TYPE Original Research PUBLISHED 18 October 2022 DOI 10.3389/fcvm.2022.1000027 Validating left atrial OPEN ACCESS fractionation and low-voltage EDITED BY Mu Qin, Shanghai Jiao Tong University, China substrate during atrial fibrillation REVIEWED BY Weichieh Lee, and sinus rhythm—A Chi Mei Medical Center, Taiwan Atsuhiko Yagishita, Tokai University Isehara Hospital, Japan high-density mapping study in *CORRESPONDENCE Amir Jadidi persistent atrial fibrillation amir.jadidi@uniklinik-freiburg.de † These authors have contributed Taiyuan Huang1† , Juan Chen2† , Björn Müller-Edenborn1 , equally to this work and share first authorship Louisa Mayer1 , Martin Eichenlaub1 , SPECIALTY SECTION Zoraida Moreno Weidmann1,3 , Juergen Allgeier1 , This article was submitted to Cardiac Rhythmology, Marius Bohnen1 , Heiko Lehrmann1 , Dietmar Trenk1 , a section of the journal Simon Schoechlin1 , Dirk Westermann1 , Thomas Arentz1 and Frontiers in Cardiovascular Medicine Amir Jadidi1* RECEIVED 21July 2022 ACCEPTED 26 September 2022 1 Department of Cardiology, Arrhythmia Division, Faculty of Medicine, University Heart Center PUBLISHED 18 October 2022 Freiburg-Bad Krozingen, University of Freiburg, Freiburg im Breisgau, Germany, 2 Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China, CITATION 3 Arrhythmia Unit, Department of Cardiology, Hospital Universitario Sant Pau, Barcelona, Spain Huang T, Chen J, Müller-Edenborn B, Mayer L, Eichenlaub M, Moreno Weidmann Z, Allgeier J, Bohnen M, Lehrmann H, Trenk D, Schoechlin S, Westermann D, Arentz T and Jadidi A (2022) Validating left atrial Background: Low-voltage-substrate (LVS)-guided ablation for persistent atrial fractionation and low-voltage fibrillation (AF) has been described either in sinus rhythm (SR) or AF. substrate during atrial fibrillation and sinus rhythm—A high-density Prolonged fractionated potentials (PFPs) may represent arrhythmogenic slow mapping study in persistent atrial conduction substrate and potentially co-localize with LVS. We assess the fibrillation. spatial correlation of PFP identified in AF (PFP-AF) to those mapped in SR (PFP- Front. Cardiovasc. Med. 9:1000027. doi: 10.3389/fcvm.2022.1000027 SR). We further report the relationship between LVS and PFPs when mapped COPYRIGHT in AF or SR. © 2022 Huang, Chen, Müller-Edenborn, Mayer, Eichenlaub, Materials and methods: Thirty-eight patients with ablation naïve persistent Moreno Weidmann, Allgeier, Bohnen, AF underwent left atrial (LA) high—density mapping in AF and SR prior to Lehrmann, Trenk, Schoechlin, Westermann, Arentz and Jadidi. This is catheter ablation. Areas presenting PFP-AF and PFP-SR were annotated during an open-access article distributed mapping on the LA geometry. Low-voltage areas (LVA) were quantified using a under the terms of the Creative Commons Attribution License (CC BY). bipolar threshold of 0.5 mV during both AF and SR mapping. Concordance of The use, distribution or reproduction in fractionated potentials (CFP) (defined as the presence of PFPs in both rhythms other forums is permitted, provided within a radius of 6 mm) was quantified. Spatial distribution and correlation of the original author(s) and the copyright owner(s) are credited and that the PFP and CFP with LVA were assessed. The predictors for CFP were determined. original publication in this journal is cited, in accordance with accepted Results: PFPs displayed low voltages both during AF (median 0.30 mV (Q1– academic practice. No use, distribution Q3: 0.20–0.50 mV) and SR (median 0.35 mV (Q1–Q3: 0.20–0.56 mV). The or reproduction is permitted which does not comply with these terms. duration of PFP-SR was measured at 61 ms (Q1–Q3: 51–76 ms). During SR, most PFP-SRs (89.4 and 97.2%) were located within LVA (<0.5 mV and <1.0 mV, respectively). Areas presenting PFP occurred more frequently in AF than in SR (median: 9.5 vs. 8.0, p = 0.005). Both PFP-AF and PFP-SR were predominantly Frontiers in Cardiovascular Medicine 01 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 located at anterior LA (>40%), followed by posterior LA (>20%) and septal LA (>15%). The extent of LVA < 0.5 mV was more extensive in AF (median: 25.2% of LA surface, Q1–Q3:16.6–50.5%) than in SR (median: 12.3%, Q1–Q3: 4.7– 29.4%, p = 0.001). CFP in both rhythms occurred in 80% of PFP-SR and 59% of PFP-AF (p = 0.008). Notably, CFP was positively correlated to the extent of LVA in SR (p = 0.004), but not with LVA in AF (p = 0.226). Additionally, the extent of LVA < 0.5 mV in SR was the only significant predictor for CFP, with an optimal threshold of 16% predicting high (>80%) fractionation concordance in AF and SR. Conclusion: Substrate mapping in SR vs. AF reveals smaller areas of low voltage and fewer sites with PFP. PFP-SR are located within low-voltage areas in SR. There is a high degree of spatial agreement (80%) between PFP-AF and PFP-SR in patients with moderate LVA in SR (>16% of LA surface). These findings should be considered when substrate-based ablation strategies are applied in patients with the left atrial low-voltage substrate with recurrent persistent AF. KEYWORDS persistent atrial fibrillation, mapping, catheter ablation, prolonged fractionated potential, pulmonary vein isolation, atrial late potentials, low voltage, substrate Introduction correlation and