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NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 1
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, HsingLong
Road, Taipei11696, Taiwan, Republic ofChina (Y.J.C.)
Correspondence to: S.A.C. epsachen@ ms41.hinet.net
Inflammation and the pathogenesis ofatrialfibrillationYu-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
AFassociated inflammation might help to identify specific
antiinflammatory strategies forthe prevention of AF.
Hu, Y.F. etal. Nat. Rev. Cardiol. advance online publication 27
January 2015; doi:10.1038/nrcardio.2015.2
IntroductionAtrial fibrillation (AF) is the most common cardiac
arrhythmia and is associated with detrimental conse-quences. In
addition to worsening patient quality of life, AF is associated
with stroke, heart failure, and increased mortality.1 Worldwide, AF
has affected >30million indi-viduals since 2010, and the
incidence of AF continues to increase.2,3 Current treatments for AF
include pre-venting its recurrence (via rhythm control) and
conse-quences (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 preven-tion 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 associ-ated
complications, problems remain.1,4,5,7 An improved understanding of
the pathophysiology underlying AF and subsequent remodelling is
necessary for the devel-opment of novel therapeutic approaches.
Increasing evidence supports the role of inflammation in the
pathophysiology of AF, which suggests that the inflam-matory
process is a potential therapeutic target.8,9 The main
pathophysiological mechanisms contributing to AF development and
progression include both electrical
and structural remodelling of the atria. Moreover, AF itself can
induce inflammation during atrial remodel-ling, 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
patho-physiological role of inflammation and its interaction with
the established mechanisms of AF. We also highlight p otential
inflammation-based therapeutic options.
Sources of inflammation in AFInflammation in patients with AF
can arise from dif-ferent sources, which might have underlying
inflam-matory mechanisms and temporal changes (Figure1). Many
systemic diseases (such as coronary artery disease, hypertension,
and obesity) are associated with low-grade in flammationand
increased levels of proinflammatory cytokines.1113
ObesityObesity 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 pro-inflammatory phenotype),16,17
as well as inflammation of adipose tissue and secreted
proinflammatory cytokines occurs in patients with obesity.1719 High
levels of inflam-matory 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
Competing interestsThe authors declare no competing
interests.
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AF than in 21 matched controls without AF, as meas-ured by
18F-fluorodeoxyglucose 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 cardiomyo-cytes 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.
HypertensionThe association between inflammation and AF in
patients with hypertension is not yet established. In
spon-taneously 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
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
antiinflammatory strategies
Therapies that target specific inflammatory cascades might be
potential therapeutic strategies for the prevention of AF
followed by atrial fibrosis.24,25 In these models,
vulner-ability to the development of AF increased by 62% after the
development of atrial fibrosis, but not inflamma-tion alone.
However, in another sheep model, in which hypertension was induced
by prenatal steroids, increased vulner ability to AF was noted, but
atrial inflammation not observed.26 In this model, plasma renin
concentra-tion and vascular reactivity to angiotensinII were not
altered, whereas in spontaneously hypertensive rats and sheep with
unilateral nephrectomy-induced hyperten-sion, the
reninangiotensinaldosterone system (RAAS) was activated.2426 The
discrepancy between these studies might imply a pathophysiological
role of RAAS in AF.
The atria of angiotensinII-treated mice are character-ized by
increased neutrophil infiltration, which is depend-ent on CD11b and
CD18 integrins.27 AngiotensinII increases inflammation by
stimulating the production of proinflammatory cytokines (such as
IL-6, IL-8, 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
angiotensin-induced inflammatory cascades (such as TNF and IL-1)
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
inflamma-tion 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
trans duction thereby increasing production of proinflammatory
cytokines, such as IL-1, IL-6, and TNF.32
Coronary artery diseaseAtrial myocardial infarction, or
ischaemia that is sec-ondary 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 com-pared with
those in sinus rhythm.34 The increased level of stromal
cell-derived factor1 is a risk factor for devel-oping coronary
artery disease and is associated with i nflammatory cell
recruitment.35,36
Surgery and ablationInflammation can also be induced by cardiac
surgery or catheter ablation. In the ARMYDA-3 study,37 high
postoperative C-reactive protein (CRP) levels were associated with
an increased risk of AF. Surgery-induced
Systemic diseaseObesity, hypertension, coronary artery
diseases
Atrial myocardial injuryAtrial ischaemia or infarction, surgical
or catheter ablation
Immune diseases with autoantibodyValvular heart diseases
Modulating factorsChronic viral infection,
epicardial fat,genetic predisposition
Mediator moleculesROS, Ang II, TGF-, MPO, PDGF, HSPs,
proinammatory cytokines
Inammation
Electrical remodelling Structural remodelling
Atrial brillation
Nature Reviews | CardiologyFigure 1 | Sources of inflammation in
patients with atrial fibrillation. Activatedinflammatory pathways
alter the electrophysiology, structure, and 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, plateletderived growth
factor; ROS, reactive oxygen species; TGF, transforming growth
factor.
