ORIGINAL RESEARCH published: 21 March 2022 doi: 10.3389/fcvm.2022.819429 Structural Remodeling and Rotational Activity in Persistent/Long-Lasting Atrial Fibrillation: Gender-Effect Differences and Impact on Post-ablation Outcome Gonzalo R. Ríos-Muñoz 1,2,3*† , Nina Soto 1,4† , Pablo Ávila 1,2 , Alejandro Carta 1,2 , Edited by: Felipe Atienza 1,2,5 , Tomás Datino 1,2 , Esteban González-Torrecilla 1,2,5 , Shaojie Chen, Francisco Fernández-Avilés 1,2,5 and Ángel Arenal 1,2* Cardioangiological Center Bethanien 1 Department of Cardiology, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Hospital General Universitario (CCB), Germany Gregorio Marañón, Madrid, Spain, 2 Center for Biomedical Research in Cardiovascular Disease Network (CIBERCV), Madrid, Reviewed by: Spain, 3 Departamento de Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Madrid, Spain, Zhiyu Ling, 4 Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain, 5 Facultad de Medicina, Universidad Chongqing Medical University, China Complutense de Madrid, Madrid, Spain Emanuele Micaglio, IRCCS San Donato Polyclinic, Italy Sotirios Nedios, Background: Structural and post-ablation gender differences are reported in atrial Helios Kliniken, Germany fibrillation (AF). We analyzed the gender differences in structural remodeling and AF *Correspondence: mechanisms in patients with persistent/long-lasting AF who underwent wide area Gonzalo R. Ríos-Muñoz gonzalo.rios.munoz@secardiologia.es circumferential pulmonary vein isolation (WACPVI). Ángel Arenal arenal@secardiologia.es Materials and Methods: Ultra-high-density mapping was used to study atrial remodeling and AF drivers in 85 consecutive patients. Focal and rotational activity (RAc) † These authors have contributed equally to this work were identified with the CartoFinder system and activation sequence analysis. The impact of RAc location on post-ablation outcomes was analyzed. Specialty section: Results: This study included 64 men and 21 women. RAc was detected in 73.4% of This article was submitted to Cardiac Rhythmology, men and 38.1% of women (p = 0.003). RAc patients had higher left atrium (LA) voltage a section of the journal (0.64 ± 0.3 vs. 0.50 ± 0.2 mV; p = 0.01), RAc sites had higher voltage than non-RAc Frontiers in Cardiovascular Medicine sites 0.77 ± 0.46 vs. 0.53 ± 0.37 mV (p < 0.001). Women had lower LA voltage than Received: 21 November 2021 Accepted: 02 February 2022 men (0.42 vs. 0.64 mV; p < 0.001), including pulmonary vein (PV) antra (0.16 vs. 0.30 mV; Published: 21 March 2022 p < 0.001) and posterior wall (0.34 vs. 0.51 mV; p < 0.001). RAc in the posterior atrium Citation: was recorded in few women (23.8 vs. 54.7% in men; p = 0.014). AF recurrence rate was Ríos-Muñoz GR, Soto N, Ávila P, higher in patients with RAc outside WACPVI than those with all RAc inside WACPVI or Carta A, Atienza F, Datino T, González-Torrecilla E, no RAc (63.4 vs. 11.1 and 31.0%; p = 0.008 and p = 0.01). Comparison of selected Fernández-Avilés F and Arenal Á patients using propensity score matching confirmed lower atrial voltage (0.4 ± 0.2 vs. (2022) Structural Remodeling and Rotational Activity in 0.7 ± 0.3 mV; p = 0.007) and less RAc (38 vs. 75%; p = 0.02) in women. Persistent/Long-Lasting Atrial Conclusion: Women have shown more advanced structural remodeling at ablation, Fibrillation: Gender-Effect Differences and Impact on Post-ablation which is associated with a lower incidence of RAc (usually located outside the WACPVI). Outcome. These findings could explain post-ablation gender differences. Front. Cardiovasc. Med. 9:819429. doi: 10.3389/fcvm.2022.819429 Keywords: atrial fibrillation, gender, rotational activity, ultra-high density mapping, AF ablation Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF INTRODUCTION acquisitions were performed using a 20-pole multi-electrode catheter (PentaRay, Biosense Webster, Diamond Bar, CA, USA) Recent studies have reported the presence of multiple gender- and tissue proximity index (TPI) active during all the procedures. related differences in patients with atrial fibrillation (AF) For the ablation, an irrigated contact-force sensing catheter (1, 2). Women are older at the moment of the procedure was used (SmartTouch, or SmartTouch SF, Biosense Webster, and the probability of recurrences after catheter ablation (3) Diamond Bar, CA, USA). The ablation targeted a wide area is significantly higher (4, 5). A recent study reported that around the PVs antra to achieve pulmonary vein isolation (PVI); after multiple procedures, women were more likely to have additional lesions were delivered at the carinas. Ablation lesions recurrences, despite that pulmonary veins (PVs) reconnection were guided by the Ablation Index (CARTO3 V7, Biosense was less