Medical Hypotheses 72 (2009) 466–467

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Oxidative stress: A possible pathogenesis of atrial fibrillation

Cong-xin Huang a,*, Yu Liu a, Wen-fang Xia b, Yan-hong Tang a, He Huang a
a
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China
b
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, PR China

a r t i c l e i n f o s u m m a r y

Article history: Atrial fibrillation (AF) is the most commonly sustained arrhythmia in clinical practice. Despite the exten-
Received 4 August 2008 sive studies, the pathophysiology of AF, however, remains incompletely understood. Studies have demon-
Accepted 18 August 2008 strated that oxidative stress may be involved in cardiac structural and electrical remodeling. More
recently, a growing body of evidence suggests that oxidative stress is associated with the development
of AF. The evidence for the hypotheses included that: (1) histological studies have demonstrated oxidative
damage in both AF patients and animal models of AF; (2) oxidative stress markers are increased in AF
patients, and are associated with the presence of AF; (3) drugs that have antioxidant properties show ben-
eficial effects on AF development. Although the studies suggest the association between oxidative stress
and AF, the exact pathogenesis of oxidative stress in AF development remains elusive and requires further
investigation. Specifically, the causality between oxidative stress and AF; the levels of the oxidative stress
in various types of AFs and their role in the pathogenesis of AF; the effects of strategies to reduce oxidative
stress on atrial structural and electrical remodeling, and their exact role in the development of AF. Oxida-
tive stress may provide a scientific basis for further research on the underlying mechanisms of AF and may
target for pharmacological interruption of AF.
Ó 2008 Elsevier Ltd. All rights reserved.

Introduction suggest that oxidative stress may directly or indirectly regulate

Atrial fibrillation (AF) is the most commonly sustained arrhyth-
mia in clinical practice. The prevalence of AF is continuously
increasing during the past few decades [1]. AF has become a major
public health problem because it is associated with increased mor-
bidity and mortality [2]. Despite the extensive studies, the patho-
physiology of AF, however, remains incompletely understood.
More recently, a growing body of evidence suggests that oxida-
tive stress has been associated with the development of AF [3].
Oxidative stress may be a possible pathogenesis of AF.
Oxidative stress and cardiac remodeling
Experimental studies have demonstrated that oxidative stress
involves modulation of signaling pathways in heart, such as trans-
forming growth factor-b1(TGF-b1) and mitogen-activated protein
kinase subfamilies including extracellular signal-regulated kina-
se(ERK), c-Jun N terminal kinase (JNK) and p38-kinase [4,5]. Acti-
vation of these signaling pathways has been reported as
molecular alterations related to the development of AF-promoting
fibrosis [6,7]. Many studies have shown that cardiac fibrosis dis-
turbs anisotropic conduction and slows electrical conduction,
which in turn results in reentry [8]. In addition, increased fibrosis
might contribute to arrhythmogenesis by induction of ectopic
activity through myocyte–fibroblast coupling [9]. These findings
* Corresponding author. Tel./fax: +86 27 88041911.
E-mail address: huangcongxin@yahoo.cn (C.-x. Huang).
the metabolism of extracellular matrix proteins, and might be in-
volved in atrial fibrotic remodeling during AF.
Studies have confirmed that changes in the intracellular redox
state can affect the gating properties of ion channels and the activ-
ity of ion transporters, including increase of the open probability of
sarcoplasmic reticulum (SR) ryanodine receptor (RyR), inhibition of
calcium-adenosine triphosphatase (Ca2+-ATPase) activity, decrease
of L-type current and activation of inositol 1,4,5 triphosphate (IP3)
receptors [10–13]. More recently, studies have demonstrated that
antioxidants can prevent redox-dependent Ca2+ leak, restore SR
Ca2+-ATPase expression and SR Ca2+-uptake activity in heart failure
[14,15]. Many studies have demonstrated that altered atrial Ca2+
homeostasis contributes to electrical remodeling in AF [16]. Sev-
eral investigators have discussed intracellular Ca2+ abnormality
as a possible initiator or perpetuator of AF, including SR Ca2+ leak,
down-regulation of SR Ca2+-ATPase and L-type Ca2+ current and
up-regulation of IP3 receptors [17–19]. These findings indicate that
oxidative stress may regulate atrial Ca2+ homeostasis, and might be
involved in atrial electrical remodeling during AF.
Oxidative stress is a possible pathogenesis of atrial fibrillation
Compelling evidence has confirmed that atrial structural and
electrical remodeling is a critical process in the pathophysiology
of AF [20]. And oxidative stress may cause atrial structural and
electrical remodeling, which plays an important role in the patho-
genesis of AF. The hypothesis is supported by the following aspects:

