Current concepts in the pathogenesis of

atrial fibrillation
Antonios Kourliouros, MRCS, Irina Savelieva, MD, Anatoli Kiotsekoglou, MD, Marjan Jahangiri, FRCS, and
John Camm, FRCP London, United Kingdom

Current evidence suggests that the pathogenesis of atrial fibrillation (AF) is multifactorial. The observation that AF, once
present, alters the electrophysiologic properties of the atrial myocardium causing self-perpetuation of the arrhythmia raised the
importance of electrical remodeling in its pathogenesis. Although these changes are potentially reversible, maintenance of AF
continues even after electrical remodeling has occurred. Clinical and experimental studies have highlighted the role of a
susceptible atrial anatomical substrate with features of myocyte degeneration and interstitial fibrosis in the initiation and
maintenance of AF. Finally, the association of increased inflammatory burden with the presence and future development of AF
has implicated inflammation in the pathogenesis of the arrhythmia. The purpose of this review is to provide current evidence
on the dominant theories on AF pathogenesis, namely, electrical remodeling, structural remodeling, and inflammation;
describe the various experimental models and methods used; and identify a cause-effect association, when present. In
addition, the interrelation between different mechanisms responsible for AF will be demonstrated, providing further insight into
the complex pathophysiology. (Am Heart J 2009;157:243-52.)

Despite new insights into the mechanisms of atrial
fibrillation (AF), no specific etiologic factor has been
identified as the sole cause or perpetuator of the
arrhythmia. Regular tachycardias or focal triggers found
in myocardial tissue of the atrial free wall or pulmonary
veins create propagating wavelets, which, in the pre-
sence of reduced refractory period and/or conduction
velocity, may lead to reentrant circuits and AF.1,2
However, ectopic foci may not always be necessary for
the initiation and maintenance of AF. In the early seminal
work by Allessie et al,3 decreased wavelength alone
(product of refractory period and conduction velocity)
allowed for the maintenance of several simultaneous
reentry circuits leading to the development of AF. The
therapeutic application of this multiple circuit reentry
hypothesis has been the termination of the arrhythmia
after surgical isolation of the reentrant pathways.
Animal studies have demonstrated that rapid atrial
pacing caused significant shortening of atrial refractori-
ness, increased susceptibility to paroxysms of AF, and
persistence of the arrhythmia when tachypacing was
prolonged. The concept of electrical remodeling, with
From the Departments of Cardiac Surgery and Cardiac and Vascular Sciences, St George's
University of London, London, United Kingdom.
Submitted June 13, 2008; accepted October 12, 2008.
Reprint requests: John Camm, FRCP, St George's University of London, Cranmer Terrace,
SW17 0RE London, United Kingdom.
E-mail: jcamm@sgul.ac.uk
0002-8703/$ - see front matter
© 2009, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2008.10.009
the associated alterations in the number and function of
ion channels, has been implicated in the progressive
nature of the disease and the notion that “AF begets AF.”4
Enhanced susceptibility to AF and the risk of domestica-
tion of the arrhythmia extend beyond the time course of
electrical remodeling reversal, suggesting “a second
factor” responsible for AF recurrence.5,6
The presence of a susceptible atrial anatomical
substrate with areas of conduction block, which may
cause spatial dissociation of the wavelets and promote
reentry, has been implicated in the perpetuation of the
arrhythmia.5 However, it remains unclear whether this
structural remodeling, with features of interstitial fibrosis
and myolysis, precedes the development of the arrhyth-
mia; whether it is purely AF-induced or simply a feature of
older age or underlying heart disease.
The observation that atrial tissue of patients with lone
AF show evidence of myocarditis and that cytokine levels
may predict the development of AF or the effect of
cardioversion highlight the role of inflammation in the
development of the arrhythmia. The direct arrhythmo-
genic effect of inflammatory cytokines on atrial myocar-
dium has been associated with the initiation of AF.7 The
increased rate of AF after cardiac surgery, which is known
to induce systemic inflammatory response, and the
beneficial effect of drugs with anti-inflammatory proper-
ties such as steroids and statins further implicates
inflammation as an important denominator for AF.
The aim of this review is to provide a comprehensive
outline of recent studies that support each of the main
pathogenetic mechanisms in AF. The experimental
models and methodology used, main outcomes, and

