International Journal of Cardiology 171 (2014) 37–43
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Does the amount of atrial mass reduction improve clinical outcomes after radiofrequency catheter ablation for long-standing persistent atrial fibrillation? Comparison between linear ablation and defragmentation☆,☆☆ Seong Woo Han a,1, Seung Yong Shin b,1, Sung Il Im c, Jin Oh Na c, Cheol Ung Choi c, Seong Hwan Kim c, Jin Won Kim c, Eung Ju Kim c, Seung-Woon Rha c, Chang Gyu Park c, Hong Seog Seo c, Dong Joo Oh c, Chun Hwang d, Hong Euy Lim c,⁎ a
Department of Cardiology, Hallym University Hangang Sacred Heart Hospital, 94-200 Yeongdeungpo-dong 2-ga, Yeongdeungpo-gu, Seoul, Republic of Korea Division of Cardiology, Heart Research Institute, College of Medicine, Chung-Ang University, 224-1 Heukseok-dong, Dongjak-gu, Seoul, Republic of Korea Division of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul, Republic of Korea d Division of Cardiology, Utah Valley Regional Medical Center, 1055 North 500 West, Provo, UT 84604, USA b c
a r t i c l e
i n f o
Article history: Received 2 July 2013 Received in revised form 9 October 2013 Accepted 17 November 2013 Available online 23 November 2013 Keywords: Atrial fibrillation Atrial mass Complex fractionated atrial electrograms Linear ablation
a b s t r a c t Background: Although a large isolated surface area of the left atrium (LA) may improve the success rate of catheter ablation (CA) for paroxysmal atrial fibrillation (AF), little is known about the relation between clinical outcomes and the amount of atrial mass reduction (AMR: ratio of total isolated and ablated areas to LA surface area) in different ablation strategies for patients with long-standing persistent AF (L-PeAF). Methods: We randomly assigned 119 consecutive L-PeAF patients to adjunctive linear ablation (n = 60) or complex fractionated atrial electrogram (CFAE)-guided ablation (n = 59) after circumferential antral pulmonary vein isolation (PVI). Linear lesions included roof and anterior lines with conduction block. LA defragmentation was performed with an automated CFAE-detection algorithm. Cavotricuspid isthmus block was performed in all patients. Creatine kinase-MB (CK-MB) and troponin-T levels were measured 1 day post-CA. Results: CK-MB and troponin-T levels were higher, ablation time was longer, and AMR was greater in the CFAEguided ablation group than in the linear ablation group. AF termination during CA was more frequently observed in the linear ablation group than in the CFAE-guided ablation group (P = 0.031). Twelve months after a single procedure, recurrence occurred in 16 (26.7%) patients with linear ablation and 27 (45.8%) patients with CFAEguided ablation (P = 0.023). On multivariate analysis, LA volume and ablation method were the only independent risk factors for arrhythmia recurrence. Conclusion: Conduction block through linear lines + PVI was an efficient ablation strategy for L-PeAF, whereas the AMR amount did not influence clinical outcomes. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary vein isolation (PVI) is currently the standard therapy for selected patient groups and has been considered a first-line therapy for those with symptomatic paroxysmal atrial fibrillation (AF) [1].
☆ Grant support: This study was supported by grants (ED12078, MD1104) from the Korea University Guro Hospital. ☆☆ Conflicts of interest: The authors have no conflicts of interest to declare. ⁎ Corresponding author at: Cardiovascular Center, Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, 97, Guro-dong, Guro-gu, Seoul 152-703, Republic of Korea. Tel.: +82 2 2626 1046; fax: +82 2 867 9093. E-mail addresses: [email protected], [email protected] (H.E. Lim). 1 The first 2 authors equally contributed to this study. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.041
However, PVI alone is not sufficient to eliminate arrhythmogenic substrates in patients with long-standing persistent AF (L-PeAF) [2]. Although several investigators have suggested that additional linear lesions or defragmentation of complex fractionated atrial electrograms (CFAE) in the left atrium (LA) may improve clinical outcomes after catheter ablation (CA) for L-PeAF [3,4], the limited clinical efficacy has led to a search for the ideal CA strategy. Because experimental and clinical evidence has revealed that a critical mass of atrial tissue is necessary to maintain AF [5], suggesting that the efficacy of AF ablation may be related to the extent of the ablated tissue, there has been a trend toward ablation of extensive lesions performed in a stepwise manner [6]. However, more extensive ablation may not only increase the risk of complications [7] but may also be associated with arrhythmia recurrence through the creation of proarrhythmic substrates caused by iatrogenic myocardial injury [8,9].
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To improve success rates, various adjunctive atrial modifications, targeting both AF triggers and the perpetuating substrate, have been incorporated into CA for L-PeAF [3,4]. However, little is known about the relation between clinical outcomes and the amount of atrial mass reduction (AMR) in different ablation strategies for L-PeAF patients. The aims of this study were to identify whether the degree of AMR influences long-term clinical outcomes after a single procedure, and to determine which of the 2 ablation strategies was more effective in patients who underwent CA for L-PeAF.
2.2. Transthoracic echocardiography All examinations were performed using a commercially available Vivid 7TM (GE Medical Systems, Vingmed, Horten, Norway) ultrasound system. All recorded echocardiograms were collected and analyzed using an offline computer analysis station (EchopacTM 6.3.4; GE Medical Systems). All measurements were taken from 3 consecutive cardiac cycles and averaged. The maximal LA volume (LAV) was measured manually using the modified Simpson's method, by tracing the endocardial border in the apical 4- and 2-chamber views over the cardiac cycle after zooming in on the LA. Each echocardiographic parameter was determined according to the recommendations of the American Society of Echocardiography [11].
2. Methods 2.3. Ablation procedure 2.1. Study population From December 2008 to August 2011, we prospectively enrolled 119 consecutive LPeAF patients who underwent CA. L-PeAF was defined according to the most recent guidelines of the Heart Rhythm Society and the European Cardiac Arrhythmia Society [10]. Exclusion criteria were the presence of visible LA thrombi on transesophageal echocardiography (TEE), previous AF ablation or cardiac surgery, cardiomyopathy, more than mild valvular disease, congenital heart disease, aortic aneurysm or dissection, an acute cerebrovascular event within the preceding 3 months, hyperthyroidism, and any acute or chronic inflammatory diseases. All antiarrhythmic drugs were discontinued at least 5 half-lives before the examination. Amiodarone was discontinued at least 8 weeks earlier. All patients were on continuous anticoagulation therapy with a target international normalized ratio of 2–3. Each participant signed an informed consent form before the study, which was approved by the Human Subjects Review Committee of Korea University Guro Hospital. The authors of this manuscript certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
Before CA, TEE and multi-slice computerized tomography (MSCT) were performed in all patients. Intracardiac electrocardiograms (ECGs) were recorded using a PruckaCardioLabTM electrophysiology system (General Electric Health Care Systems Inc., Milwaukee, WI, USA), and a 3-dimensional (3D) electroanatomical mapping system (NavX; St. Jude Medical Inc., Minnetonka, MN, USA) was used in all patients. After double transseptal puncture, systemic anticoagulation was achieved with intravenous heparin to maintain an activated clotting time between 300 and 350 s. After the 3D geometry of the LA and pulmonary veins (PVs) had been determined using the NavX mapping system and merged with the volumerendered MSCT image, all PVs were mapped with a decapolar circular catheter (Lasso; Biosense Webster, Diamond Bar, CA, USA). An open-irrigation, 3.5-mm-tip deflectable catheter (Celsius; Biosense Webster) was used for mapping and ablation. Radiofrequency energy was delivered as follows: maximum power output, 25–30 W; flow rate, 17–30 mL/min; and maximum temperature, 48 °C. The endpoint for each individual application at a given site was either total voltage abatement or current application of up to 40 s with adequate tissue contact and power delivery.
Fig. 1. Schematic algorithm of the study design and procedural outcomes. L-PeAF: long-standing persistent atrial fibrillation; PVI: pulmonary vein isolation; CFAE: complex fractionated atrial electrograms; CTI: cavotricuspid isthmus; AF: atrial fibrillation.
