Review

Advances in Atrial Fibrillation Ablation

Alicia Darge, RPA-C, *Matthew R. Reynolds, MD, MSc, Joseph J. Germano, DO From Winthrop-University Hospital, Mineola, New York, and *Beth Israel Deaconess Medical Center, Boston, Massachusetts. Disclosure: Dr. Reynolds is a consultant to Biosense Webster; Dr. Germano has received speaker honnoraria from Boston Scientific Corp., Medtronic, Inc., and St. Jude Medical. Address for correspondence: Joseph Germano, DO, Assistant Professor of Medicine, Health Science Center, SUNY Stony Brook, Winthrop-University Hospital, 120 Mineola Blvd, Suite 500, Mineola, NY 11501.
Alicia Darge, RPA-C, *Matthew R. Reynolds, MD, MSc, Joseph J. Germano, DO From Winthrop-University Hospital, Mineola, New York, and *Beth Israel Deaconess Medical Center, Boston, Massachusetts. Disclosure: Dr. Reynolds is a consultant to Biosense Webster; Dr. Germano has received speaker honnoraria from Boston Scientific Corp., Medtronic, Inc., and St. Jude Medical. Address for correspondence: Joseph Germano, DO, Assistant Professor of Medicine, Health Science Center, SUNY Stony Brook, Winthrop-University Hospital, 120 Mineola Blvd, Suite 500, Mineola, NY 11501.
Atrial fibrillation (AF) is an increasingly common and costly medical problem.1–3 Given the disappointing efficacy and side effects associated with pharmacological therapy for AF, new treatment options are needed. Over the last decade, advances in our understanding of the mechanisms of AF, coupled with iterative improvements in catheter ablation techniques, have spurred the evolution of catheter ablation for AF from an experimental procedure to an increasingly important treatment option.4 This paper will review recent advances in the approaches and outcomes of AF ablation. Mechanisms of Atrial Fibrillation Until recently, the multiple source or multiple wavelet hypothesis was the dominant model describing the mechanism of AF.5 This model depicts AF as multiple simultaneously occurring reentrant wavelets. The number of wavelets at any given time depends on the conduction velocity, atrial mass and refractory period in different parts of the atria. AF is perpetuated by slowed conduction, increased atrial mass and shorter refractory periods. This provides the theoretical foundation for catheter and surgical ablation that compartmentalizes the left atrium (LA).6 In the 1990s, it became increasingly clear that some AF (particularly paroxysmal AF) is triggered by a focal source, most commonly from muscular sleeves originating in the LA that extend into the pulmonary veins (PV). It also became evident that AF could be eliminated by ablating these triggers. Further studies demonstrated that linear lesions, like those performed in the surgical Maze procedure, were often arrhythmogenic due to gaps in the ablative lines. In addition to acting as a source for AF triggers, the PV-LA junction has also been found to be an important substrate for the maintenance of more persistent forms of AF. These data led to mapping and ablating of individual foci and PV isolation ablation rather then compartmentalization of the left atrium. Foci have also been mapped to other cardiac structures (discussed below).6–13 In addition to these models for AF, important work has been done, in both animal and human models, implicating the role of the local autonomic nervous system in the initiation and perpetuation of AF, consistent with the well-described existence of vagal triggers for AF in some individuals. Parasympathetic ganglionated plexi are located near the PV-LA junction and may be important targets for ablative therapy. Autonomic factors have also been implicated in the generation of complex fractionated atrial electrograms (CFAE), a potentially important substrate of AF.14–25 Despite these insights, the mechanisms of AF remain incompletely understood. It is now widely accepted that AF requires an initiating event and an anatomical substrate and that the PVs are intimately involved. There is evidence to support both focal and multiple source theories and therefore justification for different, or even stepwise, approaches to ablative strategies for different AF patients. In addition, multiple mechanisms may coexist based on underlying cardiac substrate and the fact that mechanisms may change as patients progress from paroxysmal to persistent patterns of AF due to remodeling.3,6,26 Patient Selection for Catheter Ablation The primary justification for catheter ablation of AF is the presence of symptoms correlated with AF, with the goal of improving quality of life.27 Recent recommendations suggest that catheter ablation should be considered after failure of at least one Class I or Class III antiarrhythmic drug (AAD) for recurrent paroxysmal AF.6 Recent data show patient selection for catheter ablation evolving to include persistent AF and patients with heart failure and reduced ejection fraction. Small studies have shown improvement in left ventricular dysfunction and a decrease in left ventricular dimensions after AF catheter ablation.6,28–30 Also, while most early series of AF ablation included relatively young patients, recent reports from selected centers have shown promising results in older patients.31,32 We expect the population of patients referred for AF ablation to become older and have a greater frequency of structural heart disease in the future. Other considerations in patient selection include patient age, LA size and duration of AF. There may be a heightened risk of