Canadian Journal of Cardiology 30 (2014) 1535e1540
Clinical Research
Residual Arrhythmogenic Foci Predict Recurrence in Long-Standing Persistent Atrial Fibrillation Patients After Sinus Rhythm Restoration Ablation Toshiya Kurotobi, MD, PhD, Yoshihisa Shimada, MD, PhD, Naoto Kino, MD, Kazato Ito, MD, Daisuke Tonomura, MD, Kentaro Yano, MD, Chiharu Tanaka, MD, Masataka Yoshida, MD, PhD, Takao Tsuchida, MD, PhD, and Histohi Fukumoto, MD, PhD Shiroyama Hospital, Cardiovascular Division, Osaka, Japan
ABSTRACT Background: The mechanism of persistent atrial fibrillation (AF) is multifactorial, and arrhythmogenic foci (AMF) might be involved in the occurrence of persistent AF. In this study, we examined the electrophysiological features of AMF during and immediately after ablation, and evaluated the relationship between the presence and number of residual AMF on the risk of AF recurrence after a vigorous sinus rhythm restoration ablation in patients with long-standing persistent AF. Methods: The study consisted of 117 consecutive patients with persistent AF who underwent catheter ablation (CA). We performed direct cardioversion to restore sinus rhythm before the pulmonary vein (PV) isolation and at the end of the CA. Then we evaluated the features of the AMF inducible with isoproterenol and the pacing-based AF inducibility. Results: After the completion of ablation, AF could still be induced in 37 of 117 patients (31.6%). Spontaneous PV AMF during CA were observed in 104 of 117 patients (91%), and non-PV AMF in 63 of 117 (54%). Residual non-PV AMF were significantly associated with the pacing-based AF inducibility and an enlarged left atrial volume. In the multivariate analysis, the AF duration (1.01 [range, 1.00-1.02] months; P ¼ 0.012), left atrial volume (1.01 [range, 1.01-1.02] mm; P ¼ 0.006), and residual AMF (3.95 [range, 1.32-11.8] yes, no; P ¼ 0.004) were independent risk factors for recurrent AF. Conclusions: Residual AMF are associated with an increased longterm AF recurrence after sinus rhythm restoration ablation for longstanding persistent AF.
Received for publication August 20, 2014. Accepted October 5, 2014. Corresponding author: Dr Toshiya Kurotobi, Cardiovascular Division, Shiroyama Hospital 2-8-1, Habikino, Habikino City, Osaka 583-0872, Japan. Tel.: þ81-6578-5557; fax: þ81-6578-5557. E-mail: [email protected] See page 1540 for disclosure information.
RESUM E canisme de la fibrillation auriculaire (FA) persistante Introduction : Le me comporte plusieurs facteurs parmi lesquels les foyers arythmogènes s dans sa survenue. Dans cette e tude, nous (FAM) semblent implique les caracte ristiques e lectrophysiologiques des FAM durant avons examine diatement après l’ablation. Nous avons e galement e value la et imme sence et le nombre de FAM sur le risque de re currence relation entre la pre de la FA après une ablation vigoureuse pour restaurer le rythme sinusal chez les patients ayant une FA persistante de longue date. thodes : L’e tude comprenait 117 patients conse cutifs souffrant de Me ter (AC). Nous FA persistante qui subissaient une ablation par cathe alise une cardioversion par de charge e lectrique pour restaurer avons re le rythme sinusal avant l’isolation des veines pulmonaires (VP) et à la fin value les caracte ristiques des FAM de l’AC. Ensuite, nous avons e re nol et l’inductibilite de la FA par la stimulation. inductibles par l’isoprote sultats : Après l’ablation, la FA pouvait encore être induite chez 37 des Re s ont e te 117 patients (31,6 %). Durant l’AC, des FAM des VP spontane s chez 104 des 117 patients (91 %) et des FAM non situe s aux VP observe te observe s chez 63 des 117 patients (54 %). Les FAM re siduels non ont e s aux VP ont e te associe s de manière significative à l’inductibilite de situe la FA par la stimulation et à un volume anormalement grand de l’oreillette e, la dure e de la FA (1,01 [e tendue, 1,00gauche. À l’analyse multivarie tendue, 1,02] mois; P ¼ 0,012), le volume de l’oreillette gauche (1,01 [e siduels (3,95 [e tendue, 1,321,01-1,02] mm; P ¼ 0,006) et les FAM re ve le s être des facteurs de risque 11,8] oui, non; P ¼ 0,004) se sont re pendants de la re currence de la FA. inde siduels sont associe s à une augmentation de Conclusions : Les FAM re currence de la FA à long terme après l’ablation pour restaurer le la re rythme sinusal de la FA persistante de longue date.
Cather ablation (CA) of persistent atrial fibrillation (AF) might commonly be performed during ongoing AF, mainly targeting sites that exhibit complex fractionated atrial electrograms (CFAEs) and/or dominant frequencies in addition to pulmonary vein (PV) isolation.1-3 However, CA during ongoing AF might be limited especially in patients with a trigger-dominant type AF.4-6 The mechanisms underlying the rapid activity from the PVs and non-PV foci might include
http://dx.doi.org/10.1016/j.cjca.2014.10.013 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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enhanced automaticity, triggered activity, and localized microre-entry, which might be involved in the initiation and maintenance of AF.7-9 Our previous studies demonstrated that an increased number of arrhythmogenic foci (AMF) are more highly observed during a vigorous sinus rhythm (SR) restoration strategy in persistent rather than paroxysmal AF,10 and the failure of the elimination of the AMF initiating an immediate recurrence of AF was significantly associated with the recurrence of persistent AF.11 Furthermore, the evaluation of the AF inducibility by atrial burst pacing during SR might also add to any latent electrophysiological properties possibly related to the AF recurrence. In this study, we performed CA based on a vigourous SR restoration strategy for long-standing persistent AF, and evaluated the relationship between the electrophysiological features of the inducible AMF and recurrent AF episodes after the CA. Methods Study population The study population consisted of 117 consecutive patients who underwent CA for long-standing persistent AF of more than 6 months. The patients’ mean age was 60 years, and 103 (88%) were male. The mean period of persistent AF was 30.4 months. The exclusion criteria were as follows: (1) a left atrial (LA) diameter of > 55 mm; (2) significant valvular disease requiring surgery; (3) an ejection fraction of < 40%; (4) hypertrophic obstructive cardiomyopathy; and (5) long-lasting AF of > 10 years. All antiarrhythmic agents (AAAs) were generally discontinued for at least 3 days before the CA. All patients provided their written informed consent for the electrophysiological study and ablation procedure. This study was approved by our institutional review committee and the subjects gave their informed consent. Electrophysiological study and CA During CA, intravenous dexmedetomidine hydrochloride (0.2-0.7 mg/kg/h) and isoproterenol (ISP; 0.5-2 mg/min) were continuously administered for sedation. A single bolus of 150 IU/kg of heparin was administered and repeated to maintain an activated clotting time of > 300 seconds. A 10-pole or 20-pole diagnostic catheter was positioned in the coronary sinus (CS) for pacing and recording. The 20-pole catheter was located in the right atrium to cover the area of the tricuspid annulus and superior vena cava (SVC). The PVs were mapped with a circumferential 10-pole or 20-pole catheter (IBI, Irvine, CA). The surface electrocardiograph and intracardiac electrograms filtered at 30-500 Hz were recorded simultaneously using a polygraph. The AF ablation strategy is summarized in Figure 1. We initially performed the PV isolation procedure using a double circular mapping catheter technique. The direct current energy was delivered with an external biphasic waveform of up to 270 J before the PV isolation. We confirmed the success of the electrical PV isolation by monitoring the circumferential electrical isolation at the antrum level: approximately 2 cm from the ostium of the right and left PVs. When the AF persisted or was still inducible after the PV isolation procedure, the creation of the LA roof line, a mitral isthmus line, or CA of the area exhibiting CFAEs in left
Canadian Journal of Cardiology Volume 30 2014
Figure 1. The summarized vigorous sinus rhythm (SR) restoration strategy during the catheter ablation (CA) according to the pacing-oriented atrial fibrillation (AF) inducibility. SR was restored using external direct cardioversion before the pulmonary vein (PV) isolation and line creation at the end of the CA. 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 patients (58.1%). At the end of the CA, residual AF was still inducible in 37 of 117 patients (31.6 %). AT, atrial tachycardia; CFAEs, complex fractionated atrial electrograms; DC, direct current.