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2.4. Study protocol
2.8. Statistical analysis
The overall study algorithm is shown in Fig. 1. We randomly assigned patients with LPeAF to either the adjunctive linear ablation or the CFAE-guided ablation group according to an optimum assignment procedure with computer-generated random numbers. All enrolled patients underwent AF ablation performed by a single operator who had an independent AF ablation experience of N700 cases. All patients underwent successful PVI, defined as the complete disappearance of the PV potentials through the circumferential antral ablation. In the linear ablation group, linear lesions were created on the roof and anterior wall of the LA (Fig. 2A). Our technique for linear ablation has been described previously [12]. In brief, radiofrequency energy was delivered from the mitral annulus area (11–12 o'clock direction in the left anterior oblique view) to the LA roofline, which joined both superior PVs anteriorly. Conduction block was verified by a differential pacing maneuver on either side of the linear lesions after the restoration of sinus rhythm (SR). In the CFAE-guided ablation group, we applied an automated CFAE detection algorithm by using the NavX mapping system, a previously described and validated software [13]. In brief, CFAE was characterized using the NavX “CFAE-mean” contact mapping tool, which provides a point-by-point map of electrogram complexity. CFAE-mean was defined as the average time duration between consecutive deflections during 6 s and recorded at each site. Deflections were identified by a detection algorithm and annotated on the electrogram. Our user settings included a refractory period of 49 ms, a P–P sensitivity of between 0.05 and 0.1 mV, and a duration of 24 ms. Sites with a CFAE-mean value within a physiologically relevant range of 80 and 250 ms were included for analysis. To ensure uniform distribution, the LA was divided into 6 segments (posterior, anterior, lateral, septal, roof, and inferior wall), and then mean CFAE signals were obtained for N20 points in each segment using a 3.5-mm irrigated-tip ablation catheter. The endpoint of CFAE-guided ablation was to achieve elimination of any CFAEs in the LA and the abolition of the local fractionated potentials (bipolar voltage b0.05 mV, Fig. 2B-2). In all patients, cavotricuspid isthmus (CTI) block was conducted after LA ablation. Acute procedural success was defined as AF termination. If AF persisted after the completion of the stepwise ablation procedure, we performed internal direct current (DC) cardioversion (5–20 J, biphasic shocks with R-wave synchronization, anodal decapolar catheter in the free wall of the right atrium to the cathodal duodecapolar catheter inside of the coronary sinus) to restore SR.
Continuous variables were compared between groups using Student's t-test. Unpaired categorical variables were compared using the χ2 or Fisher's exact test. Recurrence rates were estimated using the Kaplan–Meier method. A log–rank test was used to compare estimates between groups. Univariate and multivariate predictors were identified using Cox regression analysis. Multivariate models included all univariates with P ≤ 0.1 and were constructed using a stepwise selection of clinical and echocardiographic characteristics.
2.5. Amount of AMR Ablation points with a diameter of 3 mm were marked on the LA geometry to identify all target areas. The LA surface area was measured by pixel counting of the volumerendered MSCT image made with the NavX system. The detailed LA surface area was estimated after excluding all PVs and LA appendage at their ostia and isolated LA surface area or ablation lesions were assessed using NavX system software. Isolated antral area (IAA) was defined as the sum of isolated antral surface areas from the total LA surface area. Total ablated area (TAA) was defined as the sum of the ablation lesions from the total LA surface area. AMR was defined as the ratio of IAA + TAA to the total LA surface area (Fig. 3), expressed as a percentage according to the following equation: n o 2 2 2 þ TAA cm =Total LA surface area cm 100 ð% Þ AMR ð% Þ ¼ IAA cm
To assess inter- and intra-observer variability, total LA surface area, IAA, TAA, and AMR were independently assessed by 2 experienced investigators who were blinded to the clinical information. 2.6. Blood sampling and analysis In all subjects, a blood sample was obtained from a large antecubital vein 1 day after CA for analyzing creatine kinase-MB (CK-MB), cardiac troponin-T, and myoglobin levels. Blood samples were drawn into ice-chilled tubes containing ethylenediaminetetraacetic acid and immediately centrifuged at 3000 rpm for 20 min. All samples were frozen at −80 °C until analysis. Samples were batched together for analysis and processed by a technician who was blinded to all subject information. CK-MB, cardiac troponin-T, and myoglobin levels were measured with a Stratus CS analyzer (Dade Behring, Germany), using commercially available test materials. 2.7. Follow-up If no complications arose during the procedure, anticoagulation therapy with warfarin was initiated without any antiarrhythmic medication. All subjects were scheduled for visits to the outpatient clinic at 1, 2, 3, 6, 9, and 12 months after CA for AF. Subjects also underwent 48-h Holter monitoring at 1, 3, 6, and 12 months post-CA. An ECG was recorded during every visit and on any visit when the patient reported palpitations. Additionally, a nurse practitioner interviewed each patient by telephone at 2-week intervals during the first 3 months after CA, and all patients were instructed to call whenever they experienced symptoms. Any patient with documented AF or atrial flutter during 12 months after an index procedure without a blanking period was judged to have a clinical arrhythmia recurrence and was treated with antiarrhythmic medications after DC cardioversion.
Fig. 2. Representative examples of the 2 different ablation methods. A: representative images of the linear ablation method. B-1: representative images of the CFAE map after pulmonary vein isolation. B-2: representative images of the CFAE-guided ablation method (left) anterior–posterior view; (right) posterior–anterior view. CTI: cavotricuspid isthmus; CFAE: complex fractionated atrial electrograms; PVI: pulmonary vein isolation.
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Relative risks were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM Corp., Chicago, IL, USA). A 2-sided P b 0.05 was considered statistically significant.
3. Results The study initially included 60 subjects in each group, but 1 patient in the CFAE-guided ablation group withdrew his informed consent. Thus, a total of 119 subjects were enrolled and followed until the end of the study period (12 months after CA). The baseline demographic and imaging parameters of the study participants are summarized in Table 1. The mean age was 52.8 ± 11.3 years, and men were predominant (89.9%). There were no significant differences between the 2 groups in age, sex, comorbidities, mean AF duration, mean number of failed antiarrhythmic drugs, CHADS2/CHA2DS2-VASc score, LV ejection fraction, LAV, and total LA surface area. Table 2 summarizes the procedural findings. There were no procedure-related complications in both groups. Bidirectional conduction block along the roofline was achieved in all 60 patients, whereas conduction block on the anterior line was achieved in 53 (88.3%) patients. Local fractionated potentials were abolished in all CFAE sites. The degree of myocardial injury, represented by the ablation time, CKMB, and troponin-T, was higher in the CFAE-guided ablation group than in the linear ablation group. There was no statistically significant difference in the IAA between two groups, whereas the TAA and AMR were greater in the CFAE-guided ablation group than in the linear ablation group. However, during the ablation, AF termination was more frequently observed in the linear ablation group than in the CFAE-guided ablation group (P = 0.031). During the 12-months after CA, arrhythmia frequently recurred in the CFAE-guided ablation group than in the linear ablation group (P = 0.023), whereas there was no difference in the type of recurrence between the groups. Table 3 shows the results of univariate and multivariate analyses for predictors of arrhythmia recurrence after a single ablation procedure. On univariate analysis, the LV end-diastolic dimension, AF termination during ablation, ablation time, and ablation method were significantly
related to AF recurrence after CA for L-PeAF. On multivariate analysis, the LAV (P = 0.015) and ablation method (P = 0.049) were the only independent risk factors associated with recurrence after AF ablation. Fig. 4 illustrates the incidence and timing of recurrence during the 12-month post-CA period. The total cumulative recurrence rate was 36.1% among all subjects. Recurrence occurred early (within 3 months) in 34 (79.0%) patients, midterm (4–6 months) in 3 (7.0%) patients, and late (7–12 months) in 6 (14.0%) patients. Recurrence predominantly occurred in the first 3 months, with an average rate of 9.5% per month. Thereafter, the recurrence rate decreased to as little as 0.8% per month during 3–12 months after CA. The rate of early recurrence was significantly higher for CFAE-guided ablation than for linear ablation (39.0% vs. 18.3%, P = 0.012). Over the entire follow-up period, recurrence was more frequently observed in the CFAE-guided ablation group than in the linear ablation group (45.8% vs. 26.7%, P = 0.023). Fig. 5 shows the inter- and intra-observer variability of the total LA surface area, TAA, and AMR measurements. There were strong positive correlations between them (P b 0.001, R N 0.9). 4. Discussion The noteworthy findings of the present study are as follows: (1) the amount of AMR did not influence clinical outcomes after CA for L-PeAF; (2) the CK-MB and troponin-T levels measured 1 day after CA were significantly higher and the ablation time was longer in the CFAE-guided ablation group than in the linear ablation group; (3) the long-term success rate and the acute procedural success rate were markedly higher in the linear ablation group than in the CFAE-guide ablation group; and (4) the LAV and ablation method were the only independent risk factors for arrhythmia recurrence after CA for L-PeAF. This prospective randomized study demonstrated for the first time that catheter-based linear lesion formation has significantly better clinical efficacy than defragmentation, although CFAE-guided ablation produced a larger TAA, a higher AMR, and a longer ablation time than linear ablation. On the basis of the “critical mass of atrial tissue” theory, ablation strategies have been evolving toward being directed at more extensive lesions, performed in a stepwise manner [6]. A recent study
Fig. 3. Representative examples of the measurement of atrial mass reduction. A: isolated antral and total ablated areas were measured, and atrial mass reduction ratio was calculated in the linear ablation group. B: isolated antral and total ablated areas were measured, and atrial mass reduction ratio was calculated in the CFAE-guided ablation group. LA: left atrium; CFAE: complex fractionated atrial electrograms.
