American
Heart
Association®
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Compendium Circulation Research Compendium on Atrial Fibrillation: Atrial Fibrillation Compendium: Historical Context and Detailed Translational Perspective on an Important Clinical Problem The Clinical Profile and Pathophysiology of Atrial Fibrillation: Relationships Among Clinical Features, Epidemiology, and Mechanisms Emerging Directions in the Genetics of Atrial Fibrillation Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance and Progression Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy Mathematical Approaches to Understanding and Imaging Atrial Fibrillation: Significance for Mechanisms and Management Atrial Fibrillation Therapy Now and in the Future: Drugs, Biologicals, and Ablation Guest Editor: Stanley Nattel
Atrial Fibrillation Compendium Historical Context and Detailed Translational Perspective on an Important Clinical Problem Kunihiro Nishida, Stanley Nattel
A
trial fibrillation (AF), the most common sustained tachyarrhythmia, currently affects 1% to 2% of the general population.1 Age is arguably the strongest determinant of AF occurrence, and the prevalence of AF is increasing as the population ages, projected to increase from ≈7 million today to ≈12 to 16 million predicted for the United States in 2050 (including estimates for paroxysmal and silent AF).1 There has been a marked progress in our understanding of the basic mechanisms underlying AF for the past 20 years.2–5 The management of AF continues to face huge challenges, but advancing knowledge and new technologies have also created unprecedented opportunities, which will undoubtedly revolutionize AF management over the next 20 years.6 Recognizing the importance of this area and the rapid pace of knowledge development, the Editorial Board of Circulation Research decided to develop a Compendium on Atrial Fibrillation. The compendium includes 6 state-of-the-art review articles on themes of clinical features and pathophysiology of AF,1 molecular electrophysiology of AF initiation, maintenance, and progression,7 autonomic nervous system control of AF,8 genetic factors determining AF occurrence and risk,9 the use of mathematical modeling to understand and manage AF better,10 and the mechanisms governing present and future therapy of the arrhythmia.11 The goal of the present article is to provide a context and unifying vision for the compendium, showing
how each of the components relates to each other, to our overall understanding of AF, and to the future of the field.
Historical Perspective on AF Mechanisms Figure 1 provides a timeline illustrating major milestones of the research into AF mechanisms that has led to our present understanding. An immediate obvious point is the accelerating pace of research. Although this analysis is clearly subjective, the many important discoveries for the past 20 years greatly dwarf the quantity of discoveries in the 75 preceding years. This having been said that it is nevertheless humbling to read how much was accurately inferred by scientists of the early 20th century based on then-available relatively primitive methods, as summarized by Garrey12 in a classical review article from 1924. Garrey points out that “AF is now recognized as the commonest of all cardiac irregularities,” recognizes the inter-relationships between atrial flutter and AF, and describes experimental evidence to support competing notions that AF is maintained by (1) local ectopic foci (multiple or single with fibrillatory conduction), (2) a single re-entry circuit (in Garrey’s words, a “mother wave”) with fibrillatory conduction, or (3) multiple simultaneous functionally determined re-entry circuits. We continue to debate many of these issues today, seeking their mechanisms and application. Moe et al13 published the first computer-based mathematical model of AF
Original received March 26, 2014; revision received March 26, 2014; accepted March 28, 2014. From the Second Department of Internal Medicine, University of Toyama, Toyama, Japan (K.N.); Department of Medicine, Montreal Heart Institute, and Université de Montréal, Montreal, Quebec, Canada (S.N.); and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (S.N.). Correspondence to Stanley Nattel, MD, Department of Pharmacology and Therapeutics, McGill University, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail [email protected] (Circ Res. 2014;114:1447-1452.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.114.303466
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015 1447
1448 Circulation Research April 25, 2014
Nonstandard Abbreviations and Acronyms AF PV
atrial fibrillation pulmonary vein
in 1964, which established the multiple-wavelet concept of AF that became the dominant conceptual framework for over 30 years. In a series of classical articles beginning in 1978, principally in the French literature, Coumel et al14 championed the importance of autonomic nervous system involvement in clinical AF. In 1988, Rensma et al15 provided evidence that the key factor determining the occurrence of AF or atrial flutter is the wavelength for re-entry, an idea that remains useful for heuristic purposes but fails to reflect key AF determinants in some disease conditions and in response to Na+ channel blocking drugs.16 The pace of discovery greatly accelerated after 1995, when Wijffels et al17 published the seminal observation that AF begets AF by causing important electrophysiological alterations in the atrium, and Morillo et al18 reported that atrial tachycardia leads to an atrial cardiomyopathy with dilated atria, short refractory periods, and sustained AF. These studies introduced the notion
1920
of atrial remodeling, which has subsequently become a central concept in AF pathophysiology. The work of Haissaguerre et al19 on the role of the pulmonary veins (PVs), first reported in 1997 and then fully exposed in a landmark article in 1998,20 led to the first really effective approaches to definitive management of AF by ablation of atrial tissue and provided a novel and challenging pathophysiological paradigm in terms of the basis for PV involvement. Around the same time, the ion current mechanisms involved in atrial remodeling were first described in detail,21 and the first detailed human atrial action potential computer simulation models based on realistic mathematical representations of directly measured ion currents were reported.22,23 These models became the basis of a wide range of sophisticated mathematically based analyses of the ionic, structural, and functional determinants of AF. On the basis of pioneering work of Winfree,24 the Jalife laboratory applied the concepts of spiral waves and rotors to AF, arguing that uninterrupted activity of discrete re-entrant sites plays a central role in AF maintenance.25 Although the work of Wijffels et al17 and Morillo et al18 revealed how the rapid atrial rates induced by AF, once begun, lead to atrial vulnerability and AF promotion, the changes leading to the initial occurrence of AF remained unexplored.
