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Evaluation of the atrial substrate based on low‐voltage areas and dominant frequencies after pulmonary vein isolation in nonparoxysmal atrial fibrillation

Abstract Background This study aimed to evaluate the atrial substrate in the left atrium (LA) by low‐voltage areas (LVAs) and high‐dominant frequencies (DFs) after circumferential pulmonary vein isolation (PVI) in nonparoxysmal atrial fibrillation (AF). Methods In 70 patients with nonparoxysmal AF patients (41 persistent AF), LA voltage maps were created during sinus rhythm by external cardioversion after PVI and DF mapping. The patients were divided into AF‐free and AF‐recurrent groups. Results The AF freedom rate without antiarrhythmic drugs was 69.0% after PVI after 1 procedure during a 12‐month follow‐up. There was a significant difference in the LVA (<0.5 mV)/LA surface area after PVI between the AF‐free and AF‐recurrent groups (15% vs 23%, P = .033). AF freedom was significantly greater in those with LVAs of ≤24% than in those with LVAs of >24% during 12 months of follow‐up (78.6% vs 53.8%, Log‐rank test P = .020). Fifty‐six (72%) of the 78 high‐DF sites (≥8 Hz) overlapped with LVAs. Thirty‐one (55%) of 56 high‐DF sites overlapped with LVAs that existed at LVA border zones. There were no significant differences in number of high‐DF sites that overlapped with LVAs in the LA between the two groups. However, in persistent AF patients, the max‐DF value in the LA exhibited a significant difference between the two groups (P = .008). Conclusions LVAs were associated with AF recurrences after PVI in nonparoxysmal AF patients and overlapped with many high‐DF sites. PVI alone may be enough to treat patients with mild‐to‐moderate extent (≤24%) of LVAs.

reduction in the rate of recurrent AF has been found when either linear ablation or ablation of CFAEs was performed in addition to PVI. 4 Meanwhile, atrial sites that represent local electrograms with high-dominant frequencies (DFs≧8 Hz) may be associated with AF maintenance. 5 Spectral analysis and frequency mapping identify localized sites of high-frequency activity during AF in humans in paroxysmal and permanent AF. Ablation at these sites results in prolongation of the AFCL and termination of paroxysmal AF (who may have relatively less LVAs), indicating their role in the maintenance of AF. 6 Therefore, high-DF sites as surrogates for localized sources maintaining AF were potential AF ablation targets. A recent study reported that a high-DF site ablation following PVI was effective in paroxysmal AF patients and nonparoxysmal AF patients with continuous AF for a duration of a few years. 5 However, the significance of DF-guided ablation is controversial. 7 Meanwhile, localized electrical sources (rotor and focal impulse) have been reported to be prevalent sustaining mechanisms of human AF using a specific computational mapping device. 8 The patients who underwent a FIRM (focal impulse and rotor modulation)-guided ablation maintained a higher freedom from AF.
Low-voltage areas (LVAs) as detected by LA voltage mapping have been shown to be a predictor of atrial tachycardia and AF recurrence after AF ablation. 9,10 LVAs indicate atrial structural remodeling involving atrial fibrosis and scar tissue. Although various additional LVA-guided substrate modifications after PVI have been reported in nonparoxysmal AF patients with LVAs, the outcome and approach vary widely according to the size and distribution of the LVAs. [11][12][13] A tailored LVA-guided ablation may need a personally adapted large or complicated lesion design in some patients. However, it is difficult to modify the diffuse fibrotic atrial areas or massive fibrosis. Whether all LVA sizes should be potential targets for modification or not remains unclear.
Further, high-DF sites can be recorded not only in LVAs but also healthy atrial myocardium. The relationship of the atrial substrate between LVAs and sites with high-DFs has not yet been evaluated.
This study aimed to evaluate relationship of the LA atrial substrate between LVAs and high-DFs sites after circumferential pulmonary vein isolation in nonparoxysmal AF.

| Study population
This study included 70 patients (65 AE 9 years) with AF who underwent catheter ablation at our institution between July 2014 and December 2015. The patients included 41 with persistent AF and 29 with long-standing persistent AF (mean duration 22 AE 31 months).
Persistent AF was defined as AF lasting ≥7 days but <1 year and long-standing persistent AF as continuous AF lasting ≥1 year. 14 All antiarrhythmic drugs were discontinued for at least 5 half-lives, and no patients received any oral amiodarone therapy before the electrophysiological study. The protocol for this research project has been approved by a suitably constituted Ethics Committee of the Institution of Gunma Prefectural Cardiovascular Center (Date of IRB approval; January 23, 2017; Approval number, 28017) and it conforms to the provisions of the Declaration of Helsinki. All patients provided written informed consent for the electrophysiological study, ablation procedure, and use of their anonymized data in this study.  5 The points in each region were similar in number and nearly equally distributed.