244 Kourliouros et al
Figure 1
Pathogenesis of the development and maintenance of AF. APD indicates action potential duration; Ito, transient outward K+ current; ICa, L-type
Ca2+ current; INa, Na+ current; IKsus, sustained outward K+ current; IK1, inward rectifying K+ current; IK,Ach, G protein–coupled inward rectifying
K+ current.
associations with AF are critically discussed and tabulated
for quick reference. The interrelations between the
different pathogenetic mechanisms in AF are also high-
lighted, demonstrating the multicausal nature of AF
(Figure 1).
Electrical remodeling
The observation that the chronicity of AF is inversely
associated with successful electrical cardioversion and
that increasing duration of paroxysms of AF is linked to
the development of sustained AF led Wijffels et al4 to the
conclusion that “AF begets AF.” They demonstrated that
after implantation of atrial electrodes and automatic
induction of AF in goats, the duration of the arrhythmia
progressively increased (and became sustained at
2 weeks), followed by a shortening of the atrial effective
refractory period (ERP) and increased inducibility of AF
by a single premature stimulus. This shortening of EPR is
largely responsible for the increased susceptibility of
myocytes to reactivation from an electrical impulse,
leading to reetrant activity and AF. The concept of
“electrical remodeling” was further supported by studies,
which aimed to identify the ionic current changes and
action potential abnormalities associated with AF. Yue
et al8 were the first to report pacing-induced action
potential changes in the atria of mongrel dogs after atrial
tachypacing for 1, 7, and 42 days. Both the transient
outward (Ito) and L-type Ca2+ currents (ICa) were
American Heart Journal
February 2009
decreased with the progression of atrial pacing, leading
to reduced duration of action potentials. However,
despite the observed effect of tachypacing on the number
and conductance of ion channels, no changes were
observed in the ionic channel structure and no direct
mechanism was identified to account for the alterations
in conductance. The same group demonstrated that one
of the most important denominators of the upstroke of
the action potential, the Na+ current (INa), was signifi-
cantly reduced in left atrial myocytes from mongrel dogs
subjected to rapid atrial pacing.9 The resultant slowing of
conduction velocity was associated with shortening of
reentry wavelengths and susceptibility to AF.
The repolarization and refractoriness of atrial cardio-
myocytes is dependent on the outward K+ and inward
Ca2+ currents and their densities. One would expect that
shortening of EPR and action potential duration observed
in AF models would be caused by an increase in the
outward K+ current, a decrease in the inward Ca2+
current, or both. The hypothesis of increased density of
human atrial K+ current was tested by van Wagoner et al10
but was not validated because inactivating (Ito) and
sustained (IKsus) outward K+ current densities were
significantly reduced in patients with permanent AF
when compared with sinus rhythm (SR). The authors
suggest that these changes are most likely the result
rather than the cause of the arrhythmia. In another study
of human atrial tissue from operated patients in SR and
permanent AF, there was an increase in the inward
American Heart Journal
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Kourliouros et al 245

Table I. Studies on electrophysiologic changes associated with AF

Author, year Model Setting/methods Outcome Association with AF

Wijffels et al, 19954 Instrumented goats—
atrial electrodes
Yue et al, 19978 Instrumented mongrel
dogs
Gaspo et al, 19979 Instrumented mongrel
dogs
van Wagoner et al, Humans (cardiac surgery
199710 —AF vs SR)
Dobrev et al, 200111 Humans (cardiac surgery
—AF vs SR)
Dobrev et al, 200512 Humans (cardiac surgery
—AF vs SR)
Liu and Nattel, Mongrel dogs—
199713 atrial electrodes
Van der Velden et al, Instrumented goats—
200021 atrial electrodes
Hagendorff et al, Mice (wild type
199922 and Cx40 deficient)
Firouzi et al, 200423 Humans (with
different Cx40
genotype frequencies)
Gollob et al, 200624 Humans (with idiopathic
AF)
External automatic atrial
fibrillatory pacemaker, EP study
Atrial tachypacing 1, 4, 42 d,
whole-cell patch-clamp technique
Atrial tachypacing 7 and 42 d,
whole-cell patch-clamp techniques
Atrial tissue, nystatin-perforated
patch technique, Western blotting
Atrial tissue, whole-cell
voltage-clamp techniques,
competitive RT-PCR
Atrial tissue, whole-cell
voltage-clamp techniques
AF induction, autonomic
decentralization, vagal
and sympathetic activation
Atrial tissue, immunohistochemistry,
Western blotting, RT-PCR
Atrial tachypacing induced AF,
surface electrocardiographic
and transoesophageal EP studies
Atrial stimulation with
unipolar pacing
Genomic DNA GJA5 sequencing
Shortening of ERP, increased Maintenance, increased
AF inducibility with single susceptibility
premature stimulus
APD shortening through density Maintenance
reductions in transient outward
current (Ito) and L-type Ca2+
current (ICa)
Reduced conduction velocity and Maintenance
Na+ current density (INa)
Reduced voltage-gated outward Ionic changes likely to
K+ current densities and be the result of AF
expression of Kv1.5 protein
Up-regulation of inward Adaptation to chronic AF
rectifying K+ current (IK1),
down-regulation of G protein-coupled
inward rectifying K+ current (IK,Ach),
and attenuation of APD shortening
Increased density of inward rectifying Maintenance
K+ current (IK1) and constitutively
active IK,ACh
Vagal stimulation increases Maintenance
heterogeneity of EPR;
Sympathetic stimulation had no
significant effect on AF
Heterogeneity in Cx40 distribution Maintenance
correlated with AF stability
Increased AF inducibility with burst Initiation and
pacing in Cx40-deficient mice maintenance
Carriers of −44AA genotype had Initiation and
increased dispersion of refractoriness, maintenance
atrial vulnerability, and risk of AF
Mutations present in the GJA5 gene, Initiation and
which encodes Cx40 maintenance