myocardial perforation and thromboembolic complications in very elderly patients, and a lower probability of a successful outcome when the LA is markedly dilated or the patient has long-standing persistent AF.6 AF ablation requires high-intensity anticoagulation during the procedure with intravenous heparin. Warfarin is recommended at least short-term post-procedure. Therefore, patients with major contraindications to anticoagulation are not candidates for AF ablation. Techniques and Endpoints for Catheter Ablation The goals of AF ablation are to eliminate triggers and/or modify the arrhythmogenic substrate. Early efforts to treat AF with catheter ablation attempted to replicate the surgical Cox-Maze procedure with limited success.33–38 With the identification of PV triggers of AF, the next phase of AF ablation was to target the site of specific PV triggers.8,10,39 However, inconsistent triggers and a high incidence of PV stenosis clearly limited this approach,6,40 resulting in a shift in ablation strategy from the PV tissue itself to the antrum connecting the LA and PV. Antral PV isolation (electrically disconnecting the PV from the LA) has subsequently become the cornerstone for ablation of AF.6,41 PV isolation can be accomplished by either a segmental or circumferential approach (Figure 1) using various imaging modalities such as fluoroscopy, three-dimensional electroanatomical mapping (3-D mapping), transesophageal echocardiography (TEE) and intracardiac echocardiography (ICE). Many practitioners also take advantage of preprocedure computed tomography (CT) or magnetic resonance imaging (MRI). These modalities are used in various combinations at the discretion of the operator and institution to exclude LA thrombus, evaluate LA/PV anatomy, ease the construction of 3-D maps, assist in transseptal puncture and facilitate catheter manipulation during the procedure. The segmental (electrophysiologic) approach uses a circular mapping catheter, which is placed sequentially in the ostium of each PV. Ablation is performed in the antrum of each PV until electrical isolation is accomplished using loss of PV potentials and pacing maneuvers for confirmation.39,42,43 The more commonly used circumferential (anatomic) approach uses a continuous ablation lesion set to surround the right or left PVs (isolated separately or together). Local electrogram amplitude reduction is generally the endpoint for individual RF applications, but circular mapping catheters can also be used to confirm PV isolation.38,44,45 PV isolation alone may be an adequate strategy for paroxysmal AF without significant structural heart disease, supported by the fact that most clinical recurrences after this procedure are associated with electrical “reconnection” between the LA and one or more PVs.41,46–48 However, PV isolation alone appears to provide disappointing results in other AF patient populations (i.e., persistent AF, AF with congestive heart failure and AF with significant underlying heart disease).41,49,50 The mechanisms of initiation and maintenance of AF in these patients may differ. To improve on the results of PVI alone in patients with persistent AF, various investigators have additionally placed linear lesions through the LA and sometimes the right atrium (RA). Common linear lesions (Figure 2) include: LA roof line (connects the right superior PV and left superior PV), mitral valve isthmus line (connects left inferior PV to the mitral valve annulus), anterior LA line (connects LA roof line near left/right circumferential lesions and the mitral valve annulus) and posterior LA line (connects both sets of PVs across the posterior LA).51–54 Empiric RA cavotricuspid isthmus ablation has not been shown to improve long-term success of PV isolation unless clinical or inducible cavotricusoid isthmus-dependent atrial flutter is present55 and is therefore not recommended by most experts.6 The goal of linear ablations is to modify arrhythmogenic substrate and to prevent large atrial reentrant circuits. Another method of ablating AF is to target both PV and non-PV triggers of AF. The incidence of non-PV triggers in patients referred for AF ablation has been shown to be approximately 20% and may be as high as 35% in patients with persistent AF. Non-PV foci may originate from the superior vena cava (SVC), LA posterior wall, crista terminalis, coronary sinus (CS), ligament of Marshall, or interatrial septum.7 AF triggers can be provoked, usually with high doses of isoproterenol, and successfully ablated.56,57 By eliminating both PV and non-PV triggers, the initiation of AF can potentially be prevented. Another ablation strategy targets CFAE in both the LA and RA (Figure 2), which may represent substrate for AF maintenance. These electrograms display more then two deflections that are fractionated, have a short cycle length (Procedural Outcomes Summarizing the outcomes for AF ablation has been difficult due to the lack of standardization in the design of clinical trials, classification of AF, AF ablation technique(s), length of blanking period, definition of “success”, frequency and intensity of arrhythmia monitoring, use of post-ablation antiarrhythmic medications and inclusion/exclusion of repeat ablation procedures in reported results. In addition, clinical variables such as different patient populations, LA size and concomitant cardiac disease, as well as technical proficiency and experience will clearly affect both efficacy and complications associated with the