Cryoballoon ablation has emerged as a safe and effective strategy for treatment of atrial fibrillation (AF) for which it has recently received a 'first-line' therapy indication by the FDA. Pulmonary vein (PV) isolation (PVI) has been the cornerstone of this procedure achieving freedom from recurrent AF in up to ~80% of patients at 12 months of follow-up. However, the success has been shown to be significantly lower, in the range of 50-60% at 3-5 years of follow-up. Other more recent cryoballoon ablation studies have demonstrated marked improvements in clinical outcomes associated with concomitant PVI and cryoballoon ablation/isolation of the 'PV component' (a region of the left atrial posterior [back] wall lying between the PVs that is anatomically and embryologically related to the PVs), versus PVI alone in patients with persistent AF.

PVI+PWI using cryoballoon ablation has been widely-practiced in patients with paroxysmal AF. However, the acute/long-term safety and efficacy of this approach has not been formally investigated in paroxysmal AF. Given the mechanistic similarities between persistent and paroxysmal AF, the investigators hypothesize that similar benefits associated with PVI+PWI may also be observed in those with paroxysmal AF. Yet, due to the relative infrequency of breakthrough/recurrent arrhythmias in patients with PAF, to detect a significant difference, large sample sizes and extended follow-up (>24 months) are likely needed. Hence, the aim of this retrospective, observational study is to examine the acute and long-term efficacy and safety beyond 36 months of follow-up associated with PVI alone versus PVI+PWI using cryoballoon ablation in a large cohort of patients with PAF, performed by a single operator between 1/1/2014 and 8/31/2018 at Mercy General Hospital.

INTRODUCTION AND RATIONALE Cryoballoon ablation has emerged as a safe and effective strategy for the treatment of atrial fibrillation (AF), and based on growing evidence, it recently received an initial rhythm control strategy ('first-line' therapy) indication by the Food and Drug Administration. Pulmonary vein (PV) isolation (PVI) guided typically by cryoballoon PV occlusion remains the cornerstone of cryoballoon ablation. Although single-procedure freedom from recurrent AF following such an approach has been reported to be as high as 82% at 12 months, the success appears to be markedly diminished in the range of 50-60% during long-term follow-up. This in part may be related to the inherent limitations of cryoballoon ablation which often yields an ostial (distal) level PVI. Along these lines, prior investigations have found wide-area antral PVI encompassing the PV component (i.e., the region of the posterior wall lying between the PVs) to be superior to ostial PVI. Other more recent studies involving the cryoballoon have demonstrated marked improvements in clinical efficacy associated with concomitant PVI and posterior wall isolation (PWI) within the region of the PV component as compared to PVI alone, in patients with persistent AF. Though widely-practiced, this approach has not been formally investigated in patients with symptomatic paroxysmal AF (PAF). Given the mechanistic similarities between persistent and PAF, the investigators hypothesize that similar benefits may also be observed with PVI+PWI in the patients with PAF. Yet, given the relative infrequency of breakthrough/recurrent arrhythmias in patients with PAF, to detect a significant difference, large sample sizes and extended follow-up (>24 months) are likely needed. Hence, the aim of this retrospective, observational study is to examine the clinical efficacy and safety of PVI alone versus PVI+PWI using cryoballoon ablation, in a large cohort of patients with symptomatic PAF beyond 36 months of follow-up.

EMBRYOLOGIC EVIDENCE The PV component of the posterior left atrial wall shares a common primordial origin with the PVs. The embryologic origin of the four PVs and the PV component can be traced back to the mediastinal myocardium derived from a mid-pharyngeal strand at 6 weeks of gestation. Early on during development, a single primitive vein returns blood from the lungs to the common trabeculated atrium. As the interatrial septum forms, the single vein divides twice to give rise to the four PVs. As the PV ostia migrate away from one another, the smooth tissue of the posterior left atrial wall forms. Although this region is anatomically contiguous with the surrounding trabeculated tissue from the primitive left atrium, its embryologic origin results in electrophysiologic properties that are more similar to the muscular PV sleeves than the immediately adjacent atrial roof or floor ('true' posterior wall).

