Clinical significance of atrial
LVAs
A growing number of studies have highlighted the prognostic significance
of LVAs in AF. In a mixed cohort of AF patients undergoing ablation,
areas of very low voltage (<0.05mV) were associated with a
three-fold increased likelihood of recurrent AF during follow-up (78).
Oshima and colleagues similarly reported a negative influence of LVAs in
freedom from AF following PVI in patients with non-paroxysmal AF (79).
In their study, LVAs were defined as regions with bipolar voltage
<0.5mV, and determined LVAs covering more than 24% of the LA
surface as a threshold for discriminating the likelihood of recurrent AF
following ablation, albeit with a sensitivity of 52% and specificity of
78%. In a separate study also utilizing 0.5mV to define LVAs, the
presence of LVAs was an independent predictor for AF recurrence
following ablation (80). Interestingly, patients with PsAF and no LVAs
had similar rates of freedom from AF as individuals with PAF.
Furthermore, studies limited to subjects with PAF have similarly
correlated LVAs with AF recurrence following ablation (81,82).
Mechanistic insights have further corroborated the potential role of
LVAs in the pathogenesis of AF. Approximately three-quarters of high
dominant-frequency sites, proposed as foci of rotational activation
(83), were located within LVAs or their border zones in a cohort of 70
patients with non-paroxysmal AF (79). Left atrial bipolar voltage was
also shown to correlate with conduction velocity (84). Miyamoto et al.
reported conduction slowing in regions of the left atrial with bipolar
voltage <0.5mV and these regions were significantly more
likely to harbor CFAEs (85). Chauhan and colleagues reported
co-localization of CFAEs to regions of low voltage, with the degree of
fractionation inversely proportional to voltage (86). Potential left
atrial non-pulmonary vein triggers for AF appear more common in PsAF and
show a predilection for LVAs (87).
Temporal changes in the size of LVAs have been reported, mirroring the
progressive fibrotic remodeling seen in animal models that underpin the
increasing propensity for AF to sustain with time. AF type, either
paroxysmal or persistent, was independently associated with LVAs on
multivariable analysis in an early study of VGA (18). In the study by
Hindricks’ group, LVAs were twice as likely to be observed in PsAF than
in PAF (25). Yagishita et al. also reported higher prevalence of LVAs in
patients with non-paroxysmal forms of AF compared to those with PAF,
with LVAs covering a greater overall area of the atrium and being more
diffusely spread in those with PsAF (88).
However, the frequency and burden of LVAs observed in a number of
studies is at odds with these reports and raises several of important
issues. For example, Huang et al. measured left atrial voltage in
patients with either paroxysmal or persistent AF and found no difference
in the size of LVAs between the groups (89). Additionally, the extent of
LVAs at baseline did not predict AF recurrence following PVI. In
patients with non-paroxysmal AF, the degree of LVAs did not correlate
with AF duration (90). Birnie and colleagues used high-resolution
mapping to characterize the burden of LVAs in patients with AF (91). No
differences in the burden of LVAs were observed between patients with
paroxysmal or persistent AF, with only age and LA size, being identified
as predictors of LVAs on multivariable analysis. The study also reported
significant variability in the presence of LVAs across the cohort, and
such differences are also evident across the studies where left atrial
voltage has been examined.
In an early study of VGA, LVAs were present in 10% of patients with PAF
and 35% in those with PsAF (18). Data from the study by Kircher et al.
were broadly similar with LVAs being detected in 29% overall, with 18%
of patients with PAF and 41% of patients with PsAF (25). In contrast,
other studies have reported substantially higher prevalence of LVAs,
with nearly two-thirds of patients with PAF exhibiting LVAs (82,92) and
over 80% of patients with PsAF (79,89).
Differences in study cohorts beyond AF classification may have
contributed to such variation. However, reductions in atrial bipolar
voltage have been purported to be a surrogate for the adverse atrial
remodeling underpinning AF persistence and as such the lack of a
difference in the burden of LVAs between paroxysmal and persistent AF
within the same study, where the methods utilized for voltage mapping
would be consistent, is intriguing. Recent analyses of AF burden using
continuous ECG monitoring have highlighted that these clinical
classifications of AF type only loosely associate with AF burden, with
significant overlap in the time spent in AF between patients with
paroxysmal and persistent AF (93,94). This variability in AF burden may
be reflected in the extent of LVAs, and further endorse the need to more
patient-specific approaches to ablation.
While a small proportion of studies report presence of LVAs in the
majority of patients with PsAF, in most studies LVAs are recorded in
less than half of the study cohort. The absence of LVAs in such cases
may signify the absence of advanced remodeling where a standalone PVI
strategy may suffice. However, the absence of LVAs in such a sizeable
fraction of a cohort with sustained AF may conversely question the
sensitivity of LVAs, and/or the techniques utilized in defining them, in
characterizing the atrial substrate. Indeed, where the relationship of
conduction and voltage have been studied, not all regions of low voltage
were associated with conduction slowing and conversely some regions with
abnormal conduction properties displayed normal bipolar voltages (84).
Furthermore, approximately 30% of sites with high dominant frequency
activation are found in regions of normal voltage (79).
These issues highlight the challenges in delineating the atrial
substrate and perhaps representing this through voltage mapping in
isolation, particularly with the approaches utilized up to now, may not
do so with sufficient sensitivity and specificity. While ablation
targeting LVAs as an adjunct to PVI gains traction, it is essential to
note the significant paucity of data on precisely how voltage
measurements relate to adverse atrial remodeling in AF. In particular,
low voltage is generally considered to represent native atrial fibrosis,
however at present there is no histological data to support this
assertion. The myocardial fiber arrangement in the atrium is highly
complex with regional heterogeneity in fiber orientation and tissue
depth. Beyond this, the process of fibrosis has significant variability
in the pattern of deposition and degree of transmurality, and how this
affects voltage measurements is unclear. Added to this milieu is the
multi-faceted nature of the atrial substrate as described above. It is
unlikely that amongst the array of remodeling phenomena that have been
documented in AF, none other than fibrosis alters the recorded tissue
voltage. Therefore, while favorable outcomes have been reported in VGA
studies, many questions remain unanswered in assessing atrial voltage.