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Cardiovascular Research 54 (2002) 197–203
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Editorial
Spotlight on atrial fibrillation—the ‘complete arrhythmia’
a,
b
c
Stanley Nattel *, Maurits Allessie , Michel Haissaguerre
a
Montreal Heart Institute, Department of Pharmacology and Research Center, 5000 Belanger St., East, HIT IC8 Montreal, Quebec, Canada
b
Department of Physiology, Maastricht University, Maastricht, The Netherlands
c
ˆ
´ ˆ , University of Bordeaux, Bordeaux, France
Hopital
Cardiologique du Haut-Leveque
Received 21 February 2002; accepted 21 February 2002
1. Historical perspective
The first historical reference to what may have been AF
appeared approximately 4000 years ago, in The Yellow
Emperor’s Classic of Internal Medicine (Huang Ti Nei
Ching Su Wen): ‘‘When the pulse is irregular and tremulous and the beats occur at intervals, then the impulse of
life fades’’ [1]. In the late 1700s, William Withering
described a patient with a weak, irregular pulse that
became ‘‘more full and more regular’’ after treatment with
extracts from the foxglove (Digitalis purpurea) [1]. Bouil*Corresponding author. Tel.: 11-514-376-3330; fax: 11-514-3761355.
E-mail address: [email protected] (S. Nattel).
land described ‘‘ataxia of the pulse’’ in 1835, referring to a
pulse with varying inter-beat intervals [2]. Nothnagel used
recently-developed graphical techniques of analyzing arterial pulses to describe a condition in which ‘‘heartbeats
follow each other in complete irregularity . . . , the height
and tension of the individual pulse waves are continuously
changing’’, which he termed ‘‘delirium cordis’’ [3]. Fibrillation was first noted in response to strong, continuous
(faradic) current application to the ventricles in 1850 [4]. A
similar behavior of the atria was noted by Vulpian in 1874,
´
who applied the term ‘‘fremissement
fibrillaire’’ [5]. At the
end of the 19th century, Cushny noted the similarity
between pulse curves in clinical delirium cordis and those
in dogs with induced auricular fibrillation [6]. Fredericq
demonstrated the role of AF in causing the associated
irregularity in ventricular contraction by cutting the bundle
of His, after which the atria continued to fibrillate but the
ventricles began to beat regularly [7]. Lewis was the first
to suggest that the very fine diastolic oscillations on ECG
recordings of patients with AF are due to fibrillatory atrial
activity, which is responsible for the concomitant irregularity in intervals between QRS complexes [8].
In the early 1900s, three primary theories of AF had
evolved [9]. AF was variously considered to be due to
enhanced ectopic activity (Engelmann, Winterberg), to
rapid single-circuit reentry with fibrillatory conduction
(Lewis) or to multiple simultaneous functional reentry
circuits (Mines, Garrey). Moe’s ‘‘multiple-wavelet hypothesis’’ was a more refined version of the multiple reentry
circuit idea, and was supported by an (at the time) avantgarde computer model of atrial activity during AF [10].
The multiple-reentry notion became the dominating mechanistic framework for thinking about AF mechanisms and
antiarrhythmic actions.
The past 10 years have witnessed an explosion of
research into the mechanisms of AF that has greatly
modified our perspective and had a significant impact on
therapeutic approaches. A major impetus for this explosion
0008-6363 / 02 / $ – see front matter  2002 Published by Elsevier Science B.V.
PII: S0008-6363( 02 )00324-3
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The French sometimes refer to atrial fibrillation (AF) as
`
‘l’arythmie complete’,
which literally means ‘the complete
arrhythmia’. The actual sense in French is that AF results
in complete irregularity of cardiac rhythm. However, AF
can also be considered the ‘complete’ arrhythmia in the
sense of the consummate nature of its mechanisms and
determinants. There is evidence for involvement of all
forms of arrhythmia mechanisms in AF, including enhanced automaticity, delayed afterdepolarizations, early
afterdepolarizations and reentry. A rich and wide range of
determinants have been found to be involved in the
pathophysiology of AF—various forms of ionic remodeling, structural remodeling, changes in connexin function
and distribution, a whole gamut of signaling systems,
anatomical determinants related to the complex threedimensional atrial structure, hemodynamic factors and the
involvement of electrical activity in the great veins.
