Predictors of low‐voltage zones in patients with persistent atrial fibrillation eligible for catheter ablation: An observational study

The presence of low‐voltage zones (LVZs) in the left atrium (LA) is associated with the recurrence of atrial fibrillation (AF) following pulmonary vein isolation (PVI). However, there is variability and conflict in the data regarding predictors of LVZs as reported in previous studies. The objective of this study was to identify predictors for the presence of LVZs in a cohort of patients with persistent AF.

Although pulmonary vein isolation (PVI) remains the most commonly employed ablation treatment for atrial fibrillation (AF), the success rate in achieving arrhythmia freedom post-PVI is limited, particularly in cases of persistent AF.The success rate for paroxysmal AF is approximately 80%, 1 whereas it is only about 60% for persistent AF, 2,3 which highlights the necessity of developing additional ablation strategies for persistent AF.
Low-voltage zones (LVZs) in the left atrium (LA), as identified by electroanatomical voltage mapping, are considered indicative of atrial fibrosis. 46][7] Numerous randomized and non-randomized studies indicate that ablating LVZs, in addition to PVI, enhances the success rate of ablation, 6,8 while some studies do not support this approach. 9[12][13][14] Therefore, the aim of this study is to delineate the prevalence and distribution of LVZs outside the pulmonary vein ablation lines, and to identify predictors for LVZs in a substantial cohort of patients with persistent AF.

| Study design and patients
This observational cross-sectional study included patients ≥18 years old with symptomatic persistent AF (continuously during 1 week to 1 year) or longstanding persistent AF (continuously during more than 1 year) scheduled to undergo an AF ablation for the first time.
Participants were consecutively recruited from May 2020 to March 2023 at two sites: the Department of Electrophysiology at Karolinska University Hospital, Stockholm, Sweden, and the Department of Electrophysiology at Linköping University Hospital, Linköping, Sweden.Exclusion criteria included LA diameter >55 mm (as measured in the parasternal long axis via transthoracic echocardiography), acute coronary syndrome within the preceding 12 weeks, severe aortic or mitral valvular heart disease, adult congenital heart disease, previous percutaneous or surgical AF ablation or atrioventricular junction ablation, previous surgery that included left or right atrium, medical condition likely to limit survival to less than 1 year, contraindication for oral anticoagulants (OAC), AF attributed to a reversible condition, pregnancy, or inability or unwillingness of the patient to provide informed consent.The reason for excluding patients with severe aortic or mitral valve disease from the study was that these individuals are generally not considered eligible for AF ablation at the participating centers.We established a cutoff for the LA diameter at 55 mm, in accordance with the limits utilized in some other studies. 3,15Coronary artery disease (CAD) was defined as a history of myocardial infarction or angina pectoris accompanied by significant stenoses as evidenced by coronary angiography.No withdrawal of antiarrhythmic drugs (AADs) was undertaken before the procedure.All baseline data were prospectively collected before the procedure.The study protocol and all data collection were approved by the Swedish ethical review authority (no.2019-05251), and patient data were collected according to the institutional ethics guidelines.All participants provided written informed consent before their inclusion in the study.Study data were pseudonymized and securely stored using Research Electronic Data Capture (REDCap) version 11.1.15,an electronic data capture tool hosted at Karolinska Institute. 16,17

| Collection of voltage maps
Anticoagulation and electrophysiology procedures were conducted in accordance with conventional and local standards.Briefly, all patients were treated with OAC for a minimum of 3 weeks before the procedure, and heparin was administered during the procedure to maintain the activated clotting time (ACT) level above 300 s.All patients underwent transesophageal echocardiography or computed tomography (CT) before the ablation procedure to rule out the presence of intra-atrial thrombosis.If CT scans were performed, they were generally not merged into the electroanatomical mapping system.After access to the LA via transseptal puncture, an anatomical map was created using the three-dimensional electroanatomical system (CARTO3, Biosense Webster, Inc.) with a multipolar catheter with five splines, each with four 1-mm wide electrodes with 2-6-2 mm spacing (PentaRay: Biosense Webster) or an eight-splined catheter each with four 1-mm wide electrodes with 2-2-2, 2-5-2, or 3-3-3 mm spacing (OctaRay; Biosense Webster).All bipolar voltage maps were collected during coronary sinus (CS) pacing at a cycle length of 600 ms.If the patient arrived for the procedure in sinus rhythm, the bipolar voltage map was collected concurrently with the anatomical map.Conversely, if the patient presented in AF or atrial flutter (AFL), cardioversion (CV) was performed either before or after PVI.Subsequently, the bipolar voltage map was collected during CS pacing at 600 ms following CV.
The CONFIDENSE Module (Biosense Webster, Inc.) was utilized for continuous mapping, with manual interpretation of all points to ensure adequate tissue contact.The following settings were employed: 2-5% cycle length (CL) filtering, 4-millisecond (ms) local activation time (LAT) stability, 4-mm position stability, and maximum density.In cases where an LVZ with <0.5 mV was detected near the pacing pool of the CS catheter, the bipolar voltage was reconfirmed during sinus rhythm.If the voltage in this area was >0.5 mV during sinus rhythm, it was not classified as an LVZ.If an LVZ was detected with the multipolar mapping catheter, the area and the border zones were confirmed with the ablation catheter (SmartTouch or Q-Dot, Biosense Webster, Inc.) to ensure adequate tissue contact.If an LVZ in the septal area was evident, 3 cm 2 around the transseptal puncture was subtracted from the area to avoid misclassifying the membranous part of the septum as an LVZ.