procedure. In an attempt to correct for some of these factors, an expert consensus has provided recommendations on the conduct and reporting of future studies.6 Despite the heterogeneity in patient populations, procedural techniques and endpoint definitions, there is growing agreement that AF ablation is more effective than antiarrhythmic drugs for AF, with a relatively small risk of serious complications. A large number of nonrandomized studies have reported a single-procedure success rate in patients with paroxysmal AF between 38–78%, with an average of 60%.6 Single-procedure ablation for patients with persistent AF ranged from 22–45%, with an average of 30%, and for patients with mixed types of AF from 16–84%. Repeat ablation procedures, performed in roughly one-fourth of patients, increased efficacy by 10–20%.6 Experienced centers have pioneered tailored stepwise approaches to both paroxysmal and persistent AF, with success rates that exceed previous reported results by individualizing ablation techniques to specific patients.60,64,65 Table 1 summarizes results from eight studies that randomized patients29,30,66–71 to AF ablation or alternative management strategies now published in peer review72,73 or presented in a public setting.66 All but one of these compared ablation with AAD, and all but one included patients who had failed previous treatment with one or more AADs. Six of the eight studies included exclusively or primarily patients with paroxysmal AF. The 12-month success rate with ablation in these studies ranged from 56–89%, compared to 9–40% with AAD therapy. A recent meta-analysis of six of these trials72 reported a risk ratio of 0.33 (0.21–0.51) for ablation compared with AAD on the endpoint of AF recurrence at 12 months. These results have firmly cemented AF ablation as a second-line rhythm control option, in accordance with previously published guidelines,1 and suggest that ablation is in fact superior to drug therapy in this setting. The role of ablation relative to AAD for first-line treatment of AF is less clear. Only one small randomized study (67 patients) has addressed this question.30 While ablation did appear superior to drug therapy in this study, nearly all (96%) of the patients had paroxysmal AF, amiodarone was not used in the control group and the study involved a small number of centers. Further study is therefore needed before ablation can be endorsed as first-line therapy for AF. Intriguing results have also been recently reported regarding potential benefits of AF ablation in patients with heart failure. Following a few nonrandomized series showing improved left ventricular ejection fraction (LVEF), exercise capacity and quality of life following AF ablation in patients with preexisting heart failure,28,74 a randomized study of AF ablation in heart failure patients was organized. The Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure (PABA-CHF) trial29 randomized 81 patients to RF ablation with the intent of sinus rhythm maintenance or implantation of a biventricular pacing device with radiofrequency (RF) ablation of the AV junction. Of the patients randomized to AF ablation, 78% and 88% were in sinus rhythm with or without the use of AADs at 3 and 6 months, respectively, while all of the patients randomized to biventricular pacing remained in AF as expected. At 6 months, patients assigned to AF ablation, compared with those assigned to biventricular pacing, had higher EFs (35 ± 9% vs. 28 ± 6%; p Complications Catheter ablation of AF has approximately a 6% major complication risk. These complications are a result of thromboembolism, direct injury to cardiac structures and thermal injury to adjacent structures.2 Vascular access complications including groin hematomas, retroperitoneal bleeds and femoral pseudoaneurysms are probably the most common adverse events following AF ablation, but are most often minor.6 The most catastrophic complication of LA ablation, which carries a 50% mortality risk, is atrio-esophageal fistula formation. The exact incidence is unknown but the estimated risk is 70%. Symptoms of PV stenosis may include cough, hemoptysis, dyspnea, chest pain and recurrent lung infections.76,77 However, the severity of PV stenosis does not always correlate with symptoms. Severe or even complete PV occlusion may be asymptomatic due to the compensatory dilation of the ipsilateral vein. Post-procedure screening for PV stenosis is performed either routinely or when potential symptoms develop. Imaging modalities include CT, MRI, TEE and pulmonary venography.6 Thromboembolic events due to catheter ablation of AF have a reported risk of 0–7%, with a true incidence that is probably 1 year, with few reports of permanent damage.6 Additional rare but reported complications of AF ablation include gastric hypomotility or acute pyloric spasm as a result of injury to the periesophageal vagal plexus, injury to the recurrent laryngeal nerve, mitral valve damage secondary to trauma or catheter entrapment, air embolus and coronary ischemia, which usually results from RF delivery within the coronary sinus.6 Post-Procedural Considerations Low-molecular-weight heparin or intravenous heparin is recommended as a bridge to therapeutic anticoagulation following AF ablation. Warfarin is recommended for at least 2 months post-ablation, regardless of anticoagulation status prior to the procedure. Despite some data to suggest it may be safe to discontinue anticoagulation after this 2-month period, successful