Controversies About Atrial Fibrillation Mechanisms
2017; Lippincott Williams & Wilkins; Volume: 120; Issue: 9 Linguagem: Inglês
10.1161/circresaha.116.310489
ISSN1524-4571
AutoresStanley Nattel, Dobromir Dobrev,
Tópico(s)Cardiac Arrhythmias and Treatments
ResumoHomeCirculation ResearchVol. 120, No. 9Controversies About Atrial Fibrillation Mechanisms Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBControversies About Atrial Fibrillation MechanismsAiming for Order in Chaos and Whether it Matters Stanley Nattel and Dobromir Dobrev Stanley NattelStanley Nattel From the Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada (S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada (S.N.); and Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Germany (S.N., D.D.). and Dobromir DobrevDobromir Dobrev From the Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada (S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada (S.N.); and Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Germany (S.N., D.D.). Originally published28 Apr 2017https://doi.org/10.1161/CIRCRESAHA.116.310489Circulation Research. 2017;120:1396–1398Major electrophysiological mechanisms underlying atrial fibrillation were described around 100 years ago, but important recent improvements in biophysical theory, mapping of cardiac electric activity, and noninvasive imaging have generated significant new and controversial ideas. Here, we discuss these ideas, the evidence on which they are based, their significance for arrhythmia research and therapy, and the common underlying molecular mechanisms that may allow for therapeutic improvements even without definitive resolution of the electric processes that maintain atrial fibrillation.Atrial fibrillation (AF) is an extremely common clinical problem, with major public health implications and increasing prevalence.1 Drug therapy is widely used but has limited effectiveness and is plagued by adverse effects.2 Ablation approaches have developed rapidly over the past 20 years but continue to experience failures, recurrences, and complications. There is therefore a major need for innovative treatment strategies, and there exists a widely held (and historically justified) notion that a better understanding of underlying mechanisms is needed to improve AF management options.2 Although key basic concepts of AF pathophysiology have been available for >100 years,3 recent work has questioned the specifics of some of these longstanding ideas. There are widespread, ongoing disagreements about the interpretation of various studies and the principal mechanisms underlying AF. The objectives of this article are (1) to review briefly recent developments in mechanistic thinking about AF, their basis, and the differences among them, (2) to consider to what extent these differences really have practical consequences for therapeutic innovation, and (3) to consider approaches to improving AF therapy that might be effective whether or not we can resolve the underlying mechanism(s) maintaining the arrhythmia.Principal Concepts of AF MechanismsThe classical ideas about the mechanisms underlying AF that held sway for almost a century3 are shown in Figure (A). They consist of (1) a primary role for rapidly firing automatic foci, either a single focus with fibrillatory conduction or multiple simultaneously discharging foci (Figure [A-a]), (2) a localized rapidly discharging single circuit with fibrillatory conduction (Figure [A-b]), or (3) multiple simultaneous unstable waves of reentry coursing irregularly through atrial tissue (Figure [A-c]).3 Over the past 10 to 15 years, advances in research technology coupled to new biophysical concepts have resulted in new, experimentally based ideas about the mechanisms underlying AF maintenance. These new ideas are not so much a rejection of previous thoughts as a refinement and development of them.Download figureDownload PowerPointFigure. A representation of recent advances in understanding atrial fibrillation (AF) pathophysiology. A, Mechanisms classically thought to underlie AF maintenance. B, Recent developments in mechanistic concepts of AF maintenance. The gray areas in b represent regions of fibrosis. C, The notion that AF results from atrial cardiomyopathy has gained traction recently, with key contributory processes illustrated here. CaMKII indicates Ca2+/Calmodulin-Dependent Protein-Kinase Type II; endo, endocardium; epi, epicardium; and ROS, reactive oxygen species.One important component has been the application of the rotor (or spiral wave) concept to the functional understanding of cardiac reentry, championed initially by Arthur Winfree and subsequently applied extensively to AF by the Jalife laboratory.4 The rotor concept is essentially a way of understanding reentry that is more grounded in biophysical theory, sophisticated experimental studies (principally using high-density optical mapping), and in silico observations than earlier electrophysiologically based theories.5 The idea that single or