1950
1978
1988
1995
2014
Milestones in AF research
1995
1997
1998
1999
2000
2003 2004
2007 2008
2010
2014
Figure 1. A schematic representation of the history of atrial fibrillation (AF) research, leading to our present understanding of clinically relevant mechanisms. ANS indicates autonomic nervous system; AP, action potential; EP, electrophysiology; PV, pulmonary vein; and SNPs, single nucleotide polymorphisms.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Nishida and Nattel Introduction to Atrial Fibrillation Compendium 1449 In 1999, Li et al26 studied the substrate for AF occurrence associated with congestive heart failure, one of the most important clinical causes.1 To their surprise, the re-entrant wavelength was unaltered, challenging the widely accepted role of wavelength in determining AF occurrence; rather, there was important atrial fibrosis associated with marked local conduction abnormalities.26 This study established atrial fibrosis as a potentially important pathophysiological contributor to AF. Another potential important determinant of AF is autonomic tone. Schauerte et al27 applied Coumel’s concepts of autonomic control of AF by pioneering a detailed series of studies on the cardiac autonomic nervous system as a central player in AF and target for ablation procedures. An important biochemical motif in AF was revealed in 2001, when the potential importance of oxidative stress was noted.28,29 Although initial studies pointed to significant protection from AF with antioxidant interventions as simple as vitamin C,29 subsequent animal work suggested a more
complicated picture.30 A recent randomized, double-blind, clinical trial demonstrated the ability of a combination of antioxidant drugs to prevent postoperative AF.31 The complexity of the mechanisms connecting oxidative stress to AF, and the associated therapeutic challenges, was outlined in a recent editorial.32 Although a genetic locus for familial AF was first described in 1997,33 the culprit gene remains to be identified and sequenced. In 2003, Chen et al34 pinpointed the first gene responsible for familial AF, involving a gain-of-function mutation in KCNQ1, which encodes the α subunit of the slow delayed-rectifier K+ channel. This discovery ushered in an era of rapid progress in defining the genetic determinants of AF. A range of monogenic causes was subsequently identified, primarily involving ion channel subunit mutations, leading to faster atrial repolarization and greater risk of re-entry. The next major contribution in this field was the publication by Gudbjartsson et al35 of the first genome-wide
Figure 2. Atrial fibrillation (AF) mechanisms and contributions of various areas discussed by articles in the compendium. Each article is referenced and represented by a distinct color. Various AF mechanisms are illustrated diagrammatically in the boxes. The ultimate goal of understanding AF mechanisms is to develop new therapeutic approaches, which are depicted in detail in Figure 3. 2D indicates 2-dimensional; AP, action potential; APD, AP duration; DAD, delayed afterdepolarizations; EAD, early afterdepolarizations; and PV, pulmonary vein.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
1450 Circulation Research April 25, 2014 association study in AF. Unlike candidate gene approaches and analyses of high penetrance rare mutations, genomewide association studies allow for the identification of less powerful but much more prevalent genetic risk determinants in the population, without a priori assumptions about pathophysiology. Consequently, they provide clues to novel mechanistic determinants. The study of Gudbjartsson identified an important AF determining locus in chromosomal location 4q25, situated far away from any known gene. The closest candidate gene is Pitx2, with important roles in cardiac development, notably including that of the PVs. One of the emerging challenges emanating from genome-wide association studies, which have now identified a substantial number of AF-related gene variants,36 is to determine the mechanistic basis of the observed associations, none of which have yet been established unequivocally. Another important advancement was the establishment of the basis for atrial ectopic beat formation. Whereas, historically, the focus of understanding AF was on re-entrant mechanisms, which are readily reproduced in animal models; the role of presumed PV triggers and the observation of frequent atrial ectopic firing in patients with AF suggested an important contribution of spontaneous atrial impulse formation that is not readily reproduced in animal models. In 2004, Hove-Madsen et al37 reported that right atrial cardiomyocytes from patients with AF display more spontaneous sarcoplasmic reticulum Ca2+ releases and Ca2+ waves than cells from
sinus rhythm patients. Several subsequent studies confirmed the important potentially arrhythmogenic Ca2+-handling abnormalities in atrial cells from patients with AF. Virtually all of the patients studied had long-standing persistent AF, with extensive AF-induced remodeling and presumably little role for spontaneous ectopy in the face of rapid activation by continuously propagating complex atrial re-entry. However, Voigt et al38 recently studied atrial cardiomyocytes from patients with paroxysmal AF, confirming a susceptibility to triggered activity caused by spontaneous Ca2+ releases because of discrete Ca2+-handling disturbances. An exciting advance has been provided by the development of advanced imaging tools for the identification of mechanistic contributors to AF in man. On the basis of growing evidence for the importance of atrial fibrosis in AF, the Marrouche laboratory developed late gadolinium enhancement MRI methods to image and quantify atrial connective tissue.39 Subsequent results support the potential value of this technology in understanding the structural basis of AF and guiding management.40 Until recently, precise arrhythmia mapping in humans was limited to intraoperative contact-electrode methods. However, the Rudy laboratory labored patiently and doggedly to apply body surface mapping and inverse-problem solutions to deduce intracardiac electric events based on voltage changes on the surface of the body.41 This work finally culminated in the ability to map detailed arrhythmia mechanisms noninvasively, revealing
Figure 3. Diagnostic and therapeutic modalities and their relationship with the principal contributors to atrial fibrillation (AF) mechanisms shown in detail in Figure 2. CFAE indicates complex fractionated atrial electrogram; GP, ganglionated plexus; LGE, late gadolinium enhancement; PV, pulmonary vein; and RyR2, ryanodine receptor type-2.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Nishida and Nattel Introduction to Atrial Fibrillation Compendium 1451 the underlying basis of atrial arrhythmogenesis in man.42 More recently, Narayan et al43 developed and applied basket electrode-catheter technology and advanced analytical methods to study AF mechanisms in the electrophysiology laboratory, using the information to guide ablation therapy with apparently substantial increases in success rates.