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inflammation has been modelled in canine sterile peri-carditis,
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 3-day period, but not late
AF recurrence at 3 or 6months.41,42
Autoimmune reactions in AFWhether the inflammation in AF is
associated with an autoimmune response remains unclear. Certain
auto antibodies, 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 metalloprotein-ases (MMPs), cardiac
myolysis, and apoptosis, and might subsequently increase
inflammation and vulnerability toAF.30
Polymorphisms in the genes encoding IL-1, IL-6, and IL-10, which
are responsible for modulating expression levels of inflammatory
cytokines, are independently associated with AF in humans.4649 For
example, the 174G>C IL-6 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 devel-opment of AF, possibly through
inflammatory pro-cesses.51,52 However, the underlying mechanisms of
AF in patients with a viral infection remain unclear. In
indi-vidualswithHIV, 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 IL-6, 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 AFIn patients with lone AF, atrial
pathology reveals infil-tration 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], IL-6, IL-8, 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 new-onset AF in
several large, prospective cohorts.6062 In the Cardiovascular
Health Study60 (5,806 patients followed up for a mean period of
6.9years), higher CRP levels (>3.41 mg/l) were associated with
the presence of AF compared with lower levels (
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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 0.29 0.13 mg/dl to
0.10 0.06 mg/dl; P 50% (P 30% (P 200units) could be used to predict
AF recur-rence after catheter ablation (HR4.2, 95%CI 1.214.6, P =
0.02).90 A higher percentage of activated Tlympho-cytes (CD3+ and
HLA-DR+) was observed in the periph-eral blood of patients with
paroxysmal or persistent AF compared with healthy control
individuals (36% versus 27%; P
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NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 5
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 r ecurrence
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 off-pump CABG surgery, levels of IL-6 and IL-8 (but not
TNF) are elevated immediately after surgery (IL-6 from 0 to 435
pg/ml; IL-8 from 10 to 50 pg/ml).99 The increase in the level of
IL-6 after surgery is associated with postopera-tive AF (OR7.63 if
IL-6 >401 pg/ml, P = 0.04).99 Among patients with AF who receive
catheter ablation, the levels of IL-6 and CRP both significantly
increase after ablation (IL-6 from 1.1 2.5 to 12.4 15.3 pg/ml; P =
0.007; CRP from 2.4 2.9 to 20.1 9.2 mg/l, P = 0.001); however,
levels of IL-8, IL-10, IL-12, stromal cell-derived factor1, and TNF
remain unchanged.100
In addition to their role in allergic and immune responses, mast
cells also participate in cardiovascu-lar disease-related
inflammation.101 Mast cells might actively induce inflammation and
atrial fibrosis in patients with AF and secrete platelet-derived
growth factorA (PDGF-A) 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 pre-dictive 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 anti-inflammatory 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 mediatorsThe 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 postabla-tion AF recurrence might differ from
those underlying AF onset in the general population and could lead
to activation of different cytokines. Consequently, incon-sistent
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 TGF-1 can
increase the vulnerability to AF and atrial remod-elling, including
fibrosis and heterogeneous conduc-tion.105108 In clinical studies,
the serum or atrial tissue levels of TNF or TGF-1 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 investigat-ing 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 hospitaliza-tion 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 myeloperoxidase 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
pre-treated with angiotensinII, myeloperoxidase deficiency
decreases atrial fibrosis and protects mice from AF, which was
reversed after restoring myeloper oxidase.114 These data suggest
that TNF, TGF-1, 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
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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 7.2 0.5 ng/ml in control individuals to 6.1 0.5 ng/ml
in patients with paroxysmal AF and 4.7 0.5 ng/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 4 cm versus
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NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 7
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/NF-B pathway.131 In addition, HSP60 activates
mono-cytes, macrophages, and Tlymphocytes through TLR2 or
TLR4(Figure2).132,133
In a prospective study of 329 patients undergoing elective CABG
surgery, increased postoperative anti-HSP65 was independently
associated with post operative 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 53 g/ml versus 43 g/ml; P =