distribution remain unknown. The current study aims to analyze the spatial distribution, and quantify and Pulmonary veins (PVs), as a major trigger for AF, are identify the predictors of concordance between PFP-AF and considered the primary target site during ablation (1). While PFP-SR. In addition, the relationship of PFPs to the underlying high rates (75–85%) of sinus rhythm maintenance are achieved low-voltage substrate is assessed. with the single pulmonary vein isolation (PVI) approach in both paroxysmal and persistent AF patients without left atrial low-voltage substrate, this approach results in reduced (45– Materials and methods 55%) success rates in those presenting significant low-voltage substrate in the LA (2, 3). Previous randomized controlled Study population trials (RCTs) failed to demonstrate significant superiority of empiric extensive ablation strategies over PVI-alone in patients The study cohort consists of 38 consecutive patients with persistent AF (4–6). However, termination of AF by local presenting for their first catheter ablation procedure ablation within the left atrium before performing PVI further for symptomatic persistent AF (lasting for > 7 days indicated the existence of trigger sites outside of PVs (7, 8). and < 12 months). Exclusion criteria were the presence of atrial In the last years, two similar substrate-based approaches were thrombus on pre-procedural transesophageal echocardiography reported for ablation of persistent AF, resulting in improved or previous atrial ablation or surgery. The study protocol arrhythmia freedom rates of 70% at 1-year follow-up in followed the principles of the Helsinki Declaration and was persistent AF patients who present significant left atrial low- approved by the Human Research Ethics Committee of the voltage substrate: (1) PVI plus mapping and ablation of low University of Freiburg. All patients provided written informed voltage and prolonged fractionated potentials (PFP) during AF consent to participate in this study. (PFP-AF) (8–10). (2) PVI plus ablation of low voltage and fractionated potentials in SR (PFP-SR): the electrograms are characterized by prolonged deflections following a first atrial High-density voltage mapping in both depolarization and were reported by our team and Yang et al. atrial fibrillation and sinus rhythm (11) and named prolonged fractionated potential in SR (PFP- SR) or atrial late potentials (ALP) (12). While PFP-AF and PFP- Left atrial mapping was performed under general anesthesia SR are observed/mapped during different rhythms, their spatial via transseptal access with more than 1,200 sites per patient Frontiers in Cardiovascular Medicine 02 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 during both AF and SR. Maps were acquired using a 20- map (AF or SR) were annotated on the LA geometry during LA pole circumferential catheter (Lasso-Nav, diameter 15–25 mm; mapping. The number of areas presenting PFP-AF or PFP-SR electrode size: 1 mm; electrode spacing: 2–6–2 mm; Biosense was calculated within a radius of 6 mm covering neighboring Webster) in combination with the Carto 3 (V7) electro- mapping sites in each segment of the left atrium. anatomical mapping system. The electro-anatomic maps were acquired after respiratory gating with a low-interpolation setting (Carto 3 system, 18–20 for LA geometry acquisition). The Definition of the low-voltage area in interior projection distance (“filtering”) was set at a distance both atrial fibrillation and sinus rhythm of 5 mm to the surface of LA geometry. Areas demonstrating low voltage when mapped with the 20-pole lasso catheter were In the current study, quantification of the low-voltage reconfirmed using a contact force-enabled mapping catheter substrate in each rhythm was performed separately using a with a contact threshold of > 3 g. After mapping during the bipolar threshold of 0.5 mV in both AF and SR mapping. initial rhythm of AF or SR, individuals underwent electrical Low-voltage area (LVA) was therefore reported as separate cardioversion to SR or induction to AF by rapid pacing to results in respective rhythm and the percentage of LVA was continue mapping in different rhythms. Only mapping sites calculated by the absolute LVA divided by the total surface of that were within an adjacent distance of 5 mm contributed LA excluding mitral annulus and PV antra. The percentage of to voltage maps. PFP-SR located within low-voltage areas (in SR) < 0.5 mV as For voltage mapping during AF, we ensured a high well as LVA < 1.0 mV was assessed. mapping density (>1,000 points per atrium and rhythm). The window of interest was set to the average AF cycle length, to enable measurement of the peak-to-peak amplitude of a Definition of concordance of single AF beat (because the current CARTO system does not fractionated potentials during atrial allow measurement of average voltage of multiple consecutive fibrillation and sinus rhythm beats). However, because of the high-mapping density, multiple mapping points are recorded within a small area (<0.3 cm2 ), After annotation of PFP in both rhythms, their spatial allowing to calculate and display the average voltage of these correlation to LVA was quantified as the percentage of PFP mapping points that project to the same area. The recorded located