frequent (6). In long-standing AF, female sex was an Webster, Diamond Bar, CA, USA), targeting values of 350 or independent factor for presenting a higher degree of fibrosis 450 units at the posterior or anterior left atrial wall, respectively in the atria (7). The magnitude of this problem has been (21). Radiofrequency power was set at 35–50 W at the anterior recently highlighted. At 30 days after ablation, readmissions aspect of the veins and 25–45 W at the posterior aspect, with an were 48% higher in women than men, and the female sex irrigation flow of 30 ml/min using power control mode. was independently associated with readmission for AF/atrial tachycardia (AT) (8). These studies suggest that the structural Rotational and Focal Activity Mapping remodeling and AF drivers could be different in women. The CartoFinder module in the CARTO3 V7 system detected Multiple wandering wavelets and independent drivers have rotational and focal activity (FAc) from unipolar electrogram been proposed as the mechanisms maintaining AF (9–11), (EGM) activation patterns (17–19). The module uses the with studies ablating possible AF drivers outside PVs showing PentaRay EGMs and acquires windows of 30 s for an activation promising results (12, 13). Alleged AF drivers can be identified by sequence analysis (Figure 1). Acquisitions were accepted when wavefronts emanating from focal sources (foci or breakthrough the catheter splines were orderly deployed and in contact with sites) or by rotational activity (RAc) (11, 14–16). the atrial wall. Briefly, the module detects the local activation Ultra-high-density mapping and new tools for the detection of times (LATs) as the time instant of the maximum negative slope AF drivers (17–19), may better define the structural remodeling of unipolar EGMs. The CartoFinder module detects an RAc and the mechanisms maintaining persistent AF. We evaluated event if the LATs of the four concentric rings span >50% of the relationship between AF drivers and structural remodeling the dominant cycle length of the unipolar EGMs for two or and the gender effect. Additionally, the present study evaluated more consecutive beats (rotations). The acquisition point and the effect of the presence and anatomical distribution of alleged area covered by the catheter are highlighted on the CARTO3 3D AF drivers on AF recurrences after wide area circumferential mesh as a region of interest if a repetitive RAc is detected. Bipolar pulmonary vein isolation (WACPVI). EGMs of all acquisitions in which the CartoFinder detected RAc were reviewed by expert electrophysiologists and the presence MATERIALS AND METHODS of RAc was only confirmed if there were more than 2 rotations with staircase activation sequence and simultaneous acceleration Study Population of discrete EGMs and appearance of continuous activity (22) We studied a retrospective cohort of 90 (66 men and 23 (Figure 1A). women) consecutive patients with long-standing/persistent AF Moreover, CartoFinder provided FAc assessment. The who underwent ultra-high-density mapping during stable AF algorithm identifies unipolar EGMs that exhibit a QS pattern. and point-by-point WACPVI (16 redo procedures; 13 men, 3 The module identifies the earliest QS morphology within a women; p = 0.542). In 67 patients, AF was present at the arrival 10 mm radius and 50 ms window before its annotation. If the QS and at the electrophysiology laboratory, and in 18 patients it was pattern occurs for two or more consecutive beats, it is considered induced by rapid pacing and remained stable thereafter. In 4 repetitive (Figure 1B). patients (2 men and 2 women) AF could not be induced and The continuous electrical activity that is a footprint of therefore they were excluded since RAc mapping could not be RAc (22) was quantified in each CartoFinder acquisition. performed. The final sample size of the study was 85 patients The electrical burden of the bipolar EGMs was measured (64 men and 21 women). AF terminated (sinus rhythm or AT) using an automatic activity detection algorithm based on the in 10 patients. The study was approved by the ethics committee fully unsupervised Hidden Markov Models (HMMs) (23). The of the center. method automatically detects periods of electrical activity in AF bipolar EGMs and provides a score between 0 (no activity) and 1 Electrophysiological Study and (continuous activity), as shown in the Supplementary Material. Electroanatomical Mapping The electrophysiology study was performed under general Mapping Data Analysis anesthesia. Through the femoral vein, one decapolar catheter The EA maps and CartoFinder files (3D coordinates and EGMs was placed in the coronary sinus and transseptal puncture was signals) were exported for offline processing