small numbers of localized rotors might underlie AF has important therapeutic implications,4 particularly for AF ablation, and has obtained validation and clinical application with the use of intra-atrial basket catheters and sophisticated mathematical approaches to rotor localization.6 However, questions about the validity of such methods and competing observations have generated widespread controversy.The development of advanced mapping and computational methods has allowed investigators to obtain an unprecedented level of information relevant to AF mechanisms in the most important model: AF patients. In addition to high-density basket array mapping/signal assessment,6 these methods include the use of high-level inverse solution–based analysis of extensive body surface electrogram data coupled to sophisticated imaging approaches7 and the use of high-density contact-mapping arrays in vivo.8 These recent observations in clinical AF point to 3 novel mechanisms potentially contributing to AF maintenance (Figure [B]). Work from the Narayan et al6 suggests the presence of small numbers of rotors in more or less fixed locations as the principal AF-maintaining mechanism (Figure [B-a]). Observations from Haissaguerre et al7 also point to a role for rotors, but in contrast to Narayan et al6 results, these rotors are very evanescent and, although they tend to cluster at the edge of fibrotic zones (Figure [B-b]), their precise location varies over time. For example, the median rotor duration was 2.6 rotations (versus minutes to hours in the studies by Narayan et al6). Finally, results from van der Does et al8 suggest a key role for endocardial–epicardial dissociation in perpetuating AF by providing large numbers of breakthrough activations at either surface that maintain fibrillatory activity (Figure [B-c]).Practical Implications of Mechanisms Maintaining AFThere are unquestionably important practical implications of the electric processes that maintain AF. Because ablation therapy requires the identification and physical destruction of tissue that is central to the AF-maintaining mechanism, being able to locate and target these mechanisms is central to the success of ablation procedures. If AF is maintained by one or a small number of localized automatic foci (Figure [A-a]) or rotors with stable locations (Figure [B-a]), identification and elimination of the foci/rotors by ablation should be able to effectively suppress AF. Isolation of the pulmonary veins, a key site for AF drivers (whether focal or reentrant), has substantial effectiveness in treating paroxysmal AF.9 However, the management of persistent AF is much more of a challenge.1,6,7 If focal sources or rotors with a stable location outside the pulmonary veins maintain persistent AF, the elimination of focal firing and rotor maintenance by ablation at key regions within the foci/rotors should be highly effective. This possibility was indeed supported by very high success rates in initial studies,6 but several groups have recently reported an inability to achieve success rates with this technology that are at all comparable to the initially reported outcomes.10 If evanescent rotors primarily located at the periphery of fibrotic zones play an essential role (Figure [B-b]), targeting rotors per se would likely be ineffective. Ablation might then need to be targeted to zones with specific patterns and degrees of fibrosis. This is a much more challenging objective, but several groups are working in that direction. If endocardial–epicardial dissociation (Figure [B-c]) produces constant multiplication of AF-maintaining sources via large numbers of regional breakthroughs, as has been suggested,8 it is difficult to imagine an effective ablation strategy.Does Therapeutic Advancement Require a Precise Knowledge of AF-Maintaining Mechanisms?The precise mechanisms maintaining AF will be clarified eventually, but when this will happen is uncertain. Does that mean that therapeutic advancement is frozen in the meantime? There is increasing consideration of AF as the manifestation of underlying atrial pathophysiological processes, to which the term atrial cardiomyopathy has recently been applied.11 During the past 20 years, substantial progress has been made in our understanding of the molecular basis underlying these processes.1,12 There is reason to think that atrial cardiomyopathy development is a progressive process that may already be well established by the time clinical AF manifests, that continues to evolve after the initial presentation, and that must be interrupted as early as possible to make successful management possible.11 Irrespective of the management of arrhythmia episodes per se, whether by antiarrhythmic drugs or ablation, successful long-term control of AF will require resolution of the underlying cellular and molecular pathophysiological mechanisms and the prevention of the underlying remodeling processes that lead to atrial cardiomyopathy.1,11,12The range of potential pathophysiological