Overview of the AF Compendium The subjects of the articles in the compendium were chosen to provide a detailed perspective on key aspects of the translational pathophysiology of AF, with authors selected based on recognized leadership in their subject areas. Figure 2 illustrates the inter-relationships among the articles in the compendium, highlighting particularly the 5 articles dealing primarily with mechanisms,1,7–10 each of which is represented by a discrete color. AF mechanisms and their determinants are shown schematically in the boxes in Figure 2. Focal firing occurs mainly in PVs, via enhanced automaticity or triggered activity because of early or delayed afterdepolarizations.2–4,37,38 Reduced action potential duration and tissue fibrosis are thought to be important AF-maintaining substrates that promote re-entry.2–4,21,26 Local ectopic activity can act as an AF-maintaining ectopic driver, or can trigger AF-maintaining re-entry in a vulnerable substrate. Andrade et al1 review the detailed epidemiological aspects of AF and associated risk factors and discuss their link to underlying mechanisms. Heijman et al7 explain how complex changes in cellular and molecular electrophysiology contribute to the occurrence of focal firing via ion current and Ca2+-handling abnormalities and produce a re-entrant substrate via electric remodeling. They also review the relationship between cellular and molecular electrophysiological determinants and the progression of structural remodeling. Chen et al8 discuss important features of the cardiac autonomic innervation, including anatomy, molecular biochemistry, and function, along with their relationship with the AF substrate. They emphasize the role of both intrinsic and extrinsic autonomic neural regulation of the heart, note the importance of simultaneous sympathovagal discharge, review the notion of autonomic remodeling, and introduce therapeutic interventions targeting the autonomic nervous system.8 Tucker and Ellinor9 describe advances and challenges in understanding the genetic determinants of AF, illustrating how gene variants may alter ion channel, structural, and anatomic components to induce AF. Trayanova10 reviews the evolution of mathematical modeling and computer simulation approaches, such as atrial cell action potential models, 2-dimensional (2D) and 3D tissue models, and recent developments in the reproduction of realistic atrial tissue geometries. This article relates closely to all the others in the compendium because mathematical modeling approaches are used to test ideas about mechanisms arising from all levels and types of biological research quantitatively. Of course, the ultimate goal of mechanistic discovery is not the satisfaction of curiosity but the improvement of disease management. Advances in AF treatment, many of them emanating from improved mechanistic understanding (Figure 3), are the subject of the article by Woods and Olgin.11 They provide an overview of current and future AF therapies, including pharmacological, biological, and ablation approaches, along with novel treatment-guiding diagnostic modalities, such as
late gadolinium enhancement MRI and noninvasive arrhythmia mechanism mapping. Included are interventions targeting the autonomic nervous system (ganglionated plexus ablation, renal sympathetic denervation, and low-level vagal nerve stimulation), cellular electrophysiological determinants (atrial selective ion channel blockers, ryanodine receptor stabilizers, gap junction enhancers, and upstream therapy), genetic characteristics and risk factors (personalized therapy based on gene profiling and tissue characterization with MRI, as well as upstream therapy), and targeted ablation procedures (PV isolation, focal source and rotor ablation, noninvasive ECG imaging to guide ablation, and MAZE surgery). Mathematical methods play a key integrating role in understanding the inter-relationships among mechanistic targets and their potential therapeutic consequences.
The Future It is our conviction that the future of AF management will be determined by the application of new scientific insights into the underlying mechanistic determinants. The extensive work reviewed in this compendium highlights the dramatic advances achieved in understanding AF pathophysiology over the past 20 years, which suggests that mechanism-based therapeutic breakthroughs are just around the corner, and provides hope that medical textbooks presenting the management of AF will be radically different in 20 years.
Acknowledgments We thank France Thériault for expert secretarial assistance.
Sources of Funding This work was supported by the European-North American Atrial Fibrillation Research Alliance grant of Fondation Leducq (to Dr Nattel), the Canadian Institutes of Health Research (6757 and 44365, to Dr Nattel), and the Canadian Heart and Stroke Foundation (to Dr Nattel). Dr Nishida reports no funding sources.
Disclosures None.
