Inflammation and The Pathogenesis of Atrial Fibrillation

REVIEWS
Inflammation and the pathogenesis

ofatrialfibrillation
Yu-Feng Hu, Yi-Jen Chen, Yenn-Jiang Lin and Shih-Ann Chen
Abstract | Atrial fibrillation (AF) is the most common cardiac arrhythmia. However, the development of
preventative therapies for AF has been disappointing. The infiltration of immune cells and proteins that
mediate the inflammatory response in cardiac tissue and circulatory processes is associated with AF.
Furthermore, the presence of inflammation in the heart or systemic circulation can predict the onset of
AFand recurrence in the general population, as well as in patients after cardiac surgery, cardioversion, and
catheter ablation. Mediators of the inflammatory response can alter atrial electrophysiology and structural
substrates, thereby leading to increased vulnerability to AF. Inflammation also modulates calcium homeostasis
and connexins, which are associated with triggers of AF and heterogeneous atrial conduction. Myolysis,
cardiomyocyte apoptosis, and the activation of fibrotic pathways via fibroblasts, transforming growth factor
and matrix metalloproteases are also mediated by inflammatory pathways, which can all contribute to
structural remodelling of the atria. The development of thromboembolism, a detrimental complication of AF,
is also associated with inflammatory activity. Understanding the complex pathophysiological processes and
dynamic changes of AF-associated inflammation might help to identify specific anti-inflammatory strategies
forthe prevention of AF.
Hu, Y.F. etal. Nat. Rev. Cardiol. advance online publication 27 January 2015; doi:10.1038/nrcardio.2015.2
Introduction
Division of Cardiology,
Department of
Medicine, Taipei
Veterans General
Hospital, National
YangMing University,
Number 201,
Section2, Shipai Road,
Beitou District,
Taipei11217, Taiwan,
Republic of China
(Y.F.H., Y.J.L., S.A.C.).
Division of
Cardiovascular
Medicine, Department
of Internal Medicine,
Wan Fang Hospital,
Taipei Medical
University,
Number111,
Section3, Hsing-Long
Road, Taipei11696,
Taiwan, Republic
ofChina (Y.J.C.)
Correspondence to:
S.A.C.
epsachen@
ms41.hinet.net
Atrial fibrillation (AF) is the most common cardiac

arrhythmia and is associated with detrimental consequences. In addition to worsening patient quality of life,
AF is associated with stroke, heart failure, and increased
mortality.1 Worldwide, AF has affected >30million individuals since 2010, and the incidence of AF continues
to increase.2,3 Current treatments for AF include preventing its recurrence (via rhythm control) and consequences (by rate control and antithrombosis).4,5 In many
patients, heart-rate control is sufficient to control a rapid
rhythm and its associated symptoms, and the prevention of AF recurrence relies primarily on antiarrhythmic
drugs. Catheter ablation is considered as an alternative
to antiarrhythmic drugs because of its superiority to
medical therapy for the maintenance of sinus rhythm.1,5,6
Although major progress has been made in the treatment
of AF, its recurrence and subsequent treatment after
medication or catheter ablation, including any associated complications, problems remain.1,4,5,7 An improved
understanding of the pathophysiology underlying AF
and subsequent remodelling is necessary for the development of novel therapeutic approaches. Increasing
evidence supports the role of inflammation in the
pathophysiology of AF, which suggests that the inflammatory process is a potential therapeutic target.8,9 The
main pathophysiological mechanisms contributing to
AF development and progression include both electrical
Competing interests
The authors declare no competing interests.
and structural remodelling of the atria. Moreover, AF

itself can induce inflammation during atrial remodelling, which perpetuates the arrhythmiathe so-called
AF begets AF phenomenon. Instead of emphasizing
the clinical correlations of inflammation in different
scenarios of AF,8,10 in this Review we discuss the pathophysiological role of inflammation and its interaction
with the established mechanisms of AF. We also h
ighlight
potential inflammation-based therapeutic options.
Sources of inflammation in AF
Inflammation in patients with AF can arise from different sources, which might have underlying inflammatory mechanisms and temporal changes (Figure1).
Many systemic diseases (such as coronary artery disease,
hypertension, and obesity) are associated with low-grade
inflammationand increased levels of proinflammatory
cytokines.1113
Obesity
Obesity is associated with new-onset AF in the general
population or in patients after cardiac surgery. 14,15
Obesity-induced immune cell infiltration into the
adipose tissue, particularly by M1 macrophages (a proinflammatory phenotype),16,17 as well as inflammation of
adipose tissue and secreted proinflammatory cytokines
occurs in patients with obesity.1719 High levels of inflammatory activity in the pericardial adipose tissue has been
described in patients with AF.20 For example, epicardial
inflammatory activity was 35% higher in 21 patients with
NATURE REVIEWS | CARDIOLOGY
ADVANCE ONLINE PUBLICATION | 1

2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
Inflammation and its associated immune response are involved in the initiation
and maintenance of atrial fibrillation (AF)
AF can further promote inflammation, which contributes to the clinical
phenomenon of AF begets AF
Inflammatory pathways contribute to both electrical and structural atrial
remodelling and thrombogenesis in patients with AF
The mechanisms and dynamic changes that underlie the inflammatory
responses in different clinical scenarios of AF should be determined to enable
the development of specific, individualized anti-inflammatory strategies
Therapies that target specific inflammatory cascades might be potential
therapeutic strategies for the prevention of AF
Systemic disease
Obesity, hypertension, coronary artery diseases
Atrial myocardial injury
Atrial ischaemia or infarction, surgical or catheter ablation
Immune diseases with autoantibody
Valvular heart diseases
Modulating factors
Chronic viral infection,
epicardial fat,
genetic predisposition
Mediator molecules
ROS, Ang II, TGF-, MPO, PDGF, HSPs, proinflammatory cytokines
Inflammation
Electrical remodelling
Structural remodelling
Atrial fibrillation
Figure 1 | Sources of inflammation in patients with atrial fibrillation.

Naturestructure,
Reviews | and
Cardiology
Activatedinflammatory pathways alter the electrophysiology,
autonomic remodelling of the atria. Inflammation induced by atrial fibrillation
canestablish an inflammatory cycle that leads to increased severity of the
arrhythmia. Abbreviations: AngII, angiotensinII; HSP, heat shock protein; MPO,
myeloperoxidase; PDGF, platelet-derived growth factor; ROS, reactive oxygen
species; TGF, transforming growth factor.
AF than in 21 matched controls without AF, as measured by 18Ffluorodeoxyglucose PET.20 Proinflammatory

cytokines from adipose tissue might reach the atrium
via the circulation or paracrine factors. In a study of 34
patients, high-dominant frequencies or complex atrial
fractionated electrogram sites were located adjacent to
epicardial fat areas, which suggest that epicardial fat
might maintain AF by releasing paracrine inflammatory
mediators.21,22 Free fatty acid overload in patients with
obesity induces lipid accumulation within cardiomyocytes and apoptosis, which might also trigger regional
inflammation.23 These factors suggest that inflammation
is an important pathophysiological mechanism of AF in
patients with obesity.
Hypertension
The association between inflammation and AF in
patients with hypertension is not yet established. In spontaneously hypertensive rats and hypertensive sheep (who
received unilateral nephrectomy followed by clamping of
the remaining renal artery to 60%), leucocyte infiltration
into the atria and inflammation was observed, which was
followed by atrial fibrosis.24,25 In these models, vulnerability to the development of AF increased by 62% after
the development of atrial fibrosis, but not inflammation alone. However, in another sheep model, in which
hypertension was induced by prenatal steroids, increased
vulnerability to AF was noted, but atrial inflammation
not observed.26 In this model, plasma renin concentration and vascular reactivity to angiotensinII were not
altered, whereas in spontaneously hypertensive rats and
sheep with unilateral nephrectomy-induced hypertension, the reninangiotensinaldosterone system (RAAS)
was activated.2426 The discrepancy between these studies
might imply a pathophysiological role of RAAS in AF.
The atria of angiotensinIItreated mice are characterized by increased neutrophil infiltration, which is dependent on CD11b and CD18 integrins.27 AngiotensinII
increases inflammation by stimulating the production
of proinflammatory cytokines (such as IL6, IL8, and
tumour necrosis factor [TNF]) and directly activating
immune cells.28 Furthermore, angiotensinII can induce
the expression of adhesion molecules such as vascular cell
adhesion protein1, intercellular adhesion molecule1,
selectins, or CC motif chemokine2 (also known as
monocyte chemotactic protein1), which promote the
recruitment of immune cells.28 Blocking angiotensininduced inflammatory cascades (such as TNF and IL1)
might prevent cardiac damage in response to angio
tensinII in a mouse model of AF.29 Several mechanistic
hypotheses in addition to the role of RAAS have also been
proposed. Atrial stretch, owing to elevated left ventricular
diastolic pressure in patients with hypertension, might
activate regional RAAS, cardiac apoptosis, and oxidative
stress, which can subsequently induce regional inflammation in the heart.30 Cellular stress from reactive oxidative
species might be induced by hypertension in patients in
AF,31 and reactive oxygen species can further stimulate
signal transduction thereby increasing production of
proinflammatory cytokines, such as IL1, IL6, and TNF.32
Coronary artery disease

Atrial myocardial infarction, or ischaemia that is secondary to an occluded coronary artery, is expected to
induce myocardial damage and atrial inflammation
during the healing process, and might consequently
induce AF.33 The pathophysiology of ischaemic heart
disease is more complex than that of occluded arteries, in
which low-grade inflammation is an important factor.13
For example, the increased expression of platelet-bound
and plasma stromal cell-derived factor1 was observed
in patients with AF and ischaemic heart disease compared with those in sinus rhythm.34 The increased level
of stromal cell-derived factor1 is a risk factor for developing coronary artery disease and is associated with
inflammatory cell recruitment.35,36
Surgery and ablation
Inflammation can also be induced by cardiac surgery
or catheter ablation. In the ARMYDA3 study,37 high
postoperative Creactive protein (CRP) levels were
associated with an increased risk of AF. Surgery-induced
2 | ADVANCE ONLINE PUBLICATION
www.nature.com/nrcardio
REVIEWS
inflammation has been modelled in canine sterile pericarditis, an experimental model of postoperative AF
in humans. AF, induced by burst atrial pacing after
open chest operation in these dogs, was reduced by
60% after treatment with anti-inflammatory drugs.38,39
Radiofrequency ablation induces an inflammatory
response that develops after thermal injury and is likely
to contribute to the maturation of ablation lesions after
the procedure.5,40 Patients undergoing radiofrequency
ablation for AF have high CRP levels within 3days of
the procedure, and the extent of CRP elevation predicts
early AF recurrence within this 3day period, but not late
AF recurrence at 3 or 6months.41,42
Autoimmune reactions in AF
Whether the inflammation in AF is associated with