0.035).45 These findings indicate a patho-genic 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 neutral-ize and promote the clearance of
autoantigens.134 The HSPautoantibody complex might also induce a
com-plement 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 (>119.6 g/ml) were also associated with a 61%
reduced risk of cardio vascular complications compared with low
HSP70
levels in patients with diabetes mellitus (95%CI 0.170.87).137
Ifautoantibodies against HSPs are a trigger of inflammation,
induction of immune tolerance to HSP60 might decrease immune
responses to DAMPs via Treg-ulatory cells and inhibit the release
of proinflammatory immune cells and cytokines.138 However, if these
autoan-tibodies 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 remodellingThe detailed
pathophysiological mechanisms of electri-cal and structural
remodelling in AF have been exten-sively reviewed previously.141
Different inflammatory cytokines modulate the function of ion
channels and calcium homeostasis (Figure4). TNF induces abnor-mal
Ca2+ handling and arrhythmogenicity in pulmo-nary 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 poten-tial 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 cardiomyo-cytes, which is crucial for the
initiation of AF and atrial el ectrical
remodelling.105,106,142,143
PDGF from myofibroblasts can reduce the dura-tion of action
potentials and Ca2+ transients when directly applied to
cardiomyocytes, which supports a role for PDGF in electrical
remodelling.144 IL-2 is pre-dominantly secreted by activated
Tlymphocytes,145 and changes the amplitude of
electrically-stimulated
Increase cardiac apoptosis
Innate and adaptiveimmune cells
Inhibit TLR-4 expressionAnti-inammatory cytokines
Increase proinammatorycytokines
HSP60
HSP60HSP70
HSP27
Restore L-type calcium currentPrevent action potential duration
shorteningPrevent myolysisPrevent F-actin stress bre
TLR-2,TLR-4
Cardiomyocytes
Intracellular cardiomyocyte(HSP27, HSP70)
HSPs
Extracellular(HSP27, HSP60, HSP70)
Secrete anti-HSP autoantibodies
Nature Reviews | CardiologyFigure 3 | HSPs in atrial
fibrillation. HSPs prevent protein aggregation and stabilize
protein folding. However, HSPs can function as damageassociated
molecular patterns and induce an immune response. Intracellular
HSP27 and HSP70 restore abnormal calcium currents and prevent
shortening of the action potential duration, myolysis, and Factin
stress fibre formation, which can reverse AFrelated 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 antiHSP autoantibodies. HSP27
might inhibit TLR4 expression and its associated NFB pathway, and
increase secretion ofIL10; these responses are considered
antiinflammatory. Abbreviations: HSP, heat shock protein; TLR,
Tolllike receptor.
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andcaffeine-induced Ca2+ 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 L-type calcium channels.146 However, this
effect has not yet been demonstrated 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 con-duction
can be created by the local application of ara-chidonic 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 expres-sion or distribution of gap junction-5 protein
(com-monly known as connexin-40 [Cx40]), gap junction-1 protein
(commonly known as connexin-43 [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 cardio myocytes (which is
dispersed from the intercalated discs) in mice.106,149
In clinical studies, mediators of the inflammatory response are
associated with atrial electrical proper-ties.57,90,150 CD36 levels
are positively correlated with atrial voltage (rcoefficient=0.63, P
= 0.001).90 Low levels of HSP27 (
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NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 9
which high CRP or IL-6 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 dysfunc-tion
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 20 IU/dl increase of vWF, 95% CI 1.01.5, P = 0.06) and
vascu-lar events (RR1.2 per 20 IU/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 cardiovascu-lar events including
cardiovascular death and ischae-mic stroke (HR1.36 per 0.1 mol/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 addi-tional
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 sug-gests that endothelial dysfunction also
contributes to t hrombogenesis in AF.163
TLR4 might also be an underlying immune mecha-nism to induce
atrial endothelial dysfunction. TLR4 knock-out mice have a lower
incidence of atrial throm-bosis after thoracic transverse aortic
constriction compared with wild-type mice.83 TLR4-related NF-B
signal pathways can activate mitogen-activated protein kinase p38,
decrease phosphorylation of endothelial nitric oxide synthase, and
increase vascular cell adhe-sion protein1 and plasminogen activator
inhibitor1
expression in mice atria.83 Prothrombin and throm-bin 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 pro-thrombotic
states (Figure5).8 Proinflammatory cytokines such as IL-6 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, P-selectin, and CD36 in AF.
