Journal of Arrhythmia 31 (2015) 6–11
Contents lists available at ScienceDirect
Journal of Arrhythmia journal homepage: www.elsevier.com/locate/joa
Original Article
The optimal setting of complex fractionated atrial electrogram software in substrate ablation for atrial fibrillation Fuminori Namino, MTa,b,1, Yasuhisa Iriki, MDc,1, Ryuichi Maenosono, PhDa, Hitoshi Ichiki, MDc, Hideki Okui, MDc, Akino Yoshimura, MDc, Naoya Oketani, MDc,n, Masakaze Matsushita, MTa, Mitsuru Ohishi, MDc, Teruto Hashiguchi, MDa,b a
Clinical Laboratory Unit, Kagoshima University Hospital, Kagoshima, Japan Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan c Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan b
art ic l e i nf o
a b s t r a c t
Article history: Received 13 March 2014 Received in revised form 15 April 2014 Accepted 22 April 2014 Available online 5 June 2014
Background: Complex fractionated atrial electrogram (CFAE)-targeted catheter ablation (CFAE ablation) requires a high rate of atrial fibrillation (AF) termination to provide good outcomes. We determined the optimal settings of CFAE software. Methods: In our 430 consecutive patients, AF was terminated in 97 (234/242) and 79% (149/188) of patients with paroxysmal and persistent AF, respectively, by CFAE ablation combined with (31%) or without (69%) pulmonary vein isolation, occasionally with nifekalant infusion. We analyzed 109 consecutive patients who underwent CFAE ablation to determine the optimal settings for comparing subjective versus objective decisions by the CFAE software on CARTO3. We compared three settings: the default setting (0.05–0.15 mV, 50–120 ms) and two modified settings (#1: 0.05–0.30 mV, 40–70 ms, #2: 0.05–0.13 mV, 10–20 ms). We retrospectively analyzed 11,425 points during left atrial mapping before ablation and 10,306 points that were subjectively detected and ablated as CFAE points. An interval confidence level Z 6 denoted a site with CFAE. Results: With the default setting, the accuracy, sensitivity, specificity, positive productive value, and negative productive values were 67, 42, 77, 48, and 73%, respectively. With modified setting #1, the values were 78, 55, 87, 74, and 77%, respectively, versus 64, 82, 60, 53, and 91%, respectively, for modified setting #2. Conclusion: These data suggest that setting #1 was generally superior to the default setting, whereas setting #2 was optimal for excluding areas not requiring ablation. The optimal CFAE software setting was a voltage of 0.05–0.30 mV and an interval parameter of 40–70 ms. & 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
Keywords: Complex fractionated atrial electrograms Atrial fibrillation Catheter ablation Optimal setting
1. Introduction Catheter ablation is an effective approach for the management of patients with atrial fibrillation (AF) [1–7]. Pulmonary vein isolation (PVI) is one of the most common strategies of AF ablation, but the outcome of PVI alone for patients with persistent AF is poor [8–10]. Additional approaches such as linear ablation after PVI have been reported to improve the outcome [11–15]. Nademanee et al. also described an alternative approach for AF ablation that involved identifying the target “substrate” sites via electroanatomical
n
Corresponding author. Tel.: þ 81 99 275 5318; fax: þ 81 99 265 8447. E-mail address: [email protected] (N. Oketani). 1 Equal contribution.
mapping of complex fractionated atrial electrograms (CFAEs) [7–16,17]. Although PVI was not required with this approach, AF ablation guided by CFAEs resulted in a high rate of success in maintaining sinus rhythm in patients with either paroxysmal or persistent AF. However, the results of these studies were not replicated by others [6,18,19]. Thus, the role of CFAE-targeted catheter ablation (CFAE ablation) in treating patients with AF remains controversial. Because one of our physicians was a fellow at the Pacific Rim Electrophysiology Research Institute, all five physicians in our Institute similarly terminate AF with CFAE ablation [20,21]. In our latest study of 430 consecutive patients, AF was terminated by CFAE ablation with (n¼133) or without (n¼297) PVI in 97 (234/242) and 79% (149/188) of patients with paroxysmal and persistent AF, respectively, occasionally with nifekalant infusion without cardioversion. Thus, the use of optimal CFAE software
http://dx.doi.org/10.1016/j.joa.2014.04.006 1880-4276/& 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
F. Namino et al. / Journal of Arrhythmia 31 (2015) 6–11
7
settings on the CARTO3 may help physicians detect CFAE areas. Therefore, we determined the optimal setting of CFAE software on the CARTO3 system.
episodes) that terminates spontaneously within 7 days. Persistent AF was defined as AF that is sustained for 47 days or AF lasting o7 days but necessitating pharmacologic or electrical cardioversion. AF lasting 41 year was defined as longstanding persistent AF.
