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Does Location of Epicardial Adipose Tissue Correspond to Endocardial High Dominant Frequency or Complex Fractionated Atrial Electrogram Sites During Atrial Fibrillation? Koichi Nagashima, MD; Yasuo Okumura, MD; Ichiro Watanabe, MD; Toshiko Nakai, MD; Kimie Ohkubo, MD; Masayoshi Kofune, MD; Hiroaki Mano, MD; Kazumasa Sonoda, MD; Takafumi Hiro, MD; Mizuki Nikaido, BE; Atsushi Hirayama, MD Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 Background—Although increased epicardial adipose tissue (EAT) volume is known to be associated with increased prevalence of atrial fibrillation (AF), the exact mechanisms are unclear. Therefore, we investigated whether EAT locations were associated with high dominant frequency (DF) sites or complicated fractionated atrial electrogram sites during AF. Methods and Results—Three-dimensional reconstruction computed tomography images depicting EAT volumes (obtained by 320-detector-row multislice computed tomography) were merged with NavX-based DF and complicated fractionated atrial electrogram maps obtained during AF for 16 patients with paroxysmal AF and for 18 patients with persistent AF. Agreement between locations of the EAT, especially EAT surrounding the left atrium, and of high DF or complicated fractionated atrial electrogram sites was quantified. In addition, serum biomarker levels were determined. EAT surrounding the left atrium volumes was significantly greater in patients with persistent AF than in patients with paroxysmal AF (52.9 cm3 [95% CI, 44.2–61.5] versus 34.8 cm3 [95% CI, 26.6–43.0]; P=0.007). Serum high-sensitivity C-reactive protein and interleukin-6 levels were significantly higher in persistent AF patients than in paroxysmal AF patients (median highsensitivity C-reactive protein, 969 ng/mL [interquartile range, 307–1678] versus 320 ng/mL [interquartile range, 120– 660]; P=0.008; median interleukin-6, 2.4 pg/mL [interquartile range, 1.7–3.2] versus 1.3 [interquartile range, 0.8–2.4] pg/mL; P=0.017). EAT locations were in excellent agreement with high DF sites (κ=0.77 [95% CI, 0.71–0.82]) but in poor agreement with complicated fractionated atrial electrogram sites (κ=0.22 [95% CI, 0.13–0.31]). Conclusions—Increased EAT volume and elevation of inflammatory biomarkers are noted in persistent AF rather than paroxysmal AF patients. High DF sites are located adjacent to EAT sites. Thus, EAT may be involved in the maintenance of AF. (Circ Arrhythm Electrophysiol. 2012;5:676-683.) Key Words: atrial fibrillation ◼ dominant frequency ◼ complex fractionated atrial electrogram ◼ epicardial adipose tissue O ver the past decade, catheter-based pulmonary vein isolation (PVI) has become a widely accepted therapy for patients with symptomatic drug-refractory paroxysmal atrial fibrillation (PAF).1 Termination of persistent AF (PerAF), however, often requires extensive ablation, including ablation at complex fractionated atrial electrogram (CFAE) sites and high dominant frequency (DF) sites and multiple linear ablation in addition to PVI.2–4 There have been numerous reports regarding the role of CFAEs and high DFs in the maintenance of AF. CFAEs are now considered to be a result of dyssynchronous activation of separate cell groups at pivot points or of wave collision, far-field potentials, or repetitive activations of the AF driver(s) or local reentry circuit,5–7 whereas high DF is reported to be related to the center of a focal-firing rotor or local reentry circuit.8 Editorial see p 618 Clinical Perspective on p 683 Association of AF with metabolic syndrome and inflammation is well established.9,10 Recent studies have shown that increased epicardial adipose tissue (EAT) volume is associated with increased prevalence of AF and that EAT volume can predict the development of AF.11–14 EAT is known to secrete several activated proinflammatory cytokines, such as tumor necrosis factor-α, transforming growth factor-β, and interleukin-6 (IL-6).15,16 Nevertheless, the exact role of EAT in the maintenance of AF is unclear. Hypothesizing that delineation of the distribution of EAT around the left atrium (LA), PVs, and CFAE and high DF sites would provide insight Received January 31, 2012; accepted June 4, 2012. From the Division of Cardiology, Department of Medicine, Nihon University School of Medicine (K.N., Y.O., I.W., T.N., K.O., M.K., H.M., K.S., T.H., A.H.); and