and analysis. The performed to advance the mapping and ablation catheters to the maps were merged into a reference LA mesh for analysis with an left atrium (LA). All patients underwent electroanatomical (EA) in-house algorithm (Supplementary Figure 1). A 3D atrial shell mapping during sustained AF (20). The EA mapping and signal with well-defined PVs and LAA was selected as the reference. The Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF FIGURE 1 | Rotational and focal activity detection. (A) Rotational activity (RAc) detection with CartoFinder. Left, local activation map interactive view. One cycle of RAc is represented. Right, bipolar and unipolar EGMs from the multi-electrode catheter are shown. Electrograms (EGMs) are ordered by rings. Bipolar EGMs Penta 1–2 to Penta 17–18 form the external ring, Penta 2–3 to Penta 18–19 the middle ring, and Penta 3–4 to Penta 19-20 the internal ring. Unipolar EGMs Penta 1–17 form the external ring, Penta 2–18 form the external middle ring, Penta 3–19 form the internal middle ring, and Penta 4–20 form the internal ring. The staircase activation pattern expands the complete cycle. Long duration and low-amplitude EGMs are recorded by nearby electrodes: Penta 15–16, Penta 19–20, and Penta 18–19, where the center of rotation is located. The RAc has been highlighted by arrows. EGMs, electrograms. (B) Focal activity detection with CartoFinder. Left, the electroanatomical (EA) map view of the catheter was placed on the left atrial appendage. Focal activation is highlighted in green. Right, the darkest background window intervals show when repetitive focal activation events are detected with CartoFinder. The QS patterns are highlighted. Bipolar and unipolar EGMs are shown. 3D meshes were pre-aligned by centering them at point [0, 0, 0] atrial roof, lateral wall, septum, anterior wall, atrial floor, in the 3D axes. Then, the algorithm applied a non-rigid Iterative and mitral ring. The PV antra limits were established at Closest Point (ICP) method to merge all atrial meshes into the 1 cm of the PV ostia but at the anterior aspect of the left reference one (24). The algorithm automatically projected the superior PV, in which the antrum limit was the ridge between voltage, cycle length, and driver locations onto the reference the vein and the LAA (Supplementary Figure 2). The EA mesh. This merging method preserves the atrial structures and area and volume of the left atrium was obtained from the anatomical information and avoids manual quantification or CARTO3 software excluding the PVs and mitral valve that were visual transformations, e.g., representing the LA 3D mesh with manually removed. a 2D projection. All the EA maps were reviewed to locate the RAc events with The 3D left atrial shell was manually segmented into respect to the PV isolation lines by an author blinded to the 9 areas: left atrial appendage (LAA), PVs, posterior wall, recurrence status. Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF TABLE 1 | Baseline characteristics of the patients. Rotational activity (RAc) and gender differences. Overall Men Women P-value* N 85 (100.0) 64 (75.3) 21 (24.7) - Age (years) 60.9 ± 9.5 59.5 ± 9.3 65.2 ± 8.8 0.014 Procedure number 1.2 ± 0.5 1.2 ± 0.5 1.2 ± 0.5 0.823 Comorbidities Heart failure 13 (15.3) 13 (20.3) 4 (19.0) 0.897 Hypertension 41 (48.2) 26 (40.6) 15 (71.4) 0.028 Diabetes mellitus 17 (20.0) 11 (17.2) 6 (28.6) 0.345 Dyslipidemia 30 (35.3) 20 (31.2) 10 (47.6) 0.272 COPD 5 (5.9) 5 (7.8) 0 (0.0) 0.326 Obstructive sleep apnea 17 (20.0) 15 (23.4) 2 (9.5) 0.219 Stroke 7 (8.2) 5 (7.8) 2 (9.5) 0.803 SHD 28 (32.9) 23 (35.9) 5 (23.8) 0.448 BSA (m2 ) 2.0 ± 0.2 2.1 ± 0.2 1.8 ± 0.1 <0.001 CHA2DS2-VASc 1.9 ± 1.5 1.5 ± 1.3 3.1 ± 1.3 <0.001 New York heart association functional 9 (10.6) 6 (9.4) 3 (14.3) 0.186 classification I 28 (32.9) 25 (39.1) 3 (14.3) II 30 (35.3) 22 (34.4) 8 (38.1) III 17 (20.0) 10 (15.6) 7 (33.3) IV 1 (1.2) 1 (1.6) Diagnosis of AF (years) 3.0 (3.6) 3.2 (3.8) 2.4 (2.9) 0.284 Echocardiographic parameters LVEF (%) 55.6 ± 10.8 55.5 ± 10.3 55.7 ± 12.5 0.953 LA area (cm2 ) 29.3 ± 23.9 30.7 ± 27.1 24.9 ± 5.1 0.176 LA area/BSA (cm2 /m2 ) 14.7 ± 11.6 14.9 ± 13.1 13.9 ± 2.9 0.477 Values in the table are n (%) or mean ± SD. COPD, chronic obstructive pulmonary disease; SHD, structural heart disease; BSA, body surface area; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; and LA, left atrium. *Categorical data with the chi-square test for categorical data, continuous variables using Welch’s two-sample t-test, and proportions based on normal z-test. Bold values indicates statistical significance. Discharge and Follow-Up RESULTS Antiarrhythmic drugs were maintained for 3 months and anticoagulation therapy for 8 weeks and thereafter it was based Patient Demographic Characteristics on the CHA2DS2-VASc score. Outpatient clinical follow-up was A total of 85 (64 men and 21 women) persistent/long- scheduled at 3, 6, and 12 months and included an ECG and a 24- standing patients with AF were included in the study. Baseline h Holter recording. Any symptomatic or documented episodes of characteristics are shown in Table 1. The AF duration was AF/AT longer than 30 s were considered as recurrence. 