| Analysis of voltage maps
The LA was divided into seven anatomical zones as described by Yagishita et al. 18 : anterior, roof, posterior, inferior, septal, lateral, and left atrial appendage (LAA) (Figure 1).The analysis of the voltage maps was conducted in a blinded manner to the operator before the performance of PVI, regardless of whether the collection of the maps occurred before or after PVI.Patients were categorized into two groups depending on whether a significant LVZ was present or absent.Additionally, areas exhibiting a voltage of <1.0 mV were classified as transition zones (TZs), in line with the categorization established by Bergonti et al. 19

| Voltage mapping
A voltage map was collected for all cases.PentaRay was utilized in 93.8% of the procedures and OctaRay in 6.1%.The mean number of mapping points was 1850 ± 1100 for cases using the PentaRay catheter and 2933 ± 1585 for those using the OctaRay catheter.
Significant LVZs were identified in 25.7% of the cases (n = 113).
The median area of the LVZs was 12.7 (20.3) cm 2 .The distribution of the LVZs is further detailed in Table 2 and
A receiver operating characteristic (ROC) curve analysis of the final multivariable model yielded an area under the curve (AUC) of 0.829 (95% CI: 0.784-0.873),as depicted in Figure 4.In conducting a multivariable analysis with age and LAD as dichotomous variables, we found that for patients aged 65 years or older, the OR nearly tripled (OR: 2.82, 95% CI: 1.44−5.53,p = .003).Similarly, for patients with a LAD of 45 mm or more, the OR also more than doubled (OR: 2.25, 95% CI: 1.30-3.92)(Table S2).A sensitivity analysis was conducted using only electroanatomical maps obtained with the Pentaray catheter.
This analysis yielded a multivariate model with the same independent predictors as those identified in the main analysis, detailed in Table S3.

| DISCUSSION
The most significant finding of this study is the identification of several independent predictors for LVZs, namely female sex, advanced age, CAD, and an enlarged LA.The ROC curve analysis demonstrated a high predictive probability for the model, with an AUC of 0.829.The precise extent of LVZs that increase the risk of arrhythmia recurrence following PVI remains indeterminate.
However, evidence suggests that the risk of atrial arrhythmia recurrence intensifies as LVZs expand. 20Consequently, we have chosen a cutoff of 3 cm² for the size of LVZs, underpinning this decision with the rationale that smaller LVZs might not significantly heighten the risk of arrhythmia recurrence.We also took into account that a small LVZ might be influenced by a few inaccurately    | 1145 ablation in persistent AF was associated with a statistically significant reduction in arrhythmia recurrence. 21Anticipating the presence of LVZs may be useful in planning ablation procedures for patients.This  13 comprising 119 patients, the multivariable analysis identified age ≥67 years, LA volume/body surface area (BSA) ≥ 68 mL/m², and eGFR ≤85 mL/min/1.73m² as significant predictors.Conversely, a BMI ≥ 26 kg/m² was found to be a negative predictor of LVZs.In the study conducted by Ammar-Busch et al., 12 which included 70 patients with persistent AF, female sex, older age, and larger LA size were found to be independently associated with the presence of LVZs.Ikoma et al. 14 22 The predicted probability of our model in the ROC curve analysis was high, showing an AUC of 0.829 (95% CI: 0.784-0.873).It is worth noting that this analysis was not performed in most previous studies, making it difficult to compare our results with theirs.In our study, we exclusively included cases of persistent and long-standing persistent AF.This decision was based on evidence from previous studies, which have identified persistent AF as an independent predictor for LVZ.

