**4. The efficacy of the sinus restoration strategy to detect arrhythmogenic foci for persistent AF**

Catheter ablation (CA) of persistent AF may commonly be performed during ongoing AF, mainly targeting sites exhibiting complex atrial fractionated electrograms (CFAEs) and/or dominant frequencies (DFs) in addition to pulmonary vein (PV) isolation [35, 36, 37]. However, CA during ongoing AF may be limited especially in patients with a trigger dominant-type AF [20,38, 19]. The rapid firing from the PVs and non-PV foci may beget enhanced automaticity, triggered activity, and localized micro-reentry as AF initiation and maintenance [37, 3, 10].

Our prior data suggested that an increased number of AMF are more highly observed during a vigorous sinus rhythm (SR) restoration strategy in persistent rather than paroxysmal AF [39], and the failure of the elimination of the AMF initiating an immediate recurrence of AF was significantly associated with the recurrence of persistent AF [40]. In this study, we performed CA based on a vigorous SR restoration strategy for persistent AF and evaluated the relation‐ ship between the electrophysiological features of the inducible AMF and recurrent AF episodes after the CA in 117 persistent AF patients.

The AF ablation strategy is summarized in Figure 12. We initially performed the PV isolation procedure by using a double circular mapping catheter technique. The DC energy was delivered with an external biphasic waveform of up to 270 J before the PV isolation. The electrical PV isolation was successfully accomplished with monitoring the circumferential electrical isolation at the antrum level: approximately 1–2 cm from of both the right and left PVs ostium.

After the PV isolation procedure, an additional RF energy application was primarily applied to create an LA roof line. When the AF was still persisted or inducible after LA roof line, additional mitral isthmus line or ablation of the area showing complex fractionated atrial electrograms (CFAEs) in left atrium was accomplished. When AF could not be terminated in

carina region, and also a remarkable prolongation jump during the RF delivery was highly observed around the carina and/or adjacent anterior area. A previous report suggested that the distal exit of the MB into the upper LPV is commonly located around the inter-PV junction, possibly bypassing the LPV junction to the left atrium [34]. These specific muscle orientations and the dominant MB conduction toward the carina region could promote the preferential

In addition, the prolongation of the conduction time between the CS and LPVs during the RF delivery was significantly more commonly observed in patients with upper LPV AMF than in those without. The preferential properties of the MB connecting to the LPVs might involve cross talk that promotes an increased LPV arrhythmogenicity [3, 4, 11]. A larger amount of preserved MB muscle as a remnant of the LSVC, which is related to the conduction properties of the LPVs, may be crucial for determining the increased arrhythmogenicity of the LPVs.

**4. The efficacy of the sinus restoration strategy to detect arrhythmogenic**

Catheter ablation (CA) of persistent AF may commonly be performed during ongoing AF, mainly targeting sites exhibiting complex atrial fractionated electrograms (CFAEs) and/or dominant frequencies (DFs) in addition to pulmonary vein (PV) isolation [35, 36, 37]. However, CA during ongoing AF may be limited especially in patients with a trigger dominant-type AF [20,38, 19]. The rapid firing from the PVs and non-PV foci may beget enhanced automaticity, triggered activity, and localized micro-reentry as AF initiation and maintenance [37, 3, 10].

Our prior data suggested that an increased number of AMF are more highly observed during a vigorous sinus rhythm (SR) restoration strategy in persistent rather than paroxysmal AF [39], and the failure of the elimination of the AMF initiating an immediate recurrence of AF was significantly associated with the recurrence of persistent AF [40]. In this study, we performed CA based on a vigorous SR restoration strategy for persistent AF and evaluated the relation‐ ship between the electrophysiological features of the inducible AMF and recurrent AF episodes

The AF ablation strategy is summarized in Figure 12. We initially performed the PV isolation procedure by using a double circular mapping catheter technique. The DC energy was delivered with an external biphasic waveform of up to 270 J before the PV isolation. The electrical PV isolation was successfully accomplished with monitoring the circumferential electrical isolation at the antrum level: approximately 1–2 cm from of both the right and left

After the PV isolation procedure, an additional RF energy application was primarily applied to create an LA roof line. When the AF was still persisted or inducible after LA roof line, additional mitral isthmus line or ablation of the area showing complex fractionated atrial electrograms (CFAEs) in left atrium was accomplished. When AF could not be terminated in

conduction properties.

68 Abnormal Heart Rhythms

**foci for persistent AF**

after the CA in 117 persistent AF patients.

PVs ostium.

**Figure 12.** The summarized vigorous SR restoration strategy during the ablation according to the pacing-oriented AF inducibility. SR rhythm was restored by using external direct cardioversion before the PV isolation and line creation at the end of the ablation. AF was no longer inducible after only the PV isolation procedure in 24 of 117 patients (20.5 %). During the PV isolation, SR shifted to AF spontaneously and/or was triggered by the roving catheter in 68 of 117 pa‐ tients

these series of procedures, direct cardioversion was delivered to restore SR again in such cases. Then, we confirmed whether complete block lines were created at the roof and mitral isthmus.

