Contemporary Role of Catheter Ablation in Patients with Persistent Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia diagnosed in clinical practice. As the population ages, AF is predicted to affect 6-12 million people in the U.S. by 2050 and 17.9 million in Europe by 2060. AF significantly impairs quality of life (QoL), increases the risk of stroke, heart failure, and dementia, and is associated with increased overall mortality.¹ Therapies to maintain sinus rhythm have shown significant improvement in symptoms, QoL, and even mortality. Among available rhythm control therapies, percutaneous catheter ablation has emerged as the most effective treatment for AF, and pulmonary vein isolation (PVI) is the cornerstone ablative therapy for paroxysmal and persistent AF.² In this article, we feature a case of persistent AF and discuss our approach, along with challenges in the management of patients with non-paroxysmal AF. 

Case Description

The patient is a 72-year-old male who was referred to our institution for an AF ablation procedure. He had a history of persistent AF, hypertension, obstructive sleep apnea, and coronary artery disease. He was diagnosed with persistent AF in 2013 and underwent cardioversion, which maintained sinus rhythm for 2 years, but developed recurrence of his AF; he underwent a second cardioversion procedure, and this time was treated with sotalol for AF suppression. He maintained sinus rhythm for one more year. He reverted back to persistent AF on sotalol, and reported increasing dyspnea on exertion while in AF, particularly when walking on an incline or climbing stairs. His medications included hydrochlorothiazide, losartan, sotalol, and rivaroxaban. A previous transthoracic echocardiogram showed an ejection fraction of 55% and a moderately dilated left atrium. Similarly, he had a negative non-invasive stress echo test workup and a Holter monitor that showed a 100% burden of AF with a mean ventricular rate of 95 bpm. 

As with all of our patients undergoing AF ablation, this patient underwent a thorough multidisciplinary evaluation to ensure his cardiovascular comorbidities were well managed and not responsible for exacerbation of AF. At our institution, all AF ablation procedures are performed under general anesthesia, and guideline-recommended therapeutic doses of intravenous heparin are administered prior to transseptal puncture. We use radiofrequency catheter ablation for all of our persistent AF cases. Esophageal temperature is monitored with a multi-pole esophageal temperature probe (CIRCA S-CATH, CIRCA Scientific), and esophageal deviation (EsoSure, Northeast Scientific) is routinely performed in cases in which esophageal heating is encountered. In persistent AF ablation cases, ablation lesion strategy is individualized to operator preference and expertise, and tailored to individualized patient needs (Figure 1). In this case, it was requested that the patient discontinue sotalol five days before his procedure and not to interrupt his oral anticoagulation (OAC). He presented in sinus rhythm. Following a transseptal puncture under the guidance of intracardiac echocardiography, two sheaths (SL1 and Agilis NxT, Abbott) were introduced into the left atrium (LA). A high-density bipolar voltage map of the LA using three-dimensional geometry was created with a variable loop multipolar circular catheter (Advisor VL, Abbott) on the cardiac mapping system (EnSite Precision, Abbott). A mild amount of atrial scarring was noted on the LA bipolar voltage map (Figure 2). Our patient underwent circumferential point-by-point PV isolation. All ablations were at 25-30 Watts on the posterior wall and 35-40 W on other locations varying between 25-35 seconds, using the TactiCath Quartz Contact Force Ablation Catheter (Abbott). We used a target lesion size index (LSI) of 4-4.5 on the posterior wall and 5.0-5.5 in other locations. After the veins were encircled, entrance and exit block with the circular mapping catheter was confirmed. We then proceeded with posterior wall isolation by creating a “box lesion set” consisting of a roofline and floor line connecting the right and left antral circumferential lesion sets, and obliteration of all amplitude potentials inside the “box lesion” until the achievement of entrance block, and then confirmed exit block by the absence of pacing capture of the LA at a high pacing output (20 mA @10 ms) (Figure 3). Esophageal deviation with the EsoSure device was necessary to complete the floor line by avoiding esophageal heating. Isoproterenol at 20 mcg/minute was then given to evaluate the presence of non-PV triggers; however, no atrial premature contractions were noted during its administration and washout. Nevertheless, a catheter manipulation during isoproterenol washout induced typical flutter, which was terminated with ablation of the cavotricuspid isthmus in the right atrium. The patient was uneventfully discharged the next day on his regular home medications, including sotalol for the 3-month blanking period, which was subsequently discontinued. Our patient experienced a significant symptomatic improvement in sinus rhythm and has remained free of atrial arrhythmias for the last 15 months.