atrium was subsequently performed. When AF could not be terminated in 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. In the cases with an induced atrial tachycardia (AT), radiofrequency (RF) energy was appropriately applied to terminate the induced AT. Mapping of the macrore-entrant ATs was performed using multisite entrainment techniques and observing the P-wave morphology and activation sequence recorded from the atrial electrodes. After macrore-entrant AT was ruled out, we attempted to determine the location of a focal or localized AT. The ablation catheter was used to identify the earliest activation site with any centrifugal pattern or areas exhibiting a long conduction time with fractionated potentials. RF energy was delivered for 20-60 seconds at each site using an 8-mm tip dumb bell shaped catheter (Japan Life Line Co, Ltd, Fantasia, Tokyo, Japan) or a 4-mm irrigation tip catheter (St Jude Medical, Minneapolis, MN). The RF energy used for the 8-mm tip catheter was limited to a power of 35-40 W, and that for the irrigation tip catheter to 25-35 W. Burst pacing protocol for AF induction AF was induced by intensive burst pacing from the CS and lateral right atrium just after the PV isolation and at the end of the procedure. Atrial burst pacing was performed (10-second bursts) in decrements from 250 ms down to refractoriness or 150 ms from the distal CS and right atrium. Inducible AF was defined as sustained AF lasting for 1 minute. When the AF spontaneously terminated, induction was attempted 3 times from each of those sites. The induction and detection of the AMF ISP was administered to improve the detection of the PV/non-PV foci during CA (0.5-2 mg/min) as in our previous report, while continuously monitoring the blood pressure.6 A
Kurotobi et al. Arrhythmogenic Foci and Atrial Fibrillation
subsequent high dose of ISP of up to 20 mg/min was increased and careful monitoring for any residual AMF was carried out for at least 10 minutes at the end of the CA. AMF were defined as sites at which any of the following arose: atrial premature beats that appeared to initiate AF, reproducible atrial premature beats with coupling intervals of < 350 ms, or frequent repetitive firings. If AF persisted or spontaneously occurred during ISP administration, we attempted to cardiovert the AF up to 3 times. The direct current energy was delivered with an external biphasic waveform of up to 270 J. To detect the location of the AMF, we simultaneously used 5 multipolar catheters to record the electrograms from the PVs and outside the PVs to search for any AMF. A 20-pole catheter (2-mm interelectrode spacing) covered the area from the SVC to the crista terminalis, CS, and ostium of the left PVs. A roving catheter was located at the right superior PV ostium. The earliest activated sites were determined according to the sequence and time difference of multipolar catheters. The early activated double potentials of AMF from the PVs and SVC were reversed, and we considered the AMF that originated from each site. If the AMF were suspected to have originated from a non-PV area uncovered by the catheters, we attempted to search the location with a roving catheter around the early centrifugal activated sites. Additional ablation of the residual AMF was not performed at the end of CA.
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variables were compared using a t paired test or c2 test. The data without a normal distribution were compared using a Mann-Whitney U test, which was used for the nonparametric analysis. The significant factors related to AF recurrence (P < 0.1) from the univariable analysis were incorporated into the multivariable model, and a Cox proportional hazards analysis was used to assess the relationship between inducible and recurrent AF for the multivariate analyses. All analyses were performed using SPSS 10.0 statistical software (SPSS Inc, Chicago, IL). Results Ablation findings
An ungated 64-slice multidetector computed tomography scan (MX 8000 IDT, Philips Medical Systems, Best, The Netherlands) with retrospective gating was performed. To enhance the cardiac cavity, 100 mL of contrast medium was injected at a flow rate of 2.5 mL/s through an antecubital vein using an injector. The LA volume was measured by integrating the volume traced in each slice of the computed tomography scan from the level of the mitral annulus to the roof of the left atrium with commercially available software (EP planner, Philips Medical Systems, Haifa, Israel). Each slice was automatically traced with digital markers to exclude the PVs and the LA appendage at their ostial level. The LA appendage was excluded from the volumetric analysis.
Electrical isolation of all 4 PVs was successfully accomplished in all patients enrolled. An additional LA roof line was created in 93 of 117 (79.5%) patients after the PV isolation, and we confirmed successful block line in 86 of 93 patients (92.4%). ATs were inducible in 61 of 117 patients (52.1 %) during the CA (tricuspid-dependent AT 30, mitral annulusdependent AT; 15, septal through 5; LA anterior 5; and upper loop in right atrium 3). ATs with an unstable circuit were observed in 5 patients. A mitral isthmus line was created in 34 of 117 patients (29.0%). We confirmed a successful block line in 22 of 34 patients (64.7%), and an epicardial approach from the CS was required in 18 of 34 patients (52.9%). Ablation of the CFAEs was performed in 19 of 117 patients (16.2%). Three common atrioventricular nodal reentry tachycardias and 1 sinus nodal tachycardia were induced and successfully terminated. At the end of the CA, residual AF could still be induced in 37 of 117 patients (31.6%), and also residual ATs were still inducible in 30 of 117 (25.6%) (mitral isthmus [MI]dependent AT, 5; localized in LA anterior, 3; LA septal, 1; stable unknown, 11; and unstable, 11). Cardiac tamponade occurred in 1 of 117 (0.85%) patients during the ablation. A nonsurgical drainage was successfully performed in those cases. The mean procedural time was 174 35 minutes, and the mean fluoroscopic time was 52 16.8 minutes.
Follow-up
Features of AMF during ablation
All patients were discharged to home 3 days after the CA procedure and were seen in our hospital at 1- to 2-month intervals. CA after AT was defined as AT episodes occurring after a 2-month blanking period after the CA. Careful monitoring for any in-hospital AF episodes was carried out for at least 2 days after the CA, and the AF episodes after discharge were adequately assessed according to the patient complaints, 12-lead electrocardiograph, and 24-hour Holter electrocardiograph recordings. After the CA, AAAs were given for 3-6 months. After that, the AAAs were withdrawn and the occurrence of any AF episodes was further assessed without AAAs. The mean follow-up duration was 936 (range, 60-1523) days. One hundred ten of 117 patients (94%) could be successfully followed for more than 1 year.