EP, Electrophysiologic; APD, action potential duration; RT-PCR, reverse transcriptase-polymerase chain reaction.

rectifying K+ current (IK1); however, the G protein–
coupled inward rectifying K+ current IK,Ach, which is
associated with the autonomic-induced shortening of
action potentials, was found reduced in patients with
AF.11 This second finding is in contrast with the
anticipated increased activity of the IK,Ach in the initiation
and perpetuation of AF. The authors explain the down-
regulation of IK,ACh as a possible balancing mechanism of
the cardiomyocytes to compensate for ERP shortening in
AF. The same group in a more recent study demonstrated
that constitutively active IK,Ach is present in patients with
AF because of a higher probability and increased
frequency of channel openings.12
The impact of autonomic tone variations on the
heterogeneity of refractoriness through ERP and action
potential duration shortening has been described in
animal models, indicating the role of sympathetic and
vagal stimulation in the initiation and maintenance of
AF.13,14 Human studies of dynamic changes in autonomic
tone before the onset of AF have demonstrated a
moderate increase in adrenergic tone with loss of vagal
tone,15,16 increased vagal activity,17,18 or a combination
of primary increase in sympathetic activity followed by
vagal predominance.19
Connexins (Cx's) are a group of proteins that make up
the intercellular channels between the myocytes, allow-
ing for the transfer of small molecules and ions. Dense
arrays of these channels form the gap junctions, which
are structures predominantly found at the intercalated
disks of the cardiomyocytes and are responsible for the
conduction of electrical impulses. Cx43 is the most
abundant type in both atrial and ventricular myocardium,
but Cx40 is selectively found in the atria and the
conduction system. Chimeric mice developed from Cx43
deficient-embryonic stem cells, which exhibit a hetero-
geneous Cx43 expression, showed a marked conduction
delay in their ventricles, predisposition to ventricular
arrhythmias, and significant systolic dysfunction.20 In a
goat model of chronic AF, the distribution of Cx40 in the
myocardium was discontinuous, and the heterogeneity of
its distribution became more apparent with time. The
overall levels of Cx40 decreased with the persistence of