Nihon Kohden Co, Ltd (M.N.), Tokyo, Japan. Correspondence to Yasuo Okumura, MD, Division of Cardiology, Department of Medicine, Nihon University School of Medicine, 30-1 Ohyaguchikamicho, Itabashi-ku, Tokyo 173–8610, Japan. E-mail [email protected] © 2012 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org 676 DOI: 10.1161/CIRCEP.112.971200 Nagashima et al Epicardial Adipose Tissue and DF 677 into the mechanism responsible for maintenance of AF, we investigated whether EAT locations correspond to high DF or CFAE sites during AF. Methods Study Patients Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 The study involved 34 consecutive patients (29 men, 5 women; mean age, 56±13 years) scheduled for first catheter ablation of AF. Sixteen of these patients had PAF (ie, AF lasting <7 days), and 18 had PerAF (ie, AF lasting >7 days). No patients with congestive heart failure or a history of ischemic heart disease, cardiomyopathy, valvular heart disease, or congenital heart disease were included. All patients provided written informed consent for electrophysiological study and ablation procedures. Adequate oral anticoagulation therapy was given for at least 1 month before the ablation procedure, and all antiarrhythmic drugs were discontinued for at least 5 half-lives before the procedure. On admission, a medical history was obtained, and physical examination, 12-lead electrocardiography, chest x-ray, and transesophageal and transthoracic echocardiography were performed; values obtained were considered baseline values. The study was approved by the Institutional Review Board of Nihon University Itabashi Hospital, and all patients provided written informed consent for their participation. Hematologic Measurements Blood samples were obtained from a femoral vein before ablation in the electrophysiological laboratory. Serum hemoglobin A1c, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were measured. Specific biomarkers related to AF17–20 were measured: serum high-sensitivity C-reactive protein (hs-CRP) by particle-enhanced immunonephelometry (Behring Nephelometer II; Siemens Healthcare Diagnostics, Eschborn, Germany), serum IL-6 by ELISA (with a commercially available kit from Fujirebio Inc, Tokyo, Japan), and serum matrix metalloproteinase-2 (MMP-2) by 1-step sandwich enzyme immunoassay (with a commercially available kit from Daiichi Fine Chemical Co, Ltd, Toyama, Japan). Echocardiographic Evaluation In all patients, transthoracic echocardiography was performed 1 day before ablation with an ACUSON Sequoia C256 echocardiography system (Siemens Medical Solutions USA, Inc, Malvern, PA). Maximum LA volume was calculated by the prolate ellipsoid method,21 and left ventricular ejection fraction was assessed in the parasternal long-axis view by the Teichholz method. Measurements from 3 consecutive beats were averaged. Electrophysiological Study Electrophysiological study was performed with patients under conscious sedation achieved with propofol and fentanyl. After vascular access was obtained, single transseptal puncture was performed, and intravenous heparin was administered to maintain an activated clotting time >300 seconds. After 3 long sheaths (2 SL0 sheaths and 1 SL1 sheath; St. Jude Medical Inc, St. Paul, MN) were inserted into the LA via transseptal puncture, 3-dimensional (3D) geometry of the LA and the 4 PVs was reconstructed with an EnSite NavX mapping system (St. Jude Medical Inc, Minneapolis, MN) from data obtained with a 20-pole circular mapping catheter (1.5-mm interelectrode distance; Livewire Spiral HP catheter; St. Jude Medical). CFAE and Fast-Fourier Transform Analyses For CFAE and fast-Fourier transform analyses, bipolar signals from the mapping catheter were acquired during AF and filtered between 30 and 500 Hz. If patients were in sinus rhythm, AF was induced by decremental atrial pacing, and analysis was done after a 5-minute stabilization period of the AF rhythm. Bipolar signals were recorded from the 4 PVs; the antra of each PV; the anterior, posterior, and septal surfaces and roof and floor of the LA; the mitral annulus; and the LA appendage (LAA). The NavX mapping parameters were set to CFE-mean, by which an interval-analysis algorithm is used to measure the average index of the fractionation at each site, and a color map of the fractionation interval (CFAE map) was constructed. The fractionation