Two hundred ninety-nine AMF were found during the CA. PV foci were observed in 104 of 117 (88.9%), and nonPV foci in 63 of 117 (53.8%) patients. One hundred fifteen foci (38.5%) were confirmed as direct AF triggers, and 184 foci (61.5%) exhibited reproducible premature atrial contractions with an interval of < 350 ms or frequent repetitive firings. Foci from only PVs were detected in 47 of 117 patients (40.1%). The locations of the foci included the left superior PV (75; 25.9%), left inferior PV (35; 11.7%), right superior PV (61; 20.4%), right inferior PV (35; 11.7%), LA posterior wall (13; 4.3%), SVC (13; 4.3%), crista terminalis (9; 3.0%), left lateral area (8; 2.7%), interatrial septum (10; 3.3%), CS ostium (6; 2.0%), and other unknown sites (34; 11.4%). The mean number of AMF was 2.6 1.2, and multiple AMF were observed in 97 of 117 patients (82.9%). 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
Measurement of the LA volume
Statistical analysis The continuous variables are expressed as the mean SD. A P value < 0.05 was considered statistically significant. The
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Canadian Journal of Cardiology Volume 30 2014
LA posterior wall (n ¼ 6), SVC (n ¼ 3), crista terminalis (n ¼ 4), left lateral area (n ¼ 1), interatrial septum (n ¼ 1), CS ostium (n ¼ 1), and unknown (n ¼ 32). The number of AMF during the CA was significantly greater in the patients with residual AMF than in those without (2.3 1.2 vs 3.0 1.2; P ¼ 0.041).
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%).
The features of pacing-inducible AF during ablation
The factors related to recurrent AF episodes
The relationship between the clinical and structural factors with and without pacing-inducible AF at the end of the CA is shown in Table 1. The mean AF period was significantly longer in the patients with pacing-inducible AF than in those without (65 vs 36 months; P ¼ 0.034). The mean persistent AF duration was significantly longer in the patients with pacing-inducible AF than in those without (20 vs 8 months; P ¼ 0.028). The LA volume was significantly larger in the patients with pacing-inducible AF than in those without (128.7 45.5 vs 89.3 35.0 mL; P < 0.001). The incidence of non-PV AMF was significantly greater in the patients with pacing-inducible AF than in those without (69% vs 47%; P ¼ 0.032). The number of residual AMF were significantly greater in patients with pacing-inducible AF than in those without (67% vs 29%; P < 0.001).
The relationship between the clinical and structural factors with and without recurrent AF is shown in Table 2. The mean AF period was significantly longer in the patients with recurrent AF than in those without (60 vs 36 months; P ¼ 0.029). The relationship between the structural factors with and without inducible residual AF is shown in Table 2. The LA volume (120.0 45.5 vs 103.9 37.7 mL; P ¼ 0.034) was significantly larger in the patients with recurrent AF than in those without. The relationship of the procedural and electrophysiological findings during the CA to those with and without recurrent AF is shown in Table 3. Burst pacing-inducible AF at the end of the CA (45% vs 27%; P ¼ 0.016) was significantly greater in patients with recurrent AF than in those without. Concerning the spontaneous AMF, PV AMF were significantly fewer (83% vs 96%; P ¼ 0.016), and residual AMF at the end of the CA were significantly greater (total 57% vs 32%, P ¼ 0.016; shifted to AF, 59% vs 32%; reproducible atrial premature beats, 54% vs 32%) in the patients with recurrent AF than in those without. In the multivariable analysis, the AF duration (1.01 [range, 1.00-1.02] months; P ¼ 0.012), LA volume (1.01 [range, 1.01-1.02] mm; P ¼ 0.006), and residual AMF (3.95 [range, 1.32-11.8] yes, no; P ¼ 0.004) were independent risk factors for recurrent AF. In Figure 2, the AF recurrence ratio in the patients with and without residual AMF are shown. AF episodes after the CA were significantly greater in the patients
Clinical outcome The mean follow-up period after the CA was 937 days. The follow-up ratio was 106 of 117 patients (90.6%) at 1 year, and 86 of 117 patients (73.5%) at 2 years after the CA. In-hospital AF episodes were observed in 17 of 117 (14.5%) Table 1. The factors associated with pacing-inducible AF
Clinical findings Age, years Male sex, % SHD, % Hypertension, % AF period (range), months AF persistent duration (range), months Co-AFL, % Previous AAAs, n Structural findings LA volume, cm3 LAD, mm PV diameter LSPV LIPV RSPV RIPV LVEF, % Electrophysiological findings Burst-inducible AT after PVI, % Stable AT Unstable AT PV AMF, % Non-PV AMF, % Residual AMF, %
No inducible AF (n ¼ 80)
Inducible AF (n ¼ 37)
P
60 10 91 49 41 36 (16-87) 8 (6-32)
61 9 87 44 42 65 (18-135) 20 (7-78)
0.45 0.55 0.79 0.95 0.034 0.028
18 1.36
22 1.57
0.56 0.52
89.3 35.0 128.7 45.5 0.001 40.0 5.8 40.9 4.8 0.08 18.7 15.7 19.3 16.9 60.2
62 54 7 93 47 29
2.9 3.2 3.7 3.2 13.1
19.7 16.5 20.0 17.2 59.3
46 39 14 87 69 67
5.0 2.4 3.3 2.7 13.0
0.22 0.24 0.36 0.71 0.92 0.09 0.12 0.14 0.25 0.032 0.001
AAAs, antiarrhythmic agents; AF, atrial fibrillation; AMF, arrhythmogenic foci; AT, atrial tachycardia; co-AFL, coexistent atrial flutter; LA, left atrial; LAD, left atrial diameter; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; LVEF, left ventricular ejection fraction; PV, pulmonary vein; PVI, pulmonary vein isolation; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein; SHD, structural heart disease.
Table 2. Clinical and structural factors associated with AF recurrence
Clinical findings Age, years Male sex, % SHD, % Hypertension, % AF period (range), months AF persistent duration (range), months Co-AFL, % Previous AAAs, n Structural findings LA volume, cm3 LAD, mm PV diameter LSPV LIPV RSPV RIPV LVEF, %
No Recurrence of AF (n ¼ 75)
Recurrence of AF (n ¼ 42)
P
61 12 93 51 40 36 (12-86) 8 (6-35)
62 11 83 40 45 60 (22-120) 15 (6-60)
0.26 0.10 0.59 0.59 0.029 0.22
22 1.46
14 1.37
0.24 0.72
103.9 37.7 39.0 5.2 18.5 15.7 19.5 16.8 60.5
3.0 2.8 3.8 3.3 13.1
120.0 45.5 0.11 40.7 6.2 0.52 19.5 16.6 19.9 17.5 59.3
5.1 3.2 2.9 2.64 13.0
0.32 0.18 0.63 0.29 0.64
AAAs, antiarrhythmic agents; AF, atrial fibrillation; co-AFL, coexistent atrial flutter; LA, left atrial; LAD, left atrial diameter; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; LVEF, left ventricular ejection fraction; PV, pulmonary vein; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein; SHD, structural heart disease.
