Electro-anatomical mapping of
LVAs
The variability in the prevalence of LVAs reported in the published
literature, particularly among patient groups with seemingly similar
clinical profiles, partly reflect differing approaches in the technical
application of voltage mapping. Voltage assessment in clinical practice
is almost exclusively performed using maximum peak-to-peak voltage
measurements from bipolar electrograms. Bipolar electrograms represent
the difference in voltage between two unipolar electrograms recorded
from separate, often closely spaced, electrodes. Thus a bipolar
electrogram represents the temporal offset of unipolar electrograms
intended to record the same activation wavefront. Consequently, for a
given conduction velocity, the temporal offset and therefore the bipolar
voltage will be a function of the inter-electrode distance.
Theoretically, where the distance between the electrodes is small, or
the conduction velocity is fast, one would expect a slight temporal
offset and in turn a lower bipolar peak-to-peak voltage. Conversely
where conduction velocity is slow, often considered a marker for
diseased tissue, the temporal offset may be exaggerated and the recorded
voltage being paradoxically larger (95). LA voltages measured in SR were
higher with widely spaced electrodes compared with a shorter
inter-electrode distance (96). In in-silico models of healthy atrial
tissue, increasing electrode spacing is similarly associated with
increments in bipolar voltage up to an inter-electrode distance of 4mm,
after which the bipolar voltage plateaus, denoting the wavelength of the
activation wavefront (97).
Several other catheter-related factors may influence bipolar voltage
amplitude, including catheter orientation, tissue contact force and
electrode size. The angle of the recording bipolar electrodes relative
to the direction of the activation wavefront will modulate the bipolar
voltage amplitude. The temporal offset between the unipolar electrograms
will be most significant when they are aligned parallel to the direction
of activation, thereby recording maximal bipolar voltage (97). Where the
electrodes lie perpendicular to the excitation wavefront, both
electrodes would be activated simultaneously, producing a misleading
bipolar voltage of zero (so-called bipolar ghosting). The angle of
incidence between the catheter and endocardium further alter the
morphology and amplitude of the bipolar electrogram (95). Increasing the
angle of incidence renders the proximal electrode farther from the
tissue, reducing the nearfield contribution to the electrogram amplitude
and morphology, while also increasing the sensitivity to far-field
contamination (98).
Contemporary multipolar catheters utilize impedance measurements to
judge tissue contact. Bipolar mapping catheters with contact force
sensing capabilities have been advocated for use in voltage assessment
due to the advantage of confirming adequate tissue contact. Despite the
potential advantages of contact force feedback, a modest correlation
being contact force and bipolar voltage has been reported with marginal
increments in bipolar amplitude with increasing contact force when
contact is light (up to 5g), and no correlation was observed at moderate
or high degrees of contact (99,100).
Electrode size has been shown to have variable and interacting effects
on the recorded voltage. Marcus et al., compared voltage measurements
from 4mm and 8mm NaviStar catheters (Biosense Webster), each with 1-7-4
electrode arrangements and reported significantly higher voltages with
the larger electrode in patients with PAF (101). This would be in
keeping with larger electrodes producing a broader footprint over the
tissue being evaluated, accentuating the nearfield signal. More recent
studies have compared PBP assessment using a larger tip linear ablation
catheter with fast anatomical mapping (FAM) using multipolar catheters
with smaller electrodes. Such studies have alluded to a bidirectional
relationship between electrode size and the nature of the underlying
tissue in determining the bipolar voltage amplitude. In patients
undergoing ablation for AF, the burden of LVA was perhaps surprisingly
lower and mean bipolar voltage was higher when evaluated with a circular
multipolar catheter with 1mm electrode size compared with a larger
tipped ablation catheter (102,103). In these studies, the
inter-electrode distance was larger with the multipolar catheter,
possibly confounding the higher voltage measurements. However the
discrepancy in the size of LVAs and bipolar voltage measurements was
similarly evident when utilizing multipolar catheters with more closely
spaced electrodes (96,104).