References 1. 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. 2. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415:219–226. 3. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation. 2011;124:2264–2274. 4. Wakili R, Voigt N, Kääb S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011;121: 2955–2968. 5. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91:265–325. 6. Gillis AM, Krahn AD, Skanes AC, Nattel S. Management of atrial fibrillation in the year 2033: new concepts, tools, and applications leading to personalized medicine. Can J Cardiol. 2013;29:1141–1146. 7. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014;114:1483–1499. 8. Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res. 2014;114:1500–1515. 9. Tucker NR, Ellinor PT. Emerging directions in the genetics of atrial fibrillation. Circ Res. 2014;114:1469–1482.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
1452 Circulation Research April 25, 2014 10. Trayanova NA. Mathematical approaches to understanding and imaging atrial fibrillation: significance for mechanisms and management. Circ Res. 2014;114:1516–1531. 11. Woods CE, Olgin J. Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res. 2014;114:1532–1546. 12. Garrey WE. Auricular fibrillation. Physiol Rev. 1924;4:215–250. 13. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J. 1964;67:200–220. 14. Coumel P, Attuel P, Lavallée J, Flammang D, Leclercq JF, Slama R. The atrial arrhythmia syndrome of vagal origin. Arch Mal Coeur Vaiss. 1978;71:645–656. 15. Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res. 1988;62:395–410. 16. Comtois P, Kneller J, Nattel S. Of circles and spirals: bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace. 2005;7(suppl 2):10–20. 17. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968. 18. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588–1595. 19. Jaïs P, Haïssaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clémenty J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation. 1997;95:572–576. 20. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–666. 21. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512–525. 22. Nygren A, Fiset C, Firek L, Clark JW, Lindblad DS, Clark RB, Giles WR. Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. Circ Res. 1998;82:63–81. 23. Courtemanche M, Ramirez RJ, Nattel S. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol. 1998;275:H301–H321. 24. Winfree AT. Sudden cardiac death: a problem in topology. Sci Am. 1983;248:144–149, 152–157, 160–161. 25. Jalife J, Berenfeld O, Skanes A, Mandapati R. Mechanisms of atrial fibrillation: mother rotors or multiple daughter wavelets, or both? J Cardiovasc Electrophysiol. 1998;9:S2–12. 26. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999;100:87–95. 27. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000;102:2774–2780. 28. Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation. 2001;104:174–180.
29. Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, Kanderian A, Pavia S, Hamlin RL, McCarthy PM, Bauer JA, Van Wagoner DR. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res. 2001;89:E32–E38. 30. Shiroshita-Takeshita A, Schram G, Lavoie J, Nattel S. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation. 2004;110:2313–2319. 31. Rodrigo R, Korantzopoulos P, Cereceda M, Asenjo R, Zamorano J, Villalabeitia E, Baeza C, Aguayo R, Castillo R, Carrasco R, Gormaz JG. A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement. J Am Coll Cardiol. 2013;62:1457–1465. 32. Yang KC, Dudley SC Jr. Oxidative stress and atrial fibrillation: finding a missing piece to the puzzle. Circulation. 2013;128:1724–1726. 33. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, Brugada J, Girona J, Domingo A, Bachinski LL, Roberts R. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 1997;336:905–911. 34. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299:251–254. 35. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. 36. Lubitz SA, Lunetta KL, Lin H, et al. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. J Am Coll Cardiol. 2014;63:1200–1210. 37. Hove-Madsen L, Llach A, Bayes-Genís A, Roura S, Rodriguez Font E, Arís A, Cinca J. Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. Circulation. 2004;110:1358–1363. 38. Voigt N, Heijman J, Wang Q, Chiang DY, Li N, Karck M, Wehrens XH, Nattel S, Dobrev D. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation. 2014;129:145–156. 39. McGann CJ, Kholmovski EG, Oakes RS, Blauer JJ, Daccarett M, Segerson N, Airey KJ, Akoum N, Fish E, Badger TJ, DiBella EV, Parker D, MacLeod RS, Marrouche NF. New magnetic resonance imaging-based method for defining the extent of left atrial wall injury after the ablation of atrial fibrillation. J Am Coll Cardiol. 2008;52:1263–1271. 40. Han FT, Akoum N, Marrouche N. Value of magnetic resonance imaging in guiding atrial fibrillation management. Can J Cardiol. 2013;29:1194–1202. 41. Oster HS, Taccardi B, Lux RL, Ershler PR, Rudy Y. Electrocardiographic imaging: noninvasive characterization of intramural myocardial activation from inverse-reconstructed epicardial potentials and electrograms. Circulation. 1998;97:1496–1507. 42. Cuculich PS, Wang Y, Lindsay BD, Faddis MN, Schuessler RB, Damiano RJ Jr, Li L, Rudy Y. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation. 2010;122:1364–1372. 43. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol. 2012;60:628–636. Key Words: arrhythmias, cardiac ◼ atrial fibrillation ◼ sympathetic nervous system
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Atrial Fibrillation Compendium: Historical Context and Detailed Translational Perspective on an Important Clinical Problem Kunihiro Nishida and Stanley Nattel Circ Res. 2014;114:1447-1452 doi: 10.1161/CIRCRESAHA.114.303466 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/9/1447
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Heart
Association®
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Compendium Circulation Research Compendium on Atrial Fibrillation: Atrial Fibrillation Compendium: Historical Context and Detailed Translational Perspective on an Important Clinical Problem The Clinical Profile and Pathophysiology of Atrial Fibrillation: Relationships Among Clinical Features, Epidemiology, and Mechanisms Emerging Directions in the Genetics of Atrial Fibrillation Cellular and Molecular Electrophysiology of Atrial Fibrillation Initiation, Maintenance and Progression Role of the Autonomic Nervous System in Atrial Fibrillation: Pathophysiology and Therapy Mathematical Approaches to Understanding and Imaging Atrial Fibrillation: Significance for Mechanisms and Management Atrial Fibrillation Therapy Now and in the Future: Drugs, Biologicals, and Ablation Guest Editor: Stanley Nattel