2. Materials and methods
2.2. Mapping and ablation of AF
2.1. Study population and protocol
The AF ablation technique described by Nademanee et al. [7,16,17] was used for this study, as previously reported [20,21,23,24]. In brief, a 3.5-mm NaviStar ThermoCool catheter (DF or FJ curve; Biosense Webster, Diamond Bar, CA, USA) was used in all cases. After the coronary sinus (CS) was cannulated via the femoral vein using a decapolar catheter (Dynamic XT Decapolar Steerable-Cath; C. R. Bard, Murray Hill, NJ, USA) for recording and induction, patients underwent non-fluoroscopic electroanatomical mapping with CARTO3 (Biosense Webster). Heparin (3000 IU initial bolus, 1000–2000 IU subsequent boluses as needed to maintain the activated clotting time 4300 s) was administered for anticoagulation. All electroanatomical maps were created for patients who displayed AF, either occurring spontaneously or by induction. Burst pacing using a CS catheter to a lower limit of 1:1 capture or up to 150 ms was used to induce AF occasionally with a 0.01–0.02 μg/kg/ min isoproterenol infusion. AF was inducible in all patients at the beginning of the procedure. When AF was terminated during ablation procedure in patients with paroxysmal AF, AF was reinduced until it was no longer inducible, as paroxysmal AF could be terminated spontaneously. Electroanatomical maps were created and displayed as a shortest complex interval (SCI) map, and the areas of CFAE were also identified manually, tagged, and associated with the atrial anatomy created by CARTO3. This enabled the operators to associate areas of CFAE with the left atrium (LA), CS, and occasionally the right atrium, thereby identifying target sites for ablation. Bipolar recordings were filtered at 30–500 Hz, and the CFAEs were defined as follows: (1) fractionated electrograms composed of two or more deflections and/or a perturbation of the baseline with continuous deflection of a prolonged activation complex; and (2) atrial electrograms with an extremely short cycle length (r120 ms). Examples of two intracardiac electrocardiograms displaying CFAEs and normal atrial electrograms are shown in Fig. 1. Typical continuous CFAEs before radiofrequency (RF) applications are easy to detect, but the electrograms look different in each case and each state of ablation. When AF is organized, CFAEs are also organized. After a certain amount of RF applications, the amplitude and frequency were decreased. This may be one of the reasons that CFAE ablation has not been replicated easily by others [6]. We use CFAE software but subjectively determine which electrograms are CFAEs. All of the operators in our institute replicate CFAE ablation. Then, we tried to optimize the CFAE software to perform CFAE ablation clinically in other institutes with our subjective decision. Then, the CFAE sites in this study were defined as those that we ablated. In addition, we calculated what setting is most appropriate to match our subjective decisions. After acquiring the SCI map associated with CFAEs, we searched the areas of CFAEs referring to the tagged points because CFAE areas have temporal spatial stability. RF was delivered with a maximal power of 40 W with irrigation rates of 30 mL/min (3.5mm NaviStar ThermoCool catheter; Biosense Webster). The power was reduced to 15 W in the posterior LA close to the esophagus or in the CS. The primary endpoints during RF ablation were either complete elimination of CFAE areas or conversion of AF to sinus rhythm occasionally with the injection of nifekalant (0.3 mg/kg intravenously over 10 min, maximum twice), a Class III antiarrhythmic drug similar to ibutilide, which is not available in Japan. If the atrial arrhythmias were not successfully terminated, then internal cardioversion was performed. The endpoints of the procedure were termination of AF in patients with persistent AF
This study comprised 109 consecutive patients (22 females, 87 males; mean age of 59 710 years), including 57 (52%) patients with paroxysmal AF, 40 (37%) patients with persistent AF, and 12 (11%) patients with long-standing persistent AF with symptomatic drug refractory AF, who successfully underwent CFAE ablation combined with (n ¼44) or without (n ¼65) PVI between May 2011 and May 2012. Thirty-seven patients had histories of AF ablation. The patient characteristics and procedure data are shown in Tables 1 and 2, respectively. All antiarrhythmic drugs were discontinued at least five half-lives before ablation, excluding amiodarone, which was discontinued at least 3 months before ablation. Warfarin was not discontinued, and all patients provided written informed consent for the procedure. This study protocol was approved by our institutional ethics committee (Approval date: July 18, 2013, Approval number: 355). AF was defined in accordance with the 2007 Heart Rhythm Society Expert Consensus Statement [22]. Paroxysmal AF was defined as recurrent AF (Z2 Table 1 Patient characteristics.
Age (years) Male (%) Body mass index (kg/m2) Hypertension (%) Diabetes mellitus (%) Heart failure (%) HHD (%) DCM (%) HCM (%) Ischemic heart disease (%) Post cardiac operation (%) Left atrial diameter (mm) Left atrial volume (ml) LVEF (%) BNP (pg/ml) ANP (pg/ml)
Paroxysmal
Persistent
AF (n¼ 57)
AF (n¼ 40)
Longstanding persistent AF (n¼ 12)
59 7 11 77 24.77 3.0 56 11 14 18 4 2 7 4 39.8 76.0 61.3 7 19.9 65.0 712.1 98.6 7175.2 120.2 7528.1
587 9 85 25.17 4.2 53 20 25 33 8 13 8 3 46.7 76.2 82.7 724.9 59.4 713.1 177.9 7 129.2 74.6 7 43.9
60 77 75 27.3 7 3.5 67 25 25 17 0 0 0 0 51.7 7 5.0 99.5 7 29.9 65.7 7 6.5 113.5 7 79.4 57.0 7 27.5
HHD, hypertensive heart disease; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVEF, left ventricular ejection fraction; AF, atrial fibrillation.