Role of Ablation

In general, the natural history of AF is progressive, initially being paroxysmal or non-sustained, and predominantly and most commonly induced by pulmonary vein (PV) triggered activity. It is considered that repetitive bouts of AF induce electric alterations and remodeling of atrial myocardium, which may also promote electrical, mechanical, and inflammatory processes that accelerate atrial apoptosis and fibrosis. Once atrial scarring appears, an increased incidence of non-PV triggers, drivers, and areas for reentry and endo-epicardial dissociation are also seen; this new atrial configuration becomes the substrate around which stable rotational activity may occur, and maintenance of this activity may allow the perpetuation of the arrhythmia as persistent AF.^3,4 Clinical progression from a paroxysmal to a persistent form of AF occurs in 10% to 20% of the AF patient population at 1 year.⁵ Notably, recent evidence suggests a worse prognosis associated with AF progression related not only to the occurrence of thromboembolic events, but also to the electromechanical dysfunction related to the persistence of the arrhythmia.⁶ On this basis, there is a biological reason to believe that restoration and maintenance of sinus rhythm could prevent further pathologic changes; hence, opting for an earlier rhythm control strategy that includes more aggressive control of modifiable risk factors and consideration for early referral for ablation has been associated with a 10-fold lower chance of progression to persistent AF when compared to medical therapy alone.⁷ 

Pulmonary Vein Isolation

Durable PVI is essential to obtain adequate outcomes after catheter ablation. Although success rates are lower than in paroxysmal AF, PVI alone for persistent AF has been demonstrated to be effective therapy, as it has been consistently shown to be superior in reducing atrial arrhythmia burden, improving quality of life, and possibly improving survival when compared to AAD therapy.² The effectiveness of ablative therapy for persistent AF appears to be driven by the duration of continuous AF and the extent of atrial myopathy and substrate. However, PVI alone can potentially provide a 66% freedom from atrial arrhythmia recurrence at 1 year. More importantly, these outcomes are expected to improve as mapping and ablation technology continues to evolve. In recent years, adoption of wide antral ablation incorporating larger portions of the posterior wall of the left atrium (as opposed to ostial or segmental ablation), the introduction of contact force catheters, ablation algorithms that allow for accurate estimation of ablation volume and interlesion distance such as lesion size index (LSI, Abbott) and ablation index (VISITAG SURPOINT, Biosense Webster, Inc.), and the use of high-power short-duration (HPSD) ablation has allowed operators to deliver more efficient lesions with less likelihood of discontinuities. This has resulted in improved success rates when using radiofrequency catheter ablation. Concurrently, development of the second-generation cryoballoon with a larger and more homogeneous freezing zone has similarly resulted in more durable isolation and incorporation of a wider area of LA myocardium, resulting in similar success rates than those with RF. The near future is promising, as outcomes of PVI may continue to improve with forthcoming novel technology such as the development of catheters capable of delivering very HPSD ablation lesions, one-shot isolation radiofrequency balloons, large thermal footprint temperature control catheters, and the introduction of tissue electroporation as ablative energy.  

Mechanistically, PVI is a more effective procedure in paroxysmal AF patients, in whom spontaneous PV firing is frequently the only trigger for AF paroxysms, than those with persistent AF in whom atrial complex structural and electrophysiological changes may have already occurred. To date, there is no strict consensus on an ideal adjunctive ablation strategy in addition to PVI in patients with persistent AF. Several ablation strategies have been proposed to increase success rates among patients with persistent AF, including additional linear ablation mimicking surgical AF ablation and substrate modification by ablation of continuous fractionated electrograms (CFAEs) and organized rotational activity; however, none of these approaches have been definitively shown to be superior to PVI alone. 