Atrial Fibrillation Compendium Historical Context and Detailed Translational Perspective on an Important Clinical Problem Kunihiro Nishida, Stanley Nattel
A
trial fibrillation (AF), the most common sustained tachyarrhythmia, currently affects 1% to 2% of the general population.1 Age is arguably the strongest determinant of AF occurrence, and the prevalence of AF is increasing as the population ages, projected to increase from ≈7 million today to ≈12 to 16 million predicted for the United States in 2050 (including estimates for paroxysmal and silent AF).1 There has been a marked progress in our understanding of the basic mechanisms underlying AF for the past 20 years.2–5 The management of AF continues to face huge challenges, but advancing knowledge and new technologies have also created unprecedented opportunities, which will undoubtedly revolutionize AF management over the next 20 years.6 Recognizing the importance of this area and the rapid pace of knowledge development, the Editorial Board of Circulation Research decided to develop a Compendium on Atrial Fibrillation. The compendium includes 6 state-of-the-art review articles on themes of clinical features and pathophysiology of AF,1 molecular electrophysiology of AF initiation, maintenance, and progression,7 autonomic nervous system control of AF,8 genetic factors determining AF occurrence and risk,9 the use of mathematical modeling to understand and manage AF better,10 and the mechanisms governing present and future therapy of the arrhythmia.11 The goal of the present article is to provide a context and unifying vision for the compendium, showing
how each of the components relates to each other, to our overall understanding of AF, and to the future of the field.
Historical Perspective on AF Mechanisms Figure 1 provides a timeline illustrating major milestones of the research into AF mechanisms that has led to our present understanding. An immediate obvious point is the accelerating pace of research. Although this analysis is clearly subjective, the many important discoveries for the past 20 years greatly dwarf the quantity of discoveries in the 75 preceding years. This having been said that it is nevertheless humbling to read how much was accurately inferred by scientists of the early 20th century based on then-available relatively primitive methods, as summarized by Garrey12 in a classical review article from 1924. Garrey points out that “AF is now recognized as the commonest of all cardiac irregularities,” recognizes the inter-relationships between atrial flutter and AF, and describes experimental evidence to support competing notions that AF is maintained by (1) local ectopic foci (multiple or single with fibrillatory conduction), (2) a single re-entry circuit (in Garrey’s words, a “mother wave”) with fibrillatory conduction, or (3) multiple simultaneous functionally determined re-entry circuits. We continue to debate many of these issues today, seeking their mechanisms and application. Moe et al13 published the first computer-based mathematical model of AF
Original received March 26, 2014; revision received March 26, 2014; accepted March 28, 2014. From the Second Department of Internal Medicine, University of Toyama, Toyama, Japan (K.N.); Department of Medicine, Montreal Heart Institute, and Université de Montréal, Montreal, Quebec, Canada (S.N.); and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (S.N.). Correspondence to Stanley Nattel, MD, Department of Pharmacology and Therapeutics, McGill University, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail [email protected] (Circ Res. 2014;114:1447-1452.) © 2014 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.114.303466
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015 1447
1448 Circulation Research April 25, 2014
Nonstandard Abbreviations and Acronyms AF PV
atrial fibrillation pulmonary vein
in 1964, which established the multiple-wavelet concept of AF that became the dominant conceptual framework for over 30 years. In a series of classical articles beginning in 1978, principally in the French literature, Coumel et al14 championed the importance of autonomic nervous system involvement in clinical AF. In 1988, Rensma et al15 provided evidence that the key factor determining the occurrence of AF or atrial flutter is the wavelength for re-entry, an idea that remains useful for heuristic purposes but fails to reflect key AF determinants in some disease conditions and in response to Na+ channel blocking drugs.16 The pace of discovery greatly accelerated after 1995, when Wijffels et al17 published the seminal observation that AF begets AF by causing important electrophysiological alterations in the atrium, and Morillo et al18 reported that atrial tachycardia leads to an atrial cardiomyopathy with dilated atria, short refractory periods, and sustained AF. These studies introduced the notion
1920
of atrial remodeling, which has subsequently become a central concept in AF pathophysiology. The work of Haissaguerre et al19 on the role of the pulmonary veins (PVs), first reported in 1997 and then fully exposed in a landmark article in 1998,20 led to the first really effective approaches to definitive management of AF by ablation of atrial tissue and provided a novel and challenging pathophysiological paradigm in terms of the basis for PV involvement. Around the same time, the ion current mechanisms involved in atrial remodeling were first described in detail,21 and the first detailed human atrial action potential computer simulation models based on realistic mathematical representations of directly measured ion currents were reported.22,23 These models became the basis of a wide range of sophisticated mathematically based analyses of the ionic, structural, and functional determinants of AF. On the basis of pioneering work of Winfree,24 the Jalife laboratory applied the concepts of spiral waves and rotors to AF, arguing that uninterrupted activity of discrete re-entrant sites plays a central role in AF maintenance.25 Although the work of Wijffels et al17 and Morillo et al18 revealed how the rapid atrial rates induced by AF, once begun, lead to atrial vulnerability and AF promotion, the changes leading to the initial occurrence of AF remained unexplored.