AF ablation is not widely accepted as a factor in determining whether anticoagulation should be discontinued.6,79 It is recommended that the decision of whether to treat patients with long-term anticoagulation after AF ablation should be based on clinical indices, although data in this subset of patients is limited. Discontinuation of warfarin post-ablation is generally not recommended in patients with a CHADS2 score > 2.6 This is based partially on the fact that patients have fewer symptoms with ongoing AF post-ablation.83 It follows that discontinuation of anticoagulation is not a widely accepted indication for catheter ablation until prospective, randomized trials can be completed.6,79 Evolving Ablation Technologies A number of technical advances have already had a major impact on AF ablation, and more are expected. At the inception of AF ablation, procedures were performed using what were then standard RF ablation catheters with 4-mm tips. Among early technical refinements was the development of catheters with larger ablation tips, which could create larger area lesions for each application, potentially shortening procedure duration and improving efficacy. Newer RF catheters use saline irrigation systems, which employ active cooling of the catheter tip to prevent overheating of the electrode, while permitting the delivery of more energy to the tissue, potentially making the ablation of tissue more effective and efficient. Externally irrigated RF catheters also seem less apt to forming coagulum on the tip during AF ablation, and may therefore be associated with a lower risk of thromboembolic complications. One externally irrigated catheter, following a rigorous randomized trial, has become the first ablation catheter of any kind approved by the FDA for AF ablation.66 The use of 3-D mapping systems, with or without ICE, greatly facilitates real-time assessment of LA anatomy, and can help operators target and track sites for ablation. These systems also allow for catheter manipulation, with a reduced need for fluoroscopy and its attendant radiation exposure. Commercially available magnetic (Stereotaxis, Inc., St. Louis, Missouri) and robotic (Hansen Medical, Inc., Mountain View, California) catheter guidance systems are currently FDA-approved and have been shown to be safe and effective for AF ablation.18,84 Although their ultimate role in AF ablation is not yet firmly established, these technologies will hopefully improve patient and operator safety, as well as the procedural efficacy of AF ablation, particularly in the hands of less experienced operators. Other systems, such as the Remote Catheter Manipulation System (Catheter Robotics, Inc., New Jersey), may offer a simplified, less expensive option to remote catheter manipulation and is currently in the evaluation phase.85 Several new catheter designs and energy sources for ablation are also under active investigation. One system (Ablation Frontiers, Inc., Carlsbad, California) aims to assist in AF ablation using specially shaped catheters capable of mapping, pacing and delivering RF through multiple electrodes at once, potentially making it faster and easier to isolate the PVs or create linear lesions. This system has been successfully used for PV isolation86,87 and is currently being evaluated in larger multicenter studies of ablation of paroxysmal AF in Europe (Multi-Array Ablation of Pulmonary Veins for Paroxysmal Atrial Fibrillation or MAP-PAF study) and persistent AF in the United States (Tailored Treatment of Permanent Atrial Fibrillation or TTOP AF study). Other novel energy sources for ablation include ultrasound, laser and cryoablation.6 Cryotherapy is a particularly attractive option for endocardial ablation, as it can be delivered via a conventional catheter, a circular catheter or a cryoballoon without the thrombogenic and PV stenosis potential associated with RF energy. Ablation with a cryoballoon offers the possibility of simplifying AF ablation by achieving consistent PV isolation with limited applications and reduced procedure times. Initial trials have demonstrated efficacy similar to RF ablation. An uncommon, but important complication of this system is right phrenic nerve paralysis.88–90 Despite apparent antral location of the balloon catheter, lesions tend to occur at the distal LA-PV junction, potentially limiting the efficacy of such systems in treating persistent AF.91 While the ultimate value of these novel ablation technologies awaits the conclusion of a number of studies, there is optimism that electrophysiologists will soon have better tools for performing AF ablation, compared with the tools with which the field began. Conclusion AF is the most common tachyarrhythmia and the most difficult to treat. AAD therapy has limited efficacy, frequent adverse reactions and potential for increased mortality. Catheter ablation of AF has been shown to be the most effective therapy for managing this condition in various patient populations. This review provides contemporary information on the constantly evolving indications, techniques, outcomes and technologies associated with AF ablation. Acknowledgements. We would like to thank John Sherman, senior field clinical engineer, St. Jude Medical, Atrial Fibrillation Division, for his technical expertise in helping to create the figures in this manuscript.
References
1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation — Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol 2006;48:854–906.

