Europace Advance Access published March 3, 2015
CLINICAL RESEARCH
Europace doi:10.1093/europace/euu403
Interatrial septal thickness is associated with the extent of left atrial complex fractionated atrial electrograms and acute procedural outcome in patients with persistent atrial fibrillation Yae Min Park, Hwan Cheol Park, Ji-Eun Ban, Jong-Il Choi, Hong Euy Lim, Sang Weon Park, and Young-Hoon Kim* Division of Cardiology, Anam Hospital, Korea University Medical Center, Korea University, 126-1 Anam-Dong 5Ga, Seongbuk-Gu, Seoul 136-705, South Korea Received 9 June 2014; accepted after revision 21 December 2014
Aims
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Interatrial septal thickness † Complex fractionated atrial electrograms † Atrial fibrillation
Introduction Epicardial adipose tissue can provoke chronic inflammation of the left atrium (LA), which may contribute to the genesis or perpetuation of atrial fibrillation (AF).1,2 We previously demonstrated that interatrial septal thickness (IAST) was significantly correlated with total epicardial adipose tissue and independently associated with structural remodelling of the LA in patients with persistent AF.3 Several reports have shown that atrial arrhythmias are related to thickening of IAST with fibrosis or fatty infiltration of the interatrial septum,
either as a cause or as a result of the arrhythmia.4,5 Thinning of the IAST after conversion to sinus rhythm was demonstrated.6 Interestingly, complex fractionated atrial electrograms (CFAEs), which are targeted to modify the atrial substrate for AF during catheter ablation, are typically found on the interatrial septum of remodelled LA.7,8 Both IAST and CFAEs might independently reflect the extent of atrial substrate for the development and maintenance of AF; however, little is known about the association of IAST and CFAEs. The aims of this study were (i) to investigate the association between IAST and the extent of CFAEs in the LA and (ii) to assess
* Corresponding author. Tel: +82 2 920 6394; fax: +82 2 927 1478. E-mail address: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
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The interatrial septal thickness (IAST) reflects the changes of the atrial wall in patients with atrial fibrillation (AF). Complex fractionated atrial electrograms (CFAEs) were consistently positioned on the interatrial septum, especially in the remodelled left atrium (LA). We sought to characterize the relationship between IAST and LA CFAE area, as well as the acute procedural and clinical outcomes of catheter ablation in persistent AF patients. ..................................................................................................................................................................................... Methods This study included 71 patients who underwent catheter ablation for drug-refractory persistent AF. A stepwise ablation approach included circumferential pulmonary vein isolation followed by LA and right atrial CFAE-guided ablation. Interaand results trial septal thickness was measured 1 cm inferior to the fossa ovalis on cardiac computed tomography (CT). The extent of LA CFAEs was assessed by CFAE area and index (CFAE area/LA surface area × 100). Patients were grouped into tertiles according to the value of IAST. The mean IAST of the first, second, and third tertile was 4.69 + 0.79, 6.44 + 0.45, and 9.12 + 1.42 mm, respectively (P , 0.001). The mean CFAE areas (5.6 + 6.9, 18.5 + 20.3, and 24.3 + 26.6 mm2, P ¼ 0.005) and CFAE indexes (3.1 + 4.2, 9.2 + 10.7, and 11.8 + 15.3, P ¼ 0.025) in LA were significantly different among the three groups. More patients in the highest IAST tertile did not terminate AF during catheter ablation (12.5% vs. 26.1% vs. 37.5%, P ¼ 0.048). ..................................................................................................................................................................................... Conclusions Interatrial septal thickness measured by cardiac CT is associated with the extent of CFAE area within the LA and is related to acute procedural success of catheter ablation. These findings suggest that IAST reflects the degree of atrial substrate and remodelling in patients with persistent AF.
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What’s new? † We evaluated the association between interatrial septal thickness (IAST) with the extent of complex fractionated atrial electrograms (CFAEs) in the left atrium (LA) and acute procedural results in patients with persistent atrial fibrillation (AF). † This study demonstrates that IAST measured by cardiac CT is significantly associated with the extent of LA CFAEs and CFAE area index irrespective of LA size or body mass index in persistent AF patients. Acute procedural success rate was greater in the group of thinner IAST.
the relationship of IAST with acute procedural results and clinical outcomes after catheter ablation.
Y.M. Park et al.
(.80%), electrical silence, organized atrial tachycardia (AT), or termination of AF. Complex fractionated atrial electrograms of the RA were targeted if AF persisted after extensive LA ablation. Linear ablation at the cavotricuspid isthmus was performed in all patients either before or after restoring the sinus rhythm and bidirectional conduction block was confirmed. When AF converted to AT, activation mapping and ablation for AT were performed until a sinus rhythm was restored. If a patient had more than one stable AT, an attempt was made to map and ablate all ATs. The endpoint of catheter ablation was the termination of AF or AT and then noninducibility of AT [cycle length (CL) .280 ms] by burst atral pacing.10 If AF or AT did not terminate after ablating all target sites, the sinus rhythm was restored by electrical cardioversion. Radiofrequency ablation was delivered at a target temperature of 488C and power in the range of 25–35 W (Stockert generator, Biosense Webster, Inc., Diamond Bar, CA, USA or IBI 1500T11, St. Jude Medical, Inc., MN, USA) using a 4 mm open irrigated-tip catheter (Thermocool, Biosense Webster, Inc., Diamond Bar, CA, USA or Cool Path Duo, St. Jude Medical, Inc., MN, USA).
Cardiac computed tomography and measurement of interatrial septal thickness
Patients
All patients underwent cardiac CT within 24 h prior to ablation. Contrast-enhanced cardiac CT was performed using a dual-source, 64-multislice scanner (Somatom, Siemens, Inc., Germany). Imaging parameters were: 120 kV, 850 mAs, 0.6 mm beam collimation, and a 0.32 s rotation time. The reconstructed image slice thickness measured 0.76 mm and the field of view was 20 cm. During an end-expiratory breath-hold of 20 s, intravenous 70 mL of non-diluted iodinated contrast agent (Ultravist, Schering, Inc., Germany) at a rate of 5 mL/s was administrated followed by 30 mL of normal saline at a rate of 5 mL/s. Finally, end-systolic imaging data were recorded and used for 3D cardiac reconstruction on a 512 × 512 pixel matrix. Measurements were made using electronic callipers at the point of maximum thickness of the interatrial septum, 1 cm inferior to the fossa ovalis. Representative examples of IAST measurement are shown in Figure 1. This location was used because the fossa ovalis is easily recognized as a focal area of soft tissue density traversing the interatrial septum. Therefore, measurements in all subjects could be taken at equivalent levels. The measurements were obtained twice by single observer with the time lag 2 weeks and random order who was blinded to patients’ clinical characteristics and the mean value was calculated. Intra-observer correlations was excellent, with correlation coefficients (r) being ≥0.90. The volume of the LA, excluding the LA appendage and PVs, was automatically measured in the reconstructed 3D cardiac CT image.
This is a retrospective study. Seventy-one patients with persistent AF who underwent cardiac computed tomography (CT) prior to catheter ablation were enrolled. Patients with three-dimensional (3D) automated detection of CFAE and ablation in LA beyond pulmonary vein (PV) isolation were included in this study. All patients had previously failed to respond to anti-arrhythmic drugs and had symptomatic AF. Persistent AF was defined according to the HRS/EHRA/ECAS 2012 Consensus Statement on Catheter and Surgical Ablation of AF as AF with duration longer than 7 days or AF requiring electrical or pharmacological cardioversion to restore sinus rhythm.9 The local Institutional Review Board approved this study and all patients provided written informed consent.