Interestingly the divergence in voltage measurements appears more
pronounced in regions with low voltage generally. Anter et al., compared
atrial voltage measurements from a linear ablation catheter and
multipolar catheter in a group of healthy subjects, and reported no
difference in bipolar voltage amplitudes (104). Zghaib et al., also
reported comparable voltages measurements from the two catheter types in
areas of left atria where voltages were generally preserved, whereas in
regions of low voltages recordings from the multipolar catheter were
left shifted (i.e. lower) compared to the linear catheter (105). In
patients undergoing ablation for PsAF, Mano and colleagues paired
mapping points recorded by each catheter according to location, and
analyzed electrogram properties (106). Bipolar voltage amplitudes
recorded using a multipolar catheter were higher across the entire
distribution of voltages, however in regions defined as healthy,
voltages recorded by the large tipped linear catheter correlated well
with those from the multipolar catheter. In contrast, no such
relationship was observed in regions with voltages <0.5mV.
Computer modelling studies previously demonstrated degradation in
spatial resolution associated with increasing electrode size (98).
Increasing the electrode size can augment the near-field contribution to
the electrogram, but may also render the electrogram more susceptible to
far-field signals. Moreover, the larger recording footprint of the
electrode also represents an electrogram over a larger span of tissue,
expressing differing electrical properties from a collection of fibers
in a single electrogram. In heterogeneous tissue, for example regions
with patchy fibrosis or complex fiber orientation, larger electrodes may
average voltages from a range of tissue types and/or complex excitation
wavefronts, yielding electrograms that are comparatively smoother,
longer in duration and attenuated in amplitude. Alternatively,
electrodes of smaller size appear to be better able to discriminate
between surviving myocardial fibers embedded within an area of general
low voltage, yielding a higher resolution voltage map with smaller LVAs
and higher mean bipolar voltage.
The influence of tissue properties on recorded bipolar voltage extends
beyond electrode size. Mirroring the effect of electrode size, larger
LVAs and lower mean voltages within low voltage zones were derived when
using multipolar catheters with wider electrode spacing than equivalent
catheters with more closely spaced electrodes, presumably also
reflecting the summation of signals over a heterogeneous substrate. From
a clinical perspective, the variability in voltage measurements seems to
be most significant in precisely the regions requiring high resolution
to correctly identify areas of possible pathogenic potential, while not
extending targets for ablation to regions of normal activity. In this
context, catheters with larger, more widely spaced electrodes appear
more susceptible to far-field contamination, averaging and signal
cancellation.
Aside from these catheter-related factors, the other major technical
determinant of the size of LVAs is the voltage threshold employed to
define low voltage. It must be borne in mind that at present there is no
histological data corroborating bipolar voltage measurements with native
atrial fibrosis. Initial studies of atrial voltage mapping used a value
of 0.05mV to identify regions of dense scar, a value founded on the
baseline noise levels in early iterations of the then available EAM
systems (107). Most recent studies have adopted a threshold of 0.5mV to
classify regions of abnormally low voltage, irrespective of the voltage
mapping technique employed. This value was somewhat arbitrarily utilized
in early investigations of potential atrial fibrosis (108,109) and has
gained traction through more recent reports validating its application.
Kapa et al., evaluated the distribution of left atrial voltage
measurements in 10 patients with PAF and found 95% of all recordings on
the posterior wall had amplitudes >0.2mV and
>0.45mV throughout the rest of the left atrium (110). In a
similar study, also of 10 patients with a history of PAF, Anter et al.
demonstrated the fifth centile of LA voltages being 0.5mV and based upon
this considered normal LA voltage to be ≥0.5mV (104).
Other studies have applied a similar approach in patients without a
known history of AF or structural heart disease to derive reference
values for normal voltage. Detailed left atrial voltage maps were
analyzed in 9 patients with either left sided accessory pathways of
focal atrial tachycardia and the fifth centile of voltages was reported
as 0.5mV (111). Lin et al. also assessed left atrial voltage in 10
patients undergoing ablation for accessory pathway mediated tachycardia
and demonstrated 95% of all voltage measurements being above 0.38mV,
and thus advanced 0.4mV as a cut-off for low voltage (112).
In assessing LA voltage measurements in 6 control patients without a
history of AF, results from a study by Arruda and colleagues challenge
the 0.5mV cut-off. Overall, their findings suggest that such voltage
assessment of atrial remodeling may be far more nuanced (88). The study
highlighted regional differences in mean bipolar voltage within the LA
and noted the inferior and septal territories displayed lower voltages
in control hearts. Applying the 95% cut-off strategy to voltage
measurements acquired from the septal segments where mean voltage was
lowest of all, they identified a threshold of 1.17mV. In a mixed cohort
of patients with AF without LVAs <0.5mV, 43% had abnormal
voltage readings of 0.5-1.17mV and these patients were at significantly
greater risk of recurrent atrial arrhythmias after ablation. Several
studies have similarly reported significant regional variations in mean
bipolar voltage, suggesting a single voltage threshold may not be
universally applicable (82,110,113). Regional variation in the
distribution of LVAs also appears to differ in hearts depending on the
classification of AF. Chang et al. reported lower bi-atrial voltages in
PsAF compared to PAF, with limited areas of low voltage in the context
PAF but becoming far more diffuse where AF was persistent (108).