3.2 ± 3.8 years for men and 2.4 ± 2.9 for women (p = 0.284). A left ventricular ejection fraction (LVEF) <50% was observed in 16 of the patients. Overall, women were Statistical Analysis older, had a higher CHA2DS2VASc score (p < 0.001), and We present categorical values as absolute and relative a higher prevalence of hypertension (p = 0.028). These percentages (frequencies), and normally distributed variables values and the BSA were used as covariates to perform the are summarized by the mean and SD. We tested categorical propensity score matching technique. Supplementary Table 1 data with the chi-square test, continuous variables using includes the paired baseline analysis by gender with no Welch’s two-sample t-test, and proportions based on normal significant differences. z-test. Contingency tables were analyzed using the chi-tests or Fisher’s exact tests when appropriate. A logistic regression EA and AF Drivers Mapping propensity score matching was applied to reduce the effect Differences Related to RAc and Gender of baseline differences in the data population by gender, Differences between patients with and without RAc and Supplementary Table 4. The propensity score analysis is between men and women are shown in Table 2. Propensity detailed in the Supplementary Material. The analysis was score matching analysis is shown in Supplementary Table 2. performed in Python (PyCharm 2020.1.3) and JMP statistical The left atrial structural remodeling was assessed by ultra- software (14.3.0). All tests were 2-tailed, and a p < 0.05 was high-density mapping, 7.952.3 ± 3.325.8 points per map in considered statistically significant. men and 7.000.1 ± 2.924.2 points per map in women, p Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF TABLE 2 | Electroanatomical (EA) and AF drivers mapping. RAc and gender differences. Overall No RAc RAc P-value* Men Women P-value* N 85 (100.0) 30 (35.3) 55 (64.7) - 64 (75.3) 21 (24.7) - Electroanatomical mapping Num. EA points 7,717.0 ± 3,240.7 6,985.5 ± 2,961.6 8,116.0 ± 3,341.7 0.113 7,952.3 ± 3,325.8 7,000.1 ± 2,924.2 0.219 Num. cartofinder sites 36.4 ± 14.7 31.1 ± 15.6 39.3 ± 13.5 0.018 37.8 ± 15.0 32.3 ± 13.2 0.124 LA volume (cm3 ) 148.3 ± 38.7 135.3 ± 34.2 155.4 ± 39.5 0.017 153.4 ± 38.5 132.9 ± 36.0 0.033 LA area (cm2 ) 164.3 ± 31.7 150.8 ± 33.9 171.7 ± 28.0 0.006 167.9 ± 32.5 153.4 ± 26.9 0.049 LA volume/BSA (cm3 /m2 ) 74.0 ± 19.3 69.9 ± 19.2 76.3 ± 19.2 0.146 74.5 ± 19.1 72.6 ± 20.3 0.710 LA area/BSA (cm2 /m2 ) 82.0 ± 5.9 77.5 ± 18.0 84.5 ± 14.2 0.070 81.4 ± 16.0 83.3 ± 15.6 0.553 Total procedural time (min) 258 ± 36 241 ± 22 245 ± 41 0.560 260 ± 38 248 ± 33 0.172 Total mapping time (min) 61 ± 18 51 ± 17 66 ± 17 <0.001 63 ± 16 56 ± 25 0.239 Voltage mapping Mean bipolar voltage (mV) 0.6 ± 0.3 0.5 ± 0.2 0.6 ± 0.3 0.017 0.6 ± 0.3 0.4 ± 0.2 <0.001 LA area <0.5 mV (%) 66.8 ± 20.4 73.5 ± 18.7 63.1 ± 20.6 0.021 62.4 ± 19.9 80.0 ± 16.1 <0.001 LA area <0.35 mV (%) 52.5 ± 21.3 60.3 ± 21.5 48.2 ± 20.2 0.015 47.1 ± 19.0 68.7 ± 19.4 <0.001 LA area <0.1 mV (%) 20.3 ± 8.5 21.7 ± 8.0 19.6 ± 8.8 0.270 19.1 ± 7.6 24.2 ± 10.1 0.044 EGM signal analysis EGMs cycle length (ms) 174.9 ± 33.7 188.4 ± 42.4 167.5 ± 25.4 0.018 167.4 ± 23.0 197.7 ± 48.7 0.011 EGM electrical burden 0.3 ± 0.2 0.2 ± 0.1 0.3 ± 0.2 0.021 0.3 ± 0.2 0.2 ± 0.2 0.029 Mechanistic mapping: rotational activity drivers Num. patients with RAc 55 0 (0.0) 55 (100.0) 1.000 47 (73.4) 8 (38.1) 0.003 RAc sites per patient with RAc 3.8 ± 3.2 - 3.8 ± 3.2 - 3.9 ± 3.4 3.1 ± 1.4 0.296 RAc events per patient with RAc 82.8 ± 129.4 - 82.8 ± 129.4 - 89.3 ± 138.1 44.5 ± 35.3 0.073 RAc events per acquisition per patient 2.5 ± 4.4 - 2.5 ± 4.4 - 2.6 ± 4.7 1.8 ± 2.0 0.431 with RAc RAc event duration (ms) 586.2 ± 531.9 - 586.2 ± 531.9 - 586.8 ± 550.1 582.0 ± 378.0 0.863 Total RAc event durations per RAc 4,361.5 ± 3,536.4 - 4,361.5 ± 3,536.4 - 4,314.8 ± 3,613.6 4,703.3 ± 2,886.8 0.552 acquisition (ms) Dominant cycle length for RAc 161.3 ± 25.5 - 161.3 ± 25.5 - 159.0 ± 24.5 177.8 ± 26.3 0.002 acquisitions Mechanistic mapping: focal activity drivers Num. patients with FAc 85 (100.0) 30 (100.0) 55 (100.0) 1.000 64 (100.0) 21 (100.0) 1.000 FAc sites per patient with FAc 13.4 ± 9.2 10.4 ± 7.0 15.0 ± 9.9 0.017 14.3 ± 9.7 10.6 ± 6.9 0.066 FAc events per patient with FAc 793.6 ± 947.3 486.9 ± 432.8 960.9 ± 1,098.0 0.007 886.3 ± 1,037.9 511.0 ± 493.2 0.032 FAc events per acquisition per patient 20.7 ± 19.6 16.1 ± 13.8 23.2 ± 21.7 0.072 22.3 ± 20.8 15.5 ± 14.0 0.102 with FAc FAc event duration per FAc 274.6 ± 228.8 293.6 ± 248.7 269.2 ± 222.6 <0.001 268.0 ± 217.3 307.8 ± 277.2 <0.001 acquisitions (ms) Total FAc event durations per FAc 5,743.1 ± 5,907.5 5,135.9 ± 5,436.0 5,961.2 ± 6,053.1 0.030 5,803.8 ± 5,978.9 5,497.5 ± 5,602.9 0.473 acquisition (ms) Dominant cycle length for FAc 172.5 ± 29.2 181.4 ± 33.5 169.3 ± 26.7 <0.001 169.1 ± 27.0 186.2 ± 33.1 <0.001 acquisitions Values in the table are n (%) or mean ± SD. AF, atrial fibrillation; EA, Electroanatomical; LA, left atrium; RAc, rotational activity; FA, focal activity; EGM, electrogram. * Categorical data with the chi-square test for categorical data, continuous variables using Welch’s two-sample t-test, and proportions based on normal z-test. Bold values indicates statistical significance. = 0.219. Structural remodeling in the light of lower voltage RAc was found in 55 patients (64.7%), with a total of and larger low-voltage areas was more advanced in patients 4,555 RAc events in 208 different CartoFinder acquisitions. with no RAc and women (Figure 2). In women, only the Areas with RAc showed a higher voltage than no-RAC areas LAA and the lateral wall had an average voltage above the (0.77 ± 0.46 vs. 0.53 ± 0.37 mV, p < 0.001). Revision threshold of 0.35 mV which better correlates with delayed of bipolar sequences by electrophysiologists confirmed the enhancement MRI (25). presence of RAc in all acquisitions in which CartoFinder CartoFinder analyzed 46,425 bipolar EGMs from 3,095 detected RAc. acquisitions (37.8 ± 15.0 per man and 32.3 ± 13.2 per Rotational activity was more frequently recorded in men woman) in which the PentaRay splines were orderly deployed. than women (73.4 vs. 38.1%, p = 0.003). The anatomical Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF FIGURE 2 | Voltage analysis. (A) Bipolar voltage maps differences by gender. Bipolar voltage maps were obtained averaging all recorded points that were projected onto a reference left atrium (LA) mesh. (A) Averaged bipolar voltage map from 21 women in which the extension of low-voltage areas is appreciated, the LAA seems to avoid the extension of fibrosis. (B) Averaged bipolar voltage map from 64 men where the voltage is preserved in the whole atrium. (C) Bipolar voltage points distributions by gender. (D) Gender bipolar voltage differences by area. Bipolar voltage was significantly higher in men. In women only, the LAA had a voltage higher than 0.5 mV. LAA, left atrial appendage; PVs, pulmonary veins. Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF FIGURE 3 | Location of RAc. (A) Top: RAc in women. Bottom: RAc in men. RAc was located outside low-voltage areas. This explains why in women RAc converges in and around the LAA. In men as voltage around PV antra is well-preserved RAc is frequently observed. (B) Differences in RAc by regions. This figure shows the percentage (%) of patients with RAc at the pre-specified regions of the LA. RAc, rotational activity; LAA, left atrial appendage; PVs, pulmonary veins. locations of all rotational events are displayed in Figure 3A. Focal Activity There were gender differences in the anatomical distribution of The number of focal events was 67.454 (56.723 in men and 10.731 RAc (Figure 3B), such as the posterior wall (42.0% of men vs. in women), and were present in 1.136 different acquisitions 9.5% of women, p = 0.006) and the posterior atrium, such as (914 men and 222 women). All patients presented FAc and PVs and posterior wall (54.7% of men vs. and 23.8% of women; p the number of focal events per patient was significantly higher = 0.01). The LAA was the area that most frequently hosted RAc in men (p = 0.032, Table 2). The anatomical distribution events in women. of FAc was similar between genders (Figure 4). The area Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF FIGURE 4 | Location of focal activity. (A) Top: focal activity in women. Bottom: focal activity in men. Focal activity located in all the LA, with high density predominance in the LAA where it is more frequently detected for all the patients. (B) Differences in focal activity by regions. This figure shows the percentage (%) of patients with focal activity at the pre-specified regions of the LA. LAA, left atrial appendage; PVs, pulmonary veins. that exhibited more FAc was the LAA for both men and in Supplementary Table 3. The association between AF/AT women (98.4 vs. 90.5%, p = 0.086). recurrences and AF drivers was analyzed in 79 patients with a follow-up longer than the 3 months post-ablation blanking Predictors of Post-ablation AF/AT period