Electrophysiology study Anti-arrhythmic medications were discontinued at least five half-lives before the procedure. Amiodarone was discontinued at least 1 month before the ablation procedure. The ablation procedure was performed under sedation with intravenous propofol with continuous monitoring of blood pressure and oxygen saturation. The high right atrium (RA), low RA, and coronary sinus were mapped with a decapolar catheter (Bard Electrophysiology, Inc., Lowell, MA, USA) and steerable duodecapolar catheter (St. Jude Medical, Inc., Minnetonka, MN, USA) inserted through the left femoral vein. A quadripolar catheter was also placed in the superior vena cava. Intracardiac electrograms were recorded using an electrophysiology system (Prucka CardioLabTM General Electric Health Care System, Inc., Milwaukee, WI, USA). After double transseptal puncture, anticoagulation was started with unfractionated heparin, maintaining an activated clotting time between 300 and 350 s. We used 3D-mapping-guided geometry (NavX System, St. Jude Medical, Inc., St. Paul, MN, USA) for electroanatomical mapping in all patients.
Ablation strategy The stepwise approach for ablation was performed under the guidance of fluoroscopic and 3D mapping. All patients initially underwent circumferential antral ablation with the endpoint being the electrical PV exit and entrance block or dissociation. If AF was sustained following antral ablation of the PVs, further ablation was guided by automated CFAE maps of the LA and then the RA, which were defined previously.8 The endpoints of CFAE-guided ablation were a significant reduction in the CFAE amplitude
Measurement of complex fractionated atrial electrograms We defined the CFAE area as previously reported.8,11 In brief, CFAEs were (i) atrial electrograms with fractionation and composed of two or more defections and/or with continuous activity of the baseline or (ii) atrial electrograms with a CL ≤120 ms. These electrograms were recorded with the ablation catheter in a stable position for at least 6 s (to avoid artefacts) using the 3D automated software of the NavX system.12 This area was coded in white and pink on the CFAE map. Complex fractionated atrial electrogram area and surface area of LA were measured. Left atrium CFAE area index was defined as CFAE area/LA surface area × 100. Complex fractionated atrial electrogram areas and CFAE area index in the RA were measured with the same method among available patients. Representative examples of CFAE measurement in LA are shown in Figure 1. When IAST or CFAEs were measured, the physician was blinded to the results of each other.
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Patients and methods
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IAST is associated with CFAEs in LA
A
B
Figure 1 Interatrial septal thickness was measured 1 cm inferior to the fossa ovalis on cardiac CT imaging. Representative examples of IAST and
Post-procedural management and follow-up Patients were monitored overnight and anticoagulation was continued for at least 2 months after the procedure. Patients resumed the antiarrhythmic medications they had been taking before the catheter ablation. The patients were seen in an outpatient clinic at 1 week and 1, 3, 6, 9, and 12 months after the procedure and then every 6 months thereafter. A 12-lead surface electrocardiogram was performed at every visit. Patients were evaluated by 24 or 48 h Holter monitoring or a 7-day event recorder at 3, 6, 9, and 12 months after the ablation and then at every 6 months thereafter. A detailed history of any symptoms suggesting potential AF or AT recurrence was taken. Recurrence was defined as an episode of an atrial arrhythmia of at least 30 s that occurred after a blanking period of 12 weeks after ablation.9 Anti-arrhythmic agents were discontinued at the 3 months visit if there was no evidence of recurrence. Warfarin therapy was discontinued in patients without a previous history of stroke, and aspirin was substituted if the electrocardiogram consistently demonstrated sinus rhythm. Success was defined as the absence of any documented arrhythmia or symptoms suggestive of arrhythmia recurrence without anti-arrhythmic drugs.
Statistical analysis Patients were grouped into tertiles according to IAST value. Continuous variables are reported as a mean + SD, while categorical variables are reported as a number or percentage. One-way ANOVA testing was used to compare continuous variables, while categorical variables were compared using a x 2 test or Fisher’s exact test, as appropriate among groups. Pearson’s correlation method was used to calculate the relationship between the IAST and the extent of CFAEs and CFAE index. To analyse independent predictors of acute procedural failure, we used multivariable logistic regressions. Univariate variables with P , 0.30
and known significant variables (LA size and volume) were entered in the model (control for confounding). Cumulative arrhythmia-free survival (any recurrence of atrial arrhythmia) was estimated using the Kaplan –Meier method and arrhythmia-free survival among groups was compared using a Wilcoxon log-rank test. All statistical analyses were performed using SPSS 12.0 software (SPSS Inc., Chicago, IL, USA). All tests were two tailed and a P-value of ,0.05 was considered significant.
Results Baseline characteristics The mean age was 55.6 + 9.6 years and 64 patients (90.1%) were male. The mean duration of AF before catheter ablation was 7.1 + 5.5 years. The mean anteroposterior LA diameter measured by transthoracic echocardiography was 43.8 + 5.7 mm and the mean LA volume as measured by cardiac CT was 132.4 + 42.0 mL. The mean left ventricular ejection fraction was 53.2 + 7.1%. Baseline characteristics according to groups are compared in Table 1. There were no significant differences in age, gender, AF duration, body mass index, the presences of comorbidities, LA size, or LA volume. The mean IAST of each group was 4.69 + 0.79, 6.44 + 0.45, and 9.12 + 1.42 mm (P , 0.001), respectively.
Correlation between interatrial septal thickness and complex fractionated atrial electrograms area The mean CFAE area (5.6 + 6.9 mm2 vs. 18.5 + 20.3 mm2 vs. 24.3 + 26.6 mm2, P ¼ 0.005) and CFAE area index (3.1 + 4.2 vs.
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CFAE measurements are shown. (A) Interatrial septal thickness measured 3.26 mm, so the patient was categorized into the first tertile. Complex fractionated atrial electrogram area (surrounded by black line) was 13.7 mm2 in this patient. (B) Interatrial septal thickness measured 9.68 mm, so the patient was categorized into the third tertile. Complex fractionated atrial electrogram area was 27.3 mm2. CFAE, complex fractionated atrial electrogram; CT, computed tomography; IAST, interatrial septal thickness.
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Table 1 Baseline characteristics of the study population by IAST tertile First tertile (n 5 24)
Second tertile (n 5 23)
Third tertile (n 5 24)
P-value
............................................................................................................................................................................... Age (years)
56.3 + 10.8
54.7 + 9.5
55.8 + 8.8
0.846
Male, n (%) AF duration (years)
21 (87.5) 7.6 + 6.9
22 (95.7) 6.9 + 5.2
21 (87.5) 6.8 + 4.1
0.559 0.866
BMI (kg/m2)
24.5 + 2.9
25.0 + 3.0
25.3 + 2.9
0.597
HTN, n (%) DM, n (%)
12 (50.0) 1 (4.2)
11 (47.8) 2 (8.7)
9 (37.5) 1 (4.2)
0.650 0.741
History of CVA, n (%)
1 (4.2)
1 (4.3)
1 (4.2)
0.999
CAD, n (%) LVEF (%)
0 52.1 + 8.0
1 (4.3) 54.1 + 6.0
2 (8.3) 53.5 + 7.3
0.357 0.618
LA diameter (mm)
42.5 + 5.5
44.7 + 5.9
44.2 + 5.7
0.397
LA volume measured by cardiac CT (mL) IAST (mm)
130 + 49 4.69 + 0.79
131 + 41 6.44 + 0.45
135 + 37 9.12 + 1.42
0.911 ,0.001‡
AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CVA, cerebrovascular attack; DM, diabetes mellitus; HTN, hypertension; IAST, interatrial septal thickness; LA, left atrial; LVEF, left ventricular ejection fraction. ‡ P , 0.001.
B
r = 0.435
r = 0.383 P = 0.001*
P < 0.001‡ 60 LA CFAE area index
LA CFAE area (mm2)
100 80 60 40
40
20
20 0
0 2
4
6
8
10
12
IAST (mm)
2
4
6
8
10
12
IAST (mm)
Figure 2 Interatrial septal thickness showed significant positive correlation with (A) LA CFAE area and (B) CFAE area index. CFAE, complex fractionated atrial electrogram; IAST, interatrial septal thickness; LA, left atrial. *P , 0.05, ‡P , 0.001.