in LVA < 0.5 mV (or in 1 cm border of LVA) from the high-density voltage maps in AF are therefore highly consistent respective map. Subsequently, we overlapped SR and AF maps to with regard to the extent and distribution of low-voltage visualize the spatial distribution between PFP-AF and PFP-SR. areas (13). Although the electro-anatomical system in CARTO has Left atrial area (LAA) and left atrial volume (LAV) were high-spatial accuracy (<1 mm), the same atrial location may be measured using the CARTO mapping system with exclusion of slightly shifted/moved between the two rhythms (slight spatial the PV ostia and mitral annulus. discrepancies between the first map in AF and the second map in SR). This may be due to different factors: (1) slight movement of the patient during the electrical cardioversion; (2) change in Definition of prolonged fractionated the left atrial volume and contraction behavior during AF vs. potentials-in-atrial fibrillation and SR. To account for these slight location differences between the prolonged fractionated AF and SR maps, we therefore defined “concordant fractionated potentials-in-sinus rhythm potentials (CFP; Figures 1A,B),” if concomitant PFP occurred at LA locations within a 6 mm radius during both SR and AF. Illustrations of PFP-AF and PFP-SR are presented in Figures 1A,B, 2A,B, respectively. As reported previously (9, 12), PFP-AF was defined as electrograms lasting ≥70% local AF Statistical analysis cycle length (AFCL) on single or multiple neighboring bipoles of the circumferential catheter, with high-temporal consistency Continuous variables were expressed as mean ± SD or (8/10 consecutive AF beats with an electrogram “observation median ± interquartile range based upon distribution status, period” of 15 s at the same location; Figure 1A). PFP-SR were categorical variables were expressed as frequency and percentage defined as electrograms with ≥5 deflections or electrograms (%). Comparison between two paired groups was performed with a delayed low-voltage component (median voltage 0.35 using the paired t-test or the Wilcoxon rank test. Categorical mV) following a first component (depolarization event) on a variables were expressed as frequency and percentage (%) and single bipolar recording in SR (see Figures 1B, 2A,B). The left were compared by the Chi-square test or Fisher’s exact test. atrium was divided into six segments, including the anterior Correlation between variables was performed using Pearson wall, posterior wall, septum, roof, inferior, wall, and lateral wall or Spearman correlation analyses. In the current study, the (see Supplementary Figure 1). Areas presenting PFP in each percentage of CFP was defined as an independent variable. As it Frontiers in Cardiovascular Medicine 03 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 FIGURE 1 Illustration of PFP-AF and PFP-SR. (A,B) Illustrate voltage mapping during AF and SR, respectively. A bipolar threshold of 0.5 mV was adopted in both maps to identify LVA. Mapping points presenting PFP-AF and PFP-SR are annotated in light blue and yellow, respectively. Panel (A) illustrates electrogram examples of PFP-AF and panel (B) examples of PFP-SR. PFP-AF is defined as electrograms with prolonged activity lasting ≥70% local AF cycle length (Lasso 8–9 and 9–10) on a single or on multiple consecutive bipoles, with high-temporal consistency (8/10 consecutive AF beats with an electrogram “observation period” of 15 s at the same location. The curved white arrow illustrates spatio-temporal dispersion on Lasso 5–6 to Lasso 10–11). PFP-SR is defined as electrograms with ≥5 deflections or electrograms with a delayed electrogram component following a first depolarization event on a single bipolar recording in SR. Characteristic delayed electrogram components of PFP-SR are illustrated with yellow arrows in panel (B). (C) Depicted the electrophysiological characteristics of PFP-AF (red) and PFP-SR (blue). Voltage and duration are expressed as median, 25th and 75th percentiles. PFP, prolonged fractionated potential; AF, atrial fibrillation; SR, sinus rhythm. FIGURE 2 Illustrates another patient example with PFP-SR [posterior view in (A) and anterior view in the (B)]. Characteristic delayed electrogram components of PFP-SR are illustrated with yellow arrows. Frontiers in Cardiovascular Medicine 04 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 was defined as the proportion of CFP in PFP-AF or PFP-SR. The projected to both maps (voltage in AF in Figure 1A and voltage absolute number of PFP in either map was hereby considered in SR in Figure 1B). The late components of PFP-SR and the as an intermediate factor. Additionally, we used the percentage PFP-AF sites display low voltages: a median voltage of 0.30 of LVA as a parameter to quantify the extent of LVA, which was mV (Q1–Q3: 0.20–0.50 mv) in PFP-AF and 0.35 mV (Q1–Q3: divided by the surface of LA. In this context, LA surface was 0.20–0.56 mv) in PFP-SR, and the median duration of PFP-SR also classified as an intermediate factor. After the exclusion of measured 61 ms (Q1–Q3: 51–76 ms; Figure 1C). potential intermediate factors, linear regression was performed using a stepwise approach to identify significant predictors of CFP. A reference map (SR or AF map) was selected based on