Disclosures
No funding sources are relevant to this piece of work, and there are no
conflicts of interest to disclose.
Pulmonary vein (PV) isolation (PVI) remains the foundation of atrial
fibrillation (AF) ablation, however, PVI durability remains lower in
persistent compared with paroxysmal AF, irrespective of ablation
strategy.[1] Indeed, despite demonstrable atrial electroanatomical
remodeling, thought to be a major driver of AF maintenance, substrate
modification techniques have not improved ablation outcomes beyond
PVI-alone in persistent AF.[2,3].
The question of the extent to which pulmonary vein electrical activity
continues to contribute the maintenance of AF, rather than simply a
trigger for its initiation, still remains largely unanswered.
Alternatively, pulmonary vein electrical activity may simply be a
‘passive’ marker of atrial substrate, rather than an active determinant
of AF outcomes. A significant part of the problem is the absence of a
reliable, reproducible and feasible method to characterise pulmonary
vein activity. It is in this context, that Spera and colleagues propose
a novel approach to assessing pulmonary vein activity in AF.
Spera and colleagues propose a novel, non-automated methodology
for AF CL evaluation, coined the FARS10-CL measurement,
with the objectives of (1) evaluating the intra-observer reproducibility
of this novel measurement approach; (2) comparison with traditional AF
CL measurements; and (3) determining the predictive performance of the
FARS10-CL measurement on long-term outcomes following
wide antral PVI-only ablation in a prospective cohort of 100 patients
with persistent AF. Measurements were conducted offline using manual
method of measuring the mean of 10 consecutive “Fastest Atrial
Repetitive Similar morphology signal CL” within a 1-minute
observational window. Selection of the fastest 10 consecutive CLs was
performed manually using visual assessment.
The study reported a high degree of intra-observer reproducibility
utilising repeated FARS10-CL measurement across various
left and right atrial structures and when compared with traditional AF
CL measurement methodologies and a low reproducibility of traditional AF
CL measurement of consecutive continuously fragmented CS signals.
Few studies have examined the relationship between AF cycle length (CL)
and ablation outcomes with reported discrepant findings. Pascale et al
performed a retrospective analysis of 97 patients with persistent AF and
determined a PV to left atrial (LA) appendage (LAA) ratio
<69% predicted acute AF termination and was associated with
more favourable ablation outcomes.[4] Conversely, Prabhu et al
prospectively analysed 123 patients undergoing PVI with posterior wall
isolation and found no clear association between PV activity and AF
ablation outcomes in persistent AF.[5] Both studies involved
non-automated PVCL measurement averaged over 100 consecutive beats.
These seemingly contrasting findings are likely driven by a paucity of
data, relatively small population size and a distinct lack of a
standardised approach to PVCL measurement. This is in part due to
varying morphology and amplitude, significant CL fluctuations including
sudden accelerations and organised activity, presence of fractionation
obfuscating the dominant wavefront and poor inter-observer variability.
PV activity and AF recurrenceThe authors determined that a PV-FARS10-CL threshold of
140ms (PV-FARS10-CL >140ms reflecting
slower PV activity) in the fastest PV was associated with more marked
atrial substrate (characterised by high burden low voltage zone (LVZ)
during LA electroanatomical mapping) and was a good predictor for
arrhythmia recurrence.
Perhaps not surprisingly, patients with faster PV activity
(PV-FARS10-CL < 140ms) had more
favourable clinical characteristics including younger age, lower
CHADS2VASc score, small LA volume, less prevalent coronary artery
disease, a greater likelihood of AF termination during PVI and a lower
likelihood of arrhythmia recurrence. The authors suggested that regions
of faster PV activity (PV-FARS10-CL< 140ms) may reflect host drivers of persistent AF,
which may help to identify individuals in whom a PVI-only strategy may
be favourable.
When analysed by LVZ extent, individuals with a higher burden of LVZ
(>16%) had higher CHADS2VASc score, lower left ventricular
(LV) ejection fraction (LVEF) LVEF and slower
PV-FARS10-CL. Moreover, of those with high burden LVZ,
none met the critical threshold of PV-FARS10-CL< 140ms.
This analysis confirms the findings from previous studies that slower PV
activity is associated with higher burden atrial substrate. Moreover,
they reported relatively normal FARS10-CL measurements
in other atrial structures including the SVC, RAA and LAA, despite
slower PV activity, suggesting a possible preferential impact of LVZ on
PV activity. They posited that slower PV activity may reflect regional
PV electrical and structural remodeling preceding the remaining LA
regions or may indicate the absence of fast PV drivers in patients with
high LVZ burden. Additionally, while those with slow PV activity were
more likely to have high burden LVZ and lower mean LVEF, as reported in
previous studies,[6] the relationship between slower
PV-FARS10-CL activity and high LVZ burden extended to
those with mid-range and normal EF without heart failure (HF),
highlighting the utility of PV activity as a reliable and reproducible
surrogate of atrial remodeling, irrespective of HF status.
