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.
