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Catheter ablation of persistent atrial fibrillation
Kim Rajappan*,1 & Matthew Ginks1
Abstract: Catheter ablation of atrial fibrillation (AF) is performed increasingly worldwide and with the development of new technologies the procedures have become safer and more effective after a single attempt, particularly with paroxysmal AF. However, success rates for persistent AF ablation remain far lower than paroxysmal AF and there is large variation in the strategies used worldwide. This review describes the background to persistent AF ablation, the different strategies used and their associated risks and benefits, developing technologies and the authors’ perspective on the future of this rapidly evolving area. Atrial fibrillation (AF) is a common arrhythmia and may result in unpleasant symptoms and consequences. The current estimates of AF prevalence are up to 2% of the general population and this is set to increase further  . It is a major cause of stroke  and may lead to heart failure in certain individuals  . In paroxysmal AF, rhythm control may take the form of regular antiarrhythmic drug treatment. In persistent AF, cardioversion may be used in combination with antiarrhythmic drugs (AADs) to maintain sinus rhythm. Large randomized controlled studies (including the AFFIRM trial) observed rate and rhythm control using drugs to be equivalent in terms of mortality  . This can largely be attributed to the poor efficacy and harmful side effects of antiarrythmic drugs  . AAD therapy carries the risk of proarrhythmia and sudden cardiac death  . In those patients who receive a symptomatic benefit from being in sinus rhythm, rhythm control is the preferred treatment strategy. Therefore in the past decade or so, there has been a worldwide effort to achieve a more permanent form of rhythm control in the form of catheter ablation. Catheter ablation, as a curative technique, has been used for a variety of arrhythmias for more than 20 years  . However the technique for AF has evolved from an experimental and new approach to a widely performed procedure in many centers around the world. Initially the technique involved pulmonary vein isolation (PVI) and segmental ostial ablation, as reported by Haissaguerre, from the Bordeaux group  . Around the same time, the Italian group, led by Pappone, reported similar results from left atrial circumferential ablation where the end point was voltage abolition of the tissue around the pulmonary vein antra rather than PVI per se  . AF ablation is currently performed as a routine procedure in many large electrophysiology centers  . Furthermore, AF ablation is recommended as a treatment, under certain criteria, in all of the major AF clinical guidelines [1,11,12] . A recent meta-analysis of six studies comparing catheter ablation and AAD therapy reported that more than half of patients randomly assigned to medical therapy crossed over to the catheter ablation arm during the course of the trials. This may reflect both side effects and poor efficacy of AADs  .
• atrial fibrillation • catheter ablation • mapping • persistent • technology
1 Cardiac Department, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Headley Way, Headington, Oxford, OX3 9DU, UK *Author for correspondence: Tel.: +44 1865 220454; Fax: +44 1865 740409; [email protected]
10.2217/FCA.14.40 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(4), 553–562
Review Rajappan & Ginks Problems with assessing the data There are a number of limitations that need to be taken into consideration when reviewing catheter ablation of AF  . Outcomes used in studies and reported in the literature vary widely. In some the outcome is predominantly a clinical end point, reflecting freedom from symptomatic AF. While clinically valid, international societies suggest that a much more rigorous end point be applied, defined as freedom from any AF lasting more than 30 s whether symptomatic or not, off AADs  . The further issue with this end point is how frequently the rhythm is assessed. In order to truly assess this, the use of implantable loop recorders that can detect AF 100% reliably (which none can presently) is required. The next problem is the report of single procedure success versus multiple procedure success. Particularly for persistent AF, it is well recognized that multiple procedures may be required to achieve success, but single procedure success is a common end point based on the belief that this is the ultimate goal. Finally, the definition of AF itself as an inclusion criterion is highly variable particularly in the ‘persistent’ category. It is widely accepted that the patients included in these studies may be nearer the paroxysmal end of the spectrum, although technically the AF is persistent as it lasts for more than 7 days, while other patients fall into the long standing persistent AF category  . Catheter ablation of persistent AF ●●Strategies & success rates
Ostial segmental ablation & PVI
The original description of this technique by the team in Bordeaux  set the foundation for many of the current approaches to AF ablation, both paroxysmal and persistent. The technique has been described in numerous manuscripts and a diagram is shown in Figure 1 (figure of OSA/PVI). The key part of this approach is the confirmed electrical isolation of the pulmonary veins (PVs) from the rest of the left atrium, ideally with both entry block into the vein and exit block out of the vein. For persistent AF this results in relatively modest 2-year success rates at best with a single procedure of approximately 20%; multiple procedures of approximately 40%; and with AADs of approximately 50% [15–17] . PV antral ablation without or with PV isolation