an autoimmune response remains unclear. Certain
autoantibodies, such as those against the muscarinic
acetylcholine receptorM2 and heat shock proteins
(HSPs), have also been associated with AF.4345 However,
whether these autoantibodies cause or are only released
in response to AF is unknown. Valvular heart diseases
are associated with volume or pressure overload in the
atrium and also increase atrial stretch, which activates
RAAS, reactive oxygen species, matrix metalloproteinases (MMPs), cardiac myolysis, and apoptosis, and might
subsequently increase inflammation and vulnerability
toAF.30
Polymorphisms in the genes encoding IL1, IL6, and
IL10, which are responsible for modulating expression
levels of inflammatory cytokines, are independently
associated with AF in humans. 4649 For example, the
174G>C IL6 polymorphism is associated with the
new onset of AF after surgery.50 In two large cohort
studies of patients with viral infection, such as HIV
or herpes simplex virus, both latent and chronic viral
infection were independently associated with the development of AF, possibly through inflammatory processes.51,52 However, the underlying mechanisms of AF
in patients with a viral infection remain unclear. In individualswithHIV, several mechanisms were proposed
to explain the HIV-induced dilated cardiomyopathy.
For example, theendothelium in the heart can act as a
reservoir of HIV particles and cytokines, such as TNF
and IL6, and reactive oxygen species, which all increase
inflammation.53 Moreover, HIV-associated proteins, such
as immunodeficiency virus transactivating regulatory
protein (Tat), can lead to destruction of mitochondria,
which results in myocardial damage.54
Inflammation leads to AF
In patients with lone AF, atrial pathology reveals infiltration of lymphomononuclear cells and necrosis of the
adjacent myocytes, which is not present in patients who
are in sinus rhythm.55 In a number of case-controlled
studies, higher levels of inflammatory markers (such as
CRP, HSP 1 [commonly known as HSP27], IL6, IL8,
and TNF) as well as elevated neutrophil and lymphocyte
ratios have been reported in patients with AF compared
with those in sinus rhythm.8,10,5659 Increased CRP levels
have been reported to predict the development of newonset AF in several large, prospective cohorts.6062 In the
Cardiovascular Health Study 60 (5,806 patients followed
up for a mean period of 6.9years), higher CRP levels
(>3.41mg/l) were associated with the presence of AF
compared with lower levels (<0.97mg/l; adjusted OR1.8,
95%CI 1.22.5). Moreover, baseline CRP could be used
to predict the risk of developing AF (adjusted HR1.24 for
1SD increase, 95%CI 1.111.40).60 These data suggest
that a persistent inflammatory state can promote AF.
Preventing inflammation using corticosteroid therapy
can also decrease AF recurrence after electrical cardioversion. In a double-blind, placebo-controlled study, 104
patients with symptomatic AF were randomly assigned
after cardioversion to receive the corticosteroid methylprednisolone or placebo.63 After a follow-up period of
2years, fewer patients who received methylprednisolone
had a recurrence of AF (9.6% versus 50%; P<0.001).63
Maximal CRP levels on the second day after CABG
surgery were also associated with the development
of AF in a study that included 19 patients (R2=0.41,
P=0.0037).64 However, in a meta-analysis that included
a total of 3,323 patients from 50 randomized controlled
trials, prophylactic corticosteroid treatment during adult
cardiac surgery reduced the risk of AF compared with
placebo (25.1% versus 35.1%; relative risk0.74, 95%CI
0.630.86, P<0.01).65
An animal model further supports the link between
AF and inflammation. In a canine sterile pericarditis
model, vulnerability to developing AF is substantially
increased.38,39 This model of pericarditis is characterized
by atrial infiltration of neutrophils, myeloperoxidase
accumulation (0.720.09 versus 0.180.03 change in
OD/min/mg; P<0.001), and increased systemic levels
of CRP (11.71.3 versus 7.60.5mg/dl; P<0.0001) and
IL6 (142.019.6 versus 112.037.3pg/ml; P<0.01).38,39
In these studies, corticosteroid treatment reduced the
incidence of inducible AF from 100% to 33%, and n3
polyunsaturated fatty acid treatment reduced the number
of AF episodes from 2810.3 to 117.4 (P<0.001).38,39
In patients with AF, inflammation might be a systemic
phenomenon or local process that influences the diagnostic and therapeutic strategies. However, most studies
have not been designed to differentiate between these
processes. Nevertheless, the prevention of AF by suppression of inflammation further highlights the link between
inflammation and this arrhythmia.
AF promotes inflammation
Pre-existing inflammation can initiate AF, which subsequently generates an inflammatory response that
further enhances atrial remodelling and perpetuates the
arrhythmiathe so-called AF begets AF phenomenon.
In patients with AF, markers of the inflammatory response
are elevated during the arrhythmia, compared with individuals in sinus rhythm who have a history of AF.66,67
For example, CRP and IL6 levels are higherin blood
samples drawn from patients during AF than inthose
from patients during sinus rhythm (CRP: 3.1mg/dl
versus 1.7mg/dl; IL6: 2.3ng/ml versus 1.5ng/ml).66,67

REVIEWS
Lone AF
Comorbidities: CAD, obesity, CHF,
hypertension, valvular heart diseases
Postoperative AF
AF recurrence after catheter ablation
Angiotensin II infusion mice
DAMP: necrotic cells, degraded ECM,

amyloid A, HSP27, HSP60, HSP70, oxLDL
TLR-2, TLR-4 (through NFB, AP-1)
T lymphocyte
Macrophage
IL-2, IL-6,
IL-10
TNF, MCP-1,
IL-1, IL-8, IL-10
TLR-activated
proinflammatory signals
Interact
Endothelial
cells
Neutrophil
Mast cell
MPO
PDGF
Cardiomyocytes
TGF-1
HSPs
Fibroblasts
Figure 2 | Inflammatory cell regulation in lone and postoperative

AF. DAMPs
Nature Reviews
| Cardiology
canactivate cells via TLR2 and TLR4, including immune cells, cardiomyocytes,
fibroblasts, and endothelial cells, which induce inflammatory cascades. Innate and
adaptive immune reactions lead to two distinct infiltration patterns of immune
cells. In patients with lone AF (green boxes), AF with comorbidities, or structural
heart disease, the pattern of inflammatory cell infiltration differs from the pattern
of immune cell infiltration after surgery, catheter ablation, or angiotensin induction
(yellow boxes). These mechanisms can interact and coexist in patients with AF
despite the activation of different inflammatory cascades. Endothelial cells,
cardiomyocytes, and fibroblasts can also secrete proinflammatory cytokines. Both
HSP and TGF activate inflammation in many different cell types. Abbreviations:
AF,atrial fibrillation; CAD, coronary artery disease; CHF, congestive heart failure,
DAMPs, danger-associated molecular patterns; ECM, extracellular matrix; HSP,
heatshock protein; MCP1, monocyte chemoattractant protein1; MPO,
myeloperoxidase; oxLDL, oxidized LDL; PDGF, platelet-derived growth factor; TLR,
Toll-like receptor; TGF, transforming growth factor; TNF, tumour necrosis factor.
Graded increases in the levels of CRP, HSP27, and

TNF are also observed in patients with persistent AF
compared with those with paroxysmal AF or without
arrhythmias.57,68,69 The maintenance of sinus rhythm
after cardioversion or catheter ablation of persistent
or long-lasting AF leads to a gradual decrease in CRP
levels relative to levels before the procedure (from
0.290.13mg/dl to 0.100.06mg/dl; P<0.001 in patients
after cardiov ersion). 66,70,71 However, CRP levels in
patientswith recurrent AF after treatment procedures do
not change.66,70,71 These findings suggest that AF might
further promote the inflammatory process, a concept
supported by the canine rapid atrial pacing model of AF.72
In this model, rapid atrial pacing for 1week increased
serum CRP levels, shortened the atrial effective refractory period, and increased the inducibility of AF. This
effect was prevented by the anti-inflammatory drug prednisolone, which reduced the mean duration of AF from
962317s to 2811s.72 AF might also lead to calcium
overload in atrial myocytes, resulting in cell death,
danger-associated molecular pattern (DAMP) release,
and subsequent low-grade inflammatory response activation to repair the damage.10,73 However, the underlying
mechanisms by which AF induces inflammation remain
poorlyunderstood.
Immune reactions in AF
Cardiac injury releases DAMPs from cells or the

degraded extracellular matrix, which can initiate cardiac
inflammation (Figure2). Cell surface Toll-like receptors
that recognize DAMPs can induce the expression of proinflammatory genes (such as those encoding cytokines or
chemokines) via nuclear factor NFB and transcription
factor AP1 in a cell-specific manner, and subsequently
activate the innate and adaptive immune responses.74,75
Several DAMPs, including necrotic cells, degraded extracellular matrix, amyloidA, HSP27, HSP60, HSP70, and
oxidized LDL identified from immunological studies
of myocardial ischemia,76 have been also been associated with AF.43,7780 However, whether specific DAMPs
are associated with different triggers of AF, or whether
common mechanisms are shared, is unclear.
Toll-like receptor2 (TLR2) levels are increased in both
the monocytes and atrial tissue of patients with AF,81,82
and increased atrial levels of Toll-like receptor4 (TLR4)
were noted in patients with AF and heart failure.83 TLR2
and TLR4 not only activate immune cells, but also initiate NFB-dependent responses in cardiomyocytes,
which leads to contractile dysfunction and secretion
of proinflammatory cytokines.84,85 In a rat study, TLR4
stimulation by lipopolysaccharides reduced the transient outward K+ current (Ito) by >50% (P<0.001), and
increased Na+/Ca2+ exchanger activity by >30% (P<0.01)
in the ventricles, which suggests a link between TLR4
and arrhythmogenesis.86
Lymphomononuclear cells are the predominant
immune cells that infiltrate the atrial myocardium of
patients with lone AF, and in those with AF and comorbidities or structural heart disease, which suggests
that these patients have chronic inflammation. 55,87,88
Macrophage recruitment is associated with a gradient
of adhesion molecules (such as intercellular adhesion
molecule1 and vascular cell adhesion protein1) from
the endocardium to the epicardium.87,89 The levels of
monocyte-derived CD36 in the systemic circulation,
which modulates inflammatory cytokines, are higher
in patients with AF than those without, and the level of
CD36 (>200units) could be used to predict AF recurrence after catheter ablation (HR4.2, 95%CI 1.214.6,
P=0.02).90 A higher percentage of activated Tlympho
cytes (CD3+ and HLADR+) was observed in the peripheral blood of patients with paroxysmal or persistent
AF compared with healthy control individuals (36%
versus 27%; P<0.001). 91 This activation is reversed
if sinus rhythm is maintained after cardioversion.91
Lymphomononuclear cells secrete high levels of TNF,
transforming growth factor (TGF)1, and IL6 in the
atrium, which can subsequently contribute to atrial
fibrosis and electrical remodelling.39,87,92
Pericardiotomy, atriotomy, or catheter ablation
typically induces acute inflammation, and neutrophils
compose the majority of the immune cells in these
patients. 38,39,93 In a mouse model of AF (induced by
angiotensinII infusion or aortic constriction), neutrophil infiltration in the atria has also been reported.27,94
An increased postoperative ratio of neutrophils to
REVIEWS
lymphocytes (3.0 in mice with AF versus 2.4 in mice
without AF; P=0.001) in the peripheral circulation
has been associated with an increased incidence of
new-onset AF (OR1.10 per unit increase, P=0.04).95
An elevated neutrophil-to-lymphocyte ratio before or
after catheter ablation is associated with increased AF
recurrence after the procudure.96,97
The contributions of acute and chronic inflammation in
AF, which might mediate distinct inflammatory cascades
and signals, remain poorly understood. Atrial neutrophil
infiltration is mediated by CD11bintegrin in patients
with AF.27 Myeloperoxidase is most abundantly expressed
in neutrophil granulocytes.98 In patients undergoing offpump CABG surgery, levels of IL6 and IL8 (but not
TNF) are elevated immediately after surgery (IL6 from 0
to 435pg/ml; IL8 from 10 to 50pg/ml).99 The increase in
the level of IL6 after surgery is associated with postoperative AF (OR7.63 if IL6>401pg/ml, P=0.04).99 Among
patients with AF who receive catheter ablation, the levels
of IL6 and CRP both significantly increase after ablation
(IL6 from 1.12.5 to 12.415.3pg/ml; P=0.007; CRP
from 2.42.9 to 20.19.2mg/l, P=0.001); however, levels
of IL8, IL10, IL12, stromal cell-derived factor1, and
TNF remain unchanged.100
In addition to their role in allergic and immune
responses, mast cells also participate in cardiovascular disease-related inflammation.101 Mast cells might
actively induce inflammation and atrial fibrosis in
patients with AF and secrete platelet-derived growth
factorA (PDGFA) and promote cell proliferation and
collagen expression in cardiac fibroblasts (Figure2).94
Cardiomyocytes, fibroblasts, and endothelial cells can
also induce inflammatory responses;85 however, whether
innate and adaptive immune responses lead to different
infiltration patterns in AF requires additional studies.
Acute and chronic inflammation might also interact
and contribute to the pathogenesis of AF. For example,
preoperative and postoperative CRP levels are both predictive of the development of AF after cardiac surgery.58
Cardiac injury after myocardial infarction is associated
with early stimulation of inflammatory signalling.85 The
timely increase of anti-inflammatory mediators can
stop excessive inflammatory injury and repair cardiac
tissue.85 However, the dynamic changes in inflammatory
responses during different stresses before the onset or
maintenance of AF have yet to be defined. Understanding
the temporal changes in these inflammatory responses
might be important for the selection of appropriate
inflammatory pathway targets to treat AF.
Many subpopulations of Tlymphocytes and monocyte
or macrophages have different proinflammatory or antiinflammatory responses. For example, M1 macrophages
are proinflammatory and recruited early during tissue
damage to clear debris and dead cells.102 By contrast, M2
macrophages, which are recruited after M1 macrophages,
have reparative functions and secrete proangiogenic or
fibrotic mediators to promote wound healing.102 CD4+
(Thelper1 or Thelper2 cells), CD8+, natural killer,
and Tregulatory cells all have different roles during
chronic inflammation.103 However, little is known about
how these subpopulations of immune cells and their

temporary changes affect the pathogenesis of AF.
Cytokines, chemokines, and mediators
The involvement of different inflammation-associated

