CLINICAL RESEARCH
Europace (2014) 16, 1007–1014 doi:10.1093/europace/eut399
Ablation for atrial fibrillation
Amiodarone reduces the amount of ablation during catheter ablation for persistent atrial fibrillation Yosuke Miwa, Hitoshi Minamiguchi, Anil K. Bhandari, David S. Cannom, and Ivan C. Ho* Department of Cardiology, Good Samaritan Hospital, 1225 Wilshire Boulevard, Third floor, Los Angeles, CA 90017, USA Received 28 August 2013; accepted after revision 22 November 2013; online publish-ahead-of-print 19 January 2014
Aims
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Catheter ablation † Complex fractionated atrial electrograms † Amiodarone
Introduction A step-wise approach to catheter ablation for persistent atrial fibrillation (AF) is commonly required to achieve optimal outcome, beginning with pulmonary vein isolation (PVI), then proceeding with ablation of the complex fractionated atrial electrograms (CFAEs) and linear lesions until sinus rhythm (SR) is achieved. Ablation of the CFAEs has been shown to improve outcomes for patients with persistent AF.1,2 However, this approach entails an extensive amount of ablation, which prolongs the procedure time and may increase the incidence of adverse events. In addition, this approach requires considerable substrate ablation and often precipitates the macroreentry circuits that results in subsequent atrial tachycardia
(AT) or atrial flutter (AFL). An alternative strategy that minimizes the amount of ablation while maintaining procedural success would be desirable. In patients with persistent AF, amiodarone and other antiarrhythmic drugs (AADs) have been reported to reduce conduction velocity,3 widen excitable gap,4,5 prolong refractory period6 and cycle length (CL),7 and organize CFAEs.5,8 According to recent guidelines,9 amiodarone and other AADs are often used for the termination of AF and the maintenance of SR. However, it is unknown whether amiodarone reduces the burden of CFAE lesions and reduces the amount of ablation required to achieve procedural success. Amiodarone differs from other AADs in that its pharmacological effects on cardiac tissues are far more longlasting unless it is discontinued 4–6 weeks prior to the procedure. The aim of this
* Corresponding author. Tel: +1 213 977 2239 ; fax: +1 213 977 2209, E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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The step-wise approach to catheter ablation for persistent atrial fibrillation (AF) requires considerable substrate modification targeting at complex fractionated atrial electrograms (CFAEs) in addition to pulmonary vein (PV) isolation. An alternative strategy that minimizes the amount of ablation would be desirable. The aim of this study was to investigate whether the use of pre-procedural amiodarone affects: (i) the amount of ablation required to achieve procedural success, and (ii) long-term outcomes. ..................................................................................................................................................................................... Methods We studied 121 consecutive patients with persistent AF who underwent catheter ablation. The patients were divided into two groups: Group 1, amiodarone (n ¼ 31); Group 2, other antiarrhythmic drugs or rate control (n ¼ 90). All the patients and results underwent a step-wise ablation procedure beginning with PV isolation, then proceeding with ablation of the CFAEs and linear lesions until sinus rhythm was achieved. Mean left atrial cycle length of AF (AFCL) was recorded at each step. The number of CFAE ablation sites was recorded. The number of CFAE sites in Group 1 was significantly less than that in Group 2 (P ¼ 0.0121). The AFCLs after each step in Group 1 were significantly longer than those in Group 2. The procedure time and the radiofrequency time of CFAE ablation in Group 1 were significantly shorter than that in Group 2 (P ¼ 0.0276 and P ¼ 0.0458, respectively). There was no significant difference between the two groups in early and long-term outcomes. ..................................................................................................................................................................................... Conclusion Use of pre-procedural amiodarone prolongs AFCL during catheter ablation and reduces the number of CFAE sites requiring ablation to achieve procedural success while maintaining equivalent long-term results.
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What’s new? † Use of pre-procedural amiodarone prolongs atrial fibrillation cycle length during catheter ablation to atrial fibrillation (AF). † Amiodarone reduces the number of complex fractionated atrial electrogram sites requiring ablation to achieve termination of persistent AF. † There is no significant difference in long-term outcome among patients with antiarrhythmic drugs regardless of class and with rate-control drugs.
study was to investigate whether the pre-procedural use of antiarrhythmic medications affects (i) the amount of ablation required to achieve procedural success, and (ii) long-term outcomes.
Y. Miwa et al.
tip catheter was used for endocardial mapping and ablation. Bipolar electrograms were recorded, by using a GE Cardiolab multichannel system (GE Medical Systems) at a bandpass between 30 and 500 Hz. Multislice computed tomography images of the left atrium (LA) and the PVs were imported into the CARTO MergeTM electroanatomical mapping system (Biosense Webster) or into the NavX system (Velocity version 2.1, St Jude Medical) for registration with the geometry created by the circular mapping catheter. This enabled the navigation of the ablation catheter and the display of the ablation sites on the segmented LA surface. Radiofrequency energy between 20 and 40 W was delivered to reach a maximum temperature of 408C during open irrigation of the catheter tip at a flow rate of 17 – 30 mL/min. For applications near the PV ostia, in the posterior LA, or inside the coronary sinus, the power was lowered to 20 W and the flow rate increased to 30 mL/min. Oesophageal temperature was monitored per standard protocol during all the procedures (Figure 1).
Circumferential pulmonary vein isolation
Methods Study population
Administration of amiodarone and other antiarrhythmic drugs The patients in Group 1 received 200– 400 mg per day of oral amiodarone, while the patients in Group 2 received sotalol (160 – 240 mg per day), dofetilide (500 – 1000 mcg per day), dronedarone (800 mg per day), disopyramide (600 mg per day), or flecanide (200 mg per day), or for rate control with either b-blockers (50 – 200 mg per day of metoprolol or 12.5 – 25 mg per day of carvedilol), diltiazem (120 – 480 mg per day), or digoxin (0.125 – 0.25 mg per day). In this study, amiodarone and other AADs were used in common dosage and administration. All the patients had been treated by the AADs including amiodarone for 3 months or more. Amiodarone was not discontinued prior to ablation while other AADs were discontinued more than three times of drugs half-life before.
Procedural description The PVs were mapped by using a 10- or 20-pole, circular LassoNav 2515TM mapping catheter (Biosense Webster), or a 20-pole, circular SpiralTM or OptimaTM mapping catheter (St Jude Medical). A 3.5 mm Thermocool NavistarTM (Biosense Webster) open-irrigation, deflectable
Non-pulmonary vein ablation According to a previous study,10 the CFAEs were defined as electrograms with highly fractionated potentials or with a very short CL (120 ms), and low-voltage multiple potential signals between 0.06 and 0.25 mV. Non-PV ablation targeted regions with CFAE until AF terminated. Determination of the CFAEs was by visual examination of the electrograms by the operator. We determined the endpoint of CFAE ablation when no EGMs throughout the atria met the criteria of the CFAE at the end of the CFAE ablation effort while the patient was still in AF (the nontermination group). When the AF organized into AT or AFL, subsequent ablation was guided by activation and/or entrainment mapping of the AT or the AFL. In cases with macroreentrant AFL, linear ablation in the LA was designed to incorporate the circuit with the known anatomical structures such as the LA roof and the mitral isthmus, including the roof and/or the mitral isthmus lines. If the AF remained after the CFAE ablation, 1 mg of ibutilide was administered intravenously. If ibutilide converted the AF into AT or AFL, the rhythm was mapped, and linear lesions were deployed based on the mapping results. Finally, electrical cardioversion was performed in patients without organization of AF or with nonconversion into the SR.
Follow-up After the ablation procedure, the patients were hospitalized overnight with telemetry monitoring. Amiodarone was (re)started after the
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Approval was granted from our institutional review board for this retrospective analysis at a private, tertiary referral hospital. The electronic database was searched for all the patients who underwent radiofrequency (RF) catheter ablation between January 2009 and May 2011. The patients were included only if the ablation studied was their first procedure, and only if they were in AF at the beginning of the procedure. The patients were excluded if they had prior ablation procedures for AF or if they were in a rhythm other than AF at the beginning of the procedure. According to the expert consensus statement on the catheter and surgical ablation of AF, persistent and long-standing persistent AF were defined. Patients were divided into two groups: Group 1 included patients on amiodarone at the time of ablation; Group 2 included patients taking other AADs (class III, Ia, or Ic) or patients who were on ratecontrol medications but were not taking AADs. For a separate analysis, the patients were stratified based on the procedural success into conversion and non-conversion (requiring cardioversion) groups. Electronic medical records and catheter ablation procedures were reviewed and pertinent data points were recorded.