interval was defined as the average time interval between consecutive deflections during a 5-second recording period. The settings included a refractory period of 40 ms, a peak-to-peak sensitivity between 0.05 mV and 0.1 mV, and a duration of 10 ms. Continuous CFAEs were defined as having a mean fractionation interval <50 ms and variable CFAEs as having a fractionation interval of 50 to 120 ms.22–24 For fast-Fourier transform analysis, DF Figure 1. Twenty-two segments of the left atrium and pulmonary veins (PVs) for quantitative assessment of the distribution of epicardial adipose tissue, high-dominant frequency sites, and complex fractionated atrial electrograms. LSPV indicates left superior PV; LIPV, left inferior PV; RSPV, right superior PV; RIPV, right inferior PV; LAA, left atrial appendage; MV, mitral valve; AP, anteroposterior; PA, posteroanterior; RAO, right anterior oblique; LAO, left anterior oblique. 678 Circ Arrhythm Electrophysiol August 2012 distribution was analyzed, and a DF map was constructed by means of DF software installed in the NavX mapping system (sampling rate 1200 Hz, resolution 0.14 Hz, with a Hamming window function).22,23 The bipolar signals obtained from the 5-second recording were analyzed, and the highest peak frequency of the resulting spectrum was identified as the DF. On the DF map produced by the NavX system, a high DF site was defined as a site with a frequency >8 Hz and colored bright purple.25 Multidetector Computed Tomography and EAT Measurements Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 Details of EAT detection have been described previously.11 In brief, EAT volume was calculated from noncontrast images obtained with a 3D spiral computed tomography (CT) scanner (320-row detector, dynamic volume CT scanner; Aquilion ONE, Toshiba Medical Systems, Tokyo, Japan; 0.35-second gantry rotation time, 120 kV, and 350–450 mA) within 1 week before PVI. Gated studies were performed under an ECG-triggered scanning protocol. To minimize motion artifacts, patients were given β-blockers and underwent CT scanning only if their heart rate was >80 beats per minute. On a workstation (ZIO M900 QUADRA; Amin Co, Ltd, Tokyo, Japan), total EAT was detected by assigning Hounsfield units ranging from −50 to −200 to fat, and the total EAT volume was semiautomatically reconstructed from contiguous 0.5-mm slices of axial images from the bifurcation of the pulmonary artery to the diaphragm. Thereafter, the volume of EAT surrounding the LA (LA-EAT) was manually segmented from the total EAT, ie, it was obtained by deleting EAT volume from the left ventricular side anterior to the mitral annulus and the right atrial side anterior to the right superior PV and then from the lower side of the coronary sinus from the total EAT, leaving the EAT surrounding the LA. In addition, axial CT images were transferred to the NavX mapping system equipped with NavX system image integration software (EnSite Verismo; St. Jude Medical).26 The surface reconstruction of LA plus PV volume was segmented from each chamber of interest. LA-EAT was also segmented and reconstructed after detection by assignment of Hounsfield units from −50 to −200. Quantitative Assessment of Distributions of EAT, High DF Sites, and CFAEs 3D LA and LA-EAT CT images were merged with NavX-based DF and CFAEs maps during AF, as previously reported.26 Thereafter, we divided the PVs and LA into 15 segments: the 4 PVs; the antra of each PV; the anterior, posterior, and septal surfaces and roof and floor of the LA; the mitral isthmus; and the LAA, as shown in Figure 1. The presence of EAT, high DF sites, and CFAE sites in the PVs and LA segments was assessed, and the correspondence between the EAT locations and the high DF and CFAE sites was quantified. Statistical Analysis Continuous variables are expressed as the mean and 95% CI. Distributions of the serum triglyceride, hs-CRP, and IL-6 levels were skewed and are, therefore, expressed as median and interquartile ranges; Mann-Whitney U test was used to analyze differences in these variables between patients with PAF and those with PerAF. Because the other continuous variables (including baseline values, κ values, total agreement of EAT with high DF/CFAE, and DF/CFAE values) were normally distributed, absolute differences (along with 95% CIs) were calculated and analyzed by Student t test. Fisher exact probability