window. After a mean follow-up period of 357 days, Recurrences AF/AT recurred in 36 patients, 25 men, and 11 women, with Table 3 shows the differences between patients with and a median recurrence of 177.5 days. The LA volume and area without recurrences. Propensity score matching analysis is shown were significantly larger in patients with recurrences than Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF TABLE 3 | Atrial fibrillation/Atrial tachycardia (AT) recurrence analysis. Overall Follow-up AF/AT-Free AF/AT Recurrence P-value* N 79 43 (54.4) 36 (45.6) Gender Men 58 33 (56.9) 25 (43.1) 0.634 Women 21 10 (47.6) 11 (52.3) Electroanatomical mapping Num. EA points 7,637.2 ± 3265.0 7,405.3 ± 3,047.5 7,914.1 ± 3,531.0 0.500 Num. CartoFinder sites 36.4 ± 15.0 32.1 ± 10.1 41.6 ± 18.1 0.007 LA volume (cm3 ) 148.2 ± 39.5 134.0 ± 33.1 165.1 ± 40.4 <0.001 LA area (cm2 ) 164.1 ± 32.5 155.8 ± 24.1 174.0 ± 38.5 0.017 Voltage mapping Mean bipolar voltage (mV) 0.6 ± 0.3 0.6 ± 0.3 0.5 ± 0.2 0.114 LA area <0.5 mV (%) 67.2 ± 20.1 63.3 ± 20.1 71.9 ± 19.1 0.047 LA area <0.35 mV (%) 53.1 ± 21.2 48.7 ± 20.1 58.3 ± 21.2 0.046 LA area <0.1 mV (%) 20.6 ± 8.5 19.2 ± 7.0 22.22 ± 9.8 0.130 EGM signal analysis EGMs cycle length (ms) 174.4 ± 80.6 176.2 ± 84.2 175.6 ± 82.0 0.851 EGM electrical burden 0.3 ± 0.3 0.3 ± 0.2 0.2 ± 0.2 <0.001 Mechanistic mapping: rotational activity drivers Num. patients with RAc 50 (63) 23 (53) 27 (75) 0.048 RAc sites per patient with RAc 3.7 ± 3.0 2.8 ± 1.8 4.5 ± 3.6 0.040 RAc events per patient with RAc 71.2 ± 110.1 57.9 ± 77.8 82.5 ± 130.5 0.424 RAc events per acquisition per patient with RAc 2.0 ± 3.0 1.9 ± 2.8 2.1 ± 3.1 0.799 RAc event duration (ms) 588.9 ± 459.7 591.2 ± 458.9 587.8 ± 460.1 0.887 Total RAc event durations per RAc acquisition (ms) 4,351.4 ± 3529.5 4,212.0 ± 3,363.6 4,425.2 ± 3,612.0 0.692 Dominant cycle length for RAc acquisitions 164.8 ± 24.4 167.0 ± 28.5 163.6 ± 21.8 0.397 Mechanistic mapping: focal activity drivers Num. patients with FA 79 43 (54.4) 36 (45.6) FA sites per patient with FA 13.4 ± 9.2 12.8 ± 8.8 14.2 ± 9.6 0.518 FA events per patient with FA 758.3 ± 901.4 640.8 ± 600.8 898.6 ± 1,147.1 0.236 FA events per acquisition per patient with FA 19.7 ± 18.1 19.4 ± 16.1 20.1 ± 20.3 0.870 FA event duration per FA acquisitions (ms) 276.8 ± 230.2 272.1 ± 222.2 281.1 ± 237.1 <0.001 Total FA event durations per FA acquisition (ms) 5,653.7 ± 5816.1 5,419.9 ± 5,544.3 5,898.5 ± 6,078.0 0.185 Dominant cycle length for FA acquisitions 173.5 ± 28.9 174.9 ± 30.3 172.1 ± 27.2 0.108 RAc presence location No RAc 29 (36.7) 20 (69.0) 9 (31.0) 0.002 RAc only inside WACPVI 9 (11.4) 8 (88.9) 1 (11.1) RAc outside WACPVI 41 (51.9) 15 (36.6) 26 (63.4) Values in the table are n (%) or mean ± SD. AF, atrial fibrillation; AT, atrial tachycardia; RAc, rotational activity; WACPVI, wide area circumferential pulmonary vein isolation. *Categorical data with the chi-square test for categorical data, continuous variables using Welch’s two-sample t-test, and proportions based on normal z-test. Bold values indicates statistical significance. those free of AF episodes. Patients with AF/AT recurrences DISCUSSION had a higher incidence of RAc, more RAc sites, and higher electrical burden. The differences between patients with and Main Findings without recurrences regarding the distribution of the RAc in This study describes the relationship between structural relation to the ablation line during WACPVI are also shown remodeling and AF drivers that could explain some in Table 3. When RAc was only recorded inside the ablation gender differences in patients with persistent AF. First, line, most patients were free of recurrences and there was a RAc distribution in the LA seems related to the degree strong association between RAc outside the ablation and AF/AT of structural remodeling which at the ablation time is recurrences which remained as the main predictor of recurrence more intense in women despite having a similar AF after being adjusted for LA volume, surface, and ≤0.5 mV area duration. Second, consequently with previous findings, (Table 4 and Figure 5A). women in comparison with men have much less RAc Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF which is commonly located outside the PV antra. Third, Structural Remodeling post-ablation AF recurrence was associated with RAc Voltage mapping was performed during AF based on previous outside WACPVI. data in which the correlation between low-voltage and contrast- enhanced MRI is significantly better when EGMs are acquired during AF than during sinus rhythm (25). Structural changes TABLE 4 | Predictors of AF recurrence analysis after WACPVI ablation. in LA in women are more extensive as suggested by the Univariate analysis Multivariate