Differential baseline voltage measurements between atrial regions,
together with reducing overall mean voltages and proliferation of LVZs
with increasing duration of AF have also been reported in a number of
other studies (112,114,115). However no consistent trend in the
geographical distribution of such LVZs has become apparent to date.
The distribution of voltages across the atrium likely, in part, reflect
regional differences in the architectural arrangement of muscle fibers
and the overall tissue mass. Indeed in post-mortem analyses, left atrial
wall thickness varies between regions (116,117), and wall thickness has
previously been shown to modulate bipolar voltage amplitudes (118) and
account for differences in the prevalence of LVAs (119). The
organization of left atrial muscle fibers also shows significant
regional heterogeneity with some areas displaying a high dispersion in
the transmural orientation of fibers, while in other areas, fiber
orientation is fairly constant through its thickness (117,120). The
heterogeneity in transmural fiber orientation is therefore likely to
contribute to regional variation in voltage. Importantly, while such
arrangement of fibers was broadly consistent between most hearts,
alternative fiber configurations were also observed. This variation
together with the differing distribution of LVAs seen would advocate a
bespoke approach to ablation rather than recourse to pre-defined lesion
sets.
Extrinsic factors also likely to contribute to regional differences in
LA voltage. Regions of high atrial wall stress appear to be associated
with lower bipolar amplitudes. Such areas were commonly observed at
flexures such as the appendage ridge and points of deformation due to
external structures (121). The imprint of the ascending aorta on the
anterior LA and vertebrae to the posterior wall correlate with LVAs in
both paroxysmal and persistent AF (122,123). While atrial wall stress
and stretch may induce localized fibrotic remodeling and contribute to
increased risk of AF associated with conditions where these occur, other
processes may also contribute to the low voltage measurements. For
example acute reduction in LA size are seen following treatment for
mitral stenosis, accompanied by an immediate increase in bipolar voltage
across all segments, normalization conduction velocity and reduction in
AF inducibility (124). Such brisk recovery in bipolar voltage underline
the involvement of electrical remodeling such as a role for
stretch-sensitive ion channels (125,126), emphasizing that not all LVAs
are accounted for by fibrosis and in some cases the underlying atrial
myocardial may ostensibly be normal.
Studies evaluating the efficacy of VGA differ in the atrial rhythm
during voltage mapping and this appears to be an important source of
variation in the burden of LVAs. Ndrepepa et al. reported a three-fold
reduction in mean LA voltage when measured in AF compared with SR (127).
Furthermore the difference in voltage between AF and SR were greatest in
regions with shorter AF cycle lengths, where the tissue is likely to be
partially refractory through rapid fibrillatory activation. The
simultaneous recording of multiple wavefronts in AF and variation in the
direction of activation relative to the catheter are also likely to have
contributed to the observed disparity. Accordingly, voltage differences
in organized atrial arrhythmias are more modest. Shivkumar and
colleagues reported higher right atrial voltages when mapping in atrial
flutter compared to SR (128).
In keeping with these studies, data from Sarkozy’s group further
highlight the importance of disorganized activity and variable cycle
lengths on atrial voltage (129). Mean left atrial voltage was highest
when assessed in SR, intermediate in atrial flutter and significantly
lower when mapped in AF. SR voltage moderately correlated with voltage
in AF (Kendall’s tau = 0.56) with a voltage in AF of 0.31mV suggested to
predict a SR voltage of 0.5mV with reasonable accuracy (sensitivity
0.82, specificity 0.95). Importantly, correlation between repeated AF
voltages was modest (Kendall’s tau = 0.52), highlighting the impact of
disorganized activation on reproducibility. Yagishita et al., also
reported higher voltages in SR than AF with a moderate correlation
between the two (r = 0.707) (88). Mean LA voltage was higher in PAF than
PsAF, though interestingly the correlation between SR and AF voltages
was stronger in PsAF cases. Indeed in both studies, voltage measurements
in AF better correlated with those in SR where bipolar amplitudes were
at the lower end of the spectrum, perhaps suggesting that where
remodeling is most pronounced lower voltages are evident irrespective of
the specifics of the mapping approach. Where remodeling is less
extensive, bipolar voltage is sensitive to the mapping rhythm,
displaying functional reductions when being activated more rapidly.