1950
1978
1988
1995
2014
Milestones in AF research
1995
1997
1998
1999
2000
2003 2004
2007 2008
2010
2014
Figure 1. A schematic representation of the history of atrial fibrillation (AF) research, leading to our present understanding of clinically relevant mechanisms. ANS indicates autonomic nervous system; AP, action potential; EP, electrophysiology; PV, pulmonary vein; and SNPs, single nucleotide polymorphisms.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Nishida and Nattel Introduction to Atrial Fibrillation Compendium 1449 In 1999, Li et al26 studied the substrate for AF occurrence associated with congestive heart failure, one of the most important clinical causes.1 To their surprise, the re-entrant wavelength was unaltered, challenging the widely accepted role of wavelength in determining AF occurrence; rather, there was important atrial fibrosis associated with marked local conduction abnormalities.26 This study established atrial fibrosis as a potentially important pathophysiological contributor to AF. Another potential important determinant of AF is autonomic tone. Schauerte et al27 applied Coumel’s concepts of autonomic control of AF by pioneering a detailed series of studies on the cardiac autonomic nervous system as a central player in AF and target for ablation procedures. An important biochemical motif in AF was revealed in 2001, when the potential importance of oxidative stress was noted.28,29 Although initial studies pointed to significant protection from AF with antioxidant interventions as simple as vitamin C,29 subsequent animal work suggested a more
complicated picture.30 A recent randomized, double-blind, clinical trial demonstrated the ability of a combination of antioxidant drugs to prevent postoperative AF.31 The complexity of the mechanisms connecting oxidative stress to AF, and the associated therapeutic challenges, was outlined in a recent editorial.32 Although a genetic locus for familial AF was first described in 1997,33 the culprit gene remains to be identified and sequenced. In 2003, Chen et al34 pinpointed the first gene responsible for familial AF, involving a gain-of-function mutation in KCNQ1, which encodes the α subunit of the slow delayed-rectifier K+ channel. This discovery ushered in an era of rapid progress in defining the genetic determinants of AF. A range of monogenic causes was subsequently identified, primarily involving ion channel subunit mutations, leading to faster atrial repolarization and greater risk of re-entry. The next major contribution in this field was the publication by Gudbjartsson et al35 of the first genome-wide
Figure 2. Atrial fibrillation (AF) mechanisms and contributions of various areas discussed by articles in the compendium. Each article is referenced and represented by a distinct color. Various AF mechanisms are illustrated diagrammatically in the boxes. The ultimate goal of understanding AF mechanisms is to develop new therapeutic approaches, which are depicted in detail in Figure 3. 2D indicates 2-dimensional; AP, action potential; APD, AP duration; DAD, delayed afterdepolarizations; EAD, early afterdepolarizations; and PV, pulmonary vein.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
1450 Circulation Research April 25, 2014 association study in AF. Unlike candidate gene approaches and analyses of high penetrance rare mutations, genomewide association studies allow for the identification of less powerful but much more prevalent genetic risk determinants in the population, without a priori assumptions about pathophysiology. Consequently, they provide clues to novel mechanistic determinants. The study of Gudbjartsson identified an important AF determining locus in chromosomal location 4q25, situated far away from any known gene. The closest candidate gene is Pitx2, with important roles in cardiac development, notably including that of the PVs. One of the emerging challenges emanating from genome-wide association studies, which have now identified a substantial number of AF-related gene variants,36 is to determine the mechanistic basis of the observed associations, none of which have yet been established unequivocally. Another important advancement was the establishment of the basis for atrial ectopic beat formation. Whereas, historically, the focus of understanding AF was on re-entrant mechanisms, which are readily reproduced in animal models; the role of presumed PV triggers and the observation of frequent atrial ectopic firing in patients with AF suggested an important contribution of spontaneous atrial impulse formation that is not readily reproduced in animal models. In 2004, Hove-Madsen et al37 reported that right atrial cardiomyocytes from patients with AF display more spontaneous sarcoplasmic reticulum Ca2+ releases and Ca2+ waves than cells from
sinus rhythm patients. Several subsequent studies confirmed the important potentially arrhythmogenic Ca2+-handling abnormalities in atrial cells from patients with AF. Virtually all of the patients studied had long-standing persistent AF, with extensive AF-induced remodeling and presumably little role for spontaneous ectopy in the face of rapid activation by continuously propagating complex atrial re-entry. However, Voigt et al38 recently studied atrial cardiomyocytes from patients with paroxysmal AF, confirming a susceptibility to triggered activity caused by spontaneous Ca2+ releases because of discrete Ca2+-handling disturbances. An exciting advance has been provided by the development of advanced imaging tools for the identification of mechanistic contributors to AF in man. On the basis of growing evidence for the importance of atrial fibrosis in AF, the Marrouche laboratory developed late gadolinium enhancement MRI methods to image and quantify atrial connective tissue.39 Subsequent results support the potential value of this technology in understanding the structural basis of AF and guiding management.40 Until recently, precise arrhythmia mapping in humans was limited to intraoperative contact-electrode methods. However, the Rudy laboratory labored patiently and doggedly to apply body surface mapping and inverse-problem solutions to deduce intracardiac electric events based on voltage changes on the surface of the body.41 This work finally culminated in the ability to map detailed arrhythmia mechanisms noninvasively, revealing
Figure 3. Diagnostic and therapeutic modalities and their relationship with the principal contributors to atrial fibrillation (AF) mechanisms shown in detail in Figure 2. CFAE indicates complex fractionated atrial electrogram; GP, ganglionated plexus; LGE, late gadolinium enhancement; PV, pulmonary vein; and RyR2, ryanodine receptor type-2.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Nishida and Nattel Introduction to Atrial Fibrillation Compendium 1451 the underlying basis of atrial arrhythmogenesis in man.42 More recently, Narayan et al43 developed and applied basket electrode-catheter technology and advanced analytical methods to study AF mechanisms in the electrophysiology laboratory, using the information to guide ablation therapy with apparently substantial increases in success rates.