test was used to compare the distribution of dichotomous variables between PAF and PerAF patients. Simple linear regression analysis was performed to test the correlation of total EAT and LA-EAT with hs-CRP. Bland and Altman plots with 95% limits of agreement were used to assess interobserver and intraobserver reproducibility of EAT measurements. Agreement between the location of EAT and the high DF and CFAE sites in the 15 LA and PV segments was assessed by κ statistic, which was calculated by subtracting the proportion of the readings expected to agree by chance, which we called Pe, from the overall agreement, Po, and dividing the remainder by the number Table 1. Demographics and Baseline Values in Overall Patient Series and Per Study Group Variable Total Patients (n=34) PAF Group (n=16) PerAF Group (n=18) P Value (PAF vs PerAF) Age, y 56 (51–60) 55 (47–62) 56 (50–63) 0.73 Sex: male (%) 29 (85) 14 (88) 15 (83) 1.0 BMI, kg/m2 23.3 (22.2–24.4) 22.2 (20.6–23.9) 7 (44) 24.2 (22.7–25.8) 7 (39) 0.07 Hypertension (%) 14 (41) HbA1c, % 5.4 (5.2–5.5) 5.3 (5.1–5.5) 5.5 (5.2–5.8) 1.0 0.28 HDL-C, mg/dL 59 (52–65) 64 (55–73) 54 (45–64) 0.12 LDL-C, mg/dL 113 (104–121) 119 (106–131) 107 (94–120) 0.18 Triglyceride, mg/dL 130 (99–157) 122 (66–151) 144 (113–165) 0.16 LAV, mL 41.4 (33.9–48.8) 38.1 (30.5–45.7) 46.5 (34.2–58.8) 0.24 LVEF, % 64.5 (61.7–67.4) 65.4 (62.7–68.1) 63.7 (58.6–68.8) 0.56 173.2 (151.5–194.8) 148.7 (119.9–177.6) 194.9 (164.2–225.5) 0.028 44.4 (37.4–51.3) 34.8 (26.6–43.0) 52.9 (44.2–61.5) 0.007 hs-CRP, ng/mL 500 (216–1280) 320 (120–660) 969 (307–1678) 0.008 IL-6, pg/mL 2.0 (1.0–2.9) 1.3 (0.8–2.4) 2.4 (1.7–3.2) 0.017 MMP-2, ng/mL 759 (712–807) 702 (645–759) 810 (739–881) 0.019 Echocardiographic measures EAT Total EAT, cm3 LA-EAT, cm3 Biomarkers of AF PAF indicates paroxysmal atrial fibrillation; PerAF, persistent AF; BMI, body mass index; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LAV, left atrial volume; LVEF, left ventricular ejection fraction; EAT, epicardial adipose tissue; LA-EAT, left atrium EAT; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; MMP-2, matrix metalloproteinase-2. Values shown are mean (95% CI), median (25th percentile, 75th percentile), or n (%). Nagashima et al Epicardial Adipose Tissue and DF 679 of cases in which agreement was not expected to occur by chance: κ=(Po−Pe)/(1−Pe). Kappa statistic values range from −1.0 to +1.0, with 0 indicating chance agreement and +1.0 indicating perfect agreement. κ>0.75 implies excellent agreement, values 0.40 to 0.75 suggest fair-to-good agreement, and values <0.4 imply poor agreement.27 P<0.05 was considered statistically significant. All statistical analyses except derivation of the κ statistics were performed with JMP 8 software (SAS Institute, Cary, NC). Results Baseline Characteristics, Biomarker Levels, and Echocardiographic Features of PAF and PerAF Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 Patients’ baseline characteristics, laboratory values, and echocardiographic features of PAF and PerAF are shown in Table 1. There were no differences in baseline characteristics, standard blood chemistry values, or echocardiographic LA volume and left ventricular ejection fraction between the 2 groups. EAT volumes were significantly greater in patients with PerAF than in those with PAF (total EAT, 194.9 cm3 [95% CI, 164.2–225.5] versus 148.7 cm3 [95% CI, 119.9–177.6]; absolute difference, 46.1 cm3 [95% CI, 5.4–86.9]; P=0.028; LA-EAT, 52.9 cm3 [95% CI, 44.2–61.5] versus 34.8 cm3 [95% CI, 26.6–43.0]; absolute difference, 18.1 cm3 [95% CI, 5.4–30.7]; P=0.007). Serum hs-CRP, IL-6, and MMP-2 levels were significantly higher in patients with PerAF than in those with PAF (hs-CRP, 969 ng/mL [307–1678] versus 320 ng/mL [120–660]; P=0.008; IL-6, 2.4 pg/mL [1.7–3.2] versus 1.3 pg/mL [0.8–2.4]; P=0.017; MMP-2, 810 ng/mL [95% CI, 739–881] v ersus 702 ng/mL [95% CI, 645–759]; absolute difference, 108 ng/mL [95% CI, 19–197]; P=0.019). In addition, the correlations between EAT volumes and hsCRP levels were as follows: r=0.57, P=0.0005 for total EAT; r=0.55, P=0.0009 for LA-EAT. Reproducibility of the EAT Measurements EAT volume was measured by 2 independent operators. Interobserver reproducibility was high according to Bland and Altman analysis, with bias of 1.8 cm3 and 95% CI for the estimate of the bias of −0.9 to 4.6 for total EAT and bias of 0.7 cm3 and 95% CI of −1.2 to 2.5 for LA-EAT. Intraobserver reproducibility was also high, with bias of 0.1 cm3 and 95% CI of −2.3 to 2.6 for total EAT and bias of 0.9 cm3 and 95% CI of −2.0 to 0.1 for LA-EAT. Relationships Between Location of EAT and High DF and CFAE Sites Before PVI, 343±98 data points per patient were acquired for the creation of NavX-based LA and PV maps. Representative examples of a DF map and a CFAE map merged with EAT are shown in Figure 2. The incidences of EAT, Figure 2. A representative case of paroxysmal atrial fibrillation showing the distribution of epicardial adipose tissue (EAT), high-dominant frequency (DF) sites, and complex fractionated atrial electrogram (CFAE) sites on NavX maps. On the DF map, the areas in bright purple are defined as the high DF sites with a frequency of >8 Hz. Whereas on the CFAE map, the white areas are defined as continuous CFAEs with a mean fractionation interval (FI) <50 ms, and the areas in red, orange, yellow, green, or blue are variable CFAEs having an FI of 50 to 120 ms. Note that EAT is located at the anterior portion of the right superior pulmonary vein (PV) and left superior PV, antra of 4 PVs, roof and floor of the left atrium (LA), mitral isthmus, LA appendage; these locations are adjacent to the high DF sites rather than the CFAE sites. CFE indicates complex fractionated electrogram. 680 Circ Arrhythm Electrophysiol August 2012 Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 high DF, and CFAE at each LA/PV segment are shown in Table 2. The incidences of EAT were >60% at the antra of the left superior PV, left inferior PV, and right superior PV; the anterior surface, roof, and floor of the LA; the mitral isthmus; and the LAA. Similarly, high DF sites were often located at the antra of each PV; the anterior surface, roof, and floor of the LA; the mitral isthmus; and the LAA. In contrast, CFAEs were often located at the antra of each PV and throughout the LA body (roof, floor, septal portion, anterior and posterior surfaces of the LA, and the LAA). Most high DF sites corresponded to the EAT sites; the CFAE sites did not correspond as frequently with the EAT sites (Table 2). Overall, the average total agreement of EAT with high DFs in LA/PV segments was significantly higher than that of EAT with CFAEs (90.0% [95% CI, 87.5–92.5] versus 68.4% [95% CI, 63.0–73.8]; absolute difference, 21.6% [95% CI, 16.6–26.6]; P<0.0001). There was also excellent agreement between EAT locations and high DF sites (κ=0.77 [95% CI, 0.71–0.82]), but there was poor agreement between EAT locations and CFAE sites (κ=0.22 [95% CI, 0.13–0.31]). When comparing the prevalence with the total agreement of EAT and high DFs or CFAEs between PAF and PerAF patients, no difference per segment was noted according to Fisher exact probability test (Tables 3 and 4). In fact, the good agreement between EAT locations and high DF sites and the poor agreement between EAT locations and CFAE sites were similar between PAF and PerAF patients (high DF sites, κ=0.75 [95% CI, 0.68–0.82] versus 0.78 [95% CI, 0.69–0.87], respectively; absolute difference, 0.03 [95% CI, −0.08 to 0.15]; P=0.58; CFAEs, κ=0.21 [95% CI, 0.06–0.36] versus 0.23 [95% CI, 0.10–0.36], respectively; absolute difference, 0.02 [95% CI, −0.17 to 0.21]; P=0.82). DFs and CFAEs With and Without EAT Mean DF in each LA/PVs segment corresponding to an EAT site was significantly greater than mean DF in segments without EAT (8.6 Hz [95% CI, 8.4–8.7] versus 6.4 Hz [95% CI, 6.2–6.5]; absolute difference, 2.2 Hz [95% CI, 2.0–2.5]; P<0.0001). Mean CFE-mean value at each atrial segment corresponding to an EAT site was significantly shorter than at segments without EAT (95 ms [95% CI, 90–100] versus 127 ms [95% CI, 119–136]; absolute difference, 32 ms [95% CI, 23–42]; P<0.0001). Discussion Major Findings We quantified EAT of the LA and PVs in patients with AF and evaluated its specific distribution. PerAF patients, in comparison with PAF patients, were shown to have increased total EAT and LA-EAT volumes and elevated biomarkers of inflammation and collagen turnover. High DF sites, rather than CFAE sites, corresponded to the EAT sites, and this overlap between EAT and high DF sites was observed in both PAF and PerAF patients. Presence of EAT and Its Influence on AF EAT was observed most often at the antra of the left superior PV, left inferior PV, and right superior PV; the anterior