| Ablation procedure
The PVI was performed guided by two 7-F decapolar circular catheters (Lasso, Biosense-Webster, Inc.) positioned at the ipsilateral PV ostia. At the anterior aspect of the left PVs, an ablation line was created along the ridge between the LAA and PV ostium. Each radiofrequency (RF) energy application was delivered for 40s. A 3.5 mm irrigated tip RF catheter (Safire, St. Jude Medical Inc.) was used with the temperature limited to 42°C and power to 30W (with a flow rate of 13 mL/min). A maximum power of ≤25W was used while delivering energy to sites near the esophagus. After the elimination or dissociation of the PV potentials, exit block was confirmed by pacing from circular catheters placed within the PVs.
After the PVI, frequency analyses were performed. And LA voltage map was constructed during sinus rhythm (SR) after external cardioversion. The procedure was completed with a cavotricuspid isthmus ablation in all patients who regained sinus rhythm.

| Frequencies analysis
DF mapping was performed during AF after PVI. The fast Fourier transform (FFT) method has been described previously. 5,6,15 Recordings at each site were 5 seconds in length using a high-density (HD) 20-pole mapping circular catheter (St. Jude Medical, Inc.). Signals were truncated to 5 seconds at sampling rates of 1000 Hz, providing 4096 points for analysis (resolution 0.50 Hz). The signals were rectified and processed by a Hanning window function and filtered from 2 to 20 Hz. A manual entry of the DF value was used into the NavX system. The point DF was determined as the frequency associated with the maximum peak power of the spectrum. Only DF points with a regularity index >0.2 were included. 6,15 The high-DF sites were defined as DFs of ≥8 Hz. 5,6

| LVAs mapping and analysis
After circumferential PVI, a detailed bipolar LA voltage map was constructed during SR after external cardioversion. The method of LVA mapping has been described previously. 11 The mapping points were systematically acquired with a decapolar circular catheter (Inquiry Optima or Reflexion Spiral; St. Jude Medical). An interpolation threshold of 10 mm was used for the surface color projection. Filling all color gaps provided a minimal map density in all parts of the LA.
Adequate endocardial contact was assessed by stable electrograms and consideration of the distance to the geometry surface. Only true sinus beats were selected. Bipolar electrograms were filtered by a bandpass to frequencies between 30 and 500 Hz. In accordance with previous studies 9, 16 LVA was defined as area with bipolar peakto-peak electrogram amplitude <0.5 mV and electrical scar areas high-DF sites were located within LVAs or at their border zones. 17

| Postprocedure care and follow-up
A clinical interview, surface ECG, and 24-h Holter monitoring were performed 1 day after the procedure and repeated 1, 3, 6, 9, and 12 months after the catheter ablation. Antiarrhythmic medications were continued for at least 3 months to prevent any early recurrences. AF recurrence was defined as sustained AF lasting more than 30 seonds, which occurred more than 3 months after the catheter ablation. 14

| Statistical analysis
The continuous variables are presented as the mean AE standard deviation together with 95% confidence intervals. Categorical variables are expressed as numbers and percentages. The significance of any differences between two groups was analyzed with an unpaired t test and Mann-Whitney U test for continuous variables, and with a Fisher's exact probability test for categorical variables. A predictive analysis of AF recurrence during the follow-up period was assessed using multivariate Cox proportional hazard regression models. A multivariate analysis with multivariate Cox proportional hazard regression models was performed to isolate the independent criteria of AF recurrence after ablation. Only the variables with significant P-values in the univariate analysis were included in the multivariate Cox proportional hazard regression. A Kaplan-Meier event-free survival analysis was conducted to assess the cumulative freedom from AF recurrence. A value of P < .05 was considered statistically significant.

| Patient characteristics
The patient characteristics are shown in Table

| Outcome of the catheter ablation
A PVI was successfully achieved in all PVs. AF freedom off AADs was 68.3% and 69.0%, respectively, in the persistent and long-standing AF patients after 1 procedure over a 12-month follow-up period.
The patients were divided into two groups, those in whom AF was prevented by catheter ablation (AF-free group, n = 48) and those in whom AF recurred (AF-recurrent group, n = 22). The patient characteristics and laboratory data did not differ between the two groups except for the LA diameter in the AF-recurrent group as compared to the AF-free group ( Table 1). The SR ratio at the start of the procedure and AF termination during ablation did not differ between the two groups ( Table 2). In 2 patients, the PVI was performed under SR after cardioversion due to unstable hemodynamic conditions. The RF time for the PVI and total procedure time did not differ between the two groups. There were no cases of cerebral infarctions, cardiac perforations, tamponades, PV stenosis, or atrialesophageal fistulae.