Research on the mechanisms of AF, and related therapeutic
developments, has exploded over the past 10 years, and the
present Spotlight Issue of Cardiovascular Research is
meant to express some of this effervescence.
198
S. Nattel et al. / Cardiovascular Research 54 (2002) 197 – 203
Table 1
Thematic relationships among papers
Theme
Review articles
Original articles
Theoretical considerations
Jalife [16], Waldo [17],
Kneller [46]
Atrial remodeling
Allessie [18], Goette [20],
Brundel [33]
Brundel [39], Yagi [43],
Kneller [46], Thijssen [50],
Shinagawa [51],
Kurita [54], Shi [58]
Cellular electrophysiology
Bosch [21],
Van der Velden [22]
Dobrev [41], Yagi [43],
Kneller [46],
Anyukhovsky [60]
Novel models
Olgin [28]
Scherlag [61]
Structural determinants
De Bakker [30], Chen [31],
Shimizu [32], Ho [34]
Kostin [37], Goette [40],
Shi [58], Anyukhovsky [60]
Novel therapeutics
¨ [35], Nattel [36]
Jaıs
Shinagawa [51], Kurita [54],
Shi [58], Becker [64]
2. Review articles
2.1. Basic concepts of AF
The review articles begin with an opinion piece by Jalife
et al. [16]. They discuss historical data and more recent
experimental evidence that they argue points to a single or
small number of reentrant sources located in the left atrium
underlying AF. They suggest that the differences between
paroxysmal and chronic AF may be due to the frequency
and stability of the rotor(s) driving the arrhythmia; with the
rotors being faster and more stable, perhaps because of
structural and electrophysiological remodeling, in the
chronic form.
This is followed by an evaluation by Waldo of the
relationships between atrial flutter and AF [17]. Dr. Waldo,
the world’s leading authority on the mechanisms of atrial
flutter, suggests that there is a reciprocal relationship
between atrial flutter and fibrillation. He argues that an
initial period of AF is very frequently the prelude to
sustained atrial flutter, with AF playing a crucial role in
forming a line of block between the venae cavae, without
which the reentering flutter wave would be terminated by
short-circuiting impulses. In addition, he emphasizes the
importance of single-circuit reentry (as underlies atrial
flutter) in the maintenance of many cases of AF.
2.2. Atrial remodeling
The next article, by Allessie et al. discusses electrical,
contractile and structural remodeling during AF [18]. Dr.
Allessie’s laboratory has made many seminal contributions
to the understanding of AF, among which the most
important is probably the recognition of the phenomenon
of atrial electrical remodeling by which ‘AF begets AF’
[19]. This article reviews the changes in atrial electrical
function, contractile behaviour, and structural composition
that result from maintained AF. A host of clinically-related
phenomena are indicated, and the interactions between
AF-induced alterations and underlying disease-related substrates are discussed.
Goette et al. then review the various signal transduction
systems that may be involved in atrial remodeling. They
present an exhaustive analysis of the key cardiac signaling
systems, including neurohoromones and neurotransmitters,
and discuss the evidence for their involvement in AF [20].
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was a growing recognition of the clinical importance of
AF, as well as an awareness of the inadequacy of present
therapeutic approaches. By the 1990s, ablation therapy had
become a safe and definitive approach for the treatment of
AV node reentrant and circus movement tachycardias, as
well as for most cases of atrial flutter. Malignant ventricular tachyarrhythmias were effectively dealt with by implantable cardioverter-defibrillators. However, safe and
highly-effective nonpharmacological approaches to AF
remain elusive, and all forms of drug therapy for AF have
significant limitations [11]. AF remains the most common
sustained arrhythmia in clinical practice, with an incidence
that is increasing with the aging of the population [12], is
the most common etiological factor in stroke in the elderly
[13], and may increase cardiovascular mortality [14],
especially among patients with heart failure [15].
