AF is characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function.4 Thromboembolic disease and ischemic stroke are the most important complications of AF, and their occurrence is increased in both paroxysmal (intermittent) and chronic forms of AF.3 The rate of ischemic stroke among patients with nonrheumatic AF averages 5% per year, which is 2-7 times the rate for individuals without AF.4 One of every six strokes occurs in patients with AF.4 In the Framingham Heart Study, patients with rheumatic heart disease and AF had a striking 17-fold increased risk of stroke compared to age-matched controls.5 Most importantly, ischemic stroke associated with AF is nearly twice as likely to be fatal as non-AF stroke.5 In addition, stroke recurrence is more frequent and functional deficits following an AF-related stroke are more likely to be severe with persisting neurological deficits among survivors.5,6 It has been estimated that AF leads to a substantially increased risk of mortality compared to individuals in normal sinus rhythm and the added expenditures associated with treating this condition and its sequelae are substantial.3,6 Patients afflicted with AF normally progress from experiencing lone or infrequent episodes that convert spontaneously to normal sinus rhythm, to the paroxysmal form of the syndrome, which is characterized by recurrent episodes that can resolve spontaneously, to a persistent form that may require cardioversion to achieve sinus rhythm.3 Paroxysmal AF affects approximately one-quarter to one-half of all patients, but AF paroxysms become more frequent, of longer duration, and resist cardioversion with time; approximately one-half of these patients will eventually progress to chronic AF.3,7 While some episodes of AF remain asymptomatic, many occurrences mimic the symptoms of cardiac failure and produce tremendous anxiety for the patient. The constellation of classic AF symptoms includes dyspnea, chest pain and palpitations as well as dizziness or syncope.3,4 In paroxysmal AF, sinus rhythm may abruptly give way to symptomatic episodes of AF; therefore, symptoms may be less well tolerated than in chronic AF, to which patients commonly adapt.3 Although strokes certainly account for much of the functional impairment associated with AF, the rhythm disturbances and associated clinical symptoms also produce marked deficits in quality of life.8-15 Using well-validated questionnaire instruments, such as the SF-36 health survey, a number of studies have documented significant impairment in both physical and social functioning among AF patients well below levels found in healthy normal individuals.8-15 Clearly, anxiety regarding the sudden and unpredictable onset of severe symptoms that is characteristic of paroxysmal AF in particular is likely to be the major reason for self-imposed limitations in activities of daily living.8 In fact, Dorian et al.9 found that quality of life is as impaired in patients with paroxysmal AF as in patients with significant structural heart disease. Palliative pharmacological therapy with antiarrhythmic drugs is undertaken when AF episodes become recurrent and bothersome to the patient.7 However, on average, antiarrhythmic drugs are able to suppress AF episodes and maintain normal sinus rhythm in only about 50% of patients.3,7,16 In addition, it is well documented that use of antiarrhythmic drugs is associated with a troubling frequency of severe side effects, including lethal arrhythmias as well as organ toxicity.7 In fact, in the large multi-center Canadian Trial of Atrial Fibrillation, almost 20% of AF patients randomized to treatment with low-dose amiodarone were forced to discontinue therapy due to symptomatic adverse events.10 Thus, it is not surprising that patients enrolled in this trial experienced relatively small, albeit statistically significant, improvements in quality of life as the potentially negative impact of antiarrhythmic drug therapy may have adversely affected quality of life despite a diminution of AF recurrence. These findings contrast sharply with the substantial and clinically significant improvements in quality of life realized among AF patients undergoing curative treatments such as the surgical MAZE procedure13 or atrioventricular node ablation and permanent pacemaker implantation.8 Similarly, substantial improvements in quality of life and symptom amelioration also have been demonstrated following minimally-invasive catheter ablation of the pulmonary veins even when AF episodes are not completely eliminated.11,12 Evaluation of Right Atrial Catheter Ablation in the Management of Atrial Fibrillation Because of the significant morbidity in many patients with paroxysmal or permanent AF and the lack of curative pharmacological therapies, surgical intervention is often necessary. Although a variety of open surgical methods have been developed to alleviate or control the symptoms of AF, only the MAZE procedure and its variants have been shown to be curative.17,18 While this procedure can be undertaken among patients where AF is the primary indication for surgery,13 it is usually reserved for patients undergoing surgery for other cardiac conditions, such as valvular, ischemic or congenital heart disease.17,18 The MAZE operation uses strategically placed incisions (or