Spatial distribution of prolonged results from linear regression. According to the data distribution fractionated potentials during sinus of CFP percentage from the reference map, the cut-off value rhythm and atrial fibrillation (median or mean value) between high and low concordance in PFP was determined. The receiver operating characteristics The number of areas presenting PFP-AF was significantly (ROC) curve was performed to estimate the discriminative higher than those presenting PFP-SR (median: 9.5, Q1–Q3: 6.0– power of predictors to identify the extent of concordance (high 12.0 in PFP-AF vs. median: 8.0, Q1–Q3: 5.75–10.25 in PFP-SR, or low) and to determine the optimal threshold of LVA extent by p = 0.005). Figure 3A and Table 2 depict the number and the Youden index. A radar chart was generated to visualize the percentage of areas manifesting PFP-AF and PFP-SR in each diagnostic performance of the threshold regarding sensitivity, segment as well as the global LA, respectively. The anterior specificity, positive predictive value, negative, predictive value, wall (both in AF and SR) demonstrated the most frequently and accuracy. Statistical analysis was performed with SPSS PFP among all segments with a comparable proportion between version 27.0 for Macintosh (IBM-Corporation, Armonk, NY), PFP-AF and PFP-SR (PFP-AF: 42.3%, Q1–Q3: 33.3–50.0% vs. and GraphPadPrism-V9.0 for Macintosh (GraphPad Software, PFP-SR: 40.0%, Q1–Q3: 33.3–51.6%, p = 0.531). The posterior LaJolla, CA, USA). A radar chart was performed using the wall and septum demonstrated more than 20 and 15% of total ggradar package of R version 4.2.1. PFP areas in both rhythms without a significant difference between PFP-AF and PFP-SR (p = 0.266 in the posterior wall, p = 0.088 in the septum). The remaining segments, including the Results TABLE 1 Baseline characteristics of the study group (n = 38). Patient characteristics Variable Value As listed in Table 1, the average age of participants was Age, yrs 63.76 ± 10.32 63.76 ± 10.32 years, and 57.9% were female. Hypertension and Female, n (%) 22 (57.9%) diabetes were prevalent in 55.3 and 13.2% of study participants, BMI, kg/m2 26.80 ± 7.65 respectively. Twenty-eight participants (73.7%) presented LAD, mm 42.35 ± 6.95 initially with AF and underwent electrical cardioversion LA surface, cm2 106.3 ± 37.65 after voltage mapping in AF was completed. Six patients LAV, ml 156.51 ± 39.21 experienced reinitiation of AF shortly (within 20 s) after LVEDD, mm 48.78 ± 5.94 electrical cardioversion to SR. In these cases, AF voltage LVESD, mm 32.51 ± 6.79 mapping was first acquired. After completion of PVI, all six LVEF,mm 56.35 ± 11.33 patients were cardioverted to SR and maintained SR, allowing Hypertension, n 21 (55.3%) them to acquire an LA voltage map in SR. Ten participants (%) (26.3%) were initially in SR and underwent AF induction after Diabetes, n (%) 5 (13.2%) voltage mapping in SR. CAD, n (%) 6 (15.8%) Stroke/TIA, n 1 (2.6%) (%) Electrophysiological characteristics CHA2DS2-Vasc 2.00 ± 1.00 and spatial distribution of prolonged Score fractionated potentials in atrial Creatine, 73.96 ± 17.52 (mg/dl) fibrillation and sinus rhythm maps Mapping points 1,258 ± 524 In Figures 1A,B, 2A,B, examples of PFPs are provided in BMI, body mass index; LAD, left atrial diameter; LA, left atrial; LAV, left atrial volume; LVEDD, left ventricular atrial end-diastolic diameter; LVESD, left ventricular atrial end- both AF and SR. The distribution of PFP-SR and PFP-AF is systolic diameter; LVEF, left ventricular ejection fraction; CAD, coronary artery disease; illustrated as yellow and blue markers, respectively, that are TIA, transient ischemic attack. Frontiers in Cardiovascular Medicine 05 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 FIGURE 3 Distribution of areas presenting prolonged fractionated potential and low voltage area. (A) Illustrates the number of areas presenting PFP-AF (red) and PFP-AF (blue) in global LA and each segment. (B) Illustrates the distribution LVA in LA at bipolar threshold of 0.5mV in AF (violet) and SR (light blue) maps. All values are expressed as median (upper margin of bar plot), 25th and 75th percentile (error bar in black). (C,D) Display the correlation between PFP and percentage of LVA during AF mapping (red) and SR mapping (blue), correlation coefficient and p value are annotated, respectively. PFP, prolonged fractionated potential; AF, atrial fibrillation; SR, sinus rhythm; LVA, low voltage area; LA, left atrium. roof, inferior wall, and lateral wall, on the other hand, showed area of) LVA (<0.5 mV in AF) with a significant correlation significantly less prevalence of PFP-AF and PFP-SR. between the number of PFP-AF and the extent of LVA in LA (Correlation coefficient: 0.39, p = 0.016; Figure 3C). During SR mapping, 89.4% (Q1–Q3: 72.1–100%) of PFP-SR located in Spatial distribution of low voltage areas (or within the 1 cm bordering area of) LVA (<0.5 mV in SR). Moreover, most PFP-SRs (97.2%) are located within LVA (<1.0 and prolonged fractionated potentials mV in SR). Accordingly, a significant correlation between PFP- in atrial fibrillation and sinus rhythm SR and the extent of LVA (<0.5 mV in SR) during SR was observed (Correlation coefficient: 0.399, p = 0.016; Figure 3D). As presented in Figure 