S.W. Han et al. / International Journal of Cardiology 171 (2014) 37–43 Table 1 Baseline characteristics of patients with long-standing persistent atrial fibrillation. Variables
Age (years) Male (%) Body mass index (kg/m2) AF duration (months) Number of AAD Hypertension (%) Diabetes mellitus (%) Coronary artery disease (%) Heart failure (%) COPD (%) OSA (%) CHADS2 score CHA2DS2-VASc score Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) Echocardiography LVIDd (mm) LVEF (%) LA dimension (mm) MSCT LA volume (mL) Total LA surface area (cm2)
Total
Linear ablation
CFAE ablation
P
(n = 119)
(n = 60)
(n = 59)
52.8 ± 11.3 107 (89.9) 25.4 ± 2.6 18.1 ± 2.9 1.6 ± 0.6 65 (54.6) 19 (16.0) 11 (9.2) 10 (8.4) 3 (2.5) 8 (6.7) 1.4 ± 1.1 1.9 ± 1.5 177.1 ± 37.0 161.1 ± 103.7 45.0 ± 11.5 112.0 ± 32.7
53.8 ± 10.5 54 (90.0) 25.4 ± 2.6 17.7 ± 2.8 1.7 ± 0.6 33 (55.0) 11 (18.3) 7 (11.7) 7 (11.7) 3 (5.0) 3 (5.0) 1.5 ± 1.1 1.9 ± 1.5 174.7 ± 35.3 161.3 ± 92.1 44.9 ± 11.8 109.1 ± 31.7
51.8 ± 12.1 53 (91.5) 25.3 ± 2.5 18.5 ± 3.0 1.5 ± 0.6 32 (54.2) 8 (13.6) 4 (6.8) 3 (5.1) 0 (0.0) 5 (8.5) 1.4 ± 1.1 1.8 ± 1.5 179.6 ± 38.8 161.0 ± 115.1 45.2 ± 11.3 115.0 ± 33.8
0.333 0.976 0.695 0.153 0.103 0.934 0.481 0.362 0.199 0.083 0.453 0.580 0.805 0.480 0.985 0.886 0.338
50.1 ± 4.4 62.9 ± 8.4 43.3 ± 6.5
49.8 ± 4.4 63.3 ± 7.7 43.5 ± 6.0
50.4 ± 4.5 62.5 ± 9.2 43.1 ± 7.0
0.450 0.608 0.766
107.2 ± 45.3 133.3 ± 27.8
106.6 ± 38.6 107.7 ± 51.6 130.3 ± 25.4 136.4 ± 30.0
0.900 0.229
Data are shown as mean ± standard deviation (SD) or as number (%). CFAE: complex fractionated atrial electrograms; AF: atrial fibrillation; AAD: antiarrhythmic drug; COPD: chronic obstructive pulmonary disease; OSA: obstructive sleep apnea; LVIDd: left ventricular internal dimension, diastolic; LVEF: left ventricular ejection fraction; LA: left atrium; MSCT: multislice computed tomography.
revealed that a larger IAA was associated with a significantly lower recurrence rate after a single ablation procedure in patients with paroxysmal AF [14]. The authors suggested that a wide ablation line encircling the entire PV antrum could better eliminate both AF triggers and substrate. In the present study, there was no difference in the amount of IAA between both groups because we performed the circumferential antral PVI in the same manner in all patients. However, TAA was significantly smaller and clinical outcomes were better in the linear ablation group than in the CFAE-guided ablation group. Therefore, these results indicated that AMR itself did not influence the clinical outcomes in patients with L-PeAF. To improve the therapeutic outcome of CA for L-PeAF, most investigators attempt to add subsequent substrate modifications to circumferential antral PVI, which has been a common ablation strategy in all AF patients. Although 2 adjunctive ablation methods (creation of additional linear lesions and defragmentation of CFAE) have been Table 2 Procedural, laboratory, and clinical findings after radiofrequency catheter ablation for long-standing persistent atrial fibrillation. Variables
Ablation time (min) Creatine kinase-MB (ng/mL) Troponin-T (ng/mL) Myoglobin (ng/mL) Isolated antral area (cm2) Total ablated area (cm2) Atrial mass reduction (%) AF termination during ablation (%) Type of recurrence AF (%) Atypical atrial flutter (%) Total (%)
Linear ablation
CFAE ablation
(n = 60)
(n = 59)
139.5 ± 40.7 15.2 ± 5.1 2.7 ± 0.9 108.3 ± 69.5 15.2 ± 5.6 21.4 ± 5.9 28.6 ± 7.9 50 (83.3)
155.1 ± 38.9 19.9 ± 8.7 3.6 ± 0.8 110.8 ± 44.7 15.8 ± 5.4 26.7 ± 7.2 31.5 ± 7.1 39 (66.1)
0.035 0.005 b 0.001 0.873 0.594 b0.001 0.040 0.031
5 (31.3) 11 (68.7) 16 (26.7)
11 (40.7) 16 (59.3) 27 (45.8)
0.099 0.253 0.023
AF: atrial fibrillation; CFAE: complex fractionated atrial electrograms.