2. O’Neill MD, Jais P, Hocini M, et al. Catheter ablation for atrial fibrillation. Circulation 2007;116:1515–1523.

3. Savelieva I, Camm J. Update on atrial fibrillation: Part I. Clin Cardiol 2008;31:55–62.

4. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833.

5. Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J 1964;67:200–220.

6. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS Expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007;4:816–861.

7. Chen SA, Tai CT. Catheter ablation of atrial fibrillation originating from the non-pulmonary vein foci. J Cardiovasc Electrophysiol 2005;16:229–232.

8. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–666.

9. Haissaguerre M, Marcus FI, Fischer B, Clementy J. Radiofrequency catheter ablation in unusual mechanisms of atrial fibrillation: Report of three cases. J Cardiovasc Electrophysiol 1994;5:743-751.

10. Jais P, Haissaguerre M, Shah DC, et al. A focal source of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 1997;95:572–576.

11. Jongbloed MR, Schalij MJ, Poelmann RE, et al. Embryonic conduction tissue: A spatial correlation with adult arrhythmogenic areas. J Cardiovasc Electrophysiol 2004;15:349–355.

12. Kumagai K. Patterns of activation in human atrial fibrillation. Heart Rhythm 2007;4:S7–S12.

13. Nathan H, Eliakim M. The junction between the left atrium and the pulmonary veins. An anatomic study of human hearts. Circulation 1966;34:412–422.

14. Hou Y, Scherlag BJ, Lin J, et al. Ganglionated plexi modulate extrinsic cardiac autonomic nerve input: Effects on sinus rate, atrioventricular conduction, refractoriness, and inducibility of atrial fibrillation. J Am Coll Cardiol 2007;50:61–68.

15. Hou Y, Scherlag BJ, Lin J, et al. Interactive atrial neural network: Determining the connections between ganglionated plexi. Heart Rhythm 2007;4:56–63.

16. Lin J, Scherlag BJ, Zhou J, et al. Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE). J Cardiovasc Electrophysiol 2007;18:1197–1205.

17. Lu Z, Scherlag BJ, Lin J, et al. Autonomic mechanism for complex fractionated atrial electrograms: Evidence by fast fourier transform analysis. J Cardiovasc Electrophysiol 2008;19:835–842.

18. Pappone C, Vicedomini G, Manguso F, et al. Robotic magnetic navigation for atrial fibrillation ablation. J Am Coll Cardiol 2006;47:1390–1400.