analysis lower average voltage and larger scar areas. Since AF duration was similar, these changes could be due to the fact that OR (95% CI) P-value OR (95% CI) P-value women were older and had more hypertension. Nevertheless, RAc outside 4.2 (1.6–11.2) 0.002 4.4 (1.5–13.8) 0.007 the analysis based on propensity score matching suggests that WACPVI differences in remodeling are not explained by differences in Scar (<0.5 mV) 5.4 (0.9–35.3) 0.06 10.2 (1.3–91) 0.1 risk factors alone, but are also due to a gender effect. A LA area (cm2 ) 83 (2.7–4,183) 0.01 13.0 (0.4–776) 0.8 previous study has revealed that women with longstanding LA volume (cm3 ) 69.9 (6.3–1,036.7) 0.001 32.0 (0.8–6462) 0.08 persistent AF had a higher degree of fibrosis that could be due to the inherent differential expression of fibrosis- RAc, rotational activity; WACPVI, wide area circumferential pulmonary vein isolation; LA, left atrium; OR, odds ratio; CI, confidence interval. Bold values indicates statistical related genes (7). Voltage mapping suggests that in women significance. fibrosis affects the posterior atrium more significantly than FIGURE 5 | (A) Example of a woman with AF recurrence after PVI. Left: RAc was detected only at the LAA, the remaining atrium had low voltage and RAc was not recorded inside the ablation line. Right: the rotational event expands the whole EGM cycle, highlighted with white arrows. The rotational event stops and the cycle length increases with almost simultaneous EGM activations. (B) Example of a man with no AF recurrence after PVI. The voltage is almost normal in the whole atrium (left), RAc was detected in the left inferior PV antra (right). The rotational event starts at the same time that acceleration of discrete EGMs appears (Penta 13–14 EGM) and fragmentation in middle ring electrodes (from Penta 3–4 to Penta 11–12 EGMs). AF, atrial fibrillation; PVI, pulmonary vein isolation; LAA, left atrial appendage; EGM, electrogram; PV, pulmonary vein. Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF the LAA, which seems to resist the advance of fibrosis from recurrence, especially in women, suggesting that there (Figure 2). are unidentified mechanisms other than RAc involved in AF recurrence after ablation. Rotational Activity With the use of new mapping techniques, several studies have Study Limitations suggested that rotors are a part of the electrophysiological AF This was a retrospective single cohort and single-center study. substrate (26), but controversy remains over whether the RAc is The proportion of women and men in this study was not balanced critical for the maintenance of AF or if it is merely due to the possibly representing the real practice in which women are collision of wandering atrial activation wave-fronts (27). underrepresented in catheter ablation series (34). In the study, CartoFinder software has been reported to identify with high we included 69 first ablation and 16 redo procedures, equally reproducibility RAc during both paroxysmal and persistent AF distributed among men and women (p = 0.542). Patients in when applied to basket catheter recordings (17). In this study, sinus rhythm in whom stable fibrillation was not induced to we applied the CartoFinder software to endocardial recordings allow mapping of the RAc were not included. The right atrium obtained with a high-resolution catheter that allows assessing the was not explored and remapping was not done after ablation. activation sequence with high-quality bipolar EGMs in which far- Ablation was not guided by RAc. We did not quantify the inter- field activity is canceled. The presence of RAc was not only based intraobserver correlation of RAc. on signal processing since all CartoFinder acquisitions were revised by electrophysiologists who confirmed the RAc when CONCLUSION the sequential activation spanned the whole cycle length and it coincided with the appearance of high-frequency low amplitude In women, structural remodeling at the ablation time is at the inner rings and the acceleration of discrete EGMs more severe and affects more intensively the posterior atrium. (Figure 5). The fact that high-resolution catheters were used Structural remodeling could determine RAc distribution. RAc to detect RAc and assess structural remodeling reinforces the outside the ablation line is the main predictor of AF/AT relationship between structural remodeling and the anatomical recurrence suggesting RAc is mechanistically involved in distribution of RAc. AF maintenance. The incidence of RAc was lower than in previous studies in which RAc was detected based on the signal processing of unipolar EGMs (15, 28, 29). It could be that high-resolution DATA AVAILABILITY STATEMENT mapping was more specific to detect