ablations) to allow sinus nodal impulses to activate the atrium along only labyrinthine paths too narrow to support re-entrant wavelets, thereby restoring atrial contractions and potentially reducing thromboembolic risk. Complete elimination of AF episodes and symptoms has been demonstrated in over 90% of patients undergoing this surgical procedure.17,18 Unfortunately, this method must be undertaken during open cardiac surgery, usually via median sternotomy, and patients are therefore subject to the attendant surgical complications, including a slight increase in the risk of mortality.4 Consequently, there has been a growing impetus toward developing, testing and validating minimally-invasive catheter-based ablation techniques using radiofrequency energy that emulate the MAZE procedure, but avoid the associated risks involved in open cardiac surgery.19-25 AF is generally believed to be caused by multiple re-entrant wavelets occurring variably in the atrium that are initiated by triggering foci located predominantly in the pulmonary veins and, to a lesser extent, in the right atrium.26-28 While triggering foci appear to start the process, changes in the electrical and structural properties of the atrium associated with AF facilitate the progression from paroxysmal to persistent to permanent AF.29 Indeed, initiation and perpetuation of AF may be partly dependent on the many anatomic and functional obstacles that exist in the right atrium.30 Therefore, it is possible that right atrial compartmentalization alone, or in combination with previously ineffective antiarrhythmic drugs (i.e., hybrid therapy),31 may prevent triggering arrhythmias from initiating or maintaining AF by preventing propagation of the initiating wavefront, preventing re-entry around anatomic obstacles, and/or reducing the critical mass of tissue required for multiple wavelet re-entry. For these reasons and because of the procedural ease associated with catheter deployment, initial studies of catheter ablation have focused on the right atrium. The procedural goal of this approach is to emulate a portion of the MAZE procedure by compartmentalizing the right atrium via the creation of linear lesions, thereby reducing the amount of contiguous myocardium available for the propagation of the wavelets.21 Seminal work in evaluating the role of right atrial catheter ablation in the management of highly symptomatic and drug refractory paroxysmal AF has been undertaken by Haissaguerre, Jais and coworkers.19,20 This research group has published a series of articles describing their evolving experience with right atrial ablation.27,28,32-36 Initial feasibility case studies in small numbers of patients showed complete elimination of subsequent AF episodes following catheter ablation of distinct arrhythmogenic foci located in the right atrium.27,28,32,33 Complete elimination of episodes in right atrial focal AF with catheter ablation has also been confirmed by others.37 In a larger (n = 45), more heterogeneous group of drug refractory paroxysmal AF patients, Haissaguerre et al.34 demonstrated that more than one-half (24/45) of patients treated with right atrial ablation alone showed either complete elimination of AF episodes (n = 6), elimination of AF episodes with previously ineffective antiarrhythmic drugs (n = 9) or substantial reduction of AF episodes and related symptoms (n = 9). Ten patients with an unsuccessful outcome after right atrial ablation underwent a subsequent ablation procedure in the left atrium resulting in an additional 6 patients achieving normal sinus rhythm following the staged procedure. Long-term follow-up (mean, 26 months) of these patients showed some deterioration of ablation effectiveness with infrequent AF recurrence in a small subgroup of patients.36 This finding may be due to a combination of disease progression, incomplete linear block and/or ineffective ablation of arrhythmogenic triggers. Based on the pioneering work of Haissaguerre and Jais, a number of subsequent studies aimed at creating more continuous lesions in the right atrium with linear array catheter technology have been undertaken.21 Gaita et al.38 found that 9 out of 16 patients (56%) with highly symptomatic idiopathic paroxysmal AF had no AF recurrence approximately 1 year following right atrial ablation. Five of these successful patients required hybrid therapy with previously ineffective antiarrhythmic drugs to maintain sinus rhythm. Similarly, Pappone et al.39 showed that right atrial ablation alone produced complete elimination of AF in 4 out of 8 patients (50%). This cure rate was increased to 85% (12/14) among patients undergoing a biatrial procedure. Calkins et al.40 observed less impressive results after right atrial ablation with 12 out of 15 patients (80%) showing some recurrence of AF after 3 months of follow-up. Attempting to create more complete conduction block and right atrial compartmentalization with aggressive linear ablation, Garg et al.41 demonstrated AF suppression in 8 out of 12 patients (67%) on previously ineffective medication or no medication. Natale et al.42 also showed that more than 60% of AF patients (11/18) could realize complete episode elimination after right atrial ablation. Encouraging results with right atrial ablation also were observed by