Converging Towards an Effective Cure for Persistent AF: A Review of Techniques, and the Case for a First-Line Multidisciplinary Approach

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and the treatment of AF has been a work in progress over the years.¹ Although the majority of triggers in paroxysmal AF are believed to originate from the pulmonary veins, non-pulmonary vein triggers and other arrhythmogenic substrates have an increased role in persistent and longstanding persistent AF. Given the heterogeneity of AF sources and mechanisms, a consistently effective endocardially-based treatment strategy has been elusive. 

Review of Current Approaches

Pulmonary Vein Isolation (PVI)

The cornerstone for AF ablation has been the isolation of the pulmonary veins. PVI has proven to be effective for the ablation of paroxysmal AF since the majority of paroxysmal AF triggers originate from the PVs; however, multiple procedures are frequently required to achieve a satisfactory result. A 2009 meta-analysis reported a 57% overall single-procedure success rate off antiarrhythmic drug therapy and a 71% multiple-procedure success rate off antiarrhythmic therapy.² Patients with persistent AF have even lower rates of success. Another meta-analysis reported a single-procedure success rate of 50.8% at one year and 41.6% success at 3 years for patients with persistent AF.³

One of the major reasons why AF recurs is because of lesion gaps around the PVs. Complete circumferential antral ablation scar was only seen in 7% of patients in a delayed-enhancement MRI study.⁴ PV reconnections were noted in 417 of 423 patients who underwent repeat ablation.³ Most of these patients had paroxysmal AF. Recent technology has focused on effective delivery of contiguous circumferential lesions around the PVs: force-sensing radiofrequency ablation catheters, cryoballoon, circular ablation catheters, and laser balloon. While recent results are encouraging, the majority of the treated patients had paroxysmal AF and the most optimal strategy for treating persistent AF has yet to be determined. 

Linear Ablation and Complex Fractionated Atrial Electrogram Ablation

Most electrophysiologists create linear lesions in addition to PVI in patients with persistent AF. PVI alone has a single-procedure drug-free success rate of approximately 22% at 2 years.⁵ Creation of a left atrial roof line, mitral isthmus line, and right intercaval and/or cavotricuspid isthmus lines add to the success of AF ablation. However, there appears to be a limit to the benefit of linear ablation due to the risk of creating an incomplete line. Bidirectional block across a mitral isthmus line can be particularly difficult to achieve. If a line is incomplete, a zone of slow conduction would allow for macro-reentrant atrial tachycardias to develop. The addition of complex fractionated atrial electrogram (CFAE) ablation showed initial promise; however, recent analyses have not found CFAE ablation to be useful as an adjunct or solo strategy.⁶

Rotors

Rotors are areas of functional reentry which drive AF. Atrial tissue remodeling and fibrosis are thought to facilitate and stabilize rotor formation. The posterior wall and the regions around the PVs harbor the majority of rotors and focal drivers.⁷ Data from the CONFIRM trial (72% of patients had persistent AF) demonstrated that focal impulse and rotor modulation-guided therapy achieved a higher freedom from any atrial tachyarrhythmia than conventional ablation only (70.6% vs 39.1%; P=0.001).⁸ Unfortunately, a recent single-center experience could not replicate the same success.⁹ An additional concern is that while the concept of rotor ablation treats the active functional trigger/mechanism of AF, it may not prevent the future development of AF substrate. 

The Stress/Stretch-Fibrosis Hypothesis

To better treat AF, one should perhaps ask why AF develops. Since the progressive geographic distribution of atrial remodeling is often similar,¹⁰ it may indicate a common mechanism for the creation of AF substrate. The frequently implicated areas of AF triggers and rotors appear to parallel areas of high stress near the pericardial reflections (Figure 1). This does not appear to be mere coincidence. The pericardium supports the heart against gravity and is attached to the posterior left atrium, inferior vena cava, superior vena cava, and PVs. The mismatch of elasticity modulus between stiffer pericardial tissue and more elastic atrial tissue favors stress-mediated tissue remodeling. Tension between the regions of elasticity mismatch may cause atrial stretch and the activation of signaling pathways that cause interstitial fibrosis and perivascular fibrosis. 

There is growing literature that atrial fibrosis is a common feature of AF. Increased collagen deposition has been documented in patients with AF versus patients in sinus rhythm without AF.¹¹ Atrial fibrosis interrupts fiber-bundle continuity and causes local conduction disturbances and the formation of reentry circuits which may promote AF.¹² The left atrium surrounding the PVs is a particularly frequent area for interstitial fibrotic changes.^13-15 Additionally, stretch-sensitive ion channels have been shown to mediate rapid firing from the PVs.¹⁶

Epicardial Fat

Recent studies have also implicated epicardial fat in the creation of AF substrate. Adipose tissue is frequently found in the atrioventricular and interventricular grooves extending to the apex of the heart.¹⁷ (Figure 2) There are also minor regions of fat that are located subepicardially around the 2 appendages and in the free walls of the atria. Epicardial fat may have direct electrophysiologic effects as well as possible paracrine effects by cytokines or other signaling molecules.¹⁸ Epicardial adipose tissue express a wide range of inflammatory mediators and demonstrate increased activity of matrix metalloproteinases which likely contribute to interstitial fibrosis,^19,20 Since epicardial fat is often associated with fatty infiltration deep into the myocardial tissue, this disorganized tissue may contribute to local arrhythmogenic substrate. 