surface, roof, and floor of the LA; the mitral isthmus; and the LAA, and these sites corresponded to the high DF sites rather than the CFAE Table 2. Segmental Distribution of EAT, High DFs, and CFAEs and Total Agreement in Distribution Among Total Patients (n=34) High DFs Sensitivity, % Specificity, % CFAEs Segment EAT (%) Presence (%) Total Agreement With EAT (%) Presence (%) Sensitivity, % Specificity, % Total Agreement With EAT, (%) LSPV 15 (44) 16 (47) 81 89 29 (85) 13 (38) 62 67 22 (65) LSPV antrum 23 (68) 22 (65) 83 73 27 (79) 26 (76) 83 36 23 (68) LIPV 20 (59) 20 (59) 100 100 34 (100) 12 (35) 83 50 21 (62) LIPV antrum 27 (79) 24 (71) 89 100 31 (91) 21 (62) 67 57 22 (65) RSPV 18 (53) 16 (47) 100 89 32 (94) 12 (35) 67 55 20 (59) RSPV antrum 28 (82) 23 (68) 82 100 29 (85) 25 (74) 79 50 25 (74) RIPV 10 (29) 10 (29) 100 100 34 (100) 9 (26) 78 88 29 (85) RIPV antrum 26 (34) 24 (71) 92 100 32 (94) 26 (76) 81 38 24 (71) LA roof 33 (97) 31 (91) 100 25 31 (91) 27 (79) 100 14 28 (82) LA septum 17 (50) 20 (59) 85 100 31 (91) 27 (79) 48 43 16 (47) LA anterior 23 (68) 23 (68) 100 100 34 (100) 27 (79) 74 57 24 (71) LA posterior 16 (47) 19 (56) 74 87 27 (79) 31 (91) 48 67 17 (50) LA floor 27 (79) 26 (76) 100 88 33 (97) 31 (91) 77 0 24 (71) Mitral isthmu 33 (97) 28 (82) 100 17 29 (85) 25 (74) 96 0 24 (71) LAA 34 (100) 25 (74) 74 NA 25 (74) 30 (88) 89 NA 30 (88) EAT indicates epicardial adipose tissue; DF, dominant frequency; CFAEs, complex fractionated atrial electrograms; LSPV, left superior pulmonary vein; LIPV, left inferior PV; RSPV, right superior PV; RIPV, right inferior PV; LA, left atrium; LAA, LA appendage. Agreement with EAT, correspondence between EAT distribution and high DF and CFAE distributions in each LA/PV segment. The numbers and percentages of the patients are shown. The presence, patient number, and percentage of patient numbers divided by 34 total patients with high DFs or CFAEs in each segment are given. Nagashima et al Epicardial Adipose Tissue and DF 681 Table 3. Segmental Distribution of EAT, High DFs, and CFAEs and Total Agreement in Distribution Among PAF Patients (n=16) High DFs Segment EAT (%) Presence (%) Sensitivity, % Specificity, % CFAEs Total Agreement With EAT (%) Presence (%) Sensitivity, % Specificity, % Total Agreement With EAT (%) LSPV 7 (44) 6 (38) 83 80 13 (81) 6 (38) 50 60 9 (56) LSPV antrum 9 (56) 10 (63) 89 71 13 (81) 14 (88) 100 29 11 (69) LIPV 8 (50) 8 (50) 100 100 16 (100) 4 (25) 50 50 8 (50) 12 (75) 12 (75) 100 100 16 (100) 10 (63) 67 50 10 (63) 6 (38) 4 (25) 100 83 14 (88) 7 (44) 43 67 9 (56) 12 (75) 8 (50) 67 100 12 (75) 13 (81) 83 25 11 (69) 6 (38) 6 (38) 100 100 16 (100) 5 (31) 100 91 15 (94) LIPV antrum RSPV RSPV antrum anterior RIPV RIPV antrum anterior 12 (75) 12 (75) 100 100 LA roof 16 (100) 15 (94) 100 0 16 (100) 11 (69) 75 50 11 (69) 14 (88) 12 (75) 100 0 12 (75) LA septum 9 (56) 11 (69) 82 100 14 (88) 13 (81) 54 33 8 (50) LA anterior 12 (75) 12 (75) 100 100 16 (100) 14 (88) 79 50 12 (75) Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 5 (31) 6 (38) 67 90 13 (81) 15 (94) 33 100 6 (38) LA floor 11 (69) 10 (63) 100 83 15 (94) 15 (94) 67 0 10 (63) Mitral isthmus 15 (94) 12 (75) 100 25 13 (81) 13 (81) 92 0 12 (75) LAA 16 (100) 11 (69) 69 NA 11 (69) 14 (88) 88 NA 14 (88) LA posterior The presence, patient number, and percentage of patient numbers divided by 16 PAF patients with high DFs or CFAEs in each segment are given. EAT indicates epicardial adipose tissue; DF, dominant frequency; CFAEs, complex fractionated atrial electrograms; PAF, paroxysmal atrial fibrillation; LSPV, left superior pulmonary vein; LIPV, left inferior PV; RSPV, right superior PV; RIPV, right inferior PV; LA, left atrium; LAA, LA appendage. sites. Recently, CFAEs have been thought to represent localized reentry, AF drivers, wavefront collision, and conduction through channels of functional block and pivot points.7 In contrast, high DF sites indicate local synchronous high-frequency activations that are likely to be closely linked to localized reentry or the AF driver(s).8 Detailed analysis of the NavX-based DF and CFAE maps showed that most CFAE activity occurred near a high DF site and that the cores of the widely distributed continuous CFAEs sites correlated with the high DF sites.23 Therefore, overlap between the locations of EAT and the high DF sites implies that EAT is most likely to harbor high-frequency