P
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commonly used in patients who underwent CA for L-PeAF, little data exist from a direct comparison of clinical efficacy between the different adjunctive ablation strategies. Previous randomized controlled trials have assessed whether the addition of CFAE-guided ablation to PVI improves clinical outcomes, with conflicting results. Elayi et al. [3] reported a 61% success rate with the biatrial CFAE + PVI approach, compared with 40% with PVI alone, in patients who had L-PeAF for N12 months. In contrast, Oral et al. [15] reported that the addition of CFAE-guided LA ablation to PVI resulted in an equally poor success rate (36%) compared with PVI alone. Therefore, the benefits of CFAE-guided ablation as an adjunctive therapy for L-PeAF remain unclear. Other comparison studies revealed that the Cox–Maze procedure is more effective than catheter-based ablation in treating AF patients [16,17]. The Cox–Maze procedure was originally designed as an empirical operation to interrupt all possible reentrant circuits during AF by making surgical incisions in both atria to create lines of conduction block. It has been reported that freedom from AF occurs in approximately 80%–90% of patients treated with the Cox–Maze operation. From this point of view, we hypothesized that, for interrupting multiple wavelets propagating in the LA, conduction block and compartmentalization might be a more effective therapeutic goal, rather than the degree of AMR itself. Concerning the linear lesion set, combined anterior line and roofline lesions have been created in previous studies [12,18]. A thoracoscopic ablation study showed that conduction block across the roof and anterior lines was confirmed in 96.6% of patients with PeAF and L-PeAF [18]. We also demonstrated in a previous study that anterior line lesions resulted in a better outcome with a higher rate of bidirectional conduction block than lateral perimitral line lesions [12]. The anterior line connecting this roofline to the mitral annulus was directed to the root of the aorta at the junction of the left coronary and the noncoronary cusp (left fibrous trigone lesion). Our previous study also revealed that low-voltage sites were mainly located on the LA anterior wall. Theoretically, a low-voltage area contributes to regional conduction delay and serves as the substrate for reentry. Therefore, anterior linear ablation across the low-voltage area may not only be easier for achieving
Table 3 Cox regression analysis of preprocedural and postprocedural parameters for predicting recurrence after catheter ablation for long-standing persistent atrial fibrillation. Variables
Age Male sex Body mass index Hypertension Diabetes mellitus Coronary artery disease Heart failure COPD OSA CHA2DS2 score CHA2DS2-VASc score CK-MB Troponin-T Myoglobin LVIDd LVEF LA dimension LA volume Total LA surface area Isolated antral area Total ablated area Atrial mass reduction AF termination during ablation Ablation time Ablation method
Univariate analysis
Multivariate analysis
P
HR (95% CI)
P
HR (95% CI)
0.933 0.675 0.894 0.341 0.555 0.987 0.791 0.999 0.502 0.499 0.238 0.870 0.284 0.863 0.044 0.067 0.180 0.050 0.079 0.922 0.140 0.585 0.026 0.012 0.032
1.00 (0.97–1.04) 0.77 (0.23–2.60) 1.01 (0.87–1.17) 1.44 (0.68–3.05) 1.35 (0.50–3.67) 1.01 (0.28–3.67) 1.20 (0.32–4.50) 0.00 (0.00–0.00) 0.57 (0.11–2.95) 1.14 (0.81–1.61) 1.16 (0.91–1.48) 1.07 (0.99–1.15) 1.32 (0.79–2.21) 1.00 (0.99–1.00) 1.10 (1.00–1.20) 0.96 (0.91–1.00) 1.04 (0.98–1.10) 1.01 (1.00–1.02) 1.02 (1.00–1.04) 1.00 (0.94–1.07) 1.04 (0.99–1.10) 0.99 (0.94–1.04) 0.38 (0.16–0.89) 1.01 (1.00–1.02) 0.43 (0.20–0.93)
0.500 0.692
1.04 (0.93–1.16) 0.99 (0.93–1.05)
0.015 0.083
1.02 (1.00–1.04) 0.97 (0.93–1.01)
0.395 0.296 0.049
0.64 (0.23–1.78) 1.01 (1.00–1.02) 0.42 (0.17–0.99)
HR: hazard ratio; CI: confidence interval; COPD: chronic obstructive pulmonary disease; OSA: obstructive sleep apnea; CK-MB: creatine kinase-MB; LVIDd: left ventricular internal dimension, diastolic; LVEF: left ventricular ejection fraction; LA: left atrium.
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Fig. 4. Kaplan–Meier curve for the rate and timing of the first recurrence after a single ablation procedure. A: overall recurrence. B: linear vs. CFAE-guided ablation subgroup. CFAE: complex fractionated atrial electrograms.
Fig. 5. Inter- and intra-observer variability total LA surface area, total ablated area, and atrial mass reduction measurements. LA: left atrium.
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bidirectional conduction block but may also eliminate CFAE sites, which are usually located on the anterior wall or base of the LA appendage. Acute myocardial injury and the subsequent inflammatory response provide a potentially reversible proarrhythmic substrate because of alterations in the conduction velocity and the refractoriness of atrial myocytes [8,9,19]. Our previous study revealed that iatrogenic myocardial injury induced by CA releases proinflammatory substances into the systemic circulation from the damaged myocardium, which contribute to early recurrence after AF ablation [8]. Our previous study demonstrated that a neutrophil/lymphocyte ratio indicating systemic inflammation was an independent predictor for early recurrence after CA and significantly associated with the degree of myocardial injury [9]. Furthermore, several investigators have demonstrated that early recurrence increases the risk of late recurrence [9,20]. Theoretically, recurrent AF may beget AF by shortening the atrial effective refractory period and impairing the rate-adaptation response in electrical remodeling [21]. AF also causes inflammation, which might cause AF. Consequently, early recurrence caused by acute inflammation occurring after extensive ablation strategies is more likely to lead to late recurrence. In the present study, we demonstrated that the CFAE-guided ablation group had a greater degree of myocardial injury, TAA, and AMR than the linear ablation group. Furthermore, early and late recurrence rates were higher in the CFAE-guided ablation group than in the linear ablation group. These findings strongly support the results from other previous studies [9,20]. 5. Limitations In the present study, 73% of patients in the linear ablation group remained free of arrhythmia without antiarrhythmic drugs during 12 months after a single procedure. These results are slightly superior to those of other studies, which reported a wide range of success rates from 11% to 74% at approximately 1.5 years [22]. However, the metaanalysis has the intrinsic limitation of being unable to make direct comparisons because of the dissimilar baseline characteristics in the enrolled subjects, different ablation techniques, and inherent operator factors. Therefore, the same approach can produce significantly different outcomes. In our study, the enrolled subjects were relatively young and healthy, and had relatively small LA size and preserved left ventricular ejection fraction. Furthermore, the ablation procedure was conducted by a single operator with an independent AF ablation experience of N 700 cases. Thus, procedure-related bias was kept to a minimum. Second, we could not confirm the elimination of all CFAE site, because we only verified the abolition of the CFAE site by voltage abatement of the local fractionated potentials. For the purpose of verification, conducting second CFAE map might be helpful, but it has limitation in inducing AF in patients with AF termination during ablation procedure. In addition, 54% of the CFAE-guided ablation group remained free from AF during the 12-month period after CA. This finding is comparable to the meta-analysis data, which showed that PVI and CFAE ablation resulted in a drug-free clinical success rate of 36% to 68% at 1 year [22]. Finally, the sample size was relatively small. A large-scale, multicenter study is needed to have a greater clinical perspective. 6. Conclusions In patients with L-PeAF, the amount of AMR itself did not influence clinical outcomes, whereas conduction block through linear lesions (roof and anterior lines) in conjunction with circumferential antral PVI was an efficient ablation strategy to maintain SR without antiarrhythmic drugs after a single procedure. CFAE-guided ablation had limited clinical efficacy and provoked extensive myocardial injury, which could result in a greater risk of LA functional deterioration and thromboembolic complications compared with linear ablation.
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Acknowledgments The authors thank Seok-Man Moon, BS for his support in this study.