246 Kourliouros et al
AF, whereas the distribution and the amount of Cx43
remained stable throughout.21 In a study of Cx40-
deficient mice, the apparent disturbance in the sinoatrial
electrophysiology was associated with increased
arrhythmogenicity and atrial vulnerability after atrial
burst stimulation.22 An effective decrease in the number,
as well as alterations in the spatial arrangement of gap
junctions, of which Cx's are major components, can
cause heterogeneity of pulse propagation followed by
the initiation and perpetuation of atrial arrhythmias. In a
comparative study of 30 patients with and without
history of AF, polymorphism of the Cx40 gene
promoter, which possibly leads to reduced Cx40 levels,
was associated with development of and vulnerability to
AF and led to an increased spatial dispersion of
refractoriness.23 In another study, mutations in the gene
(GJA5) that is responsible for encoding of Cx40 were
identified in 4 of 15 patients with idiopathic AF.24 The
possible genetic basis of AF, as suggested in the 2
previous studies, is in line with a population-based study
of 2,243 individuals, where presence of parental AF
doubled the risk of AF in the offspring.25 However,
experimental evidence suggests that AF is a genetically
heterogeneous disorder.26
The available data correlating electrical remodeling
with AF are mostly derived from animal models after atrial
tachypacing and less frequently from operated patients
with AF (Table I). The possibility of species differences
and the fact that these results may not be extrapolated to
humans are known limitations of animal studies.
The observed ionic changes, which eventually lead to
shortening of EPR and action potential duration, may
partially explain susceptibility to AF and its maintenance
but provide little evidence on initiation of the arrhythmia.
In addition, animal models subjected to atrial tachypacing
interrupted by appropriate periods of SR led to increased
AF stability despite the reversal of electrical remodeling
that occurred during restoration of SR.6 The concept of a
“second factor” beyond the electrophysiologic changes
associated with AF has involved the role of atrial
anatomical changes to provide the susceptible substrate
for the arrhythmia.
Atrial structural changes and fibrosis
Structural changes in the atria of patients with AF are
identified at the level of cardiomyocytes and extracellular
matrix (ECM). It is not clear whether these changes
precede or follow development of the arrhythmia. In the
dominant model of multiple circuit reentry in AF, an
ectopic complex fails to activate a neighboring zone of
atrial tissue if myocytes are in their refractory period.
Interstitial fibrosis creates conduction delay causing the
electrical impulse to propagate through alternative path-
ways and eventually impinge on tissue that has already
recovered excitability, causing reactivation and further
American Heart Journal
February 2009
increase in the number of reentrant circuits.2,5 Atrial
dilatation, which is a known risk factor for the initiation
and sustainability of AF, has also been associated with
fibrosis and subsequent heterogeneity of conduction.27 If
atrial dilatation was histologically homogenous, then the
increase in surface area and the increase of reentrant
circuits would be proportional, and, according to the
multiple reentry hypothesis, not necessarily associated
with higher incidence of AF.
The concept of fibrosis and myocyte degeneration in
AF has been studied in humans with operated mitral valve
disease.28 Cellular hypertrophy and degeneration were
apparent upon electron microscopy of atrial myocytes.
The predominant features were large cell diameter,
increased numbers of myofilaments, mitochondria and
ribosomes, abnormal Z bands, and interstitial fibrosis
with increased number of abnormal elastic fibers.
However, these changes were mostly attributable to the
underlying valvular disease, of which AF is a common
sequence, rather than to the arrhythmia itself.
In an animal model of chronic AF, which was
developed and studied by Morillo et al,29 atrial structural
changes and electrophysiologic abnormalities were
associated with the sustained arrhythmia. More specifi-
cally, 22 mongrel dogs underwent continuous transve-
nous atrial tachypacing at a rate of 400/min for 6 weeks.
Two-dimensional echocardiography before, and at the
end of, this period revealed that the dimensions of both
atria were significantly increased (45% for the left and
67% for the right atrium). Furthermore, electron micro-
scopy demonstrated disorientated atrial fibers, increased
number and size of mitochondria, enlarged nuclei, and
abnormalities in both the sarcoplasmic and rough
endoplasmic reticula. Significant shortening of ERP was
also observed, and that was correlated to the sustain-
ability of AF. The absence of any other underlying cardiac
pathology in this model rendered the above histologic
electrophysiologic findings specific to the arrhythmia.
A goat model of chronic AF with instrumented epicardial
pacing confirmed the above findings, and in addition
demonstrated myolysis, glycogen accumulation and
chromatin changes.30 In this model, myolysis initiated
from around the nucleus and extended to the plasma
membrane. The observed loss of sarcomeres did not lead
to cell atrophy but caused enlargement instead due to
deposition of glycogen in areas of myolysis. The more
homogenous distribution of heterochromatin in the
nucleoplasm of the abnormal myocytes resembled
embryonic levels of development, leading to the notion
that AF is associated with dedifferentiation of myocytes
rather than degeneration. This dedifferentiation of
myolytic myocytes has also been described in a study of
human atrial myocardium.31 Once more, observed
depletion of the contractile apparatus and presence of
α-actin and β-myosin heavy chain proteins, which are
predominantly found during the fetal development of
American Heart Journal
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Kourliouros et al 247

