1112 INOUE K et al. Circulation Journal ORIGINAL ARTICLE Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Arrhythmia/Electrophysiology Current Status of Catheter Ablation for Atrial Fibrillation – Updated Summary of the Japanese Catheter Ablation Registry of Atrial Fibrillation (J-CARAF) – Koichi Inoue, MD, PhD; Yuji Murakawa, MD; Akihiko Nogami, MD; Morio Shoda, MD; Shigeto Naito, MD; Koichiro Kumagai, MD; Yasushi Miyauchi, MD; Teiichi Yamane, MD; Norishige Morita, MD; Ken Okumura, MD on behalf of the Japanese Heart Rhythm Society Members

Background: The purpose of this study was to provide precise data on the current status of catheter ablation for atrial fibrillation (AF) in .

Methods and Results: The Japanese Heart Rhythm Society requested that members retrospectively register data for AF ablation performed in September 2011, March 2012, and September 2012. A total of 165 centers submitted data for 3,373 patients (age, 62±11 years; male, 76.1%; paroxysmal AF, 64.4%). Pulmonary vein isolation (PVI) and additional ablation were performed in 97.5% and 77.4% of patients, respectively. 3-D mapping systems and irrigat- ed-tip catheters were used in 94.8% and 87.7% of the patients, respectively. Although the mean CHADS2 score was 1.0±1.0, the majority received oral anticoagulant (OAC) during and following the procedure (69.8% and 97%, re- spectively). Vitamin K antagonist (VKA) prescription, however, decreased (1st vs. 3rd survey, during and following the procedure, 59.3% vs. 47.8% and 81.7% vs. 55.2%, respectively, P<0.0001, both) and that of new OAC (NOAC) increased drastically (9.6% vs. 24.2% and 15.8% vs. 42.1%, respectively, P<0.0001). Early complications were re- ported in 4.5% of the patients, but no instance of early death was reported.

Conclusions: In addition to PVI, additional ablation procedures are also performed very frequently. Although the mean CHADS2 score was low, peri-procedural OAC therapy was commonly performed, and NOAC drastically su- perseded VKA. (Circ J 2014; 78: 1112 – 1120)

Key Words: Atrial fibrillation; Catheter ablation; Complication; Oral anticoagulant; Pulmonary vein isolation

trial fibrillation (AF) is the most common tachyarrhyth- ablation, the ablation procedure, ablation strategy, complication mia in the Japanese population, and catheter ablation and perioperative prescription are very important. The Japanese A (CA) to manage AF is increasingly being used. Pul- Heart Rhythm Society (JHRS) initiated the Japanese Catheter monary vein isolation (PVI) is currently the cornerstone pro- Ablation Registry (JCAR)2,3 and the Japanese Catheter Abla- cedure for AF ablation,1 but these procedures have not yet at- tion Registry of AF (J-CARAF).4 The aim of J-CARAF is to tained a high degree of perfection because of the controversy collect objective data to assess the performance and safety of concerning ablation strategy, the relatively high recurrence rate, CA for AF in Japan. This registry consists of data collected in and specific complications. Significant progress in AF ablation, surveys conducted thrice at different intervals. The summary of however, has been made and so not only the ablation result but the first survey has been reported previously,4 and we now pres- also understanding of the current status of patients receiving AF ent a summary of the whole survey and investigate the changes

Received October 6, 2013; revised manuscript received December 11, 2013; accepted January 7, 2014; released online March 17, 2014 Time for primary review: 60 days Cardiovascular Center, Sakurabashi Watanabe Hospital, (K.I.); Fourth Department of Internal Medicine, Teikyo University Mizonokuchi Hospital, Kawasaki (Y. Murakawa); Cardiovascular Division, Faculty of Medicine, University of , Tsukuba (A.N.); Department of Cardiology, Women’s Medical University, Tokyo (M.S.); Division of Cardiology, Gunma Prefectural Cardiovascular Center, (S.N.); Heart Rhythm Center, Sanno Hospital, Fukuoka (K.K.); Department of Cardiovascular Medicine, Nippon Medical School, Tokyo (Y. Miyauchi); Department of Cardiology, The Jikei University School of Medicine, Tokyo (T.Y.); Division of Cardiology, Department of Medicine, Tokai University Hachioji Hospital, Hachioji (N.M.); and Division of Cardiology, Hirosaki University Graduate School of Medicine, Hirosaki (K.O.), Japan Mailing address: Koichi Inoue, MD, PhD, Cardiovascular center, Sakurabashi Watanabe Hospital, 2-4-32 Umeda, Kita-ku, Osaka 530-0001, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-13-1179 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