| Age
Consistent with findings from previous studies, our study also demonstrated that increasing age is a predictor of LVZs.More advanced atrial fibrosis in older patients has been demonstrated by MRI. 23The mechanisms behind this are complex and not yet fully understood, involving key processes such as fibroblast activation and collagen production. 24

| Female sex
In line with the findings of the majority of previous studies, our study also indicates that female sex appears to be a predictor of LVZs.Some studies suggest that menopause-associated reduction in estrogen affects epicardial fat, pro-inflammatory signaling pathways, and fibrotic remodeling mechanisms, 25 which may influence the development of LVZ.One study has demonstrated that females exhibit more advanced atrial remodeling as evidenced by highdensity voltage mapping, along with a lower mean voltage, 26 suggesting that hormonal factors play a significant role.

| LA size
In our study, we observed that dilated LA is a predictor of LVZ, a finding that aligns with the results of several previous studies.The pathogenesis of structural, functional, and electrical remodeling in relation to atrial dilatation has been described by Thomas et al. 27

| Coronary artery disease
Contrary to the findings of most previous studies, we identified CAD as an independent predictor of LVZs.However, it is noted in existing literature that patients with CAD have a higher risk of developing AF. 28,29Hojo et al. 30  in conjunction with ventricular infarctions and this is also associated with supraventricular arrhythmias. 31Research conducted on pigs has also demonstrated that atrial infarctions induced in these animals correspond to LVZs detected through voltage mapping. 32

| Other factors
Diabetes mellitus has been identified as an independent predictor of LVZs in some previous studies. 10,11In our study, we did not observe this association, however, given its potential clinical importance, we opted to include it in our final multivariable regression analysis, despite its lack of statistical significance in the univariable analysis.
The prevalence of diabetes mellitus in our cohort was lower, at 8%, compared to 17% and 16% in the other studies, respectively and this discrepancy in prevalence may account for the differences in findings.The type of AF is a well-recognized factor affecting outcomes following PVI, with evidence showing better results in cases of paroxysmal AF compared to persistent AF. 33,34 All of the aforementioned studies investigating predictors of LVZs and encompassing both paroxysmal and persistent AF have identified persistent AF as an independent factor associated with LVZs.Our study exclusively included patients with persistent AF.However, we did not find an association between the duration of AF, including both the time since the first onset of AF and the length of the longest AF episode, and the presence of LVZs.Additionally, our study found no significant difference in outcomes between patients with persistent and longstanding persistent AF.These findings are in line with those reported in the previous study by Ammar-Busch et al. 12

| Clinical implications
A considerable proportion (25.7%) of patients with persistent AF in our cohort exhibited LVZs.The ability to predict the presence of LVZs before ablation is of importance, especially during the planning phase of the ablation procedure.Women aged 65 or older, with a LAD of 45 mm or more and CAD, were identified as a high-risk population for the presence of LVZs.In contrast, men under the age of 65, without CAD and with an LAD of less than 45 mm, are considered to be at low risk for LVZs.Patients assessed with low risk of LVZs may be considered for single-shot AF ablation, while patients identified with high risk of LVZs should be planned for a more advanced procedure using radiofrequency ablation.However, additional randomized studies are required to thoroughly assess the potential advantages of ablation targeting LVZs.

| Limitations
This study has some limitations that warrant attention.First, the predictors identified in this study have not been tested in a separate prospective cohort to assess their validity, presenting a potential subject for future research.Second, our study lacks follow-up data to demonstrate the outcomes of ablation in this cohort.However, the primary objective of this study was to describe the prevalence and identify predictors of LVZs, which have been associated with poor outcomes in numerous previous studies.Third, the voltage maps in this study were collected during CS pacing rather than in sinus rhythm, which could potentially alter the distribution of LVZs.
However, it is important to note that all LVZs located near the pacing pool of the CS catheter were subsequently confirmed during sinus rhythm.The primary rationale for collecting the voltage maps during CS pacing was to ensure a stable rhythm throughout the mapping.Fourth, some of the maps were collected before PVI and some after PVI, which may have influenced the distribution of LVZ.
However, considering that measurements of LVZs were confined to areas outside the wide antral circumferential ablation lines, and that operators were blinded to the voltage maps before PVI, this issue is deemed to be of minor concern.Fifth, two different mapping catheters were used (PentaRay and OctaRay); however, the sensitivity analysis (analyzing only PentaRay maps) did not reveal any significant alterations in the results.An additional limitation of this study is the underrepresentation of female participants, which could be attributed to physician selection bias.This may be influenced by the generally later onset of atrial AF in women and the perceived higher risk of complications during the ablation procedure. 35Finally, our study was limited to patients with persistent AF, rendering the findings inapplicable to those with paroxysmal AF.

| CONCLUSIONS
Twenty-five percent of patients with persistent AF exhibited significant LVZs outside the pulmonary veins.Advanced age, female sex, dilated LA, and CAD were identified as independent predictors of LVZs in the LA, thereby indicating a higher risk of AF recurrence following PVI.These findings should be considered when ablating persistent AF and suggest that ablation treatment should be individualized to each patient.

