results will be updated if there
is progress in follow-up research.
13
Molecular Biotechnology (2022) 64:758–772
Conclusions
The novel proposal in this review is the use of LncRNAs as
AF biomarkers, which updates the field of clinical applica-
tion. Studies have shown that circulating LncRNAs have
diagnostic and prognostic value and can be used as early
biomarkers of AF, prognostic prediction of AF, and pre-
diction of the recurrence of atrial arrhythmia after RFCA.
GAS5 and ANRIL, for example, are described in the article.
Multiple studies have shown that LncRNAs exert impor-
tant contributions to the pathogenesis of AF. LncRNAs can
be used as new targets to interfere with the occurrence and
development of AF, new AF treatments can be developed
based on LncRNAs, while circulating LncRNAs can be used
as novel diagnostic and prognostic markers. At present, more
research is needed to clarify the “identity” of LncRNAs in
AF and transform this information into clinical practice.
Acknowledgements  The literature search was completed in June
2021. We apologize to colleagues whose work was not cited in this
review due to page limitations. All authors read and approved the final
manuscript.
Author contributions  All authors contributed to the study conception
and design. WW and BT had the idea for the article, WW performed
the literature search and data analysis, ZN and XL critically revised the
work. All authors read and approved the final manuscript.
Funding  This research was funded by the Key Specialty of Disci-
pline Construction Project of Shanghai Health Committee (Grant No.
ZK2019B25), and the Research Project of Science and Technology
Commission of Pudong New Area (Grant No. PKJ2019-Y40).
Declarations 
Conflict of interest  The authors declare no conflicts of interest.
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