References [1] Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophsiol 2010;3:32–8. [2] Willems S, Klemm H, Rostock T, et al. Substrate modification combined with pulmonary vein isolation improves outcome of catheter ablation in patients with persistent atrial fibrillation: a prospective randomized comparison. Eur Heart J 2006;27:2871–8. [3] Elayi CS, Verma A, Di Biase L, et al. Ablation for longstanding permanent atrial fibrillation: results from a randomized study comparing three different strategies. Heart Rhythm 2008;5:1658–64. [4] Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354:934–41. [5] Lee AM, Aziz A, Didesch J, Clark KL, Schuessler RB, Damiano Jr RJ. Importance of atrial surface area and refractory period in sustaining atrial fibrillation: testing the critical mass hypothesis. J Thorac Cardiovasc Surg 2013;146:593–8. [6] Matsuo S, Lellouche N, Wright M, et al. Clinical predictors of termination and clinical outcome of catheter ablation for persistent atrial fibrillation. J Am Coll Cardiol 2009;54:788–95. [7] Gibson DN, Di Biase L, Mohanty P, et al. Stiff left atrial syndrome after catheter ablation for atrial fibrillation: clinical characterization, prevalence, and predictors. Heart Rhythm 2011;8:1364–71. [8] Lim HE, Choi CU, Na JO, et al. Effects of iatrogenic myocardial injury on coronary microvascular function in patients undergoing radiofrequency catheter ablation of atrial fibrillation. Circ Arrhythm Electrophsiol 2013;6:318–26. [9] Im SI, Shin SY, Na JO, et al. Usefulness of neutrophil/lymphocyte ratio in predicting early recurrence after radiofrequency catheter ablation in patients with atrial fibrillation. Int J Cardiol 2013;168:4398–400. [10] Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm 2012;9:632–96 [e21]. [11] Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification. Eur J Echocardiogr:J Work Group Echocardiogr Eur Soc Cardiol 2006;7:79–108. [12] Pak HN, Oh YS, Lim HE, Kim YH, Hwang C. Comparison of voltage map-guided left atrial anterior wall ablation versus left lateral mitral isthmus ablation in patients with persistent atrial fibrillation. Heart Rhythm 2011;8:199–206. [13] Verma A, Novak P, Macle L, et al. A prospective, multicenter evaluation of ablating complex fractionated electrograms (CFEs) during atrial fibrillation (AF) identified by an automated mapping algorithm: acute effects on AF and efficacy as an adjuvant strategy. Heart Rhythm 2008;5:198–205. [14] Kiuchi K, Kircher S, Watanabe N, et al. Quantitative analysis of isolation area and rhythm outcome in patients with paroxysmal atrial fibrillation after circumferential pulmonary vein antrum isolation using the pace-and-ablate technique. Circ Arrhythm Electrophsiol 2012;5:667–75. [15] Oral H, Chugh A, Yoshida K, et al. A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation. J Am Coll Cardiol 2009;53:782–9. [16] Stulak JM, Dearani JA, Sundt III TM, Daly RC, Schaff HV. Ablation of atrial fibrillation: comparison of catheter-based techniques and the Cox–Maze III operation. Ann Thorac Surg 2011;91:1882–8. [17] Liu X, Tan HW, Wang XH, et al. Efficacy of catheter ablation and surgical CryoMaze procedure in patients with long-lasting persistent atrial fibrillation and rheumatic heart disease: a randomized trial. Eur Heart J 2010;31:2633–41. [18] Edgerton JR, Jackman WM, Mahoney C, Mack MJ. Totally thorascopic surgical ablation of persistent AF and long-standing persistent atrial fibrillation using the “Dallas” lesion set. Heart Rhythm 2009;6:S64–70. [19] Arujuna A, Karim R, Caulfield D, et al. Acute pulmonary vein isolation is achieved by a combination of reversible and irreversible atrial injury after catheter ablation: evidence from magnetic resonance imaging. Circ Arrhythm Electrophsiol 2012;5:691–700. [20] Cai L, Yin Y, Ling Z, et al. Predictors of late recurrence of atrial fibrillation after catheter ablation. Int J Cardiol 2013;164:82–7. [21] Rostock T, Steven D, Lutomsky B, et al. Atrial fibrillation begets atrial fibrillation in the pulmonary veins on the impact of atrial fibrillation on the electrophysiological properties of the pulmonary veins in humans. J Am Coll Cardiol 2008;51:2153–60. [22] Brooks AG, Stiles MK, Laborderie J, et al. Outcomes of long-standing persistent atrial fibrillation ablation: a systematic review. Heart Rhythm 2010;7:835–46.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Does the amount of atrial mass reduction improve clinical outcomes after radiofrequency catheter ablation for long-standing persistent atrial fibrillation? Comparison between linear ablation and defragmentation☆,☆☆ Seong Woo Han a,1, Seung Yong Shin b,1, Sung Il Im c, Jin Oh Na c, Cheol Ung Choi c, Seong Hwan Kim c, Jin Won Kim c, Eung Ju Kim c, Seung-Woon Rha c, Chang Gyu Park c, Hong Seog Seo c, Dong Joo Oh c, Chun Hwang d, Hong Euy Lim c,⁎ a
Department of Cardiology, Hallym University Hangang Sacred Heart Hospital, 94-200 Yeongdeungpo-dong 2-ga, Yeongdeungpo-gu, Seoul, Republic of Korea Division of Cardiology, Heart Research Institute, College of Medicine, Chung-Ang University, 224-1 Heukseok-dong, Dongjak-gu, Seoul, Republic of Korea Division of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul, Republic of Korea d Division of Cardiology, Utah Valley Regional Medical Center, 1055 North 500 West, Provo, UT 84604, USA b c
a r t i c l e
i n f o
Article history: Received 2 July 2013 Received in revised form 9 October 2013 Accepted 17 November 2013 Available online 23 November 2013 Keywords: Atrial fibrillation Atrial mass Complex fractionated atrial electrograms Linear ablation
a b s t r a c t Background: Although a large isolated surface area of the left atrium (LA) may improve the success rate of catheter ablation (CA) for paroxysmal atrial fibrillation (AF), little is known about the relation between clinical outcomes and the amount of atrial mass reduction (AMR: ratio of total isolated and ablated areas to LA surface area) in different ablation strategies for patients with long-standing persistent AF (L-PeAF). Methods: We randomly assigned 119 consecutive L-PeAF patients to adjunctive linear ablation (n = 60) or complex fractionated atrial electrogram (CFAE)-guided ablation (n = 59) after circumferential antral pulmonary vein isolation (PVI). Linear lesions included roof and anterior lines with conduction block. LA defragmentation was performed with an automated CFAE-detection algorithm. Cavotricuspid isthmus block was performed in all patients. Creatine kinase-MB (CK-MB) and troponin-T levels were measured 1 day post-CA. Results: CK-MB and troponin-T levels were higher, ablation time was longer, and AMR was greater in the CFAEguided ablation group than in the linear ablation group. AF termination during CA was more frequently observed in the linear ablation group than in the CFAE-guided ablation group (P = 0.031). Twelve months after a single procedure, recurrence occurred in 16 (26.7%) patients with linear ablation and 27 (45.8%) patients with CFAEguided ablation (P = 0.023). On multivariate analysis, LA volume and ablation method were the only independent risk factors for arrhythmia recurrence. Conclusion: Conduction block through linear lines + PVI was an efficient ablation strategy for L-PeAF, whereas the AMR amount did not influence clinical outcomes. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary vein isolation (PVI) is currently the standard therapy for selected patient groups and has been considered a first-line therapy for those with symptomatic paroxysmal atrial fibrillation (AF) [1].
☆ Grant support: This study was supported by grants (ED12078, MD1104) from the Korea University Guro Hospital. ☆☆ Conflicts of interest: The authors have no conflicts of interest to declare. ⁎ Corresponding author at: Cardiovascular Center, Division of Cardiology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, 97, Guro-dong, Guro-gu, Seoul 152-703, Republic of Korea. Tel.: +82 2 2626 1046; fax: +82 2 867 9093. E-mail addresses: [email protected], [email protected] (H.E. Lim). 1 The first 2 authors equally contributed to this study. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.041
However, PVI alone is not sufficient to eliminate arrhythmogenic substrates in patients with long-standing persistent AF (L-PeAF) [2]. Although several investigators have suggested that additional linear lesions or defragmentation of complex fractionated atrial electrograms (CFAE) in the left atrium (LA) may improve clinical outcomes after catheter ablation (CA) for L-PeAF [3,4], the limited clinical efficacy has led to a search for the ideal CA strategy. Because experimental and clinical evidence has revealed that a critical mass of atrial tissue is necessary to maintain AF [5], suggesting that the efficacy of AF ablation may be related to the extent of the ablated tissue, there has been a trend toward ablation of extensive lesions performed in a stepwise manner [6]. However, more extensive ablation may not only increase the risk of complications [7] but may also be associated with arrhythmia recurrence through the creation of proarrhythmic substrates caused by iatrogenic myocardial injury [8,9].
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To improve success rates, various adjunctive atrial modifications, targeting both AF triggers and the perpetuating substrate, have been incorporated into CA for L-PeAF [3,4]. However, little is known about the relation between clinical outcomes and the amount of atrial mass reduction (AMR) in different ablation strategies for L-PeAF patients. The aims of this study were to identify whether the degree of AMR influences long-term clinical outcomes after a single procedure, and to determine which of the 2 ablation strategies was more effective in patients who underwent CA for L-PeAF.
2.2. Transthoracic echocardiography All examinations were performed using a commercially available Vivid 7TM (GE Medical Systems, Vingmed, Horten, Norway) ultrasound system. All recorded echocardiograms were collected and analyzed using an offline computer analysis station (EchopacTM 6.3.4; GE Medical Systems). All measurements were taken from 3 consecutive cardiac cycles and averaged. The maximal LA volume (LAV) was measured manually using the modified Simpson's method, by tracing the endocardial border in the apical 4- and 2-chamber views over the cardiac cycle after zooming in on the LA. Each echocardiographic parameter was determined according to the recommendations of the American Society of Echocardiography [11].