DATA AVAILABILITY STATEMENT
The data underpinning this article are not available for public disclosure due to the privacy considerations of the individuals involved in the study.Access to the data will be granted upon reasonable request to the corresponding author, subject to compliance with institutional ethical guidelines, regulations, and legislation.
NORDIN ET AL.
| 1147 Continuous variables were assessed for normal distribution using the Shapiro-Wilk test.Data with normal distribution are presented as means ± standard deviations (SDs), and data without normal distribution are presented as medians and interquartile range (IQR).Continuous variables were compared using Student's t test or the Wilcoxon rank-sum test, as appropriate.Categorical variables are presented as counts and percentages and were compared using Pearson's χ2 test or Fisher's exact test, as appropriate.Variables were examined for correlation using Pearson's correlation coefficient, and no significant correlations were identified.Binary logistic regression, including univariable and multivariable backward logistic regression analyses, was employed to identify independent predictors for significant LVZs in the LA.Variables tested were demographical data, comorbidity, echocardiographic, and biochemical data.Variables incorporated into the final model were either statistically significant in the univariable analysis or deemed clinically relevant.Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the factors included in the final regression model.All tests were two-sided and a p value < .05 was considered statistically significant.A sensitivity analysis focused solely on cases mapped with PentaRay was also performed.All analyses were carried out using STATA SE version 16.1 (Stata Corporation).
illustrated in Figure 1.The anterior wall of the LA was the most common location for LVZs, and 75 patients (66.4%) had LVZs in more than one part of the LA.Examples of the voltage map can be viewed in Figure 2.Among the 326 cases without significant LVZs (≥3.0 cm²), 131 (40.3%) exhibited transition zones (TZs) characterized by a voltage of less than 1.0 mV.The septal part was the most common location for these TZs.F I G U R E 1 Distribution of significant LVZs.AP, anteroposterior; LAA, left atrial appendage; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; LVZ, low-voltage zone; PA, posteroanterior; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein.

F
I G U R E 2 (A) Voltage map showing anterior LVZ of 10.5 cm 2 .(B) Voltage map showing posterior LVZ of 8.7 cm 2 .AP, anteroposterior; LVZ, low-voltage zone; PA, posteroanterior.takenpoints due to poor contact.Contradictory results have been observed in randomized trials that aim to clarify the benefits of ablating fibrotic areas in addition to PVI.ERASE-AF 8 reported improved outcomes in terms of arrhythmia freedom with the addition of LVZ ablation, however DECAAF II,9 where atrial fibrosis was guided by magnetic resonance imaging (MRI), these results were not found.A meta-analysis, which included 11 studies encompassing both randomized and non-randomized trials, revealed that LVZ T A B L E 3 Predictors of significant LVZ.
predictive information could guide decisions to opt for longer and more advanced ablation procedures, and to potentially forgo the use of single-shot devices.In patients who exhibit few symptoms but possess a high risk for LVZs, the option of ablation might be reconsidered due to the potential for poor prognosis.Multiple scoring systems have been proposed for the prediction of LVZs and rhythm outcomes.The DR-FLASH score, is derived from a study involving 238 patients, of which 152 had persistent AF.This score incorporates several factors: diabetes mellitus, renal dysfunction, the persistent form of AF, LA diameter greater than 45 mm, age over 65 years, female sex, and hypertension.In the SPEED score, 10 which analyzed a cohort of 1004 patients, including 513 with persistent AF, several factors were independently associated with the presence of LVZs.These factors included female sex, persistent AF, age of 70 years or older, elevated brain natriuretic peptide levels of ≥100 pg/mL or NTproBNP levels of ≥400 pg/mL, and diabetes mellitus.In a study of a cohort with persistent AF by Schade et al., reported that a high coronary artery calcium score, as measured by coronary CT, serves as an independent predictor of LVZs, with this association being particularly pronounced in men.The arterial supply to the LA is primarily provided by branches originating from the right coronary artery or the left circumflex artery.In the literature, atrial infarctions, which could potentially lead to fibrosis and LVZs, are almost invariably described F I G U R E 4 Receiver operating characteristics curve analysis of the association between factors included in the multivariable regression model and prevalence of LVZ.AUC, area under the curve; LVZ, low-voltage zone.
This work was supported by the Swedish Research Council (grant/