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Table 1. AF Ablation Patient Background First survey Second survey Third survey Total No. patients n=932 n=1,195 n=1,246 n=3,373 Age (years) 62.1±10.4 62.3±10.8 62.1±10.6 62.2±10.6 Male 716 (76.8) 917 (76.7) 934 (75) 2,567 (76.1) Type of AF Paroxysmal AF 612 (65.7) 766 (64.1) 795 (63.8) 2,173 (64.4) Persistent AF 180 (19.3) 273 (22.8) 280 (22.5) 733 (21.7) Long-standing persistent AF 140 (15.0) 156 (13.1) 171 (13.7) 467 (13.8) Frequency of paroxysmal AF attack <1/month 70 (11.4) 138 (18) 155 (19.5) 363 (16.7)* <1/week 206 (33.7) 243 (31.7) 257 (32.3) 706 (32.5) <1/day 206 (33.7) 203 (26.5) 202 (25.4) 611 (28.1)* >1/day 75 (12.3) 82 (10.7) 83 (10.4) 240 (11) Lone AF 208 (22.3) 281 (23.5) 281 (22.6) 770 (22.8) Congestive heart failure 127 (13.6) 174 (14.6) 148 (11.9) 449 (13.3) Age 65–74 years old 392 (39.7) 351 (29.4) 532 (42.9) 1,400 (41.5) Age >75 years old 77 (8.3) 138 (11.5) 108 (8.7) 323 (9.6) Hypertension 483 (51.8) 592 (49.5) 611 (49.0) 1,686 (50) Diabetes 110 (11.8) 148 (12.4) 170 (13.6) 428 (12.7) Stroke or TIA 78 (8.4) 83 (6.9) 112 (9) 273 (8.1) Vascular disease 52 (5.6) 65 (5.4) 76 (6.1) 193 (5.7) CAD 57 (6.1) 71 (5.9) 71 (5.7) 199 (5.9) Dilated cardiomyopathy 16 (1.7) 20 (1.7) 19 (1.5) 55 (1.6) HCM 37 (4.0) 38 (3.2) 26 (2.1) 101 (3)** Cardiomyopathy other 7 (0.8) 7 (0.6) 8 (0.6) 22 (0.7) Sick sinus syndrome 67 (7.2) 61 (5.1) 77 (6.2) 205 (6.1) Hyperthyroidism 23 (2.5) 20 (1.7) 29 (2.3) 72 (2.1) COPD 20 (2.1) 15 (1.3) 11 (0.9) 46 (1.4) Congestive heart disease 8 (0.9) 9 (0.8) 9 (0.7) 26 (0.8) Valvular disease 19 (2.0) 37 (3.1) 37 (3) 93 (2.8) CKD on HD 15 (1.6) 12 (1.0) 20 (1.6) 47 (1.4) Post-open heart surgery 22 (2.3) 32 (2.7) 18 (1.4) 72 (2.1) Session of AF ablation First 722 (77.5) 922 (77.2) 966 (77.7) 2,610 (77.4) Second 184 (19.7) 230 (19.2) 230 (18.5) 644 (19.1) Third 22 (2.4) 37 (3.1) 43 (3.4) 102 (3) >Fourth 4 (0.4) 6 (0.5) 7 (0.6) 17 (0.5) Echocardiographic data LVEF (%) 63.5±9.5 63.2±10.5 64.4±9.5 63.7±9.9 LA dimension (mm) 40.7±15.2 40.8±7.2 40.3±6.7 40.4±6.8 LA volume (ml) 70.4±33.8 70.3±33 69.2±33 69.9±33.2 History of AAD use 738 (79.2) 892 (74.6) 914 (73.3) 2,544 (75.4)*** Average CHA2DS2-VASc score 1.5±1.3 1.7±1.5 1.7±1.3 1.7±1.4 CHA2DS2-VASc score 0 240 (25.8) 281 (23.5) 258 (20.7) 779 (23.1)# 1 276 (29.6) 332 (27.8) 356 (28.6) 964 (28.6) 2 223 (23.9) 265 (22.2) 343 (27.5) 831 (24.6) 3 119 (12.8) 172 (14.4) 177 (14.2) 468 (13.9) 4 54 (5.8) 100 (8.4) 77 (6.2) 231 (6.8)## ≥5 20 (2.1) 45 (3.8) 52 (4.2) 117 (3.4) Average CHADS2 score 1.0±1.0 1.1±1.0 1.0±1.0 1.0±1.0 CHADS2 score 0 326 (35.0) 443 (37.1) 457 (36.7) 1,226 (36.3) 1 364 (39.1) 436 (36.5) 470 (37.7) 1,270 (37.7) 2 162 (17.4) 206 (17.2) 204 (16.4) 572 (17) 3 60 (6.4) 83 (6.9) 81 (6.5) 224 (6.6) 4 15 (1.6) 19 (1.6) 28 (2.2) 62 (1.8) ≥5 5 (0.5) 8 (0.7) 6 (0.5) 19 (0.5) Data given as mean ± SD or n (%). *P<0.0001; **P=0.0098; ***P=0.0023; #P=0.0053; ##P=0.013 between the 3 surveys (Cochran-Armitage test for trend). AAD, anti-arrhythmic drug; AF, atrial fibrillation; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HCM, hypertrophic cardiomyopathy; HD, hemodialysis; LA, left atrium; LVEF, left ventricular ejection fraction; TIA, transient ischemic attack.

Circulation Journal Vol.78, May 2014 1114 INOUE K et al.

Figure 1. Change in pre-procedural arrhythmic attack frequency in patients undergoing abla- tion for paroxysmal atrial fibrillation. *P<0.0001.

that occurred during the registry period. ablation submitted increased to 1,195 and 1,245 sessions from 144 and 165 centers, respectively. The median number of AF Editorial p 1055 procedures per center per month also increased to 6 (lower and upper quartiles, 3 and 13, respectively) in both surveys. The largest center performed 81 AF ablation procedures per month Methods in the third survey. Finally, the data from 3,373 ablations were Data Collection submitted to J-CARAF. An online questionnaire was used to perform registration ret- rospectively. JHRS members were notified by mail. The study Patient Background periods of the first, second and third surveys were September Patient background is given in Table 1. The average age was 2011, March 2012, and September 2012, respectively. If AF 62.2±10.6 years, and the majority of patients (76.1%) were ablation procedures were performed within the respective male. Paroxysmal AF accounted for 64.4% of all cases, where- periods, precise data regarding patient background, AF abla- as persistent AF and long-standing persistent AF accounted for tion procedure and strategy, acute results, and acute complica- 21.7% and 13.8% of cases, respectively. Lone AF was noted tions were registered by JHRS members. The same patient in a minority of cases (22.3%), and half of the present patients variables were collected for all the surveys.4 had a history of hypertension as comorbidity. Of all AF abla- tion patients, 77.4% were undergoing their first session, 19.1% Statistical Analysis the second session, and 3.5%, subsequent sessions. Average Continuous variables are expressed as mean ± SD, whereas left ventricular (LV) ejection fraction remained unchanged categorical variables are expressed as number and frequency. (63.5%±9.5%) and the average left atrial (LA) remodeling was Group means for continuous variables were compared using moderate (LA volume, 70.4±33.8 ml; dimension, 40.7±15.2 mm). 1-way analysis of variance between the 3 surveys. Compari- The average CHADS2 score and CHA2DS2-VASc scores were sons of categorical variables among the 3 surveys were per- 1.0±1.0 and 1.7±1.4, respectively. The average number of ab- formed using Cochran-Armitage test for trend. Comparison lation sessions was 1.27±0.54, and the maximum was 6. The between pairs from among the 3 surveys was done using Bon- average number of previous anti-arrhythmic drugs (AAD) used ferroni correction, and the alpha value for each comparison was 1.12±0.96 and no history of AAD use was reported in 819 was then set equal to 0.05/3. All statistical analysis was done patients (24.6%). The proportion of patients with a history of using MedCalc version 12.7.2. AAD use significantly decreased during the surveys (P=0.0023). The proportion of paroxysmal AF patients with low fre- quent attacks (<1/month) increased but that with relatively Results frequent attacks (<1/day) decreased significantly during the Number of Patients survey period (P<0.0001, respectively; Table 1; Figure 1). In the first survey, as reported previously,4 the AF ablation data from 932 patients were submitted to J-CARAF from 128 Ablation Procedure and Strategy electrophysiological centers, with a median of 5 AF proce- Table 2 lists the AF ablation procedure data. The preoperative dures (lower and upper quartiles, 2 and 9, respectively) per investigation consisted of transesophageal echocardiography center per month. The largest center performed 56 AF ablation (TEE) and cardiac computed tomography (CT) for 80.8% and procedures per month. 82.1% of the patients, respectively; cardiac magnetic resonance In the second and third surveys, the numbers of cases of AF imaging (MRI) was performed in only 2.2% of the patients.