Kurotobi et al. Arrhythmogenic Foci and Atrial Fibrillation
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Table 3. Electrophysiological and procedural factors during CA associated with AF recurrence No Recurrence Recurrence of of AF (n ¼ 75) AF (n ¼ 42) Pacing-inducible AF/AT Burst-inducible AF after PVI, % Burst-inducible AT after PVI, % Stable AT Unstable AT Burst inducible residual AF, % Arrhythmogenic foci during CA PV AMF, % Non-PV AMF, % Residual AMF, % Additional ablation LA roof line creation, % Mitral isthmus line, % CA of CFAEs, % Fluoroscopy time, minutes Procedural time, minutes
P
77 56 47 7 27
83 58 54 12 45
0.53 0.53 0.50 0.23 0.016
96 52 32
83 61 57
0.019 0.36 0.009
79 28 12 51 16 169 32
82 32 17 55 17 184 38
0.89 0.69 0.50 0.06 0.09
AF, atrial fibrillation; AMF, arrhythmogenic foci; AT, atrial tachycardia; CA, catheter ablation; CFAEs, complex fractionated atrial electrograms; LA, left atrial; PV, pulmonary vein; PVI, pulmonary vein isolation.
with residual AMF than in those without (50% vs 26%; P ¼ 0.002). Discussion In this study, we performed the CA based on a vigourous SR restoration strategy for long-standing persistent AF, and evaluated the electrophysiological properties during CA. Spontaneous AMF were observed at a high rate, and the presence of residual non-PV AMF at the end of CA, and a longer AF duration and enlarged LA volume were significant independent related factors for recurrent AF. Novelty of the present study The features of AMF during ablation have not been clarified in patients with long-standing AF, and it remains unclear whether the presence of residual AMF after CA might be
Figure 2. Atrial fibrillation (AF) recurrence ratio in the patients with and without residual arrhythmogenic foci (AMF) during the follow-up. Residual AMF were observed in 48 of 117 patients (41%). The AF-free ratio between both groups was compared using a log rank analysis, and number of AF episodes after the catheter ablation were significantly greater in the patients with residual AMF than in those without (50% vs 26%; P ¼ 0.002). The mean follow-up period was 937 days.
associated with subsequent increased AF recurrences. The results of this study demonstrated that residual AMF were a useful predictive parameter for the outcome of the CA, and the clinical course was impressively favourable in patients without residual AMF (AF recurrence after the initial session at 2 years; 26%). Efficacy of CA during SR There are some merits of performing CA during SR, such as the ability to clearly identify local small potentials at the ablation site, and even small atrial potentials including a fragmented segment, which might reflect the crucial conduction that maintains persistent AF. We can assess the serial changes in the amplitude of the local potentials during the RF application, and hence the power and/or duration of the RF at the ablation site might be suitably controlled. PVs still remain as the dominant source of the maintenance of persistent AF, although extra multifactorial evidence for maintaining AF is involved in AF persistency. After only a PV isolation, AF was no longer inducible in approximately one-fifth of the patients with a favourable 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. In contrast, nonPV foci were also highly confirmed even in patients with persistent AF.10 Several studies have addressed the importance of modifying the non-PV foci to improve the outcome of CA for AF.4,12 A vigourous SR restoration strategy might facilitate determining the non-PV arrhythmogenicity. The AMF during CA PV/non-PV foci were observed at a high rate in our study. Residual non-PV AMF were observed in 48 of 117 (41%) patients, and the presence of those was an independent related factor for an AF recurrence. The data from our previous study suggest that multiple AMF, whether from PV or non-PV sites, could be involved in AF persistency.10 The mechanism of spontaneous AMF, including enhanced automaticity or triggered activity mechanisms with an intracellular calcium increase might be involved in the initiation of AF.13 Furthermore, the data from our study also showed that non-PV AMF were closely associated with the AF pacing inducibility during CA. The development of the atrial remodelling process might enhance the triggered activity of the non-PV lesions, because the increased non-PV arrhythmogenicity might be associated with the atrial remodelling process including an enlarged LA.14,15 A recent study demonstrated that the response to ISP after CA more accurately predicted AF recurrences in patients with paroxysmal AF.5 Residual AMF could increase the chance of AF initiation, and the significance of those might be especially pronounced, particularly in patients who develop atrial remodelling. Pacing-inducible AF and AF recurrence Pacing-induced AF seemed to have some effect on AF recurrences after the CA, but was not independently related to AF recurrences in the present study. However, previous studies support the suggestion that the pacing-based noninducibility of AF is likely to be associated with a better
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clinical outcome.16,17 A stepwise ablation protocol based on the pacing inducibility of AF could imply a residual AF burden that maintains AF in each step, therefore, this finding could still be a useful index for a better outcome of CA with some linkage of other clinical factors possibly related to the development of the atrial remodelling process. Conclusions In this study, we evaluated latent AF characteristics in patients with long-standing persistent AF revealed after a vigorous SR restoration ablation strategy. Residual AMF were associated with an increased inducibility of AF immediately after the ablation procedure and an increased long-term risk of AF recurrence. These data support the role of arrhythmogenic triggers in determining eventual recurrences in patients with previous long-standing persistent AF, and point to AMF as a potentially valuable early index of a long-term ablation success. Disclosures The authors have no conflicts of interest to disclose. References 1. O’Neill MD, Wright M, Knecht S, et al. Long-term follow-up of persistent atrial fibrillation ablation using termination as a procedural endpoint. Eur Heart J 2009;30:1105-12. 2. Nademanee K. Trials and travails of electrogram-guided ablation of chronic atrial fibrillation. Circulation 2007;115:2592-4. 3. Lin YJ, Tsao HM, Chang SL, et al. Role of high dominant frequency sites in nonparoxysmal atrial fibrillation patients: insights from high-density frequency and fractionation mapping. Heart Rhythm 2010;7:1255-62. 4. Lin WS, Tai CT, Hsieh MH, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 2003;107:3176-83. 5. Crawford T, Chugh A, Good E, et al. Clinical value of noninducibility by high-dose isoproterenol versus rapid atrial pacing after catheter ablation of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:13-20. 6. Kurotobi T, Ito H, Inoue K, et al. Marshall vein as arrhythmogenic source in patients with atrial fibrillation: correlation between its anatomy and electrophysiological findings. J Cardiovasc Electrophysiol 2006;17:1062-7. 7. Po SS, Li Y, Tang D, et al. Rapid and stable re-entry within the pulmonary vein as a mechanism initiating paroxysmal atrial fibrillation. J Am Coll Cardiol 2005;45:1871-7.
Canadian Journal of Cardiology Volume 30 2014 8. Patterson E, Po SS, Scherlag BJ, Lazzara R. Triggered firing in pulmonary veins initiated by in vitro autonomic nerve stimulation. Heart Rhythm 2005;2:624-31. 9. Chen YJ, Chen YC, Yeh HI, Lin CI, Chen SA. Electrophysiology and arrhythmogenic activity of single cardiomyocytes from canine superior vena cava. Circulation 2002;105:2679-85. 10. Kurotobi T, Iwakura K, Inoue K, et al. Multiple arrhythmogenic foci associated with the development of perpetuation of atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:39-45. 11. Inoue K, Kurotobi T, Kimura R, et al. Trigger-based mechanism of the persistence of atrial fibrillation and its impact on the efficacy of catheter ablation. Circ Arrhythm Electrophysiol 2012;5:295-301. 12. Chen SA, Tai CT, Hsieh MH, et al. Radiofrequency catheter ablation of atrial fibrillation initiated by spontaneous ectopic beats. Curr Cardiol Rep 2000;2:322-8. 13. Voigt N, Li N, Wang Q, et al. Enhanced sarcoplasmic reticulum Ca2þ leak and increased Naþ-Ca2þ exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 2012;125:2059-70. 14. Haissaguerre M, Jais P, Shah DC, et al. Electrophysiological end point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci. Circulation 2000;101:1409-17. 15. Pak HN, Hwang C, Lim HE, et al. Electroanatomic characteristics of atrial premature beats triggering atrial fibrillation in patients with persistent versus paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2006;17:818-24. 16. Oral H, Chugh A, Lemola K, et al. Noninducibility of atrial fibrillation as an end point of left atrial circumferential ablation for paroxysmal atrial fibrillation: a randomized study. Circulation 2004;110:2797-801. 17. Jais P, Hocini M, Sanders P, et al. Long-term evaluation of atrial fibrillation ablation guided by noninducibility. Heart Rhythm 2006;3: 140-5.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.10.013.