Table II. Studies on structural remodeling associated with AF

Author, year Model Setting/methods Outcome Association with AF

Thiedemann and
Ferrans, 197728
Morillo et al, 199529
Ausma et al, 199730
Rucker-Martin et al,
200231
Xu et al, 200433
Lin et al, 200734
Verheule et al, 200438
Boldt et al, 200339
Mariscalco et al, 200640
Humans (operated mitral
disease—AF vs SR)
Mongrel dogs
Instrumented goats
Humans (operated cardiac
disease—AF vs SR)
Humans (transplant for
end-stage heart failure)
Pigs (atrial tachypacing
vs sham)
Mice (transgenic with over
expression of TGF-β1
vs wild type)
Humans (operated for
lone AF, AF with MVD,
and other)
Humans (CABG,
no history of AF)
Light and electron microscopy
of atrial tissue
Atrial tachypacing, echocardio-
graphy, microscopy, and
electrophysiologic study
Atrial tachypacing, light
and electron microscopy
of atrial tissue
Atrial tissue immunohisto-
chemistry and myocyte culture
Atrial tissue, immunohisto
chemistry for collagen, and
Western blotting for MMPs
Atrial tissue, cDNA microarray—
PCR, immunohistochemistry,
Western blot analysis
Transesophageal electrical
stimulation, atrial tissue
for histology
Atrial tissue, immunohistochemistry
and Western blotting
Atrial tissue, light and
electron microscopy
Severe cellular degeneration Outcome of underlying
and interstitial fibrosis in disease and AF
patients with AF
Atrial dilatation, increase in Maintenance
the number and size of the
mitochondria, disruption of
sarcoplasmic reticulum,
ERP shortening
Cellular enlargement, Maintenance
myolysis, absence of connective
tissue proliferation
Myolysis, dedifferentiation, Initiation and
and fibroblast proliferation maintenance
Up-regulation of MMP-2 Maintenance and
and collagen type I in patients recurrence
with permanent AF compared
with controls
Up-regulation of fibronectin 1, Initiation and
fibrillin 1, and fibromodulin maintenance
with increased accumulation
in ECM
Atrial fibrosis and increased Initiation
AF inducibility in transgenic mice
Up-regulation of angiotensin II Initiation and
eceptor subtype 1 in the left maintenance
atrium of patients with AF
Myocyte vacuolization and Initiation
nuclear derangement were
independent predictors of
postoperative AF

MVD, Mitral valve disease; CABG, coronary artery bypass grafting.

myocytes, suggest a regression of the fibrillating myo-
cardium toward a more immature stage of development.
This is also supported by the finding that myocytes from
the fibrillating atria share common structural character-
istics with myocytes undergoing prolonged culture in
vitro, a process that is known to result in gradual cellular
dedifferentiation.
In an attempt to delineate whether cellular remodeling
is a reversible process or not, Aime-Sempe et al32 studied
human myocytes and hypothesized that patients in AF or
with impaired ventricular function demonstrate
increased myolysis in their atria, leading to programmed
cell death. Myolytic myocytes with abnormal nuclear
structure and without evidence of necrosis (which
requires membrane disassembly) showed increased
expression of caspase 3, a protease that is involved in the
final step of apoptosis. Moreover, the antiapoptotic
protein BCL-2 was reduced in the abnormal myocytes.
These findings suggest that apoptotic cell death was more
pronounced in the fibrillating atria and that this effect
may not be reversible.
Structural alterations outside the cellular and molecular
levels have also been reported as potential factors in the
development and perpetuation of AF. Collagen, which is
the main component of the ECM, has been associated
with sustained AF in a study of 53 patients with end-stage
heart failure and cardiomyopathy.33 Persistent and
permanent AF was present in 37 patients; the concen-
tration of collagen type I was increased in the AF group
when compared with the SR group, whereas levels of
collagen type III were not influenced. The abundance of
thick collagen type I fibers provide the appropriate
substrate by creating areas of different conduction
properties within the atria. Collagen synthesis and
degradation are influenced by the action of matrix
metalloproteinases (MMPs). The same group demon-
strated up-regulation of MMP-2, which is related to atrial
fibrosis, and down-regulation of its tissue inhibitor (TIMP-
2) in patients with sustained AF on the background of
cardiomyopathy and end-stage heart failure. However,
these findings may primarily reflect the advanced under-
lying cardiac pathology rather the development and
sustainability of AF itself.
The presence of altered expression of ECM proteins
other than collagen has recently been described in a
porcine model of sustained AF.34 Connective tissue
quantification showed that the extent of ECM substrate
was significantly higher in the AF group compared with