Table 2 Procedure data. Paroxysmal Persistent AF (n¼ 57) CFAE ablation combined with PVI (%) 56 Procedure time (min) 222 7 45 Radiofrequency duration (min) 85 7 24 Fluoroscopic time (min) 16 7 10 Mapping points before ablation 105 7 30 Mapping duration (min) 57 2 Use of cardioversion (%) 5 Use of nifekalant (%) 49
Longstanding persistent AF (n¼ 40) AF (n ¼12)
48 229 7 46 87 7 20 147 10 1097 48 672 10 70
33 257 7 47 1147 20 107 7 1247 27 57 1 33 92
Mapping site/time; needed site/time for creating an electroanatomical map. AF, atrial fibrillation; CFAE, complex fractionated atrial electrogram; PVI, pulmonary vein isolation.
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F. Namino et al. / Journal of Arrhythmia 31 (2015) 6–11
Fig. 1. Examples of complex fractionated atrial electrograms. (a) Fractionated electrograms with a continuous prolonged activation complex over the septal areas. (b) Normal atrial electrograms during atrial fibrillation in the left atrial appendage in the same patient.
and non-inducibility of AF in patients with paroxysmal AF. If many CFAE areas were identified before the delivery of RF ablation and AF was terminated and non-inducible after ablation in limited areas, this was the endpoint. However, AF was inducible until ablation in the majority of CFAE areas in the majority of patients. We did not attempt to eliminate CFAE areas in sinus rhythm because of difficulties in detecting these areas in sinus rhythm.
0.08, 0.10, 0.13, 0.15, 0.18, 0.20, 0.23, 0.25, 0.28, 0.30, 0.33, 0.35, 0.38, and 0.40 mV. In pilot studies, we identified two possible settings (#1: 0.05–0.30 mV, 40–70 ms, #2: 0.05–0.13 mV, 10–20 ms). We then compared the two modified settings to the default setting and calculated the accuracy, sensitivity, specificity, positive productive value, and negative productive value for each setting. An interval confidence level Z6 was considered to denote a site with CFAE.
2.3. Evaluation of optimal setting 3. Results A pilot study was performed to determine the optimal setting in some cases. In CFAE software on CARTO3, minimum and maximum duration values were attempted for all combinations of the following values: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, and 150 ms. In addition, minimum and maximum threshold values were attempted for all combinations of the following values: 0.01, 0.03, 0.05,
We retrospectively analyzed 11,425 points during left atrial mapping before ablation and 10,306 points that were subjectively detected and ablated as CFAE points on CARTO3. We compared the default setting (default: 0.05–0.15 mV, 50–120 ms) and two modified settings according to a pilot study (#1: 0.05–0.30 mV, 40–70 ms, #2:
F. Namino et al. / Journal of Arrhythmia 31 (2015) 6–11
Table 3 Comparison of the settings.
Accuracy (%) Sensitivity (%) Specificity (%) Positive productive value (%) Negative productive value (%)
Default setting
Setting #1
Setting #2
67 42 77 48 73
78 55 87 74 77
64 82 60 53 91
Table 4 Comparison of the settings with the duration of atrial fibrillation Paroxysmal AF/ Persistent AF/Longstanding persistent AF. Default setting
Setting #1
Setting #2
68/66/64 41/39/55 77/78/71 44/51/55 75/70/68
79/77/78 57/50/66 87/88/86 71/75/81 79/76/73
67/62/60 82/80/91 62/58/62 49/55/64 93/87/94
9
0.05–0.13 mV, 10–20 ms). We calculated the accuracy, sensitivity, specificity, positive productive value, and negative productive value for each setting. For the default setting, the accuracy, sensitivity, specificity, positive productive value, and negative productive value were 67, 42, 77, 48, and 73%, respectively. For modified setting #1, these values were 78, 55, 87, 74, and 77%, respectively, compared to 64, 82, 60, 53, and 91%, respectively, for modified setting #2 (Table 3). A comparison of each setting with the duration of AF is presented in Table 4, and a comparison between de novo and repeat sessions for each setting is presented in Table 5. Two example cases are shown in Figs. 2 and 3. These data suggested that setting #1 is the optimal setting in general, whereas setting #2 was optimal for excluding areas that do not require ablation.
4. Discussion Accuracy (%) Sensitivity (%) Specificity (%) Positive productive value (%) Negative productive value (%)
Table 5 Comparison between the de novo and redo sessions for each setting First session/ Repeat session.