Clinical Research
Residual Arrhythmogenic Foci Predict Recurrence in Long-Standing Persistent Atrial Fibrillation Patients After Sinus Rhythm Restoration Ablation Toshiya Kurotobi, MD, PhD, Yoshihisa Shimada, MD, PhD, Naoto Kino, MD, Kazato Ito, MD, Daisuke Tonomura, MD, Kentaro Yano, MD, Chiharu Tanaka, MD, Masataka Yoshida, MD, PhD, Takao Tsuchida, MD, PhD, and Histohi Fukumoto, MD, PhD Shiroyama Hospital, Cardiovascular Division, Osaka, Japan
ABSTRACT Background: The mechanism of persistent atrial fibrillation (AF) is multifactorial, and arrhythmogenic foci (AMF) might be involved in the occurrence of persistent AF. In this study, we examined the electrophysiological features of AMF during and immediately after ablation, and evaluated the relationship between the presence and number of residual AMF on the risk of AF recurrence after a vigorous sinus rhythm restoration ablation in patients with long-standing persistent AF. Methods: The study consisted of 117 consecutive patients with persistent AF who underwent catheter ablation (CA). We performed direct cardioversion to restore sinus rhythm before the pulmonary vein (PV) isolation and at the end of the CA. Then we evaluated the features of the AMF inducible with isoproterenol and the pacing-based AF inducibility. Results: After the completion of ablation, AF could still be induced in 37 of 117 patients (31.6%). Spontaneous PV AMF during CA were observed in 104 of 117 patients (91%), and non-PV AMF in 63 of 117 (54%). Residual non-PV AMF were significantly associated with the pacing-based AF inducibility and an enlarged left atrial volume. In the multivariate analysis, the AF duration (1.01 [range, 1.00-1.02] months; P ¼ 0.012), left atrial volume (1.01 [range, 1.01-1.02] mm; P ¼ 0.006), and residual AMF (3.95 [range, 1.32-11.8] yes, no; P ¼ 0.004) were independent risk factors for recurrent AF. Conclusions: Residual AMF are associated with an increased longterm AF recurrence after sinus rhythm restoration ablation for longstanding persistent AF.
Received for publication August 20, 2014. Accepted October 5, 2014. Corresponding author: Dr Toshiya Kurotobi, Cardiovascular Division, Shiroyama Hospital 2-8-1, Habikino, Habikino City, Osaka 583-0872, Japan. Tel.: þ81-6578-5557; fax: þ81-6578-5557. E-mail: [email protected] See page 1540 for disclosure information.
RESUM E canisme de la fibrillation auriculaire (FA) persistante Introduction : Le me comporte plusieurs facteurs parmi lesquels les foyers arythmogènes s dans sa survenue. Dans cette e tude, nous (FAM) semblent implique les caracte ristiques e lectrophysiologiques des FAM durant avons examine diatement après l’ablation. Nous avons e galement e value la et imme sence et le nombre de FAM sur le risque de re currence relation entre la pre de la FA après une ablation vigoureuse pour restaurer le rythme sinusal chez les patients ayant une FA persistante de longue date. thodes : L’e tude comprenait 117 patients conse cutifs souffrant de Me ter (AC). Nous FA persistante qui subissaient une ablation par cathe alise une cardioversion par de charge e lectrique pour restaurer avons re le rythme sinusal avant l’isolation des veines pulmonaires (VP) et à la fin value les caracte ristiques des FAM de l’AC. Ensuite, nous avons e re nol et l’inductibilite de la FA par la stimulation. inductibles par l’isoprote sultats : Après l’ablation, la FA pouvait encore être induite chez 37 des Re s ont e te 117 patients (31,6 %). Durant l’AC, des FAM des VP spontane s chez 104 des 117 patients (91 %) et des FAM non situe s aux VP observe te observe s chez 63 des 117 patients (54 %). Les FAM re siduels non ont e s aux VP ont e te associe s de manière significative à l’inductibilite de situe la FA par la stimulation et à un volume anormalement grand de l’oreillette e, la dure e de la FA (1,01 [e tendue, 1,00gauche. À l’analyse multivarie tendue, 1,02] mois; P ¼ 0,012), le volume de l’oreillette gauche (1,01 [e siduels (3,95 [e tendue, 1,321,01-1,02] mm; P ¼ 0,006) et les FAM re ve le s être des facteurs de risque 11,8] oui, non; P ¼ 0,004) se sont re pendants de la re currence de la FA. inde siduels sont associe s à une augmentation de Conclusions : Les FAM re currence de la FA à long terme après l’ablation pour restaurer le la re rythme sinusal de la FA persistante de longue date.