248 Kourliouros et al
the SR group. Moreover, the gene expression of the ECM-
related proteins fibronectin 1, fibrillin 1 and fibromodu-
lin, examined with cDNA microarray and real-time PCR,
demonstrated up-regulation of the genes. Porcine atria
with AF demonstrated increased intercellular distribution
of fibronectin 1 and fibrillin 1 when compared with SR
tissue, as confirmed with Western blot analysis and
immunohistochemical staining.
The association of transforming growth factor β1
(TGF-β1) with production of ECM proteins and tissue
fibrosis has previously been described.35 Increased gene
expression and synthesis of TGF-β1 have not only been
associated with accumulation of ECM proteins and
myocardial fibrosis but significantly preceded its devel-
opment. This was shown in a rat model with chronic
inhibition of nitric oxide synthesis, where TGF-β1
mRNA levels were up-regulated well before the
observed perivascular and myocardial interstitial fibro-
sis.36 In another study, transgenic mice with increased
levels of active myocardial TGF-β1 demonstrated
increased fibrosis in the atria, which was not paired
with an anticipated fibrosis of the ventricles.37 Despite
the observed hypertrophy of ventricular cardiomyo-
cytes, no fibrosis was present in the ventricular
myocardium, which indicates the differential effect of
TGF-β1 on atrial over ventricular myocardium, leading
to selective atrial structural remodeling. The over-
expression of TGF-β1 with its consequent atrial fibrosis,
as observed in transgenic mice, was linked to AF
vulnerability in another study by Verheule et al.38
Despite the absence of significant differences in most
electrophysiologic parameters in the transgenic mice
and their wild-type littermates, AF inducibility after
transesophageal burst pacing of the left atrium was
significantly increased in the transgenic mice.
The relation of angiotensin and its receptor with
myocardial structural remodeling and fibrosis has pre-
viously been described. In a study by Boldt et al,39 the
subtype 1 of the angiotensin II receptor (AT1) was found
to be up-regulated in the left atria of patients with AF,
suggesting an association between increased AT1 activity,
enhanced synthesis of ECM components, and develop-
ment of AF.
Structural remodeling is a dominant contributor in the
sustainability of AF (Table II). Although atrial fibrosis
appears to follow the development of the arrhythmia, it
still remains unclear whether preexisting structural
changes are responsible for the initiation of AF. Atrial
tissue from patients undergoing cardiac surgery demon-
strated occasional interstitial fibrosis, myocyte vacuoli-
zation, and nuclear derangement in those who
developed postoperative AF.40 It is possible that under-
lying cardiac pathologies gradually create a structural
substrate, which may lead to the arrhythmia under the
influence of electrical remodeling or a potent trigger
such as inflammation.
American Heart Journal
February 2009
Inflammation
The association of inflammation with the development
of AF is composite (Table III). The first study to support
the role of inflammation in AF pathogenesis was reported
in 1997, when Frustaci et al41 demonstrated histologic
changes consistent with myocarditis in atrial tissue of
patients with lone AF. The increased rate of AF after
cardiac surgery highlights the role of inflammation in the
development of the arrhythmia. Moreover, the efficacy of
drugs with anti-inflammatory properties in the preven-
tion of AF supports the association between inflamma-
tion and AF.42,43
C-reactive protein (CRP) is an acute-phase protein, a
component of the innate immune system. It is produced
in the liver as a response to interleukins (ILs) 1 and 6.
Elevated plasma CRP levels have been associated with an
increased risk of cardiovascular events, and its predictive
value has been validated in various prospective epide-
miological studies.44 A large population-based cohort
study of 5,806 individuals older than 65 years, with a 6.9 ±
1.6-year follow-up, showed that baseline CRP levels were
significantly and independently associated with the
development of future AF.45 A case-control study of 131
patients with atrial arrhythmias versus 71 controls
demonstrated that CRP was significantly higher in the
arrhythmia group. Moreover, patients in persistent AF
had higher CRP levels than the paroxysmal AF and the
control groups, indicating the possible relationship
between CRP levels and chronicity of AF.46
In another study to examine the association between
AF and CRP, 50 patients with recent-onset paroxysmal AF
who underwent chemical cardioversion with amiodar-
one were assessed against 50 matched controls. Once
more, baseline CRP levels were higher in the paroxysmal
AF group when compared with the control group. After
the attempted chemical cardioversion, patients with
higher baseline CRP levels had significantly lower
cardioversion success rates.47 This study suggested that
CRP could be a potent predictor of successful AF
cardioversion. A recent meta-analysis, which aimed to
identify baseline CRP levels and AF recurrence after
successful electrical cardioversion, confirmed that higher
baseline CRP levels were associated with an increased
risk of recurrent AF.48 However, the heterogeneity of the
individual studies was a limitation of the meta-analysis,
and AF prediction based on CRP alone was therefore
deemed not conclusive.
The hypothesis that CRP may not be a reflection of
the arrhythmia itself but a result of confounding
underlying cardiac pathology led Ellinor et al49 to study
patients in lone AF and compare their CRP levels to
controls. As no significant difference was demonstrated
between the 2 groups, they suggested that CRP might not
be a marker of the arrhythmia but an outcome of the
underlying cardiac pathology.
American Heart Journal
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Kourliouros et al 249