cytokines and chemokines has been proposed in the
pathogenesis of AF (Figure2, Table1). Clinical data
indicate an important association between CRP levels
and AF. However, in the prospective Copenhagen
City Heart Study, 61 increases in CRP levels owing to
genetic polymorphisms (CRP polymorphism: rs1205,
rs1130864, rs3091244, and rs3093077) did not increase
the incidence of AF, suggesting that CRP indicates the
systemic or regional inflammatory state, but does not
have a pathophysiological role. Substantial differences
exist between the studies to investigate cytokines and
chemokines in the pathogenesis of AF, including study
design, patient number, enrolled populations, sample
collection, treatment, and follow-up strategies. The
mechanisms that underlie postoperative or postablation AF recurrence might differ from those underlying
AF onset in the general population and could lead to
activation of different cytokines. Consequently, inconsistent results among these studies are not unexpected.
Furthermore, only CRP has been linked to new-onset AF
in the generalpopulation.104
In mice, cardiac-specific expression of TNF or TGF1
can increase the vulnerability to AF and atrial remodelling, including fibrosis and heterogeneous conduction.105108 In clinical studies, the serum or atrial tissue
levels of TNF or TGF1 increase in patients with AF,
compared with individuals in sinus rhythm, which
further supports a detrimental role for these proteins in
AF.88,92,109111 The TGF inhibitor tranilast can prevent
atrial remodelling and development of AF in a canine
model, 112 but no reports exist of studies investigating anti-TNF strategies in the treatment or prevention
of AF in humans. However, in the ATTACH trial, 113
the use of anti-TNF antibodies in the treatment of
patients with heart failure was associated with a higher
combined risk of death from any cause or hospitalization for heart failure than placebo (HR2.84, 95%CI
1.017.97, P=0.043). Because heart failure is a common
comorbidity in patients with AF, an anti-TNF antibody
as a cytokine therapy must be used with caution. The
levels of m
yeloperoxidase in atrial tissue are higher in
patients with AF than in individuals in sinus rhythm,
and increased myeloperoxidase levels in the blood have
been associated with early AF recurrence after catheter
ablation (HR2.12, 95%CI 1.713.27, P=0.032).42,114,115
Increased atrial myeloperoxidase levels are also associated
with AF vulnerability in canine models.39 In mice pretreated with angiotensinII, myeloperoxidase deficiency
decreases atrial fibrosis and protects mice from AF, which
was reversed after restoring myeloperoxidase.114 These
data suggest that TNF, TGF1, and myeloperoxidase
might be therapeutic targets for the treatment of AF.
HSPs have multifunctional cardioprotective roles.116
HSPs are a family of proteins that prevent toxic protein
aggregation by binding to unfolded proteins,117 and can

REVIEWS
Table 1 | Evidence for the roles of inflammatory mediators in the pathogenesis of AF
Protein
Serum
levels*
Atrial
tissue
levels*
Predictor
of AF
Predictor
of AF after
surgery
Predictor of
AF after
cardioversion
Predictor
of AF after
ablation
AF vulnerability
in animal
models
Remodelling
mechanism
References
CD36
ND
ND
ND
ND
ND
ND
90
CRP
ND
Serum (#)
ND
ND
60,104,109,191
HSP27
ND
Tissue (+)
ND
Electricaland
structural
57,80,119,120,192
HSP70
ND
Tissue (+),
serum ()
ND
ND
Electricaland
structural
45,57,79,80,122,123,
193195
IL-1
ND
ND
ND
ND
ND
ND
ND
196,197
IL-2
ND
ND
ND
Serum (+)
ND
ND
Electrical
58,146,198,199
IL-6
Serum (#)
ND
ND
58,88,109,191,200,201
IL-8
ND
Serum (+)
ND
ND
ND
ND
92,202204
IL10
ND
Serum (+)
ND
ND
ND
ND
57,92,198,203
IL18
ND
ND
ND
ND
ND
ND
ND
155
MCP1
ND
ND
ND
ND
ND
69,104,205
MPO
ND
ND
ND
Structural
42,93,104,114,115
PDGF
ND
ND
ND
ND
ND
ND
Electricaland
structural
94,144
TGF-
ND
Electricaland
structural
107,108,110112,
190,206,207
TNF
Serum ()
ND
Electricaland
structural
57,88,92,104,109,
191,208
*Cross-sectional study. Prospective study. Basic study. Abbreviations: +, protein levels differ between presence and absence of AF (predictor of AF occurrence); , protein levels do not differ
between presence and absence of AF (not a predictor of AF occurrence); #, conflicting results; AF, atrial fibrillation; CRP, Creactive protein; HSP, heat shock protein; ND, not determined; MCP1,
CC motif chemokine2 (also known as monocyte chemoattractant protein1); MPO, myeloperoxidase; PDGF, platelet-derived growth factor; TGF, transforming growth factor.
prevent AF by reversing atrial structural remodelling

(by mediating apoptosis, fibrosis, and myolysis) and
abnormal calcium homeostasis.118 Most studies of HSPs
in patients with AF focus on HSP27, HSP60, and HSP70
(Figure3).117118 HSP27 levels progressively decrease
from 7.20.5ng/ml in control individuals to 6.10.5ng/
ml in patients with paroxysmal AF and 4.70.5ng/ml
in those with persistent AF (P=0.02 for the trend).57
Moreover, HSP27 levels are correlated with increased left
atrial size (left atrial diameter 4cm versus <4cm is associated with 4.770.43ng/ml versus 6.250.54ng/ml of
HSP27, respectively; P=0.03).57 Serum HSP27 levels
can also be used to predict AF recurrence after catheter
ablation.57 Different tissue expression of atrial HSP27 has
been noted in patients with AF compared with those
without the arrhythmia. Higher expressions of atrial
HSP27 were noted in patients with paroxysmalAF
than in individualsin sinus rhythm or with persistent
AF; these HSP27 levels are inversely correlated to AF
duration (rcoefficient=0.54, P=0.001) and myolysis
(rcoefficient=0.70, P<0.01).80,119 Increased expression of HSP27 in patients with paroxysmal AF might
also protect cardiomyocytes from myolysis and prevent
the progression to persistent AF.80 In tachypacing cell
and canine models of AF, preinduction of HSPs by nontoxic heat shock or geranylgeranylacetone can prevent
atrial electrical and structural remodelling by restoring
the calcium transient amplitude and Ltype Ca2+ current,
and thereby prevent shortening of the action potential
duration. 120 Elevated expression ofphosphorylated
HSP27 (but not HSP70) contributes to these HSP or

geranylgeranylacetone-related benefits.120 HSP27 also
prevents tachypacing-induced Factin stress fibre formation and contractile dysfunction. 120,121 In a rabbit
model of heart failure, HSP-inducing agents (geranyl
geranylacetone) decreased triggered activity, action
potential duration alternation, atrial fibrosis, atrial conduction time, and AF incidence, potentially through
the specific induction of HSP70. 122,123 HSP60 protein
expression was higher in right atrial samples from
patients with chronic AF than in those from individuals in sinus rhythm,124 and increased anti-HSP60 levels
were also associated with AF after cardiac surgery.43
However, the role of HSP60 in AF electrical remodelling
remains unclear.
HSPs can also modulate inflammation. For example,
HSP27 can downregulate TNF expression and upregulate
IL10 levels.57 HSP27 increases IL10 secretion in monocytes and inhibits the expression of TLR4,125 and interacts with inhibitor of nuclear factorB kinase subunit,
which might lead to inhibition of NFB that is associated with proinflammatory signalling.116 However, in a
2014 study, HSP27 increased NFB activation and IL6
production and depressed contractility through TLR2
and TLR4 in mouse hearts after global ischaemia. 126
HSP70 might also function as a DAMP to activate
TLR2 and TLR4 in immune cells and TLR2 in cardiomyocytes, which subsequently activate proinflammatory
pathways and increase atrial remodelling.127,128 During
cell stress or apoptosis, HSP60 translocates from the
REVIEWS
Restore L-type calcium current
Prevent action potential duration shortening
Prevent myolysis
Prevent F-actin stress fibre
Intracellular cardiomyocyte
(HSP27, HSP70)
HSPs
Cardiomyocytes
Extracellular
(HSP27, HSP60, HSP70)
TLR-2,
TLR-4
Innate and adaptive
immune cells
HSP60
HSP27
HSP60
HSP70
Increase cardiac apoptosis

Inhibit TLR-4 expression
Anti-inflammatory cytokines
Increase proinflammatory
cytokines
Secrete anti-HSP autoantibodies
Figure 3 | HSPs in atrial fibrillation. HSPs prevent protein aggregation and stabilize protein folding. However, HSPs can
Reviews
| Cardiology
function as damage-associated molecular patterns and induce an immune response. IntracellularNature
HSP27
and HSP70
restore abnormal calcium currents and prevent shortening of the action potential duration, myolysis, and Factin stress fibre
formation, which can reverse AF-related electrical and structural remodelling in cardiomyocytes. Extracellular HSP70 and
HSP60 activate TLR2 and TLR4 on immune cells and cardiomyocytes. HSP60 can induce cardiomyocyte apoptosis. HSP60
and HSP70 also activate immune cells that secrete proinflammatory cytokines and induce humoral responses to produce
anti-HSP autoantibodies. HSP27 might inhibit TLR4 expression and its associated NFB pathway, and increase secretion
ofIL10; these responses are considered anti-inflammatory. Abbreviations: HSP, heat shock protein; TLR, Toll-like receptor.
mitochondria and cytosol to the plasma membrane and

is released to the extracellular space.129 HSP60 induces
cardiomyocyte apoptosis partially via TLR4129,130 and
cytokine production through the TLR4MYD88p38/
NFB pathway.131 In addition, HSP60 activates monocytes, macrophages, and Tlymphocytes through TLR2
or TLR4(Figure2).132,133
In a prospective study of 329 patients undergoing
elective CABG surgery, increased postoperative antiHSP65 was independently associated with postoperative
AF (OR1.4, P=0.04),43 and higher anti-HSP70 levels
were recorded in patients with persistent AF than in
those with paroxysmal AF (median 53g/ml versus
43g/ml; P=0.035).45 These findings indicate a pathogenic role of humoral immune responses in patients
with AF.43,45 However, ongoing studies to address the
mechanisms of a humoral immune response in AF
have not yet been reported. Whether an anti-HSP60
or anti-HSP70 autoantibody functions as a trigger
or inhibitor for AF-related inflammation remains
unclear. HSPs that function as autoantigens might
induce an adaptive immune response and activate
Blymphocytes to produce antibodies that neutralize and promote the clearance of autoantigens.134 The
HSPautoantibody complex might also induce a complement pathway that leads to macrophage activation
and consequently promote inflammation. For example,
anti-HSP60 autoantibodies can induce atherosclerosis
via endothelial damage.135,136 Autoantibodies against
HSP60 canmediate endothelial injury by activating
complement-mediated or antibody-dependent cellular
cytotoxicity by peripheral blood mononuclear cells.135,136
Conversely, the binding of autoantibodies to HSPs
enables the clearance of extracellular HSPs from the
tissue and prevents the continuous activation of immune
systems.135,137 High serum anti-HSP70 levels (>119.6g/
ml) were also associated with a 61% reduced risk of
cardiovascular complications compared with low HSP70
levels in patients with diabetes mellitus (95%CI 0.17

0.87).137 Ifautoantibodies against HSPs are a trigger of
inflammation, induction of immune tolerance to HSP60
might decrease immune responses to DAMPs via Tregulatory cells and inhibit the release of proinflammatory
immune cells and cytokines.138 However, if these autoantibodies are an inhibitor of inflammation, they might
be used as a new DAMP-specific anti-inflammatory
therapy to treat AF,139 in an approach similar to that of
IgM antibodies against oxidised LDL, which can prevent
inflammation and atherosclerosis.140
Inflammation and electrical remodelling
The detailed pathophysiological mechanisms of electrical and structural remodelling in AF have been extensively reviewed previously.141 Different inflammatory
cytokines modulate the function of ion channels and
calcium homeostasis (Figure4). TNF induces abnormal Ca2+ handling and arrhythmogenicity in pulmonary vein cardiomyocytes.142 TNF can also decrease the
expression of sarcoplasmic/endoplasmic reticulum Ca2+
ATPase2a (SERCA2a) by enhancing methylation in the
promoter region.143 Mice that selectively overexpress
TNF in myocardial tissue have prolonged action potential and Ca2+ transient durations, and higher diastolic
and lower systolic Ca2+ currents than those with normal
TNF levels.105,106 Furthermore, mice with an elevated TNF
level have increased vulnerability to AF and also develop
spontaneous episodes of AF.105,106 These findings suggest
that TNF can directly alter Ca2+ handling in cardiomyocytes, which is crucial for the initiation of AF and atrial
electrical remodelling.105,106,142,143
PDGF from myofibroblasts can reduce the duration of action potentials and Ca 2+ transients when
directly applied to cardiomyocytes, which supports a
role for PDGF in electrical remodelling.144 IL2 is predominantly secreted by activated Tlymphocytes,145
and changes the amplitude of electrically-stimulated

REVIEWS
Activated immune cells and inflammatory mediators
TNF
IL-2
PDGF
TNF
TGF-
MMPs
HSPs
Abnormal calcium
handling
Abnormal trigger
MPO
HSPs
PDGF
TNF
Cx40, Cx43
Action potential
duration shortening
Fibrosis
TNF
HSPs
Cardiomyocyte
Apoptosis
Myolysis
Slow conduction
Conduction
heterogeneity
Electrical remodelling
Atrial dilatation
Structural remodelling
Figure 4 | Inflammatory cells and mediators of inflammation modulate

