Voltage and Conduction Properties
The median distance between merged chamber surfaces was 6.0mm (IQR
3.4-10.7). The voltage in regions of high frequency LIA was 1.09mv (IQR
0.55-1.94) compared to 1.07mv (IQR 0.51-1.94) in the remainder of the
chamber (p=0.9936).
A total of 53 paired maps at long and short cycle length were obtained
for the LA and RA in a subset of 9 patients (in 1 participant only 2
sites were obtained due to AF induction). The MAT across all maps
obtained in regions with high frequency LIA was 7.5ms (IQR 6.6-8.9)
compared to 6.0ms (IQR 5.2-7.7) in the remainder of the chamber, a
statistically significant difference of 1.5ms, p<0.0005.
Extrastimulus pacing resulted in a significant increase in CHI in
regions of high frequency LIA from 3.3 (IQR 2.3-4.4) to 4.0 (IQR
3.1-5.4) (p=0.0480), but no increase in the remainder of the chamber
(p=0.4636) as shown in figure S9.
Discussion
This study demonstrates that regions with LIA patterns show high
spatiotemporal stability. In contrast rotational activation patterns,
closest to the ‘rotors’ identified using other mapping techniques, show
the least spatiotemporal stability. Regions of high frequency FF are
relatively more stable whereas infrequent FF is not. Mapping durations
of 20-25s are required to identify all temporally variable propagation
patterns although shorter durations will identify the most stable LIA
and FF. Although bipolar voltage amplitude in these regions is normal,
they demonstrate an increase in conduction heterogeneity during short
coupled extrastimulus pacing.
The aim of technologies designed to facilitate electrophysiological
mapping and ablation of AF mechanisms is to identify repetitive patterns
within a characteristically disorganised rhythm. The total duration
analysed has a significant impact on how a repetitive pattern is defined
and there have been limited efforts previously to determine the optimum
duration required. Studies often do not report the duration of AF mapped
but may report that patterns identified are stable over several minutes
and separate recordings.(1, 9, 10) Other studies have used recording
durations of between 10 seconds and 5 minutes.(3, 5, 11) Of note a
retrospective analysis where 5 minute initial recordings were used found
that 89% of the mechanistic sites identified were also seen when 30s
recording durations were analysed.(12) However, shorter durations than
this were not assessed. It may be revealing that when only 10s recording
durations have been chosen, in the study by Child et al using a
technique of basket contact mapping and phase singularity analysis,
spatially stable patterns were not identified.(3) Rotational activation
patterns demonstrate the least stability between and during recordings,
with 10s of mapping showing only very moderate correlation with the
results obtained from 30s mapping (kappa 0.55) and a variability in
rotational activation pattern frequency of approximately 20% at a
duration of 10s. Of note, of course, is that durations beyond 30s were
not assessed and it may be that accuracy improves yet further if longer
analyses are performed.
Traditional electrophysiological assessment has involved mapping of
either the endocardial or epicardial surfaces. There is increasing
recognition that the remodelling involved in the development and
progression of AF is a three-dimensional process resulting in activation
time differences between atrial surfaces.(13, 14) In this context,
epicardial propagation that results in local breakthrough conduction
will manifest as a focal activation pattern on the endocardial surface.
The sites of epicardial breakthrough are likely to either be randomly
distributed, if arising from chaotic 3-dimensional propagation, or recur
at specific sites where the remodelling process promotes breakthrough to
the endocardial surface. Sporadic focal activations and random
breakthroughs are likely to display minimal consistency across
recordings whilst high frequency activations or sites of recurrent
breakthrough are likely to be consistent. This was supported by the
finding of much greater correlation at high frequency sites
(R2 value 0.83, IQR 0.17) than when all activations
are considered (R2 0.64, IQR 0.19). However,
distinguishing between a site of recurrent breakthrough and true focal
activation is not possible using the mapping methods described here.
There similarly appears to be earlier stabilisation of focal firing
variability following pulmonary vein isolation. This suggests a greater
degree of stability in non-pulmonary vein sites of focal activation.
The spatial consistency of LIA detection between separate recordings is
illustrated in figure 5. Bipolar voltage amplitude in these regions is
normal, which suggests that the activation properties observed are not
the result of dense fibrosis. However, bipolar voltage amplitude is a
relatively crude tool and is highly dependent on both rate and vector of
activation(15). Studies using late gadolinium enhanced magnetic
resonance imaging reveal patchy areas of fibrosis out of keeping with
the burden seen on voltage mapping studies(16, 17) suggesting the
existence of interstitial fibrosis that is not revealed by measuring
bipolar voltage amplitude. The MAT during pacing within LIA zones was
longer, suggestive of slower conduction velocity, and short coupled
extrastimulus pacing resulted in an increase in CHI in these regions
that was not observed in the remainder of the chamber. Although these
sites may represent anatomically normal regions of changing fibre
orientation resulting in anisotropic conduction, they may represent
disrupted conduction caused by underlying atrial interstitial fibrosis
resulting in fibre disarray and rate dependent conduction abnormalities
that manifest as local irregular activation patterns during AF. In a
study by Walters et al. using surgically placed epicardial plaques in
patients with longstanding persistent AF, disorganised activation was
frequently observed, which did not satisfy criteria for either rotors or
focal activations but was stable over multiple recordings of 10s
duration taken over a period of 10 minutes(18). This disorganised
activation may represent similar propagation patterns to the irregular
activation observed using charge density mapping, which was similarly
stable even at short mapping durations. Walters also reported that
rotors were frequently transient, in keeping with the results outlined
here.
Both the non-hierarchical multiple-wavelet hypothesis and the competing
“mother-rotor”, or focal driver, hypothesis describe a process of
wave-break in the formation of fibrillatory wavefronts involved in
maintenance of cardiac fibrillation.(19, 20) Tissue homogeneity is
thought to play a significant role in the susceptibility to
fibrillation(21) with regions of structural inhomogeneity likely
responsible for the wave-break that results in
fibrillatory conduction.(22) The anatomical regions demonstrating stable
LIA patterns identified in this study may therefore reflect sites of
structural heterogeneity responsible for wave-break, and therefore play
an important role in AF maintenance.
Importantly, this study was not designed to assess ablation strategy or
effectiveness and is not able to determine the impact of the phenomena
identified on AF maintenance. This requires further detailed work.
However, an understanding of the transient properties of rotational
activity and low frequency focal activations observed in short mapping
segments is crucial to designing ablation strategies that can be tested
in clinical trials and suggests they are unlikely to occur as a result
of anatomical substrate, such as scar or myofibre architecture.
Targeting a fixed therapy to transient, migratory activation patterns is
likely to be ineffective.