All the patients underwent circumferential PV ablation, with a goal of achieving complete isolation of all the PVs, defined as the elimination or dissociation of the PV potentials in the SR or the AF (entrance and exit blocks). The presence of complete PVI was confirmed by pacing and recordings made from the circular mapping catheter positioned at the PV ostia. Pulmonary vein exit block was confirmed after the SR was achieved either from ablation or cardioversion. Standard pacing technique from circular mapping catheter inside the PV ostia was used to confirm the exit block at that point. If the PV– LA conduction persisted after the circumferential ablation, attempts were made to identify the conduction gaps and eliminate them by applying RF energy within or just outside the circular lesions. If the AF terminated after isolation of all the four PVs, attempts were made to induce AF by burst pacing inside the coronary sinus to a CL of 180 ms, before and during the administration of intravenous isoproterenol, 1.0 – 20.0 mg/min. If AF persisted after complete PVI, substrate-based ablations of the CFAEs and the linear lesions were then started.
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Effect of amiodarone on the amount of ablation for persistent AF
B Posteroanterior projection
A Anteroposterior projection LS
RS
LS
RS
LI
RI
LAA
LI
RI
AP
CFAE lesion 200 ms
PA
CFAE lesion
200 ms
CFAEs
Figure 1 Representative three-dimensional reconstruction of the LA and the PVs during PVI and CFAE ablation. The red and green tags indicate the ablation sites. The CFAE lesion was observed in a widespread area. LAA, left atrial appendage; LI (S), left inferior (superior) PV; RI (S), right inferior (superior) PV .
Statistical analysis Continuous variables are expressed as the mean + standard deviation. Student’s t-test was used to compare the two groups. Categorical variables were compared, by using a x2 analysis and Yate’s correction, if necessary. Repeated analysis of variance (ANOVA) was performed to compare the atrial fibrillation cycle lengths (AFCLs) during step-wise ablation in the two groups. A logistic regression analysis was performed to identify the predictors of early recurrences of atrial tachyarrhythmias after the ablation procedure. All the parameters with a significance ,0.05 in the univariate analysis were entered into the multivariate model. The time to an atrial tachyarrhythmia recurrence was estimated by the Kaplan – Meier method, with comparisons made by using the log-rank test. A Cox regression analysis was also used to identify any predictors of recurrences of atrial tachyarrhythmias during the follow-up period. A P value ,0.05 was considered significant.
Results Patient characteristics One hundred and twenty-one consecutive patients were studied, including 31 patients on amiodarone in Group 1, 90 patients on other AADs or rate control in Group 2 (Table 1). Overall, the patients were 62 + 10 years of age and mostly male (90%). The mean duration of the AF was 53.8 + 55.3 months and 76 patients (63%) had longstanding persistent AF, hypertension was present in 74%, but diabetes (15%) and structural heart disease (19%) were less common. Average left ventricular ejection fraction (LVEF) was 54.6 + 11.7%. The baseline characteristics differed between the two groups regarding only in left atrial dimension (LAD) and LVEF (P ¼ 0.0239 and P ¼ 0.0369, respectively).
Effect of amiodarone and other antiarrhythmic drugs on the ablation To assess the effect of amiodarone and other AADs to the CFAE and the other ablation procedure, we evaluated the mean CL in the LA during the AF in each step. We divided the atria into seven lesions and mapped all the lesions. The number of CFAE was calculated as the number of CFAE lesions as taken by the electroanatomical points. Although there was no significant difference of each site of the CFAE among the two groups, the number of CFAE sites in Group 1 is significantly smaller than that in Group 2 (P ¼ 0.0121) as shown in Table 2. At the baseline, the AFCL in Group 1 was significantly longer than Group 2 (P ¼ 0.0045). The AFCL after PVI in Group 1 was significantly longer than Group 2 (P ¼ 0.0031). The AFCL after CFAE ablation in Group 1 was also significantly longer than Group 2 (P ¼ 0.0002). Repeated ANOVA showed that there
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ablation immediately. During the blanking period of 3 months, amiodarone was continued. If no recurrence of AF was observed, amiodarone was discontinued after the blanking period. The patients returned for clinical evaluation at 1, 3, 6, 9, and 12 months after the ablation procedure. The patients were instructed to call a clinical coordinator if they experienced symptoms suggestive of arrhythmias. The follow-up screening included: (i) 12-lead electrocardiogram at each follow-up visit; (ii) 24 h Holter every 6 months; and (iii) symptom-driven event monitoring. The ongoing symptoms were investigated with an event monitor. Recurrent atrial tachyarrhythmias were diagnosed when (i) the patient reported symptoms suggestive of a tachycardia, or (ii) a .30 s episode of atrial tachyarrhythmias was recorded on a 12-lead electrocardiogram or a 24 h ambulatory Holter monitor, or by event monitoring or by implanted cardiac device. Recurrence of atrial tachyarrhythmias was defined as all episodes that occurred after ablation, including AF, AFL, and AT.
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Y. Miwa et al.
Table 1 Comparison of the baseline characteristics between the two groups Group 1 (n 5 31)
Group 2 (n 5 90)
P value
................................................................................ 62 + 9
62 + 10
0.7070
Gender, male/female BMI, kg/m2
25/6 31.9 + 5.8
70/20 31.4 + 15.1
0.7375 0.8718
BMI . 30%
20/31
42/90
0.0864
Duration of AF, month Long-standing persistent AF, n (%) Structural heart disease, n (%)
51.4 + 42.5 18 (58)
54.7 + 59.2 58 (64)
0.7764 0.5262
16 (18)
0.5567
LAD, (mm)
44.6 + 6.7
41.7 + 6.0
0.0239
LAD ≥ 46 mm (≥25 percentile)
10/31
20/90
0.2644
LVEF, % LVEF , 35%
50.8 + 13.9 4/31
55.9 + 10.7 4/90
0.0369 0.1021
Hypertension, n (%)
27 (87)
63 (70)
0.0600
13 (14) 1.1 + 0.7
0.8202 0.1441
Age, years
Diabetes, n (%) CHADS2 score
7 (23)
5 (16) 1.3 + 0.8
Antiarrhythmic drugs 31 (100) 0 (0)
0 (0) 30 (33)
0 (0)
1 (1)
Class Ic antiarrhythmic drugs, n (%)
0 (0)
4 (4)
18 (58) 4 (13)
49 (54) 22 (24)
b-blockers, n (%) Calcium-channel blockers, n (%) Digoxin, n (%)
6 (19)
Ablation outcomes Pulmonary vein isolation was achieved in all the patients (Figure 3). Three patients converted to SR after PVI alone. Two patients converted to AT/AFL after PVI and each achieved SR following linear or focal ablations. Complex fractionated atrial electrogram ablation was performed in 116 of 121 patients (96%) and resulted in SR in 60 of 116 patients (52%). Twenty patients developed AT/AFL after CFAE ablation. Linear or other substrate ablations converted 16 of these 20 patients to SR. The remaining 40 patients were successfully electrically cardioverted. All the patients were in SR at the conclusion of the procedure. Analysis was also performed in comparison of the clinical factors between conversion (the conversion group) and
Table 3 Comparison of AFCL and difference of AFCL in each step between the two groups Amiodarone Non-amiodarone (n 5 31) (n 5 90)
20 ()
BMI, body mass index; AF, atrial fibrillation; LAD, left atrial dimension; LVEF, left ventricular ejection fraction; NS, no significance.
Table 2 Comparison of each site and the number of CFAE among the three groups Group 1 (n 5 29)
Group 2 (n 5 87)
P value
Septum (%)
27/29 (93)
83/87 (95)
0.3704
CS (%) Roof of LA (%)
22/29 (76) 24/29 (83)
71/87 (82) 80/87 (92)
0.4314 0.0933
MVA (%)
15/29 (52)
60/87 (69)
0.0783
CTI (%) AA (%)
0/29 (0) 21/29 (72)
2/87 (2) 78/87 (90)
.0.9999 0.0171
SVC (%)
0/29 (0)
2/87 (2)
.0.9999
Total number of CFAE lesions
3.5 + 1.3
4.2 + 1.2
................................................................................
0.0121
Septum, septum including the Bachmann bundle; CS, left posterior mitral annulus and coronary sinus ostium; LA, left atrium; MVA, mitral annulus; CTI, cavotricuspid isthmus; AA, right and left atrial appendages and antra; SVC, superior vena cava– right atrial junction
P value
................................................................................ Baseline AFCL (ms) AFCL After PVI (ms)
196 + 52 226 + 58
173 + 32 197 + 40
0.0045 0.0031
AFCL PVI baseline (ms)
29 + 31
24 + 27
0.3700
250 + 50
0.0002
56 + 43
0.0563
287 + 58
0.0389
101 + 38
0.9963
AFCL After CFAE 295 + 64 (ms) AFCL CFAE-PVI 74 + 47 (ms) AFCL before 315 + 80* conversion (ms) Procedure time of PVI 101 + 37 (min) Procedure time of 36 + 24 CFAE ABL (min) RF time of PVI (s) 3118 + 785
47 + 26
0.0276
2862 + 955
0.1812
1035 + 701
1325 + 687
0.0458
84 + 22
85 + 21
0.8028
74 + 20
72 + 18
0.5405
RF time of CFAE ABL (s) Total number of ablations Total fluoroscopic time (min) Conversion to sinus rhythm
19/31
54/90
0.8992
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Amiodarone, n (%) Other class III antiarrhythmics, n (%) Class Ia antiarrhythmic drugs, n (%)
were significant differences of the AFCL in each step between the two groups (P ¼ 0.0011) (Table 3 and Figure 2). Procedure time, RF time, and total fluoroscopic time among the three groups are also shown as Table 3. While the total number of ablation lesions, PVI time, and total fluoroscopic time were not significantly different, the procedure and the RF times of the CFAE ablation to achieve the endpoint in Group 1 were significantly shorter than those in Group 2 (P ¼ 0.0276 and P ¼ 0.0458, respectively). Furthermore, although the frequencies of each CFAE site were not significantly different between the two groups except for the atrial appendages, the total number of CFAEs identified and ablated at each of the predefined segments in the electroanatomical maps in Group 1 was significantly less than that in Group 2 (P ¼ 0.0121).