Cather ablation (CA) of persistent atrial fibrillation (AF) might commonly be performed during ongoing AF, mainly targeting sites that exhibit complex fractionated atrial electrograms (CFAEs) and/or dominant frequencies in addition to pulmonary vein (PV) isolation.1-3 However, CA during ongoing AF might be limited especially in patients with a trigger-dominant type AF.4-6 The mechanisms underlying the rapid activity from the PVs and non-PV foci might include
http://dx.doi.org/10.1016/j.cjca.2014.10.013 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
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enhanced automaticity, triggered activity, and localized microre-entry, which might be involved in the initiation and maintenance of AF.7-9 Our previous studies demonstrated that an increased number of arrhythmogenic foci (AMF) are more highly observed during a vigorous sinus rhythm (SR) restoration strategy in persistent rather than paroxysmal AF,10 and the failure of the elimination of the AMF initiating an immediate recurrence of AF was significantly associated with the recurrence of persistent AF.11 Furthermore, the evaluation of the AF inducibility by atrial burst pacing during SR might also add to any latent electrophysiological properties possibly related to the AF recurrence. In this study, we performed CA based on a vigourous SR restoration strategy for long-standing persistent AF, and evaluated the relationship between the electrophysiological features of the inducible AMF and recurrent AF episodes after the CA. Methods Study population The study population consisted of 117 consecutive patients who underwent CA for long-standing persistent AF of more than 6 months. The patients’ mean age was 60 years, and 103 (88%) were male. The mean period of persistent AF was 30.4 months. The exclusion criteria were as follows: (1) a left atrial (LA) diameter of > 55 mm; (2) significant valvular disease requiring surgery; (3) an ejection fraction of < 40%; (4) hypertrophic obstructive cardiomyopathy; and (5) long-lasting AF of > 10 years. All antiarrhythmic agents (AAAs) were generally discontinued for at least 3 days before the CA. All patients provided their written informed consent for the electrophysiological study and ablation procedure. This study was approved by our institutional review committee and the subjects gave their informed consent. Electrophysiological study and CA During CA, intravenous dexmedetomidine hydrochloride (0.2-0.7 mg/kg/h) and isoproterenol (ISP; 0.5-2 mg/min) were continuously administered for sedation. A single bolus of 150 IU/kg of heparin was administered and repeated to maintain an activated clotting time of > 300 seconds. A 10-pole or 20-pole diagnostic catheter was positioned in the coronary sinus (CS) for pacing and recording. The 20-pole catheter was located in the right atrium to cover the area of the tricuspid annulus and superior vena cava (SVC). The PVs were mapped with a circumferential 10-pole or 20-pole catheter (IBI, Irvine, CA). The surface electrocardiograph and intracardiac electrograms filtered at 30-500 Hz were recorded simultaneously using a polygraph. The AF ablation strategy is summarized in Figure 1. We initially performed the PV isolation procedure using a double circular mapping catheter technique. The direct current energy was delivered with an external biphasic waveform of up to 270 J before the PV isolation. We confirmed the success of the electrical PV isolation by monitoring the circumferential electrical isolation at the antrum level: approximately 2 cm from the ostium of the right and left PVs. When the AF persisted or was still inducible after the PV isolation procedure, the creation of the LA roof line, a mitral isthmus line, or CA of the area exhibiting CFAEs in left
Canadian Journal of Cardiology Volume 30 2014
Figure 1. The summarized vigorous sinus rhythm (SR) restoration strategy during the catheter ablation (CA) according to the pacing-oriented atrial fibrillation (AF) inducibility. SR was restored using external direct cardioversion before the pulmonary vein (PV) isolation and line creation at the end of the CA. 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 patients (58.1%). At the end of the CA, residual AF was still inducible in 37 of 117 patients (31.6 %). AT, atrial tachycardia; CFAEs, complex fractionated atrial electrograms; DC, direct current.
atrium was subsequently performed. When AF could not be terminated in 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. In the cases with an induced atrial tachycardia (AT), radiofrequency (RF) energy was appropriately applied to terminate the induced AT. Mapping of the macrore-entrant ATs was performed using multisite entrainment techniques and observing the P-wave morphology and activation sequence recorded from the atrial electrodes. After macrore-entrant AT was ruled out, we attempted to determine the location of a focal or localized AT. The ablation catheter was used to identify the earliest activation site with any centrifugal pattern or areas exhibiting a long conduction time with fractionated potentials. RF energy was delivered for 20-60 seconds at each site using an 8-mm tip dumb bell shaped catheter (Japan Life Line Co, Ltd, Fantasia, Tokyo, Japan) or a 4-mm irrigation tip catheter (St Jude Medical, Minneapolis, MN). The RF energy used for the 8-mm tip catheter was limited to a power of 35-40 W, and that for the irrigation tip catheter to 25-35 W. Burst pacing protocol for AF induction AF was induced by intensive burst pacing from the CS and lateral right atrium just after the PV isolation and at the end of the procedure. Atrial burst pacing was performed (10-second bursts) in decrements from 250 ms down to refractoriness or 150 ms from the distal CS and right atrium. Inducible AF was defined as sustained AF lasting for 1 minute. When the AF spontaneously terminated, induction was attempted 3 times from each of those sites. The induction and detection of the AMF ISP was administered to improve the detection of the PV/non-PV foci during CA (0.5-2 mg/min) as in our previous report, while continuously monitoring the blood pressure.6 A
Kurotobi et al. Arrhythmogenic Foci and Atrial Fibrillation
subsequent high dose of ISP of up to 20 mg/min was increased and careful monitoring for any residual AMF was carried out for at least 10 minutes at the end of the CA. AMF were defined as sites at which any of the following arose: atrial premature beats that appeared to initiate AF, reproducible atrial premature beats with coupling intervals of < 350 ms, or frequent repetitive firings. If AF persisted or spontaneously occurred during ISP administration, we attempted to cardiovert the AF up to 3 times. The direct current energy was delivered with an external biphasic waveform of up to 270 J. To detect the location of the AMF, we simultaneously used 5 multipolar catheters to record the electrograms from the PVs and outside the PVs to search for any AMF. A 20-pole catheter (2-mm interelectrode spacing) covered the area from the SVC to the crista terminalis, CS, and ostium of the left PVs. A roving catheter was located at the right superior PV ostium. The earliest activated sites were determined according to the sequence and time difference of multipolar catheters. The early activated double potentials of AMF from the PVs and SVC were reversed, and we considered the AMF that originated from each site. If the AMF were suspected to have originated from a non-PV area uncovered by the catheters, we attempted to search the location with a roving catheter around the early centrifugal activated sites. Additional ablation of the residual AMF was not performed at the end of CA.
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variables were compared using a t paired test or c2 test. The data without a normal distribution were compared using a Mann-Whitney U test, which was used for the nonparametric analysis. The significant factors related to AF recurrence (P < 0.1) from the univariable analysis were incorporated into the multivariable model, and a Cox proportional hazards analysis was used to assess the relationship between inducible and recurrent AF for the multivariate analyses. All analyses were performed using SPSS 10.0 statistical software (SPSS Inc, Chicago, IL). Results Ablation findings
An ungated 64-slice multidetector computed tomography scan (MX 8000 IDT, Philips Medical Systems, Best, The Netherlands) with retrospective gating was performed. To enhance the cardiac cavity, 100 mL of contrast medium was injected at a flow rate of 2.5 mL/s through an antecubital vein using an injector. The LA volume was measured by integrating the volume traced in each slice of the computed tomography scan from the level of the mitral annulus to the roof of the left atrium with commercially available software (EP planner, Philips Medical Systems, Haifa, Israel). Each slice was automatically traced with digital markers to exclude the PVs and the LA appendage at their ostial level. The LA appendage was excluded from the volumetric analysis.
Electrical isolation of all 4 PVs was successfully accomplished in all patients enrolled. An additional LA roof line was created in 93 of 117 (79.5%) patients after the PV isolation, and we confirmed successful block line in 86 of 93 patients (92.4%). ATs were inducible in 61 of 117 patients (52.1 %) during the CA (tricuspid-dependent AT 30, mitral annulusdependent AT; 15, septal through 5; LA anterior 5; and upper loop in right atrium 3). ATs with an unstable circuit were observed in 5 patients. A mitral isthmus line was created in 34 of 117 patients (29.0%). We confirmed a successful block line in 22 of 34 patients (64.7%), and an epicardial approach from the CS was required in 18 of 34 patients (52.9%). Ablation of the CFAEs was performed in 19 of 117 patients (16.2%). Three common atrioventricular nodal reentry tachycardias and 1 sinus nodal tachycardia were induced and successfully terminated. At the end of the CA, residual AF could still be induced in 37 of 117 patients (31.6%), and also residual ATs were still inducible in 30 of 117 (25.6%) (mitral isthmus [MI]dependent AT, 5; localized in LA anterior, 3; LA septal, 1; stable unknown, 11; and unstable, 11). Cardiac tamponade occurred in 1 of 117 (0.85%) patients during the ablation. A nonsurgical drainage was successfully performed in those cases. The mean procedural time was 174 35 minutes, and the mean fluoroscopic time was 52 16.8 minutes.