Accuracy (%) Sensitivity (%) Specificity (%) Positive productive value (%) Negative productive value (%)
Default Setting
Setting #1
Setting #2
63/75 41/43 74/82 51/42 68/83
77/82 61/42 85/93 75/70 75/83
62/68 88/70 55/73 57/45 91/91
This is the first study to evaluate the optimal settings for CFAE software on CARTO3 using maps with high rates of AF termination with subjective determination. We first performed a pilot study to identify the optimal setting. However, the CFAEs varied substantially for each patient. For example, AF was organized particularly in repeat cases, although CFAEs were also organized. Next, we identified two optimal settings: settings #1 and #2. For setting #1, the accuracy, sensitivity, and specificity were 78, 55, and 87%, respectively, whereas the positive and negative predictive values were 74 and 77%, respectively. Our ablation points matched the CFAE areas on SCI maps in setting #1. For setting #2, the sensitivity (82%) was higher than that for setting #1, whereas the specificity (60%) was lower. Setting #2 could more widely recognize the CFAE areas. As the negative predictive value (91%) of setting #2 was higher than that of setting #1, this allowed us to easily exclude the areas that did not
Fig. 2. Example CARTO maps of a patient. The shortest complex interval (SCI) map with red areas indicates complex fractionated atrial electrograms (CFAEs), and that with purple areas indicates normal atrial electrograms. In the default setting (a), the ablated points do not match the red areas. In setting #1 (b, SCI: 0.05–0.30 mV, 40–70 ms), the abated points match the red areas compared with the default setting, especially in the areas of the anterior septal wall and the antrum of the left superior pulmonary vein. In setting #2 (c, SCI: 0.05–0.13 mV, 10–20 ms), the ablated points match the red areas, although non-ablated areas are also red. Setting #2 overestimates the CFAE areas, but it may helpful to identify the areas that do not require ablation.
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F. Namino et al. / Journal of Arrhythmia 31 (2015) 6–11
Fig. 3. Examples of CARTO maps of a repeat case. In the default setting (a) and setting #1 (b), the anterior wall is not shown as a red area. However, in the optimized setting #2 (c) the anterior wall is shown in red. The abated areas are large, but there are few ablated points excluding the red areas. Thus, setting #2 is useful for excluding the areas that do not require ablation.
require ablation in setting #2. These data suggest that our two optimal settings provide a more sensitive and specific detection of CFAE areas, which may aid physicians in CFAE ablation procedures. Nevertheless, it remains possible that there are better settings than those we determined, as we compared all of the settings only for some patients in the pilot study, but we did not compare all of the settings for all patients owing to time constraints. There are several types of electrograms that we consider CFAEs. In the original study [7], two types of electrograms were mentioned as CFAEs: 1) fractionated electrograms composed of two or more deflections and/or a perturbation of the baseline with continuous deflection of a prolonged activation complex; and 2) atrial electrograms with an extremely short cycle length (r120 ms). The software attempted to cover both types of electrograms, requiring a wider interval setting. Most electrograms requiring ablation are continuous and more fractionated, for which a shorter interval setting may be better in general.
Sources of funding This study was supported by Fukuda Foundation for Medical Technology of Japan.
Conflict of interest There is nothing to disclose for this study.
Acknowledgments We would like to give a special thanks to Dr. Koonlawee Nademanee. Our ablations and studies depended on the knowledge that we obtained in his Institute. References
5. Limitation The present study had several limitations. (1) CFAEs were evaluated visually by each operator in this study; however, CFAEs were not universally defined among the physicians. (2) Limited software settings were evaluated in this study, and it is possible that there are better settings. (3) The study design is retrospective.
6. Conclusions The optimal settings of CFAE software on CARTO3 system were a voltage range of 0.05–0.30 mV and an interval range of 40–70 ms.
[1] Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. [2] Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. J Am Med Assoc 2005;293:2634–40. [3] Pappone C, Rosanio S, Augello G, et al. Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomized long-term study. J Am Coll Cardiol 2003;42:185–97. [4] Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circulation 2005;111:1100–5. [5] Stabile G, Bertaglia E, Senatore G, et al. Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multi-centre, randomized, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study). Eur Heart J 2006;27:216–21.
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[6] Oral H, Chugh A, Good E, et al. Radiofrequency catheter ablation of chronic atrial fibrillation guided by complex electrograms. Circulation 2007;115: 2606–12. [7] Nademanee K, McKenzie J, Kosar E, et al. A new approach for catheter ablation of atrial fibrillation: mapping of electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044–53. [8] Kanagaratnam L, Tomassoni G, Schweikert R, et al. Empirical pulmonary vein isolation in patients with chronic atrial fibrillation using a three-dimensional nonfluoroscopic mapping system: long-term follow-up. Pacing Clin Electrophysiol 2001;24:1774–9. [9] Oral H, Knight BP, Tada H, et al. Pulmonary vein isolation for paroxysmal and persistent atrial fibrillation. Circulation 2002;105:1077–81. [10] 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. [11] Pappone C, Oreto G, Rosanio S, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001;104:2539–44. [12] Stabile G, Turco P, La Rocca V, et al. Is pulmonary vein isolation necessary for curing atrial fibrillation? Circulation 2003;108:657–60. [13] Haïssaguerre M, Sanders P, Hocini M, et al. Catheter ablation of long-lasting persistent atrial fibrillation: critical structures for termination. J Cardiovasc Electrophysiol 2005;16:1125–37. [14] Oral H, Chugh A, Good E, et al. A tailored approach to catheter ablation of paroxysmal atrial fibrillation. Circulation 2006;113:1824–31. [15] Senga M, Fujii E, Sugiura S, et al. Efficacy of linear block at the left atrial roof in atrial fibrillation. J Cardiol 2010;55:322–7. [16] Nademanee K, Schwab MC, Kosar EM, et al. Clinical outcomes of catheter substrate ablation for high-risk patients with atrial fibrillation. J Am Coll Cardiol 2008;51:843–9.