Nature Reviews | Cardiology
cardiacelectrophysiology and structural properties. Calcium homeostasis
incardiomyocytes is regulated by TNF, PDGF, and IL2, which are associated
withincreased triggering and shortening of the action potential duration. The
atrialexpression of Cx40 and Cx43 is downregulated by inflammation via TNF.
MPO,PDGF, and TNF activate fibroblasts, which express MMPs and TGF1
leadingto increased collagen synthesis and atrial fibrosis. TNF also increases
cardiomyocyteapoptosis and myolysis. These changes contribute to
heterogeneous atrial conduction and increased vulnerability to atrial fibrillation.
HSPs protect cardiomyocytes from abnormal calcium handling, apoptosis, and
myolysis. Abbreviations: Cx, connexin; HSP, heat shock protein; MCP1, CC
motifchemokine2 (also known as monocyte chemoattractant protein1);
MMP,matrix metallopeptidase; MPO, myeloperoxidase; PDGF, plateletderivedgrowth factor; TGF, transforming growth factor; TLR, Toll-like receptor;
TNF,tumour necrosis factor.
andcaffeine-induced Ca 2+ transients in ventricular

myocytes, which has a similar effect to, and might be
explained by, a suppression of SERCA2a function and
increase of Na+/Ca2+ exchanger activity without changing
Ltype calcium channels.146 However, this effect has not
yet been d
emonstrated in atrial myocytes.
Inflammation also alters the conduction properties of
the atria. Acute atrial inflammation after right atriotomy
in dogs increases the heterogeneity of conduction and
AF duration, which can be prevented by the systemic
administration of methylprednisolone.39 The increased
heterogeneity of conduction also correlates with higher
atrial myeloperoxidase activity.39 Heterogeneous conduction can be created by the local application of arachidonic acid (a mediator of inflammation) in the left
atria of dogs and be prevented by the topical application
of methylprednisolone.147 Furthermore, heterogeneous
conduction might be the result of the altered expression or distribution of gap junction5 protein (commonly known as connexin40 [Cx40]), gap junction1
protein (commonly known as connexin43 [Cx43]), or
atrial fibrosis.108,148 Reduced expression and transmural
gradient of Cx40 and Cx43 (both of which are absent
in the epicardium, decreased in the mid-myocardium,
and normal in the endocardium) in the canine sterile
pericarditis model is associated with markedly abnormal
atrial conduction and vulnerability to the induction and

maintenance of AF.148 TNF also downregulates Cx40
andchanges the intracellular distribution of Cx43 in
cardiomyocytes (which is dispersed from the intercalated
discs) in mice.106,149
In clinical studies, mediators of the inflammatory
response are associated with atrial electrical properties.57,90,150 CD36 levels are positively correlated with
atrial voltage (rcoefficient=0.63, P=0.001).90 Low levels
of HSP27 (<3.85ng/ml) or CRP (<2.9mg/l) are associated with low atrial voltage (HSP27, 1.80.2 versus
2.20.1mV, P=0.01; CRP 1.70.7 versus 1.90.7mV,
P=0.045).57,150 CRP is also associated with an increased
number of identified nonpulmonary vein ectopies and
high-frequency sites in the left atrium.57,90,150 The signalaveraged Pwave duration increases after physical exertion, accompanied by transient increases in the levels of
CRP, IL6, and TNF although atrial volumes do not differ,
which indicates that the acute change in inflammatory
cytokines is linked to atrial electrical conduction and
vulnerability to AF.151
Inflammation and structural remodelling
TNF activates the TGF signalling pathway and myo

fibroblasts, and increases the secretion of MMP2 and
MMP9, which mediate atrial remodelling.149 Conversely,
anti-TNF antibodies decrease MMP2 and MMP9 activity and prevent collagen synthesis and deposition.152
Leucocyte activation and myeloperoxidase expression
in the atrium after angiotensinII infusion also increase
MMP2 and MMP9 activity and atrial fibrosis, and slow
atrial conduction.114 Myeloperoxidase-deficient mice
pretreated with angiotensinII had reduced MMP2
and MMP9 activity and reduced atrial fibrosis compared with wild-type control mice. 114 Furthermore,
myeloperoxidase-deficient mice are protected from
AF, which can be reversed if intravenous recombinant
myeloperoxidase is infused.114
Cardiac pressure overload by aortic constriction in
mice induces mast cell infiltration and increases PDGFA
synthesis in the atria.94 PDGFA, which promotes cell
proliferation and collagen expression in cardiac fibroblasts, increases atrial fibrosis and susceptibility to AF,
which can be reversed by a mast cell stabilizer (cromolyn) and a PDGFA blocker (the neutralizing PDGF
receptorspecific antibody).94 PDGF and its receptor
are more strongly expressed in atrial fibroblasts than ventricular fibroblasts, and PDGF contributes to the differential fibrotic response of the atria versus ventricles.153
Furthermore, HSPs, especially HSP27, prevent cardiomyocytes from undergoing myolysis and apoptosis and
decrease fibrosis, which can further prevent atrial structural remodelling.118 In clinical studies, high levels of
CRP, HSP27, and IL6, and low levels of IL18, are associated with increased atrial size, which further supports a
role for inflammation in atrial remodelling.57,154,155
Inflammation and thrombogenicity
The role of inflammation in AF-related thrombo

embolism has been indicated in prospective studies in
REVIEWS
Atrium
Plateletleucocyte
interaction
von Willebrand factor
Platelet
P-selectin
Damaged
endothelium
Coagulation
factor
CD40
Thrombus
Immune
cell
infiltration
Thrombin
Tissue factor
CD36
PAR-1
eNOS
Neutrophil
Proinflammatory
cytokines: IL-6
Monocyte
Figure 5 | The pathophysiological link between inflammation and thrombogenesis.

Nature Reviews | Cardiology
Immune cell infiltration induces endothelial dysfunction, which decreases
eNOSexpression, but increases the expression of vonWillebrand factor, thrombin,
tissue factor, and PAR1 on the atrial endocardium. Leucocytes (neutrophils
andmonocytes) that are partially activated by proinflammatory cytokines might
interact with and activate platelets via CD36, CD40, and Pselectin. The adhesion
and activation of platelets and coagulation factors also contributes to a
thromboticclot. Abbreviations: eNOS, endothelial nitric oxide synthase; PAR1,
proteinaseactivated receptor1.
which high CRP or IL6 levels independently predicted

stroke in patients with AF. 156,157 These mechanisms
might be associated with hypercoagulation, platelet
activation, and endothelial dysfunction (Figure5). The
vonWillebrand factor (vWF) and asymmetric dimethyl
arginine (ADMA), biomarkers of endothelial dysfunction were both predictors of stroke in patients with
AF in a prospective cohort.158160 In 994 patients in the
SPAFIII trial,158 levels of vWF independently predicted
the occurrence of stroke (relative risk1.2 per 20IU/dl
increase of vWF, 95% CI 1.01.5, P=0.06) and vascular events (RR1.2 per 20IU/dl increase of vWF, 95%
CI 1.01.4, P=0.02). ADMA levels were also used, in a
single hospital cohort, to predict adverse cardiovascular events including cardiovascular death and ischaemic stroke (HR1.36 per 0.1mol/l increase of ADMA,
95%CI 1.071.74, P=0.01).160 In patients with AF, atrial
lymphomononuclear infiltration was concomitant with
increased expression of vWF and tissue factor.161,162 High
endocardial levels of vWF are also associated with additional platelet adhesion and thrombus formation on the
atrial endocardium.163 A lack of endothelial cells and
endothelial nitric oxide synthase in the cellular region
with platelet adhesion and thrombus formation suggests that endothelial dysfunction also contributes to
thrombogenesis in AF.163
TLR4 might also be an underlying immune mechanism to induce atrial endothelial dysfunction. TLR4
knock-out mice have a lower incidence of atrial thrombosis after thoracic transverse aortic constriction
compared with wild-type mice.83 TLR4-related NFB
signal pathways can activate mitogen-activated protein
kinase p38, decrease phosphorylation of endothelial
nitric oxide synthase, and increase vascular cell adhesion protein1 and plasminogen activator inhibitor1
expression in mice atria.83 Prothrombin and thrombin receptor (protease-activated receptor1) were also
highly expressed in left atrial endocardium concomitant
with monocyte infiltration and tissue fibrosis.164 Tissue
factor and thrombin activate intrinsic coagulation
pathways and platelet aggregation, further contributing
tothrombogenesis.164
Proinflammatory cytokines from immune cells and
leucocyteplatelet interactions might also mediate prothrombotic states (Figure5).8 Proinflammatory cytokines
such as IL6 can induce platelet activation165 and are
associated with spontaneous echo contrast and adverse
cardiovascular outcomes in patients with AF.157,166 Acute
onset of AF will induce plateletleucocyte interactions.167
Platelets can interact with neutrophils and monocytes
and be activated via CD40, Pselectin, and CD36 in AF.
However, in clinical studies, inconsistent results linking
the levels of soluble CD40 or Pselectin to thromboembolism in AF have been reported.156,168,169 Whether
monocyte CD36 is associated with thromboembolism
is currently unclear.
Current anti-inflammatory therapies
To date, no drug has been designed to target the inflammatory pathway specifically in patients with AF, but
most drugs used to prevent AF are arbitrarily considered anti-inflammatory as part of their pleiotropic
effects. Angiotensin-converting-enzyme inhibitors,
angiotensin-receptor blockers, statins, and n3 polyunsaturated fatty acids have been studied in large, prospective, randomized trials and meta-analyses for both
primary and secondary prevention of AF.4,5,170 Owing
to the heterogeneity between studies and disappointing
results in prospective trials, only angiotensin-convertingenzyme inhibitors and angiotensin-receptor blockers are
considered reasonable approaches for the primary prevention of new-onset AF in patients with heart failure
and reduced left ventricular ejection fraction (classIIa
indication, level of evidenceB).4
These findings should not discourage the development of anti-inflammatory therapies in the prevention
of AF, because most of these studies did not demonstrate
a downregulation of inflammation after drug application.171 Even among positive results, the prevention of AF
does not seem to be the result of reduced inflammation.
For example, in the ARMYDA3 trial,37 treatment with
atorvastatin significantly reduced the incidence of postoperative AF after elective cardiac surgery with cardiopulmonary bypass surgery (OR0.39, 95%CI 0.180.85,
P=0.017); however, CRP levels did not significantly
decrease after statin use. Colchicine might prevent AF
by treating pericarditis after surgery or ablation. For
example, colchicine seems to reduce postoperative AF
(from 22.0% to 12.0%; P=0.02) and decreases the complication rate and length of hospital stay.172,173 Colchicine
also prevents early AF recurrences in patients at
3months after pulmonary vein isolation (from 33.5% to
16.0%; P=0.01).174 This effect is associated with a significant decrease in inflammatory mediators, including CRP
and IL6 (CRP: 0.46mg/l; interquartile range: 0.78