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Table 2. AF Ablation Procedure First survey Second survey Third survey Total No. patients n=932 n=1,195 n=1,246 n=3,373 Preoperative investigation TEE 745 (79.9) 984 (82.3) 997 (80) 2,726 (80.8) MRI 10 (1.1) 28 (2.3) 35 (2.8) 73 (2.2) CT 753 (80.8) 965 (80.7) 1,047 (84) 2,765 (82.1) TEE or MRI/CT 881 (94.5) 1,134 (94.8) 1,183 (94.9) 3,198 (94.8) Procedure time (h) 3.6±1.3 3.5±1.3 3.5±1.3 3.5±1.3 Fluoroscopy time (min) 72.9±52.7 68.9±56.7 65.2±47.2 68.5±52.3 Diagnostic and therapeutic instruments CARTO system use 676 (72.5) 866 (72.5) 859 (68.9) 2,401 (71.2) EnSite system use 208 (22.3) 263 (22) 326 (26.2) 797 (23.6) Irrigation catheter use 817 (87.7) 1,043 (87.3) 1,112 (89.2) 2,972 (88.1) OAC use during procedure 643 (68.9) 815 (68.2) 897 (72) 2,355 (69.8) Vitamin-K antagonist 553 (59.3) 662 (55.4) 590 (47.4) 1,805 (53.5)* Direct thrombin inhibitor 87 (9.3) 152 (12.7) 265 (21.2) 504 (14.9)* Factor Xa inhibitor 3 (0.3) 0 (0) 37 (3) 40 (1.2) Anesthesia Local anesthesia 929 (99.7) 1,179 (98.7) 1,232 (98.9) 3,340 (99) without sedation 30 (3.2) 43 (3.6) 32 (2.6) 105 (3.1) with conscious sedation 405 (43.5) 597 (50) 691 (55.5) 1,693 (50.2)* with deep sedation 494 (53.0) 540 (45.2) 511 (41) 1,545 (45.8)* General anesthesia 3 (0.3) 9 (0.8) 4 (0.3) 16 (0.5) Intraoperative monitoring Arterial pressure 741 (79.5) 945 (79) 979 (78.6) 2,665 (79) Oxygen saturation 932 (100) 1,174 (98.2) 1,230 (98.7) 3,336 (98.9) End tidal CO2 19 (2.0) 25 (2.1) 20 (1.6) 64 (1.9) Bispectral index 106 (11.4) 162 (13.6) 176 (14.1) 444 (13.2) Postoperative steroid use 66 (7.1) 54 (4.5) 53 (4.3) 173 (5.2) For treatment of pericarditis 26 (2.8) 7 (0.6) 16 (1.3) 49 (1.5) For recurrence prevention 40 (4.3) 47 (3.9) 37 (3.0) 124 (3.7) Data given as mean ± SD or n (%). *P<0.0001 among the 3 surveys (Cochran-Armitage test for trend). CT, computed tomography; MRI, magnetic resonance imaging; TEE, trans-esophageal echocardiography. Other abbreviation as in Table 1.

One or more pre-operative investigations (TEE, MRI, and 59.3% in the first survey and significantly decreased to 55.5% MDCT) that enable evaluation of thrombus in the LA append- and 47.8% in the second and third surveys, respectively age were performed in 3,198 patients (94.8%). In 1,665 pa- (P<0.0001). Instead of VKA, the use of new OAC (NOAC: a tients with CHA2DS2-VASc score 0–1, TEE and 1 or more of direct thrombin inhibitor and factor Xa inhibitor) a direct these investigations were performed in 1,347 patients (80.9%) thrombin inhibitor, increased consistently (1st, 2nd and 3rd, and 1,581 patients (95%), respectively. Two 3-D mapping 9.6%, 12.7% and 21.2%, P<0.0001). systems were used during AF ablation for 94.8% of the pa- Table 3 lists the AF ablation strategies. PVI was performed tients: the CARTO system (Biosense Webster, CA, USA) for in the majority (98.1%) of AF ablation procedures. Ipsilateral 71.2% and the EnSite system (St. Jude Medical, MN, USA) encircling PVI (79.5%)5 was the standard PVI method fol- for 23.6% of the patients. Irrigated catheter was used in 88.1% lowed; individual PVI (11.6%)6 and box isolation (5.8%)7 were of the patients. The procedure time was 3.5±1.3 h, and the also performed. Ablation adjunctive to PVI was performed in fluoroscopy time was 68.5±52.3 min. 77.4% of cases; the cavotricuspid isthmus (CTI) was ablated AF ablation was performed under sedation in most cases in 56.6% of cases, and adjunctive ablation other than CTI abla- (96.0%), but the level of sedation tended to be lighter; the tion was performed in 48.1% of cases. LA linear ablation was proportion of patients who received deep sedation decreased performed in 22.3% of the patients, of whom ablation was from 53% in the first survey to 45% and 41% in the second and performed on the LA roof in 19% and at other sites in 15.3% third surveys, respectively (P<0.0001; Figure 2). In contrast, of patients. The execution rate of complex fractionated atrial the proportion of patients who received conscious sedation electrogram (CFAE) ablation was 12.2%; LA CFAE ablation increased from 43.5% in the first survey to 49.6% and 55.2% was performed in 11.8% and right atrial CFAE ablation in 4% in the second and third surveys, respectively (P<0.0001). of cases. LA linear ablation was performed more frequently The prevalence of oral anticoagulation (OAC) therapy dur- than CFAE ablation (linear vs. CFAE ablation, 22.3% vs. ing AF ablation was consistently high (69.8%), but the number 12.2%, respectively, P<0.0001). A total of 74 patients (7.9%) of patients who took vitamin K antagonists (VKA) decreased underwent both LA linear ablation and CFAE ablation. The significantly during the term of the survey (Figure 2); it was proportions of patients who underwent focal ablation,8 coro-