Teh et al., reported significantly higher voltages and smaller LVAs
during coronary sinus pacing compared with AF (115). Other than in the
anterior wall, they reported no correlation in LA voltages between AF
and coronary sinus pacing. Moreover, regions of low voltage and CFAEs
observed in AF appeared largely normal when assessed during the paced
rhythm. Voltage mapping in SR or under conditions of regular pacing may
therefore not adequately unmask functional electrophysiological
properties that form part of the arrhythmogenic substrate (figure 2).
Masuda et al. on the other reported good correlation between SR and AF
voltages (r = 0.73) in areas where electrogram morphology was normal in
both rhythms (130). However regions displaying normal electrograms in SR
frequently exhibited fractionation in AF, with poor correlation in
bipolar voltages at such sites. The pathological significance of low
voltage and electrogram fractionation in AF therefore remains unclear,
as do the validity of methods posited for voltage adjustment between
rhythms (88,129,131).
The technical aspects of EAM clearly have a significant impact on LA
substrate assessment The rhythm during mapping and catheter properties
such as electrode spacing are important, yet perhaps under-appreciated,
determinants of voltage. Indeed the variety of voltage assessment
techniques utilized in the VGA studies (Table 1) highlight a lack of
consensus as to the most appropriate approach for devising a substrate
guided ablation strategy. Such differences in treatment strategies poses
challenges in comparing study outcomes.
In the context of such caveats, there remains significant uncertainty as
to what areas of low bipolar voltage represent at the tissue level and
how this relates to arrhythmogenic potential. Importantly histological
data corroborating atrial fibrosis with voltage measurements is
exceedingly limited. In an animal study of post-myocardial infarction,
ventricular scar correlated with a bipolar voltage threshold of 0.5 mV
(132). Harrison et al. examined ablation induced scar in porcine right
atria following ablation along the intercaval line (133). Mean bipolar
voltage along the line acutely after ablation was 0.6 mV, and 0.3 mV at
8 weeks post-ablation. Such values might suggest that the commonly
employed thresholds of 0.05 mV for dense scar and 0.4 - 0.5 mV for scar
might underestimate the overall LA low voltage burden. Moreover the
study also alludes to crucial limitations in current assessment and
ablation of LVAs, and the need for a more detailed assessment. Firstly,
if higher bipolar voltage thresholds were utilized to distinguish LA
scar from healthy tissue, this could extend the ablation target in a VGA
strategy to a large proportion of the LA, which may not be feasible or
desirable due to potential risks. Secondly, ablation scar is more likely
to be associated with dense and predictable fibrosis. Native atrial
fibrosis is on the other hand interspersed with surviving myocardial
bundles, and thus less amenable to dichotomizing as scar tissue versus
normal tissue. Rather, fibrotic remodeling is progressive, and the goal
is therefore to delineate arrhythmogenic tissue from tissue which
activates passively.
In keeping with the paradigm of progressive fibrotic infiltration, Node
and colleagues recently assessed the degree of fibrosis and compared
this to global LA voltage (134). Increasing percentage of septal
fibrosis negatively correlated with mean global LA voltage. Moreover a
high burden of LVAs was associated with reduction in LA voltage when
assessed globally, but also across all individual segments of the LA,
together suggesting that fibrosis and reductions in LA voltage are
progressive and diffuse. Although reductions in LA voltage and
increasing burden of LVAs have been shown to increase the risk of AF
recurrence, threshold values at which this risk increases significantly
remains unclear. Furthermore, recent histological analysis noted no
difference in fibrosis burden between control patients and those with
either paroxysmal or persistent AF (135). Additionally, the study report
no overlap between areas of fibrosis and low voltage, nor arrhythmogenic
electrophysiological properties, questioning the role of fibrosis
altogether in the pathogenesis of AF. It must be noted that analyses
were limited to tissue from the right and left atrial appendages and the
overall number of patients was small, however highlights important gaps
in our understanding of AF persistence and issues that we need to bridge
to devise more effective treatment strategies.