However, in clinical studies, inconsistent results linking the
levels of soluble CD40 or P-selectin to thrombo-embolism in AF have
been reported.156,168,169 Whether monocyte CD36 is associated with
thromboembolism is currently unclear.
Current anti-inflammatory therapiesTo date, no drug has been
designed to target the inflam-matory pathway specifically in
patients with AF, but most drugs used to prevent AF are arbitrarily
consid-ered anti-inflammatory as part of their pleiotropic effects.
Angiotensin-converting-enzyme inhibitors, a ngiotensin-receptor
blockers, statins, and n-3 poly-unsaturated fatty acids have been
studied in large, pro-spective, 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-converting-enzyme inhibitors
and angiotensin-receptor blockers are considered reasonable
approaches for the primary pre-vention 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 develop-ment of
anti-inflammatory therapies in the prevention of AF, because most
of these studies did not demonstrate a downregulation of
inflammation after drug applica-tion.171 Even among positive
results, the prevention of AF does not seem to be the result of
reduced inflammation. For example, in the ARMYDA-3 trial,37
treatment with atorvastatin significantly reduced the incidence of
post-operative AF after elective cardiac surgery with
cardio-pulmonary 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
com-plication 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 signifi-cant decrease in inflammatory
mediators, including CRP and IL-6 (CRP: 0.46 mg/l; interquartile
range: 0.78
Platelet
P-selectinCD36
CD40Thrombus
Neutrophil
Monocyte
Proinammatorycytokines: IL-6
von Willebrand factor
Damagedendothelium
Thrombin
Tissue factor
PAR-1
eNOS
Atrium
Immunecell
inltration
Plateletleucocyteinteraction Coagulation
factor
Nature Reviews | CardiologyFigure 5 | The pathophysiological
link between inflammation and thrombogenesis. 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.
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to 0.08 mg/l, P
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NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 11
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AcknowledgementsThis authors were supported in part by the
Ministry ofScience and Technology, Taiwan (NSC1022325B010005,
NSC1012321B075004, and NSC1022911I008001).
Author contributionsAll authors substantially contributed to the
discussionof content, researched data for thearticle,and wrote,
reviewed, and edited the manuscript before submission.
REVIEWS
2015 Macmillan Publishers Limited. All rights reserved
Inflammation and the pathogenesis ofatrialfibrillationYu-Feng
Hu, Yi-Jen Chen, Yenn-Jiang Lin and Shih-Ann
ChenIntroductionSources of inflammation in AFKey pointsFigure 1 |
Sources of inflammation in patients with atrial fibrillation.
Activatedinflammatory pathways alter the electrophysiology,
structure, and autonomic remodelling of the atria. Inflammation
induced by atrial fibrillation canestablish an inflammatAutoimmune
reactions in AFInflammation leads to AFAF promotes
inflammationFigure 2 | Inflammatory cell regulation in lone and
postoperative AF. DAMPs can activate cells via TLR2 and TLR4,
including immune cells, cardiomyocytes, fibroblasts, and
endothelial cells, which induce inflammatory cascades. Innate and
adaptive immune reImmune reactions in AFCytokines, chemokines, and
mediatorsInflammation and electrical remodellingFigure 3 | HSPs in
atrial fibrillation. HSPs prevent protein aggregation and stabilize
protein folding. However, HSPs can function as damage-associated
molecular patterns and induce an immune response. Intracellular
HSP27 and HSP70 restore abnormal calciuFigure 4 | Inflammatory
cells and mediators of inflammation modulate
cardiacelectrophysiology and structural properties. Calcium
homeostasis in cardiomyocytes is regulated by TNF, PDGF, and IL2,
which are associated with increased triggering and
shortenInflammation and structural remodellingInflammation and
thrombogenicityFigure 5 | The pathophysiological link between
inflammation and thrombogenesis. Immune cell infiltration induces
endothelial dysfunction, which decreases eNOS expression, but
increases the expression of vonWillebrand factor, thrombin, tissue
factor, and Current anti-inflammatory therapiesFuture targeting of
inflammation in AFConclusionsAcknowledgementsAuthor
contributions