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Figure 2. Changes that occurred during the registry period. Variables with significant change during the registry period on Co- chran-Armitage test for trend were compared between each pair among the 3 surveys. Level of significance was set equal to 0.1666 using Bonferroni correction. AAD, anti-arrhythmic drug; APA, antiplatelet agent; CA, catheter ablation; GP, ganglion plexus; HCM, hypertrophic cardiomyopathy; LA, left atrium; NOAC, new oral anticoagulant; RAS, renin-angiotensin system; VKA, vitamin K antagonist. *P<0.016; **P<0.005; ***P<0.001; #P<0.0005; ##P<0.0001.

nary sinus ablation, and ganglion plexus (GP) ablation9 were registry period, but the breakdown of OAC varied (Figure 2). 7.2%, 3.9%, and 3.7%, respectively. The execution rate of each In the first survey, 81.7% of the patients were taking VKA as ablation procedure was almost unchanged throughout the sur- a post-procedural OAC, but the proportion of patients receiv- vey period, with 2 exceptions: linear ablation was performed ing it drastically decreased to 55.2% (P<0.0001). In contrast, less frequently in the second and third surveys compared with the proportion of those receiving NOAC increased from the first survey (P=0.038), and the use of GP ablation increased 15.8% to 42.2% (P<0.0001). Of the post-procedural OAC for marginally but significantly during the survey period (P=0.021; patients who did not receive OAC during the procedure, use Table 3; Figure 2). By performing these ablation procedures, of VKA in the third survey decreased to one-third that in the 98% of the AF ablation sessions resulted in sinus rhythm. first survey (1st survey vs. 3rd survey, 22.4% vs. 7.4%, re- Table 4 lists the complications of AF ablation. A total of spectively, P<0.0001). In contrast, use of NOAC in the third 155 acute complications were reported in 151 patients (4.5%). survey increased by >3-fold that in the first survey (6.5% The majority of the complications (72%, 112/155 instances of vs.21.9%, respectively, P<0.0001). Prescriptions for a renin- complication) were hemorrhagic. Pericardial effusions oc- angiotensin system (RAS) inhibitor (angiotensin-converting curred in 75 cases (2.2%), and emergency drainage of a car- enzyme inhibitor and angiotensin II receptor blocker) de- diac tamponade was required in 43 cases (1.3%). Symptomatic creased significantly in the third survey (3rd survey vs. 1st cerebral infarctions occurred in 5 patients (0.1%), and CT or survey, 25.2% vs. 30.5%, respectively; P=0.006, respective- MRI was used to diagnose asymptomatic cerebral infarctions ly). The prescription of statin also decreased significantly in in 6 patients (0.2%). Other major complications were hemo- the third survey (11.2% vs. 16.4% and 17.2%, respectively; thorax in 1 patient, prolonged phrenic nerve palsy in 5 patients, P=0.0003 and <0.0001, respectively; Table 5; Figure 2). gastric hypomotility in 8 patients, and air embolism in 5 pa- tients. No deaths or atrio-esophageal fistulas were reported in this registry. Discussion Table 5 lists the discharge prescriptions. Most patients J-CARAF was started to investigate the current status of AF (97%) received OAC at discharge consistently throughout the ablation in Japan as a supplement to the JHRS summary of the

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Table 3. Ablation Strategy and Acute Result First survey Second survey Third survey Total No. patients n=932 n=1,195 n=1,246 n=3,373 PVI 910 (97.6) 1,164 (97.4) 1,197 (96.1) 3,271 (97) Ipsilateral encircling PVI 743 (79.7) 961 (80.4) 979 (78.6) 2,683 (79.5) Box isolation 54 (5.8) 58 (4.9) 57 (4.6) 169 (5) Individual PVI 96 (10.3) 139 (11.6) 155 (12.4) 390 (11.6) PVI, other 17 (1.8) 6 (0.5) 6 (0.5) 29 (0.8) Adjunctive Abl 731 (78.8) 896 (75) 984 (79) 2,611 (77.4) CTI 527 (56.5) 662 (55.4) 721 (57.9) 1,910 (56.6) Adjunctive Abl other than CTI 453 (48.6) 552 (46.2) 618 (49.6) 1,623 (48.1) Abl to CFAE 123 (13.1) 131 (11) 157 (12.6) 411 (12.2) CFAE in LA 119 (12.8) 128 (10.7) 152 (12.2) 399 (11.8) CFAE in RA 45 (4.8) 39 (3.3) 50 (4) 134 (4%) Focal Abl 70 (7.5) 88 (7.4) 86 (6.9) 244 (7.2) Focal Abl to LA 30 (3.2) 49 (4.1) 50 (4) 308 (9.1) Focal Abl to RA 44 (4.7) 49 (4.1) 46 (3.7) 139 (4.1) LA linear Abl 238 (25.5) 246 (20.6) 268 (21.5) 752 (22.3)* LA roofline Abl 209 (22.4) 203 (17) 229 (18.4) 641 (19%) LA linear Abl other than roofline 164 (17.6) 164 (13.7) 189 (15.2) 517 (15.3) SVC Abl 155 (16.6) 212 (17.7) 211 (16.9) 578 (17.1) Coronary sinus Abl 44 (4.7) 46 (3.8) 41 (3.3) 131 (3.9) Ganglion plexus Abl 25 (2.7) 44 (3.7) 57 (4.6) 126 (3.7)* ECV during procedure, Abl 396 (42.4) 539 (45.1) 522 (41.9) 1,457 (43.2) AF induction by burst pacing after Abl Induced and persisted ≥5 min 76 (8.2) 121 (10.1) 91 (7.3) 288 (8.5) Induced and persisted <5 min 408 (43.8) 512 (42.8) 590 (47.4) 1,510 (44.8) Cardiac rhythm at end of the procedure Sinus rhythm 920 (98.7) 1,164 (97.4) 1,222 (98.1) 3,306 (98) AF 6 (0.6) 11 (0.9) 8 (0.6) 25 (0.7) Other 5 (0.5) 9 (0.8) 4 (0.3) 18 (0.5) Data given as n (%). *P=0.038; **P=0.021 among the 3 surveys (Cochran-Armitage test for trend). Adjunctive abla- tion, ablation procedure other than PVI. Abl, ablation; CFAE, complex fractionated electrogram; CTI, cavotricuspid isthmus; ECV, electrical cardioversion; PVI, pulmonary vein isolation; RA, right atrium; SVC, superior vena cava. Other abbreviations as in Table 1.