2. Methods 2.3. Ablation procedure 2.1. Study population From December 2008 to August 2011, we prospectively enrolled 119 consecutive LPeAF patients who underwent CA. L-PeAF was defined according to the most recent guidelines of the Heart Rhythm Society and the European Cardiac Arrhythmia Society [10]. Exclusion criteria were the presence of visible LA thrombi on transesophageal echocardiography (TEE), previous AF ablation or cardiac surgery, cardiomyopathy, more than mild valvular disease, congenital heart disease, aortic aneurysm or dissection, an acute cerebrovascular event within the preceding 3 months, hyperthyroidism, and any acute or chronic inflammatory diseases. All antiarrhythmic drugs were discontinued at least 5 half-lives before the examination. Amiodarone was discontinued at least 8 weeks earlier. All patients were on continuous anticoagulation therapy with a target international normalized ratio of 2–3. Each participant signed an informed consent form before the study, which was approved by the Human Subjects Review Committee of Korea University Guro Hospital. The authors of this manuscript certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
Before CA, TEE and multi-slice computerized tomography (MSCT) were performed in all patients. Intracardiac electrocardiograms (ECGs) were recorded using a PruckaCardioLabTM electrophysiology system (General Electric Health Care Systems Inc., Milwaukee, WI, USA), and a 3-dimensional (3D) electroanatomical mapping system (NavX; St. Jude Medical Inc., Minnetonka, MN, USA) was used in all patients. After double transseptal puncture, systemic anticoagulation was achieved with intravenous heparin to maintain an activated clotting time between 300 and 350 s. After the 3D geometry of the LA and pulmonary veins (PVs) had been determined using the NavX mapping system and merged with the volumerendered MSCT image, all PVs were mapped with a decapolar circular catheter (Lasso; Biosense Webster, Diamond Bar, CA, USA). An open-irrigation, 3.5-mm-tip deflectable catheter (Celsius; Biosense Webster) was used for mapping and ablation. Radiofrequency energy was delivered as follows: maximum power output, 25–30 W; flow rate, 17–30 mL/min; and maximum temperature, 48 °C. The endpoint for each individual application at a given site was either total voltage abatement or current application of up to 40 s with adequate tissue contact and power delivery.
Fig. 1. Schematic algorithm of the study design and procedural outcomes. L-PeAF: long-standing persistent atrial fibrillation; PVI: pulmonary vein isolation; CFAE: complex fractionated atrial electrograms; CTI: cavotricuspid isthmus; AF: atrial fibrillation.
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2.4. Study protocol
2.8. Statistical analysis
The overall study algorithm is shown in Fig. 1. We randomly assigned patients with LPeAF to either the adjunctive linear ablation or the CFAE-guided ablation group according to an optimum assignment procedure with computer-generated random numbers. All enrolled patients underwent AF ablation performed by a single operator who had an independent AF ablation experience of N700 cases. All patients underwent successful PVI, defined as the complete disappearance of the PV potentials through the circumferential antral ablation. In the linear ablation group, linear lesions were created on the roof and anterior wall of the LA (Fig. 2A). Our technique for linear ablation has been described previously [12]. In brief, radiofrequency energy was delivered from the mitral annulus area (11–12 o'clock direction in the left anterior oblique view) to the LA roofline, which joined both superior PVs anteriorly. Conduction block was verified by a differential pacing maneuver on either side of the linear lesions after the restoration of sinus rhythm (SR). In the CFAE-guided ablation group, we applied an automated CFAE detection algorithm by using the NavX mapping system, a previously described and validated software [13]. In brief, CFAE was characterized using the NavX “CFAE-mean” contact mapping tool, which provides a point-by-point map of electrogram complexity. CFAE-mean was defined as the average time duration between consecutive deflections during 6 s and recorded at each site. Deflections were identified by a detection algorithm and annotated on the electrogram. Our user settings included a refractory period of 49 ms, a P–P sensitivity of between 0.05 and 0.1 mV, and a duration of 24 ms. Sites with a CFAE-mean value within a physiologically relevant range of 80 and 250 ms were included for analysis. To ensure uniform distribution, the LA was divided into 6 segments (posterior, anterior, lateral, septal, roof, and inferior wall), and then mean CFAE signals were obtained for N20 points in each segment using a 3.5-mm irrigated-tip ablation catheter. The endpoint of CFAE-guided ablation was to achieve elimination of any CFAEs in the LA and the abolition of the local fractionated potentials (bipolar voltage b0.05 mV, Fig. 2B-2). In all patients, cavotricuspid isthmus (CTI) block was conducted after LA ablation. Acute procedural success was defined as AF termination. If AF persisted after the completion of the stepwise ablation procedure, we performed internal direct current (DC) cardioversion (5–20 J, biphasic shocks with R-wave synchronization, anodal decapolar catheter in the free wall of the right atrium to the cathodal duodecapolar catheter inside of the coronary sinus) to restore SR.
Continuous variables were compared between groups using Student's t-test. Unpaired categorical variables were compared using the χ2 or Fisher's exact test. Recurrence rates were estimated using the Kaplan–Meier method. A log–rank test was used to compare estimates between groups. Univariate and multivariate predictors were identified using Cox regression analysis. Multivariate models included all univariates with P ≤ 0.1 and were constructed using a stepwise selection of clinical and echocardiographic characteristics.
2.5. Amount of AMR Ablation points with a diameter of 3 mm were marked on the LA geometry to identify all target areas. The LA surface area was measured by pixel counting of the volumerendered MSCT image made with the NavX system. The detailed LA surface area was estimated after excluding all PVs and LA appendage at their ostia and isolated LA surface area or ablation lesions were assessed using NavX system software. Isolated antral area (IAA) was defined as the sum of isolated antral surface areas from the total LA surface area. Total ablated area (TAA) was defined as the sum of the ablation lesions from the total LA surface area. AMR was defined as the ratio of IAA + TAA to the total LA surface area (Fig. 3), expressed as a percentage according to the following equation: n o 2 2 2 þ TAA cm =Total LA surface area cm 100 ð% Þ AMR ð% Þ ¼ IAA cm
To assess inter- and intra-observer variability, total LA surface area, IAA, TAA, and AMR were independently assessed by 2 experienced investigators who were blinded to the clinical information. 2.6. Blood sampling and analysis In all subjects, a blood sample was obtained from a large antecubital vein 1 day after CA for analyzing creatine kinase-MB (CK-MB), cardiac troponin-T, and myoglobin levels. Blood samples were drawn into ice-chilled tubes containing ethylenediaminetetraacetic acid and immediately centrifuged at 3000 rpm for 20 min. All samples were frozen at −80 °C until analysis. Samples were batched together for analysis and processed by a technician who was blinded to all subject information. CK-MB, cardiac troponin-T, and myoglobin levels were measured with a Stratus CS analyzer (Dade Behring, Germany), using commercially available test materials. 2.7. Follow-up If no complications arose during the procedure, anticoagulation therapy with warfarin was initiated without any antiarrhythmic medication. All subjects were scheduled for visits to the outpatient clinic at 1, 2, 3, 6, 9, and 12 months after CA for AF. Subjects also underwent 48-h Holter monitoring at 1, 3, 6, and 12 months post-CA. An ECG was recorded during every visit and on any visit when the patient reported palpitations. Additionally, a nurse practitioner interviewed each patient by telephone at 2-week intervals during the first 3 months after CA, and all patients were instructed to call whenever they experienced symptoms. Any patient with documented AF or atrial flutter during 12 months after an index procedure without a blanking period was judged to have a clinical arrhythmia recurrence and was treated with antiarrhythmic medications after DC cardioversion.
Fig. 2. Representative examples of the 2 different ablation methods. A: representative images of the linear ablation method. B-1: representative images of the CFAE map after pulmonary vein isolation. B-2: representative images of the CFAE-guided ablation method (left) anterior–posterior view; (right) posterior–anterior view. CTI: cavotricuspid isthmus; CFAE: complex fractionated atrial electrograms; PVI: pulmonary vein isolation.
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Relative risks were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 20.0 (IBM Corp., Chicago, IL, USA). A 2-sided P b 0.05 was considered statistically significant.