Overview of the AF Compendium The subjects of the articles in the compendium were chosen to provide a detailed perspective on key aspects of the translational pathophysiology of AF, with authors selected based on recognized leadership in their subject areas. Figure 2 illustrates the inter-relationships among the articles in the compendium, highlighting particularly the 5 articles dealing primarily with mechanisms,1,7–10 each of which is represented by a discrete color. AF mechanisms and their determinants are shown schematically in the boxes in Figure 2. Focal firing occurs mainly in PVs, via enhanced automaticity or triggered activity because of early or delayed afterdepolarizations.2–4,37,38 Reduced action potential duration and tissue fibrosis are thought to be important AF-maintaining substrates that promote re-entry.2–4,21,26 Local ectopic activity can act as an AF-maintaining ectopic driver, or can trigger AF-maintaining re-entry in a vulnerable substrate. Andrade et al1 review the detailed epidemiological aspects of AF and associated risk factors and discuss their link to underlying mechanisms. Heijman et al7 explain how complex changes in cellular and molecular electrophysiology contribute to the occurrence of focal firing via ion current and Ca2+-handling abnormalities and produce a re-entrant substrate via electric remodeling. They also review the relationship between cellular and molecular electrophysiological determinants and the progression of structural remodeling. Chen et al8 discuss important features of the cardiac autonomic innervation, including anatomy, molecular biochemistry, and function, along with their relationship with the AF substrate. They emphasize the role of both intrinsic and extrinsic autonomic neural regulation of the heart, note the importance of simultaneous sympathovagal discharge, review the notion of autonomic remodeling, and introduce therapeutic interventions targeting the autonomic nervous system.8 Tucker and Ellinor9 describe advances and challenges in understanding the genetic determinants of AF, illustrating how gene variants may alter ion channel, structural, and anatomic components to induce AF. Trayanova10 reviews the evolution of mathematical modeling and computer simulation approaches, such as atrial cell action potential models, 2-dimensional (2D) and 3D tissue models, and recent developments in the reproduction of realistic atrial tissue geometries. This article relates closely to all the others in the compendium because mathematical modeling approaches are used to test ideas about mechanisms arising from all levels and types of biological research quantitatively. Of course, the ultimate goal of mechanistic discovery is not the satisfaction of curiosity but the improvement of disease management. Advances in AF treatment, many of them emanating from improved mechanistic understanding (Figure 3), are the subject of the article by Woods and Olgin.11 They provide an overview of current and future AF therapies, including pharmacological, biological, and ablation approaches, along with novel treatment-guiding diagnostic modalities, such as
late gadolinium enhancement MRI and noninvasive arrhythmia mechanism mapping. Included are interventions targeting the autonomic nervous system (ganglionated plexus ablation, renal sympathetic denervation, and low-level vagal nerve stimulation), cellular electrophysiological determinants (atrial selective ion channel blockers, ryanodine receptor stabilizers, gap junction enhancers, and upstream therapy), genetic characteristics and risk factors (personalized therapy based on gene profiling and tissue characterization with MRI, as well as upstream therapy), and targeted ablation procedures (PV isolation, focal source and rotor ablation, noninvasive ECG imaging to guide ablation, and MAZE surgery). Mathematical methods play a key integrating role in understanding the inter-relationships among mechanistic targets and their potential therapeutic consequences.
The Future It is our conviction that the future of AF management will be determined by the application of new scientific insights into the underlying mechanistic determinants. The extensive work reviewed in this compendium highlights the dramatic advances achieved in understanding AF pathophysiology over the past 20 years, which suggests that mechanism-based therapeutic breakthroughs are just around the corner, and provides hope that medical textbooks presenting the management of AF will be radically different in 20 years.
Acknowledgments We thank France Thériault for expert secretarial assistance.
Sources of Funding This work was supported by the European-North American Atrial Fibrillation Research Alliance grant of Fondation Leducq (to Dr Nattel), the Canadian Institutes of Health Research (6757 and 44365, to Dr Nattel), and the Canadian Heart and Stroke Foundation (to Dr Nattel). Dr Nishida reports no funding sources.
Disclosures None.
References 1. 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. 2. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415:219–226. 3. Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation. 2011;124:2264–2274. 4. Wakili R, Voigt N, Kääb S, Dobrev D, Nattel S. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011;121: 2955–2968. 5. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91:265–325. 6. Gillis AM, Krahn AD, Skanes AC, Nattel S. Management of atrial fibrillation in the year 2033: new concepts, tools, and applications leading to personalized medicine. Can J Cardiol. 2013;29:1141–1146. 7. Heijman J, Voigt N, Nattel S, Dobrev D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014;114:1483–1499. 8. Chen PS, Chen LS, Fishbein MC, Lin SF, Nattel S. Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. Circ Res. 2014;114:1500–1515. 9. Tucker NR, Ellinor PT. Emerging directions in the genetics of atrial fibrillation. Circ Res. 2014;114:1469–1482.
