Impact of Box Isolation on Rotors and Multiple Wavelets in Persistent Atrial Fibrillation

Abstract

Background: Additional benefits of posterior left atrial (LA) box isolation (BOXI) over pulmonary vein isolation (PVI) in persistent atrial fibrillation (perAF) have been reported, but the mechanism is still unclear. We evaluated the effects of BOXI on rotors and multiple wavelets in the whole LA.

Methods and Results: Twenty patients with perAF (including 12 cases of longstanding perAF) underwent PVI. Real-time phase mapping (ExTRa Mapping) was performed in the whole LA during AF. Subsequently, BOXI was added and re-ExTRa Mapping was performed again at the same site. The nonpassively activated ratio (%NP), the ratio of the form of rotors and multiple wavelets to the recording time, was compared before and after BOXI. After BOXI, the %NP significantly decreased in the anterior wall (from 53±22% to 39±23%, P=0.010), inferior wall (from 51±16% to 34±19%, P=0.001), and LA appendage (from 23±27% to 16±19%, P=0.049). However, there were no significant differences in the septum (49±19% vs. 49±18%, P=0.562) or lateral wall (41±19% vs. 38±15%, P=0.526).

Conclusions: BOXI not only reduced the critical mass for maintenance of AF, but also decreased the rotors and multiple wavelets in the anterior wall, inferior wall and LA appendage during perAF.

Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation of atrial fibrillation (AF) and highly effective in paroxysmal AF.¹ However, it may not be enough to cure persistent or longstanding AF, and further modification of the atrial substrate may be necessary. Previous studies have demonstrated that the posterior left atrium (LA) plays an important role as the AF substrate, including conduction delay, triggers and drivers.^2–7 Additional benefits of the posterior LA Box isolation (BOXI) over PVI in persistent AF (perAF) have been reported in previous studies.^8–18

On the other hand, an individualized approach to AF ablation based on low-voltage areas (LVAs), which correlate with atrial fibrosis, has been proposed.^19–22 However, we demonstrated that additional ablation of LVAs after BOXI did not significantly improve the success rate in perAF patients with LVAs.¹¹ It is unclear why the LVAs outside of the posterior LA were not related to the outcomes. Therefore, we evaluated the effects of BOXI on rotors and multiple wavelets in the whole LA using a novel real-time phase mapping system.

Methods

Patients’ Characteristics

The study group comprised 25 consecutive patients with perAF (n=11) and longstanding perAF (n=14) underwent catheter ablation. AF was terminated in 1 patient during PVI and in 4 patients during BOXI, so these 5 patients were excluded from the study. The study population therefore consisted of 20 patients with perAF (n=8) and longstanding perAF (n=12). Their clinical characteristics are shown in Table 1. All patients were taking a direct oral anticoagulant before the ablation. Transesophageal echocardiography was performed on the day before the procedure in all patients. All antiarrhythmic drugs were stopped at least 5 half-lives before the procedure. Amiodarone was not prescribed in any patients.

Table 1. Patients’ Characteristics

Age, years	61±9
Female, n (%)	2 (10)
Duration of AF, months	29±26
Longstanding persistent AF, n (%)	12 (60)
CHADS2 score	0.7±1.0
BNP, pg/mL	98±61
LA diameter, mm	46±6
LVEF, %	62±7
LA appendage flow, cm/s	35±15

AF, atrial fibrillation; BNP, B-type natriuretic peptide; LA, left atrium; LVEF, left ventricular ejection fraction.

PerAF was defined as AF that was sustained for >7 days but which required pharmacologic or electrical cardioversion. Longstanding perAF was defined as continuous AF that had lasted >1 year. Written informed consent was given by all patients and the study was approved by the Fukuoka Sanno Hospital’s Institutional Review Board.

Preparation

A duo-decapolar catheter (Bee-AT, Japan-Lifeline Co., Ltd., Tokyo, Japan) was inserted in the coronary sinus from the right internal jugular vein. After a double transseptal puncture, a 20-pole circular mapping catheter (Optima^TM or Reflexion HD^TM, St. Jude Medical, St. Paul, MN, USA) and irrigated-tip ablation catheter (FlexAbility^TM, St. Jude Medical) were inserted into the LA for mapping and ablation, respectively. The 3D geometry of the LA was created and fused with the preoperative 3D CT using the EnSite NavX^TM system (St. Jude Medical). A temperature monitoring probe (SensiTherm^TM, St. Jude Medical) was inserted into the esophagus.