Because of the rapid pace of research on AF, its clinical
importance, and the need for discussion and interaction
among investigators in order to develop improved therapeutic approaches, the editorial board of Cardiovascular
Research decided to dedicate a Spotlight Issue of the
journal to the problem. We are delighted and honoured to
have been asked by the editorial board to serve as guest
editors. The product, presented in this issue of the journal,
consists of 14 review articles and 13 original papers. Table
1 shows the thematic inter-relationships among reviews
and original papers, which are discussed in more detail
below.
S. Nattel et al. / Cardiovascular Research 54 (2002) 197 – 203
2.3. Cellular electrophysiology
2.4. Role of pulmonary veins
A key development in the understanding of AF mechanisms was the publication by Haissaguerre et al. of their
landmark observations regarding the role of pulmonary
veins as initiators of AF [29]. Two review articles in this
issue deal with this subject. The basic and clinical electrophysiology of pulmonary veins is the subject of a
review by de Bakker et al. [30]. They discuss the properties of extracellular and intracellular potentials recorded
in the pulmonary vein region, as well as the anisotropic
properties of the myocardial sleeve around pulmonary
veins, in relationship to atrial arrhythmogenesis. Chen et
al. review the evidence suggesting a role for the pulmonary
veins in nonparoxysmal AF [31]. They conclude that these
data suggest that pulmonary vein activity is not only an
initiator of AF, but may be central to AF maintenance.
2.5. Determinants and treatment of AF in man
The next few articles deal with observations specifically
dealing with AF in man. Shimizu and Centurion review the
abnormalities noted during electrophysiological studies of
patients with AF [32]. They discuss in detail atrial
electrograms and refractory properties, suggesting that
shorter refractory periods, greater refractoriness dispersion,
conduction delays and fragmented electrograms are more
common in AF.
Brundel et al. discuss the available information regarding molecular mechanisms of remodeling in human AF
[33]. The evidence for ion-channel remodeling at the
mRNA and protein levels is reviewed, as are changes in
proteins determining Ca 21 homeostasis and structural
remodeling. The potential role of Ca 21 overload in remodeling is considered, and preliminary evidence is presented relating to the activation of the Ca 21 -dependent
enzyme, calpain, in AF.
The next review article is a detailed analysis by Ho et al.
of the morphological basis of atrial conduction [34]. They
present the complex anatomy of the atria and the interrelationships between anatomical features in man. Extensive use is made of anatomical specimens, with accompanying line sketches to clarify the subtle structural details
on the original specimens. The relationship to findings in
animal models is mentioned. This paper will serve as a
learning atlas for those interested in the structural determinants of AF and potential targets for ablation therapy.
Having reviewed the structural determinants of atrial
conduction, we pass to a state-of-the-art review paper on
ablation therapy by Jais et al. [35]. This article is written
by the group that has consistently been at the forefront of
the development of innovative ablation approaches for AF,
and reviews in detail the history, present status and likely
future directions in this field. The authors note that AF is
the only arrhythmia for which curative ablation therapy is
directed against the trigger for reentry.
The final review paper, by Nattel, addresses the notion
that new knowledge about AF mechanisms can be applied
to improve therapeutics [36]. Since most of the reviews in
the Spotlight Issue relate to the elucidation of AF mechanisms, it is appropriate to consider whether the results
obtained to date have contributed to the treatment of AF.
Mechanistic insights have resulted in an improved understanding of present treatment modalities and the development of potential new therapeutic approaches. At the same
time, much work remains to be done in order to optimize
treatment of this arrhythmia.
3. Original articles
3.1. Determinants of clinical AF
The original articles begin with a thoroughly-performed
evaluation of the structural correlates of AF in man [37].
Kostin et al. applied immunoconfocal and electron microscopy to analyze changes in connexin and collagen dis-
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This paper is followed by a detailed review of the
cellular electrophysiology of AF by Bosch and Nattel [21].
A variety of action potential abnormalities have been
described in different forms of AF in experimental and
clinical models, and there has been extensive recent
investigation of the underlying ionic mechanisms. The
authors describe these findings, dealing with the cellular
electrophysiology of AF associated with atrial tachycardiaremodeling, congestive heart failure, thyrotoxicosis, and
the postoperative state.