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Effect of amiodarone on the amount of ablation for persistent AF
non-conversion (the non-conversion group) into the SR (Table 4). Enlargement of the LA over 46 mm was more frequent in the nonconversion group than in the conversion group (P ¼ 0.0128), but
Table 4 Comparison of the characteristics between conversion into the SR and the non-conversion groups Non-conversion (n 5 40)
P value
................................................................................
340 320 300 AFCL (ms)
Conversion into the SR (n 5 81)
280 260 240 Group 1 Group 2
220 200 180
P = 0.0011
160 Baseline
After PVI
After CFAE
Before conversion
Steps during step-wise ablation
Figure 2 Interaction plot for the AFCL in each step during step-
61 + 10
63 + 10
62/19
33/7
0.4530
Duration of AF, month
46.0 + 47.1
57.7 + 58.8
0.9446
Longstanding persistent AF, n (%)
54 (67)
22 (55)
0.2116
Structural heart disease, n (%) LAD, mm
14 (17)
9 (23)
0.4915
43.9 + 5.9
41.7 + 6.3
0.0695
LAD . 46 mm (.25percentile), n (%) LVEF (%)
14 (17)
16 (40)
0.0128
54.8 + 10.2
54.5 + 12.5
0.8675
LVEF , 35%, n (%)
7 (9)
1 (3)
0.2683
BMI, kg/m2 BMI . 30%, n (%)
30.6 + 5.2 39 (48)
32.0 + 15.9 23 (58)
0.5901 0.3330
Amiodarone, n (%)
24 (30)
7 (18)
0.1505
AF before procedure; n = 121
PV isolation; n = 121
Sinus rhythm; n=3
AT/AFL; n=2
Linear/focal ablation; n = 2
Sinus rhythm; n=2
0.2957
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wise ablation between the two groups. Repeated ANOVA were performed and showed that there were significant differences of the AFCL in each step between the two groups.
Age, years Gender, male/female
AF; n = 116
CFAE ablation; n = 116
Sinus rhythm; n = 60*
DC cardioversion; n = 36
*Including 36 patients after.
AT/AFL; n = 20
Linear/focal ablation; n = 20
Sinus rhythm; n = 16
DC cardioversion; n=4
Figure 3 Study profile detailing the outcomes of the 121 patients who underwent catheter ablation for persistent AF.
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Table 5 Cox regression analyses for predictors of long-term recurrences of atrial fibrillation or atrial tachyarrhythmias Univariate analysis
.........................................
Cumulative probability of recurrence-free (%)
Y. Miwa et al.
100 P = 0.02 80 60
HR
95% CI
P value
Age, years
0.98
0.94– 1.01
0.1344
Gender, male BMI (kg/m2)
1.13 1.01
0.48– 2.65 0.97– 1.04
0.7865 0.7217
BMI . 30
1.14
0.56– 2.33
0.7191
LVEF (%) LVEF , 35%
0.99 2.56
0.96– 1.02 0.76– 8.33
0.4831 0.1278
Number at risk
LAD (mm)
1.04
0.99– 1.10
0.1529
Conversion into SR
40
28
23
21
10
8
2
LAD ≥ 46 mm Duration of AF, month
1.81 1.00
0.84– 3.91 0.99– 1.01
0.1292 0.9610
Non-conversion
81
56
36
27
18
8
3
Long-standing persistent AF
2.53
1.15– 5.57
0.0212
Structural HD CHADS2 score
2.10 1.04
0.85– 5.24 0.63– 1.73
0.1098 0.8739
Hypertension
1.11
0.50– 2.44
0.7866
Diabetes Groups 1 vs. 2
1.72 1.41
0.52– 5.71 0.66– 3.02
0.3736 0.3807
Conversion into the SR
0.45
0.22– 0.93
0.0306
20
Conversion into SR Non-conversion
0 0 3
8
28
13 18 23 Follow-up period (month)
33
100 80 60 40 20 Group 1 Group 2
0 0
3
28 13 18 23 Follow-up period (month)
8
33
38
Number at risk Group 1
31
24
17
12
4
3
1
Group 2
90
60
42
36
24
13
4
Figure 5 Kaplan– Meier event-free survival curve for the recurrences of atrial tachyarrhythmias in Groups 1 and 2.
Follow-up
Discussion
During the mean follow-up of 15 + 12 months (6–37 months), of the 87 patients who maintained the SR for the first 3 months as the blanking period, 29 patients (24%) recurred into the ATs after the blanking period. On univariate analyses, long-standing persistent AF and conversion into the SR were significantly associated with the endpoint of recurrence-free survival, with a hazards ratio (HR) of 2.53 (95% CI: 1.15 –5.57; P ¼ 0.0212) and 0.45 (95% CI: 0.22 –0.93; P ¼ 0.0306), respectively, (Table 5 and Figure 4), while on multivariate analysis, their HR were 2.46 (95% CI: 1.12– 5.41, P ¼ 0.0256), and 0.46 (95% CI: 0.23–0.96; P ¼ 0.0378), respectively. However, the recurrence-free survival rate during the entire period of follow-up was not different between Groups 1 and 2 (Figure 5).
In recent years, as patients with persistent AF have been increasingly considered for catheter ablation, the lesion sets have become more aggressive and complex. While the technique of persistent AF ablation has been well established and validated by many studies, debate remains whether ‘more is better’ in terms of amount of RF ablation performed and the concept of LA substrate ‘debulking’. On the one hand, it seems logical to remove as much substrate as possible during aggressive RF ablation for persistent AF to reduce the LA’s ability to maintain AF. However, on the other hand, the prolonged duration of the procedure, associated endocardial inflammation from extensive amount of ablation, and potential for more arrhythmogenic circuits from incomplete ablation lesion sets can potentially
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there was no significant difference between the two groups in the other clinical factors. Logistic regression analysis was also performed to identify the significant predictors of conversion into the SR. Enlargement of the LA was still the only significant predictor of failure to conversion into the SR during the AF ablation with an odds ratio of 3.19 [95% confidence interval (CI): 1.36–7.52; P ¼ 0.0079]. There was no difference between Group 1 (amiodarone) and Group 2 (other AADs or rate-control drugs) in the probability of conversion into the SR during the procedure. When the patients treated with amiodarone, other AADs and atrioventricular node blockers were compared, although there was no significant difference among the three groups regarding the rate of conversion into SR, the total number of CFAE lesions in patients with amiodarone was significantly smaller than in other groups (Table 2).
40
Figure 4 Kaplan– Meier event-free survival curve for the recurrences of atrial tachyarrhythmias in the conversion and the nonconversion groups.
Cumulative probability of recurrence-free (%)
................................................................................
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Effect of amiodarone on the amount of ablation for persistent AF
lead to higher incidence of peri-procedural adverse events and poor long-term outcomes. In this study, use of amiodarone preprocedurally was compared with the use of other AADs (or on AADs) to see if the long-lasting pharmacological effect of amiodarone would make a difference in the achievement of immediate proprocedural endpoints, as well as long-term procedural success. The main finding of this study is that the pre-procedural use of amiodarone can prolong AFCL at each step of the ablation, reduce the number of CFAE sites identified and the RF time spent on the CFAE ablation, while not affecting the long-term recurrence rate of the atrial arrhythmias. This study is the first to retrospectively validate this combined approach by using the pharmacological property of amiodarone to assist in the reduction in the amount of substrate ablation while maintaining clinical success, which is opposite to the common practice of discontinuing AADs well before the procedure to allow more complete substrate ablation in the atria.
Role of amiodarone
The step-wise approach to the catheter ablation of persistent AF, which usually involves a considerable amount of LA substrate modification, carries the common goal of conversion into the SR. Elayi et al.13 have shown in an earlier study that there is no significant difference in the clinical characteristics between the patients who converted into the SR or the AT, and those who failed to terminate or organize during the ablation. However, in this study, although the use of pre-procedural AADs, regardless of class, is not associated with an increase rate of conversion into the SR during step-wise ablation for persistent AF, an enlarged LA of more than 46 mm was strongly associated with failure to convert into the SR. Boyden et al.14 have shown that an enlarged LA is associated with electric and structural changing of the atrium, and the result of this study showed the close correlation between atrial remodelling and the inability to convert into the SR even in the pharmacologically ‘prepared’ atrium.