REVIEWS
to 0.08mg/l, P<0.01; IL6: 0.10pg/l, 0.30 to 0.10pg/
ml, P<0.01).174,175 Large clinical trials are necessary to
confirm the efficacy of colchicine.
Corticosteroids, which target the anti-inflammatory
pathway more specifically than colchicine, have been
studied in postoperative AF and AF recurrence after
catheter ablation; however, these results are inconsistent and require further investigation.170,176181 Although
corticosteroids can reduce the relative risk of post
procedural AF, the potential adverse effects of this treatment, such as infection, gastrointestinal bleeding, and
hyperglycaemia, might offset the benefit.65 In patients
who received catheter ablation to treat AF, the investigators of one study identified that steroid treatment
increased the difficulty of radiofrequency ablation and
dormant pulmonary vein conduction (from 21.1% to
32.8%; P=0.03).178
Notably, AF recurrence after ablation is not only
associated with enhanced inflammation, but is also
dependent on each individual operator and procedure.
For example, recurrence rates after simple pulmonary
vein isolation differ between patients with persistent or
paroxysmal AF (74.8% versus 84.0%; OR0.57, 95%CI
0.490.66, P<0.001). 182 Moreover, because adjunctive procedures, especially to treat persistent AF, vary
between centres,183 a potential bias might occur when
studying inflammation in patients after catheter ablation
because increased inflammation might arise from extensive ablation, instead of the disease perse. Similar biases
might also occur when comparing the efficiency of antiinflammatory agents to prevent AF recurrence after
catheter ablation.
Future targeting of inflammation in AF
The complex interactions between inflammationassociated cytokines and AF have prevented the identification of proximal triggers and development of a
therapeutic target. A systematic analysis of DAMPs,
cytokines, or autoantibodies might provide a different
explanation of the pathogenesis of this arrhythmia.184,185
However, inflammatory cytokines are also important
for the maintenance of normal cardiac physiology.85,184
Complete and long-term suppression of mediators of
inflammation might be detrimental to the heart, and
identifying the presence of inflammation at an early
stage is critical for anti-inflammatory therapy for AF.
Short-term suppression of the immune system at an
early stage of AF might stop the cycle of inflammatory
responses and minimize the adverse effects in patients
receiving such therapy.186 Furthermore, even therapy that
completely inhibits inflammation might not reverse the
pathological changes in the atrium owing to electrical or
structuralremodelling.187
Different cytokines and their mediators have been
studied in both animal and human investigations, and
CRP still seems to be the most practical and reproducible
indicator of inflammation to predict AF occurrence.6163
However, AF-associated inflammation might be a local
process in the atria rather than a systemic phenomenon,
and biomarkers of systemic circulation might not detect
early-stage atrial inflammation.188 Imaging techniques,

such as 18Ffluorodeoxyglucose PET with concurrent
structural imaging (either CT or MRI), might be used to
delineate regional inflammation ofatherosclerotic plaque
and be useful for the detectionof regional atrial inflammation.189 Increasing expression of anti-inflammatory
mediators might also avoid the detrimental consequences
of inhibiting physiologically important cytokines and
actively suppressing overactivated proinflammatory
cascades. Inducing inhibitory molecules and activating pathways that suppress inflammation, including the
targeting of HSP27, HSP60, IL10, or antibodies against
DAMPs, might also be potential therapeutic strategies
for AF.138
Simultaneously targeting the complex interactions
between inflammation and other causes of AF (such
as oxidative stress and RAAS) might prevent inflammation and adequately suppress proinflammatory cascades. Systemic inflammatory markers such as CRP
or TGF1 might be useful clinical indicators to guide
therapy, and inflammatory markers might predict
ablation outcomes in future studies. Patients who are at
increased risk of developing recurrent AF and progressive remodelling even after repeated ablation might also
be identified using inflammatory markers before the procedure, thereby enabling the consideration of alternative therapeutic strategies. For example, in patients with
nonparoxysmal AF who receive catheter ablation, high
TGF1 levels (>31.3ng/ml) in those with large atriums
(anteroposterior diameter >43mm) are associated with
an 89% recurrence of AF (P<0.001), which suggests that
ablation by targeting pulmonary veins and complex fractionated atrial electrograms might not fulfil therapeutic
demand.190 However, the use of biomarkers of inflammation that can identify patients at risk of developing
AF is still challenging. Standardizing the methodology
to detect inflammatory markers is critical to accumulate data and validate the relevance of biomarkers from
different research centres.
Finally, the inflammatory mechanisms underlying AF
might also differ between patients, and identifying different inflammatory signatures in these patients might
help to guide specific therapies. For example, in patients
with AF and high IL6 levels owing to a genetic polymorphism, IL6 continuously modulates the pathogenesis of
AF.50 Consequently, new therapies might require the specific targeting of IL6 in addition to the modification of
other factors to produce beneficial results.
Conclusions
Inflammation has an important role in the initiation and

maintenance of AF. The electrophysiology and structural
properties of the atria are critically affected by inflammatory processes, and the efficacy of the proposed
anti-inflammatory drugs remains far from satisfactory.
A comprehensive understanding of the complexity of
inflammatory pathophysiology underlying different
clinical scenarios in AF is necessary for the development of future therapeutic strategies for the primary or
secondary prevention of this arrhythmia.
REVIEWS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Camm, A.J. etal. 2012 focused update of the

ESC guidelines for the management of atrial
fibrillation: an update of the 2010 ESC
guidelines for the management of atrial
fibrillationdeveloped with the special
contribution of the European Heart Rhythm
Association. Europace 14, 13851413 (2012).
Chugh, S.S. etal. Worldwide epidemiology of
atrial fibrillation: a Global Burden of Disease
2010 Study. Circulation 129, 837847 (2014).
Naccarelli, G.V., Varker, H., Lin, J.
&Schulman,K.L. Increasing prevalence of
atrialfibrillation and flutter in the United States.
Am. J. Cardiol. 104, 15341539 (2009).
January, C.T. etal. 2014 AHA/ACC/HRS
guideline for the management of patients with
atrial fibrillation: a report of the American
College of Cardiology/American Heart
Association Task Force on Practice Guidelines
and the Heart Rhythm Society. J. Am. Coll. Cardiol.
64, e1e76 (2014).
Calkins, H. etal. 2012HRS/EHRA/ECAS expert
consensus statement on catheter and surgical
ablation of atrial fibrillation: recommendations
for patient selection, procedural techniques,
patient management and follow-up, definitions,
endpoints, and research trial design: a report
ofthe Heart Rhythm Society (HRS) Task Force
onCatheter and Surgical Ablation of Atrial
Fibrillation. Developed in partnership with the
European Heart Rhythm Association (EHRA),
aregistered branch of the European Society
ofCardiology (ESC) and the European Cardiac
Arrhythmia Society (ECAS); and in collaboration
with the American College of Cardiology (ACC),
American Heart Association (AHA), the Asia
Pacific Heart Rhythm Society (APHRS), and the
Society of Thoracic Surgeons (STS). Endorsed
bythe governing bodies of the American College
of Cardiology Foundation, the American Heart
Association, the European Cardiac Arrhythmia
Society, the European Heart Rhythm Association,
the Society of Thoracic Surgeons, the Asia
Pacific Heart Rhythm Society, and the Heart
Rhythm Society. Heart Rhythm 9, 632696.e21
(2012).
Morillo, C.A. etal. Radiofrequency ablation
vsantiarrhythmic drugs as first-line treatment
ofparoxysmal atrial fibrillation (RAAFT2):
arandomized trial. JAMA 311, 692700 (2014).
Calkins, H. etal. Treatment of atrial fibrillation
with antiarrhythmic drugs or radiofrequency
ablation: two systematic literature reviews and
meta-analyses. Circ. Arrhythm. Electrophysiol. 2,
349361 (2009).
Guo, Y., Lip, G.Y. & Apostolakis, S.
Inflammationin atrial fibrillation. J. Am. Coll.
Cardiol. 60, 22632270 (2012).
Savelieva, I., Kakouros, N., Kourliouros, A.
&Camm, A.J. Upstream therapies for
management of atrial fibrillation: review of
clinical evidence and implications for European
Society of Cardiology guidelines. PartI: primary
prevention. Europace 13, 308328 (2011).
Patel, P., Dokainish, H., Tsai, P. & Lakkis, N.
Update on the association of inflammation and
atrial fibrillation. J. Cardiovasc. Electrophysiol. 21,
10641070 (2010).
Gregor, M.F. & Hotamisligil, G.S. Inflammatory
mechanisms in obesity. Annu. Rev. Immunol. 29,
415445 (2011).
Harrison, D.G. etal. Inflammation, immunity,
and hypertension. Hypertension 57, 132140
(2011).
Marzilli, M. etal. Obstructive coronary
atherosclerosis and ischemic heart disease:
anelusive link! J. Am. Coll. Cardiol. 60, 951956
(2012).
14. Wang, T.J. etal. Obesity and the risk of newonset atrial fibrillation. JAMA 292, 24712477
(2004).
15. Zacharias, A. etal. Obesity and risk of new-onset
atrial fibrillation after cardiac surgery. Circulation
112, 32473255 (2005).
16. Lumeng, C.N., DelProposto, J.B., Westcott, D.J.
& Saltiel, A.R. Phenotypic switching of adipose
tissue macrophages with obesity is generated
byspatiotemporal differences in macrophage
subtypes. Diabetes 57, 32393246 (2008).
17. Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R.
Obesity induces a phenotypic switch in adipose
tissue macrophage polarization. J. Clin. Invest.
117, 175184 (2007).
18. Hotamisligil, G.S., Arner, P., Caro, J.F.,
Atkinson,R.L. & Spiegelman, B.M. Increased
adipose tissue expression of tumor necrosis
factor-alpha in human obesity and insulin
resistance. J. Clin. Invest. 95, 24092415 (1995).
19. Mohamed-Ali, V. etal. Subcutaneous adipose
tissue releases interleukin6, but not tumor
necrosis factor-alpha, invivo. J. Clin. Endocrinol.
Metab. 82, 41964200 (1997).
20. Mazurek, T. etal. Relation of proinflammatory
activity of epicardial adipose tissue to the
occurrence of atrial fibrillation. Am. J. Cardiol.
113, 15051508 (2014).
21. Nagashima, K. etal. Does location of epicardial
adipose tissue correspond to endocardial high
dominant frequency or complex fractionated
atrial electrogram sites during atrial fibrillation?
Circ. Arrhythm. Electrophysiol. 5, 676683
(2012).
22. Kanazawa, H. etal. Importance of pericardial
fatin the formation of complex fractionated
atrial electrogram region in atrial fibrillation.
Int.J. Cardiol. 174 557564 (2014).
23. Poirier, P. etal. Obesity and cardiovascular
disease: pathophysiology, evaluation, and effect
of weight loss: an update of the 1997 American
Heart Association Scientific Statement on
Obesity and Heart Disease from the Obesity
Committee of the Council on Nutrition,
PhysicalActivity, and Metabolism. Circulation
113, 898918 (2006).
24. Lau, D.H. etal. Hypertension and atrial
fibrillation: evidence of progressive atrial
remodeling with electrostructural correlate in a
conscious chronically instrumented ovine model.
Heart Rhythm 7, 12821290 (2010).
25. Lau, D.H. etal. Atrial arrhythmia in ageing
spontaneously hypertensive rats: unraveling the
substrate in hypertension and ageing. PLoS ONE
8, e72416 (2013).
26. Kistler, P.M. etal. Atrial electrical and structural
abnormalities in an ovine model of chronic
blood pressure elevation after prenatal
corticosteroid exposure: implications for
development of atrial fibrillation. Eur. Heart J.
27, 30453056 (2006).
27. Friedrichs, K. etal. Induction of atrial fibrillation
by neutrophils critically depends on CD11b/
CD18 integrins. PLoS ONE 9 e89307 (2014).
28. Suzuki, Y. etal. Inflammation and angiotensin II.
Int. J. Biochem. Cell Biol. 35, 881900 (2003).
29. Wang, Y. etal. TNF- and IL1 neutralization
ameliorates angiotensinIIinduced cardiac
damage in male mice. Endocrinology 155,
26772687 (2014).
30. De Jong, A.M. etal. Mechanisms of atrial
structural changes caused by stretch occurring
before and during early atrial fibrillation.
Cardiovasc. Res. 89, 754765 (2011).
31. Zhang, J. etal. NOX4-dependent hydrogen
peroxide overproduction in human atrial
fibrillation and HL1 atrial cells: relationship to
hypertension. Front. Physiol. 3, 140 (2012).
32. Hori, M. & Nishida, K. Oxidative stress and

leftventricular remodelling after myocardial
infarction. Cardiovasc. Res. 81, 457464
(2009).
33. Sinno, H. etal. Atrial ischemia promotes atrial
fibrillation in dogs. Circulation 107, 19301936
(2003).
34. Stellos, K. etal. Expression of platelet-bound
stromal cell-derived factor1 in patients with
nonvalvular atrial fibrillation and ischemic heart
disease. J. Thromb. Haemost. 10, 4955 (2012).
35. Mehta, N.N. etal. The novel atherosclerosis
locus at 10q11 regulates plasma CXCL12
levels. Eur. Heart J. 32, 963971 (2011).
36. Kim, D. etal. CXCL12 secreted from adipose
tissue recruits macrophages and induces insulin
resistance in mice. Diabetologia 57, 14561465
(2014).
37. Patti, G. etal. Randomized trial of atorvastatin
for reduction of postoperative atrial fibrillation
inpatients undergoing cardiac surgery: results
of the ARMYDA3 (Atorvastatin for Reduction of
MYocardial Dysrhythmia After cardiac surgery)
study. Circulation 114, 14551461 (2006).
38. Zhang, Z. etal. n3 polyunsaturated fatty acids
prevents atrial fibrillation by inhibiting
inflammation in a canine sterile pericarditis
model. Int. J. Cardiol. 153, 1420 (2011).
39. Ishii, Y. etal. Inflammation of atrium after
cardiacsurgery is associated with inhomogeneity
of atrial conduction and atrial fibrillation.
Circulation 111, 28812888 (2005).
40. Grubman, E. etal. Histopathologic effects of
radiofrequency catheter ablation in previously
infarcted human myocardium. J. Cardiovasc.
Electrophysiol. 10, 336342 (1999).
41. Lim, H.S. etal. Time course of inflammation,
myocardial injury, and prothrombotic response
after radiofrequency catheter ablation for atrial
fibrillation. Circ. Arrhythm. Electrophysiol. 7,
8389 (2014).
42. Richter, B. etal. Markers of oxidative stress
afterablation of atrial fibrillation are associated
with inflammation, delivered radiofrequency
energy and early recurrence of atrial fibrillation.
Clin. Res. Cardiol. 101, 217225 (2012).
43. Mandal, K. etal. Association of anti-heat shock
protein 65 antibodies with development of
postoperative atrial fibrillation. Circulation 110,
25882590 (2004).
44. Li, H. etal. Atrial tachycardia provoked in the
presence of activating autoantibodies to
2adrenergic receptor in the rabbit. Heart Rhythm
10, 436441 (2013).
45. Kornej, J. etal. Response of circulating heat
shock protein 70 and anti-heat shock protein
70antibodies to catheter ablation of atrial
fibrillation. J. Transl. Med. 11, 49 (2013).
46. Kato, K. etal. Genetic factors for lone atrial
fibrillation. Int. J. Mol. Med. 19, 933939 (2007).
47. Lin, H. etal. Targeted sequencing in candidate
genes for atrial fibrillation: the Cohorts for
Heartand Aging Research in Genomic
Epidemiology (CHARGE) Targeted Sequencing
Study. HeartRhythm 11, 452457 (2014).
48. Marcus, G.M. etal. Interleukin6 and atrial
fibrillation in patients with coronary artery
disease: data from the Heart and Soul Study.
Am. Heart J. 155, 303309 (2008).
49. Gungor, B. etal. Assessment of interleukin1
gene cluster polymorphisms in lone atrial
fibrillation: new insight into the role of
inflammation in atrial fibrillation. Pacing Clin.
Electrophysiol. 36, 12201227 (2013).
50. Gaudino, M. etal. The 174G/C interleukin6
polymorphism influences postoperative
interleukin6 levels and postoperative atrial
fibrillation. Is atrial fibrillation an inflammatory