9.2 + 10.7 vs. 11.8 + 15.3, P ¼ 0.025) in the LA were significantly different among groups. Interatrial septal thickness showed significant positive correlation with CFAE area and CFAE area index of LA (r ¼ 0.435, P , 0.001 and r ¼ 0.383, P ¼ 0.001, respectively) (Figure 2). However, the IAST was not significantly associated with gender, age, AF duration, and ejection fraction of the left ventricle. The correlation between IAST and body mass index was also not significant (r ¼ 0.195, P ¼ 0.103). The CFAE area in LA was not significantly correlated with LA size or volume (r ¼ 20.073, P ¼ 0.5453 and r ¼ 20.140, P ¼ 0.247, respectively). The proportion of patients who showed CFAEs in the LA septal area was significantly higher as IAST getting thicker [45.8% (11/24)
vs. 56.5% (13/23), 75.0% (18/24), P ¼ 0.041]. Those septal CFAEs were preferentially targeted during ablation procedure in patients who had thick IAST and septal CFAEs. The representative example is illustrated in Figure 3. The same endpoints of CFAE-guided ablation, in terms of significant reduction in the CFAE amplitude (.80%) or electrical silence, were applied during septal ablation. The proportion of patients who needed additional RA ablation after PV isolation and extensive LA ablation was not significantly different among three groups [54.2% (13/24) vs. 43.5% (10/23), 66.7% (16/24), P ¼ 0.278]. Complex fractionated atrial electrogram area and CFAE area index in RA were available in 25 patients who underwent CFAE mapping and ablation in RA. The mean CFAE area (6.7 +
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A 120
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IAST is associated with CFAEs in LA
A
B
Figure 3 (A) Left atrium septal area showed that substantial extent of CFAEs (white arrows) and (B) those septal CFAE areas was preferentially targeted during ablation procedure. Interatrial septal thickness measured 8.11 mm in this patient and the patient was categorized into the third tertile. CFAE, complex fractionated atrial electrogram; IAST, interatrial septal thickness; LA, left atrial.
Procedural characteristics Patients in the lowest IAST tertile showed significantly higher rates of acute procedural success by means of AF termination, either converting to sinus rhythm or AT during catheter ablation (87.5% vs. 73.9% vs. 62.5%, P ¼ 0.048). The proportion of patients who converted to sinus rhythm tended to be higher in the lowest IAST tertile without statistical significance (70.8% vs. 56.5% vs. 50.0%, P ¼ 0.145) (Figure 4). Procedural characteristics are summarized in Table 2. Multivariable analysis incorporating LA size and volume, CFAE area, CFAE area index, the presence of CFAEs in LA septal area, and IAST group was performed to evaluate the predictors of acute procedural failure during catheter ablation. Only third IAST tertile group was a borderline significant independent predictor of acute procedural failure (hazard ratio 4.701, 95% confidence interval: 0.903–24.468, P ¼ 0.060).
Clinical outcome during follow-up During a mean follow-up of 27.7 + 8.2 months after a single ablation procedure, 29 patients (40.8%) maintained sinus rhythm without anti-arrhythmic drugs. The proportion of patients with clinical 1-year success [12/24 (50.0%) vs. 13/23 (56.5%) vs. 12/24 (50.0%), P ¼ 0.876) and long-term success [9/24 (37.5%) vs. 11/23 (47.8%) vs. 9/24 (37.5%), P ¼ 0.710) was similar among the three groups.
Discussion Main finding This study demonstrates that IAST measured by cardiac CT is significantly associated with the extent of LA CFAEs and CFAE area index irrespective of LA size or body mass index in persistent AF patients. The incidence of CFAEs in LA septal area was higher in thick IAST patients. Acute procedural success rate was greater in the group of thinner IAST.
Role of epicardial adipose tissue in atrial fibrillation The close anatomical relationship of epicardial adipose tissue to the adjacent myocardium allows for local interactions that may provoke electrical or structural remodelling in the atrium.13 Inflammatory mediators such as adipocytokines and proinflammatory cytokines produced by epicardial adipose tissue can directly or systemically produce myocardial remodelling and enhance inflammation in addition to the effects of direct interactions between adipocytes and neighbouring atrial cardiomyocytes.14 – 16 Epicardial fat is also a source of several inflammatory mediators, including interleukin-1b, interleukin-6, tumour necrosis factor-a, and monocyte chemoattractant protein-1. Paracrine interactions of these cytokines and mediators contribute to perivascular inflammation.14,17 Thus, such proinflammatory cytokines produced by epicardial adipose tissue may directly or systemically produce myocardial remodelling. Adipose tissue frequently contains ganglionated plexi, which have been shown to play an important role in the initiation and maintenance of AF.18 In addition, the inflammatory mediators produced by neighbouring adipose tissue may influence these ganglionated plexi to perpetuate AF. The posterior LA fat thickness at the oesophagus was associated with increased AF burden independently of body
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13.6 mm2 vs. 30.8 + 40.9 mm2 vs. 38.8 + 52.4 mm2, P ¼ 0.164) and CFAE area index (4.2 + 9.3 vs. 16.2 + 20.5 vs. 17.3 + 21.8, P ¼ 0.204) in RA were not significantly different among groups. However, CFAE area and CFAE area index in RA showed significant positive correlation (r ¼ 0.494, P ¼ 0.012 and r ¼ 0.480, P ¼ 0.015, respectively) with IAST.
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Y.M. Park et al.
P = 0.048*
A 100%
3/24 12.5%
B 100% Remain in AF
6/23 26.1%
80%
9/24 37.5%
Conversion to AT or SR
60%
40%
P = 0.145 Non-termination 7/24 29.2%
80%
10/23 43.5%
Conversion to SR 12/24 50.0%
60% 21/24 87.5%
17/23 73.9%
40%
17/24 70.8%
15/24 62.5%
20%
13/23 56.5%
20%
0%
12/24 50.0%
0% 1st tertile 2nd tertile 3rd tertile
1st tertile
2nd tertile
3rd tertile
Figure 4 Patients with the lowest tertile of IAST group showed (A) significant higher rates of acute procedural success by means of AF termination, either converting to SR or AT during catheter ablation (87.5% vs. 73.9% vs. 62.5%) (P ¼ 0.048) and (B) tendency of higher proportion of converting to sinus rhythm (P ¼ 0.145). AT, atrial tachycardia; IAST, interatrial septal thickness; SR, sinus rhythm. *P , 0.05.
First tertile (n 5 24)
Second tertile (n 5 23)
Third tertile (n 5 24)
P-value
LA CFAE area (mm2) LA CFAE area index
5.61 + 6.86 3.08 + 4.24
18.5 + 20.3 9.16 + 10.73
24.3 + 26.6 11.79 + 15.33
0.005* 0.025*
Patients with LA septal CFAEs, n (%)
11 (45.8)
13 (56.5)
18 (75.0)
0.041*
Additional RA ablation, n (%) Conversion to SR, n (%)
13 (54.2) 17 (70.8)
10 (43.5) 13 (56.5)
16 (66.7) 12 (50.0)
0.278 0.145
Conversion to AT or SR, n (%)
21 (87.5)
17 (73.9)
15 (62.5)
0.048*
...............................................................................................................................................................................