PV antral (PVA) ablation describes predominantly antral anatomic ablation around the
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pulmonary veins, with an end point of online voltage abatement and a circumferential lesion set  . With the additional end point of PV isolation, pulmonary vein antrum isolation results not only in abolition of signals in the antrum but also electrical disconnection of the encircled veins within the ablated margins (Figure 1) . While the latter may be more difficult to achieve, there is evidence to suggest that doing this increases single procedure success of approximately 45% at 1 year; with multiple procedures of approximately 60%; and with AADs of approximately 75% compared with PVI alone [18–20] . PVA alone may give similar success rates but the data have to be interpreted with caution as the definition of persistent AF varied  . ●●Linear ablation
The addition of linear ablation to any of the previous strategies has been reported by several studies. The type of linear ablation commonly described includes the left atrial roof line, the mitral isthmus line, the box lesion set on the posterior wall of the left atrium (LA), the cavotricuspid isthmus line and the intercaval line in the right atrium (Figure 1) . Success rates differ significantly from one study to another with single procedure success rates being spread from 11 to 74% in patients with otherwise structurally normal hearts [19,22–24] . One explanation for this very wide range is the different lesion sets used. However assessment of lesion continuity and ‘block’ across the lines performed was also variable and may contribute to lower success rates with proarrhythmic ‘partial’ ablation. In the opinion of the authors, if linear ablation is to be undertaken then every effort needs to be made to assess and achieve bidirectional block across that line. Complex fractionated atrial electrogram ablation
Another approach that can be used is to target putative electrical substrate in both the left and right atria, based upon the electrogram characteristics at an individual site (Figure 1) . The original description by Nadamanee in 2004 reported pure complex fractionated atrial electrogram (CFAE) ablation without PVI as an end point and success rates with a single procedure, AAD-free success rate of 63% at 12 months, which improved to 77% with repeat procedures in 30% of patients  . In this report the assessment of a CFAE was subjective, based
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Catheter ablation of persistent atrial fibrillation upon characteristics that were assessed by the operator alone. Furthermore, it is possible for patients to reach one of several end points with this approach – the AF may terminate directly to sinus rhythm while ablating CFAEs; the AF might organize into an atrial tachycardia/flutter that can then be mapped and ablated to sinus rhythm; and finally the patient may remain in AF after all the apparent CFAEs have been ablated and the patient is cardioverted chemically and/or electrically. In a randomized controlled trial of patients with a CFAE approach those that did best were when AF terminated to sinus rhythm during ablation  . This improvement in success rates with termination to sinus rhythm during ablation is a common theme. Subsequent attempts have been made to make this a more objective approach and combine it with more conventional components of AF ablation. In one of the earliest an automated algorithm was used to identify CFAEs using CARTO (Biosense Webster, CA, USA) in addition to conventional ablation. In addition to primary CFAE ablation, PVA/PVI, roof and mitral isthmus lines were deployed  . At 1-year follow-up after a single procedure 68% of patients had a clinically successful result, without the need for AADs. Verma et al. performed a randomized controlled trial comparing PVA/PVI versus CFAE alone versus PVA/PVI plus CFAE ablation in both the left and right atria using an automated algorithm and the EnSiteNavX system (St Jude Medical, MN, USA)  . Although only 35% of the patients studied had persistent AF, they were evenly distributed between the three groups. There was a significantly better 1-year outcome in the PVA/PVI plus CFAE group (82%) compared with both the PVA/PVI only (50%) and CFAE only (42%) groups. The STAR AF II study is a follow on to this looking at three different strategies in patients with persistent AF PVA/PVI alone, PVA/PVI plus left atrial roof line and mitral isthmus line, and PVA/PVI plus CFAE ablation in both the LA and right atrium (RA) using the EnSite NavX system and automated algorithm again  . The approach used for CFAE ablation in this study represents an objective approach to targeting CFAEs (Figure 2) . However there are now multiple algorithms available for identifying these CFAE sites and how they are identified varies. There has been demonstration that these can vary over time and are affected by ablation in other areas, for example, during PVA/PVI  .