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[17] Nademanee K, Lockwood E, Oketani N, et al. Catheter ablation of atrial fibrillation guided by complex fractionated atrial electrogram mapping of atrial fibrillation substrate. J Cardiol 2010;55:1–12. [18] Estner HL, Hessling G, Ndrepepa G, et al. Electrogram-guided substrate ablation with or without pulmonary vein isolation in patients with persistent atrial fibrillation. Europace 2008;10:1281–7. [19] Deisenhofer I, Estner H, Reents T, et al. Does electrogram guided substrate ablation add to the success of pulmonary vein isolation in patients with paroxysmal atrial fibrillation? A prospective, randomized study J Cardiovasc Electrophysiol 2009;20:514–21. [20] Iriki Y, Ishida S, Oketani N, et al. Relationship between clinical outcomes and unintentional pulmonary vein isolation during substrate ablation of atrial fibrillation guided solely by complex fractionated atrial electrogram mapping. J Cardiol 2011;58:278–86. [21] Ichiki H, Oketani N, Ishida S, et al. Incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation guided by complex fractionated atrial electrogram. J Cardiovascular Electrophysiol 2012;23: 567–73. [22] Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: recommendations for personnel, policy, procedures and follow-up. A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm 2007;4:816–61. [23] Maenosono R, Oketani N, Ishida S, et al. Effectiveness of esophagus detection by three-dimensional electroanatomical mapping to avoid esophageal injury during ablation of atrial fibrillation. J Cardiol 2012;60:119–25. [24] Ichiki H, Oketani N, Ishida S, et al. The incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation: comparison of warfarin and dabigatran. Pacing Clin Electrophysiol 2013;36:1328–35.
Contents lists available at ScienceDirect
Journal of Arrhythmia journal homepage: www.elsevier.com/locate/joa
Original Article
The optimal setting of complex fractionated atrial electrogram software in substrate ablation for atrial fibrillation Fuminori Namino, MTa,b,1, Yasuhisa Iriki, MDc,1, Ryuichi Maenosono, PhDa, Hitoshi Ichiki, MDc, Hideki Okui, MDc, Akino Yoshimura, MDc, Naoya Oketani, MDc,n, Masakaze Matsushita, MTa, Mitsuru Ohishi, MDc, Teruto Hashiguchi, MDa,b a
Clinical Laboratory Unit, Kagoshima University Hospital, Kagoshima, Japan Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan c Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan b
art ic l e i nf o
a b s t r a c t
Article history: Received 13 March 2014 Received in revised form 15 April 2014 Accepted 22 April 2014 Available online 5 June 2014
Background: Complex fractionated atrial electrogram (CFAE)-targeted catheter ablation (CFAE ablation) requires a high rate of atrial fibrillation (AF) termination to provide good outcomes. We determined the optimal settings of CFAE software. Methods: In our 430 consecutive patients, AF was terminated in 97 (234/242) and 79% (149/188) of patients with paroxysmal and persistent AF, respectively, by CFAE ablation combined with (31%) or without (69%) pulmonary vein isolation, occasionally with nifekalant infusion. We analyzed 109 consecutive patients who underwent CFAE ablation to determine the optimal settings for comparing subjective versus objective decisions by the CFAE software on CARTO3. We compared three settings: the default setting (0.05–0.15 mV, 50–120 ms) and two modified settings (#1: 0.05–0.30 mV, 40–70 ms, #2: 0.05–0.13 mV, 10–20 ms). We retrospectively analyzed 11,425 points during left atrial mapping before ablation and 10,306 points that were subjectively detected and ablated as CFAE points. An interval confidence level Z 6 denoted a site with CFAE. Results: With the default setting, the accuracy, sensitivity, specificity, positive productive value, and negative productive values were 67, 42, 77, 48, and 73%, respectively. With modified setting #1, the values were 78, 55, 87, 74, and 77%, respectively, versus 64, 82, 60, 53, and 91%, respectively, for modified setting #2. Conclusion: These data suggest that setting #1 was generally superior to the default setting, whereas setting #2 was optimal for excluding areas not requiring ablation. The optimal CFAE software setting was a voltage of 0.05–0.30 mV and an interval parameter of 40–70 ms. & 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
Keywords: Complex fractionated atrial electrograms Atrial fibrillation Catheter ablation Optimal setting
1. Introduction Catheter ablation is an effective approach for the management of patients with atrial fibrillation (AF) [1–7]. Pulmonary vein isolation (PVI) is one of the most common strategies of AF ablation, but the outcome of PVI alone for patients with persistent AF is poor [8–10]. Additional approaches such as linear ablation after PVI have been reported to improve the outcome [11–15]. Nademanee et al. also described an alternative approach for AF ablation that involved identifying the target “substrate” sites via electroanatomical
n
Corresponding author. Tel.: þ 81 99 275 5318; fax: þ 81 99 265 8447. E-mail address: [email protected] (N. Oketani). 1 Equal contribution.