Long-term outcomes Elayi et al.13 described that AF and AT termination during the procedure were not associated with a better clinical outcome, similar to the results of Estner et al.15 Although previous studies16 – 18 found a correlation between AF termination during ablation and better success rate at follow-up, there is no available information regarding the effect of pre-procedural administration of the AADs to the long-term outcomes. This is the first report to show that not only could conversion into the SR during ablation of persistent AF predict long-term SR maintenance, it also showed that the use of pre-procedural AADs, including amiodarone, would not affect long-term outcome. However, AF that meets the definition of long-standing persistent AF predicts higher probability of recurrence of atrial tachyarrhythmias even with conversion during procedure. The results of this study also revealed that there is no significant difference in the long-term outcome among patients with AADs regardless of the class and with the rate-control drugs, while the amount of CFAE sites and the RF duration of the CFAE ablation could be reduced with the use of amiodarone.
Study limitations Our study has several limitations. First, the CFAE were identified by subjective visual inspection, although this is a methodology widely used and accepted in the previous studies.10,19 Secondly, the postprocedural monitoring of arrhythmias in patients was not uniform, and thus some patients with asymptomatic atrial tachyarrhythmias recurrences might have been missed. Thirdly, selections of the AADs were not randomized but were dependent on the patients’ tolerance to the AADs according to the guidelines. Fourthly, if CFAE mapping after PVI was performed, it could be likely that there had been already a decrease in area with CFAE after the circumferential PVI. However, PVI was not only an established manoeuvre to paroxysmal AF but also persistent and long-standing persistent AF. The result of this study could be useful information in the actual clinical setting, because CFAE ablation in most patients could be considered after PVI. Fifthly, this study is a retrospective analysis and could have potentially some bias. However, there was no significant difference
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Use of amiodarone could allow one to identify the CFAE sites responsible for maintaining AF. This mechanism may be related to the longer baseline AFCL in Group 1. During PVI and substrate ablation, there was more AFCL prolongation in the amiodarone group than in the group with the other AADs. These clinical findings are consistent with the basic studies of Shan et al.,8 who demonstrated that the use of cibenzoline can reduce LA fractionation in a goat model of AF, and Singh et al.,11 who described that acute administration of ibutilide reduces CFAE area. Rostock et al.12 also described that the changes in CFAE area correlated with the overall prolongation in the LA CL in the human LA. Thus, the slowing or organization of the LA with the acute administration of an AAD may facilitate the identification of the CFAE sites actively participating in the maintenance of AF by eliminating the CFAEs generated as a result of passive atrial activation. However, previous studies have raised concerns that premature conversion into the SR facilitated by AAD use may undermine the amount of substrate modification that otherwise would be needed before the endpoint is met. Currently, there are no data regarding the use of pre-procedural AADs and the probability of conversion into the SR during step-wise ablation for persistent AF. In this study, use of pre-procedural amiodarone, compared with other AADs or rate-control drugs, can reduce the number of CFAE sites that require ablation and promote the prolongation of AFCL during persistent AF ablation while achieving the same procedural endpoints and long-term outcomes with less RF ablation. While the amiodarone group did not have a higher probability of conversion compared with the group with the other AADs, the amount of substrate modification required to achieve the same outcome was less. Other AADs were grouped together with the rate control in comparison with amiodarone due to the short half-lives and the predictable pharmacokinetics of most AADs other than amiodarone, and the pharmacological influence of these drugs on the patients during the ablation are probably minimal after withholding one to two doses before the procedure. Moreover, the pre-procedural continuation of the AADs, regardless of class, is not associated with an increased rate of conversion into the SR during the step-wise ablation for persistent AF.
Acute outcomes of atrial fibrillation ablation
1014 regarding the well-known risk factors between the two groups. A further randomized control study with large number and long-term follow-up could be needed to clarify the difference.
Y. Miwa et al.
7.
8.
Conclusion 9.
Use of pre-procedural amiodarone could reduce the number of CFAE sites that require ablation and promote prolongation of AFCL during persistent AF ablation before achieving procedural endpoint of conversion into the SR. While amiodarone was not associated with an increased rate of conversion into the SR during the step-wise ablation for persistent AF and has similar long-term SR maintenance compared with the other AADs, these same outcomes could be achieved with a reduced amount of ablation with the pharmacological influence of amiodarone on the atrial electrophysiological substrate.
10.
11.
12.
13.
Conflict of interest: none declared. 14.
References 15.
16.
17.
18.
19.
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1. Nademanee K, Schwab MC, Kosar EM, Karwecki M, Moran MD, Visessook N et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol 2008;51:843 –9. 2. Estner HL, Hessling G, Ndrepepa G, Wu J, Reents T, Fichtner S et al. Electrogramguided substrate ablation with or without pulmonary vein isolation in patients with persistent atrial fibrillation. Europace 2008;10:1281 –7. 3. Sager PT, Nademanee K, Antimisiaris M, Pacifico A, Pruitt C, Godfrey R et al. Antiarrhythmic effects of selective prolongation of refractoriness. Electrophysiologic actions of sematilide HCl in humans. Circulation 1993;88:1072 –82. 4. Wijffels MC, Dorland R, Mast F, Allessie MA. Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and D-sotalol. Circulation 2000;102:260 –7. 5. Kawase A, Ikeda T, Nakazawa K, Ashihara T, Namba T, Kubota T et al. Widening of the excitable gap and enlargement of the core of reentry during atrial fibrillation with a pure sodium channel blocker in canine atria. Circulation 2003;107:905 –10. 6. Esato M, Shimizu A, Chun YH, Tatsuno H, Yamagata T, Matsuzaki M. Electrophysiologic effects of a class I antiarrhythmic agent, cibenzoline, on the refractoriness
and conduction of the human atrium in vivo. J Cardiovasc Pharmacol 1996;28: 321 – 7. Fujiki A, Sakabe M, Nishida K, Mizumaki K, Inoue H. Role of fibrillation cycle length in spontaneous and drug-induced termination of human atrial fibrillation. Circ J 2003; 67:391 – 5. Shan Z, Van Der voort PH, Blaauw Y, Duytschaever M, Allessie MA. Fractionation of electrograms and linking of activation during pharmacologic cardioversion of persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 2004;15:572 –80. Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ et al. HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. Europace 2007;9:335 –79. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, Vasavakul T et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044 –53. Singh SM, D’Avila A, Kim SJ, Houghtaling C, Dukkipati SR, Reddy VY. Intraprocedural use of ibutilide to organize and guide ablation of complex fractionated atrial electrograms: preliminary assessment of a modified step-wise approach to ablation of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:608–16. Rostock T, Rotter M, Sanders P, Takahashi Y, Jaı¨s P, Hocini M et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibrillation. Heart Rhythm 2006;3:27–34. Elayi CS, Di Biase L, Barrett C, Ching CK, al Aly M, Lucciola M et al. Atrial fibrillation termination as a procedural endpoint during ablation in long-standing persistent atrial fibrillation. Heart Rhythm 2010;7:1216 – 23. Boyden PA, Tilley LP, Pham TD, Liu SK, Fenoglic JJ Jr, Wit AL. Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis. Am J Cardiol 1982;49:1896 –908. Estner HL, Hessling G, Ndrepepa G, Luik A, Schmitt C, Konietzko A et al. Acute effects and long-term outcome of pulmonary vein isolation in combination with electrogram-guided substrate ablation for persistent atrial fibrillation. Am J Cardiol 2008;101:332 –7. Elayi CS, Verma A, Di Biase L, Ching CK, Patel D, Barrett C et al. Ablation for longstanding permanent atrial fibrillation: results from a randomized study comparing three different strategies. Heart Rhythm 2008;5:1658 –64. Oral H, Chugh A, Good E, Crawford T, Sarrazin JF, KuhneM et al. Randomized evaluation of right atrial ablation after left atrial ablation of complex fractionated atrial electrograms for long-lasting persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2008;1:6–13. Haı¨ssaguerre M, Hocini M, Sanders P, Sacher F, Rotter M, Takahashi Y et al. Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol 2005;16:1138 –47. Lee G, Roberts-Thomson K, Madry A, Spence S, Teh A, Heck PM et al. Relationship among complex signals, short cycle length activity, and dominant frequency in patients with long-lasting persistent AF: a high-density epicardial mapping study in humans. Heart Rhythm 2011;8:1714 –9.