3. Results The study initially included 60 subjects in each group, but 1 patient in the CFAE-guided ablation group withdrew his informed consent. Thus, a total of 119 subjects were enrolled and followed until the end of the study period (12 months after CA). The baseline demographic and imaging parameters of the study participants are summarized in Table 1. The mean age was 52.8 ± 11.3 years, and men were predominant (89.9%). There were no significant differences between the 2 groups in age, sex, comorbidities, mean AF duration, mean number of failed antiarrhythmic drugs, CHADS2/CHA2DS2-VASc score, LV ejection fraction, LAV, and total LA surface area. Table 2 summarizes the procedural findings. There were no procedure-related complications in both groups. Bidirectional conduction block along the roofline was achieved in all 60 patients, whereas conduction block on the anterior line was achieved in 53 (88.3%) patients. Local fractionated potentials were abolished in all CFAE sites. The degree of myocardial injury, represented by the ablation time, CKMB, and troponin-T, was higher in the CFAE-guided ablation group than in the linear ablation group. There was no statistically significant difference in the IAA between two groups, whereas the TAA and AMR were greater in the CFAE-guided ablation group than in the linear ablation group. However, during the ablation, AF termination was more frequently observed in the linear ablation group than in the CFAE-guided ablation group (P = 0.031). During the 12-months after CA, arrhythmia frequently recurred in the CFAE-guided ablation group than in the linear ablation group (P = 0.023), whereas there was no difference in the type of recurrence between the groups. Table 3 shows the results of univariate and multivariate analyses for predictors of arrhythmia recurrence after a single ablation procedure. On univariate analysis, the LV end-diastolic dimension, AF termination during ablation, ablation time, and ablation method were significantly
related to AF recurrence after CA for L-PeAF. On multivariate analysis, the LAV (P = 0.015) and ablation method (P = 0.049) were the only independent risk factors associated with recurrence after AF ablation. Fig. 4 illustrates the incidence and timing of recurrence during the 12-month post-CA period. The total cumulative recurrence rate was 36.1% among all subjects. Recurrence occurred early (within 3 months) in 34 (79.0%) patients, midterm (4–6 months) in 3 (7.0%) patients, and late (7–12 months) in 6 (14.0%) patients. Recurrence predominantly occurred in the first 3 months, with an average rate of 9.5% per month. Thereafter, the recurrence rate decreased to as little as 0.8% per month during 3–12 months after CA. The rate of early recurrence was significantly higher for CFAE-guided ablation than for linear ablation (39.0% vs. 18.3%, P = 0.012). Over the entire follow-up period, recurrence was more frequently observed in the CFAE-guided ablation group than in the linear ablation group (45.8% vs. 26.7%, P = 0.023). Fig. 5 shows the inter- and intra-observer variability of the total LA surface area, TAA, and AMR measurements. There were strong positive correlations between them (P b 0.001, R N 0.9). 4. Discussion The noteworthy findings of the present study are as follows: (1) the amount of AMR did not influence clinical outcomes after CA for L-PeAF; (2) the CK-MB and troponin-T levels measured 1 day after CA were significantly higher and the ablation time was longer in the CFAE-guided ablation group than in the linear ablation group; (3) the long-term success rate and the acute procedural success rate were markedly higher in the linear ablation group than in the CFAE-guide ablation group; and (4) the LAV and ablation method were the only independent risk factors for arrhythmia recurrence after CA for L-PeAF. This prospective randomized study demonstrated for the first time that catheter-based linear lesion formation has significantly better clinical efficacy than defragmentation, although CFAE-guided ablation produced a larger TAA, a higher AMR, and a longer ablation time than linear ablation. On the basis of the “critical mass of atrial tissue” theory, ablation strategies have been evolving toward being directed at more extensive lesions, performed in a stepwise manner [6]. A recent study
Fig. 3. Representative examples of the measurement of atrial mass reduction. A: isolated antral and total ablated areas were measured, and atrial mass reduction ratio was calculated in the linear ablation group. B: isolated antral and total ablated areas were measured, and atrial mass reduction ratio was calculated in the CFAE-guided ablation group. LA: left atrium; CFAE: complex fractionated atrial electrograms.
S.W. Han et al. / International Journal of Cardiology 171 (2014) 37–43 Table 1 Baseline characteristics of patients with long-standing persistent atrial fibrillation. Variables
Age (years) Male (%) Body mass index (kg/m2) AF duration (months) Number of AAD Hypertension (%) Diabetes mellitus (%) Coronary artery disease (%) Heart failure (%) COPD (%) OSA (%) CHADS2 score CHA2DS2-VASc score Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) Echocardiography LVIDd (mm) LVEF (%) LA dimension (mm) MSCT LA volume (mL) Total LA surface area (cm2)
Total
Linear ablation
CFAE ablation
P
(n = 119)
(n = 60)
(n = 59)
52.8 ± 11.3 107 (89.9) 25.4 ± 2.6 18.1 ± 2.9 1.6 ± 0.6 65 (54.6) 19 (16.0) 11 (9.2) 10 (8.4) 3 (2.5) 8 (6.7) 1.4 ± 1.1 1.9 ± 1.5 177.1 ± 37.0 161.1 ± 103.7 45.0 ± 11.5 112.0 ± 32.7
53.8 ± 10.5 54 (90.0) 25.4 ± 2.6 17.7 ± 2.8 1.7 ± 0.6 33 (55.0) 11 (18.3) 7 (11.7) 7 (11.7) 3 (5.0) 3 (5.0) 1.5 ± 1.1 1.9 ± 1.5 174.7 ± 35.3 161.3 ± 92.1 44.9 ± 11.8 109.1 ± 31.7
51.8 ± 12.1 53 (91.5) 25.3 ± 2.5 18.5 ± 3.0 1.5 ± 0.6 32 (54.2) 8 (13.6) 4 (6.8) 3 (5.1) 0 (0.0) 5 (8.5) 1.4 ± 1.1 1.8 ± 1.5 179.6 ± 38.8 161.0 ± 115.1 45.2 ± 11.3 115.0 ± 33.8
0.333 0.976 0.695 0.153 0.103 0.934 0.481 0.362 0.199 0.083 0.453 0.580 0.805 0.480 0.985 0.886 0.338
50.1 ± 4.4 62.9 ± 8.4 43.3 ± 6.5
49.8 ± 4.4 63.3 ± 7.7 43.5 ± 6.0
50.4 ± 4.5 62.5 ± 9.2 43.1 ± 7.0
0.450 0.608 0.766
107.2 ± 45.3 133.3 ± 27.8
106.6 ± 38.6 107.7 ± 51.6 130.3 ± 25.4 136.4 ± 30.0
0.900 0.229
Data are shown as mean ± standard deviation (SD) or as number (%). CFAE: complex fractionated atrial electrograms; AF: atrial fibrillation; AAD: antiarrhythmic drug; COPD: chronic obstructive pulmonary disease; OSA: obstructive sleep apnea; LVIDd: left ventricular internal dimension, diastolic; LVEF: left ventricular ejection fraction; LA: left atrium; MSCT: multislice computed tomography.
revealed that a larger IAA was associated with a significantly lower recurrence rate after a single ablation procedure in patients with paroxysmal AF [14]. The authors suggested that a wide ablation line encircling the entire PV antrum could better eliminate both AF triggers and substrate. In the present study, there was no difference in the amount of IAA between both groups because we performed the circumferential antral PVI in the same manner in all patients. However, TAA was significantly smaller and clinical outcomes were better in the linear ablation group than in the CFAE-guided ablation group. Therefore, these results indicated that AMR itself did not influence the clinical outcomes in patients with L-PeAF. To improve the therapeutic outcome of CA for L-PeAF, most investigators attempt to add subsequent substrate modifications to circumferential antral PVI, which has been a common ablation strategy in all AF patients. Although 2 adjunctive ablation methods (creation of additional linear lesions and defragmentation of CFAE) have been Table 2 Procedural, laboratory, and clinical findings after radiofrequency catheter ablation for long-standing persistent atrial fibrillation. Variables
Ablation time (min) Creatine kinase-MB (ng/mL) Troponin-T (ng/mL) Myoglobin (ng/mL) Isolated antral area (cm2) Total ablated area (cm2) Atrial mass reduction (%) AF termination during ablation (%) Type of recurrence AF (%) Atypical atrial flutter (%) Total (%)
Linear ablation
CFAE ablation
(n = 60)
(n = 59)
139.5 ± 40.7 15.2 ± 5.1 2.7 ± 0.9 108.3 ± 69.5 15.2 ± 5.6 21.4 ± 5.9 28.6 ± 7.9 50 (83.3)
155.1 ± 38.9 19.9 ± 8.7 3.6 ± 0.8 110.8 ± 44.7 15.8 ± 5.4 26.7 ± 7.2 31.5 ± 7.1 39 (66.1)
0.035 0.005 b 0.001 0.873 0.594 b0.001 0.040 0.031
5 (31.3) 11 (68.7) 16 (26.7)
11 (40.7) 16 (59.3) 27 (45.8)
0.099 0.253 0.023
AF: atrial fibrillation; CFAE: complex fractionated atrial electrograms.