mapping of complex fractionated atrial electrograms (CFAEs) [7–16,17]. Although PVI was not required with this approach, AF ablation guided by CFAEs resulted in a high rate of success in maintaining sinus rhythm in patients with either paroxysmal or persistent AF. However, the results of these studies were not replicated by others [6,18,19]. Thus, the role of CFAE-targeted catheter ablation (CFAE ablation) in treating patients with AF remains controversial. Because one of our physicians was a fellow at the Pacific Rim Electrophysiology Research Institute, all five physicians in our Institute similarly terminate AF with CFAE ablation [20,21]. In our latest study of 430 consecutive patients, AF was terminated by CFAE ablation with (n¼133) or without (n¼297) PVI in 97 (234/242) and 79% (149/188) of patients with paroxysmal and persistent AF, respectively, occasionally with nifekalant infusion without cardioversion. Thus, the use of optimal CFAE software
http://dx.doi.org/10.1016/j.joa.2014.04.006 1880-4276/& 2014 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.
F. Namino et al. / Journal of Arrhythmia 31 (2015) 6–11
7
settings on the CARTO3 may help physicians detect CFAE areas. Therefore, we determined the optimal setting of CFAE software on the CARTO3 system.
episodes) that terminates spontaneously within 7 days. Persistent AF was defined as AF that is sustained for 47 days or AF lasting o7 days but necessitating pharmacologic or electrical cardioversion. AF lasting 41 year was defined as longstanding persistent AF.
2. Materials and methods
2.2. Mapping and ablation of AF
2.1. Study population and protocol
The AF ablation technique described by Nademanee et al. [7,16,17] was used for this study, as previously reported [20,21,23,24]. In brief, a 3.5-mm NaviStar ThermoCool catheter (DF or FJ curve; Biosense Webster, Diamond Bar, CA, USA) was used in all cases. After the coronary sinus (CS) was cannulated via the femoral vein using a decapolar catheter (Dynamic XT Decapolar Steerable-Cath; C. R. Bard, Murray Hill, NJ, USA) for recording and induction, patients underwent non-fluoroscopic electroanatomical mapping with CARTO3 (Biosense Webster). Heparin (3000 IU initial bolus, 1000–2000 IU subsequent boluses as needed to maintain the activated clotting time 4300 s) was administered for anticoagulation. All electroanatomical maps were created for patients who displayed AF, either occurring spontaneously or by induction. Burst pacing using a CS catheter to a lower limit of 1:1 capture or up to 150 ms was used to induce AF occasionally with a 0.01–0.02 μg/kg/ min isoproterenol infusion. AF was inducible in all patients at the beginning of the procedure. When AF was terminated during ablation procedure in patients with paroxysmal AF, AF was reinduced until it was no longer inducible, as paroxysmal AF could be terminated spontaneously. Electroanatomical maps were created and displayed as a shortest complex interval (SCI) map, and the areas of CFAE were also identified manually, tagged, and associated with the atrial anatomy created by CARTO3. This enabled the operators to associate areas of CFAE with the left atrium (LA), CS, and occasionally the right atrium, thereby identifying target sites for ablation. Bipolar recordings were filtered at 30–500 Hz, and the CFAEs were defined as follows: (1) fractionated electrograms composed of two or more deflections and/or a perturbation of the baseline with continuous deflection of a prolonged activation complex; and (2) atrial electrograms with an extremely short cycle length (r120 ms). Examples of two intracardiac electrocardiograms displaying CFAEs and normal atrial electrograms are shown in Fig. 1. Typical continuous CFAEs before radiofrequency (RF) applications are easy to detect, but the electrograms look different in each case and each state of ablation. When AF is organized, CFAEs are also organized. After a certain amount of RF applications, the amplitude and frequency were decreased. This may be one of the reasons that CFAE ablation has not been replicated easily by others [6]. We use CFAE software but subjectively determine which electrograms are CFAEs. All of the operators in our institute replicate CFAE ablation. Then, we tried to optimize the CFAE software to perform CFAE ablation clinically in other institutes with our subjective decision. Then, the CFAE sites in this study were defined as those that we ablated. In addition, we calculated what setting is most appropriate to match our subjective decisions. After acquiring the SCI map associated with CFAEs, we searched the areas of CFAEs referring to the tagged points because CFAE areas have temporal spatial stability. RF was delivered with a maximal power of 40 W with irrigation rates of 30 mL/min (3.5mm NaviStar ThermoCool catheter; Biosense Webster). The power was reduced to 15 W in the posterior LA close to the esophagus or in the CS. The primary endpoints during RF ablation were either complete elimination of CFAE areas or conversion of AF to sinus rhythm occasionally with the injection of nifekalant (0.3 mg/kg intravenously over 10 min, maximum twice), a Class III antiarrhythmic drug similar to ibutilide, which is not available in Japan. If the atrial arrhythmias were not successfully terminated, then internal cardioversion was performed. The endpoints of the procedure were termination of AF in patients with persistent AF
This study comprised 109 consecutive patients (22 females, 87 males; mean age of 59 710 years), including 57 (52%) patients with paroxysmal AF, 40 (37%) patients with persistent AF, and 12 (11%) patients with long-standing persistent AF with symptomatic drug refractory AF, who successfully underwent CFAE ablation combined with (n ¼44) or without (n ¼65) PVI between May 2011 and May 2012. Thirty-seven patients had histories of AF ablation. The patient characteristics and procedure data are shown in Tables 1 and 2, respectively. All antiarrhythmic drugs were discontinued at least five half-lives before ablation, excluding amiodarone, which was discontinued at least 3 months before ablation. Warfarin was not discontinued, and all patients provided written informed consent for the procedure. This study protocol was approved by our institutional ethics committee (Approval date: July 18, 2013, Approval number: 355). AF was defined in accordance with the 2007 Heart Rhythm Society Expert Consensus Statement [22]. Paroxysmal AF was defined as recurrent AF (Z2 Table 1 Patient characteristics.