3B, LVA in AF and SR maps were separately quantified using a bipolar voltage threshold of 0.5 mV in each rhythm. During AF, the absolute extent of LVA was measured at 25.85 cm2 (Q1–Q3: 13.78–45.28 cm2 ) and in SR Evaluation of concordance of at 10.45 cm2 (Q1–Q3: 4.08–32.88 cm2 ). The relative extent of fractionated potentials LVA (defined as the percentage of LA surface displaying LVA) was significantly more extensive in AF (median: 25.2%, Q1– We defined “CFP (Figures 1A,B)” if concomitant prolonged Q3:16.6–50.5%) than in SR (median: 12.3%, Q1–Q3: 4.7–29.4%, fractionation occurred at LA locations within a 6 mm radius p = 0.001). Detailed LVA distribution and comparison between during both SR and AF. The number of areas with CFP in AF and SR maps in each segment are listed in Supplementary the SR map is illustrated in Figure 4A, in accordance with Table 1. Notably, among all sites presenting PFP, 100% (Q1–Q3: PFP distribution, CFP also displayed preponderant distribution 89.7–100%) of PFP-AF were located in (or in the 1 cm-border in the anterior, posterior wall, and septum. Moreover, we Frontiers in Cardiovascular Medicine 06 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 TABLE 2 Spatial distribution of prolonged fractionated potentials-atrial fibrillation (PFP-AF) and prolonged fractionated potentials-sinus rhythm (PFP-SR). PFP-AF PFP-SR p value Number of areas Median Q1 Q3 Median Q1 Q3 Global LA 9.50 6.00 12.00 8.00 5.75 10.25 0.005 Anterior wall 4.00 2.75 5.25 3.50 2.00 4.00 0.059 Posterior wall 2.00 1.75 3.00 2.00 1.00 3.00 0.023 Septum 1.00 0.75 2.00 1.00 1.00 2.00 0.661 Roof 0.00 0.00 1.00 0.00 0.00 0.00 0.011 Inferior wall 0.00 0.00 1.00 0.00 0.00 1.00 0.088 Lateral wall 1.00 0.00 1.00 0.00 0.00 1.00 0.046 PFP-AF PFP-SR p value Distribution (%) Median Q1 Q3 Median Q1 Q3 Anterior wall 42.26 33.33 50.00 40.00 33.33 51.56 0.531 Posterior wall 21.83 16.67 33.33 22.65 9.58 34.09 0.266 Septum 15.48 4.17 20.00 17.42 7.81 25.89 0.088 Roof 0.00 0.00 10.28 0.00 0.00 0.00 0.038 Inferior wall 0.00 0.00 11.11 0.00 0.00 10.28 0.747 Lateral wall 6.46 0.00 11.11 0.00 0.00 11.46 0.751 PFP, prolonged fractionated potentials; AF, atrial fibrillation; SR, sinus rhythm; LA, left atrium. Q1, 25th percentile; Q3, 75th percentile. compared the percentage of CFP between PFP-AF and PFP-SR: may be related to functional and rhythm- and rate-dependent CFP was found at a significantly higher proportion of PFP-SR fractionation. sites than sites displaying PFP-AF (in PFP-SR: 80%, Q1–Q3: Additionally, we performed a sensitivity analysis to test 61.88–89.17% vs. in PFP-AF: 58.6% CFP, Q1–Q3: 48.86–81.39%, the correlation between LVA in AF and CFP: By setting the p = 0.008). Subgroup analysis in each segment is listed in Table 3; AF map as a reference, however, the correlation between CFP however, a significant difference in CFP percentage was only percentage in PFP-AF and LVA extent in the AF map failed observed in the anterior wall (p = 0.008). to reach significance (Correlation coefficient: 0.201, p = 0.226; Supplementary Figure 2). Correlation between concordance of fractionated potentials and low voltage Predictor of concordance of areas fractionated potentials by linear regression Given the significantly higher concordance between PFP- AF and PFP-SR that was observed during SR mapping, the In the current study, the percentage of CFP was defined as correlation between CFP and LVA was first analyzed in the an independent variable. As it was defined as the proportion SR voltage map. The distribution of CFP in LVA is shown of CFP in PFP-AF or PFP-SR. The absolute number of PFP in in Figure 4A. In accordance with PFP in LVA, CFP in either map was hereby considered as an intermediate factor. LVA displayed a consistent pattern in spatial distribution Additionally, we used the percentage of LVA as a parameter that mostly in the anterior wall, followed by the posterior to quantify the extent of LVA, which was divided by the wall and septum. Notably, a significant positive correlation surface of LA. In this context, LA surface and the number was also observed between the percentage of CFP in PFP- of PFP-AF or PFP-SR were excluded before linear regression SR and LVA extent in SR (Correlation coefficient: 0.475, for predictors of CFP percentage. As listed in Table 4, the p = 0.004; Figure 4B). This finding reveals that in patients extent of LVA in SR was the only significant predictor for with significant underlying LVA in SR, the percentage of percentage of CFP in PFP-SR (p = 0.009). However, when concordant fractionation is high, whereas patients with no/little using CFP percentage in PFP-AF as an independent variable, underlying LVA in SR display a highly variable degree of no significant predictor was identified, which is consistent concordance in fractionation between both rhythms, which with the results in correlation analysis. A sensitivity analysis Frontiers in Cardiovascular Medicine 07 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 FIGURE 4 Evaluation of concordance of fractionated potentials (CFP). (A) Illustrates the distribution of areas presenting CFP and those located in LVA in SR map. (B) Displays the correlation between percentage of CFP in PFP-SR and LVA extent in SR map. (C) Displays the ROC curve of high concordance (>80%) between