AT, atrial tachycardia; CFAE, complex fractionated atrial electrogram; SR, sinus rhythm. *P , 0.05.
mass index. This suggests involvement of atrial structural remodelling in AF.19
Significance of interatrial septal fat We previously reported a correlation between IAST and total epicardial adipose tissue in different patient groups. However, among epicardial fat deposits, the thicknesses of the periventricular epicardial adipose tissue were not different between AF subjects and matched controls, which suggest a possible local effect of interatrial septal fat deposits.3 Previous studies revealed that localized interatrial septal fat, known as lipomatous septal hypertrophy, was associated with a significantly higher prevalence of atrial arrhythmias, including AF.20,21 Significant increase in IAST as measured by transesophageal echocardiography in AF patients was found independent of patient age, height, weight, and degree of interventricular septal thickness compared with normal controls.22 The increase in IAST in patients with AF suggests changes in the atrial wall, either as a cause or as a result of AF. As such, it has been proposed that IAST
may have potential use as a parameter to assess systolic atrial function, particularly with regard to maintenance of sinus rhythm after conversion from AF.6,23 Changes in atrial wall thickness might correspond to changes in the atrial extracellular matrix components, which may trigger atrial remodelling.
Complex fractionated atrial electrograms as an atrial substrate and targets for atrial fibrillation ablation Prior work demonstrated that CFAEs were mostly observed in areas of slow conduction and/or at pivot points of wavelets turnaround at the end of functional block arcs. Complex fractionated atrial electrograms were found to be critical sites for AF perpetuation and can therefore serve as target sites for AF ablation. It has been shown that radiofrequency applications resulting in complete elimination of the CFAEs were often associated with increasing tachycardia CLs before AF termination, even though the CLs were measured from the electrical reference of an area remote from the ablation site.11
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Table 2 Procedural characteristics of the study population by IAST tertile
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IAST is associated with CFAEs in LA
Limitations There were several limitations to our study. Similar clinical outcomes observed in our study may have resulted from relatively small population in each group and different monitoring methods. Sometimes persistent AF becomes paroxysmal after catheter ablation and 12-lead surface electrocardiogram and 24 or 48 h Holter monitoring might have limitations for detecting asymptomatic paroxysmal AF in those patients while 7-day event recorder yields higher detection rate of paroxysmal arrhythmia. The CFAE area in the RA was not evaluated in all patients. Only trend of difference in RA CFAE area and CFAE area index according to groups despite significant correlation with IAST might be resulted from too small population. Previously, the degree of IAST correlated with total epicardial adipose tissue amount, but whether IAST reflects real interatrial septal fat infiltration is unknown. Moreover, thin IAST may result from fibrotic scar change secondary to dilation of LA. Interatrial septal thickness was measured at a single site 1 cm inferior to the fossa ovalis. In our experience, this is the thickest area of the interatrial septum, and allows for clear visualization of measurements on cardiac CT images. Finally, whether eventual thinning of the interatrial septum occurs was not evaluated in patients with clinical success.
Conclusions In this study, we showed for the first time that IAST, which is readily measureable by cardiac CT, is associated with the extent of CFAE
area in the LA. Interatrial septal thickness also appears to be predictive of the acute procedural success rate of catheter ablation for persistent AF. These findings suggest that IAST can be a marker of atrial substrate and electrical remodelling of the LA in patients with persistent AF. Further large-scale, prospective studies will be required to define the pathophysiological role of the interatrial septum in atrial remodelling and clinical outcome after catheter ablation in persistent AF. Conflict of interest: none declared.
References 1. Iacobellis G, Leonetti F, Singh N, Sharma AM. Relationship of epicardial adipose tissue with atrial dimensions and diastolic function in morbidly obese subjects. Int J Cardiol 2007;115:272 – 3. 2. Lin YK, Chen YJ, Chen SA. Potential atrial arrhythmogenicity of adipocytes: implications for the genesis of atrial fibrillation. Med Hypotheses 2010;74:1026 –9. 3. Shin SY, Yong HS, Lim HE, Na JO, Choi CU, Choi JI et al. Total and interatrial epicardial adipose tissues are independently associated with left atrial remodeling in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:647 – 55. 4. Kluge WF. Lipomatous hypertrophy of the interatrial septum. Northwest Med 1969; 68:25 –30. 5. Hutter AM Jr, Page DL. Atrial arrhythmias and lipomatous hypertrophy of the cardiac interatrial septum. Am Heart J 1971;82:16–21. 6. Galzerano D, Tuccillo B, Lama D, Paolisso G, Mirra G, Giasi M. Morpho-functional assessment of interatrial septum: a transesophageal echocardiographic study. Int J Cardiol 1995;51:73– 7. 7. Park JH, Park SW, Kim JY, Kim SK, Jeoung B, Lee MH et al. Characteristics of complex fractionated atrial electrogram in the electroanatomically remodeled left atrium of patients with atrial fibrillation. Circ J 2010;74:1557 –63. 8. Park JH, Pak HN, Kim SK, Jang JK, Choi JI, Lim HE et al. Electrophysiologic characteristics of complex fractionated atrial electrograms in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2009;20:266 –72. 9. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA et al. 2012 HRS/ EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace 2012;14:528 – 606. 10. Nagamoto Y, Park JS, Tanubudi D, Ko YK, Ban JE, Kwak JJ et al. Clinical significance of induced atrial tachycardia after termination of longstanding persistent atrial fibrillation using a stepwise approach. J Cardiovasc Electrophysiol 2012;23:1171 –8. 11. Nademanee K, McKenzie J, Kosar E, Schwab M, Sunsaneewitayakul B, Vasavakul T et al. A new approach for catheter ablation of atrial fibrillation: mapping of the electrophysiologic substrate. J Am Coll Cardiol 2004;43:2044 – 53. 12. Scherr D, Dalal D, Cheema A, Cheng A, Henrikson CA, Spragg D et al. Automated detection and characterization of complex fractionated atrial electrograms in human left atrium during atrial fibrillation. Heart Rhythm 2007;4: 1013 – 20. 13. Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2005;2: 536 –43. 14. Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003;108: 2460 –6. 15. Malavazos AE, Ermetici F, Coman C, Corsi MM, Morricone L, Ambrosi B. Influence of epicardial adipose tissue and adipocytokine levels on cardiac abnormalities in visceral obesity. Int J Cardiol 2007;121:132 –4. 16. Marfella R, Esposito K, Siniscalchi M, Cacciapuoti F, Giugliano F, Labriola D et al. Effect of weight loss on cardiac synchronization and proinflammatory cytokines in premenopausal obese women. Diabetes Care 2004;27:47– 52. 17. Chatterjee TK, Stoll LL, Denning GM, Harrelson A, Blomkalns AL, Idelman G et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res 2009;104:541 – 9. 18. Nakagawa H, Scherlag BJ, Patterson E, Ikeda A, Lockwood D, Jackman WM. Pathophysiologic basis of autonomic ganglionated plexus ablation in patients with atrial fibrillation. Heart Rhythm 2009;6:S26 –34. 19. Batal O, Schoenhagen P, Shao M, Ayyad AE, Van Wagoner DR, Halliburton SS et al. Left atrial epicardial adiposity and atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3:230–6. 20. Shirani J, Roberts WC. Clinical, electrocardiographic and morphologic features of massive fatty deposits (“lipomatous hypertrophy”) in the atrial septum. J Am Coll Cardiol 1993;22:226 – 38.