JCAR. The registrations were performed 3 times every 6 AF Ablation Strategy months, and the results of the first survey (n=932) were re- AF ablation was performed with the use of a 3-D mapping ported recently.4 A total of 3,373 AF ablation patients were system in most cases (94.8%), and 3-D imaging of LA and PVs registered in the 3 surveys. In this report, we summarized all using CT or MRI was performed in 84.3% of cases. Typical survey results and compared the results among the 3 surveys. AF ablation might be performed using a 3-D-mapping system with merge or fusion functions. The percentage of patients who AF Ablation Patients received OAC therapy during the procedure was high (69.8%), The typical patients who underwent AF ablation were middle- and this rate remained unchanged from the first to third sur- aged men with preserved LV function and mild LA remodeling veys. The percentage of those who received NOAC, however, who had a relatively low risk of cardiogenic cerebral infarc- increased from 9.6% in the first survey to 24.2% in the third tion. We speculate that the purpose of AF ablation was to im- survey. The rate of VKA use during the procedure decreased prove their compromised quality of life rather than the progno- from 59.3% of patients to 47.8%. These data indicate that the sis. Although the background of the AF ablation patients was use of NOAC was spreading very rapidly and replacing the use very similar throughout the registry, the proportion of the pa- of VKA, although studies report that VKA therapy during the tients with a history of AAD use was lower in the second and procedure was safe.11 Dabigatran, rivaroxaban, and apixaban third surveys than in the first survey. This would indicate that were approved for stroke risk reduction in non-valvular AF by more patients began to receive AF ablation as a first-line ther- Japanese Ministry of Health, Labour and Welfare in March apy for AF. Precise information on AAD therapy will be re- 2011, April 2012, and February 2013, respectively. The great ported in another article.10 In this survey, the number of pa- majority of AF ablations (96.0%) were performed under seda- tients who had paroxysmal AF attack less than once per month tion, and deep sedation was being replaced by conscious seda- but who received ablation increased significantly during the tion. It is conceivable that the sedation used during the proce- survey period (Figure 1). This might indicate that application dure was gradually decreased in strength, although the reason of AF ablation was expanding to patients with infrequent par- for this change is still under speculation. oxysmal AF attacks.

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Table 4. Acute Complications of AF Ablation First survey Second survey Third survey Total No. patients n=932 n=1,195 n=1,246 n=3,373 Total (incidents) 58 (6.2) 45 (3.8) 52 (4.2) 155 (4.6) Total (patients) 55 (5.9) 45 (3.8) 51 (4.1) 151 (4.5) PE requiring drainage 10 (1.1) 15 (1.3) 18 (1.4) 43 (1.3) PE not requiring drainage 19 (2.0) 8 (0.7) 5 (0.4) 32 (0.9) Valve injury 0 (0) 0 (0) 0 (0) 0 (0) Transient high-degree AV block 1 (0.1) 2 (0.2) 1 (0.1) 4 (0.1) Sinus arrest 2 (0.2) 5 (0.4) 4 (0.3) 11 (0.3) Transient ischemic attack 0 (0) 1 (0.1) 0 (0) 1 (0.03) Symptomatic cerebral infarction 2 (0.2) 0 (0) 1 (0.1) 3 (0.1) Asymptomatic cerebral infarction 2 (0.2) 2 (0.2) 2 (1.6) 6 (0.2) Pneumothorax 0 (0) 1 (0.1) 0 (0) 1 (0.03) Hemothorax 1 (0.1) 0 (0) 0 (0) 1 (0.03) Prolonged phrenic nerve paralysis 1 (0.1) 3 (0.3) 1 (0.1) 5 (0.1) Air embolism 1 (0.1) 1 (0.1) 3 (0.2) 5 (0.1) Severe PV stenosis 0 (0) 0 (0) 0 (0) 0 (0) Hematoma at the puncture site 11 (1.2) 7 (0.6) 11 (0.9) 29 (0.9) Pseudoaneurysm 4 (0.4) 0 (0) 0 (0) 4 (0.1) Arteriovenous fistula 0 (0) 1 (0.1) 2 (0.1) 3 (0.1) Gastric hypomotility 4 (0.4) 1 (0.1) 3 (0.2) 8 (0.2) Atrio-esophageal fistula 0 (0) 1 (0.1) 0 (0) 1 (0.03) Others 0 (0) 0 (0) 1 (0.1) 1 (0.03) Death 0 (0) 0 (0) 0 (0) 0 (0) Data given as n (%). AV, atrioventricular; PE, pericardial effusion; PV, pulmonary vein. Other abbreviation as in Table 1.

Table 5. Discharge Prescription First survey Second survey Third survey Total No. patients n=932 n=1,195 n=1,246 n=3,373 OAC use 908 (97.5) 1,154 (96.6) 1,211 (97.2) 3,273 (97) VKA 761 (81.7) 869 (72.7) 688 (55.2) 2,318 (68.7)* Direct thrombin inhibitor 147 (15.8) 285 (23.8) 478 (38.4) 910 (27)* Factor Xa inhibitor 0 (0) 0 (0) 46 (3.7) 46 (1.4) Anti-platelets agents 43 (4.6) 71 (5.9) 83 (6.7) 197 (5.8) Anti-arrhythmic drugs 492 (53.6) 565 (47.3) 614 (49.3) 1,671 (49.6) Verapamil 64 (6.9) 66 (5.5) 73 (5.9) 203 (6) β-blocker 253 (25.7) 371 (31) 348 (27.9) 972 (28.8) Digitalis 13 (1.4) 28 (2.3) 19 (1.5) 60 (1.8) ACEI 51 (5.5) 67 (5.6) 53 (4.3) 171 (5.1) ARB 233 (25.0) 281 (23.5) 261 (20.9) 775 (23)** Statin 153 (16.4) 206 (17.2) 139 (11.2) 498 (14.8)*** *P<0.0001; **P=0.024; ***P=0.0002 among the 3 surveys (Cochran-Armitage test for trend). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; OAC, oral anti-coagulant; VKA, vitamin K antagonist.