Van der Velden and Jongsma follow with an article
regarding connexin changes in AF [22]. Connexins are the
hemichannel proteins responsible for intercellular communication. A confusing array of changes in atrial connexins has been described in AF, including an increase in
connnexin43 [23], a spatially-heterogeneous decrease in
connexin40 [24,25], an increase in connexin40 [26], and an
increase in connexin40 with altered cellular distribution of
connexins towards lateral membranes [27]. The authors
deal with this complex subject, and discuss the potential of
connexins as a novel therapeutic target for AF.
Olgin and Verheule follow with a discussion of novel
genetic models of AF in the mouse [28]. They illustrate the
value of such models by discussing the evidence regarding
the role of connexins in AF based on connexin knockout
models. Preliminary results are presented from a transforming growth factor-b overexpression model, in which
increased fibrosis appears to form the substrate for AF.
Although to date relatively little work has been performed
to study AF mechanisms in genetically-manipulated mice,
this approach would appear to have tremendous potential
for the future.
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200
S. Nattel et al. / Cardiovascular Research 54 (2002) 197 – 203
3.2. Pathophysiology of atrial-tachycardia remodeling
The next three papers provide new insights into the
pathophysiology of electrical remodeling associated with
atrial tachycardias. Yagi et al. study inward-current downregulation in dogs with atrial tachypacing-induced AF
[43]. They present novel findings suggesting that the
mechanisms of L-type Ca 21 -current downregulation may
differ in dogs with sustained AF from those in which
sustained AF fails to develop. They also show that INa is
reduced in dogs with AF, confirming the observations of
Gaspo et al. [44]. Bosch et al. did not find evidence for
decreased INa in atrial myocytes of patients with AF
[45]—in conjuction with the prior report [44], the results
of Yagi et al. suggest either that there are significant
species differences in the response of INa to atrial tachycardia or that confounding factors prevented Bosch et al. from
detecting the effect of AF on INa in their patient population.
The next paper, by Kneller et al., evaluates the role of
changes in Ca 21 -handling in the atrial refractoriness ratemaladaptation typical of atrial tachycardia-remodeling
[46]. Loss of refractoriness rate-adaptation is a characteristic finding in rate-related atrial electrical remodeling
[18,19] and in clinical AF patients [47]. A recently-developed detailed mathematical representation of the canine
atrial action potential was able to reproduce many experimental behaviours based on presumed ionic mechanisms; however, when the ion-channel remodeling caused
by atrial tachycardia was reproduced, atrial rate-adaptation
was not fully explained [48]. Kneller et al. modified the
ionically-based canine action potential model to faithfully
reproduce intracellular Ca 21 -transients under control conditions and in the presence of atrial-tachycardia induced
Ca 21 -handling abnormalities [49]. When the changes in
Ca 21 -handling were included, the model fully reproduced
rate-maladaptation, indicating that alterations in cellular
Ca 21 -handling play a role in the action potential abnormalities caused by atrial tachycardia remodeling.
Thijssen et al. use the method of differential display to
analyze alterations in gene expression occurring after |14
weeks of sustained AF in the goat [50]. They observed
changes in 125 fragments, of which 21 represented genes
known to be involved in cardiomyocyte structure, metabolism, expression-regulation or de-differentiation. The results were verified by a modified Northern blot procedure
and by dot-blot analysis, and are consistent with atrial
myocyte de-differentiation, as well as with transient ischemia in the early phases of remodeling. This is the first
report of the use of this powerful new technique in the
analysis of atrial remodeling.
3.3. Experimental studies of remodeling prevention
The next series of papers deals with studies of drug
therapy intended to modify atrial remodeling. Shinagawa
et al. evaluate the effects of inhibiting Na 1 / H 1 -exchange
or angiotensin-converting enzyme on atrial-tachycardia
remodeling [51]. Previous studies of short-term (several
hour) AF have shown promise of these interventions in
preventing remodeling [52,53]. Since both Na 1 / H 1 -exchange blockers and angiotensin antagonists are available
for clinical use, they are potentially quite interesting
compounds for the prevention of atrial remodeling. Unfortunately, despite a very careful experimental design,
Shinagawa et al. were unable to demonstrate protective
effects of these interventions against the electrophysiologi-
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tribution. They found lateralization of connexins40 and 43,
as well as of the gap junctional protein N-cadherin, in AF.