PFP-AF and PFP-SR, which is predicted by LVA extent in SR. (D) Illustrates the diagnostic performance of optimal LVA extent threshold (16% of LA displaying LVA) to predict high concordance of fractionated potentials. CFP, concordance of fractionated potentials; LVA, low voltage area; PFP, prolonged fractionated potential; SR, sinus rhythm; AF, atrial fibrillation; LA, left atrium; PPV, positive predictive value; NPV, negative predictive value. TABLE 3 Percentage of concordance of fractionated potentials (CFP) in prolonged fractionated potentials-atrial fibrillation (PFP-AF) and prolonged fractionated potentials-sinus rhythm (PFP-SR). CFP as percentage of PFP-AF CFP as percentage of PFP-SR P value Distribution (%) Median Q1 Q3 Median Q1 Q3 Anterior wall 66.67 47.50 87.50 81.67 50.00 100.00 0.008 Posterior wall 66.67 25.00 100.00 90.00 25.00 100.00 0.452 Septum 50.00 0.00 100.00 50.00 0.00 100.00 0.504 Roof 0.00 0.00 50.00 0.00 0.00 56.25 0.414 Inferior wall 0.00 0.00 0.00 0.00 0.00 0.00 0.18 Lateral wall 0.00 0.00 100.00 0.00 0.00 100.00 0.102 CFP, concordance of fractionated potentials; PFP, prolonged fractionated potential; AF, atrial fibrillation; SR, sinus rhythm; Q1, 25th percentile; Q3, 75th percentile. was performed to validate the predictive value of LVA for The number of PFP-AF and PFP-SR remained intermediate CFP by setting the absolute number of areas presenting factors. As a result (Supplementary Table 2), LVA in SR CFP as an independent variable. In this context, LVA in was the only significant predictor for the number of CFP AF and SR maps were analyzed as an absolute value, and (p = 0.004), whereas the LVA in AF remained insignificant the LA surface was considered as a confounder instead. (p = 0.128). Frontiers in Cardiovascular Medicine 08 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 TABLE 4 Stepwise linear regression for a predictor of concordance of fractionated potentials. β coefficient p value Collinearity statistics Selected variable Tolerance VIF LVA percentage in SR map 0.393 0.009 1 1 Excluded variable Age 0.066 0.687 0.924 1.082 Sex –0.036 0.82 0.998 1.002 Intial Rhythm 0.015 0.927 0.918 1.09 BMI –0.088 0.583 0.963 1.038 LAD –0.084 0.615 0.89 1.123 LAV 0.01 0.952 0.899 1.113 LVEF –1.41 0.372 0.991 1.009 Creatine 0.014 0.929 0.946 1.057 Diabets –0.08 0.617 0.975 1.026 Stroke 0.203 0.196 0.996 1.004 Hypertension –0.227 0.155 0.953 1.05 CAD 0.135 0.394 0.984 1.016 LVA, low-voltage area; SR, sinus rhythm; VIF, variance inflation factor, BMI, body mass index; LAD, left atrial diameter; LAV, left atrial volume; LVEF, left ventricular ejection fraction; CAD, coronary artery disease. The extent of low voltage areas in sinus fractionation during both rhythms. 4. Presence of ≥16% low- rhythm predicts the degree of voltage extent (with mapping in SR and <0.5 mV threshold) was highly predictive of a high degree of spatial concordance (above concordance in fractionation 80%) between PFP-AF and PFP-SR. Based on the aforementioned results, we used the SR map as a reference and dichotomized the CFP percentage in SR to classify “high concordance” and “normal concordance.” Electrogram fractionation and Based on data distribution (median: 80%, Q1–Q3: 61.88– arrhythmogenesis 89.17%), we defined a CFP percentage of 80% as a cut-off value between high concordance and normal concordance Electrogram fractionation may result from wave collision, groups. Subsequently, the optimal threshold of LVA percentage pivoting, slow conduction, or conduction block (14). Substrate- in the SR map was determined using ROC analysis. As guided ablation therapy for persistent AF may be necessary shown in Figure 4C, an AUC value of 0.864 (95%CI: 0.747– for a subset of patients who do not respond well to PVI 0.981) was achieved. After calculating the Youden index, the and who do present atrial low-voltage substrate harboring optimal threshold was determined as 16% of LVA percentage fractionated delayed potentials. However, selective identification in the SR map with a sensitivity of 75% and specificity and ablation of fractionated sites that are involved in of 88.9%, the diagnostic performance of this threshold arrhythmogenesis and slow conduction are necessary to limit was calculated using a confusion matrix and illustrated in harm to healthy atrial myocardium. We recently identified PFP- Figure 4D. SR, also named “atrial late potentials (ALP),” as a potential underlying slow conduction substrate located at and around acute AF termination sites (12). Moreover, Yang et al. reported that a strategy of PVI plus ablation of PFP-SR and low- Discussion voltage areas mapped in SR improved outcomes in persistent AF patients (11). In a similar study, we reported improved The current study revealed four main findings: 1. PFPs sinus rhythm rates by performing PVI plus selective ablation of are more frequent and low-voltage areas more extensive when low-voltage areas with selective PFP-AF that extended > 70% mapping is performed during AF than SR. 2. PFPs both in AF of the local AF cycle length and were observable with high- and SR maps predominantly locate to the anterior, posterior temporal consistency (≥80% of beats displayed prolonged or wall, and septal LA walls. 