Europace (2014) 16, 1007–1014 doi:10.1093/europace/eut399
Ablation for atrial fibrillation
Amiodarone reduces the amount of ablation during catheter ablation for persistent atrial fibrillation Yosuke Miwa, Hitoshi Minamiguchi, Anil K. Bhandari, David S. Cannom, and Ivan C. Ho* Department of Cardiology, Good Samaritan Hospital, 1225 Wilshire Boulevard, Third floor, Los Angeles, CA 90017, USA Received 28 August 2013; accepted after revision 22 November 2013; online publish-ahead-of-print 19 January 2014
Aims
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Catheter ablation † Complex fractionated atrial electrograms † Amiodarone
Introduction A step-wise approach to catheter ablation for persistent atrial fibrillation (AF) is commonly required to achieve optimal outcome, beginning with pulmonary vein isolation (PVI), then proceeding with ablation of the complex fractionated atrial electrograms (CFAEs) and linear lesions until sinus rhythm (SR) is achieved. Ablation of the CFAEs has been shown to improve outcomes for patients with persistent AF.1,2 However, this approach entails an extensive amount of ablation, which prolongs the procedure time and may increase the incidence of adverse events. In addition, this approach requires considerable substrate ablation and often precipitates the macroreentry circuits that results in subsequent atrial tachycardia
(AT) or atrial flutter (AFL). An alternative strategy that minimizes the amount of ablation while maintaining procedural success would be desirable. In patients with persistent AF, amiodarone and other antiarrhythmic drugs (AADs) have been reported to reduce conduction velocity,3 widen excitable gap,4,5 prolong refractory period6 and cycle length (CL),7 and organize CFAEs.5,8 According to recent guidelines,9 amiodarone and other AADs are often used for the termination of AF and the maintenance of SR. However, it is unknown whether amiodarone reduces the burden of CFAE lesions and reduces the amount of ablation required to achieve procedural success. Amiodarone differs from other AADs in that its pharmacological effects on cardiac tissues are far more longlasting unless it is discontinued 4–6 weeks prior to the procedure. The aim of this
* Corresponding author. Tel: +1 213 977 2239 ; fax: +1 213 977 2209, E-mail: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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The step-wise approach to catheter ablation for persistent atrial fibrillation (AF) requires considerable substrate modification targeting at complex fractionated atrial electrograms (CFAEs) in addition to pulmonary vein (PV) isolation. An alternative strategy that minimizes the amount of ablation would be desirable. The aim of this study was to investigate whether the use of pre-procedural amiodarone affects: (i) the amount of ablation required to achieve procedural success, and (ii) long-term outcomes. ..................................................................................................................................................................................... Methods We studied 121 consecutive patients with persistent AF who underwent catheter ablation. The patients were divided into two groups: Group 1, amiodarone (n ¼ 31); Group 2, other antiarrhythmic drugs or rate control (n ¼ 90). All the patients and results underwent a step-wise ablation procedure beginning with PV isolation, then proceeding with ablation of the CFAEs and linear lesions until sinus rhythm was achieved. Mean left atrial cycle length of AF (AFCL) was recorded at each step. The number of CFAE ablation sites was recorded. The number of CFAE sites in Group 1 was significantly less than that in Group 2 (P ¼ 0.0121). The AFCLs after each step in Group 1 were significantly longer than those in Group 2. The procedure time and the radiofrequency time of CFAE ablation in Group 1 were significantly shorter than that in Group 2 (P ¼ 0.0276 and P ¼ 0.0458, respectively). There was no significant difference between the two groups in early and long-term outcomes. ..................................................................................................................................................................................... Conclusion Use of pre-procedural amiodarone prolongs AFCL during catheter ablation and reduces the number of CFAE sites requiring ablation to achieve procedural success while maintaining equivalent long-term results.
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What’s new? † Use of pre-procedural amiodarone prolongs atrial fibrillation cycle length during catheter ablation to atrial fibrillation (AF). † Amiodarone reduces the number of complex fractionated atrial electrogram sites requiring ablation to achieve termination of persistent AF. † There is no significant difference in long-term outcome among patients with antiarrhythmic drugs regardless of class and with rate-control drugs.
study was to investigate whether the pre-procedural use of antiarrhythmic medications affects (i) the amount of ablation required to achieve procedural success, and (ii) long-term outcomes.
Y. Miwa et al.
tip catheter was used for endocardial mapping and ablation. Bipolar electrograms were recorded, by using a GE Cardiolab multichannel system (GE Medical Systems) at a bandpass between 30 and 500 Hz. Multislice computed tomography images of the left atrium (LA) and the PVs were imported into the CARTO MergeTM electroanatomical mapping system (Biosense Webster) or into the NavX system (Velocity version 2.1, St Jude Medical) for registration with the geometry created by the circular mapping catheter. This enabled the navigation of the ablation catheter and the display of the ablation sites on the segmented LA surface. Radiofrequency energy between 20 and 40 W was delivered to reach a maximum temperature of 408C during open irrigation of the catheter tip at a flow rate of 17 – 30 mL/min. For applications near the PV ostia, in the posterior LA, or inside the coronary sinus, the power was lowered to 20 W and the flow rate increased to 30 mL/min. Oesophageal temperature was monitored per standard protocol during all the procedures (Figure 1).
Circumferential pulmonary vein isolation
Methods Study population
Administration of amiodarone and other antiarrhythmic drugs The patients in Group 1 received 200– 400 mg per day of oral amiodarone, while the patients in Group 2 received sotalol (160 – 240 mg per day), dofetilide (500 – 1000 mcg per day), dronedarone (800 mg per day), disopyramide (600 mg per day), or flecanide (200 mg per day), or for rate control with either b-blockers (50 – 200 mg per day of metoprolol or 12.5 – 25 mg per day of carvedilol), diltiazem (120 – 480 mg per day), or digoxin (0.125 – 0.25 mg per day). In this study, amiodarone and other AADs were used in common dosage and administration. All the patients had been treated by the AADs including amiodarone for 3 months or more. Amiodarone was not discontinued prior to ablation while other AADs were discontinued more than three times of drugs half-life before.
Procedural description The PVs were mapped by using a 10- or 20-pole, circular LassoNav 2515TM mapping catheter (Biosense Webster), or a 20-pole, circular SpiralTM or OptimaTM mapping catheter (St Jude Medical). A 3.5 mm Thermocool NavistarTM (Biosense Webster) open-irrigation, deflectable
Non-pulmonary vein ablation According to a previous study,10 the CFAEs were defined as electrograms with highly fractionated potentials or with a very short CL (120 ms), and low-voltage multiple potential signals between 0.06 and 0.25 mV. Non-PV ablation targeted regions with CFAE until AF terminated. Determination of the CFAEs was by visual examination of the electrograms by the operator. We determined the endpoint of CFAE ablation when no EGMs throughout the atria met the criteria of the CFAE at the end of the CFAE ablation effort while the patient was still in AF (the nontermination group). When the AF organized into AT or AFL, subsequent ablation was guided by activation and/or entrainment mapping of the AT or the AFL. In cases with macroreentrant AFL, linear ablation in the LA was designed to incorporate the circuit with the known anatomical structures such as the LA roof and the mitral isthmus, including the roof and/or the mitral isthmus lines. If the AF remained after the CFAE ablation, 1 mg of ibutilide was administered intravenously. If ibutilide converted the AF into AT or AFL, the rhythm was mapped, and linear lesions were deployed based on the mapping results. Finally, electrical cardioversion was performed in patients without organization of AF or with nonconversion into the SR.
Follow-up After the ablation procedure, the patients were hospitalized overnight with telemetry monitoring. Amiodarone was (re)started after the
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Approval was granted from our institutional review board for this retrospective analysis at a private, tertiary referral hospital. The electronic database was searched for all the patients who underwent radiofrequency (RF) catheter ablation between January 2009 and May 2011. The patients were included only if the ablation studied was their first procedure, and only if they were in AF at the beginning of the procedure. The patients were excluded if they had prior ablation procedures for AF or if they were in a rhythm other than AF at the beginning of the procedure. According to the expert consensus statement on the catheter and surgical ablation of AF, persistent and long-standing persistent AF were defined. Patients were divided into two groups: Group 1 included patients on amiodarone at the time of ablation; Group 2 included patients taking other AADs (class III, Ia, or Ic) or patients who were on ratecontrol medications but were not taking AADs. For a separate analysis, the patients were stratified based on the procedural success into conversion and non-conversion (requiring cardioversion) groups. Electronic medical records and catheter ablation procedures were reviewed and pertinent data points were recorded.
All the patients underwent circumferential PV ablation, with a goal of achieving complete isolation of all the PVs, defined as the elimination or dissociation of the PV potentials in the SR or the AF (entrance and exit blocks). The presence of complete PVI was confirmed by pacing and recordings made from the circular mapping catheter positioned at the PV ostia. Pulmonary vein exit block was confirmed after the SR was achieved either from ablation or cardioversion. Standard pacing technique from circular mapping catheter inside the PV ostia was used to confirm the exit block at that point. If the PV– LA conduction persisted after the circumferential ablation, attempts were made to identify the conduction gaps and eliminate them by applying RF energy within or just outside the circular lesions. If the AF terminated after isolation of all the four PVs, attempts were made to induce AF by burst pacing inside the coronary sinus to a CL of 180 ms, before and during the administration of intravenous isoproterenol, 1.0 – 20.0 mg/min. If AF persisted after complete PVI, substrate-based ablations of the CFAEs and the linear lesions were then started.