| LVAs and frequencies analysis
The characteristics of the LVAs and frequencies are shown in Table 2. LA voltage maps were created during SR in all patients with 1175 AE 363 mapping points per patient. There was a significant difference in the LA LVAs (<0.5 mV) after PVI between the AF-free and AF-recurrent groups among all patients with persistent and long-standing persistent AF (14 cm 2 vs 23 cm 2 , P = .018; 15% vs 23%, P = .033). No LVAs were identified in 13 (19%) patients. LVAs were frequently identified at the septum, anterior, inferior, and posterior wall of the LA. There were significant differences in the LVAs at the anterior, lateral, and posterior wall of the LA between the two groups. A cut-off of 24% for the LVAs was determined for the freedom from AF recurrence with a 52.2% sensitivity and 78.0% specificity (area under the receiver operating characteristic curve of 0.654, P = .035). A Kaplan-Meier event-free survival analysis was conducted to assess the cumulative freedom from AF recurrence. AF freedom was significantly greater in those with LVAs of ≤24% than in those with LVAs of>24% after 1 procedure during 12 months of follow-up (78.6% vs 53.8%, log-rank test P = .020; Figure 1). AF freedom in patients without LVAs was 12 (93%) of 13.  Table 3 shows the overlap between the LVAs and high-DF sites.
High-DF sites were found in 39 (85%) of 46 patients in whom DF mapping was performed during AF after the PVI. The number of the high-DF sites in the LA and RA was 1.7 and 0.6 per patient after the PVI, respectively. The max-DF value was found at the LVAs in 31 (79.5%) of 39 patients with high-DF sites. The max-DF value in the LA and RA did not differ between the AF-free and AF-recurrent groups ( Table 2).   in persistent AF patients, the LA max-DF value, not LVAs, exhibited a significant difference between the two groups.

| Previous reports of LVAs
LVAs were defined as areas with bipolar peak-to-peak voltage amplitudes of <0.5 mV. The definition of the value was based on the minimum grade of LA fibrosis evaluated by delayed-enhancement magnetic resonance imaging (MRI). 9 An increased amount of fibrosis as detected by LA voltage mapping has been shown to be a predictor of atrial tachycardia and AF recurrence after AF ablation. [9][10][11][12][13] LVAs have the electrophysiological effects of altered conduction, heterogeneous refractoriness, and rapid repetitive activity. 18,19 In addition, LVAs have a regional distribution of the septum, anterior, inferior, and posterior wall of the LA as we described in this study, which may be related to contact from external structures, including the aorta and vertebrae. 20

| Optimal size of LVAs for substrate modification
The relationship between the size of the LVAs and AF recurrence has not been fully evaluated. In the previous report using delayed-

| Relationship between LVAs and High-DF sites
Atrial sites that represent local electrograms with high-DFs may be associated with AF maintenance. 5,6,15 In a previous report, high-DF sites were mainly observed on the septum and bottom of the LA.
High-DF sites after PVI were observed at an average of 6.0 AE 3. Therefore, the high-DF sites were closely related to LVAs in nonparoxysmal AF. LVAs are known to be associated with the electrophysiological effects of an altered conduction velocity, heterogeneous refractoriness, and rapid repetitive activity. [18][19][20] Ablation of sites harboring distinct regional electrogram characteristics within/in the vicinity of low-voltage areas in addition to PVI is more effective than conventional PVI only strategy for persistent AF. 24 Therefore, fractionated activity, rotational activity, or discrete rapid local activity during AF may contribute to the formation of high-DFs. 24

| LVAs in persistent AF
In persistent AF patients, the LA max-DF value, not the LVA/LA surface area, had significant differences between the AF-free and AF-recurrent groups, which differed from the findings including long-standing persistent AF. This may support that a high-DF site ablation following PVI is effective in persistent AF patients as described in a previous report. 5 Therefore, in patients with a lesser amount of LVAs, high-DF sites may be a potential target for sustaining AF.

| Study limitations
The present study was limited in several ways. First, the number of patients included in the present study was too small to draw definite conclusions. Second, we did not evaluate the relationship between LVAs and the max-DF value of <8 Hz sites. In many patients with a severe AF burden, high-DF sites often could not be found. Therefore, the effect of LVAs overlapping with DF sites of <8 Hz for AF recurrence is unclear. Third, AF recurrence was evaluated using surface ECGs and 24-h Holter monitoring. Accordingly, asymptomatic AF recurrences may have been overlooked in the present study. An implantable loop recorder may reveal a more accurate AF recurrence rate. 26 Fourth, LVAs mapping in RA could not be performed due to a long procedure. Therefore, we could not investigate the relationship between LVAs and DF in RA. Fifth, there may be possibility that voltage mapping was not adequately performed with sufficient catheter contact with atrial tissue because we did not use a contact force sensing catheter in mapping. Finally, the overlap between LVAs and high-DF sites was not ablated after the PVI in the present study.
Accordingly, it is unclear whether RF applications at the overlap between the LVAs and high-DF sites were actually effective for AF freedom. This strategy may avoid atrial arrhythmias caused by excessive RF applications as compared with an additional LVA-based substrate modification as described previously. To draw definite conclusions, further prospective study is needed with additional RF applications performed at overlaps between LVAs and high-DF sites as compared to PVI alone.

| CONCLUSIONS
LVAs were associated with AF recurrences after PVI in nonparoxysmal AF patients and overlapped with many high-DF sites. PVI alone may be enough to treat patients with mild-to-moderate extent (≤24%) of LVAs.

ACKNOWLEDG EMENTS
We would like to thank Naoki Hattori and Kenji Zama for their technical assistance, and John Martin for his linguistic help in preparing this manuscript.

CONFLI CT OF INTERESTS
Authors declare no conflict of interests for this article.