Follow-up
Features of AMF during ablation
All patients were discharged to home 3 days after the CA procedure and were seen in our hospital at 1- to 2-month intervals. CA after AT was defined as AT episodes occurring after a 2-month blanking period after the CA. Careful monitoring for any in-hospital AF episodes was carried out for at least 2 days after the CA, and the AF episodes after discharge were adequately assessed according to the patient complaints, 12-lead electrocardiograph, and 24-hour Holter electrocardiograph recordings. After the CA, AAAs were given for 3-6 months. After that, the AAAs were withdrawn and the occurrence of any AF episodes was further assessed without AAAs. The mean follow-up duration was 936 (range, 60-1523) days. One hundred ten of 117 patients (94%) could be successfully followed for more than 1 year.
Two hundred ninety-nine AMF were found during the CA. PV foci were observed in 104 of 117 (88.9%), and nonPV foci in 63 of 117 (53.8%) patients. One hundred fifteen foci (38.5%) were confirmed as direct AF triggers, and 184 foci (61.5%) exhibited reproducible premature atrial contractions with an interval of < 350 ms or frequent repetitive firings. Foci from only PVs were detected in 47 of 117 patients (40.1%). The locations of the foci included the left superior PV (75; 25.9%), left inferior PV (35; 11.7%), right superior PV (61; 20.4%), right inferior PV (35; 11.7%), LA posterior wall (13; 4.3%), SVC (13; 4.3%), crista terminalis (9; 3.0%), left lateral area (8; 2.7%), interatrial septum (10; 3.3%), CS ostium (6; 2.0%), and other unknown sites (34; 11.4%). The mean number of AMF was 2.6 1.2, and multiple AMF were observed in 97 of 117 patients (82.9%). 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
Measurement of the LA volume
Statistical analysis The continuous variables are expressed as the mean SD. A P value < 0.05 was considered statistically significant. The
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Canadian Journal of Cardiology Volume 30 2014
LA posterior wall (n ¼ 6), SVC (n ¼ 3), crista terminalis (n ¼ 4), left lateral area (n ¼ 1), interatrial septum (n ¼ 1), CS ostium (n ¼ 1), and unknown (n ¼ 32). The number of AMF during the CA was significantly greater in the patients with residual AMF than in those without (2.3 1.2 vs 3.0 1.2; P ¼ 0.041).
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%).
The features of pacing-inducible AF during ablation
The factors related to recurrent AF episodes
The relationship between the clinical and structural factors with and without pacing-inducible AF at the end of the CA is shown in Table 1. The mean AF period was significantly longer in the patients with pacing-inducible AF than in those without (65 vs 36 months; P ¼ 0.034). The mean persistent AF duration was significantly longer in the patients with pacing-inducible AF than in those without (20 vs 8 months; P ¼ 0.028). The LA volume was significantly larger in the patients with pacing-inducible AF than in those without (128.7 45.5 vs 89.3 35.0 mL; P < 0.001). The incidence of non-PV AMF was significantly greater in the patients with pacing-inducible AF than in those without (69% vs 47%; P ¼ 0.032). The number of residual AMF were significantly greater in patients with pacing-inducible AF than in those without (67% vs 29%; P < 0.001).
The relationship between the clinical and structural factors with and without recurrent AF is shown in Table 2. The mean AF period was significantly longer in the patients with recurrent AF than in those without (60 vs 36 months; P ¼ 0.029). The relationship between the structural factors with and without inducible residual AF is shown in Table 2. The LA volume (120.0 45.5 vs 103.9 37.7 mL; P ¼ 0.034) was significantly larger in the patients with recurrent AF than in those without. The relationship of the procedural and electrophysiological findings during the CA to those with and without recurrent AF is shown in Table 3. Burst pacing-inducible AF at the end of the CA (45% vs 27%; P ¼ 0.016) was significantly greater in patients with recurrent AF than in those without. Concerning the spontaneous AMF, PV AMF were significantly fewer (83% vs 96%; P ¼ 0.016), and residual AMF at the end of the CA were significantly greater (total 57% vs 32%, P ¼ 0.016; shifted to AF, 59% vs 32%; reproducible atrial premature beats, 54% vs 32%) in the patients with recurrent AF than in those without. In the multivariable analysis, the AF duration (1.01 [range, 1.00-1.02] months; P ¼ 0.012), LA volume (1.01 [range, 1.01-1.02] mm; P ¼ 0.006), and residual AMF (3.95 [range, 1.32-11.8] yes, no; P ¼ 0.004) were independent risk factors for recurrent AF. In Figure 2, the AF recurrence ratio in the patients with and without residual AMF are shown. AF episodes after the CA were significantly greater in the patients
Clinical outcome The mean follow-up period after the CA was 937 days. The follow-up ratio was 106 of 117 patients (90.6%) at 1 year, and 86 of 117 patients (73.5%) at 2 years after the CA. In-hospital AF episodes were observed in 17 of 117 (14.5%) Table 1. The factors associated with pacing-inducible AF
Clinical findings Age, years Male sex, % SHD, % Hypertension, % AF period (range), months AF persistent duration (range), months Co-AFL, % Previous AAAs, n Structural findings LA volume, cm3 LAD, mm PV diameter LSPV LIPV RSPV RIPV LVEF, % Electrophysiological findings Burst-inducible AT after PVI, % Stable AT Unstable AT PV AMF, % Non-PV AMF, % Residual AMF, %
No inducible AF (n ¼ 80)
Inducible AF (n ¼ 37)
P
60 10 91 49 41 36 (16-87) 8 (6-32)
61 9 87 44 42 65 (18-135) 20 (7-78)
0.45 0.55 0.79 0.95 0.034 0.028
18 1.36
22 1.57
0.56 0.52
89.3 35.0 128.7 45.5 0.001 40.0 5.8 40.9 4.8 0.08 18.7 15.7 19.3 16.9 60.2
62 54 7 93 47 29
2.9 3.2 3.7 3.2 13.1
19.7 16.5 20.0 17.2 59.3
46 39 14 87 69 67
5.0 2.4 3.3 2.7 13.0
0.22 0.24 0.36 0.71 0.92 0.09 0.12 0.14 0.25 0.032 0.001
AAAs, antiarrhythmic agents; AF, atrial fibrillation; AMF, arrhythmogenic foci; AT, atrial tachycardia; co-AFL, coexistent atrial flutter; LA, left atrial; LAD, left atrial diameter; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; LVEF, left ventricular ejection fraction; PV, pulmonary vein; PVI, pulmonary vein isolation; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein; SHD, structural heart disease.
Table 2. Clinical and structural factors associated with AF recurrence
Clinical findings Age, years Male sex, % SHD, % Hypertension, % AF period (range), months AF persistent duration (range), months Co-AFL, % Previous AAAs, n Structural findings LA volume, cm3 LAD, mm PV diameter LSPV LIPV RSPV RIPV LVEF, %
No Recurrence of AF (n ¼ 75)
Recurrence of AF (n ¼ 42)
P
61 12 93 51 40 36 (12-86) 8 (6-35)
62 11 83 40 45 60 (22-120) 15 (6-60)
0.26 0.10 0.59 0.59 0.029 0.22
22 1.46
14 1.37
0.24 0.72
103.9 37.7 39.0 5.2 18.5 15.7 19.5 16.8 60.5
3.0 2.8 3.8 3.3 13.1
120.0 45.5 0.11 40.7 6.2 0.52 19.5 16.6 19.9 17.5 59.3
5.1 3.2 2.9 2.64 13.0
0.32 0.18 0.63 0.29 0.64
AAAs, antiarrhythmic agents; AF, atrial fibrillation; co-AFL, coexistent atrial flutter; LA, left atrial; LAD, left atrial diameter; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; LVEF, left ventricular ejection fraction; PV, pulmonary vein; RIPV, right inferior pulmonary vein; RSPV, right superior pulmonary vein; SHD, structural heart disease.