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The atrial septum was shown to be the most common site for CFAEs8 and ablation of these areas resulted in termination of AF in 95% of patients and a 1 year success rate of 76% with a single procedure.11 Previous studies demonstrated that the additional substrate modification targeting of CFAEs increased the procedural success rate and improved outcomes compared with PV isolation alone for the treatment of persistent AF.24 – 28 This study is the first to demonstrate a relationship between IAST and CFAEs of LA in AF. Previous studies found that patients with metabolic syndrome, characterized by endothelial dysfunction and obesity, had shorter fractionation intervals and a higher dominant frequency of atrial electrograms during AF. Notably, different distributions of CFAE sites and higher incidence of AF recurrence from non-PV origins were found in patients with metabolic syndrome, which suggests that metabolic syndrome may have a potential electrical effect on the atrium.29 Expanded epicardial fat infiltration may interfere with atrial conduction in patients with metabolic syndrome. As also seen in our study, the linear association between the IAST and the area of CFAEs in the LA suggests that interatrial septal fat infiltration may be directly involved in atrial conduction and electrical remodelling. In turn, the degree of IAST may serve a predictive marker for the acute intraprocedural success of AF ablation. In the previous study, the CFAE sties in LA did not correspond with exact epicardial adipose tissue locations surrounding LA;30 however, we found that the total CFAE extent can reflect total amount of epicardial adipose tissue through the degree of IAST. Even though the detailed spatial distribution was not fully evaluated, septal positioning of CFAE was well correlated with the degree of IAST.
Page 8 of 8 21. Heyer CM, Kagel T, Lemburg SP, Bauer TT, Nicolas V. Lipomatous hypertrophy of the interatrial septum: a prospective study of incidence, imaging findings, and clinical symptoms. Chest 2003;124:2068 –73. 22. Lopez-Candales A, Grewal H, Katz W. The importance of increased interatrial septal thickness in patients with atrial fibrillation: a transesophageal echocardiographic study. Echocardiography 2005;22:408–14. 23. Manning WJ, Leeman DE, Gotch PJ, Come PC. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol 1989;13:617 – 23. 24. Hunter RJ, Berriman TJ, Diab I, Baker V, Finlay M, Richmond L et al. Long-term efficacy of catheter ablation for atrial fibrillation: impact of additional targeting of fractionated electrograms. Heart 2010;96:1372 –8. 25. Elayi CS, Verma A, Di Biase L, Ching CK, Patel D, Barrett C et al. Ablation for longstanding permanent atrial fibrillation: results from a randomized study comparing three different strategies. Heart Rhythm 2008;5:1658 –64.
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26. Park YM, Choi JI, Lim HE, Park SW, Kim YH. Is pursuit of termination of atrial fibrillation during catheter ablation of great value in patients with longstanding persistent atrial fibrillation? J Cardiovasc Electrophysiol 2012;23:1051 –8. 27. Yorgun H, Aytemir K, Canpolat U, S¸ahiner L, Kaya EB, Oto A. Additional benefit of cryoballoon-based atrial fibrillation ablation beyond pulmonary vein isolation: modification of ganglionated plexi. Europace 2014;16:645 –51. 28. Mikhaylov E, Kanidieva A, Sviridova N, Abramov M, Gureev S, Szili-Torok T et al. Outcome of anatomic ganglionated plexi ablation to treat paroxysmal atrial fibrillation: a 3-year follow-up study. Europace 2011;13:362 –70. 29. Chang SL, Tuan TC, Tai CT, Lin YJ, Lo LW, Hu YF et al. Comparison of outcome in catheter ablation of atrial fibrillation in patients with versus without the metabolic syndrome. Am J Cardiol 2009;103:67–72. 30. Nagashima K, Okumura Y, Watanabe I, Nakai T, Ohkubo K, Kofune M et al. Does location of epicardial adipose tissue correspond to endocardial high dominant frequency or complex fractionated atrial electrogram sites during atrial fibrillation? Circ Arrhythm Electrophysiol 2012;5:676 –83.
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CLINICAL RESEARCH
Europace doi:10.1093/europace/euu403
Interatrial septal thickness is associated with the extent of left atrial complex fractionated atrial electrograms and acute procedural outcome in patients with persistent atrial fibrillation Yae Min Park, Hwan Cheol Park, Ji-Eun Ban, Jong-Il Choi, Hong Euy Lim, Sang Weon Park, and Young-Hoon Kim* Division of Cardiology, Anam Hospital, Korea University Medical Center, Korea University, 126-1 Anam-Dong 5Ga, Seongbuk-Gu, Seoul 136-705, South Korea Received 9 June 2014; accepted after revision 21 December 2014
Aims
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Interatrial septal thickness † Complex fractionated atrial electrograms † Atrial fibrillation
Introduction Epicardial adipose tissue can provoke chronic inflammation of the left atrium (LA), which may contribute to the genesis or perpetuation of atrial fibrillation (AF).1,2 We previously demonstrated that interatrial septal thickness (IAST) was significantly correlated with total epicardial adipose tissue and independently associated with structural remodelling of the LA in patients with persistent AF.3 Several reports have shown that atrial arrhythmias are related to thickening of IAST with fibrosis or fatty infiltration of the interatrial septum,
either as a cause or as a result of the arrhythmia.4,5 Thinning of the IAST after conversion to sinus rhythm was demonstrated.6 Interestingly, complex fractionated atrial electrograms (CFAEs), which are targeted to modify the atrial substrate for AF during catheter ablation, are typically found on the interatrial septum of remodelled LA.7,8 Both IAST and CFAEs might independently reflect the extent of atrial substrate for the development and maintenance of AF; however, little is known about the association of IAST and CFAEs. The aims of this study were (i) to investigate the association between IAST and the extent of CFAEs in the LA and (ii) to assess
* Corresponding author. Tel: +82 2 920 6394; fax: +82 2 927 1478. E-mail address: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
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The interatrial septal thickness (IAST) reflects the changes of the atrial wall in patients with atrial fibrillation (AF). Complex fractionated atrial electrograms (CFAEs) were consistently positioned on the interatrial septum, especially in the remodelled left atrium (LA). We sought to characterize the relationship between IAST and LA CFAE area, as well as the acute procedural and clinical outcomes of catheter ablation in persistent AF patients. ..................................................................................................................................................................................... Methods This study included 71 patients who underwent catheter ablation for drug-refractory persistent AF. A stepwise ablation approach included circumferential pulmonary vein isolation followed by LA and right atrial CFAE-guided ablation. Interaand results trial septal thickness was measured 1 cm inferior to the fossa ovalis on cardiac computed tomography (CT). The extent of LA CFAEs was assessed by CFAE area and index (CFAE area/LA surface area × 100). Patients were grouped into tertiles according to the value of IAST. The mean IAST of the first, second, and third tertile was 4.69 + 0.79, 6.44 + 0.45, and 9.12 + 1.42 mm, respectively (P , 0.001). The mean CFAE areas (5.6 + 6.9, 18.5 + 20.3, and 24.3 + 26.6 mm2, P ¼ 0.005) and CFAE indexes (3.1 + 4.2, 9.2 + 10.7, and 11.8 + 15.3, P ¼ 0.025) in LA were significantly different among the three groups. More patients in the highest IAST tertile did not terminate AF during catheter ablation (12.5% vs. 26.1% vs. 37.5%, P ¼ 0.048). ..................................................................................................................................................................................... Conclusions Interatrial septal thickness measured by cardiac CT is associated with the extent of CFAE area within the LA and is related to acute procedural success of catheter ablation. These findings suggest that IAST reflects the degree of atrial substrate and remodelling in patients with persistent AF.
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What’s new? † We evaluated the association between interatrial septal thickness (IAST) with the extent of complex fractionated atrial electrograms (CFAEs) in the left atrium (LA) and acute procedural results in patients with persistent atrial fibrillation (AF). † This study demonstrates that IAST measured by cardiac CT is significantly associated with the extent of LA CFAEs and CFAE area index irrespective of LA size or body mass index in persistent AF patients. Acute procedural success rate was greater in the group of thinner IAST.
the relationship of IAST with acute procedural results and clinical outcomes after catheter ablation.