Extensive electrical isolation for PVs was successfully performed in all enrolled patients. An LA roof line was additionally created in 93 of 117 (80 %) patients after the extensive PV delineation, and the successful block line was confirmed in 86 of 93 patients (92 %). ATs were inducible in 61 of 117 patients (52.1 %) during the CA (tricuspid-dependent AT, 30; mitral annulus-dependent AT, 15; septal through, 5; LA anterior, 5; and upper loop in right atrium, 3). ATs with an unstable circuit were observed in five patients. A mitral isthmus line was additionally created in 34 of 117 patients (29 %). We confirmed a successful mitral block in 22 of 34 patients (65 %). Epicardial approach from the CS was needed in 18 out of 34 patients (53 %). Ablation targeted to the CFAEs was performed in 19 of 117 patients (16 %). Three common atrioventricular nodal reentry tachycardias (AVNRT) and one sinus nodal tachycardia (SANRT) were induced and successfully terminated.

At the end of the CA, residual AF could still be induced in 37 out of 117 patients (31.6 %), and also residual ATs were still inducible in 30 of 117 (25.6 %) (MI-dependent AT, 5; localized in LA anterior, 3; LA septal, 1; stable unknown, 11; and unstable, 11). Cardiac tamponade occurred in one of 117 (0.85 %) patients during the ablation. A nonsurgical drainage was successfully performed in those cases. The mean procedural time was 174±35 min, and the mean fluoroscopic time was 52±16.8 min.

At the end of the CA, residual AMF were still found in 48 of 117 patients (41.0 %) (directly shifted to AF, 22; reproducible atrial premature beats, [26]. The locations included the left atrial posterior wall [6], superior vena cava [3], crista terminalis [4], left lateral area [1], interatrial septum [1], coronary sinus ostium [1], and unknown [32]. The number of AMF during the CA was significantly higher in the patients with residual AMF than in those without (2.3±1.2 vs. 3.0±1.2, p=0.041).

The incidence of non-PV AMF was significantly higher in the patients with pacing inducible AF than in those without [69 % vs. 47 %, p=0.032). The residual AMF were significantly higher in the patients with pacing-inducible AF than in those without (67 % vs. 29 %, p<0.001).

The mean follow-up period after the CA was 937 days. The follow-up ratio was 106 out of 117 patients (90.6 %) at one year and 86 of 117 patients (73.5 %) at two years after the CA. In-hospital AF episodes were observed in 17 of 117 (14.5 %) patients, and a long-term AF recurrence was observed in 42 of 117 (35.9 %) patients. AT episodes after the CA were observed in 31 of 117 patients (26.4 %), and those were only observed within 3 months after the CA in 11 of 31 patients (35.4 %). AT episodes coexisted with the AF episodes in 16 of 31 patients (52 %). In the multivariable analysis, the AF duration (1.01 (1.00–1.02), p=0.012), LA volume (1.01 (1.01–1.02), p=0.006), and residual AMF (3.95 (1.32–11.8), p=0.004) were independent risk factors for recurrent AF. Figure 13 demonstrates the AF recurrence ratio in the patients with and without residual AMF. AF episodes after the CA were significantly greater in the patients with residual AMF than in those without (50 % vs. 26 %, p=0.002). The result of the study demonstrated that the residual AMF was a useful predicting parameter for the outcome of CA, and the clinical course was impressively favorable in patients without residual AMF (AF recurrence after initial session at two years was 26%). (58.1 %). At the end of the ablation, residual AF was still inducible in 37 of 117 patients (31.6 %).

**Figure 13.** The AF recurrence ratio in the patients with and without residual arrhythmogenic foci during the follow-up. Residual foci were observed in 48 of 117 patients (41 %). The AF free ratio between both groups was compared by a log rank analysis, and AF episodes after the CA were significantly higher in the patients with residual foci than in those without (50 % vs. 26 %, p=0.002). The mean follow-up period was 937 days.

After only a PV isolation, AF was no longer inducible in approximately one fifth of the patients with a favorable outcome even though they underwent a less aggressive intervention. This information might allow us to reduce the number of unnecessary additional RF applications during CA. On the other hand, non-PV foci were also highly confirmed even in patients with persistent AF [39]. Several studies have also addressed the importance of modifying the non-PV foci to improve the outcome of CA for AF [20, 23]. A vigorous SR restoration strategy might facilitate determining the non-PV arrhythmogenicity.

The data from this study also showed that non-PV AMF were closely associated with the AF pacing inducibility during CA. The development of the atrial remodeling process might enhance the triggered activity of the non-PV lesions, because the increased non-PV arrhyth‐ mogenicity may be associated with the atrial remodeling process including an enlarged LA [25, 41]. A recent study demonstrated that the response to ISP after CA more accurately predicted AF recurrences in patients with paroxysmal AF [38]. Residual AMF could increase the chance of AF initiation, and the significance of those may be especially pronounced particularly in cases that develop atrial remodeling.

In conclusion, these data support the role of arrhythmic triggers in determining eventual recurrences in patients with persistent AF and point to AMF as a potentially valuable early index of long-term ablation success.