RAc. Inaccuracies during The data of this study are available from the corresponding rotor identification may explain why the Randomized Evaluation authors on request. of Atrial Fibrillation Treatment With Focal Impulse and Rotor Modulation Guided Procedures (REAFFIRM) trial found no difference between rotor ablation and conventional ablation (30). ETHICS STATEMENT We have not observed RAc in low voltage areas which The studies involving human participants were reviewed and is consistent with prior studies (26). Computational studies approved by Local Ethics Committee of the institution and demonstrated that rotational drivers perpetuating AF were following the European and Spanish regulations on the subject localized in boundary zones between fibrotic and non-fibrotic (Code: GÉNERO-FA, Approval date: 8th March 2021). The tissue (31) and that the moderate levels of fibrotic tissue, i.e., Ethics Committee waived the requirement of written informed 40% of fibrotic elements, can anchor re-entry activity (32). consent for participation. Nevertheless, the higher levels of fibrosis can block the fast propagation of the electrical wavefronts since the interactions between myocytes are reduced (33). Low voltage areas probably AUTHOR CONTRIBUTIONS (because of extensive fibrosis) may have more difficulties for housing a functional re-entry, this explains the lower incidence of PÁ, AC, FA, TD, EG-T, and FF-A collected data and gave final RAc in the women group and suggests that RAc is not the main approval of the manuscript. ÁA, NS, and GR-M conceived and mechanism maintaining persistent AF in women and patients designed the study, analyzed the data, drafted the manuscript, with extensive fibrosis. and gave final approval of the manuscript. All authors substantially contributed to conducting the underlying research RAc and WACPVI Efficacy and drafting the manuscript. Although this study did not probe RAc as a mechanism that maintains persistent AF, the association between the presence FUNDING and dispersion of RAc and the post-ablation AF recurrences highlights the role of RAc in AF. RAc outside the ablation This study was supported by the Instituto de Salud Carlos area was the main predictor of AF recurrence and when III, Madrid, Spain (PI18/01895 and DTS21/00064), Red de RAc was included in the ablation line recurrences were very Terapia Celular from the Instituto de Salud Carlos III, low, suggesting that AF drivers were eliminated. However, the Madrid, Spain (RD16/0011/0029), Ricors—Red de Investigación absence of RAc outside WACPVI did not ensure freedom Cooperativa Orientada a Resultados en Salud – RICORS TERAV Frontiers in Cardiovascular Medicine | www.frontiersin.org 11 March 2022 | Volume 9 | Article 819429 Ríos-Muñoz et al. Drivers and Gender in AF (RD21/0017/0002), and the Sección del Ritmo de la Sociedad SUPPLEMENTARY MATERIAL Española de Cardiología (Grant: Beca de la Asociacion del Ritmo para formación en investigacion post-residencia en centros The Supplementary Material for this article can be found españoles de la Sección del Ritmo de la Sociedad Española de online at: https://www.frontiersin.org/articles/10.3389/fcvm. Cardiología), Madrid, Spain. 2022.819429/full#supplementary-material REFERENCES computational analysis of multielectrode recordings during atrial fibrillation and flutter in humans. JACC Clin Electrophysiol. (2017) 1. Anselmino M, Battaglia A, Gallo C, Gili S, Matta M, Castagno D, et 3:207–16. doi: 10.1016/j.jacep.2016.08.001 al. Atrial fibrillation and female sex. J Cardiovasc Med. (2015) 16:795– 18. Honarbakhsh S, Schilling RJ, Providencia R, Keating E, Sporton S, Lowe M, 801. doi: 10.2459/JCM.0000000000000239 et al. 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Hindricks G, Potpara T, Dagres N, Arbelo E, Bax J, Blomström-Lundqvist Copyright © 2022 Ríos-Muñoz, Soto, Ávila, Carta, Atienza, Datino, González- C, et al. 2020 ESC guidelines for the diagnosis and management Torrecilla, Fernández-Avilés and Arenal. This is an open-access article distributed of atrial fibrillation developed in collaboration with the european under the terms of the Creative Commons Attribution License (CC BY). The association of cardio-thoracic surgery (EACTS). Eur Heart J. (2021) use, distribution or reproduction in other forums is permitted, provided the 42:373–498. doi: 10.1093/eurheartj/ehaa612 original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Conflict of Interest: PÁ received teaching honoraria from Medtronic and served No use, distribution or reproduction is permitted which does not comply with these as an Advisory Board member for Boston Scientific. FA served as an Advisory terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 13 March 2022 | Volume 9 | Article 819429