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(.80%), electrical silence, organized atrial tachycardia (AT), or termination of AF. Complex fractionated atrial electrograms of the RA were targeted if AF persisted after extensive LA ablation. Linear ablation at the cavotricuspid isthmus was performed in all patients either before or after restoring the sinus rhythm and bidirectional conduction block was confirmed. When AF converted to AT, activation mapping and ablation for AT were performed until a sinus rhythm was restored. If a patient had more than one stable AT, an attempt was made to map and ablate all ATs. The endpoint of catheter ablation was the termination of AF or AT and then noninducibility of AT [cycle length (CL) .280 ms] by burst atral pacing.10 If AF or AT did not terminate after ablating all target sites, the sinus rhythm was restored by electrical cardioversion. Radiofrequency ablation was delivered at a target temperature of 488C and power in the range of 25–35 W (Stockert generator, Biosense Webster, Inc., Diamond Bar, CA, USA or IBI 1500T11, St. Jude Medical, Inc., MN, USA) using a 4 mm open irrigated-tip catheter (Thermocool, Biosense Webster, Inc., Diamond Bar, CA, USA or Cool Path Duo, St. Jude Medical, Inc., MN, USA).
Cardiac computed tomography and measurement of interatrial septal thickness
Patients
All patients underwent cardiac CT within 24 h prior to ablation. Contrast-enhanced cardiac CT was performed using a dual-source, 64-multislice scanner (Somatom, Siemens, Inc., Germany). Imaging parameters were: 120 kV, 850 mAs, 0.6 mm beam collimation, and a 0.32 s rotation time. The reconstructed image slice thickness measured 0.76 mm and the field of view was 20 cm. During an end-expiratory breath-hold of 20 s, intravenous 70 mL of non-diluted iodinated contrast agent (Ultravist, Schering, Inc., Germany) at a rate of 5 mL/s was administrated followed by 30 mL of normal saline at a rate of 5 mL/s. Finally, end-systolic imaging data were recorded and used for 3D cardiac reconstruction on a 512 × 512 pixel matrix. Measurements were made using electronic callipers at the point of maximum thickness of the interatrial septum, 1 cm inferior to the fossa ovalis. Representative examples of IAST measurement are shown in Figure 1. This location was used because the fossa ovalis is easily recognized as a focal area of soft tissue density traversing the interatrial septum. Therefore, measurements in all subjects could be taken at equivalent levels. The measurements were obtained twice by single observer with the time lag 2 weeks and random order who was blinded to patients’ clinical characteristics and the mean value was calculated. Intra-observer correlations was excellent, with correlation coefficients (r) being ≥0.90. The volume of the LA, excluding the LA appendage and PVs, was automatically measured in the reconstructed 3D cardiac CT image.
This is a retrospective study. Seventy-one patients with persistent AF who underwent cardiac computed tomography (CT) prior to catheter ablation were enrolled. Patients with three-dimensional (3D) automated detection of CFAE and ablation in LA beyond pulmonary vein (PV) isolation were included in this study. All patients had previously failed to respond to anti-arrhythmic drugs and had symptomatic AF. Persistent AF was defined according to the HRS/EHRA/ECAS 2012 Consensus Statement on Catheter and Surgical Ablation of AF as AF with duration longer than 7 days or AF requiring electrical or pharmacological cardioversion to restore sinus rhythm.9 The local Institutional Review Board approved this study and all patients provided written informed consent.
Electrophysiology study Anti-arrhythmic medications were discontinued at least five half-lives before the procedure. Amiodarone was discontinued at least 1 month before the ablation procedure. The ablation procedure was performed under sedation with intravenous propofol with continuous monitoring of blood pressure and oxygen saturation. The high right atrium (RA), low RA, and coronary sinus were mapped with a decapolar catheter (Bard Electrophysiology, Inc., Lowell, MA, USA) and steerable duodecapolar catheter (St. Jude Medical, Inc., Minnetonka, MN, USA) inserted through the left femoral vein. A quadripolar catheter was also placed in the superior vena cava. Intracardiac electrograms were recorded using an electrophysiology system (Prucka CardioLabTM General Electric Health Care System, Inc., Milwaukee, WI, USA). After double transseptal puncture, anticoagulation was started with unfractionated heparin, maintaining an activated clotting time between 300 and 350 s. We used 3D-mapping-guided geometry (NavX System, St. Jude Medical, Inc., St. Paul, MN, USA) for electroanatomical mapping in all patients.
Ablation strategy The stepwise approach for ablation was performed under the guidance of fluoroscopic and 3D mapping. All patients initially underwent circumferential antral ablation with the endpoint being the electrical PV exit and entrance block or dissociation. If AF was sustained following antral ablation of the PVs, further ablation was guided by automated CFAE maps of the LA and then the RA, which were defined previously.8 The endpoints of CFAE-guided ablation were a significant reduction in the CFAE amplitude
Measurement of complex fractionated atrial electrograms We defined the CFAE area as previously reported.8,11 In brief, CFAEs were (i) atrial electrograms with fractionation and composed of two or more defections and/or with continuous activity of the baseline or (ii) atrial electrograms with a CL ≤120 ms. These electrograms were recorded with the ablation catheter in a stable position for at least 6 s (to avoid artefacts) using the 3D automated software of the NavX system.12 This area was coded in white and pink on the CFAE map. Complex fractionated atrial electrogram area and surface area of LA were measured. Left atrium CFAE area index was defined as CFAE area/LA surface area × 100. Complex fractionated atrial electrogram areas and CFAE area index in the RA were measured with the same method among available patients. Representative examples of CFAE measurement in LA are shown in Figure 1. When IAST or CFAEs were measured, the physician was blinded to the results of each other.
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Patients and methods
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IAST is associated with CFAEs in LA
A
B
Figure 1 Interatrial septal thickness was measured 1 cm inferior to the fossa ovalis on cardiac CT imaging. Representative examples of IAST and
Post-procedural management and follow-up Patients were monitored overnight and anticoagulation was continued for at least 2 months after the procedure. Patients resumed the antiarrhythmic medications they had been taking before the catheter ablation. The patients were seen in an outpatient clinic at 1 week and 1, 3, 6, 9, and 12 months after the procedure and then every 6 months thereafter. A 12-lead surface electrocardiogram was performed at every visit. Patients were evaluated by 24 or 48 h Holter monitoring or a 7-day event recorder at 3, 6, 9, and 12 months after the ablation and then at every 6 months thereafter. A detailed history of any symptoms suggesting potential AF or AT recurrence was taken. Recurrence was defined as an episode of an atrial arrhythmia of at least 30 s that occurred after a blanking period of 12 weeks after ablation.9 Anti-arrhythmic agents were discontinued at the 3 months visit if there was no evidence of recurrence. Warfarin therapy was discontinued in patients without a previous history of stroke, and aspirin was substituted if the electrocardiogram consistently demonstrated sinus rhythm. Success was defined as the absence of any documented arrhythmia or symptoms suggestive of arrhythmia recurrence without anti-arrhythmic drugs.
Statistical analysis Patients were grouped into tertiles according to IAST value. Continuous variables are reported as a mean + SD, while categorical variables are reported as a number or percentage. One-way ANOVA testing was used to compare continuous variables, while categorical variables were compared using a x 2 test or Fisher’s exact test, as appropriate among groups. Pearson’s correlation method was used to calculate the relationship between the IAST and the extent of CFAEs and CFAE index. To analyse independent predictors of acute procedural failure, we used multivariable logistic regressions. Univariate variables with P , 0.30
and known significant variables (LA size and volume) were entered in the model (control for confounding). Cumulative arrhythmia-free survival (any recurrence of atrial arrhythmia) was estimated using the Kaplan –Meier method and arrhythmia-free survival among groups was compared using a Wilcoxon log-rank test. All statistical analyses were performed using SPSS 12.0 software (SPSS Inc., Chicago, IL, USA). All tests were two tailed and a P-value of ,0.05 was considered significant.
