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Cardiovascular Research 2002 54(2):197-203; doi:10.1016/S0008-6363(02)00324-3
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Copyright © 2002, European Society of Cardiology

Spotlight on atrial fibrillation—the ‘complete arrhythmia’

Stanley Nattela,*, Maurits Allessieb and Michel Haissaguerrec

aMontreal Heart Institute, Department of Pharmacology and Research Center, 5000 Belanger St., East, HIT IC8 Montreal, Quebec, Canada
bDepartment of Physiology, Maastricht University, Maastricht, The Netherlands
cHôpital Cardiologique du Haut-Lévêque, University of Bordeaux, Bordeaux, France

nattel{at}icm.umontreal.ca

* Corresponding author. Tel.: +1-514-376-3330; fax: +1-514-376-1355

Received 21 February 2002; accepted 21 February 2002

The French sometimes refer to atrial fibrillation (AF) as ‘l'arythmie complète’, 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 three-dimensional 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.


   1 Historical perspective
Top
 1 Historical perspective
2 Review articles
 3 Original articles
 4 Concluding remarks
 Acknowledgments
 References
 
The first historical reference to what may have been AF appeared approximately 4000 years ago, in The Yellow Emperor's Classic of Internal Medicine (Huang Ti Nei Ching Su Wen): "When the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]. Bouilland 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 "frémissement 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) avant-garde 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 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.


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  		Table 1 Thematic relationships among papers

 

   2 Review articles
Top
 1 Historical perspective
 2 Review articles
3 Original articles
 4 Concluding remarks
 Acknowledgments
 References
 
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].

2.3 Cellular electrophysiology
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 tachycardia-remodeling, 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-β 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.

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 Ca2+ homeostasis and structural remodeling. The potential role of Ca2+ overload in remodeling is considered, and preliminary evidence is presented relating to the activation of the Ca2+-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 inter-relationships 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
Top
 1 Historical perspective
 2 Review articles
 3 Original articles
4 Concluding remarks
 Acknowledgments
 References
 
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 distribution. 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 Ca2+- 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 Ca2+-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+-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 previously-reported 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.

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 Ca2+-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 Ca2+-handling in the atrial refractoriness rate-maladaptation 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 Ca2+-transients under control conditions and in the presence of atrial-tachycardia induced Ca2+-handling abnormalities [49]. When the changes in Ca2+-handling were included, the model fully reproduced rate-maladaptation, indicating that alterations in cellular Ca2+-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+/H+-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+/H+-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 electrophysiological alterations and AF promotion resulting from 1 week of atrial-tachypacing.

Kurita et al. evaluate the effect of oral verapamil against atrial remodeling caused by 2 weeks of atrial tachypacing [54]. They find that verapamil begun 1 week before tachypacing attenuated atrial remodeling, but that verapamil begun 2 days after the onset of tachypacing was without effect. These results would suggest that L-type Ca2+ channel blockers have to be initiated before atrial tachycardia or AF begin to prevent remodeling, and might explain some of the discrepancies in the clinical literature regarding the effects of Ca2+-antagonists on maintenance of sinus rhythm after AF cardioversion [55,56]. On the other hand, diltiazem begun 4 days before experimental atrial tachypacing failed to alter atrial remodeling [57], so further work is needed to resolve the issue of Ca2+-antagonist effects on atrial remodeling.

The next paper, by Shi et al., evaluates the effects of enalapril on atrial function and AF maintenance in dogs with ventricular tachypacing-induced congestive heart failure [58]. They report that enalapril reduces atrial enlargement and impaired hemodynamic function associated with congestive heart failure, while reducing the duration of AF induced by atrial burst pacing. These results suggest that, in addition to beneficial effects on atrial mitogen-activated protein kinases and fibrosis [59], enalapril's effects to counteract heart failure-induced AF promotion may also be related to reduced atrial size and stretch.

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
Top
 1 Historical perspective
 2 Review articles
 3 Original articles
 4 Concluding remarks
Acknowledgments
 References
 
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.


   Acknowledgments
Top
 1 Historical perspective
 2 Review articles
 3 Original articles
 4 Concluding remarks
 Acknowledgments
References
 
The authors thank Luce Bégin 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.


   References
Top
 1 Historical perspective
 2 Review articles
 3 Original articles
 4 Concluding remarks
 Acknowledgments
 References
 

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What is needed for a good 'Decaf'?
Europace, March 1, 2009; 11(3): 278 - 279.
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