19. Po SS, Scherlag BJ, Yamanashi WS, et al. Experimental model for paroxysmal atrial fibrillation arising at the pulmonary vein-atrial junctions. Heart Rhythm 2006;3:201–208.

20. Schauerte P, Scherlag BJ, Patterson E, et al. Focal atrial fibrillation: Experimental evidence for a pathophysiologic role of the autonomic nervous system. J Cardiovasc Electrophysiol 2001;12:592–599.

21. Schauerte P, Scherlag BJ, Pitha J, et al. Catheter ablation of cardiac autonomic nerves for prevention of vagal atrial fibrillation. Circulation 2000;102:2774–2780.

22. Scherlag BJ, Nakagawa H, Jackman WM, et al. Electrical stimulation to identify neural elements on the heart: Their role in atrial fibrillation. J Interv Card Electrophysiol 2005;13(Suppl 1):37–42.

23. Scherlag BJ, Yamanashi W, Patel U, et al. Autonomically induced conversion of pulmonary vein focal firing into atrial fibrillation. J Am Coll Cardiol 2005;45:1878–1886.

24. Zhang Y, Scherlag BJ, Lu Z, et al. Comparison of atrial fibrillation inducibility by electrical stimulation of either the extrinsic or the intrinsic autonomic nervous systems. J Interv Card Electrophysiol 2009;24:5–10.

25. Zhou J, Scherlag BJ, Edwards J, et al. Gradients of atrial refractoriness and inducibility of atrial fibrillation due to stimulation of ganglionated plexi. J Cardiovasc Electrophysiol 2007;18:83–90.

26. 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.

27. Reynolds MR, Ellis E, Zimetbaum P. Quality of life in atrial fibrillation: Measurement tools and impact of interventions. J Cardiovasc Electrophysiol 2008;19:762–768.

28. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med 2004;351:2373–2383.

29. Khan MN, Jais P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008;359:1778–1785.

30. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs. antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: A randomized trial. JAMA 2005;293:2634–2640.

31. Spragg DD, Dalal D, Cheema A, et al. Complications of catheter ablation for atrial fibrillation: Incidence and predictors. J Cardiovasc Electrophysiol 2008;19:627–631.

32. Zado E, Callans DJ, Riley M, et al. Long-term clinical efficacy and risk of catheter ablation for atrial fibrillation in the elderly. J Cardiovasc Electrophysiol 2008;19:621–626.

33. Calkins H, Hall J, Ellenbogen K, et al. A new system for catheter ablation of atrial fibrillation. Am J Cardiol 1999;83:227D–236D.

34. Gaita F, Riccardi R, Calo L, et al. Atrial mapping and radiofrequency catheter ablation in patients with idiopathic atrial fibrillation. Electrophysiological findings and ablation results. Circulation 1998;97:2136–2145.

35. Haissaguerre M, Jais P, Shah DC, et al. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1996;7:1132–1144.

36. Jais P, Shah DC, Takahashi A, et al. Long-term follow-up after right atrial radiofrequency catheter treatment of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 1998;21:2533–2538.

37. Natale A, Leonelli F, Beheiry S, et al. Catheter ablation approach on the right side only for paroxysmal atrial fibrillation therapy: Long-term results. Pacing Clin Electrophysiol 2000;23:224–233.

38. Pappone C, Oreto G, Lamberti F, et al. Catheter ablation of paroxysmal atrial fibrillation using a 3D mapping system. Circulation 1999;100:1203–1208.

39. Haissaguerre M, Shah DC, Jais P, et al. Electrophysiological breakthroughs from the left atrium to the pulmonary veins. Circulation 2000;102:2463–2465.

40. Robbins IM, Colvin EV, Doyle TP, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation. Circulation 1998;98:1769–1775.

41. Wright M, Haissaguerre M, Knecht S, et al. State of the art: Catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2008;19:583–592.

42. Gerstenfeld EP, Dixit S, Callans D, et al. Utility of exit block for identifying electrical isolation of the pulmonary veins. J Cardiovasc Electrophysiol 2002;13:971–979.

43. Oral H, Knight BP, Ozaydin M, et al. Segmental ostial ablation to isolate the pulmonary veins during atrial fibrillation: Feasibility and mechanistic insights. Circulation 2002;106:1256–1262.

44. Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: Efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001;104:2539–2544.