Age (years) Male (%) Body mass index (kg/m2) Hypertension (%) Diabetes mellitus (%) Heart failure (%) HHD (%) DCM (%) HCM (%) Ischemic heart disease (%) Post cardiac operation (%) Left atrial diameter (mm) Left atrial volume (ml) LVEF (%) BNP (pg/ml) ANP (pg/ml)
Paroxysmal
Persistent
AF (n¼ 57)
AF (n¼ 40)
Longstanding persistent AF (n¼ 12)
59 7 11 77 24.77 3.0 56 11 14 18 4 2 7 4 39.8 76.0 61.3 7 19.9 65.0 712.1 98.6 7175.2 120.2 7528.1
587 9 85 25.17 4.2 53 20 25 33 8 13 8 3 46.7 76.2 82.7 724.9 59.4 713.1 177.9 7 129.2 74.6 7 43.9
60 77 75 27.3 7 3.5 67 25 25 17 0 0 0 0 51.7 7 5.0 99.5 7 29.9 65.7 7 6.5 113.5 7 79.4 57.0 7 27.5
HHD, hypertensive heart disease; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVEF, left ventricular ejection fraction; AF, atrial fibrillation.
Table 2 Procedure data. Paroxysmal Persistent AF (n¼ 57) CFAE ablation combined with PVI (%) 56 Procedure time (min) 222 7 45 Radiofrequency duration (min) 85 7 24 Fluoroscopic time (min) 16 7 10 Mapping points before ablation 105 7 30 Mapping duration (min) 57 2 Use of cardioversion (%) 5 Use of nifekalant (%) 49
Longstanding persistent AF (n¼ 40) AF (n ¼12)
48 229 7 46 87 7 20 147 10 1097 48 672 10 70
33 257 7 47 1147 20 107 7 1247 27 57 1 33 92
Mapping site/time; needed site/time for creating an electroanatomical map. AF, atrial fibrillation; CFAE, complex fractionated atrial electrogram; PVI, pulmonary vein isolation.
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Fig. 1. Examples of complex fractionated atrial electrograms. (a) Fractionated electrograms with a continuous prolonged activation complex over the septal areas. (b) Normal atrial electrograms during atrial fibrillation in the left atrial appendage in the same patient.
and non-inducibility of AF in patients with paroxysmal AF. If many CFAE areas were identified before the delivery of RF ablation and AF was terminated and non-inducible after ablation in limited areas, this was the endpoint. However, AF was inducible until ablation in the majority of CFAE areas in the majority of patients. We did not attempt to eliminate CFAE areas in sinus rhythm because of difficulties in detecting these areas in sinus rhythm.
0.08, 0.10, 0.13, 0.15, 0.18, 0.20, 0.23, 0.25, 0.28, 0.30, 0.33, 0.35, 0.38, and 0.40 mV. In pilot studies, we identified two possible settings (#1: 0.05–0.30 mV, 40–70 ms, #2: 0.05–0.13 mV, 10–20 ms). We then compared the two modified settings to the default setting and calculated the accuracy, sensitivity, specificity, positive productive value, and negative productive value for each setting. An interval confidence level Z6 was considered to denote a site with CFAE.
2.3. Evaluation of optimal setting 3. Results A pilot study was performed to determine the optimal setting in some cases. In CFAE software on CARTO3, minimum and maximum duration values were attempted for all combinations of the following values: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, and 150 ms. In addition, minimum and maximum threshold values were attempted for all combinations of the following values: 0.01, 0.03, 0.05,
We retrospectively analyzed 11,425 points during left atrial mapping before ablation and 10,306 points that were subjectively detected and ablated as CFAE points on CARTO3. We compared the default setting (default: 0.05–0.15 mV, 50–120 ms) and two modified settings according to a pilot study (#1: 0.05–0.30 mV, 40–70 ms, #2:
F. Namino et al. / Journal of Arrhythmia 31 (2015) 6–11
Table 3 Comparison of the settings.