Ganglionated Plexi

Epicardial fat also contains a rich supply of autonomic ganglionated plexi (GP), which has gained attention in the creation of AF substrate. GPs are found embedded along the ligament of Marshall, along the great vessels, at the right superior PV-atrial junction, at the left superior PV-atrial junction, at the left inferior PV-atrial junction, and at the junction of the inferior vena cava and both atria.^21,22 (Figure 2) GP stimulation by the autonomic nervous system has been hypothesized to release neurotransmitters that increase PV ectopy,²³ reduce PV sleeve action potential duration,²⁴ and shorten the fibrillation cycle length.²⁵ These factors appear to stimulate triggers and enable the perpetuation of AF.²⁶ The ablation of GP in addition to PVI confers significantly higher success rates in patients with paroxysmal and persistent AF.^27,28 

Surgical Ablation

How much better is a surgical approach? Ninety-five percent of patients who had undergone the cut-and-sew Maze III procedure were in normal sinus rhythm after 5 years of follow-up.²⁹ The physical separation and electrical compartmentalization of the atrium is perhaps the most effective method to cure AF; however, it is the most invasive. Short of that, other surgical approaches have been developed to mimic the cut-and-sew lesion set. In a mixed population of paroxysmal and persistent AF patients, an endocardial Cox-Maze with cardiopulmonary bypass support yielded an 87% success rate off antiarrhythmic medications at 1 year of follow-up, whereas a thoracoscopic epicardial surgical ablation yielded a 72% success rate.³⁰ Patients with persistent AF achieve only a 39-62% success rate with epicardial surgical ablation off antiarrhythmic drugs at 6 months.³¹ In addition, there appears to be a higher incidence of pacemaker implantation in patients undergoing surgical ablation.³² Therefore, thoracoscopic epicardial ablation alone does not appear to have a significant advantage over endocardial ablation. 

Favorable Experience with the Convergent Procedure

The strengths of an endocardial and surgical approach have been combined in what is called the Convergent Procedure. This procedure utilizes a transdiaphragmatic cannula and the EPi-Sense^® Guided Coagulation System with VisiTrax (nContact, Inc.). The EPi-Sense device is used to create epicardial lesions along the entire posterior wall and around the PVs. The pericardial reflections limit the epicardial ablation of the superior aspect of the veins and the region below the right inferior PV. The lesion set is therefore completed endocardially by an electrophysiologist and bidirectional block is confirmed across the veins (Figure 3). A right cavotricuspid isthmus line is also created. 

This lesion set encompasses the posterior wall and therefore treats the gamut of AF mechanisms and triggers. The epicardial and endocardial approach to PVI increases the chances for a durable transmural isolation. (Figure 4) In addition, the epicardial ablation across the posterior wall creates an effective roof line and posterior box while minimizing the concern for collateral damage to the esophagus. Rotors and CFAEs in the posterior wall and around the pulmonary veins would be eliminated. Regions of epicardial fat and GP are also eliminated. 

The Convergent Procedure has reproducibly yielded excellent results at 1 year ranging 79%-95% with antiarrhythmic therapy and 64%-81% off antiarrhythmic therapy (repeat ablation rate ranging 2%-8%).³³ The effectiveness of this procedure may be multifactorial: successful creation of electrical block, the modulation of autonomics via ablation of epicardial fat and GP, and debulking of the left atrium. Debulking of the posterior left atrium may serve to eliminate AF on the basis of the critical mass hypothesis.³⁴ It has been suggested that the probability of sustaining AF may be directly related to the atrial substrate size. Reducing the atrial area below a critical atrial mass may prevent sustained AF.³⁵ Additionally, the lesion set of the Convergent Procedure encompasses high stress areas bordered by the pericardial reflections which may prevent the progression of disorganized fibrosis and future triggers and substrates of AF. 

Since 2012, Maimonides Medical Center has been performing Convergent AF ablation with excellent results in patients with persistent AF. We generally perform the Convergent Procedure in a single anesthesia setting in one of our hybrid operating rooms. Following the procedure, a pericardial drain is left overnight and 2mg/kg of triamcinolone in 45cc of warm saline is instilled into the pericardial space for 12-24 hours before drain removal. Colchicine is also prescribed for one month. We have experienced a very low rate of pericarditis (2 of 49 patients) using this protocol. Having performed the procedure in 49 patients, we have achieved a 70-80% freedom from atrial tachyarrhythmias with a single procedure. Only 6 patients had a prior history of AF ablation. Eight patients underwent repeat endocardial ablation, increasing the freedom from atrial tachyarrhythmias to ~90%. Three of these patients had atrial tachyarrhythmias from the vein of Marshall region, which in 2 patients were successfully treated using alcohol ablation. The overwhelming majority of patients are off antiarrhythmic therapy. There have been no cases of phrenic nerve palsy, esophageal fistulas, strokes, or deaths. Our experience has been in line with other studies utilizing the Convergent Procedure. 

Conclusion

Persistent AF is often the end result of abnormal atrial remodeling that has created areas of abnormal automaticity and a tissue substrate that can maintain fibrillatory activity. Whether or not a specific individual is able to sustain AF due to PV triggers, perivenous or posterior wall rotors, or contributions from epicardial fat and GP, the Convergent Procedure lesion set appears to treat the vast majority of these factors. Early results of this multidisciplinary approach to treat this multifaceted disease process have been very favorable. 

Disclosures: The author has no conflicts of interest to report regarding the content herein.   

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