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Effect of amiodarone on the amount of ablation for persistent AF
B Posteroanterior projection
A Anteroposterior projection LS
RS
LS
RS
LI
RI
LAA
LI
RI
AP
CFAE lesion 200 ms
PA
CFAE lesion
200 ms
CFAEs
Figure 1 Representative three-dimensional reconstruction of the LA and the PVs during PVI and CFAE ablation. The red and green tags indicate the ablation sites. The CFAE lesion was observed in a widespread area. LAA, left atrial appendage; LI (S), left inferior (superior) PV; RI (S), right inferior (superior) PV .
Statistical analysis Continuous variables are expressed as the mean + standard deviation. Student’s t-test was used to compare the two groups. Categorical variables were compared, by using a x2 analysis and Yate’s correction, if necessary. Repeated analysis of variance (ANOVA) was performed to compare the atrial fibrillation cycle lengths (AFCLs) during step-wise ablation in the two groups. A logistic regression analysis was performed to identify the predictors of early recurrences of atrial tachyarrhythmias after the ablation procedure. All the parameters with a significance ,0.05 in the univariate analysis were entered into the multivariate model. The time to an atrial tachyarrhythmia recurrence was estimated by the Kaplan – Meier method, with comparisons made by using the log-rank test. A Cox regression analysis was also used to identify any predictors of recurrences of atrial tachyarrhythmias during the follow-up period. A P value ,0.05 was considered significant.
Results Patient characteristics One hundred and twenty-one consecutive patients were studied, including 31 patients on amiodarone in Group 1, 90 patients on other AADs or rate control in Group 2 (Table 1). Overall, the patients were 62 + 10 years of age and mostly male (90%). The mean duration of the AF was 53.8 + 55.3 months and 76 patients (63%) had longstanding persistent AF, hypertension was present in 74%, but diabetes (15%) and structural heart disease (19%) were less common. Average left ventricular ejection fraction (LVEF) was 54.6 + 11.7%. The baseline characteristics differed between the two groups regarding only in left atrial dimension (LAD) and LVEF (P ¼ 0.0239 and P ¼ 0.0369, respectively).
Effect of amiodarone and other antiarrhythmic drugs on the ablation To assess the effect of amiodarone and other AADs to the CFAE and the other ablation procedure, we evaluated the mean CL in the LA during the AF in each step. We divided the atria into seven lesions and mapped all the lesions. The number of CFAE was calculated as the number of CFAE lesions as taken by the electroanatomical points. Although there was no significant difference of each site of the CFAE among the two groups, the number of CFAE sites in Group 1 is significantly smaller than that in Group 2 (P ¼ 0.0121) as shown in Table 2. At the baseline, the AFCL in Group 1 was significantly longer than Group 2 (P ¼ 0.0045). The AFCL after PVI in Group 1 was significantly longer than Group 2 (P ¼ 0.0031). The AFCL after CFAE ablation in Group 1 was also significantly longer than Group 2 (P ¼ 0.0002). Repeated ANOVA showed that there
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ablation immediately. During the blanking period of 3 months, amiodarone was continued. If no recurrence of AF was observed, amiodarone was discontinued after the blanking period. The patients returned for clinical evaluation at 1, 3, 6, 9, and 12 months after the ablation procedure. The patients were instructed to call a clinical coordinator if they experienced symptoms suggestive of arrhythmias. The follow-up screening included: (i) 12-lead electrocardiogram at each follow-up visit; (ii) 24 h Holter every 6 months; and (iii) symptom-driven event monitoring. The ongoing symptoms were investigated with an event monitor. Recurrent atrial tachyarrhythmias were diagnosed when (i) the patient reported symptoms suggestive of a tachycardia, or (ii) a .30 s episode of atrial tachyarrhythmias was recorded on a 12-lead electrocardiogram or a 24 h ambulatory Holter monitor, or by event monitoring or by implanted cardiac device. Recurrence of atrial tachyarrhythmias was defined as all episodes that occurred after ablation, including AF, AFL, and AT.
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Table 1 Comparison of the baseline characteristics between the two groups Group 1 (n 5 31)
Group 2 (n 5 90)
P value
................................................................................ 62 + 9
62 + 10
0.7070
Gender, male/female BMI, kg/m2
25/6 31.9 + 5.8
70/20 31.4 + 15.1
0.7375 0.8718
BMI . 30%
20/31
42/90
0.0864
Duration of AF, month Long-standing persistent AF, n (%) Structural heart disease, n (%)
51.4 + 42.5 18 (58)
54.7 + 59.2 58 (64)
0.7764 0.5262
16 (18)
0.5567
LAD, (mm)
44.6 + 6.7
41.7 + 6.0
0.0239
LAD ≥ 46 mm (≥25 percentile)
10/31
20/90
0.2644
LVEF, % LVEF , 35%
50.8 + 13.9 4/31
55.9 + 10.7 4/90
0.0369 0.1021
Hypertension, n (%)
27 (87)
63 (70)
0.0600
13 (14) 1.1 + 0.7
0.8202 0.1441
Age, years
Diabetes, n (%) CHADS2 score
7 (23)
5 (16) 1.3 + 0.8
Antiarrhythmic drugs 31 (100) 0 (0)
0 (0) 30 (33)
0 (0)
1 (1)
Class Ic antiarrhythmic drugs, n (%)
0 (0)
4 (4)
18 (58) 4 (13)
49 (54) 22 (24)
b-blockers, n (%) Calcium-channel blockers, n (%) Digoxin, n (%)
6 (19)
Ablation outcomes Pulmonary vein isolation was achieved in all the patients (Figure 3). Three patients converted to SR after PVI alone. Two patients converted to AT/AFL after PVI and each achieved SR following linear or focal ablations. Complex fractionated atrial electrogram ablation was performed in 116 of 121 patients (96%) and resulted in SR in 60 of 116 patients (52%). Twenty patients developed AT/AFL after CFAE ablation. Linear or other substrate ablations converted 16 of these 20 patients to SR. The remaining 40 patients were successfully electrically cardioverted. All the patients were in SR at the conclusion of the procedure. Analysis was also performed in comparison of the clinical factors between conversion (the conversion group) and
Table 3 Comparison of AFCL and difference of AFCL in each step between the two groups Amiodarone Non-amiodarone (n 5 31) (n 5 90)
20 ()
BMI, body mass index; AF, atrial fibrillation; LAD, left atrial dimension; LVEF, left ventricular ejection fraction; NS, no significance.
Table 2 Comparison of each site and the number of CFAE among the three groups Group 1 (n 5 29)
Group 2 (n 5 87)
P value
Septum (%)
27/29 (93)
83/87 (95)
0.3704
CS (%) Roof of LA (%)
22/29 (76) 24/29 (83)
71/87 (82) 80/87 (92)
0.4314 0.0933
MVA (%)
15/29 (52)
60/87 (69)
0.0783
CTI (%) AA (%)
0/29 (0) 21/29 (72)
2/87 (2) 78/87 (90)
.0.9999 0.0171
SVC (%)
0/29 (0)
2/87 (2)
.0.9999
Total number of CFAE lesions
3.5 + 1.3
4.2 + 1.2
................................................................................
0.0121
Septum, septum including the Bachmann bundle; CS, left posterior mitral annulus and coronary sinus ostium; LA, left atrium; MVA, mitral annulus; CTI, cavotricuspid isthmus; AA, right and left atrial appendages and antra; SVC, superior vena cava– right atrial junction
P value
................................................................................ Baseline AFCL (ms) AFCL After PVI (ms)
196 + 52 226 + 58
173 + 32 197 + 40
0.0045 0.0031
AFCL PVI baseline (ms)
29 + 31
24 + 27
0.3700
250 + 50
0.0002
56 + 43
0.0563
287 + 58
0.0389
101 + 38
0.9963
AFCL After CFAE 295 + 64 (ms) AFCL CFAE-PVI 74 + 47 (ms) AFCL before 315 + 80* conversion (ms) Procedure time of PVI 101 + 37 (min) Procedure time of 36 + 24 CFAE ABL (min) RF time of PVI (s) 3118 + 785
47 + 26
0.0276
2862 + 955
0.1812
1035 + 701
1325 + 687
0.0458
84 + 22
85 + 21
0.8028
74 + 20
72 + 18
0.5405
RF time of CFAE ABL (s) Total number of ablations Total fluoroscopic time (min) Conversion to sinus rhythm
19/31
54/90
0.8992
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Amiodarone, n (%) Other class III antiarrhythmics, n (%) Class Ia antiarrhythmic drugs, n (%)
were significant differences of the AFCL in each step between the two groups (P ¼ 0.0011) (Table 3 and Figure 2). Procedure time, RF time, and total fluoroscopic time among the three groups are also shown as Table 3. While the total number of ablation lesions, PVI time, and total fluoroscopic time were not significantly different, the procedure and the RF times of the CFAE ablation to achieve the endpoint in Group 1 were significantly shorter than those in Group 2 (P ¼ 0.0276 and P ¼ 0.0458, respectively). Furthermore, although the frequencies of each CFAE site were not significantly different between the two groups except for the atrial appendages, the total number of CFAEs identified and ablated at each of the predefined segments in the electroanatomical maps in Group 1 was significantly less than that in Group 2 (P ¼ 0.0121).