sites, producing a favorable condition for maintenance of AF. Two potential mechanisms explaining the correspondence between EAT and high DF sites can be considered. Table 4. Segmental Distribution of EAT, High DFs, and CFAEs and Total Agreement in Distribution Among PerAF Patients (n=18) High DFs Segment LSPV LSPV antrum EAT (%) Presence (%) Sensitivity, % Specificity, % CFAEs Total Agreement With EAT (%) Presence (%) Sensitivity, % Specificity, % Total Agreement With EAT (%) 8 (44) 10 (56) 80 100 16 (89) 7 (39) 71 73 13 (72) 14 (78) 12 (67) 79 75 14 (78) 12 (67) 71 50 12 (67) LIPV 12 (67) 12 (67) 100 100 18 (100) 8 (44) 100 50 13 (72) LIPV antrum 15 (83) 12 (67) 80 100 15 (83) 11 (61) 67 67 12 (67) RSPV 12 (67) 12 (67) 100 100 18 (100) 5 (28) 100 46 11 (61) RSPV antrum 16 (89) 15 (83) 94 100 17 (94) 12 (67) 75 100 14 (78) 4 (22) 4 (22) 100 100 18 (100) 4 (22) 50 86 14 (78) RIPV antrum RIPV 14 (78) 12 (67) 86 100 16 (89) 15 (83) 86 25 13 (72) LA roof 17 (94) 16 (89) 100 50 17 (94) 15 (83) 100 33 16 (89) 8 (44) 9 (50) 89 100 17 (94) 14 (78) 43 50 8 (44) 12 (67) LA septum LA anterior 11 (61) 11 (61) 100 100 18 (100) 13 (72) 69 60 LA posterior 11 (61) 13 (72) 77 80 14 (78) 16 (89) 63 50 11 (61) LA floor 16 (89) 16 (89) 100 100 18 (100) 16 (89) 88 0 16 (89) Mitral isthmus 18 (100) 16 (89) 100 0 16 (89) 12 (67) 100 0 12 (67) LAA 18 (100) 14 (78) 78 NA 14 (78) 16 (89) 89 NA 16 (89) The presence, patient number, and percentage of patient numbers divided by 18 PerAF patients with high DFs or CFAEs in each segment are given. EAT indicates epicardial adipose tissue; DF, dominant frequency; CFAEs, complex fractionated atrial electrograms; PerAF, persistent atrial fibrillation; LSPV, left superior pulmonary vein; LIPV, left inferior PV; RSPV, right superior PV; RIPV, right inferior PV; LA, left atrium; LAA, LA appendage. 682 Circ Arrhythm Electrophysiol August 2012 Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 First, several activated proinflammatory cytokines are secreted from the EAT.15,16 Its proximity to atria without fascial boundaries and its blood supply from the coronary arteries suggest that EAT may interact locally with atrial myocardium through endocrine and paracrine secretion of proinflammatory cytokines.11–16 In fact, levels of serum inflammatory cytokines, such as hs-CRP and IL-6, were higher in our PerAF patients having a greater EAT volume than in our PAF patients. These cytokines released from EAT may change the electrophysiological characteristics of atrial and PV cardiomyocytes, which in turn may be the substrate for development of high DF sites, leading to the progression of AF.28 It was previously reported that serum MMP-2 is implicated in atrial remodeling.20 The MMP-2 level was higher in our PerAF patients than in our PAF patients. This increased MMP-2 level in patients with greater EAT volume supports contribution of EAT to the progression of atrial remodeling. The second possibility is the relationship between ganglionated plexi (GP) and AF. EAT contains abundant GP, which are a critical element responsible for the initiation and maintenance of AF.29 The GPs are located at the LA roof, medial to the left superior PV and often extending to the medial aspect of the LAA (left superior GP), the anterior portion to the right superior PV and often extending from the anterior region to the right inferior PV (right anterior GP), the inferior portions of the left and right inferior PVs (left inferior GP and right inferior GP), and within the ligament of Marshall (Marshall tract GP).29 We found total agreement between high DF and EAT to be >80% at 4 PVs and their antra except left superior PV, the anterior surface, the septal portion, roof, and floor of the LA, and the mitral isthmus. Notably, these sites corresponded to the locations of GP. GP activation includes both parasympathetic and sympathetic stimulation of the atria/ PVs adjacent to the GP. Parasympathetic stimulation shortens the action potential duration, and sympathetic stimulation increases calcium loading and calcium release from the sarcoplasmic reticulum. The combination of the short action potential duration and longer calcium release induces triggered firing resulting from delayed afterdepolarization of the atria/ PVs adjacent to the GP as manifested by the high DF sites. Overlap between EAT and high DF locations was seen in both the PAF and PerAF