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Figure 1. Diagrams showing common lesion sets used foratrial fibrillation ablation. (A) Ostial segmental ablation lesion set shown in red on a left atrium. (B) A pulmonary vein antral lesion set is shown with ablation lines between the veins (the carina) and also the roof of the left atrium and between the mitral annulus and left PVs (the so-called mitral isthmus line). (C) Complex fractionated atrial electrogram sites are identified and ablated in this approach. AP: Anteroposterior; LLat: Left lateral; PA: Posteroanterior.
The ‘stepwise’ approach
This approach was f irst described by Haissaguerre and colleagues and consists of PVI  ; CFAE ablation of the LA targeting regions with rapid atrial activity, continuous fractionation and centrifugal atrial activation; linear ablation; RA ablation. Before the beginning of the procedure and after each step, simultaneous recording of atrial fibrillation cycle length (AFCL) at both LA and RA appendages is performed to monitor the impact of ablation  . Conversion to sinus rhythm or atrial tachycardia is preceded by progressive increase in AFCL to a critical level of 180–200 ms. Using this ablation strategy, 153 patients with chronic AF (mean duration: 22 months), underwent catheter ablation, AF was terminated in only 5% of patients by PVI, but when electrogram-based ablation and linear ablation were added the rate of termination was 60 and 84%, respectively. Multivariate analysis incorporating LA dimensions and structural heart disease demonstrated that AFCL was the strongest independent predictor of procedural AF termination, with the baseline AFCL cut-off of less than 140 ms
Review Rajappan & Ginks
Figure 2. Complex fractionated atrial electrogram ablation approach in STAR AF II study. (A) A 3D map using the St Jude Medical Velocity system (St Jude Medical, MN, USA) is used to define areas of complex fractionated atrial electrogram (CFAE) activity after pulmonary vein isolation with wide area encirclement. The red dots represent the lesions that encircle the pulmonary veins and the white areas are CFAE as defined by an average cycle length of 21 months for AF duration and AF cycle length of ≤142 ms to be associated with lower rates of freedom from AF over a mean follow-up period of 28 months  . Larger left atrial size has also been associated with lower rates of freedom from arrhythmia during follow-up after catheter ablation for persistent AF  , although in meta-analysis the only reproducible predictor of AF recurrence is nonparoxysmal AF  . In recent years, the use of DE-MRI to evaluate left atrial fibrosis has been developed. It has been suggested that the degree of fibrosis is predictive of recurrent AF after catheter ablation. However, at present this experience is largely limited to a single center  . ●●Facilitating catheter manipulation
& delivery of effective lesions
Manipulation of the ablation catheter within the left atrium may be performed with a fixed (nonsteerable) or a steerable sheath. The latter approach has been shown in a randomized study to be an independent predictor of treatment success and a reduction in fluoroscopy time when compared with the use of a nonsteerable trans-septal sheath, without impacting on complication rates  . It has also been suggested that the use of a steerable sheath may facilitate mitral isthmus ablatibon in the context of AF ablation  . Remote catheter navigation has been introduced to allow the operator to sit at a work station in proximity to the intracardiac electrograms and electro-anatomic mapping system. This has potential advantages in operator comfort and reducing radiation exposure. The two technologies that have been developed for this purpose include the robotic controlled navigation system (Hansen Medical, CA, USA) and the magnetic navigation system (Stereotaxis Inc., MO, USA). To date these technologies have not
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been compared with manual catheter manipulation in a randomized fashion to evaluate effects of safety, efficacy or other procedural aspects in ablation of persistent AF. However, systematic reviews have suggested similar long-term freedom from AF  although there appears to be a learning curve on initial use of these systems  . Reductions in fluoroscopy time with an increase in overall procedure time have been reported [38,40] . Suboptimal contact between the ablation catheter and the endocardial surface has been proposed as a reason for delivery of ineffective ablation lesions and reduced procedural success. Historically the operator relied on the combination of tactile feedback, electrogram quality and impedance values to ascertain catheter–tissue contact. In recent years, novel technologies have been developed to provide more accurate assessment of the quality and stability of contact between the catheter and the myocardium. The intention is to facilitate delivery of durable, transmural lesions. Contact force sensing has been integrated in several ablation catheter platforms (TactiCath, St Jude Medical; SmartTouch, Biosense Webster) and it has been demonstrated that pulmonary vein reconnection sites occur more frequently in areas of ablation with lower contact force or force–time integral  . In a small number of patients, ablation force–time integral has been correlated with late gadolinium enhancement on MRI  . The use of electrical coupling information that can be derived from impedance-based measurements (St Jude Medical) was associated with higher rates of PVI after anatomical encircling in a pilot study  . ●●Optimizing mapping of AF
Electro-anatomic mapping systems
While catheter ablation of AF can be performed using fluoroscopy alone, the vast majority of operators use one of two electro-anatomic mapping systems (Carto, Biosense Webster; NavX Velocity, St Jude Medical), which allow the operator to create a geometric model of the chamber of interest and visualize the catheters without the need for fluoroscopy. The main advantages of these systems are reduction in radiation dose and the ability to record where therapy has been delivered on a geometric model of the atrium. In addition, such systems facilitate mapping of organized atrial tachycardias, which are frequently seen in patients undergoing AF ablation.