REVIEWS
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
complication? Circulation 108 (Suppl.1),

II195II199 (2003).
Chiang, C.H. etal. Herpes simplex virus
infection and risk of atrial fibrillation:
anationwide study. Int. J. Cardiol. 164, 201204
(2013).
Hsu, J.C. etal. Atrial fibrillation and atrial flutter
in human immunodeficiency virus-infected
persons: incidence, risk factors, and association
with markers of HIV disease severity. J. Am. Coll.
Cardiol. 61, 22882295 (2013).
Yearley, J.H. etal. Antigenic stimulation in the
simian model of HIV infection yields dilated
cardiomyopathy through effects of TNF. AIDS
22, 585594 (2008).
Raidel, S.M. etal. Targeted myocardial
transgenic expression of HIV tat causes
cardiomyopathy and mitochondrial damage. Am. J.
Physiol. Heart Circ. Physiol. 282, H1672H1678
(2002).
Frustaci, A. etal. Histological substrate of atrial
biopsies in patients with lone atrial fibrillation.
Circulation 96, 11801184 (1997).
Boos, C.J., Anderson, R.A. & Lip, G.Y. Is atrial
fibrillation an inflammatory disorder? Eur. Heart J.
27, 136149 (2006).
Hu, Y.F. etal. Electrophysiological correlation
and prognostic impact of heat shock protein 27
in atrial fibrillation. Circ. Arrhythm. Electrophysiol.
5, 334340 (2012).
Jacob, K.A. etal. Inflammation in newonsetatrial fibrillation after cardiac surgery:
asystematic review. Eur. J. Clin. Invest. 44,
402428 (2014).
Smit, M.D. etal. Role of inflammation in
earlyatrial fibrillation recurrence. Europace 14,
810817 (2012).
Aviles, R.J. etal. Inflammation as a risk factor
for atrial fibrillation. Circulation 108, 30063010
(2003).
Marott, S.C. etal. Does elevated Creactive
protein increase atrial fibrillation risk?
AMendelian randomization of 47,000
individuals from the general population. J. Am.
Coll. Cardiol. 56, 789795 (2010).
Conen, D. etal. A multimarker approach
toassess the influence of inflammation on
theincidence of atrial fibrillation in women.
Eur.Heart J. 31, 17301736 (2010).
Dernellis, J. & Panaretou, M. Relationship
between Creactive protein concentrations
during glucocorticoid therapy and recurrent
atrial fibrillation. Eur. Heart J. 25, 11001107
(2004).
Bruins, P. etal. Activation of the complement
system during and after cardiopulmonary bypass
surgery: postsurgery activation involves
Creactive protein and is associated with
postoperative arrhythmia. Circulation 96,
35423548 (1997).
Ho, K.M. & Tan, J.A. Benefits and risks of
corticosteroid prophylaxis in adult cardiac
surgery: a doseresponse meta-analysis.
Circulation 119, 18531866 (2009).
Marcus, G.M. etal. Markers of inflammation
before and after curative ablation of atrial flutter.
Heart Rhythm 5, 215221 (2008).
Marcus, G.M. etal. Intracardiac and
extracardiac markers of inflammation during
atrial fibrillation. Heart Rhythm 7, 149154
(2010).
Chung, M.K. etal. Creactive protein elevation
inpatients with atrial arrhythmias: inflammatory
mechanisms and persistence of atrial
fibrillation. Circulation 104, 28862891 (2001).
Li, J. etal. Role of inflammation and oxidative
stress in atrial fibrillation. Heart Rhythm 7,
438444 (2010).
70. Kallergis, E.M. etal. The role of the postcardioversion time course of hs-CRP levels in
clarifying the relationship between inflammation
and persistence of atrial fibrillation. Heart 94,
200204 (2008).
71. Rotter, M. etal. Decline in Creactive protein
aftersuccessful ablation of long-lasting
persistent atrial fibrillation. J. Am. Coll. Cardiol.
47, 12311233 (2006).
72. Shiroshita-Takeshita, A., Brundel, B.J., Lavoie, J.
& Nattel, S. Prednisone prevents atrial fibrillation
promotion by atrial tachycardia remodeling in
dogs. Cardiovasc. Res. 69, 865875 (2006).
73. Aime-Sempe, C. etal. Myocardial cell death in
fibrillating and dilated human right atria. J. Am.
Coll. Cardiol. 34, 15771586 (1999).
74. Tabas, I. & Glass, C.K. Anti-inflammatory
therapy in chronic disease: challenges and
opportunities. Science 339, 166172 (2013).
75. Das, M. etal. Induction of hepatitis by JNKmediated expression of TNF-. Cell 136, 249260
(2009).
76. Arslan, F., de Kleijn, D.P. & Pasterkamp, G.
Innate immune signaling in cardiac ischemia.
Nat. Rev. Cardiol. 8, 292300 (2011).
77. Tousoulis, D. etal. Oxidative stress and
inflammatory process in patients with atrial
fibrillation: the role of left atrium distension.
Int.J. Cardiol. 136, 258262 (2009).
78. Steiner, I. & Hajkova, P. Patterns of isolated
atrialamyloid: a study of 100 hearts on autopsy.
Cardiovasc. Pathol. 15, 287290 (2006).
79. Afzal, A.R. etal. Association of Met439Thr
substitution in heat shock protein 70 gene with
postoperative atrial fibrillation and serum HSP70
protein levels. Cardiology 110, 445452 (2008).
80. Brundel, B.J. etal. Heat shock protein
upregulation protects against pacing-induced
myolysis in HL1 atrial myocytes and in human
atrial fibrillation. J. Mol. Cell. Cardiol. 41, 555562
(2006).
81. Ichiki, H. etal. The role of infection in the
development of non-valvular atrial fibrillation:
upregulation of Toll-like receptor 2 expression
levels on monocytes. J. Cardiol. 53, 127135
(2009).
82. Wang, J. etal. TLR2 was overexpressed
independent of IL6 in patients with valvular atrial
fibrillation. J. Biomed. Res. 25, 178184 (2011).
83. Katoh, S. etal. Atrial endothelial impairment
through Toll-like receptor 4 signaling causes
atrial thrombogenesis. Heart Vessels 29, 263272
(2014).
84. Boyd, J.H., Mathur, S., Wang, Y., Bateman, R.M.
& Walley, K.R. Toll-like receptor stimulation in
cardiomyoctes decreases contractility and
initiates an NFB dependent inflammatory
response. Cardiovasc. Res. 72, 384393 (2006).
85. Frangogiannis, N.G. The inflammatory response
in myocardial injury, repair, and remodelling.
Nat.Rev. Cardiol. 11, 255265 (2014).
86. Monnerat-Cahli, G. etal. Toll-like receptor 4
activation promotes cardiac arrhythmias by
decreasing the transient outward potassium
current (Ito) through an IRF3-dependent and
MyD88-independent pathway. J. Mol. Cell. Cardiol.
76, 116125 (2014).
87. Yamashita, T. etal. Recruitment of immune
cellsacross atrial endocardium in human
atrialfibrillation. Circ. J. 74, 262270 (2010).
88. Qu, Y.C. etal. Activated nuclear factorkappaBand increased tumor necrosis factoralpha in atrial tissue of atrial fibrillation.
Scand.Cardiovasc. J. 43, 292297 (2009).
89. Goette, A. etal. Angiotensin II receptor blockade
reduces tachycardia-induced atrial adhesion
molecule expression. Circulation 117, 732742
(2008).
90. Hu, Y.F. etal. Impact of circulating monocyte