contributors to atrial cardiomyopathy is vast11; however, some key examples are provided in Figure (C). A range of risk factors, genetic variants, and signaling changes can affect the atria and make them more prone to AF, which itself induces regulatory deviations that alter atrial properties to promote pathological alterations in atrial electrophysiological properties, structure, and function.1,11,12 Risk factors, such as obesity, sleep apnea, hypertension, and cigarette smoking, are linked epidemiologically to AF, and candidate mechanisms connecting risk factors to AF have been identified.1 Furthermore, risk factor intervention has been shown to prevent AF recurrences, and the underlying molecular mechanisms are under active investigation.1,2There is extensive evidence pointing to an important role of the renin–angiotensin system in AF-promoting pathology, particularly under conditions like heart failure and hypertension.13 Similarly, CaMKII (Ca2+/Calmodulin-Dependent Protein-Kinase Type II) is activated in a range of experimental and clinical AF models and acts on cardiac ion channels, Ca2+-handling mechanisms, and cardiomyocyte viability to favor AF occurrence through a wide range of mechanisms.2,12 AF is associated with increased production of reactive oxygen species and abnormalities in redox balance.9 Reactive oxygen species in turn modulate a wide range of targets, including CaMKII, to produce atrial pathology and AF.9 A variety of interventions are being developed to prevent AF by acting on underlying signaling processes, including CaMKII and reactive oxygen species generation.The genetic contributors to AF have been investigated in many genome-wide association studies, and numerous risk loci related to ion channels, transcription factors, signal transducers, and proteins of unknown cardiac function have been identified that associate independently with AF.14 Identifying the precise mechanisms linking gene variants to AF pathophysiology remains a major challenge.14 Nevertheless, developments in high-throughput genotyping and the molecular pathophysiology of AF promise to enable the use of genetic information to guide AF risk estimation, management choices, and therapeutic innovation.14The obstacles to the prevention of atrial cardiomyopathy development and progression should not be underestimated, nor should it be considered that our understanding of the underlying mechanisms is completely clear or lacking in controversy. For example, there is work suggesting that CaMKII-mediated intracellular Ca2+ leak from the sarcoplasmic reticulum is central to AF progression in a clinically relevant mouse model, and that CaMKII activation enhances sarcoplasmic reticulum Ca2+ leak, inducing delayed afterdepolarizations and associated ectopic activity in longstanding persistent AF.2 On the other hand, studies in rabbit and human tissues suggest that high atrial rate silences intracellular Ca2+ propagation.15 There are also many obstacles to successful translation of promising candidates identified in experimental studies to clinical indications.2 Nevertheless, the apparently successful application of risk factor interventions and renin–angiotensin intervention to AF prevention2 indicates the feasibility of targeting atrial cardiomyopathy evolution as a component of AF management.ConclusionsRecent developments in our ability to detect and appreciate the mechanisms underlying AF have generated exciting new ideas, but at the same time controversy and in some cases confusion. Nevertheless, these developments will ultimately lead to greatly improved understanding. In the meantime, the controversies should not induce paralysis or sterile arguments, but rather should lead to further innovation on many fronts that will allow for improved clinical care in the near future.AcknowledgmentsWe thank Jennifer Bacchi for excellent secretarial help with the manuscript.Sources of FundingThe work was supported by grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada (Dr Nattel); and National Institutes of Health (HL131517) and DZHK (German Center for Cardiovascular Research, Dr Dobrev), and the German Research Foundation (DO 769/4-1, Dr Dobrev).DisclosuresDr. Nattel is on the Scientific Advisory Board of Amgen and received a speaker's fee from Pfizer. His laboratory executed research contracts for Omeicos and Cardiome. Dr Dobrev is on the Scientific Advisory Board of Omeicos Therapeutics and received a speaker's fee from Boston Scientific, Daiichi Sankyo, and Servier. His laboratory executed research contracts for Omeicos and Nissan.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Stanley Nattel, MD, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail [email protected]References1. Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms.Circ Res. 2014; 114:1453–1468. doi: 10.1161/CIRCRESAHA.114.303211.LinkGoogle Scholar2. Heijman J, Algalarrondo V, Voigt N, Melka J, Wehrens XH, Dobrev D, Nattel S. 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