Review Rajappan & Ginks Panoramic mapping of the atria
Current understanding of the pathophysiology of AF suggests both focal impulses and highfrequency re-entrant drivers, or ‘rotors’ are responsible for sustaining AF. These may be viewed as stable sources of AF, hence they represent a target for AF ablation. However, one of the limitations of catheter ablation of AF is the fact that real-time electrical information is only available from the surface ECG and a limited number of intra-cardiac electrograms from catheters located at discrete sites at any given point in time. There have been interesting recent developments in two key areas that have been postulated to allow real-time mapping of localized sources of AF. ●● Invasive panoramic electrophysiological mapping; ●● Noninvasive panoramic ECG imaging.
Invasive panoramic mapping of the atria using multielectrode ‘basket’ catheters (Constellation, Boston Scientific, MA, USA) was investigated by Narayan and colleagues as an approach to identify and target localized sources of AF  . These investigators, from two US centers, demonstrated a huge increase in success from AF ablation using a Focal Impulse and Rotor Modulation (FIRM)-guided approach when compared with a conventional strategy. Interestingly the morphology of electrograms seen at sites of successful ablation to sinus rhythm correlated poorly with sites of complex fractionated electrograms  . This approach relies on proprietary computer software to identify areas of high-frequency activation with spatial and temporal stability. To date, the high success rates seen in this two-center study have not been reproduced in a multicenter trial setting, but this represents a promising approach to improve our understanding of the mechanisms of persistent AF as well as the success rates from catheter ablation. A noninvasive approach to identify localized sources of AF has been developed using an array of body surface electrodes (an ‘ECG jacket’; CardioInsight Inc., OH, USA). Noncontrast thoracic CT imaging is performed to acquire anatomical information along with the electrode positions. The unipolar electrograms can be analyzed using the inverse method to generate an epicardial activation map in order localize sources of AF. The feasibility of this approach was demonstrated in patients with AF  and
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it has now been validated in patients with atrial tachycardia in a multicenter study  . Anticoagulation following AF ablation There is a recognized periprocedural thrombembolic risk associated with AF ablation. This is present both during the procedure  and afterwards for a period of time, irrespective of baseline risk  . Furthermore the guidelines mandate its use  . Analysis of the available data shows that continuing warfarin through the procedural period and afterwards is a very safe approach that lowers thromboembolic risk  . There are limited data available on the use of novel oral anticoagulants after AF ablation. Dabigatran has the most evidence available with comparison with warfarin appearing fairly favorable  but large randomized controlled trials are still needed on the best regime to use. There is very little evidence for rivaroxaban  and currently none for apixaban or edoxaban. Irrespective of the anticoagulant used there are no data conclusively to support the discontinuation of anticoagulation in all patients after AF ablation. In fact the contrary is true with postablation thromboembolic risk appearing to be related to the same risk factors as prior to ablation, that is, CHADS2 and CHADS2VA2Sc [52,53] . For this reason patients with anything other than the lowest risk should be continued on oral anticoagulation after AF ablation indefinitely, at least until there is clear evidence from randomized prospective trials to support the safety of its discontinuation. Impact on morbidity & mortality There are some data available to support the premise that successful AF ablation may reduce the risk of adverse cardiovascular outcomes including stroke and death. One international multicenter registry compared outcomes of over 1000 patients undergoing catheter ablation with a cohort with AF treated medically in the Euro Heart Survey, and a hypothetical cohort without AF, age and gender matched to the general population. Analysis of stroke and death was carried out after the first procedure (including periprocedural events) regardless of success, on an intention-to-treat basis. Rates of stroke and death were significantly lower in this cohort (both 0.5% per patient-year) compared with those treated medically in the Euro Heart Survey (2.8 and 5.3%, respectively; p