0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2008.08.031
 C.-x. Huang et al. / Medical Hypotheses 72 (2009) 466–467
Histological studies have demonstrated oxidative damage in
both AF patients and animal models of AF. Mihm et al. first reported
the linking of oxidative stress to AF. The authors demonstrated sub-
stantial oxidative damage in right atrial appendages obtained from
AF patients who were undergoing the Maze procedure [21]. In an
experimental model of AF, Carnes et al. revealed that dogs with sus-
tained AF demonstrated increased protein nitration suggesting en-
hanced oxidative stress [22]. At the genetic level, Kim et al.
examined the gene transcriptional profiles in human atrial tissue ob-
tained from 26 patients with permanent AF undergoing the Maze
procedure, and found that five genes associated with the production
of reactive oxygen species (ROS) increased, whereas two genes re-
lated to antioxidants decreased [23]. More recently, Kim et al. mea-
sured nicotinamide adenosine dinucleotide phosphate (NADPH)-
stimulated superoxide production in the right atrial appendage
samples from 170 consecutive patients undergoing coronary artery
bypass surgery. The authors found that patients who developed AF
after surgery had a significant increase in atrial NADPH oxidase
activity than patients who remained in sinus rhythm, and increased
atrial NADPH oxidase activity was independently associated with an
increased risk of post-operative AF [24].
More recently, clinical studies have shown that oxidative stress
markers are increased in AF, and are associated with the presence
of AF. In a cross-sectional case-control design study, Neuman et al.
showed that oxidative stress markers were significantly elevated
in persistent AF patients, and oxidative stress but not inflammatory
markers were associated with AF [25]. In addition, Ramlawi et al.
investigated oxidative stress markers in patients undergoing
coronary artery bypass grafting or valve procedures. They found that
patients with post-operative atrial fibrillation (PAF) after cardiac
surgery had significantly more elevation in total peroxide levels in
serum compared to patients in sinus rhythm at 6 h after surgery [26].
Furthermore, drugs that have antioxidant properties show bene-
ficial effects on AF development. In chronically instrumented dogs,
Carnes et al. found that pre-treatment of dogs with ascorbate atten-
uated the pacing-induced atrial ERP shortening. In addition, the
authors demonstrated that patients undergoing cardiac bypass graft
surgery receiving perioperative treatment with ascorbate were
associated with a significant benefit in preventing AF [22]. A ran-
domized, double-blind, placebo-controlled trial demonstrated that
patients receiving perioperative treatment with steroids were asso-
ciated with a significant decrease in post-operative AF [27]. In an-
other study, Korantzopoulos et al. found that patients receiving
treatment with vitamin C reduced early recurrence rates after elec-
trical cardioversion of persistent AF [28].
Future directions and implications
Although studies suggest that oxidative modifications have con-
siderable impact on the atrial remodeling, the exact pathogenesis
of oxidative stress in AF remains elusive and requires further inves-
tigation. Specifically, the causality between oxidative stress and
AF; the levels of the oxidative stress in various types of AFs and
their role in the pathogenesis and perpetuation of AF; the effects
of strategies to reduce oxidative stress on atrial structural and elec-
trical remodeling, and their exact role in the development of AF. If
the hypothesis is confirmed, drugs that have antioxidant properties
may be used to prevent the atrial structural and electrical remod-
eling. It will be a new target point to treat AF.
Conclusion
Several studies have suggested that oxidative stress may be in-
volved in atrial structural and electrical remodeling during AF. Oxi-
dative stress is associated with the development of AF, and may be
467
a possible pathogenesis of AF. It may provide a scientific basis for
further research on the underlying mechanisms of AF. Further clar-
ification of the role of oxidative stress in the development of AF
may target for effective pharmacological interruption of AF.
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