groups, indicating that cytokine secretion or GP firing from EAT may be related to maintenance of AF, regardless of the AF type. This agrees with the fact that extensive PVI and CFAE/DF-based substrate modification is clinically effective not only for PAF, but also for PerAF; extensive circumferential PV isolation and ablation target sites for substrate modification include most of the EAT or GP sites.29 Study Limitations Several study limitations must be considered. First, the study involved a relatively small number of patients. We, therefore, meticulously analyzed the distribution of EAT, high DF sites, and CFAE sites on NavX maps by acquiring a large number of data points. Second, the automatic CFE-mean algorithm is a specific method for detecting CFAEs available only on the NavX system. However, the algorithm has been confirmed by catheter ablation results in many reports.22 Third, we do not have sufficient data to show that the high DFs are generated directly by the EAT, proinflammatory cytokines secreted locally from the EAT, or migration of the axon to the atrium from the epicardial GPs. It is difficult to confirm a causal relationship between EAT and high DFs on the basis of clinical observations. Finally, we did not assess the relationships between EAT and mapped DF and CFAE sites after PVI. The circumferential lesions of our extensive PVI-based catheter ablation cover several high DF sites adjacent to EAT, and this hinders us in clarifying the influence of EAT on the electrophysiological properties of the LA body in AF. Conclusions Increased EAT volume and elevated biomarkers of inflammation and collagen turnover are noted in PerAF patients compared with the measurements in PAF patients. High DF sites are located adjacent to EAT sites. Thus, EAT may be involved in the maintenance of AF. Disclosures None. References 1. 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J Cardiovasc Electrophysiol. 2009;20:1186–1189. CLINICAL PERSPECTIVE Numerous studies have shown that increased epicardial adipose tissue (EAT) volume is associated with an increased prevalence of atrial fibrillation (AF) and that EAT volume can predict the development of AF. Indeed, EAT is a source of several inflammatory mediators, which might be linked to the development of AF. However, the mechanisms for how EAT impacts the atria remain unclear. High dominant frequency (DF) and complex fractionated atrial electrogram sites are well known to be key electrophysiological parameters reflecting microreentrant circuits or sites of focal-firing that drive AF. These parameters are often used by electrophysiologists as electrogram-based target sites for AF ablation. Hypothesizing that EAT might promote high DF and complex fractionated atrial electrogram sites, we sought to investigate whether EAT locations correspond to high DF or complex fractionated atrial electrogram sites during AF through a unique 3-dimentional merge process, ie, the NavX-based complex fractionated atrial electrogram and DF left atrial map with 3-dimensional reconstructed EAT. The present study found a good association between high DF sites during AF and the distribution of EAT. Furthermore, the serum level of the high-sensitivity C-reactive protein, which is a kind of inflammatory cytokine, was elevated in patients with remodeled atria and increased EAT volume. Those findings indicated that EAT was involved in the development of high DF sites because of the secretion of inflammatory cytokines and the induction of firing of ganglionated plexi, which are abundant in EAT. The present article should provide new insight into the key drivers of AF. Does Location of Epicardial Adipose Tissue Correspond to Endocardial High Dominant Frequency or Complex Fractionated Atrial Electrogram Sites During Atrial Fibrillation? Koichi Nagashima, Yasuo Okumura, Ichiro Watanabe, Toshiko Nakai, Kimie Ohkubo, Masayoshi Kofune, Hiroaki Mano, Kazumasa Sonoda, Takafumi Hiro, Mizuki Nikaido and Atsushi Hirayama Downloaded from http://circep.ahajournals.org/ by guest on June 18, 2017 Circ Arrhythm Electrophysiol. 2012;5:676-683; originally published online July 6, 2012; doi: 10.1161/CIRCEP.112.971200 Circulation: Arrhythmia and Electrophysiology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2012 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-3149. 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