AF Ablation Procedure er than the complication rate of CTI-dependent atrial flutter PVI was performed in most cases (97%) and constituted the (AFl) with AF, CTI ablation was performed even in those minimum of treatment in AF ablation. Adjunctive ablation without a history of clinical and inducible CTI-dependent AFl. other than PVI was performed in approximately 77.4% of cases, In addition, CTI ablation seemed to be performed as a routine although long-standing persistent AF had been treated in a and empirical substrate modification. We also observed 2 sig- minority of the cases. Adjunctive ablation other than CTI abla- nificant changes in ablation strategy during the period of the tion was also performed in 48.1% of the patients who under- 3 surveys (Figure 2). Linear ablation decreased significantly went AF ablation, even though 64.4% were diagnosed with more in the second and third surveys than in the first survey, paroxysmal AF. Because the execution rate of CTI ablation in although the proportion of patients with non-paroxysmal AF this registry was very high (56.6%) and would be much high- was similar among the surveys. Physicians preferred LA linear

Circulation Journal Vol.78, May 2014 Catheter Ablation for AF in Japan 1119 ablation to CFAE ablation for substrate modification even in Study Limitations the third survey (LA linear ablation vs. CFAE ablation, 21.5% There are some limitations to this study. First, the J-CARAF vs. 12.6%, respectively, P<0.0001). The motivation to perform is a voluntary survey and some centers might not respond to linear ablation, however, may have gradually decreased, pos- the request to attend this registry. Hospitals with high-volume sibly because they believed that it was an unnecessary or inef- AF ablation were repeatedly contacted by the JHRS if they fective procedure for some AF patients who had already under- had not registered their data, but low-volume hospitals or gone linear ablation previously. In contrast, ablation of the GP centers who had started AF ablation recently were not. The increased slightly. GP ablation is a relatively new approach and J-CARAF therefore might not reflect the current status of AF seems to be gradually increasing in use. We are also collecting ablation at low volume centers in Japan to some extent, al- data on the ablation results, and the efficacy of the adjunctive though this is a national registry. Second, the registration of ablation strategy, which will be reported in the future. AF cases was retrospective, and this may result in underesti- mation of the complication rate. Finally, the efficacy of AF Acute Complications of AF Ablation ablation was not given in this report. The clinical follow-up Acute complications of AF ablation were reported in 4.5% data for the J-CARAF patients were prospectively collected, (151/3,373) of patients, which is similar to that of a previous but these cohort data are still under investigation, and are not worldwide survey (4.5–6.0%).12,13 In contrast, no cases of early available as yet. death were recorded in this registry, and the lethal complica- tion rate in the Japanese survey tended to be lower than in the previous worldwide survey (0.05–1.3%). In the present pa- Conclusions tients, approximately 70% were taking OAC during the proce- AF ablation was typically performed in relatively young men dure. Although the majority of the incidents (72%, 112/155 of with low CHADS2 score, and the use of a 3-D mapping system incidents) were hemorrhagic complications (cardiac tampon- and an irrigated-tip catheter preserved heart function. In addi- ade, hemothorax, pseudoaneurysm, and arteriovenous fistula), tion to PVI, adjunctive ablation procedures were also per- symptomatic cerebral infarction was observed in only 3 cases. formed frequently, even in patients with paroxysmal AF. OAC In this registry, the thromboembolic complication rate (0.3%) therapy after ablation was performed in the majority of pa- was very low compared with that of previous surveys (0.9– tients, and VKA was drastically superseded as a peri-proce- 1.0%),12,13 and the complication rate of cardiac tamponade dural OAC agent by NOAC. (pericardial effusion requiring drainage, 1.3%) was similar to that previously reported (1.2–1.3%). No peri-procedural death Acknowledgments was recorded in this registry, although deaths in 0.098% of None of the authors has any conflicts of interest to declare. patients were reported in a previous study.14 These data indi- cate that OAC therapy during the procedures was adequate. References 1. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, et Prescription at Discharge al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter A number of clinical trials that have not found an upstream and surgical ablation of atrial fibrillation: Recommendations for pa- effect of RAS inhibitors in secondary prevention of AF have tient selection, procedural techniques, patient management and fol- been published in succession.15–18 Currently, the consensus is low-up, definitions, endpoints, and research trial design. Heart Rhythm 2012; 9: 632 – 696. e21, doi:10.1016/j.hrthm.2011.12.016. that RAS inhibitors do not have a secondary prevention effect 2. Murakawa Y, Nogami A, Hirao K, Shoda M, Aonuma K, Ikeguchi S, on AF. Prescription of RAS inhibitors decreased significantly et al. A brief report on the nationwide survey of catheter ablation in in the third survey in spite of the unchanged morbidity of hy- Japan/The Japanese catheter ablation registry (JCAR). J Arrhythmia pertension and congestive heart failure, which might indicate 2012; 28: 122 – 126. 3. Murakawa Y, Nogami A, Hirao K, Shoda M, Aonuma K, Ikeguchi S, that some doctors stopped prescribing RAA inhibitors for et al. A brief report on the nationwide survey of catheter ablation in secondary prevention of AF after ablation. Prescription of Japan: Japanese Catheter Ablation Registry (JCAR): Part 2 catheter statins, which are another type of agent used for upstream ablation of atrial fibrillation. J Arrhythmia 2012; 28: 202 – 205. therapy of AF,19 also decreased significantly in the third sur- 4. Inoue K, Murakawa Y, Nogami A, Shoda M, Naito S, Kumagai K, et al. National survey of catheter ablation for atrial fibrillation: The vey. Post-procedural OAC is recommended for all patients Japanese catheter ablation registry of atrial fibrillation (J-CARAF). who undergo AF ablation at least 2 months following the J Arrhythmia 2013; 29: 221 – 227. procedure, when the risk of systemic thromboembolism is 5. Ouyang F, Bansch D, Ernst S, Schaumann A, Hachiya H, Chen M, high because of stunned myocardium in the LA after sinus et al. Complete isolation of left atrium surrounding the pulmonary veins: New insights from the double-lasso technique in paroxysmal conversion and injured endocardium due to RF energy deliv- atrial fibrillation. Circulation 2004; 110: 2090 – 2096. ery. In this registry most patients (97%) received OAC agents 6. Yamane T, Date T, Kanzaki Y, Inada K, Matsuo S, Shibayama K, et al. at discharge consistently throughout the period of the registry, Segmental pulmonary vein antrum isolation using the “large-size” lasso despite the relatively low CHADS2 and CHA2DS2-VASc catheter in patients with atrial fibrillation. Circ J 2007; 71: 753 – 760. scores at discharge, possibly because of the recommendation 7. Kumagai K, Muraoka S, Mitsutake C, Takashima H, Nakashima H. A new approach for complete isolation of the posterior left atrium of post-procedural OAC therapy. OAC therapy related to AF including pulmonary veins for atrial fibrillation.J Cardiovasc Elec- ablation, however, especially OAC started after AF ablation trophysiol 2007; 18: 1047 – 1052. procedures, has drastically shifted from VKA to NOAC 8. Inoue K, Kurotobi T, Kimura R, Toyoshima Y, Itoh N, Masuda M, (Figure 2). NOACs have some advantages over VKA such as et al. Trigger-based mechanism of the persistence of atrial fibrillation and its impact on the efficacy of catheter ablation. Circ Arrhythm rapid onset of action, simple dosing, unnecessary dose adjust- Electrophysiol 2012; 5: 295 – 301. ment and monitoring, and minimal food and drug interac- 9. Nakagawa H, Scherlag BJ, Patterson E, Ikeda A, Lockwood D, Jackman tions.20 These advantages provide immediate anticoagulation WM. Pathophysiologic basis of autonomic ganglionated plexus abla- without concern for suboptimal or insufficient effect at the tion in patients with atrial fibrillation. Heart Rhythm 2009; 6: S26 – S34. initiation of use. Although there is a report that recommends 10. Murakawa Y, Nogami A, Shoda M, Inoue K, Naito S, Kumagai K, VKA as a peri-procedural OAC,21 operators preferred NOAC et al. Nationwide survey of catheter ablation for atrial fibrillation: to VKA as peri-procedural OAC agents. The Japanese catheter ablation registry of atrial fibrillation (J-CA-