PVI

PVI was performed using the irrigation catheter. Radiofrequency (RF) energy was applied for 30 s at each point in a dragging fashion with a temperature limit of 40℃, and a power limit of 40 W around PVs and 20–30 W near the esophagus. Continuous lesions at the anterior antral portions of the ipsilateral superior and inferior PVs were initially created. Ablation was started at the superior wall and continued around the anterior and inferior venous perimeter. There was no vertical lesion line created at the posterior portions of the PVs. However, when PVs were not isolated by only anterior lines, segmental ablation at the breakthrough points of the posterior portions of the PVs was performed. PVI was confirmed using a circular mapping catheter (Optima^TM, St. Jude Medical).

Real-Time Phase Mapping

After PVI, mapping was performed using an online real-time phase mapping system (ExTRa Mapping^TM, Nihon Kohden Co., Tokyo, Japan) in the whole LA divided into the 6 parts of anterior, posterior, inferior, lateral wall, septum and LA appendage (LAA) during AF. This mapping system was based on 41 bipolar intraatrial electrograms (including 9 virtual electrograms) recorded by a deflectable 20-pole spiral-shaped catheter with a diameter of 2.5 cm (Reflexion HD^TM, St. Jude Medical). The contact was confirmed by the recorded electrograms, fluoroscopy and 3D geometry. The distance between a mapping point and the geometry surface created by EnSite NavX was set at 5 mm. The data sampling was adopted as good contact at the areas where sufficient electrograms could be recorded from the vast majority of the electrodes. When sufficient electrograms were not detected, the sensing threshold was decreased from 0.03 mV to 0.01 mV. Based on the 5-s wave dynamics during AF, each phase map was automatically created by ExTRa Mapping.

Nonpassively activated areas, in which rotational activations were frequently observed, were automatically detected by ExTRa Mapping. The value of the “nonpassively activated ratio” (%NP), which is the ratio of the form of rotors and multiple wavelets assumed to contain AF drivers to the recording time, was automatically calculated from the 5-s real-time phase map created by ExTRa Mapping.²³ We measured the %NP at the best contact site in each area several times, and the median value was adopted. Of the 5-s map, the activation sequences during 720 ms (60 ms×12 consecutive time windows) of the representative episodes were depicted as images.

BOXI

After conducting ExTRa Mapping, BOXI was subsequently performed during AF. Ablation of the LA roof and floor was performed by creating a contiguous line to isolate the posterior LA. RF energy was applied in a dragging fashion with a power limit of 40 W on the roof, and floor, and 30 W near the esophagus. If the esophageal temperature was higher than 40℃, RF applications were interrupted. When electrograms were found within the Box lesion using the ablation catheter or the circular mapping catheter placed on the posterior LA, they were ablated until the complete absence of electrograms. Entrance block of the Box lesion was confirmed by complete electrical silence on the posterior LA.

After the completion of BOXI, ExTRa Mapping was assessed again in the same regions as before BOXI. The %NPs of the 6 regions were compared with those before BOXI.

Statistical Analysis

All statistical analyses were performed with SAS 9.4 software (SAS Institute Inc., Cary, NC, USA). Continuous variables were compared before and after BOXI by the Wilcoxon signed-rank test, and data are presented as the mean±SD. Statistical significance was set at P<0.05.

Results

PVI was completely achieved in all patients, after which the ExTRa Mapping was performed and sufficient contact of all electrodes could be obtained in all areas in all patients.

Analysis of Consecutive Activation Patterns of the Posterior LA During AF

Figure 1 presents the electrograms and consecutive activation maps of ExTRa Mapping of the posterior LA during AF after PVI. The mean AF cycle length was 167 ms (Figure 1A). In Figure 1B, window 1 (top) shows that a wave front traveling from the LA roof merged with a wave coming from the inferior wall (window 1, bottom) and formed a rotor lasting for 3 rotations (windows 1–8) with a cycle length of 170 ms. In window 10 (bottom), a wave front traveling from the inferior wall moved away to the roof. In this case, the %NP was 54%. Thus, in this case, multiple wavelets traveling from the LA roof and septum merged and formed a rotor, but reentry was unstable and short-lived. Wave fronts traveling from the anterior LA and the inferior wall may play an important role in the formation of rotors.

Figure 1.