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Effect of amiodarone on the amount of ablation for persistent AF
non-conversion (the non-conversion group) into the SR (Table 4). Enlargement of the LA over 46 mm was more frequent in the nonconversion group than in the conversion group (P ¼ 0.0128), but
Table 4 Comparison of the characteristics between conversion into the SR and the non-conversion groups Non-conversion (n 5 40)
P value
................................................................................
340 320 300 AFCL (ms)
Conversion into the SR (n 5 81)
280 260 240 Group 1 Group 2
220 200 180
P = 0.0011
160 Baseline
After PVI
After CFAE
Before conversion
Steps during step-wise ablation
Figure 2 Interaction plot for the AFCL in each step during step-
61 + 10
63 + 10
62/19
33/7
0.4530
Duration of AF, month
46.0 + 47.1
57.7 + 58.8
0.9446
Longstanding persistent AF, n (%)
54 (67)
22 (55)
0.2116
Structural heart disease, n (%) LAD, mm
14 (17)
9 (23)
0.4915
43.9 + 5.9
41.7 + 6.3
0.0695
LAD . 46 mm (.25percentile), n (%) LVEF (%)
14 (17)
16 (40)
0.0128
54.8 + 10.2
54.5 + 12.5
0.8675
LVEF , 35%, n (%)
7 (9)
1 (3)
0.2683
BMI, kg/m2 BMI . 30%, n (%)
30.6 + 5.2 39 (48)
32.0 + 15.9 23 (58)
0.5901 0.3330
Amiodarone, n (%)
24 (30)
7 (18)
0.1505
AF before procedure; n = 121
PV isolation; n = 121
Sinus rhythm; n=3
AT/AFL; n=2
Linear/focal ablation; n = 2
Sinus rhythm; n=2
0.2957
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wise ablation between the two groups. Repeated ANOVA were performed and showed that there were significant differences of the AFCL in each step between the two groups.
Age, years Gender, male/female
AF; n = 116
CFAE ablation; n = 116
Sinus rhythm; n = 60*
DC cardioversion; n = 36
*Including 36 patients after.
AT/AFL; n = 20
Linear/focal ablation; n = 20
Sinus rhythm; n = 16
DC cardioversion; n=4
Figure 3 Study profile detailing the outcomes of the 121 patients who underwent catheter ablation for persistent AF.
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Table 5 Cox regression analyses for predictors of long-term recurrences of atrial fibrillation or atrial tachyarrhythmias Univariate analysis
.........................................
Cumulative probability of recurrence-free (%)
Y. Miwa et al.
100 P = 0.02 80 60
HR
95% CI
P value
Age, years
0.98
0.94– 1.01
0.1344
Gender, male BMI (kg/m2)
1.13 1.01
0.48– 2.65 0.97– 1.04
0.7865 0.7217
BMI . 30
1.14
0.56– 2.33
0.7191
LVEF (%) LVEF , 35%
0.99 2.56
0.96– 1.02 0.76– 8.33
0.4831 0.1278
Number at risk
LAD (mm)
1.04
0.99– 1.10
0.1529
Conversion into SR
40
28
23
21
10
8
2
LAD ≥ 46 mm Duration of AF, month
1.81 1.00
0.84– 3.91 0.99– 1.01
0.1292 0.9610
Non-conversion
81
56
36
27
18
8
3
Long-standing persistent AF
2.53
1.15– 5.57
0.0212
Structural HD CHADS2 score
2.10 1.04
0.85– 5.24 0.63– 1.73
0.1098 0.8739
Hypertension
1.11
0.50– 2.44
0.7866
Diabetes Groups 1 vs. 2
1.72 1.41
0.52– 5.71 0.66– 3.02
0.3736 0.3807
Conversion into the SR
0.45
0.22– 0.93
0.0306
20
Conversion into SR Non-conversion
0 0 3
8
28
13 18 23 Follow-up period (month)
33
100 80 60 40 20 Group 1 Group 2
0 0
3
28 13 18 23 Follow-up period (month)
8
33
38
Number at risk Group 1
31
24
17
12
4
3
1
Group 2
90
60
42
36
24
13
4
Figure 5 Kaplan– Meier event-free survival curve for the recurrences of atrial tachyarrhythmias in Groups 1 and 2.
Follow-up
Discussion
During the mean follow-up of 15 + 12 months (6–37 months), of the 87 patients who maintained the SR for the first 3 months as the blanking period, 29 patients (24%) recurred into the ATs after the blanking period. On univariate analyses, long-standing persistent AF and conversion into the SR were significantly associated with the endpoint of recurrence-free survival, with a hazards ratio (HR) of 2.53 (95% CI: 1.15 –5.57; P ¼ 0.0212) and 0.45 (95% CI: 0.22 –0.93; P ¼ 0.0306), respectively, (Table 5 and Figure 4), while on multivariate analysis, their HR were 2.46 (95% CI: 1.12– 5.41, P ¼ 0.0256), and 0.46 (95% CI: 0.23–0.96; P ¼ 0.0378), respectively. However, the recurrence-free survival rate during the entire period of follow-up was not different between Groups 1 and 2 (Figure 5).
In recent years, as patients with persistent AF have been increasingly considered for catheter ablation, the lesion sets have become more aggressive and complex. While the technique of persistent AF ablation has been well established and validated by many studies, debate remains whether ‘more is better’ in terms of amount of RF ablation performed and the concept of LA substrate ‘debulking’. On the one hand, it seems logical to remove as much substrate as possible during aggressive RF ablation for persistent AF to reduce the LA’s ability to maintain AF. However, on the other hand, the prolonged duration of the procedure, associated endocardial inflammation from extensive amount of ablation, and potential for more arrhythmogenic circuits from incomplete ablation lesion sets can potentially
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there was no significant difference between the two groups in the other clinical factors. Logistic regression analysis was also performed to identify the significant predictors of conversion into the SR. Enlargement of the LA was still the only significant predictor of failure to conversion into the SR during the AF ablation with an odds ratio of 3.19 [95% confidence interval (CI): 1.36–7.52; P ¼ 0.0079]. There was no difference between Group 1 (amiodarone) and Group 2 (other AADs or rate-control drugs) in the probability of conversion into the SR during the procedure. When the patients treated with amiodarone, other AADs and atrioventricular node blockers were compared, although there was no significant difference among the three groups regarding the rate of conversion into SR, the total number of CFAE lesions in patients with amiodarone was significantly smaller than in other groups (Table 2).
40
Figure 4 Kaplan– Meier event-free survival curve for the recurrences of atrial tachyarrhythmias in the conversion and the nonconversion groups.
Cumulative probability of recurrence-free (%)
................................................................................
1013
Effect of amiodarone on the amount of ablation for persistent AF
lead to higher incidence of peri-procedural adverse events and poor long-term outcomes. In this study, use of amiodarone preprocedurally was compared with the use of other AADs (or on AADs) to see if the long-lasting pharmacological effect of amiodarone would make a difference in the achievement of immediate proprocedural endpoints, as well as long-term procedural success. The main finding of this study is that the pre-procedural use of amiodarone can prolong AFCL at each step of the ablation, reduce the number of CFAE sites identified and the RF time spent on the CFAE ablation, while not affecting the long-term recurrence rate of the atrial arrhythmias. This study is the first to retrospectively validate this combined approach by using the pharmacological property of amiodarone to assist in the reduction in the amount of substrate ablation while maintaining clinical success, which is opposite to the common practice of discontinuing AADs well before the procedure to allow more complete substrate ablation in the atria.
Role of amiodarone
The step-wise approach to the catheter ablation of persistent AF, which usually involves a considerable amount of LA substrate modification, carries the common goal of conversion into the SR. Elayi et al.13 have shown in an earlier study that there is no significant difference in the clinical characteristics between the patients who converted into the SR or the AT, and those who failed to terminate or organize during the ablation. However, in this study, although the use of pre-procedural AADs, regardless of class, is not associated with an increase rate of conversion into the SR during step-wise ablation for persistent AF, an enlarged LA of more than 46 mm was strongly associated with failure to convert into the SR. Boyden et al.14 have shown that an enlarged LA is associated with electric and structural changing of the atrium, and the result of this study showed the close correlation between atrial remodelling and the inability to convert into the SR even in the pharmacologically ‘prepared’ atrium.