Results Baseline characteristics The mean age was 55.6 + 9.6 years and 64 patients (90.1%) were male. The mean duration of AF before catheter ablation was 7.1 + 5.5 years. The mean anteroposterior LA diameter measured by transthoracic echocardiography was 43.8 + 5.7 mm and the mean LA volume as measured by cardiac CT was 132.4 + 42.0 mL. The mean left ventricular ejection fraction was 53.2 + 7.1%. Baseline characteristics according to groups are compared in Table 1. There were no significant differences in age, gender, AF duration, body mass index, the presences of comorbidities, LA size, or LA volume. The mean IAST of each group was 4.69 + 0.79, 6.44 + 0.45, and 9.12 + 1.42 mm (P , 0.001), respectively.
Correlation between interatrial septal thickness and complex fractionated atrial electrograms area The mean CFAE area (5.6 + 6.9 mm2 vs. 18.5 + 20.3 mm2 vs. 24.3 + 26.6 mm2, P ¼ 0.005) and CFAE area index (3.1 + 4.2 vs.
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CFAE measurements are shown. (A) Interatrial septal thickness measured 3.26 mm, so the patient was categorized into the first tertile. Complex fractionated atrial electrogram area (surrounded by black line) was 13.7 mm2 in this patient. (B) Interatrial septal thickness measured 9.68 mm, so the patient was categorized into the third tertile. Complex fractionated atrial electrogram area was 27.3 mm2. CFAE, complex fractionated atrial electrogram; CT, computed tomography; IAST, interatrial septal thickness.
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Table 1 Baseline characteristics of the study population by IAST tertile First tertile (n 5 24)
Second tertile (n 5 23)
Third tertile (n 5 24)
P-value
............................................................................................................................................................................... Age (years)
56.3 + 10.8
54.7 + 9.5
55.8 + 8.8
0.846
Male, n (%) AF duration (years)
21 (87.5) 7.6 + 6.9
22 (95.7) 6.9 + 5.2
21 (87.5) 6.8 + 4.1
0.559 0.866
BMI (kg/m2)
24.5 + 2.9
25.0 + 3.0
25.3 + 2.9
0.597
HTN, n (%) DM, n (%)
12 (50.0) 1 (4.2)
11 (47.8) 2 (8.7)
9 (37.5) 1 (4.2)
0.650 0.741
History of CVA, n (%)
1 (4.2)
1 (4.3)
1 (4.2)
0.999
CAD, n (%) LVEF (%)
0 52.1 + 8.0
1 (4.3) 54.1 + 6.0
2 (8.3) 53.5 + 7.3
0.357 0.618
LA diameter (mm)
42.5 + 5.5
44.7 + 5.9
44.2 + 5.7
0.397
LA volume measured by cardiac CT (mL) IAST (mm)
130 + 49 4.69 + 0.79
131 + 41 6.44 + 0.45
135 + 37 9.12 + 1.42
0.911 ,0.001‡
AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CVA, cerebrovascular attack; DM, diabetes mellitus; HTN, hypertension; IAST, interatrial septal thickness; LA, left atrial; LVEF, left ventricular ejection fraction. ‡ P , 0.001.
B
r = 0.435
r = 0.383 P = 0.001*
P < 0.001‡ 60 LA CFAE area index
LA CFAE area (mm2)
100 80 60 40
40
20
20 0
0 2
4
6
8
10
12
IAST (mm)
2
4
6
8
10
12
IAST (mm)
Figure 2 Interatrial septal thickness showed significant positive correlation with (A) LA CFAE area and (B) CFAE area index. CFAE, complex fractionated atrial electrogram; IAST, interatrial septal thickness; LA, left atrial. *P , 0.05, ‡P , 0.001.
9.2 + 10.7 vs. 11.8 + 15.3, P ¼ 0.025) in the LA were significantly different among groups. Interatrial septal thickness showed significant positive correlation with CFAE area and CFAE area index of LA (r ¼ 0.435, P , 0.001 and r ¼ 0.383, P ¼ 0.001, respectively) (Figure 2). However, the IAST was not significantly associated with gender, age, AF duration, and ejection fraction of the left ventricle. The correlation between IAST and body mass index was also not significant (r ¼ 0.195, P ¼ 0.103). The CFAE area in LA was not significantly correlated with LA size or volume (r ¼ 20.073, P ¼ 0.5453 and r ¼ 20.140, P ¼ 0.247, respectively). The proportion of patients who showed CFAEs in the LA septal area was significantly higher as IAST getting thicker [45.8% (11/24)
vs. 56.5% (13/23), 75.0% (18/24), P ¼ 0.041]. Those septal CFAEs were preferentially targeted during ablation procedure in patients who had thick IAST and septal CFAEs. The representative example is illustrated in Figure 3. The same endpoints of CFAE-guided ablation, in terms of significant reduction in the CFAE amplitude (.80%) or electrical silence, were applied during septal ablation. The proportion of patients who needed additional RA ablation after PV isolation and extensive LA ablation was not significantly different among three groups [54.2% (13/24) vs. 43.5% (10/23), 66.7% (16/24), P ¼ 0.278]. Complex fractionated atrial electrogram area and CFAE area index in RA were available in 25 patients who underwent CFAE mapping and ablation in RA. The mean CFAE area (6.7 +
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A 120
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IAST is associated with CFAEs in LA
A
B
Figure 3 (A) Left atrium septal area showed that substantial extent of CFAEs (white arrows) and (B) those septal CFAE areas was preferentially targeted during ablation procedure. Interatrial septal thickness measured 8.11 mm in this patient and the patient was categorized into the third tertile. CFAE, complex fractionated atrial electrogram; IAST, interatrial septal thickness; LA, left atrial.
Procedural characteristics Patients in the lowest IAST tertile showed significantly higher rates of acute procedural success by means of AF termination, either converting to sinus rhythm or AT during catheter ablation (87.5% vs. 73.9% vs. 62.5%, P ¼ 0.048). The proportion of patients who converted to sinus rhythm tended to be higher in the lowest IAST tertile without statistical significance (70.8% vs. 56.5% vs. 50.0%, P ¼ 0.145) (Figure 4). Procedural characteristics are summarized in Table 2. Multivariable analysis incorporating LA size and volume, CFAE area, CFAE area index, the presence of CFAEs in LA septal area, and IAST group was performed to evaluate the predictors of acute procedural failure during catheter ablation. Only third IAST tertile group was a borderline significant independent predictor of acute procedural failure (hazard ratio 4.701, 95% confidence interval: 0.903–24.468, P ¼ 0.060).
Clinical outcome during follow-up During a mean follow-up of 27.7 + 8.2 months after a single ablation procedure, 29 patients (40.8%) maintained sinus rhythm without anti-arrhythmic drugs. The proportion of patients with clinical 1-year success [12/24 (50.0%) vs. 13/23 (56.5%) vs. 12/24 (50.0%), P ¼ 0.876) and long-term success [9/24 (37.5%) vs. 11/23 (47.8%) vs. 9/24 (37.5%), P ¼ 0.710) was similar among the three groups.
Discussion Main finding This study demonstrates that IAST measured by cardiac CT is significantly associated with the extent of LA CFAEs and CFAE area index irrespective of LA size or body mass index in persistent AF patients. The incidence of CFAEs in LA septal area was higher in thick IAST patients. Acute procedural success rate was greater in the group of thinner IAST.