(A) Electrograms of the posterior left atrium (LA) before BOXI. Intraatrial bipolar electrograms recorded by a 20-pole spiral-shaped catheter during atrial fibrillation (AF) are shown. Mean AF cycle length is 167 ms. (B) ExTRa Mapping of the posterior LA before BOXI. The activation sequences during 720 ms of data (60-ms×12 consecutive time windows) are shown. White lines indicate the head of the wave fronts, and white arrows indicate the direction of the wave fronts. In this case, a wave front traveling from the LA roof forms a rotor lasting for 3 rotations. The nonpassively activated ratio (%NP) is 54%. BOXI, Box isolation.

BOXI

BOXI was completely achieved in all patients (Figure 2A), after which the entrance block of the Box lesion was confirmed by complete electrical silence in the posterior LA (Figure 2B).

Figure 2.

(A) Box isolation (BOXI). Red dots indicate the lesions with a power of 40 W, and orange dots indicate the lesions with 30 W. (B) Electrograms of the posterior left atrium (LA) after BOXI. After BOXI, entrance block of the Box lesion is confirmed by complete electrical silence in the posterior LA.

Change of Consecutive Activation Patterns of the Anterior LA During AF Before and After BOXI

Figure 3 shows a representative episode of ExTRa Mapping of the anterior LA during AF before BOXI. The mean AF cycle length was 157 ms (Figure 3A). In Figure 3B, in window 1, 2 wave fronts traveling from the LA roof (top) and lateral wall (right) merged and formed a rotor. This rotor lasted for 2.5 rotations with a cycle length of 160 ms and disappeared in window 8. A wave front coming from the lateral wall (window 9, right) merged with a new wave from the LA roof (window 10, top left) and formed a rotor lasting for 1 rotation. In this case, the %NP was 75%. Thus, in this case, multiple wavelets traveling from the LA roof and lateral wall merged and formed a rotor. Wave fronts traveling from the posterior LA may play an important role in the formation of rotors.

Figure 3.

(A) Electrograms of the anterior left atrium (LA) before BOXI. Mean AF cycle length is 157 ms. (B) ExTRa Mapping of the anterior LA before BOXI. In this case, 2 wave fronts traveling from the LA roof and lateral wall formed a rotor lasting for 2.5 rotations. A wave front coming from the lateral wall (window 9) merged with a new wave from the LA roof (window 10) and formed a rotor lasting for 1 rotation. The nonpassively activated ratio (%NP) is 75%. BOXI, Box isolation.

Figure 4 presents the ExTRa Mapping of the anterior LA during the same AF episode as shown in Figure 3 after BOXI. The mean AF cycle length was 178 ms (Figure 4A). In Figure 4B, in window 1 (right), a wave front coming from the lateral wall went away. In window 4 (right), a new wave front coming from the lateral wall moved out to the LA roof (top). In window 7, 2 wave fronts coming from the septum (bottom) and lateral wall (right) collided and disappeared. In this case, the %NP was 32%. Thus, after BOXI, wave fronts traveling from the posterior LA across the LA roof were not observed, only those traveling from the septum and lateral wall. These wave fronts disappeared, and no rotor formed.

Figure 4.

(A) Electrograms of the anterior left atrium (LA) after BOXI. This is the same AF episode as shown in Figure 3. Mean AF cycle length is 178 ms. (B) ExTRa Mapping of the anterior LA after BOXI. After BOXI, the wave fronts traveling across the LA roof from the posterior LA are not observed, only those traveling from the septum and lateral wall. These wave fronts disappear, and no rotors are observed. The nonpassively activated ratio (%NP) is 32%. BOXI, Box isolation.

Similar activation patterns were observed in other cases, although with minor differences.

Comparison of %NP Before and After BOXI

Table 2 shows a comparison of the %NP before and after BOXI. After BOXI, it significantly decreased in the anterior wall (from 53±22% to 39±23%, P=0.010), inferior wall (from 51±16% to 34±19%, P=0.001), and LAA (from 23±27% to 16±19%, P=0.049). However, there were no significant differences in the septum (49±19% vs. 49±18%, P=0.562) or lateral wall (41±19% vs. 38±15%, P=0.526).

Table 2. Comparison of the Nonpassively Activated Ratio Before and After BOXI

	Before BOXI	After BOXI	P value
Anterior LA, %	53±22	39±23	0.010
Inferior LA, %	51±16	34±19	0.001
Septum, %	49±19	49±18	0.562
Lateral LA, %	41±19	38±15	0.526
Posterior LA, %	39±18	–	–
LA appendage, %	23±27	16±19	0.049

BOXI, Box isolation. Other abbreviations as in Table 1.

