Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05296824 |
| Other study ID # |
IMPPROVE-PAF |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2014 |
| Est. completion date |
December 31, 2021 |
Study information
| Verified date |
March 2022 |
| Source |
Sacramento EP Research |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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, we 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
(A. Aryana) between 1/1/2014 and 8/31/2018 at Mercy General Hospital.
Description:
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, we 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.
Markides et al. 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,
Mandapati et al. 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.