Gasparini et al.,43 where 18 out of 24 patients (75%) showed either no AF recurrence (n = 12) or significant episode reduction (n = 6). The most impressive results with right atrial linear ablation to date have been reported by Kocheril,44 where a long-term (mean, 19 months) cure without antiarrhythmic drugs was observed in 23 out of 29 patients (79%) using an empiric mapping technique. Ablation during active AF, and testing to reinduce AF following the procedure, make this study unique. Lastly, Montenero et al.45 compared the results of right atrial ablation between patients with 2 linear lesions and those with 3 linear lesions. Absence of AF episodes without medication was observed acutely in 40% (6/15) and 66% (6/9) of patients with 2 and 3 lesions, respectively. Similar to earlier results reported by Jais et al.,36 some deterioration in long-term (> 12 months) effectiveness was observed; 26% (4/15) and 55% (5/9) of patients with 2 lesions and 3 lesions, respectively, remained AF-free without medication. Serious procedure- or device-related complications were rarely reported in these published studies of right atrial ablation. Interpretation and Pitfalls Published studies of right atrial catheter ablation clearly indicate that this procedure can be undertaken safely with rare and easily managed complications.21,22 The procedural ease and attractive safety profile of right atrial ablation contrast with catheter ablation in the left atrium.21,22 Indeed, left atrial ablation which may include pulmonary vein isolation involves the more challenging and costly transseptal puncture for catheter deployment.12 Some studies have shown that creation of extensive lesions in the left atrium using conventional catheter tip technology carries a significant risk of thromboembolism and stroke. Furthermore, patients with longstanding AF may have adherent thrombus in the left atrium or left atrial appendage, making the prospect of catheterization of the left atrium in these patients less attractive, particularly when anticoagulant therapy is interrupted for a transseptal puncture.21 Finally, pulmonary vein ablation in the left atrium has been associated in several studies with a disturbing incidence of pulmonary vein stenosis.11,46,47 Other studies have achieved better success in reducing the likelihood of pulmonary vein stenosis after left atrial ablation.12,35 Nonetheless, it remains a probable post-ablation complication. The effectiveness of right atrial catheter ablation in eliminating or reducing the number of AF episodes is encouraging. At a minimum, it appears that approximately 20% of patients suffering from drug-resistant paroxysmal AF can realize complete episode elimination after ablation.36,40 On the other extreme, Kocheril44 demonstrated that almost 80% of patients treated with right atrial catheter ablation alone remained free of AF episodes in the long-term without the need for antiarrhythmic medication. Much of the difference in effectiveness observed between earlier studies of right atrial ablation and more currently published investigations involves improvement in catheter technology that allows for the creation of long transmural linear lesions rapidly and safely.44 These continuous linear lesions provide for greater uninterrupted compartmentalization of the atrium compared to precursor ablation techniques that required laborious placement of contiguous punctate lesions or the use of a continuous pullback or drag technique allowing for the possibility of incomplete conduction block.23 It is not surprising that even the best success rate with right atrial ablation is inferior to the cure rate achieved with the MAZE procedure, as only a portion of the MAZE procedure is emulated. Nevertheless, while the cardiac surgeon has only one chance during the MAZE procedure of curing atrial fibrillation, the interventional electrophysiologist can perform endocardial catheter ablation of AF as a staged procedure and patients in whom AF recurs after right atrial ablation can return for additional ablation procedures.21 In any case, undertaking right atrial ablation as a first intervention effectively spares a substantial percentage (between 20% and 80%) of drug refractory paroxysmal AF patients with the complications and morbidity associated with more aggressive catheter interventions such as left atrial ablation, pulmonary vein isolation or atrioventricular node ablation/modification that renders the patient pacemaker dependent. Several published studies demonstrated that right atrial ablation allows for the maintenance of normal sinus rhythm with the addition of previously ineffective antiarrhythmic medication.38,41,42,45 The modification of the effect of antiarrhythmic drugs that were ineffective before ablation referred to as hybrid therapy may be a sign that the electrophysiological substrate has been modified by the lesions.31 If the lesion created is not continuous enough to block the conduction in that area, it could be sufficient to reduce the number of wavelets sustaining the arrhythmia; therefore, the medications may cause a further reduction in the number of wavelets, preventing the maintenance of AF.38 This outcome may delay or obviate the need for additional ablation interventions, especially if drug adherence can be maintained