Table III. Studies on inflammation and AF

Author, year Model Setting/methods Outcome Association with AF

Frustaci et al, Humans (lone AF) Endomyocardial biopsies, Interatrial septum specimens (66%) Initiation
199741 histology, electron microscopy consistent with myocarditis
Aviles et al, Humans Baseline CRP levels and Elevated CRP in patients with AF Initiation and
200345 7-y follow-up at baseline. Increased CRP maintenance
predicted future AF
Chung et al, Humans (persistent AF, High-sensitivity CRP assay CRP N2-fold increase in AF Maintenance
200146 paroxysmal AF, SR) vs control; higher CRP in the persistent
vs paroxysmal vs SR groups
Liu et al, Humans (persistent AF) Meta-analysis of 7 studies Raised baseline CRP levels in patients Maintenance
200748 on CRP and maintenance with AF recurrence (but significant
of SR after successful heterogeneity across the studies)
electrical cardioversion
Ellinor et al, Humans (lone AF, High-sensitivity CRP assay No CRP difference between groups No association
200649 AF and hypertension,
controls)
Lo et al, 200550 Humans (CABG with Preoperative high-sensitivity Continuous baseline CRP was Initiation
or without CPB) CRP assay an independent predictor of
postoperative AF
Bruins et al, Humans (CABG Plasma IL-6, CRP, C3a, C3b/c, Baseline C4b/c and the day 2 Initiation
199754 with CPB) C4b/c, complement-CRP complexes C4d-CRP associated with
postoperative AF
Dernellis and Humans (healthy Baseline CRP and components High CRP and C3-C4 levels Initiation
Panaretou, individuals, no of complement system C3 and associated with new-onset AF
200655 history of AF) C4, 4-y follow-up
Conway et al, Humans (permanent CRP, IL-6, tissue factor, plasma Raised CRP, IL-6, tissue factor, No significant
200456 AF vs controls) viscosity, von Willebrand factor,
and plasma viscosity in AF population; association
soluble P-selectin became nonsignificant after
multivariate adjustment
Psychari et al, Humans (permanent CRP, IL-6, left atrial size Raised CRP and IL-6 in the Maintenance
200557 and persistent AF and ventricular function AF group; CRP was an
vs controls) independent predictor
Gaudino et al, Humans (CABG) −174G/C IL-6 promoter gene GG genotype was the only Initiation
200358 polymorphisms, CRP, IL-6, fibrinogen independent predictor of
postoperative AF
Marcus et al, Humans (CAD) IL-6, CRP, TNF-α, CD40 ligand, MCP- CC genotype and IL-6 Initiation and
200859 1, fibrinogen, −174G/C IL-6 promoter independently associated maintenance
gene polymorphisms with AF
Sawaya et al, Transgenic mice with Epicardial activation mapping, Sustained inflammatory Initiation and
200761 targeted cardiac over immunohistochemistry signaling caused reduced ERP, maintenance
expression of TNF vs control down-regulation of Cx40, and
atrial arrhythmias
Sata et al, Humans (AF undergoing CRP, IL-6, TNF-α before and after Increased baseline CRP, IL-6, Initiation and
200462 cardioversion vs controls) chemical cardioversion and TNF-α in patients with AF maintenance
Ishida et al, Humans (off-pump CABG) CRP, TNF-α, IL-6, and IL-8 pre- Highest quartile of IL-6 level Initiation
200663 and postoperatively immediately after surgery predicted
postoperative AF
Mandal et al, Humans (CABG) CRP and HSP65 antibodies HSP65 antibodies independently Initiation
200464 predicted postoperative AF

CPB, Cardiopulmonary bypass; CAD, coronary artery disease; MCP, monocyte chemoattractant protein.