Connexin43 concentration was decreased by |50%
throughout the atria, whereas connexin40 was reduced by
54% in appendages but tended to be increased in the RA
free wall. Collagen content was substantially increased in
AF, accompanied by extensive interstitial fibrosis. This
observation is consistent with previous experimental observations suggesting an important role for interstitial
fibrosis in AF promotion [38].
This study of structural correlates is followed by an
analysis of proteolytic activity and associated alterations in
human AF by Brundel et al. [39]. The authors note
increased calpain I proteolytic activity in atrial tissues from
AF patients, along with increased calpain I protein expression. Calpain activity correlated with AF-related changes
in Ca 21 - and Kv1.5-channel subunit protein, with the
occurrence of histological changes (contraction bands and
alterations associated with hibernating myocardium) and
with altered refractoriness adaptation to rate change. The
demonstration of increased Ca 21 -dependent proteolytic
activity is certainly interesting and potentially quite important; however, it remains to be determined whether the
correlations with other AF-related changes are due to a
causal role for calpain activation or whether the same
factor(s) that activate calpain also lead to the other changes
observed.
The next two original articles deal with postoperative
AF, a discrete and clinically-problematic entity. Goette et
al. studied the determinants of AF after open-heart surgery
[40]. They found that increased age is associated with
increased P-wave duration and fibrosis, and that the latter
two variables predicted the occurrence of postoperative
AF. Dobrev et al. study inward-rectifier K 1 -currents in
patients with and without AF prior to cardiac surgery, and
in the sinus-rhythm group relate inward-rectifier currents to
postoperative AF [41]. They confirm their previouslyreported finding that IKACh is upregulated, and IK downregulated, in AF [42]. They extend these observations by
showing that sinus-rhythm patients who develop postoperative AF do not have different inward-rectifier currents
from patients that maintain sinus rhythm. This observation
supports the notion of a discrete pathophysiological basis
for postoperative AF.
S. Nattel et al. / Cardiovascular Research 54 (2002) 197 – 203
3.4. Diverse experimental paradigms
The following contribution by Anyukhovsky et al. is a
detailed evaluation of changes in atrial cellular electrophysiology with aging in the dog [60]. Advancing age is
a very important risk factor for the occurrence of AF [12].
The authors find that aging shifts the action potential
plateau voltage in the negative direction and prolongs the
action potential. Phase 0 upstroke velocity is not substantially altered, but conduction velocity is reduced, particularly during premature stimulation. These observations
are consistent with the notion that changes in atrial cell
coupling and architecture, such as those caused by interstitial fibrosis, may play an important role in the predilection
of older individuals to develop AF.
Scherlag et al. then present a novel model of paroxysmal
AF, induced by endovascular stimulation within the pulmonary arteries [61]. AF appeared to be due to autonomic
reflex function, and could be abolished by atropine pretreatment. These observations may cast light on the
pathophysiology of the previously-reported syndrome of
vagally-mediated AF [62].
In the final paper of the issue, Becker et al. describe an
evaluation of the effects of atrial multisite and septal
pacing on AF induction in dogs with sterile pericarditis
[63]. They found that four-site pacing and septal pacing
reduced the number of AF episodes that could be induced
by premature stimulation. These results are interesting and
relevant to novel pacing approaches for AF prevention.
The interpretation of the data is limited by the lack of
correlation with atrial activation changes caused by pacing,
as presented in earlier work from this laboratory [64], and
by the lack of information about changes in the vulnerable
window for AF induction.
4. Concluding remarks
We would be remiss in concluding these comments
without a strong expression of thanks to the Cardiovascular
Research Editors assigned to this project, Tobias Opthof
and Ruben Coronel. Their support, help, enthusiastic
collaboration and tireless effort were essential to the
success of this Spotlight Issue.
Acknowledgements
´
The authors thank Luce Begin
for excellent secretarial
help with the manuscript and Dr. Marc Dubuc for his
linguistic insights on the term ‘l’arythmie complete’. They
also wish to thank the personnel in the editorial office of
Cardiovascular Research for its help and its efficient
handling of manuscripts and editorial correspondence.
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