CD36 level on atrial fibrillation and subsequent
catheter ablation. Heart Rhythm 8, 650656
(2011).
91. Liu, L. etal. Activation of peripheral blood CD3+
Tlymphocytes in patients with atrial fibrillation.
Int. Heart J. 53, 221224 (2012).
92. Corradi, D. etal. Persistent lone atrial fibrillation:
clinicopathologic study of 19 cases. Heart Rhythm
11, 12501258 (2014).
93. Schuessler, R.B. etal. The effects of
inflammation on heart rate and rhythm in a
canine model of cardiac surgery. Heart Rhythm
9, 432439 (2012).
94. Liao, C.H. etal. Cardiac mast cells cause atrial
fibrillation through PDGFAmediated fibrosis in
pressure-overloaded mouse hearts. J. Clin. Invest.
120, 242253 (2010).
95. Gibson, P.H. etal. Usefulness of neutrophil/
lymphocyte ratio as predictor of new-onset atrial
fibrillation after coronary artery bypass grafting.
Am. J. Cardiol. 105, 186191 (2010).
96. Canpolat, U. etal. Role of preablation
neutrophil/lymphocyte ratio on outcomes of
cryoballoon-based atrial fibrillation ablation.
Am.J. Cardiol. 112, 513519 (2013).
97. Guo, X. etal. Postablation neutrophil/lymphocyte
ratio correlates with arrhythmia recurrence
aftercatheter ablation of lone atrial fibrillation.
Chin. Med. J. 127, 10331038 (2014).
98. Klebanoff, S.J. Myeloperoxidase. Proc. Assoc.
Am. Physicians 111, 383389 (1999).
99. Ishida, K. etal. Relation of inflammatory
cytokines to atrial fibrillation after off-pump
coronary artery bypass grafting. Eur. J.
Cardiothorac. Surg. 29, 501505 (2006).
100. Stein, A. etal. Systemic inflammatory changes
after pulmonary vein radiofrequency ablation do
not alter stem cell mobilization. Europace 10,
444449 (2008).
101. Kennedy, S., Wu, J., Wadsworth, R.M.,
Lawrence, C.E. & Maffia, P. Mast cells and
vascular diseases. Pharmacol. Ther. 138, 5365
(2013).
102. Chinetti-Gbaguidi, G., Colin, S. & Staels, B.
Macrophage subsets in atherosclerosis.
Nat.Rev. Cardiol. 12, 1017 (2014).
103. Kared, H., Camous, X. & Larbi, A. Tcells and
their cytokines in persistent stimulation of the
immune system. Curr. Opin. Immunol. 29, 7985
(2014).
104. Schnabel, R.B. etal. Relation of multiple
inflammatory biomarkers to incident atrial
fibrillation. Am. J. Cardiol. 104, 9296 (2009).
105. Saba, S. etal. Atrial contractile dysfunction,
fibrosis, and arrhythmias in a mouse model of
cardiomyopathy secondary to cardiac-specific
overexpression of tumor necrosis factor. Am. J.
(2005).
106. Sawaya, S.E. etal. Downregulation of
connexin40 and increased prevalence of atrial
arrhythmias in transgenic mice with cardiacrestricted overexpression of tumor necrosis
factor. Am. J. Physiol. Heart Circ. Physiol. 292,
H1561H1567 (2007).
107. Verheule, S. etal. Increased vulnerability to atrial
fibrillation in transgenic mice with selective
atrialfibrosis caused by overexpression of
TGF1. Circ. Res. 94, 14581465 (2004).
108. Choi, E.K. etal. Triggered firing and atrial
fibrillation in transgenic mice with selective
atrialfibrosis induced by overexpression of
TGF1. Circ. J. 76, 13541362 (2012).
109. Wu, N. etal. Association of inflammatory
factorswith occurrence and recurrence of atrial
fibrillation: a meta-analysis. Int. J. Cardiol. 169,
6272 (2013).
REVIEWS
110. Wang, Y., Hou, X. & Li, Y. Association between
transforming growth factor1 polymorphisms
and atrial fibrillation in essential hypertensive
subjects. J. Biomed. Sci. 17, 23 (2010).
111. Zhao, F. etal. Calreticulin overexpression
correlates with integrin-5 and transforming
growth factor-1 expression in the atria of
patients with rheumatic valvular disease and
atrial fibrillation. Int. J. Cardiol. 168, 21772185
(2013).
112. Nakatani, Y. etal. Tranilast prevents atrial
remodeling and development of atrial fibrillation
in a canine model of atrial tachycardia and left
ventricular dysfunction. J. Am. Coll. Cardiol. 61,
582588 (2013).
113. Chung, E.S., Packer, M., Lo, K.H.,
Fasanmade,A.A. & Willerson, J.T. Randomized,
double-blind, placebo-controlled, pilot trial of
infliximab, a chimeric monoclonal antibody to
tumor necrosis factor, in patients with moderateto-severe heart failure: results of the anti-TNF
Therapy Against Congestive Heart Failure (ATTACH)
trial. Circulation 107, 31333140 (2003).
114. Rudolph, V. etal. Myeloperoxidase acts as a
profibrotic mediator of atrial fibrillation. Nat. Med.
16, 470474 (2010).
115. Li, S.B. etal. Myeloperoxidase and risk of
recurrence of atrial fibrillation after catheter
ablation. J. Investig. Med. 61, 722727 (2013).
116. Ghayour-Mobarhan, M., Saber, H. & Ferns, G.A.
The potential role of heat shock protein 27 in
cardiovascular disease. Clin. Chim. Acta 413,
1524 (2012).
117. Brundel, B.J. etal. Heat shock proteins as
molecular targets for intervention in atrial
fibrillation. Cardiovasc. Res. 78, 422428 (2008).
118. Hoogstra-Berends, F. etal. Heat shock proteininducing compounds as therapeutics to restore
proteostasis in atrial fibrillation. Trends Cardiovasc.
Med. 22, 6268 (2012).
119. Yang, M. etal. Expression of heat shock proteins
in myocardium of patients with atrial fibrillation.
Cell Stress Chaperones 12, 142150 (2007).
120. Brundel, B.J. etal. Induction of heat shock
response protects the heart against atrial
fibrillation. Circ. Res. 99, 13941402 (2006).
121. Ke, L. etal. HSPB1, HSPB6, HSPB7 and
HSPB8protect against RhoA GTPase-induced
remodeling in tachypaced atrial myocytes.
PLoSONE 6, e20395 (2011).
122. Chang, S.L. etal. Heat shock protein inducer
modifies arrhythmogenic substrate and inhibits
atrial fibrillation in the failing heart. Int. J. Cardiol.
168, 40194026 (2013).
123. Wakisaka, O. etal. Hyperthermia treatment
prevents angiotensin IImediated atrial fibrosis
and fibrillation via induction of heat-shock
protein 72. J. Mol. Cell. Cardiol. 43, 616626
(2007).
124. Schafler, A.E. etal. The expression of heat
shock protein 60 in myocardium of patients with
chronic atrial fibrillation. Basic Res. Cardiol. 97,
258261 (2002).
125. De, A.K., Kodys, K.M., Yeh, B.S.
&MillerGraziano, C. Exaggerated human
monocyte IL10 concomitant to minimal TNF
induction by heat-shock protein 27 (Hsp27)
suggests Hsp27 is primarily an antiinflammatory
stimulus. J.Immunol. 165, 39513958 (2000).
126. Jin, C. etal. Human myocardium releases heat
shock protein 27 (HSP27) after global ischemia:
the proinflammatory effect of extracellular
HSP27 through toll-like receptor (TLR)2 and
TLR4. Mol. Med. 20, 280289 (2014).
127. Asea, A. etal. Novel signal transduction pathway
utilized by extracellular HSP70: role of toll-like
receptor (TLR) 2 and TLR4. J. Biol. Chem. 277,
1502815034 (2002).
128. Mathur, S., Walley, K.R., Wang, Y.,

Indrambarya,T. & Boyd, J.H. Extracellular heat
shock protein 70 induces cardiomyocyte
inflammation and contractile dysfunction via
TLR2. Circ. J. 75, 24452452 (2011).
129. Lin, L. etal. HSP60 in heart failure: abnormal
distribution and role in cardiac myocyte
apoptosis. Am. J. Physiol. Heart Circ. Physiol.
293, H2238H2247 (2007).
130. Kim, S.C. etal. Extracellular heat shock protein
60, cardiac myocytes, and apoptosis. Circ. Res.
105, 11861195 (2009).
131. Tian, J. etal. Extracellular HSP60 induces
inflammation through activating and up-regulating
TLRs in cardiomyocytes. Cardiovasc. Res. 98,
391401 (2013).
132. Kol, A., Lichtman, A.H., Finberg, R.W., Libby, P.
&Kurt-Jones, E.A. Cutting edge: heat shock
protein (HSP) 60 activates the innate immune
response: CD14 is an essential receptor
forHSP60 activation of mononuclear cells.
J.Immunol. 164, 1317 (2000).
133. Zanin-Zhorov, A., Nussbaum, G., Franitza, S.,
Cohen, I.R. & Lider, O. Tcells respond to heat
shock protein 60 via TLR2: activation of
adhesion and inhibition of chemokine receptors.
FASEB J. 17, 15671569 (2003).
134. Rudolphi, U. etal. The Bcell repertoire of
patients with rheumatoid arthritis. II. Increased
frequencies of IgG+ and IgA+ Bcells specific for
mycobacterial heat-shock protein 60 or human
typeII collagen in synovial fluid and tissue.
Arthritis Rheum. 40, 14091419 (1997).
135. Schett, G. etal. Autoantibodies against heat
shock protein 60 mediate endothelial cytotoxicity.
J. Clin. Invest. 96, 25692577 (1995).
136. Foteinos, G., Afzal, A.R., Mandal, K.,
Jahangiri,M. & Xu, Q. Anti-heat shock protein 60
autoantibodies induce atherosclerosis in
apolipoproteinE-deficient mice via endothelial
damage. Circulation 112, 12061213 (2005).
137. Gruden, G. etal. Anti-hsp60 and Anti-hsp70
antibody levels and micro/macrovascular
complications in type1 diabetes: the EURODIAB
Study. J. Intern. Med. 266, 527536 (2009).
138. van Puijvelde, G.H. etal. Induction of oral
tolerance to HSP60 or an HSP60-peptide
activates Tcell regulation and reduces
atherosclerosis. Arterioscler. Thromb. Vasc. Biol.
27, 26772683 (2007).
139. Binder, C.J. etal. Pneumococcal vaccination
decreases atherosclerotic lesion formation:
molecular mimicry between Streptococcus
pneumoniae and oxidized LDL. Nat. Med. 9,
736743 (2003).
140. Cesena, F.H. etal. Immune-modulation by
polyclonal IgM treatment reduces
atherosclerosis in hypercholesterolemic apoE-/mice. Atherosclerosis 220, 5965 (2012).
141. Wakili, R., Voigt, N., Kaab, S., Dobrev, D.
&Nattel, S. Recent advances in the molecular
pathophysiology of atrial fibrillation. J. Clin. Invest.
121, 29552968 (2011).
142. Lee, S.H. etal. Tumor necrosis factor
alterscalcium handling and increases
arrhythmogenesis of pulmonary vein
cardiomyocytes. Life Sci. 80, 18061815
(2007).
143. Kao, Y.H. etal. Tumor necrosis factor
decreases sarcoplasmic reticulum Ca2+-ATPase
expressions via the promoter methylation in
cardiomyocytes. Crit. Care Med. 38, 217222
(2010).
144. Musa, H. etal. Inhibition of platelet-derived growth
factor-AB signaling prevents electromechanical
remodeling of adult atrial myocytes that contact
myofibroblasts. Heart Rhythm 10, 10441051
(2013).
145. Nelson, B.H. IL2, regulatory Tcells, and

tolerance. J. Immunol. 172, 39833988 (2004).
146. Cao, C.M. etal. Influence of interleukin2 on
Ca2+ handling in rat ventricular myocytes. J. Mol.
Cell. Cardiol. 35, 14911503 (2003).
147. Tselentakis, E.V., Woodford, E., Chandy, J.,
Gaudette, G.R. & Saltman, A.E. Inflammation
effects on the electrical properties of atrial
tissue and inducibility of postoperative atrial
fibrillation. J. Surg. Res. 135, 6875 (2006).
148. Ryu, K. etal. Effects of sterile pericarditis on
connexins 40 and 43 in the atria: correlation with
abnormal conduction and atrial arrhythmias. Am.J.
(2007).
149. Liew, R. etal. Role of tumor necrosis factor-alpha
in the pathogenesis of atrial fibrosis and
development of an arrhythmogenic substrate.
Circ. J. 77, 11711179 (2013).
150. Lin, Y.J. etal. Prognostic implications of the
high-sensitive Creactive protein in the catheter
ablation of atrial fibrillation. Am. J. Cardiol. 105,
495501 (2010).
151. Wilhelm, M. etal. Inflammation and atrial
remodeling after a mountain marathon. Scand. J.
Med. Sci. Sports 24, 519525 (2014).
152. Li, Y.Y. etal. Myocardial extracellular matrix
remodeling in transgenic mice overexpressing
tumor necrosis factor alpha can be modulated
by anti-tumor necrosis factor alpha therapy. Proc.
Natl Acad. Sci. USA 97, 1274612751 (2000).
153. Burstein, B., Libby, E., Calderone, A. & Nattel, S.
Differential behaviors of atrial versus ventricular
fibroblasts: a potential role for platelet-derived
growth factor in atrial-ventricular remodeling
differences. Circulation 117, 16301641 (2008).
154. Psychari, S.N. etal. Relation of elevated
Creactive protein and interleukin6 levels to left
atrial size and duration of episodes in patients
with atrial fibrillation. Am. J. Cardiol. 95, 764767
(2005).
155. Luan, Y. etal. Interleukin18 among atrial
fibrillation patients in the absence of structural
heart disease. Europace 12, 17131718
(2010).
156. Lip, G.Y., Patel, J.V., Hughes, E. & Hart, R.G.
High-sensitivity Creactive protein and soluble
CD40 ligand as indices of inflammation and
platelet activation in 880 patients with
nonvalvular atrial fibrillation: relationship to
stroke risk factors, stroke risk stratification
schema, and prognosis. Stroke 38, 12291237
(2007).
157. Roldan, V. etal. High sensitivity cardiac
troponinT and interleukin6 predict adverse
cardiovascular events and mortality in
anticoagulated patients with atrial fibrillation.
J.Thromb. Haemost. 10, 15001507 (2012).
158. Conway, D.S., Pearce, L.A., Chin, B.S., Hart,R.G.
& Lip, G.Y. Prognostic value of plasma von
Willebrand factor and soluble Pselectin as
indices of endothelial damage and platelet
activation in 994 patients with nonvalvular atrial
fibrillation. Circulation 107, 31413145 (2003).
159. Roldan, V. etal. Plasma von Willebrand factor
levels are an independent risk factor for adverse
events including mortality and major bleeding in
anticoagulated atrial fibrillation patients. J. Am.
Coll. Cardiol. 57, 24962504 (2011).
160. Chao, T.F. etal. Plasma asymmetric
dimethylarginine and adverse events in patients
with atrial fibrillation referred for coronary
angiogram. PLoS ONE 8, e71675 (2013).
161. Nakamura, Y. etal. Tissue factor expression in
atrial endothelia associated with nonvalvular
atrial fibrillation: possible involvement in
intracardiac thrombogenesis. Thromb. Res. 111,
137142 (2003).