During embryogenesis, the single vein and its surrounding tissue (in addition to the Bachmann's bundle and sinus venosus-derived structures) demonstrate the expression of genes responsible for development of cardiac conduction system. Although expression of these genes decreases during embryogenesis, it is hypothesized that their continued low-level expression may explain why certain regions within the atria are more commonly the site of origin of focal ectopy. These embryologic characteristics would certainly explain the well-accepted clinical observation that AF is frequently initiated by ectopic beats arising from the PVs and the increasingly reported observation that ectopic beats from the left atrial posterior wall can similarly initiate AF.

ANATOMIC EVIDENCE A visual examination of the PV component and the orientation of its myofibrils suggests direct continuity between this region and the PV antra as does a gross anatomical assessment of certain left atrial morphologies. Meanwhile, underneath the smooth endocardial surface of the PV component, numerous subendocardial and subepicardial muscular bundles traverse with varying fiber orientation. Fibers immediately surrounding the PVs typically encircle the veins, whereas those in the subepicardial aspect of the posterior wall are comprised of the septo-pulmonary bundle and display a more vertical or oblique orientation. Immediately adjacent to the lateral aspect of the septo-pulmonary bundle are found transversely oriented fibers which extend to the left PV ostia. It is this change in orientation that is believed to promote anisotropic conduction and therefore reentry.

Prior investigators have found that in patients with PAF, this juxtaposition of fiber orientations was associated with isochronal crowding and functional block depending on the direction of wave front propagation during sinus or paced rhythm. Similarly, mapping of fibrillatory waves during cardiac surgery in patients with AF has revealed simultaneous propagation of longitudinally dissociated fibrillation waves which are separated by continuously changing lines of block. These lines of block are once again most densely packed in the PV component, leading to the highest degree of block and dissociation and the lowest incidence of wave front boundaries formed by collision.

ELECTROPHYSIOLOGIC EVIDENCE As discussed, the PV component is derived from tissues other than the primitive cardiac tube. Hence, the PV component is believed to be related more to PV versus atrial tissue. Some studies have suggested that these tissues share more in common with the sinoatrial nodal myocytes, displaying higher diastolic calcium contents and propensity to spontaneous depolarization. Furthermore, the PV component exhibits increased conduction abnormalities, a higher incidence of delayed after depolarizations and larger late sodium and intracellular and sarcoplasmic reticulum Ca++ contents, but a smaller inward rectifier potassium currents and a reduced resting membrane potential. The posterior wall and the PV myocytes are also characterized by shorter action potential durations and slower phase 0 upstroke velocities. As such, the PV component is believed to be the site of collision of activation wave fronts as they sweep across the left atrial dome. Along these lines, prior Investigators have found this region of the left atrium to be responsible for 80% of high-frequency rotors in an isolated sheep heart model. Similarly, mapping in humans often localizes stable rotors or focal sources as well as complex fractionated electrograms in the posterior wall and the left atrial roof. The PV component has in fact been shown to be a common source of triggers accounting for up to ~40% of non-PV triggers in patients with AF.

Lastly, the PV component is also the site of the main autonomic ganglionic plexi related to the left atrial dome (i.e., the superior left atrial ganglionated plexus) which is believed to modulate extrinsic cardiac innervation and facilitate the occurrence of AF in a hyperactive autonomic state. As such, it is believed that catheter ablation of the PV component also greatly attenuates the input of these plexi to the PVs, interrupting the vagosympathetic input to the ligament of Marshall and the inferior left ganglionated plexus which have been highly implicated in the pathogenesis of AF.

Inclusion Criteria:

• Age 18 years or older
• Cryoballoon PVI+PWI
• Cryoballoon PVI alone
• Symptomatic paroxysmal atrial fibrillation

Exclusion Criteria:

• None

Patients with symptomatic paroxysmal atrial fibrillation

36 months

All subjects' electronic medical records were reviewed for any adverse events or serious adverse events for the 36 month time period following the index ablation.

Nonrandomized analysis despite extensive cohort matching may have confounded either treatment arm; PVI used during initial study phase & later PVI+PWI was used; Follow-up ambulatory ECG monitoring may have failed to detect asymptomatic atrial arrhythmia recurrences; use of implantable cardiac devices vs continuous monitoring; Asymptomatic expressions of certain complications (e.g., esophageal lesions or PV stenosis) could not be entirely excluded as routine diagnostic tests were not performed.