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RAF): Report on antiarrhythmic drug therapy. J Arrhythmia 2013 Medical University (), Kanazawa University (Kanazawa), Kansai October 21, doi:10.1016/j.joa.2013.08.003. Medical University Hospital (Hirakata), Kansai Rosai Hospital 11. Hayashi T, Kumagai K, Naito S, Goto K, Kaseno K, Ohshima S, et (), Kariya Toyota General Hospital (Kariya), Kawasaki al. Preprocedural therapeutic international normalized ratio influence Municipal Tama Hospital (Kawasaki), Keio University (Tokyo), Kimitsu on bleeding complications in atrial fibrillation ablation with contin- Chuo Hospital (Kisarazu), Kishiwada Tokushukai Hospital (Kishiwada), ued anticoagulation with warfarin. Circ J 2013; 77: 338 – 344. Kitano Hospital (Osaka), Kitasato University (), City 12. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, et al. Medical Center General Hospital (Kobe), Kobe University (Kobe), Kokura Worldwide survey on the methods, efficacy, and safety of catheter abla- Memorial Hospital (Kitakyusyu), Komaki City Hospital (Komaki), Konan tion for human atrial fibrillation. Circulation 2005; 111: 1100 – 1105. Kosei Hospital (Konan), Chuo Hospital (Kumamoto), 13. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, et Central Hospital (Kurashiki), Kushiro Kojinkai Memorial Hospital (Kushiro), al. Updated worldwide survey on the methods, efficacy, and safety Kyorin University (Tokyo), Prefectural University of Medicine of catheter ablation for human atrial fibrillation. Circ Arrhythm Elec- (Kyoto), Kyoto University (Kyoto), Kyoto Katsura Hospital (Kyoto), trophysiol 2010; 3: 32 – 38. Kyushu Kosei Nenkin Hospital (Kitakyusyu), Kyushu Medical Center 14. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, et (Fukuoka), Kyushu University (Fukuoka), Maizuru Kyosai Hospital al. Prevalence and causes of fatal outcome in catheter ablation of (Maizuru), City Hospital (Matsudo), Red Cross Hospital atrial fibrillation. J Am Coll Cardiol 2009; 53: 1798 – 1803. (Matsue), Matsumoto Kyoritsu Hospital (Matsumoto), Mie Chuo Medical 15. Yamashita T, Inoue H, Okumura K, Kodama I, Aizawa Y, Atarashi Center (Tsu), Mie Heart Center (Meiwa), Mie University (Tsu), H, et al. Randomized trial of angiotensin II-receptor blocker vs. di- Medical Association Hospital (Miyazaki), Chuo Hospital (Nagano), hydropiridine calcium channel blocker in the treatment of paroxys- Nagano Red Cross Hospital (Nagano), City East Medical Center mal atrial fibrillation with hypertension (J-RHYTHM-II study). Eu- (Nagoya), Nagoya Daini Red Cross Hospital (Nagoya), Nagoya Ekisaikai ropace 2011; 13: 473 – 479. Hospital (Nagoya), Nagoya University (Nagoya), Hospital Kinki 16. GISSI-AF Investigators, Disertori M, Latini R, Barlera S, Franzosi University Faculty of Medicine (Ikoma), Nara Medical University MG, Staszewsky L, et al. Valsartan for prevention of recurrent atrial (Kashihara), National Cerebral and Cardiovascular Center (), fibrillation.N Engl J Med 2009; 360: 1606 – 1617. National Disaster Medical Center (Tokyo), New Tokyo Hospital (Matsudo), 17. Goette A, Schon N, Kirchhof P, Breithardt G, Fetsch T, Hausler KG, Nihon University (Tokyo), University (Niigata), Nippon et al. Angiotensin II-antagonist in paroxysmal atrial fibrillation Medical School (Tokyo), Cardiovascular Hospital (Odawara), (ANTIPAF) trial. Circ Arrhythm Electrophysiol 2012; 5: 43 – 51. Oe Kyodou Hospital (Yoshinogawa), Ogaki Municipal Hospital (Ogaki), 18. Tayebjee MH, Creta A, Moder S, Hunter RJ, Earley MJ, Dhinoja Ohta Nishinouchi Hospital (Koriyama), Oita Medical Center (Oita), Oita MB, et al. Impact of angiotensin-converting enzyme-inhibitors and University (Oita), Okamura Memorial Hospital (Shimizu), angiotensin receptor blockers on long-term outcome of catheter abla- Medical Center (Okayama), Okayama University (Okayama), Ome tion for atrial fibrillation. Europace 2010; 12: 1537 – 1542. Municipal General Hospital (Tokyo), Osaka City General Hospital 19. Savelieva I, Kakouros N, Kourliouros A, Camm AJ. Upstream ther- (Osaka), Osaka City University (Osaka), Osaka General Medical Center apies for management of atrial fibrillation: Review of clinical evi- (Osaka), Osaka Koseinenkin Hospital (Osaka), Osaka Medical College dence and implications for European Society of Cardiology guide- (), Osaka Police Hospital (Osaka), Osaka Red Cross Hospital lines. Part I: Primary prevention. Europace 2011; 13: 308 – 328. (Osaka), Osaka Rosai Hospital (), Osaka Saiseikai Izuo Hospital 20. Kaseno K, Naito S, Nakamura K, Sakamoto T, Sasaki T, Tsukada N, (Osaka), Osaka University (Osaka), Saiseikai Fukuoka General Hospital et al. Efficacy and safety of periprocedural dabigatran in patients