Ablation of Non-PV Triggers 

Triggers are important for initiation of AF, as is substrate for maintenance of persistent AF. Non-PV triggers are ectopic beats emanating from structures other than PVs capable of inducing AF, and tend to cluster at sites such as the left atrial posterior wall, ligament of Marshall, superior vena cava (SVC), coronary sinus (CS), crista terminalis, interatrial septum, and the left atrial appendage (LAA); these structures may have myocardial cells capable of automatic depolarization or providing a substrate for micro-reentry. Moreover, non-PV triggers may be responsible for late recurrences observed in patients after paroxysmal and persistent AF ablation procedures. The prevalence of non-PV triggers is variable among different studies, and may be dependent on the definition of “significant” non-PV triggers, induction protocol, and mapping techniques. Whereas some consider significant non-PV triggers to be ectopic or sustained atrial arrhythmias capable of inducing AF, others consider them to be frequent ectopic or non-sustained atrial arrhythmias during protocol induction. Typically, for induction of non-PV triggers, high doses of isoproterenol are required (20-30 µg/min for 10-15 min, with concomitant adequate pressor support), and ablation of these triggers is mostly done by a focal ablation approach, although some operators may prefer complete electrical isolation of structures such as the posterior wall, SVC, CS, or LAA.⁸ 

Posterior Wall Isolation (PWI)

The LA posterior wall is an important structure involved in the initiation and maintenance of AF due to its unique intrinsic properties. Given the common embryologic background between the PV and LA posterior wall, it is not surprising that they may share similar arrhythmogenic potential.⁹ The LA posterior wall exhibits a significant amount of electroanatomical substrate known to house a high incidence of non-PV triggers and rotors in patients with persistent AF. In addition, stimulation of the main autonomic ganglionic plexi located within the epicardial fat pads of the LA posterior wall are known to play an important role in triggering and maintaining AF activity.¹⁰ Importantly, ablating the posterior wall may have more benefits than simply isolating arrhythmogenic foci. It has been suggested that atrial substrate size may be important in the maintenance of fibrillatory activity and that reducing the surface area below a critical mass can prevent persistent AF.^11,12 All of the above has led to a greater interest in pursuing PWI as an adjunctive strategy to PVI. However, clinical evidence has not been consistent in demonstrating a superior outcome in those patients undergoing PWI; a recent randomized study showed a trend toward worse outcomes among those patients with PWI¹³, while other groups have shown that among patients with proven persistent PVI along with PWI, a higher freedom of atrial arrhythmias is achieved.¹⁴ Therefore, effective lesions aiming at transmurality along with appropriate confirmation of entrance and exit block with high-output pacing may be crucial to ensure there is no epicardial conduction or residual gaps, and achieve improved outcomes. 

LAA Isolation

Recently, there has been a growing interest in the arrhythmogenic role of the LAA in triggering and sustaining AF, particularly in patients with persistent and longstanding persistent AF (LSPAF) or with recurrence of AF after a prior ablation procedure. Similarly, the LAA has been recognized as an important source for non-PV triggers, with a previous study¹⁵ showing that 27% of patients had focal firing from the LAA, but that the LAA was the only source of arrhythmia in 8.7% of patients. More importantly, this study demonstrated that complete electrical isolation of the LAA was superior to focal ablation.¹⁵ In this context, empiric LAA electrical isolation (LAAEI) by catheter ablation has previously been shown to significantly improve atrial arrhythmia-free survival rates in patients with LSPAF.¹⁶ LAAEI can be achieved with RF ablation by ostial ablation of the LAA or by creating a posterolateral mitral isthmus line and anterior line. Conversely, it can also be performed with cryoablation, or by percutaneous or surgical LAA excision. Unquestionably, LAAEI has not been embraced by a significant portion of the EP community due to its procedural complexity and concerns of an increased incidence of other organized atrial arrhythmias, procedural complications, and risks of thromboembolic events owing to loss of LAA contractility after LAAEI. However, when performed by experienced operators, and when patient compliance to OAC or subsequent LAA occlusion is ensured, the risks for complications are low. As such, LAAEI could be suitable for those patients undergoing redo ablation procedures in whom persistent PVI has been proven, other non-PV triggers have been targeted, compliance to OAC can be ensured, or in patients who are candidates for LAA occlusion.^17,18 

Conclusion

AF ablation is an effective therapy for patients with persistent AF. Durable PVI is essential to obtain adequate outcomes after catheter ablation; however, in patients with persistent AF in whom heterogeneous atrial complex structural and electrophysiological changes may have already occurred, concomitant tailored ablation in addition to PVI may be necessary to improve outcomes. 

Disclosures: The authors have no conflicts of interest to report regarding the content herein. Outside the submitted work, Dr. Hsu reports honoraria from Medtronic, Abbott, Boston Scientific, BIOTRONIK, Biosense Webster, Janssen Pharmaceuticals, AltaThera, Bristol-Myers Squibb, and ZOLL Medical; he has received research grant support from BIOTRONIK and Biosense Webster, and owns equity in Acutus Medical and Vektor Medical. 