45. Pappone C, Rosanio S, Oreto G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation 2000;102:2619–2628.

46. Cheema A, Dong J, Dalal D, et al. Incidence and time course of early recovery of pulmonary vein conduction after catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2007;18:387–391.

47. Mainigi SK, Sauer WH, Cooper JM, et al. Incidence and predictors of very late recurrence of atrial fibrillation after ablation. J Cardiovasc Electrophysiol 2007;18:69–74.

48. Ouyang F, Antz M, Ernst S, et al. Recovered pulmonary vein conduction as a dominant factor for recurrent atrial tachyarrhythmias after complete circular isolation of the pulmonary veins: Lessons from double Lasso technique. Circulation 2005;111:127–135.

49. Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: Long-term follow-up. Pacing Clin Electrophysiol 2001;24:1774–1779.

50. Oral H, Knight BP, Tada H, et al. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002;105:1077–1081.

51. Pappone C, Manguso F, Vicedomini G, et al. Prevention of iatrogenic atrial tachycardia after ablation of atrial fibrillation: A prospective randomized study comparing circumferential pulmonary vein ablation with a modified approach. Circulation 2004;110:3036–3042.

52. Ernst S, Ouyang F, Lober F, et al. Catheter-induced linear lesions in the left atrium in patients with atrial fibrillation: An electroanatomic study. J Am Coll Cardiol 2003;42:1271–1282.

53. Hocini M, Jais P, Sanders P, et al. Techniques, evaluation, and consequences of linear block at the left atrial roof in paroxysmal atrial fibrillation: A prospective randomized study. Circulation 2005;112:3688–3696.

54. Jais P, Hocini M, Hsu LF, et al. Technique and results of linear ablation at the mitral isthmus. Circulation 2004;110:2996–3002.

55. Wazni O, Marrouche NF, Martin DO, et al. Randomized study comparing combined pulmonary vein-left atrial junction disconnection and cavotricuspid isthmus ablation versus pulmonary vein-left atrial junction disconnection alone in patients presenting with typical atrial flutter and atrial fibrillation. Circulation 2003;108:2479–2483.

56. Lin WS, Tai CT, Hsieh MH, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 2003;107:3176–3183.

57. Tanner H, Hindricks G, Kobza R, et al. Trigger activity more than three years after left atrial linear ablation without pulmonary vein isolation in patients with atrial fibrillation. J Am Coll Cardiol 2005;46:338–343.

58. Konings KT, Smeets JL, Penn OC, et al. Configuration of unipolar atrial electrograms during electrically induced atrial fibrillation in humans. Circulation 1997;95:1231–1241.

59. Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: Mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–2053.

60. Oral H, Chugh A, Good E, et al. A tailored approach to catheter ablation of paroxysmal atrial fibrillation. Circulation 2006;113:1824–1831.

61. Estner HL, Hessling G, Ndrepepa G, et al. Electrogram-guided substrate ablation with or without pulmonary vein isolation in patients with persistent atrial fibrillation. Europace 2008;10:1281–1287.

62. Verma A, Novak P, Macle L, et al. A prospective, multicenter evaluation of ablating complex fractionated electrograms (CFEs) during atrial fibrillation (AF) identified by an automated mapping algorithm: Acute effects on AF and efficacy as an adjuvant strategy. Heart Rhythm 2008;5:198–205.

63. Pappone C, Santinelli V, Manguso F, et al. Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 2004;109:327–334.

64. Haissaguerre M, Hocini M, Sanders P, et al. Catheter ablation of long-lasting persistent atrial fibrillation: Clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol 2005;16:1138–1147.

65. Haissaguerre M, Sanders P, Hocini M, et al. Catheter ablation of long-lasting persistent atrial fibrillation: Critical structures for termination. J Cardiovasc Electrophysiol 2005;16:1125–1137.

66. U.S. Food and Drug Administration. Circulatory Devices Panel Meeting: Briefing Information. Available at: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4393b1-00-Index.html. Accessed 12/11/08, 2008.

67. Jais P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: The A4 study. Circulation 2008;118:2498–2505.

68. Krittayaphong R, Raungrattanaamporn O, Bhuripanyo K, et al. A randomized clinical trial of the efficacy of radiofrequency catheter ablation and amiodarone in the treatment of symptomatic atrial fibrillation. J Med Assoc Thai 2003;86(Suppl 1):S8–S16.

69. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354:934–941.

70. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: The APAF Study. J Am Coll Cardiol 2006;48:2340–2347.

71. Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: A prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). Eur Heart J 2006;27:216–221.

72. Nair GM, Nery PB, Diwakaramenon S, et al. A systematic review of randomized trials comparing radiofrequency ablation with antiarrhythmic medications in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:138–144.

73. Noheria A, Kumar A, Wylie JV Jr, Josephson ME. Catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation: A systematic review. Arch Intern Med 2008;168:581–586.

74. Chen MS, Marrouche NF, Khaykin Y, et al. Pulmonary vein isolation for the treatment of atrial fibrillation in patients with impaired systolic function. J Am Coll Cardiol 2004;43:1004–1009.

75. Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: Outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003;42:185–197.

76. Dong J, Vasamreddy CR, Jayam V, et al. Incidence and predictors of pulmonary vein stenosis following catheter ablation of atrial fibrillation using the anatomic pulmonary vein ablation approach: Results from paired magnetic resonance imaging. J Cardiovasc Electrophysiol 2005;16:845–852.

77. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: Functional characterization, evolution, and influence of the ablation strategy. Circulation 2003;108:3102–3107.

78. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005;111:1100–1105.

79. Oral H, Chugh A, Ozaydin M, et al. Risk of thromboembolic events after percutaneous left atrial radiofrequency ablation of atrial fibrillation. Circulation 2006;114:759–765.

80. Ren JF, Marchlinski FE, Callans DJ. Left atrial thrombus associated with ablation for atrial fibrillation: Identification with intracardiac echocardiography. J Am Coll Cardiol 2004;43:1861–1867.

81. Hsu LF, Jais P, Hocini M, et al. Incidence and prevention of cardiac tamponade complicating ablation for atrial fibrillation. Pacing Clin Electrophysiol 2005;28(Suppl 1):S106–109.

82. Bunch TJ, Asirvatham SJ, Friedman PA, et al. Outcomes after cardiac perforation during radiofrequency ablation of the atrium. J Cardiovasc Electrophysiol 2005;16:1172–1179.

83. Hindricks G, Piorkowski C, Tanner H, et al. Perception of atrial fibrillation before and after radiofrequency catheter ablation: Relevance of asymptomatic arrhythmia recurrence. Circulation 2005;112:307–313.

84. Saliba W, Reddy VY, Wazni O, et al. Atrial fibrillation ablation using a robotic catheter remote control system: Initial human experience and long-term follow-up results. J Am Coll Cardiol 2008;51:2407–2411.

85. Knight B, Ayers GM, Cohen TJ. Robotic positioning of standard electrophysiology catheters: A novel approach to catheter robotics. J Invasive Cardiol 2008;20:250–253.

86. Boersma LV, Wijffels MC, Oral H, et al. Pulmonary vein isolation by duty-cycled bipolar and unipolar radiofrequency energy with a multielectrode ablation catheter. Heart Rhythm 2008;5:1635–1642.

87. Kistler PM. Multielectrode ablation for paroxysmal atrial fibrillation: Pulmonary vein isolation made easy? Heart Rhythm 2008;5:1643–1644.

88. Malmborg H, Lonnerholm S, Blomstrom-Lundqvist C. Acute and clinical effects of cryoballoon pulmonary vein isolation in patients with symptomatic paroxysmal and persistent atrial fibrillation. Europace 2008;10:1277–1280.

89. Van Belle Y, Janse P, Theuns D, et al. One year follow-up after cryoballoon isolation of the pulmonary veins in patients with paroxysmal atrial fibrillation. Europace 2008;10:1271–1276.

90. Neumann T, Vogt J, Schumacher B, et al. Circumferential pulmonary vein isolation with the cryoballoon technique results from a prospective 3-center study. J Am Coll Cardiol 2008;52:273-278.

91. Phillips KP, Schweikert RA, Saliba WI, et al. Anatomic location of pulmonary vein electrical disconnection with balloon-based catheter ablation. J Cardiovasc Electrophysiol 2008;19:14–18.