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.