Clinical Outcomes

After a single procedure, 16 (80%) of 20 patients had no recurrence of atrial tachyarrhythmia during 12±4 months of follow-up.

Discussion

Main Findings

The present study demonstrated that (1) rotors and multiple wavelets were still observed in the whole LA even after PVI in patients with perAF, (2) wave fronts traveling to and from the anterior or posterior wall may play an important role in the formation of rotors, and (3) BOXI can not only eliminate the rotors and multiple wavelets within the posterior LA, but also decrease them in the anterior wall, inferior wall and LAA.

ExTRa Mapping in perAF

Sakata et al²³ demonstrated that real AF drivers were contained in the nonpassively activated areas where rotors and/or multiple wavelets were most frequently observed during the 5-s recording time, which was decided according to reproducibility. Although the recording time seems short, the reproducibility of the %NP was high.²³

In the present study using ExTRa Mapping, multiple wavelets merged, the wave front shape was highly curved and formed rotors, but the rotor was unstable and short-lived. Wave fronts traveling to and from the anterior or posterior wall may play an important role in the formation of rotors.

Mechanism of the Beneficial Effects of BOXI in perAF

Previous studies have shown that BOXI in addition to PVI results in a better outcome than PVI alone or PVI plus roofline ablation in patients with perAF.^10–18 It is possible that BOXI can eliminate the triggers and rotors in the posterior LA. We have demonstrated that BOXI facilitated AF termination and its non-inducibility.¹¹ Moreover, BOXI can serve as LVA ablation when LVAs are localized to the posterior LA. However, we have shown that addition of LVA ablation to BOXI did not significantly improve the success rate in perAF patients with LVAs.¹¹ It was unclear why the LVAs on the anterior wall were not related to the outcomes. As shown in Figure 4, after BOXI, the wave fronts traveling from the posterior LA were blocked and no rotors were observed on the anterior wall. BOXI may prevent fibrillatory conduction of wave fronts emanating from rotors within the posterior wall, at the same time reducing the overall frequency of activation. Therefore, BOXI may decrease the rotors and multiple wavelets in the anterior wall, inferior wall and LAA. However, there were no changes in the septum and lateral wall, which may be because of the wave fronts traveling from the right atrium and coronary sinus. Those results may explain why BOXI resulted in a better outcome than PVI alone or PVI plus roofline ablation, and why LVA ablation showed no benefit over BOXI in patients with perAF. Moreover, a previous study using the ExTRa Mapping system has shown that not all rotors were included in LVAs.²³

Study Limitations

We did not perform RF ablation at rotor sites, so it remains unclear whether transient rotors were critical to AF maintenance. However, Sakata et al²³ demonstrated that ExTRa Mapping-guided ablation of areas with a high %NP had a potential benefit beyond PVI.

Conclusions

BOXI can not only reduce the critical mass for maintenance of AF within the posterior LA, but also decrease the rotors and multiple wavelets in the anterior wall, inferior wall and LAA during perAF.

Conflict of Interest

The authors have received remuneration from the Nihon Kohden Corporation.