P
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commonly used in patients who underwent CA for L-PeAF, little data exist from a direct comparison of clinical efficacy between the different adjunctive ablation strategies. Previous randomized controlled trials have assessed whether the addition of CFAE-guided ablation to PVI improves clinical outcomes, with conflicting results. Elayi et al. [3] reported a 61% success rate with the biatrial CFAE + PVI approach, compared with 40% with PVI alone, in patients who had L-PeAF for N12 months. In contrast, Oral et al. [15] reported that the addition of CFAE-guided LA ablation to PVI resulted in an equally poor success rate (36%) compared with PVI alone. Therefore, the benefits of CFAE-guided ablation as an adjunctive therapy for L-PeAF remain unclear. Other comparison studies revealed that the Cox–Maze procedure is more effective than catheter-based ablation in treating AF patients [16,17]. The Cox–Maze procedure was originally designed as an empirical operation to interrupt all possible reentrant circuits during AF by making surgical incisions in both atria to create lines of conduction block. It has been reported that freedom from AF occurs in approximately 80%–90% of patients treated with the Cox–Maze operation. From this point of view, we hypothesized that, for interrupting multiple wavelets propagating in the LA, conduction block and compartmentalization might be a more effective therapeutic goal, rather than the degree of AMR itself. Concerning the linear lesion set, combined anterior line and roofline lesions have been created in previous studies [12,18]. A thoracoscopic ablation study showed that conduction block across the roof and anterior lines was confirmed in 96.6% of patients with PeAF and L-PeAF [18]. We also demonstrated in a previous study that anterior line lesions resulted in a better outcome with a higher rate of bidirectional conduction block than lateral perimitral line lesions [12]. The anterior line connecting this roofline to the mitral annulus was directed to the root of the aorta at the junction of the left coronary and the noncoronary cusp (left fibrous trigone lesion). Our previous study also revealed that low-voltage sites were mainly located on the LA anterior wall. Theoretically, a low-voltage area contributes to regional conduction delay and serves as the substrate for reentry. Therefore, anterior linear ablation across the low-voltage area may not only be easier for achieving
Table 3 Cox regression analysis of preprocedural and postprocedural parameters for predicting recurrence after catheter ablation for long-standing persistent atrial fibrillation. Variables
Age Male sex Body mass index Hypertension Diabetes mellitus Coronary artery disease Heart failure COPD OSA CHA2DS2 score CHA2DS2-VASc score CK-MB Troponin-T Myoglobin LVIDd LVEF LA dimension LA volume Total LA surface area Isolated antral area Total ablated area Atrial mass reduction AF termination during ablation Ablation time Ablation method
Univariate analysis
Multivariate analysis
P
HR (95% CI)
P
HR (95% CI)
0.933 0.675 0.894 0.341 0.555 0.987 0.791 0.999 0.502 0.499 0.238 0.870 0.284 0.863 0.044 0.067 0.180 0.050 0.079 0.922 0.140 0.585 0.026 0.012 0.032
1.00 (0.97–1.04) 0.77 (0.23–2.60) 1.01 (0.87–1.17) 1.44 (0.68–3.05) 1.35 (0.50–3.67) 1.01 (0.28–3.67) 1.20 (0.32–4.50) 0.00 (0.00–0.00) 0.57 (0.11–2.95) 1.14 (0.81–1.61) 1.16 (0.91–1.48) 1.07 (0.99–1.15) 1.32 (0.79–2.21) 1.00 (0.99–1.00) 1.10 (1.00–1.20) 0.96 (0.91–1.00) 1.04 (0.98–1.10) 1.01 (1.00–1.02) 1.02 (1.00–1.04) 1.00 (0.94–1.07) 1.04 (0.99–1.10) 0.99 (0.94–1.04) 0.38 (0.16–0.89) 1.01 (1.00–1.02) 0.43 (0.20–0.93)
0.500 0.692
1.04 (0.93–1.16) 0.99 (0.93–1.05)
0.015 0.083
1.02 (1.00–1.04) 0.97 (0.93–1.01)
0.395 0.296 0.049
0.64 (0.23–1.78) 1.01 (1.00–1.02) 0.42 (0.17–0.99)
HR: hazard ratio; CI: confidence interval; COPD: chronic obstructive pulmonary disease; OSA: obstructive sleep apnea; CK-MB: creatine kinase-MB; LVIDd: left ventricular internal dimension, diastolic; LVEF: left ventricular ejection fraction; LA: left atrium.
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S.W. Han et al. / International Journal of Cardiology 171 (2014) 37–43
Fig. 4. Kaplan–Meier curve for the rate and timing of the first recurrence after a single ablation procedure. A: overall recurrence. B: linear vs. CFAE-guided ablation subgroup. CFAE: complex fractionated atrial electrograms.
Fig. 5. Inter- and intra-observer variability total LA surface area, total ablated area, and atrial mass reduction measurements. LA: left atrium.
S.W. Han et al. / International Journal of Cardiology 171 (2014) 37–43
bidirectional conduction block but may also eliminate CFAE sites, which are usually located on the anterior wall or base of the LA appendage. Acute myocardial injury and the subsequent inflammatory response provide a potentially reversible proarrhythmic substrate because of alterations in the conduction velocity and the refractoriness of atrial myocytes [8,9,19]. Our previous study revealed that iatrogenic myocardial injury induced by CA releases proinflammatory substances into the systemic circulation from the damaged myocardium, which contribute to early recurrence after AF ablation [8]. Our previous study demonstrated that a neutrophil/lymphocyte ratio indicating systemic inflammation was an independent predictor for early recurrence after CA and significantly associated with the degree of myocardial injury [9]. Furthermore, several investigators have demonstrated that early recurrence increases the risk of late recurrence [9,20]. Theoretically, recurrent AF may beget AF by shortening the atrial effective refractory period and impairing the rate-adaptation response in electrical remodeling [21]. AF also causes inflammation, which might cause AF. Consequently, early recurrence caused by acute inflammation occurring after extensive ablation strategies is more likely to lead to late recurrence. In the present study, we demonstrated that the CFAE-guided ablation group had a greater degree of myocardial injury, TAA, and AMR than the linear ablation group. Furthermore, early and late recurrence rates were higher in the CFAE-guided ablation group than in the linear ablation group. These findings strongly support the results from other previous studies [9,20]. 5. Limitations In the present study, 73% of patients in the linear ablation group remained free of arrhythmia without antiarrhythmic drugs during 12 months after a single procedure. These results are slightly superior to those of other studies, which reported a wide range of success rates from 11% to 74% at approximately 1.5 years [22]. However, the metaanalysis has the intrinsic limitation of being unable to make direct comparisons because of the dissimilar baseline characteristics in the enrolled subjects, different ablation techniques, and inherent operator factors. Therefore, the same approach can produce significantly different outcomes. In our study, the enrolled subjects were relatively young and healthy, and had relatively small LA size and preserved left ventricular ejection fraction. Furthermore, the ablation procedure was conducted by a single operator with an independent AF ablation experience of N 700 cases. Thus, procedure-related bias was kept to a minimum. Second, we could not confirm the elimination of all CFAE site, because we only verified the abolition of the CFAE site by voltage abatement of the local fractionated potentials. For the purpose of verification, conducting second CFAE map might be helpful, but it has limitation in inducing AF in patients with AF termination during ablation procedure. In addition, 54% of the CFAE-guided ablation group remained free from AF during the 12-month period after CA. This finding is comparable to the meta-analysis data, which showed that PVI and CFAE ablation resulted in a drug-free clinical success rate of 36% to 68% at 1 year [22]. Finally, the sample size was relatively small. A large-scale, multicenter study is needed to have a greater clinical perspective. 6. Conclusions In patients with L-PeAF, the amount of AMR itself did not influence clinical outcomes, whereas conduction block through linear lesions (roof and anterior lines) in conjunction with circumferential antral PVI was an efficient ablation strategy to maintain SR without antiarrhythmic drugs after a single procedure. CFAE-guided ablation had limited clinical efficacy and provoked extensive myocardial injury, which could result in a greater risk of LA functional deterioration and thromboembolic complications compared with linear ablation.
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Acknowledgments The authors thank Seok-Man Moon, BS for his support in this study.
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