3. Compared to prolonged fractionated rapid activity) (9). However, the relationship of PFPs in SR and sites in AF, those identified during sinus rhythm (PFP-SR) AF to each other and to the underlying low-voltage substrate has more frequently (in 80%) showed concomitant/concordant not been assessed yet. Frontiers in Cardiovascular Medicine 09 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 Definitions and differences of complex Substrate mapping for the guidance of fractionated electrograms, AF-nest, ablation therapy in persistent atrial and prolonged fractionated potentials fibrillation during atrial fibrillation and sinus rhythm The current study revealed that both LVA and prolonged fractionated sites are more extensive and frequent when While complex fractionated electrograms in AF (CFAE) mapping is performed in AF than SR. However, irrespective refer to a non-specific classification comprising all kinds of of the underlying rhythm (AF or SR), several recent catheter fractionated electrograms during AF (without further precision ablation studies revealed that PVI plus additional ablation of their duration, frequency, number of deflections, duration of low-voltage areas and prolonged fractionated potentials or percentage of the continuous activity, or their voltage), we may improve the rate of sinus rhythm maintenance at 12 previously defined PFP-AF (12) with following characteristics: months in the subset of patients with the low-voltage substrate. “electrograms in AF with high-temporal consistency (≥80% of Arrhythmia freedom was improved in most studies from 50% AF beats) for the following patterns: duration ≥70% of the local to about 70% after 12 months (9, 11, 16, 17). As targeting AF cycle length (AFCL) on a single or on multiple neighboring the fewer ablation targets (identified in SR rather than AF) bipoles of the circumferential catheter or electrograms with in SR results in the same success rates (as if the mapping continuous activity [see Figure 1A and (9, 12)]. PFP-SR or was done in AF), current substrate-based ablation therapies ALPs were defined as electrograms with ≥5 deflections (11) or should be reserved for PVI-non-responders who present low- electrograms with a delayed low-voltage component (median voltage substrate in SR. In these patients, the substrate- voltage 0.35 mV) following a first depolarization event on a guided strategy should primarily map and target low voltage single bipolar recording in SR, as illustrated in Figures 1B,C, and PFP-sites in SR (instead of AF) to limit harm to the 2. In contrast, Pachon et al. define “AF-nest” potentials as atrial myocardium. fractionation without a relationship to voltage values or low- Future studies should assess if PFP-AF sites with high- voltage areas (15). Moreover, using an altered filter setting, temporal consistency (if repeated mapping at those sites they convert high-voltage components of bipolar electrograms confirms PFP-AF within a mapping interval of 30 min) have recorded with 30–500 Hz to low-voltage highly fractionated a higher concordance to underlying slow conduction substrate signals using filter settings of 300–500 Hz. In addition, they during SR and to PFP-SR, and might therefore represent a focus and rely on the frequency spectrum of bipolar signals potential ablation target. (15). Durable PVI as the main ablative Rhythm- and substrate-dependency of treatment strategy in paroxysmal and electrogram fractionation persistent AF The current work reveals that prolonged fractionation PVI is the cornerstone of catheter ablation for AF with occurs more frequently during AF than in SR. Similarly, high-arrhythmia freedom rates at 1 year both in paroxysmal the underlying low-voltage substrate is more extensive in and persistent AF when using the recent ablation technologies AF than in SR, suggesting that some of the fractionations with a high rate of durable PVI (3, 18). However, multiple and low-voltage areas in AF might be functional (e.g., studies have shown high-arrhythmia recurrence rates in due to rapid propagation in AF, but not due to fixed patients with left atrial low-voltage substrate (9, 16, 17). slow conducting tissue). Moreover, we observed concordant We recently reported that left atrial low-voltage substrate is (occurring during both AF and SR) prolonged fractionation most frequently found in persistent AF patients aged over with high consistency (>80%) in patients with underlying low- 65 years and predominantly in women (19). Although initial voltage substrate > 16% of LA surface area during SR mapping single-center studies revealed improved arrhythmia freedom with <0.5 mV threshold SR (e.g., patient in Figure 2). In rates in patients with the left atrial low-voltage substrate contrast, substantial discrepancies between PFP-AF and PFP- with a “PVI plus ablation of LVA,” the recent randomized SR were observed in patients who had no/little underlying prospective study STABLE-SR-II did not report a significant (fixed) low-voltage substrate during SR. Therefore, ablation improvement in outcome with additional substrate ablation therapy targeting PFP-AF or LVA in AF will result in larger (3). Although Yang et al. targeted low-voltage areas in SR ablated tissue than strategies targeting PFP-SR or LVA in <0.4 mV and transitional zones <1.3 mV and included SR. ablation of fractionated potentials in