Long-term outcomes Elayi et al.13 described that AF and AT termination during the procedure were not associated with a better clinical outcome, similar to the results of Estner et al.15 Although previous studies16 – 18 found a correlation between AF termination during ablation and better success rate at follow-up, there is no available information regarding the effect of pre-procedural administration of the AADs to the long-term outcomes. This is the first report to show that not only could conversion into the SR during ablation of persistent AF predict long-term SR maintenance, it also showed that the use of pre-procedural AADs, including amiodarone, would not affect long-term outcome. However, AF that meets the definition of long-standing persistent AF predicts higher probability of recurrence of atrial tachyarrhythmias even with conversion during procedure. The results of this study also revealed that there is no significant difference in the long-term outcome among patients with AADs regardless of the class and with the rate-control drugs, while the amount of CFAE sites and the RF duration of the CFAE ablation could be reduced with the use of amiodarone.
Study limitations Our study has several limitations. First, the CFAE were identified by subjective visual inspection, although this is a methodology widely used and accepted in the previous studies.10,19 Secondly, the postprocedural monitoring of arrhythmias in patients was not uniform, and thus some patients with asymptomatic atrial tachyarrhythmias recurrences might have been missed. Thirdly, selections of the AADs were not randomized but were dependent on the patients’ tolerance to the AADs according to the guidelines. Fourthly, if CFAE mapping after PVI was performed, it could be likely that there had been already a decrease in area with CFAE after the circumferential PVI. However, PVI was not only an established manoeuvre to paroxysmal AF but also persistent and long-standing persistent AF. The result of this study could be useful information in the actual clinical setting, because CFAE ablation in most patients could be considered after PVI. Fifthly, this study is a retrospective analysis and could have potentially some bias. However, there was no significant difference
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Use of amiodarone could allow one to identify the CFAE sites responsible for maintaining AF. This mechanism may be related to the longer baseline AFCL in Group 1. During PVI and substrate ablation, there was more AFCL prolongation in the amiodarone group than in the group with the other AADs. These clinical findings are consistent with the basic studies of Shan et al.,8 who demonstrated that the use of cibenzoline can reduce LA fractionation in a goat model of AF, and Singh et al.,11 who described that acute administration of ibutilide reduces CFAE area. Rostock et al.12 also described that the changes in CFAE area correlated with the overall prolongation in the LA CL in the human LA. Thus, the slowing or organization of the LA with the acute administration of an AAD may facilitate the identification of the CFAE sites actively participating in the maintenance of AF by eliminating the CFAEs generated as a result of passive atrial activation. However, previous studies have raised concerns that premature conversion into the SR facilitated by AAD use may undermine the amount of substrate modification that otherwise would be needed before the endpoint is met. Currently, there are no data regarding the use of pre-procedural AADs and the probability of conversion into the SR during step-wise ablation for persistent AF. In this study, use of pre-procedural amiodarone, compared with other AADs or rate-control drugs, can reduce the number of CFAE sites that require ablation and promote the prolongation of AFCL during persistent AF ablation while achieving the same procedural endpoints and long-term outcomes with less RF ablation. While the amiodarone group did not have a higher probability of conversion compared with the group with the other AADs, the amount of substrate modification required to achieve the same outcome was less. Other AADs were grouped together with the rate control in comparison with amiodarone due to the short half-lives and the predictable pharmacokinetics of most AADs other than amiodarone, and the pharmacological influence of these drugs on the patients during the ablation are probably minimal after withholding one to two doses before the procedure. Moreover, the pre-procedural continuation of the AADs, regardless of class, is not associated with an increased rate of conversion into the SR during the step-wise ablation for persistent AF.
Acute outcomes of atrial fibrillation ablation
1014 regarding the well-known risk factors between the two groups. A further randomized control study with large number and long-term follow-up could be needed to clarify the difference.
Y. Miwa et al.
7.
8.
Conclusion 9.
Use of pre-procedural amiodarone could reduce the number of CFAE sites that require ablation and promote prolongation of AFCL during persistent AF ablation before achieving procedural endpoint of conversion into the SR. While amiodarone was not associated with an increased rate of conversion into the SR during the step-wise ablation for persistent AF and has similar long-term SR maintenance compared with the other AADs, these same outcomes could be achieved with a reduced amount of ablation with the pharmacological influence of amiodarone on the atrial electrophysiological substrate.
10.
11.
12.
13.
Conflict of interest: none declared. 14.
References 15.
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17.
18.
19.
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1. Nademanee K, Schwab MC, Kosar EM, Karwecki M, Moran MD, Visessook N et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol 2008;51:843 –9. 2. Estner HL, Hessling G, Ndrepepa G, Wu J, Reents T, Fichtner S et al. Electrogramguided substrate ablation with or without pulmonary vein isolation in patients with persistent atrial fibrillation. Europace 2008;10:1281 –7. 3. Sager PT, Nademanee K, Antimisiaris M, Pacifico A, Pruitt C, Godfrey R et al. Antiarrhythmic effects of selective prolongation of refractoriness. Electrophysiologic actions of sematilide HCl in humans. Circulation 1993;88:1072 –82. 4. Wijffels MC, Dorland R, Mast F, Allessie MA. Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and D-sotalol. Circulation 2000;102:260 –7. 5. Kawase A, Ikeda T, Nakazawa K, Ashihara T, Namba T, Kubota T et al. Widening of the excitable gap and enlargement of the core of reentry during atrial fibrillation with a pure sodium channel blocker in canine atria. Circulation 2003;107:905 –10. 6. Esato M, Shimizu A, Chun YH, Tatsuno H, Yamagata T, Matsuzaki M. Electrophysiologic effects of a class I antiarrhythmic agent, cibenzoline, on the refractoriness
and conduction of the human atrium in vivo. J Cardiovasc Pharmacol 1996;28: 321 – 7. Fujiki A, Sakabe M, Nishida K, Mizumaki K, Inoue H. Role of fibrillation cycle length in spontaneous and drug-induced termination of human atrial fibrillation. Circ J 2003; 67:391 – 5. Shan Z, Van Der voort PH, Blaauw Y, Duytschaever M, Allessie MA. Fractionation of electrograms and linking of activation during pharmacologic cardioversion of persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 2004;15:572 –80. Calkins H, Brugada J, Packer DL, Cappato R, Chen SA, Crijns HJ et al. HRS/EHRA/ ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. Europace 2007;9:335 –79. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, Vasavakul T et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044 –53. Singh SM, D’Avila A, Kim SJ, Houghtaling C, Dukkipati SR, Reddy VY. Intraprocedural use of ibutilide to organize and guide ablation of complex fractionated atrial electrograms: preliminary assessment of a modified step-wise approach to ablation of persistent atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:608–16. Rostock T, Rotter M, Sanders P, Takahashi Y, Jaı¨s P, Hocini M et al. High-density activation mapping of fractionated electrograms in the atria of patients with paroxysmal atrial fibrillation. Heart Rhythm 2006;3:27–34. Elayi CS, Di Biase L, Barrett C, Ching CK, al Aly M, Lucciola M et al. Atrial fibrillation termination as a procedural endpoint during ablation in long-standing persistent atrial fibrillation. Heart Rhythm 2010;7:1216 – 23. Boyden PA, Tilley LP, Pham TD, Liu SK, Fenoglic JJ Jr, Wit AL. Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis. Am J Cardiol 1982;49:1896 –908. Estner HL, Hessling G, Ndrepepa G, Luik A, Schmitt C, Konietzko A et al. Acute effects and long-term outcome of pulmonary vein isolation in combination with electrogram-guided substrate ablation for persistent atrial fibrillation. Am J Cardiol 2008;101:332 –7. Elayi CS, Verma A, Di Biase L, Ching CK, Patel D, Barrett C et al. Ablation for longstanding permanent atrial fibrillation: results from a randomized study comparing three different strategies. Heart Rhythm 2008;5:1658 –64. Oral H, Chugh A, Good E, Crawford T, Sarrazin JF, KuhneM et al. Randomized evaluation of right atrial ablation after left atrial ablation of complex fractionated atrial electrograms for long-lasting persistent atrial fibrillation. Circ Arrhythm Electrophysiol 2008;1:6–13. Haı¨ssaguerre M, Hocini M, Sanders P, Sacher F, Rotter M, Takahashi Y et al. Catheter ablation of long-lasting persistent atrial fibrillation: clinical outcome and mechanisms of subsequent arrhythmias. J Cardiovasc Electrophysiol 2005;16:1138 –47. Lee G, Roberts-Thomson K, Madry A, Spence S, Teh A, Heck PM et al. Relationship among complex signals, short cycle length activity, and dominant frequency in patients with long-lasting persistent AF: a high-density epicardial mapping study in humans. Heart Rhythm 2011;8:1714 –9.