un- (Fukuoka), Saiseikai Futsukaichi Hospital (Chikushino), Saiseikai Kumamoto dergoing catheter ablation of atrial fibrillation. Circ J 2012; 76: 2337 – Hospital (Kumamoto), Medical University International Medical 2342. Center (Kawagoe), Saitama Red Cross Hospital (Saitama), Sakakibara 21. Lakkireddy D, Reddy YM, Di Biase L, Vanga SR, Santangeli P, Heart Institute of Okayama (Okayama), Sakurabashi Watanabe Hospital Swarup V, et al. Feasibility and safety of dabigatran versus warfarin (Osaka), Medical University School of Medicine (Sapporo), Self- for periprocedural anticoagulation in patients undergoing radiofre- Defense Forces Central Hospital (Tokyo), Cardiovascular Center quency ablation for atrial fibrillation: Results from a multicenter (Sendai), Sendai City Hospital (Sendai), Sendai Kousei Hospital (Sendai), prospective registry. J Am Coll Cardiol 2012; 59: 1168 – 1174. Shiga Medical Center for Adults (Moriyama), Shiga University of Medical Science (Otsu), Shimane Prefectural Central Hospital (Izumo), Shinshu University (Matsumoto), Shiroyama Hospital (Habikino), Appendix General Hospital (Shizuoka), Shizuoka Hospital (Shizuoka), This survey was performed with the voluntary support of the JHRS mem- Shizuoka Medical Center (Shizuoka), Shizuoka Saiseikai General Hospital bers. The following centers participated in the survey. (Shizuoka), Shonan Hospital (Okinawa), Shonan Kamakura General Aichi Medical University (Nagakute), Medical Center (Akita), Anjo Hospital (Kamakura), Showa University Fujigaoka Hospital (), Kosei Hospital (Anjo), Medical University (Asahikawa), Showa University School of Medicine (Tokyo), Social Insurance Chukyo Cardiovascular Institute (Tokyo), Edogawa Hospital (Tokyo), Ehime Hospital (Nagoya), St. Marianna University School of Medicine (Kawasaki), University (Touon), EP Expert Doctors Team Tsuchiya (Kumamoto), Surugadai Nihon University Hospital (Tokyo), Takai Hospital (Tenri), Fujita Health University (Toyoake), Cardiovascular Center (Fukui), Takase Clinic (), Takeda Hospital (Kyoto), Teine Keijinkai Fukui Prefectural Hospital (Fukui), Fukuoka Sanno Hospital (Fukuoka), Hospital (Sapporo), Tenri Hospital (Tenri), Toho University Ohashi Fukuyama Cardiovascular Hospital (Fukuyama), Gakkentoshi Hospital Medical Center (Tokyo), Toho University Omori Medical Center (Tokyo), (Seika), Prefectural General Medical Center (Gifu), Gifu University Tohoku University Hospital (Sendai), Tokai University Hachioji Hospital (Gifu), Gunma Prefectural Cardiovascular Center (Maebashi), Gunma (Tokyo), Red Cross Hospital (Komatsushima), Tokuyama University (Maebashi), Medical Center (Hamamatsu), Central Hospital (Tokuyama), Tokyo Medical and Dental University Hamamatsu University School of Medicine (Hamamatsu), Hayama Heart (Tokyo), Tokyo Medical University (Tokyo), Tokyo Metropolitan Hiroo Center (Hayama), Higashisumiyoshi Morimoto Hospital (Osaka), Hospital (Tokyo), Tokyo Rinkai Hospital (Tokyo), Tokyo Women’s Kyosai Hospital (Hiratsuka), Hirosaki University (Hirosaki), Medical University (Tokyo), Tominaga Hospital (Osaka), Tomishiro City Hospital (Hiroshima), Hiroshima Prefectural Hospital (Hiroshima), Central Hospital (Tomishiro), Toshiba Rinkan Hospital (Sagamihara), Cardiovascular Hospital (Sapporo), Hokkaido Medical Center Prefectural Central Hospital (Tottori), Prefectural Central (Sapporo), Hokkaido Social Insurance Hospital (Sapporo), Hokkaido Hospital (Toyama), Toyama University (Toyama), Heart Center University (Sapporo), Hokko Memorial Hospital (Sapporo), Hyogo Brain (Toyohashi), Toyota Kosei Hospital (Toyota), Tsuchiura Kyodo General and Heart Center (), Hyogo College of Medicine (), Hospital (Tsuchiura), Tsukuba Memorial Hospital (Tsukuba), University Ichinomiyanishi Hospital (Ichinomiya), IMS Heart Center of Occupational and Environmental Health (Kitakyusyu), University of (Tokyo), Ishikawa Prefectural Central Hospital (Kanazawa), Itabashi Tokyo (Tokyo), University of Tsukuba (Tsukuba), Yamagata University Chuo Medical Center (Tokyo), Japanese Red Cross Kumamoto Hospital (Yamagata), University (Ube), Yamanashi Kosei Hospital (Kumamoto), Japanese Red Cross Kyoto Daini Hospital (Kyoto), Japanese (Yamanashi), Yamato Kashihara Hospital (Kashihara), Yokohama City Red Cross Medical Center (Wakayama), Jichi Medical Minato Red Cross Hospital (Yokohama), Yokohama General Hospital University School of Medicine (Tokyo), Jikei University (Tokyo), Kagawa (Yokohama), Yokohama Minami Kyosai Hospital (Yokohama), Yokohama Prefectural Shirotori Hospital (Higashikagawa), Medical Rosai Hospital (Yokohama), Kyosai Hospital (Yokosuka). Center (Kagoshima), Kameda Medical Center (Kamogawa), Kanazawa

Circulation Journal Vol.78, May 2014