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.