In the context of cardiac surgery, baseline CRP levels
have been examined as a potential predictor for post-
operative AF. Although Lo et al50 have shown that
baseline CRP levels are associated with a higher risk after
coronary artery bypass graft surgery, other studies have
not confirmed this finding.51,52
A possible mechanism by which CRP can induce AF
involves the disarray of normal cell membrane structure
in conditions that cause energy depletion and apoptosis,
such as ischemia and oxidative stress.53 Enzymatic
interaction of secretory phospholipase A2 with the outer
leaflet phospholipids of injured cells creates lysopho-
spholipids, which provide the ligand for CRP, followed by
activation of the complement system and phagocytosis.
However, this mechanism is not specific between
irreversibly and reversibly (apoptotic) injured cells and,
as a result, tissue damage may include cells with a
potential to proliferate, such as myocytes from the
fibrillating atria or areas of myocardial infarction.32 These
changes progressively lead to loss of atrial muscle mass

250 Kourliouros et al
and interstitial fibrosis, which are known determinants of
AF, and associate the inflammatory response with
structural remodeling.
One of the first studies to suggest the association
between complement activation after cardiopulmonary
bypass and AF was carried out by Bruins et al.54 In
addition to the known complement activation during
cardiopulmonary bypass via the alternative pathway,
complement activation also occurs during the acute-
phase response for a few days after surgery. In this case,
the classic pathway is activated through C3 and C4-CRP-
mediated complexes that remain elevated up to 5 days
postoperatively. A positive correlation was identified
between baseline levels of C4, day 2 levels of C4-CRP
complex, and postoperative atrial arrhythmias. In a
population-based study of 1,011 healthy patients and a
4-year follow-up, patients with high CRP and high C3 or
C4 levels were 3 times more likely to develop AF
compared with those with normal CRP and comple-
ment levels.55
Interleukin 6 is a proinflammatory cytokine that is
responsible for the synthesis of acute-phase proteins
(such as CRP) while it exhibits cytoprotective properties.
Higher plasma IL-6 levels were identified in patients with
AF compared with controls in a study by Conway et al.56
Interleukin 6 levels have also been positively correlated,
not only with the presence of AF but also with its duration
and left atrial diameter, indicating the possible role of
inflammation in atrial remodeling.57
In a prospective study of 110 patients undergoing
cardiac surgery, postoperative AF was correlated to
increased levels of IL-6 and was independently associated
with presence of -174 C/G polymorphism of the promoter
of the IL-6 gene.58 These findings raise the possibility of a
genetic predisposition to an enhanced inflammatory
response after cardiopulmonary bypass with subsequent
development of AF. In a cross-sectional analysis of 971
unoperated patients with coronary artery disease, 46
of whom had documented AF, Marcus et al59 demon-
strated a strong association between AF, high levels of IL-6,
and −174CC genotype after appropriate regression
analysis. High IL-6 levels have also been associated with an
increased risk of thromboembolism, connecting the
inflammatory process in AF with thrombogenesis.60
Transgenic mice with cardiac specific overexpression
of tumor necrosis factor (TNF), causing sustained in-
flammatory signaling, showed down-regulation of Cx40,
reduced ERP and susceptibility to atrial arrhythmias,61
linking chronic inflammation with electrical remodeling
and AF. A study of 15 patients with first presentation of AF
who underwent successful chemical cardioversion de-
monstrated that baseline TNF-α levels were significantly
higher when compared with controls, and this elevation
remained for 2 weeks after cardioversion.62 However,
systemic TNF-α levels were not found to be significantly
different in patients who developed postoperative AF
American Heart Journal
February 2009
after off-pump coronary artery bypass grafting when
compared with patients who remained in SR.63
Previous research from our group has demonstrated an
association between heat shock proteins (HSPs), inflam-
mation, and AF after cardiac surgery. Heat shock proteins
are a group of proteins that are responsible for
preservation of cellular integrity by keeping proteins in
their correctly folded state. Inflammation-induced
expression of HSPs in the cell surface of myocytes, and
binding with circulating anti-HSP65 antibodies, may lead
to complement-mediated cell lysis with subsequent
structural and electrical changes leading to AF.64
Conclusions
Current evidence suggests that the pathogenesis of AF
is multifactorial. Electrical remodeling with resultant
atrial refractoriness abbreviation and shortening of the
action potential duration appears to be partially respon-
sible for the self-perpetuation of AF. Despite electrical
remodeling being a reversible process, the susceptibility
to AF takes significantly longer to recover, raising the
importance of a “second factor” in its pathogenesis.
Structural remodeling, with features of interstitial fibrosis
and cellular degeneration, provides a susceptible sub-
strate that promotes reentrant circuits and AF. Evolving
clinical evidence demonstrates that inflammation is
associated with new-onset and recurrent AF through a
mechanism that possibly involves cellular degeneration,
apoptosis, and subsequent atrial fibrosis. Further
research into the pathophysiologic mechanisms that
predispose to the development of AF and its perpetuation
is the cornerstone for the development of targeted
treatment modalities that may lead to effective prevention
and treatment.
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