Contact the authors on Twitter: Florentino Lupercio (@tinolupercioMD) and Jonathan C. Hsu (@JonHsuMD)

Erratum: Please note the title of this article was incorrectly listed as "Catheter Ablation of Paroxysmal AF" on EPLD's May 2020 cover. The correct abbreviated title is "Catheter Ablation of Persistent AF." We sincerely regret the error.   

Exclusive Online Content - Watch Dr. Lupercio and Dr. Hsu discuss this article in a video commentary:

1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837-847.
2. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythm. 2017;33:369-409.
3. Jalife J, Berenfeld O, Mansour M. Mother rotors and fibrillatory conduction: a mechanism of atrial fibrillation. Cardiovasc Res. 2002;54:204-216.
4. Kawai S, Mukai Y, Inoue S, et al. Non-pulmonary vein triggers of atrial fibrillation are likely to arise from low-voltage areas in the left atrium. Sci Rep. 2019;9:12271.
5. Proietti R, Hadjis A, AlTurki A, et al. A systematic review on the progression of paroxysmal to persistent atrial fibrillation: shedding new light on the effects of catheter ablation. JACC Clin Electrophysiol. 2015;1:105-115.
6. Steinberg BA, Hellkamp AS, Lokhnygina Y, et al. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. Eur Heart J. 2015;36:288-296.
7. Kuck KH, Lebedev D, Mikaylov E, et al. Catheter ablation delays progression of atrial fibrillation from paroxysmal to persistent atrial fibrillation. ESC Late-breaking Science 2019 Paris, France August 31, 2019.
8. Gianni C, Mohanty S, Trivedi C, Di Biase L, Natale A. Novel concepts and approaches in ablation of atrial fibrillation: the role of non-pulmonary vein triggers. Europace. 2018;20:1566-1576.
9. Douglas YL, Jongbloed MR, Gittenberger-de Groot AC, et al. Histology of vascular myocardial wall of left atrial body after pulmonary venous incorporation. Am J Cardiol. 2006;97:662-670.
10. Lupercio F, Lin AY, Aldaas OM, et al. Role of adjunctive posterior wall isolation in patients undergoing atrial fibrillation ablation: a systematic review and meta-analysis. J Interv Card Electrophysiol. 2019 Oct 31 [Epub ahead of print].
11. Zou R, Kneller J, Leon LJ, Nattel S. Substrate size as a determinant of fibrillatory activity maintenance in a mathematical model of canine atrium. Am J Physiol Heart Circ Physiol. 2005;289:H1002-12.
12. Lee AM, Aziz A, Didesch J, Clark KL, Schuessler RB, Damiano RJ Jr. Importance of atrial surface area and refractory period in sustaining atrial fibrillation: testing the critical mass hypothesis. J Thorac Cardiovasc Surg. 2013;146:593-598.
13. Lee JM, Shim J, Park J, et al. The electrical isolation of the left atrial posterior wall in catheter ablation of persistent atrial fibrillation. JACC Clin Electrophysiol. 2019;5(11):1253-1261.
14. Bai R, Di Biase L, Mohanty P, et al. Proven isolation of the pulmonary vein antrum with or without left atrial posterior wall isolation in patients with persistent atrial fibrillation. Heart Rhythm. 2016;13:132-140.
15. Di Biase L, Burkhardt JD, Mohanty P, et al. Left atrial appendage: an underrecognized trigger site of atrial fibrillation. Circulation. 2010;122:109-118.
16. Di Biase L, Mohanty S, Trivedi C, et al. Stroke risk in patients with atrial fibrillation undergoing electrical isolation of the left atrial appendage. J Am Coll Cardiol. 2019;74:1019-1028.
17. Nishimura M, Lupercio-Lopez F, Hsu JC. Left atrial appendage electrical isolation as a target in atrial fibrillation. JACC Clin Electrophysiol. 2019;5:407-416.
18. Romero J, Michaud GF, Avendano R, et al. Benefit of left atrial appendage electrical isolation for persistent and long-standing persistent atrial fibrillation: a systematic review and meta-analysis. Europace. 2018;20:1268-1278.
19. Kirchhof P, Calkins H. Catheter ablation in patients with persistent atrial fibrillation. Eur Heart J. 2017;38(1):20-26.