SR, this approach Frontiers in Cardiovascular Medicine 10 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 did not significantly improve arrhythmia freedom. However, Limitations as the authors of that study commented, STABLE-SR-II included 300 persistent AF patients with an average age of We reported the spatial distribution of PFP in both AF 60 years only, most of whom (68%) were men. Therefore, and SR along with the correlation between their concordance only 41% of patients randomized to “PVI plus low-voltage and LVA extent. The presented mapping results are based on a ablation” actually had significant low-voltage substrate, and the limited patient cohort (38 persistent AF patients) who presented remaining 59% underwent PVI-only because of the absence for their first mapping and AF ablation procedure. We used a 20- of low-voltage areas. In STABLE-SR-II, patients presenting pole Lasso catheter (1 mm electrode size, 2–6–2 mm spacing), low-voltage areas had a low burden of the low-voltage which has similar mapping resolution/properties as a PentaRay substrate (median low-voltage area: 4.6% of LA surface). catheter. Bipolar voltage maps were acquired at high density These factors might have minimized the differences between (mean of 1,250 mapped LA sites per rhythm) at multiple bipole the groups. The rate of arrhythmia freedom at 18 months positions during mapping to eliminate inaccuracies due to the was 56.5% in patients with atrial low-voltage substrate angle of bipole to wavefront direction (23, 24). who underwent a PVI-only approach, whereas additional ablation of low-voltage areas achieved a 64.8% success rate. The study was underpowered and could not detect an outcome difference of 8%. Future larger-scaled studies are Conclusion needed to assess if ablation of low-voltage areas <0.5 mV Substrate mapping in SR vs. AF reveals smaller areas of and elimination of fractionated late potentials may improve low voltage and fewer sites with PFP. PFP-SRs are located outcomes in those AF patients with more extensive low- within low-voltage areas in SR. There is a high degree of spatial voltage substrate who have reduced success rates after PVI- agreement (80%) between PFP-AF and PFP-SR. These findings only. should be considered when substrate-based ablation strategies Two further clinical studies have assessed the additional are applied in patients with the left atrial low-voltage substrate value of substrate-based ablation targeting left atrial late with recurrent AF despite previous PVI. Gadolinium-enhanced areas (LGE) in MRI compared to a PVI-only approach. Although different MRI post-processing techniques were used to detect left atrial LGE-areas (DECAAF- II Trial used the Utah method, whereas, in the ALICIA Trial, the Data availability statement image-intensity-ratio > 1.2 method was applied), both studies revealed the absence of additional benefit of LGE-ablation to a The raw data supporting the conclusions of this article will PVI-only strategy (20, 21). be made available by the authors, without undue reservation. Therefore, existing clinical evidence supports a high-quality circumferential PVI as the primary ablation approach in both paroxysmal and persistent AF patients. A potential positive Ethics statement impact of additional low-voltage-based ablation should be evaluated in large prospective clinical studies, which focus The studies involving human participants were reviewed on patients with the low-voltage substrate. Low-voltage-based and approved by Ethics Committee of University of Freiburg. substrate ablation may be considered in those patients who The patients/participants provided their written informed present atrial low-voltage areas and recur after a first PVI consent to participate in this study. procedure. If substrate-based ablation is performed in PVI- non-responders, prolonged fractionated potentials (atrial late potential and low-voltage areas) should be mapped and targeted during sinus rhythm to prevent extensive ablation with harm to Author contributions non-arrhythmogenic atrial myocardium. All authors listed have made a substantial, direct, and A recent case series by Hirokami et al. revealed that highly intellectual contribution to the work, and approved it fractioned PFP-SR sites (with ≥7 deflections) collocated to for publication. non-PV trigger sites in patients with AF recurrence after a previous PVI approach (22). Their results confirm our previous observations that PFP-SR frequently occurs at AF driver sites (as identified by acute termination upon focal ablation) and Funding may constitute the basis for future substrate-based ablation approaches in patients with AF or atrial tachycardia and This study was supported by the Deutsche Herzstiftung underlying fibrotic disease (12). (German Heart Foundation). Frontiers in Cardiovascular Medicine 11 frontiersin.org Huang et al. 10.3389/fcvm.2022.1000027 Conflict of interest organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or The authors declare that the research was conducted in the claim that may be made by its manufacturer, is not guaranteed absence of any commercial or financial relationships that could or endorsed by the publisher. be construed as a potential conflict of interest. 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