Kurotobi et al. Arrhythmogenic Foci and Atrial Fibrillation
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Table 3. Electrophysiological and procedural factors during CA associated with AF recurrence No Recurrence Recurrence of of AF (n ¼ 75) AF (n ¼ 42) Pacing-inducible AF/AT Burst-inducible AF after PVI, % Burst-inducible AT after PVI, % Stable AT Unstable AT Burst inducible residual AF, % Arrhythmogenic foci during CA PV AMF, % Non-PV AMF, % Residual AMF, % Additional ablation LA roof line creation, % Mitral isthmus line, % CA of CFAEs, % Fluoroscopy time, minutes Procedural time, minutes
P
77 56 47 7 27
83 58 54 12 45
0.53 0.53 0.50 0.23 0.016
96 52 32
83 61 57
0.019 0.36 0.009
79 28 12 51 16 169 32
82 32 17 55 17 184 38
0.89 0.69 0.50 0.06 0.09
AF, atrial fibrillation; AMF, arrhythmogenic foci; AT, atrial tachycardia; CA, catheter ablation; CFAEs, complex fractionated atrial electrograms; LA, left atrial; PV, pulmonary vein; PVI, pulmonary vein isolation.
with residual AMF than in those without (50% vs 26%; P ¼ 0.002). Discussion In this study, we performed the CA based on a vigourous SR restoration strategy for long-standing persistent AF, and evaluated the electrophysiological properties during CA. Spontaneous AMF were observed at a high rate, and the presence of residual non-PV AMF at the end of CA, and a longer AF duration and enlarged LA volume were significant independent related factors for recurrent AF. Novelty of the present study The features of AMF during ablation have not been clarified in patients with long-standing AF, and it remains unclear whether the presence of residual AMF after CA might be
Figure 2. Atrial fibrillation (AF) recurrence ratio in the patients with and without residual arrhythmogenic foci (AMF) during the follow-up. Residual AMF were observed in 48 of 117 patients (41%). The AF-free ratio between both groups was compared using a log rank analysis, and number of AF episodes after the catheter ablation were significantly greater in the patients with residual AMF than in those without (50% vs 26%; P ¼ 0.002). The mean follow-up period was 937 days.
associated with subsequent increased AF recurrences. The results of this study demonstrated that residual AMF were a useful predictive parameter for the outcome of the CA, and the clinical course was impressively favourable in patients without residual AMF (AF recurrence after the initial session at 2 years; 26%). Efficacy of CA during SR There are some merits of performing CA during SR, such as the ability to clearly identify local small potentials at the ablation site, and even small atrial potentials including a fragmented segment, which might reflect the crucial conduction that maintains persistent AF. We can assess the serial changes in the amplitude of the local potentials during the RF application, and hence the power and/or duration of the RF at the ablation site might be suitably controlled. PVs still remain as the dominant source of the maintenance of persistent AF, although extra multifactorial evidence for maintaining AF is involved in AF persistency. After only a PV isolation, AF was no longer inducible in approximately one-fifth of the patients with a favourable 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. In contrast, nonPV foci were also highly confirmed even in patients with persistent AF.10 Several studies have addressed the importance of modifying the non-PV foci to improve the outcome of CA for AF.4,12 A vigourous SR restoration strategy might facilitate determining the non-PV arrhythmogenicity. The AMF during CA PV/non-PV foci were observed at a high rate in our study. Residual non-PV AMF were observed in 48 of 117 (41%) patients, and the presence of those was an independent related factor for an AF recurrence. The data from our previous study suggest that multiple AMF, whether from PV or non-PV sites, could be involved in AF persistency.10 The mechanism of spontaneous AMF, including enhanced automaticity or triggered activity mechanisms with an intracellular calcium increase might be involved in the initiation of AF.13 Furthermore, the data from our study also showed that non-PV AMF were closely associated with the AF pacing inducibility during CA. The development of the atrial remodelling process might enhance the triggered activity of the non-PV lesions, because the increased non-PV arrhythmogenicity might be associated with the atrial remodelling process including an enlarged LA.14,15 A recent study demonstrated that the response to ISP after CA more accurately predicted AF recurrences in patients with paroxysmal AF.5 Residual AMF could increase the chance of AF initiation, and the significance of those might be especially pronounced, particularly in patients who develop atrial remodelling. Pacing-inducible AF and AF recurrence Pacing-induced AF seemed to have some effect on AF recurrences after the CA, but was not independently related to AF recurrences in the present study. However, previous studies support the suggestion that the pacing-based noninducibility of AF is likely to be associated with a better
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clinical outcome.16,17 A stepwise ablation protocol based on the pacing inducibility of AF could imply a residual AF burden that maintains AF in each step, therefore, this finding could still be a useful index for a better outcome of CA with some linkage of other clinical factors possibly related to the development of the atrial remodelling process. Conclusions In this study, we evaluated latent AF characteristics in patients with long-standing persistent AF revealed after a vigorous SR restoration ablation strategy. Residual AMF were associated with an increased inducibility of AF immediately after the ablation procedure and an increased long-term risk of AF recurrence. These data support the role of arrhythmogenic triggers in determining eventual recurrences in patients with previous long-standing persistent AF, and point to AMF as a potentially valuable early index of a long-term ablation success. Disclosures The authors have no conflicts of interest to disclose. References 1. O’Neill MD, Wright M, Knecht S, et al. Long-term follow-up of persistent atrial fibrillation ablation using termination as a procedural endpoint. Eur Heart J 2009;30:1105-12. 2. Nademanee K. Trials and travails of electrogram-guided ablation of chronic atrial fibrillation. Circulation 2007;115:2592-4. 3. Lin YJ, Tsao HM, Chang SL, et al. Role of high dominant frequency sites in nonparoxysmal atrial fibrillation patients: insights from high-density frequency and fractionation mapping. Heart Rhythm 2010;7:1255-62. 4. Lin WS, Tai CT, Hsieh MH, et al. Catheter ablation of paroxysmal atrial fibrillation initiated by non-pulmonary vein ectopy. Circulation 2003;107:3176-83. 5. Crawford T, Chugh A, Good E, et al. Clinical value of noninducibility by high-dose isoproterenol versus rapid atrial pacing after catheter ablation of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:13-20. 6. Kurotobi T, Ito H, Inoue K, et al. Marshall vein as arrhythmogenic source in patients with atrial fibrillation: correlation between its anatomy and electrophysiological findings. J Cardiovasc Electrophysiol 2006;17:1062-7. 7. Po SS, Li Y, Tang D, et al. Rapid and stable re-entry within the pulmonary vein as a mechanism initiating paroxysmal atrial fibrillation. J Am Coll Cardiol 2005;45:1871-7.
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Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10. 1016/j.cjca.2014.10.013.