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
1452 Circulation Research April 25, 2014 10. Trayanova NA. Mathematical approaches to understanding and imaging atrial fibrillation: significance for mechanisms and management. Circ Res. 2014;114:1516–1531. 11. Woods CE, Olgin J. Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. Circ Res. 2014;114:1532–1546. 12. Garrey WE. Auricular fibrillation. Physiol Rev. 1924;4:215–250. 13. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J. 1964;67:200–220. 14. Coumel P, Attuel P, Lavallée J, Flammang D, Leclercq JF, Slama R. The atrial arrhythmia syndrome of vagal origin. Arch Mal Coeur Vaiss. 1978;71:645–656. 15. Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res. 1988;62:395–410. 16. Comtois P, Kneller J, Nattel S. Of circles and spirals: bridging the gap between the leading circle and spiral wave concepts of cardiac reentry. Europace. 2005;7(suppl 2):10–20. 17. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968. 18. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588–1595. 19. Jaïs P, Haïssaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clémenty J. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation. 1997;95:572–576. 20. Haïssaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Métayer P, Clémenty J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659–666. 21. Yue L, Feng J, Gaspo R, Li GR, Wang Z, Nattel S. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81:512–525. 22. Nygren A, Fiset C, Firek L, Clark JW, Lindblad DS, Clark RB, Giles WR. Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. Circ Res. 1998;82:63–81. 23. Courtemanche M, Ramirez RJ, Nattel S. Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am J Physiol. 1998;275:H301–H321. 24. Winfree AT. Sudden cardiac death: a problem in topology. Sci Am. 1983;248:144–149, 152–157, 160–161. 25. Jalife J, Berenfeld O, Skanes A, Mandapati R. Mechanisms of atrial fibrillation: mother rotors or multiple daughter wavelets, or both? J Cardiovasc Electrophysiol. 1998;9:S2–12. 26. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation. 1999;100:87–95. 27. Schauerte P, Scherlag BJ, Pitha J, Scherlag MA, Reynolds D, Lazzara R, Jackman WM. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation. 2000;102:2774–2780. 28. Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation. 2001;104:174–180.
29. Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, Kanderian A, Pavia S, Hamlin RL, McCarthy PM, Bauer JA, Van Wagoner DR. Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circ Res. 2001;89:E32–E38. 30. Shiroshita-Takeshita A, Schram G, Lavoie J, Nattel S. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation. 2004;110:2313–2319. 31. Rodrigo R, Korantzopoulos P, Cereceda M, Asenjo R, Zamorano J, Villalabeitia E, Baeza C, Aguayo R, Castillo R, Carrasco R, Gormaz JG. A randomized controlled trial to prevent post-operative atrial fibrillation by antioxidant reinforcement. J Am Coll Cardiol. 2013;62:1457–1465. 32. Yang KC, Dudley SC Jr. Oxidative stress and atrial fibrillation: finding a missing piece to the puzzle. Circulation. 2013;128:1724–1726. 33. Brugada R, Tapscott T, Czernuszewicz GZ, Marian AJ, Iglesias A, Mont L, Brugada J, Girona J, Domingo A, Bachinski LL, Roberts R. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 1997;336:905–911. 34. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299:251–254. 35. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357. 36. Lubitz SA, Lunetta KL, Lin H, et al. Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. J Am Coll Cardiol. 2014;63:1200–1210. 37. Hove-Madsen L, Llach A, Bayes-Genís A, Roura S, Rodriguez Font E, Arís A, Cinca J. Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. Circulation. 2004;110:1358–1363. 38. Voigt N, Heijman J, Wang Q, Chiang DY, Li N, Karck M, Wehrens XH, Nattel S, Dobrev D. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation. 2014;129:145–156. 39. McGann CJ, Kholmovski EG, Oakes RS, Blauer JJ, Daccarett M, Segerson N, Airey KJ, Akoum N, Fish E, Badger TJ, DiBella EV, Parker D, MacLeod RS, Marrouche NF. New magnetic resonance imaging-based method for defining the extent of left atrial wall injury after the ablation of atrial fibrillation. J Am Coll Cardiol. 2008;52:1263–1271. 40. Han FT, Akoum N, Marrouche N. Value of magnetic resonance imaging in guiding atrial fibrillation management. Can J Cardiol. 2013;29:1194–1202. 41. Oster HS, Taccardi B, Lux RL, Ershler PR, Rudy Y. Electrocardiographic imaging: noninvasive characterization of intramural myocardial activation from inverse-reconstructed epicardial potentials and electrograms. Circulation. 1998;97:1496–1507. 42. Cuculich PS, Wang Y, Lindsay BD, Faddis MN, Schuessler RB, Damiano RJ Jr, Li L, Rudy Y. Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. Circulation. 2010;122:1364–1372. 43. Narayan SM, Krummen DE, Shivkumar K, Clopton P, Rappel WJ, Miller JM. Treatment of atrial fibrillation by the ablation of localized sources: CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation) trial. J Am Coll Cardiol. 2012;60:628–636. Key Words: arrhythmias, cardiac ◼ atrial fibrillation ◼ sympathetic nervous system
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
Atrial Fibrillation Compendium: Historical Context and Detailed Translational Perspective on an Important Clinical Problem Kunihiro Nishida and Stanley Nattel Circ Res. 2014;114:1447-1452 doi: 10.1161/CIRCRESAHA.114.303466 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/114/9/1447
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/
Downloaded from http://circres.ahajournals.org/ by guest on March 25, 2015