Accuracy (%) Sensitivity (%) Specificity (%) Positive productive value (%) Negative productive value (%)
Default setting
Setting #1
Setting #2
67 42 77 48 73
78 55 87 74 77
64 82 60 53 91
Table 4 Comparison of the settings with the duration of atrial fibrillation Paroxysmal AF/ Persistent AF/Longstanding persistent AF. Default setting
Setting #1
Setting #2
68/66/64 41/39/55 77/78/71 44/51/55 75/70/68
79/77/78 57/50/66 87/88/86 71/75/81 79/76/73
67/62/60 82/80/91 62/58/62 49/55/64 93/87/94
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0.05–0.13 mV, 10–20 ms). We calculated the accuracy, sensitivity, specificity, positive productive value, and negative productive value for each setting. For the default setting, the accuracy, sensitivity, specificity, positive productive value, and negative productive value were 67, 42, 77, 48, and 73%, respectively. For modified setting #1, these values were 78, 55, 87, 74, and 77%, respectively, compared to 64, 82, 60, 53, and 91%, respectively, for modified setting #2 (Table 3). A comparison of each setting with the duration of AF is presented in Table 4, and a comparison between de novo and repeat sessions for each setting is presented in Table 5. Two example cases are shown in Figs. 2 and 3. These data suggested that setting #1 is the optimal setting in general, whereas setting #2 was optimal for excluding areas that do not require ablation.
4. Discussion Accuracy (%) Sensitivity (%) Specificity (%) Positive productive value (%) Negative productive value (%)
Table 5 Comparison between the de novo and redo sessions for each setting First session/ Repeat session.
Accuracy (%) Sensitivity (%) Specificity (%) Positive productive value (%) Negative productive value (%)
Default Setting
Setting #1
Setting #2
63/75 41/43 74/82 51/42 68/83
77/82 61/42 85/93 75/70 75/83
62/68 88/70 55/73 57/45 91/91
This is the first study to evaluate the optimal settings for CFAE software on CARTO3 using maps with high rates of AF termination with subjective determination. We first performed a pilot study to identify the optimal setting. However, the CFAEs varied substantially for each patient. For example, AF was organized particularly in repeat cases, although CFAEs were also organized. Next, we identified two optimal settings: settings #1 and #2. For setting #1, the accuracy, sensitivity, and specificity were 78, 55, and 87%, respectively, whereas the positive and negative predictive values were 74 and 77%, respectively. Our ablation points matched the CFAE areas on SCI maps in setting #1. For setting #2, the sensitivity (82%) was higher than that for setting #1, whereas the specificity (60%) was lower. Setting #2 could more widely recognize the CFAE areas. As the negative predictive value (91%) of setting #2 was higher than that of setting #1, this allowed us to easily exclude the areas that did not
Fig. 2. Example CARTO maps of a patient. The shortest complex interval (SCI) map with red areas indicates complex fractionated atrial electrograms (CFAEs), and that with purple areas indicates normal atrial electrograms. In the default setting (a), the ablated points do not match the red areas. In setting #1 (b, SCI: 0.05–0.30 mV, 40–70 ms), the abated points match the red areas compared with the default setting, especially in the areas of the anterior septal wall and the antrum of the left superior pulmonary vein. In setting #2 (c, SCI: 0.05–0.13 mV, 10–20 ms), the ablated points match the red areas, although non-ablated areas are also red. Setting #2 overestimates the CFAE areas, but it may helpful to identify the areas that do not require ablation.
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Fig. 3. Examples of CARTO maps of a repeat case. In the default setting (a) and setting #1 (b), the anterior wall is not shown as a red area. However, in the optimized setting #2 (c) the anterior wall is shown in red. The abated areas are large, but there are few ablated points excluding the red areas. Thus, setting #2 is useful for excluding the areas that do not require ablation.
require ablation in setting #2. These data suggest that our two optimal settings provide a more sensitive and specific detection of CFAE areas, which may aid physicians in CFAE ablation procedures. Nevertheless, it remains possible that there are better settings than those we determined, as we compared all of the settings only for some patients in the pilot study, but we did not compare all of the settings for all patients owing to time constraints. There are several types of electrograms that we consider CFAEs. In the original study [7], two types of electrograms were mentioned as CFAEs: 1) fractionated electrograms composed of two or more deflections and/or a perturbation of the baseline with continuous deflection of a prolonged activation complex; and 2) atrial electrograms with an extremely short cycle length (r120 ms). The software attempted to cover both types of electrograms, requiring a wider interval setting. Most electrograms requiring ablation are continuous and more fractionated, for which a shorter interval setting may be better in general.
Sources of funding This study was supported by Fukuda Foundation for Medical Technology of Japan.
Conflict of interest There is nothing to disclose for this study.
Acknowledgments We would like to give a special thanks to Dr. Koonlawee Nademanee. Our ablations and studies depended on the knowledge that we obtained in his Institute. References
5. Limitation The present study had several limitations. (1) CFAEs were evaluated visually by each operator in this study; however, CFAEs were not universally defined among the physicians. (2) Limited software settings were evaluated in this study, and it is possible that there are better settings. (3) The study design is retrospective.
6. Conclusions The optimal settings of CFAE software on CARTO3 system were a voltage range of 0.05–0.30 mV and an interval range of 40–70 ms.
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