REVIEWS
162. Kaireviciute, D. etal. Intracardiac expression
ofmarkers of endothelial damage/dysfunction,
inflammation, thrombosis, and tissue
remodeling, and the development of
postoperative atrial fibrillation. J. Thromb.
Haemost. 9, 23452352 (2011).
163. Fukuchi, M. etal. Increased von Willebrand
factor in the endocardium as a local
predisposing factor for thrombogenesis in
overloaded human atrial appendage. J. Am. Coll.
Cardiol. 37, 14361442 (2001).
164. Ito, K. etal. An immunohistochemical analysis
oftissue thrombin expression in the human
atria. PLoS ONE 8, e65817 (2013).
165. Marino, M. etal. Novel path to IL6 transsignaling through thrombin-induced soluble IL6
receptor release by platelets. J. Biol. Regul.
Homeost. Agents 27, 841852 (2013).
166. Conway, D.S., Buggins, P., Hughes, E. & Lip, G.Y.
Relation of interleukin6, Creactive protein, and
the prothrombotic state to transesophageal
echocardiographic findings in atrial fibrillation.
Am. J. Cardiol. 93, 13681373 (2004).
167. Hayashi, M. etal. Platelet activation and
induction of tissue factor in acute and chronic
atrial fibrillation: involvement of mononuclear
cell-platelet interaction. Thromb. Res. 128,
e113e118 (2011).
168. Duygu, H. etal. Prognostic value of plasma
soluble CD40 ligand in patients with chronic nonvalvular atrial fibrillation. Europace 10, 210214
(2008).
169. Heeringa, J. etal. A longitudinal populationbased study of prothrombotic factors in elderly
subjects with atrial fibrillation: the Rotterdam
Study 19901999. J. Thromb. Haemost. 4,
19441949 (2006).
170. Savelieva, I., Kakouros, N., Kourliouros, A. &
Camm, A.J. Upstream therapies for management
of atrial fibrillation: review of clinical evidence
and implications for European Society of
Cardiology guidelines. Part II: secondary
prevention. Europace 13, 610625 (2011).
171. Nigam, A. etal. Fish oil for the reduction of
atrialfibrillation recurrence, inflammation,
andoxidative stress. J. Am. Coll. Cardiol. 64,
14411448 (2014).
172. Imazio, M. etal. Colchicine reduces
postoperative atrial fibrillation: results of
theColchicine for the Prevention of the
Postpericardiotomy Syndrome (COPPS) atrial
fibrillation substudy. Circulation 124, 22902295
(2011).
173. Imazio, M. etal. COlchicine for the Prevention
ofthe Post-pericardiotomy Syndrome (COPPS):
amulticentre, randomized, double-blind, placebocontrolled trial. Eur. Heart J. 31, 27492754
(2010).
174. Deftereos, S. etal. Colchicine for prevention of
early atrial fibrillation recurrence after pulmonary
vein isolation: a randomized controlled study.
J.Am. Coll. Cardiol. 60, 17901796 (2012).
175. Deftereos, S. etal. Colchicine for prevention of
atrial fibrillation recurrence after pulmonary vein
isolation: mid-term efficacy and effect on quality
of life. Heart Rhythm 11, 620628 (2014).
176. Weis, F. etal. Stress doses of hydrocortisone
inhigh-risk patients undergoing cardiac surgery:
effects on interleukin6 to interleukin10 ratio
and early outcome. Crit. Care Med. 37, 16851690
(2009).
177. Yared, J.P. etal. Effect of dexamethasone on
atrial fibrillation after cardiac surgery:
prospective, randomized, double-blind, placebocontrolled trial. J. Cardiothorac. Vasc. Anesth. 21,
6875 (2007).
178. Andrade, J.G. etal. Corticosteroid use during

pulmonary vein isolation is associated with a
higher prevalence of dormant pulmonary vein
conduction. Heart Rhythm 10, 15691575
(2013).
179. Koyama, T. etal. Prevention of atrial fibrillation
recurrence with corticosteroids after
radiofrequency catheter ablation: a randomized
controlled trial. J. Am. Coll. Cardiol. 56, 14631472
(2010).
180. Cappabianca, G., Rotunno, C.,
de Luca Tupputi Schinosa, L., Ranieri, V.M.
&Paparella, D. Protective effects of steroids in
cardiac surgery: a meta-analysis of randomized
double-blind trials. J. Cardiothorac. Vasc. Anesth.
25, 156165 (2011).
181. Won, H. etal. Effect of a single bolus
injectionoflow-dose hydrocortisone for
preventionofatrial fibrillation recurrence after
radiofrequency catheter ablation. Circ. J. 77,
5359 (2013).
182. Cappato, R. etal. Updated worldwide survey
onthe methods, efficacy, and safety of
catheterablation for human atrial fibrillation.
Circ.Arrhythm. Electrophysiol. 3, 3238 (2010).
183. Themistoclakis, S. etal. Prospective
EuropeanSurvey on atrial fibrillation ablation:
clinical characteristics of patients and ablation
strategies used in different countries.
J.Cardiovasc. Electrophysiol. 25, 10741081
(2014).
184. Kleinbongard, P., Schulz, R. & Heusch, G.
TNFinmyocardial ischemia/reperfusion,
remodeling and heart failure. Heart Fail. Rev. 16,
4969 (2011).
185. Price, J.V. etal. Protein microarray analysis
reveals BAFF-binding autoantibodies in
systemiclupus erythematosus. J. Clin. Invest.
123, 51355145 (2013).
186. Marik, P.E. & Fromm, R. The efficacy and
dosageeffect of corticosteroids for the
prevention of atrial fibrillation after cardiac
surgery: a systematic review. J. Crit. Care 24,
458463 (2009).
187. Allessie, M.A. etal. Pathophysiology and
prevention of atrial fibrillation. Circulation 103,
769777 (2001).
188. Kaireviciute, D. etal. Characterisation and validity
of inflammatory biomarkers in the prediction of
post-operative atrial fibrillation in coronary
arterydisease patients. Thromb.Haemost. 104,
122127 (2010).
189. Rudd, J.H. etal. Imaging atherosclerotic plaque
inflammation by fluorodeoxyglucose with
positron emission tomography: ready for prime
time? J. Am. Coll. Cardiol. 55, 25272535
(2010).
190. Wu, C.H. etal. Transforming growth factor-1
level and outcome after catheter ablation for
nonparoxysmal atrial fibrillation. Heart Rhythm
10, 1015 (2013).
191. Leftheriotis, D.I. etal. The predictive value of
inflammatory and oxidative markers following
the successful cardioversion of persistent lone
atrial fibrillation. Int. J. Cardiol. 135, 361369
(2009).
192. Cao, H. etal. Heat shock proteins in stabilization
of spontaneously restored sinus rhythm in
permanent atrial fibrillation patients after mitral
valve surgery. Cell Stress Chaperones 16, 517528
(2011).
193. Schafler, A.E., Hannekum, A. & Kirmanoglou, K.
Unchanged heat-shock protein 70 expression
inmyocardium of patients with permanent atrial
fibrillation. J. Cardiovasc. Surg. 51, 923927
(2010).
194. Mandal, K. etal. Association of high intracellular,

but not serum, heat shock protein 70 with
postoperative atrial fibrillation. Ann. Thorac. Surg.
79, 865871 (2005).
195. St. Rammos, K. etal. Low preoperative HSP70
atrial myocardial levels correlate significantly
with high incidence of postoperative atrial
fibrillation after cardiac surgery. Cardiovasc. Surg.
10, 228232 (2002).
196. Parthenakis, F.I. etal. Atrial fibrillation is
associated with increased neurohumoral
activation and reduced exercise tolerance in
patients with non-ischemic dilated
cardiomyopathy. Int. J. Cardiol. 118, 206214
(2007).
197. Wang, H. etal. Increased serum levels of
microvesicles in nonvalvular atrial fibrillation
determinated by ELISA using a specific
monoclonal antibody AD1. Clin. Chim. Acta 411,
17001704 (2010).
198. Hak, L. etal. Interleukin2 as a predictor
ofearlypostoperative atrial fibrillation
aftercardiopulmonary bypass graft (CABG).
J.Interferon Cytokine Res. 29, 327332 (2009).
199. Rizos, I. etal. Interleukin2 serum levels
variations in recent onset atrial fibrillation are
related with cardioversion outcome. Cytokine 40,
157164 (2007).
200. Henningsen, K.M. etal. Prognostic impact of
hsCRP and IL6 in patients undergoing
radiofrequency catheter ablation for atrial
fibrillation. Scand. Cardiovasc. J. 43, 285291
(2009).
201. Henningsen, K.M. etal. Prognostic impact of
hsCRP and IL6 in patients with persistent atrial
fibrillation treated with electrical cardioversion.
Scand. J. Clin. Lab. Invest. 69, 425432 (2009).
202. Liuba, I. etal. Source of inflammatory markers
inpatients with atrial fibrillation. Europace 10,
848853 (2008).
203. Wu, Z.K. etal. High postoperative interleukin8
levels related to atrial fibrillation in patients
undergoing coronary artery bypass surgery.
World J. Surg. 32, 26432649 (2008).
204. De Gennaro, L. etal. Inflammatory activation and
carbohydrate antigen125 levels in subjects with
atrial fibrillation. Eur. J. Clin. Invest. 42, 371375
(2012).
205. Nakano, Y. etal. Matrix metalloproteinase9
contributes to human atrial remodeling during
atrial fibrillation. J. Am. Coll. Cardiol. 43, 818825
(2004).
206. Kim, S.K. etal. Serological predictors for the
recurrence of atrial fibrillation after electrical
cardioversion. Korean Circ. J. 40, 185190
(2010).
207. Rosenberg, M.A. etal. Circulating fibrosis
biomarkers and risk of atrial fibrillation: the
Cardiovascular Health Study (CHS). Am. Heart J.
167, 723728.e2 (2014).
208. Kimura, T. etal. Serum inflammation markers
predicting successful initial catheter ablation for
atrial fibrillation. Heart Lung Circ. 23, 636643
(2014).
Acknowledgements
This authors were supported in part by the Ministry
ofScience and Technology, Taiwan (NSC1022325-B-010-005, NSC-101-2321-B075004, and
NSC102-2911-I-008-001).
Author contributions
All authors substantially contributed to the
discussionof content, researched data for
thearticle,and wrote, reviewed, and edited the
manuscript before submission.

Inflammation and The Pathogenesis of Atrial Fibrillation

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Inflammation and The Pathogenesis of Atrial Fibrillation

Uploaded by

Copyright:

Available Formats

REVIEWS

Inflammation and the pathogenesis

Atrial fibrillation (AF) is the most common cardiac

and structural remodelling of the atria. Moreover, AF

NATURE REVIEWS | CARDIOLOGY

ADVANCE ONLINE PUBLICATION | 1

Figure 1 | Sources of inflammation in patients with atrial fibrillation.

AF than in 21 matched controls without AF, as measured by 18Ffluorodeoxyglucose PET.20 Proinflammatory

Coronary artery disease

2 | ADVANCE ONLINE PUBLICATION

Whether the inflammation in AF is associated with

NATURE REVIEWS | CARDIOLOGY

ADVANCE ONLINE PUBLICATION | 3

DAMP: necrotic cells, degraded ECM,

TLR-2, TLR-4 (through NFB, AP-1)

Figure 2 | Inflammatory cell regulation in lone and postoperative

Graded increases in the levels of CRP, HSP27, and

Cardiac injury releases DAMPs from cells or the

4 | ADVANCE ONLINE PUBLICATION

how these subpopulations of immune cells and their

Cytokines, chemokines, and mediators

The involvement of different inflammation-associated

NATURE REVIEWS | CARDIOLOGY

ADVANCE ONLINE PUBLICATION | 5

prevent AF by reversing atrial structural remodelling

HSP27 (but not HSP70) contributes to these HSP or

6 | ADVANCE ONLINE PUBLICATION

Increase cardiac apoptosis

Secrete anti-HSP autoantibodies

mitochondria and cytosol to the plasma membrane and

levels in patients with diabetes mellitus (95%CI 0.17

Inflammation and electrical remodelling

NATURE REVIEWS | CARDIOLOGY

ADVANCE ONLINE PUBLICATION | 7

Figure 4 | Inflammatory cells and mediators of inflammation modulate

andcaffeine-induced Ca 2+ transients in ventricular

atrial conduction and vulnerability to the induction and

Inflammation and structural remodelling

TNF activates the TGF signalling pathway and myo

Inflammation and thrombogenicity

The role of inflammation in AF-related thrombo

8 | ADVANCE ONLINE PUBLICATION

von Willebrand factor

Figure 5 | The pathophysiological link between inflammation and thrombogenesis.

which high CRP or IL6 levels independently predicted

Current anti-inflammatory therapies

NATURE REVIEWS | CARDIOLOGY

ADVANCE ONLINE PUBLICATION | 9

Future targeting of inflammation in AF

early-stage atrial inflammation.188 Imaging techniques,

Inflammation has an important role in the initiation and

10 | ADVANCE ONLINE PUBLICATION

Camm, A.J. etal. 2012 focused update of the

NATURE REVIEWS | CARDIOLOGY

32. Hori, M. & Nishida, K. Oxidative stress and

ADVANCE ONLINE PUBLICATION | 11

complication? Circulation 108 (Suppl.1),

12 | ADVANCE ONLINE PUBLICATION

90. Hu, Y.F. etal. Impact of circulating monocyte

128. Mathur, S., Walley, K.R., Wang, Y.,

NATURE REVIEWS | CARDIOLOGY

145. Nelson, B.H. IL2, regulatory Tcells, and

ADVANCE ONLINE PUBLICATION | 13

2 | ADVANCE ONLINE PUBLICATION

4 | ADVANCE ONLINE PUBLICATION

6 | ADVANCE ONLINE PUBLICATION

8 | ADVANCE ONLINE PUBLICATION

10 | ADVANCE ONLINE PUBLICATION

12 | ADVANCE ONLINE PUBLICATION

14 | ADVANCE ONLINE PUBLICATION