by using a less toxic form or lower dosage of medication. AF episode reduction or elimination following catheter ablation procedures was documented in most studies using an event recorder, which allows the patient to transmit an electrocardiogram to a recording facility when the arrhythmia occurs. This is the preferred method of determining AF episode occurrence in paroxysmal AF, as noted by the Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation.4 This also was the method used as the primary endpoint to determine drug efficacy in the Canadian Trial of Atrial Fibrillation.16 It should be noted that patients participating in this large multi-center randomized controlled trial were instructed to transmit an electrocardiogram only if cardiac symptoms occurred. In the absence of recurrent AF symptoms and/or decrements in quality of life, lack of transmission was interpreted as treatment success.16 Moreover, the patients in all published studies of right atrial ablation were all highly symptomatic during AF, so it is likely that they would, and in fact did, recognize when they had a recurrence of AF, as documented by electrocardiogram in all instances at the time of symptomatic recurrence.41 Some caution should be used in interpreting treatment effects in published studies of right atrial ablation for the treatment of AF, as sample sizes in most studies were relatively small and concurrent control groups were uniformly lacking. As a rule, each patient served as his or her own control. It is often assumed that these types of observational study inflate positive treatment effects compared with randomized controlled trials. However, this assumption is based upon older published studies. To the contrary, two comprehensive reviews of more recently published trials encompassing multiple medical conditions found little evidence that estimates of treatment effects in observational studies reported after 1984 are either consistently larger than or qualitatively different than those obtained in randomized controlled trials.48,49 No published study of right atrial catheter ablation has included an assessment of quality of life improvement. However, marked and clinically significant improvements in quality of life as measured by the well-validated SF-36 questionnaire instrument have been realized among AF patients after treatment with pulmonary vein ablation,11 atrioventricular node ablation with permanent pacemaker implantation8 and the MAZE procedure.13 Consequently, it is highly likely that the outcome would be similar after successful right atrial ablation as quality of life improvement is strongly correlated with AF episode reduction and symptom amelioration. For example, Gerstenfeld et al.11 found that patients without recurrent AF symptoms after pulmonary vein ablation reported significantly higher quality of life than patients who underwent invasive mapping but in whom no ablation was performed. Interestingly, patients experiencing a reduction but not a complete elimination in AF episodes after ablation reported intermediate quality of life score improvements, suggesting some benefit of ablation even in the absence of complete AF suppression. Additional evidence of AF episode reduction improving quality of life can be gleaned from the Canadian Trial of Atrial Fibrillation, where patients with no symptomatic recurrences of AF had significantly higher scores for quality of life than those with AF recurrences irrespective of randomly-allocated medication received.10 Conclusion The preponderance of evidence from published clinical studies of right atrial catheter ablation strongly suggests that this procedure is safe and effective for the management of drug refractory patients with paroxysmal AF. Several broad conclusions can be reached from this synthesis: Right atrial linear catheter ablation offers procedural ease and provides a level of safety to the patient far greater than left atrial ablation procedures. This attractive safety profile, coupled with curative success in a significant proportion of afflicted, drug refractory patients, recommends this minimally-invasive procedure as a first line intervention since it inevitably spares some patients the need for and attendant risks associated with other ablation or surgical procedures. Newer ablation methods that create continuous linear lesions designed to compartmentalize the total atrial surface appear to offer superior effectiveness compared to earlier applications of radiofrequency energy on a point-by-point basis. Although evidence is scant, the effectiveness of right and left atrial ablations appears to be independent and additive with respect to AF episode reduction. Consequently, those patients who do not experience significant symptom amelioration with right atrial ablation may elect to have a subsequent staged left atrial procedure, with their probability of cure increased markedly. A substantial subset of drug refractory patients undergoing right atrial ablation will benefit from hybrid therapy by having previously ineffective antiarrhythmic medications provide effective AF suppression. These patients may or may not elect to have additional electrophysiological interventions depending in large part on drug tolerance in the long term and deterioration of cardiac health.