References

• 1.   Calkins H, Hindricks G, Cappato R, Kim YH, Saad EB, Aguinaga L, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. J Arrhythmia 2017; 33: 369–409.
• 2.   Markides V, Schilling RJ, Ho SY, Chow AW, Davies DW, Peters NS. Characterization of left atrial activation in the intact human heart. Circulation 2003; 107: 733–739.
• 3.   Roberts-Thomson KC, Stevenson IH, Kistler PM, Haqqani HM, Goldblatt JC, Sanders P, et al. Anatomically determined functional conduction delay in the posterior left atrium relationship to structural heart disease. J Am Coll Cardiol 2008; 51: 856–862.
• 4.   Roberts-Thomson KC, Stevenson I, Kistler PM, Haqqani HM, Spence SJ, Goldblatt JC, et al. The role of chronic atrial stretch and atrial fibrillation on posterior left atrial wall conduction. Heart Rhythm 2009; 6: 1109–1117.
• 5.   Kalifa J, Tanaka K, Zaitsev AV, Warren M, Vaidyanathan R, Auerbach D, et al. Mechanisms of wave fractionation at boundaries of high-frequency excitation in the posterior left atrium of the isolated sheep heart during atrial fibrillation. Circulation 2006; 113: 626–633.
• 6.   Lin WS, Tai CT, Hsieh MH, Tsai CF, Lin YK, Tsao HM, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 2003; 107: 3176–3183.
• 7.   Lim HS, Hocini M, Dubois R, Denis A, Derval N, Zellerhoff S, et al. Complexity and distribution of drivers in relation to duration of persistent atrial fibrillation. J Am Coll Cardiol 2017; 69: 1257–1269.
• 8.   Kumagai K, Muraoka S, Mitsutake C, Takashima H, Nakashima H. A new approach for complete isolation of the posterior left atrium including pulmonary veins for atrial fibrillation. J Cardiovasc Electrophysiol 2007; 18: 1047–1052.
• 9.   Kumagai K. Box isolation for atrial fibrillation. J Arrhythmia 2011; 27: 255–267.
• 10.   Cutler MJ, Johnson J, Abozguia K, Rowan S, Lewis W, Costantini O, et al. Impact of voltage mapping to guide whether to perform ablation of the posterior wall in patients with persistent atrial fibrillation. J Cardiovasc Electrophysiol 2016; 27: 13–21.
• 11.   Kumagai K, Toyama H, Zhang B. Effects of additional ablation of low-voltage areas after box isolation for persistent atrial fibrillation. J Arrhythmia 2019; 35: 197–204.
• 12.   Lim TW, Koay CH, See VA, McCall R, Chik W, Zecchin R, et al. Single-ring posterior left atrial (box) isolation results in a different mode of recurrence compared with wide antral pulmonary vein isolation on long-term follow-up: Longer atrial fibrillation-free survival time but similar survival time free of any atrial arrhythmia. Circ Arrhythm Electrophysiol 2012; 5: 968–977.
• 13.   Nalliah C, Lim TW, Bhaskaran A, Kizana E, Kovoor P, Thomas L, et al. Posterior left atrial isolation for atrial fibrillation in left ventricular diastolic impairment is associated with better arrhythmia free survival. Int J Cardiol 2015; 184: 674–679.
• 14.   O’Neill L, Hensey M, Nolan W, Keane D. Clinical outcome when left atrial posterior wall box isolation is included as a catheter ablation strategy in patients with persistent atrial fibrillation. J Interv Card Electrophysiol 2015; 44: 63–70.
• 15.   Kim JS, Shin SY, Na JO, Choi CU, Kim SH, Kim JW, et al. Does isolation of the left atrial posterior wall improve clinical outcomes after radiofrequency catheter ablation for persistent atrial fibrillation? A prospective randomized clinical trial. Int J Cardiol 2015; 181: 277–283.
• 16.   Roberts JD, Gerstenfeld EP. Concomitant isolation of the pulmonary veins and posterior wall using a box lesion set in a patient with persistent atrial fibrillation and variant pulmonary venous anatomy. Card Electrophysiol Clin 2016; 8: 145–149.
• 17.   He X, Zhou Y, Chen Y, Wu L, Huang Y, He J. Left atrial posterior wall isolation reduces the recurrence of atrial fibrillation: A meta-analysis. J Interv Card Electrophysiol 2016; 46: 267–274.
• 18.   Bai R, Di Biase L, Mohanty P, Trivedi C, Dello Russo A, Themistoclakis S, et al. Proven isolation of the pulmonary vein antrum with or without left atrial posterior wall isolation in patients with persistent atrial fibrillation. Heart Rhythm 2016; 13: 132–140.
• 19.   Rolf S, Kircher S, Arya A, Eitel C, Sommer P, Richter S, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014; 7: 825–833.
• 20.   Kottkamp H, Bender R, Berg J. Catheter ablation of atrial fibrillation: How to modify the substrate? J Am Coll Cardiol 2015; 65: 196–206.
• 21.   Kottkamp H, Berg J, Bender R, Rieger A, Schreiber D. Box Isolation of Fibrotic Areas (BIFA): A patient-tailored substrate modification approach for ablation of atrial fibrillation. J Cardiovasc Electrophysiol 2016; 27: 22–30.
• 22.   Yamaguchi T, Tsuchiya T, Nakahara S, Fukui A, Nagamoto Y, Murotani K, et al. Efficacy of left atrial voltage-based catheter ablation of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2016; 27: 1055–1063.
• 23.   Sakata K, Okuyama Y, Ozawa T, Haraguchi R, Nakazawa K, Tsuchiya T, et al. Not all rotors, effective ablation targets for nonparoxysmal atrial fibrillation, are included in areas suggested by conventional indirect indicators of atrial fibrillation drivers: ExTRa Mapping project. J Arrhythmia 2018; 34: 176–184.