Role of epicardial adipose tissue in atrial fibrillation The close anatomical relationship of epicardial adipose tissue to the adjacent myocardium allows for local interactions that may provoke electrical or structural remodelling in the atrium.13 Inflammatory mediators such as adipocytokines and proinflammatory cytokines produced by epicardial adipose tissue can directly or systemically produce myocardial remodelling and enhance inflammation in addition to the effects of direct interactions between adipocytes and neighbouring atrial cardiomyocytes.14 – 16 Epicardial fat is also a source of several inflammatory mediators, including interleukin-1b, interleukin-6, tumour necrosis factor-a, and monocyte chemoattractant protein-1. Paracrine interactions of these cytokines and mediators contribute to perivascular inflammation.14,17 Thus, such proinflammatory cytokines produced by epicardial adipose tissue may directly or systemically produce myocardial remodelling. Adipose tissue frequently contains ganglionated plexi, which have been shown to play an important role in the initiation and maintenance of AF.18 In addition, the inflammatory mediators produced by neighbouring adipose tissue may influence these ganglionated plexi to perpetuate AF. The posterior LA fat thickness at the oesophagus was associated with increased AF burden independently of body
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13.6 mm2 vs. 30.8 + 40.9 mm2 vs. 38.8 + 52.4 mm2, P ¼ 0.164) and CFAE area index (4.2 + 9.3 vs. 16.2 + 20.5 vs. 17.3 + 21.8, P ¼ 0.204) in RA were not significantly different among groups. However, CFAE area and CFAE area index in RA showed significant positive correlation (r ¼ 0.494, P ¼ 0.012 and r ¼ 0.480, P ¼ 0.015, respectively) with IAST.
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P = 0.048*
A 100%
3/24 12.5%
B 100% Remain in AF
6/23 26.1%
80%
9/24 37.5%
Conversion to AT or SR
60%
40%
P = 0.145 Non-termination 7/24 29.2%
80%
10/23 43.5%
Conversion to SR 12/24 50.0%
60% 21/24 87.5%
17/23 73.9%
40%
17/24 70.8%
15/24 62.5%
20%
13/23 56.5%
20%
0%
12/24 50.0%
0% 1st tertile 2nd tertile 3rd tertile
1st tertile
2nd tertile
3rd tertile
Figure 4 Patients with the lowest tertile of IAST group showed (A) significant higher rates of acute procedural success by means of AF termination, either converting to SR or AT during catheter ablation (87.5% vs. 73.9% vs. 62.5%) (P ¼ 0.048) and (B) tendency of higher proportion of converting to sinus rhythm (P ¼ 0.145). AT, atrial tachycardia; IAST, interatrial septal thickness; SR, sinus rhythm. *P , 0.05.
First tertile (n 5 24)
Second tertile (n 5 23)
Third tertile (n 5 24)
P-value
LA CFAE area (mm2) LA CFAE area index
5.61 + 6.86 3.08 + 4.24
18.5 + 20.3 9.16 + 10.73
24.3 + 26.6 11.79 + 15.33
0.005* 0.025*
Patients with LA septal CFAEs, n (%)
11 (45.8)
13 (56.5)
18 (75.0)
0.041*
Additional RA ablation, n (%) Conversion to SR, n (%)
13 (54.2) 17 (70.8)
10 (43.5) 13 (56.5)
16 (66.7) 12 (50.0)
0.278 0.145
Conversion to AT or SR, n (%)
21 (87.5)
17 (73.9)
15 (62.5)
0.048*
...............................................................................................................................................................................
AT, atrial tachycardia; CFAE, complex fractionated atrial electrogram; SR, sinus rhythm. *P , 0.05.
mass index. This suggests involvement of atrial structural remodelling in AF.19
Significance of interatrial septal fat We previously reported a correlation between IAST and total epicardial adipose tissue in different patient groups. However, among epicardial fat deposits, the thicknesses of the periventricular epicardial adipose tissue were not different between AF subjects and matched controls, which suggest a possible local effect of interatrial septal fat deposits.3 Previous studies revealed that localized interatrial septal fat, known as lipomatous septal hypertrophy, was associated with a significantly higher prevalence of atrial arrhythmias, including AF.20,21 Significant increase in IAST as measured by transesophageal echocardiography in AF patients was found independent of patient age, height, weight, and degree of interventricular septal thickness compared with normal controls.22 The increase in IAST in patients with AF suggests changes in the atrial wall, either as a cause or as a result of AF. As such, it has been proposed that IAST
may have potential use as a parameter to assess systolic atrial function, particularly with regard to maintenance of sinus rhythm after conversion from AF.6,23 Changes in atrial wall thickness might correspond to changes in the atrial extracellular matrix components, which may trigger atrial remodelling.
Complex fractionated atrial electrograms as an atrial substrate and targets for atrial fibrillation ablation Prior work demonstrated that CFAEs were mostly observed in areas of slow conduction and/or at pivot points of wavelets turnaround at the end of functional block arcs. Complex fractionated atrial electrograms were found to be critical sites for AF perpetuation and can therefore serve as target sites for AF ablation. It has been shown that radiofrequency applications resulting in complete elimination of the CFAEs were often associated with increasing tachycardia CLs before AF termination, even though the CLs were measured from the electrical reference of an area remote from the ablation site.11
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Table 2 Procedural characteristics of the study population by IAST tertile
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IAST is associated with CFAEs in LA
Limitations There were several limitations to our study. Similar clinical outcomes observed in our study may have resulted from relatively small population in each group and different monitoring methods. Sometimes persistent AF becomes paroxysmal after catheter ablation and 12-lead surface electrocardiogram and 24 or 48 h Holter monitoring might have limitations for detecting asymptomatic paroxysmal AF in those patients while 7-day event recorder yields higher detection rate of paroxysmal arrhythmia. The CFAE area in the RA was not evaluated in all patients. Only trend of difference in RA CFAE area and CFAE area index according to groups despite significant correlation with IAST might be resulted from too small population. Previously, the degree of IAST correlated with total epicardial adipose tissue amount, but whether IAST reflects real interatrial septal fat infiltration is unknown. Moreover, thin IAST may result from fibrotic scar change secondary to dilation of LA. Interatrial septal thickness was measured at a single site 1 cm inferior to the fossa ovalis. In our experience, this is the thickest area of the interatrial septum, and allows for clear visualization of measurements on cardiac CT images. Finally, whether eventual thinning of the interatrial septum occurs was not evaluated in patients with clinical success.
Conclusions In this study, we showed for the first time that IAST, which is readily measureable by cardiac CT, is associated with the extent of CFAE
area in the LA. Interatrial septal thickness also appears to be predictive of the acute procedural success rate of catheter ablation for persistent AF. These findings suggest that IAST can be a marker of atrial substrate and electrical remodelling of the LA in patients with persistent AF. Further large-scale, prospective studies will be required to define the pathophysiological role of the interatrial septum in atrial remodelling and clinical outcome after catheter ablation in persistent AF. Conflict of interest: none declared.
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The atrial septum was shown to be the most common site for CFAEs8 and ablation of these areas resulted in termination of AF in 95% of patients and a 1 year success rate of 76% with a single procedure.11 Previous studies demonstrated that the additional substrate modification targeting of CFAEs increased the procedural success rate and improved outcomes compared with PV isolation alone for the treatment of persistent AF.24 – 28 This study is the first to demonstrate a relationship between IAST and CFAEs of LA in AF. Previous studies found that patients with metabolic syndrome, characterized by endothelial dysfunction and obesity, had shorter fractionation intervals and a higher dominant frequency of atrial electrograms during AF. Notably, different distributions of CFAE sites and higher incidence of AF recurrence from non-PV origins were found in patients with metabolic syndrome, which suggests that metabolic syndrome may have a potential electrical effect on the atrium.29 Expanded epicardial fat infiltration may interfere with atrial conduction in patients with metabolic syndrome. As also seen in our study, the linear association between the IAST and the area of CFAEs in the LA suggests that interatrial septal fat infiltration may be directly involved in atrial conduction and electrical remodelling. In turn, the degree of IAST may serve a predictive marker for the acute intraprocedural success of AF ablation. In the previous study, the CFAE sties in LA did not correspond with exact epicardial adipose tissue locations surrounding LA;30 however, we found that the total CFAE extent can reflect total amount of epicardial adipose tissue through the degree of IAST. Even though the detailed spatial distribution was not fully evaluated, septal positioning of CFAE was well correlated with the degree of IAST.
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