Interestingly, while a high burden of LVZ, reflective of more advanced
atrial substrate, was associated with slower
PV-FARS10-CL along with traditional markers of AF
recurrence, namely higher LA volume and CHADS2VASc score and lower LVEF,
slower activity (FARS10-CL >140ms) was the
only independent predictor of arrhythmia recurrence and faster PV
activity was associated with greater arrhythmia-free survival (85% vs
59% at 24 months, p=0.0018).
The finding of FARS10-CL < 140ms as the
sole predictor of freedom from AF recurrence, where traditional
predictors appeared to be non-contributory, is worthy of note, yet may
be attributable to the relatively small and heterogeneous study
population and the relative underrepresentation of the
FARS10-CL group < 140ms, which comprised
only 27% of overall study population. One might expect that high LVZ
burden would independently predict AF recurrence given the strong
correlation between high LVZ burden and slower PV activity and the fact
that high LVZ burden was only observed among those with
PV-FARS10-CL >140ms. This would support the
well described relationship between atrial remodeling and AF recurrence
following PVI.[7,8] Moreover, previous studies have demonstrated an
association between limited LA low voltage and AF termination during
PVI, suggesting the absence of atrial low voltage or atrial remodeling
may identify a subset of patients in whom PVI alone may
suffice.[9,10]
Indeed, previous studies have reported significant associations between
clinical predictors (patient factors, AF duration and LA
characteristics) and AF ablation outcomes,[11] and given the small
sample size and low prevalence of high burden LVZ in this study, this
apparent finding probably warrants further exploration in larger
studies, powered to more rigorously evaluate this relationship.
While the 24-month study follow up certainly provided more robust
longitudinal evaluation of long-term outcomes, the reported
arrhythmia-free survival is considerably higher than one would expect
for an exclusively persistent AF population, given the mounting evidence
from observational and randomised studies of AF ablation and outcomes in
persistent AF.[8,12] This may be in part due to advances in ablation
technologies and techniques as outlined by the study authors, though
more likely reflects the lack of continuous or remote ambulatory rhythm
monitoring as has been pursued in other similar studies of this nature,
which almost certainly underestimates the true event rate and would not
capture subclinical AF recurrence episodes.
One of the major issues recognised by the study authors was the effect
of uninterrupted antiarrhythmic drug (AAD) therapy on PV CL assessment;
whereby continued AAD therapy could potentially accentuate PVCL slowing
in a heterogeneous fashion among individuals or groups. This is
particularly relevant, given the subsequent analysis of clinical
outcomes relies on a critical PVCL threshold, which may be confounded by
a differential effect of AAD therapy.
Furthermore, existing methods, predominantly utilising offline,
non-automated analysis, propose varying approaches to PVCL
measurement.[4,5] The challenge of manually annotating the dominant
wavefront lies in the chaotic nature of fibrillatory activity, which
itself limits reproducibility owing to both intra- and inter-observer
variability. This could be overcome by automated cycle length analysis
which might provide intra-procedural data which could be valuable in
guiding real-time decision-making with respect to ablation strategy.
Future studies could integrate existing methods to automated PVCL
analysis and enhance the translational impact of PVCL evaluation into
clinical management.
Overall, the authors are to be commended for a novel and informative
analysis that fills a significant knowledge gap and may enhance the
mechanistic understanding of drivers in persistent AF. This is the first
study to evaluate the performance of a novel methodology compared to
previously described methods. Moreover, this builds on exists work
exploring predictors of long-term durability of a PVI-alone strategy in
persistent AF and may help to stratify which individuals with persistent
AF patients may benefit from PVI-alone or additional ablation
strategies.
This analysis strengthens the concept of PV slowing as a reflection of
atrial remodeling, however what remains uncertain, especially given the
current paucity of evidence, is the optimal method of PVCL analysis and
whether PV activity confers prognostic information with regard to
ablation outcomes. Further studies could reconcile the apparent
discrepancies in existing literature, develop a standardised and
reproducible approach to PVCL measurement and clarify the utility of
PVCL measurement during ablation of persistent AF. This will help to
determine the real question - whether if, in fact, pulmonary vein
electrical activity is truely the ‘fuel’ behind the maintenance of AF in
the persistent AF population, or if it simply represent the passive
‘fumes’ of the more advanced atrial substrate in the persistent AF
phenotype.