CLINICAL RESEARCH
Europace (2014) 16, 840–847 doi:10.1093/europace/eut385
Ablation for atrial fibrillation
Reversal of spherical remodelling of the left atrium after pulmonary vein isolation: incidence and predictors Felipe Bisbal 1,2, Esther Guiu 1,2, Pilar Cabanas 1, Naiara Calvo1, Antonio Berruezo 1,2, Jose´ Marı´a Tolosana 1,2, Elena Arbelo 1,2, Ba´rbara Vidal 1,2, Teresa Marı´a de Caralt 1,2, Marta Sitges 1,2, Josep Brugada 1,2, and Lluı´s Mont 1,2* 1 Unitat de Fibril.lacio´ Auricular (UFA), Hospital Clı´nic, Universitat de Barcelona, 08036 Barcelona, Catalonia, Spain; and 2Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Catalonia, Spain
Received 4 June 2013; accepted after revision 13 November 2013; online publish-ahead-of-print 2 January 2014
Aims
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Catheter ablation † Remodelling † Spherical reverse remodelling † Atrial volume † Magnetic resonance
Introduction Atrial fibrillation (AF) is a well-established cause of left atrial (LA) remodelling, characterized not only by chamber enlargement,1 – 4 but also by geometrical changes including spherical deformation.5 In 1975, de Maria et al.6 showed that restoration of sinus rhythm leads to decreased LA size. Since then, extensive data have been published describing this ‘reverse remodelling’ (RR) process.
Pulmonary vein isolation (PVI) is now a routine procedure for the treatment of drug-refractory symptomatic AF.7,8 Several studies evaluating the effect of PVI on LA size have been conducted in the past decade by using different image techniques. Some reported a significant decrease in LA volume after PVI only in patients without recurrences,9 – 12 whereas others observed a decrease regardless of the clinical outcome.13 – 15 A previous study by our group showed that maximal LA volume decreased in all the patients,
* Corresponding author. Arrhythmia Section, Cardiology Department, Thorax Institute, Hospital Clinic, C/Villarroel 170, 08036 Barcelona, Spain. Tel: +34 93 2275551; fax: +34 93 4513045, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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Pulmonary vein isolation (PVI) induces left atrial (LA) volume reduction, known as reverse remodelling (RR). The related changes in LA shape have not yet been evaluated. Left atrial sphericity (LASP) is a new shape-based marker of remodelling that compares LA geometry and a perfect sphere and is a powerful predictor of PVI success. We aimed to evaluate the effect of PVI on LASP and describe the concept of spherical and volumetric RR. ..................................................................................................................................................................................... Methods Left atrial sphericity and volume were automatically obtained with self-customized software using a magnetic resonance and results imaging-based three-dimensional reconstruction of LA. Reverse remodelling was defined as improvement in LASP (spherical RR) or volume reduction (volumetric RR). In a series of 102 patients, spherical and volumetric RR was observed in 42.2 and 69%, respectively. Patients with paroxysmal atrial fibrillation (AF) had higher probability to present spherical RR as compared with patients with persistent AF (50.8 vs. 29.3%, P ¼ 0.03). Patients with persistent AF showed significant post-procedural worsening of LASP (81.9 vs. 82.9%, P ¼ 0.04). Patients with no recurrence showed a trend towards a higher proportion of spherical RR compared with those with recurrences (46.2 vs. 32.4%, respectively); no differences were observed in volumetric RR (62.1 vs. 62.9%, respectively). Paroxysmal AF was the only independent predictor of spherical RR. ..................................................................................................................................................................................... Conclusion Pulmonary vein isolation leads to spherical RR in a substantial proportion of patients, and in higher proportion of patients with paroxysmal AF. Reverse remodelling may be caused by a combination of scarring and myocardial structural recovery. Changes in LASP might be more specific than volume reduction to detect favourable remodelling.
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What’s new? † Left atrial sphericity (LASP) is a new method to evaluate and quantify the structural remodelling associated with atrial fibrillation (AF). † Left atrial sphericity has independent predictive value for AF recurrence after catheter ablation. † The present study is the first evaluating the effect of catheter ablation on LASP, defining the concept of spherical reverse remodelling, and correlating the changes in left atrial shape with changes in volume. † Atrial fibrillation ablation improves atrial geometry in a substantial proportion of patients, and a higher proportion of patients with paroxysmal AF. † Post-ablation reverse remodelling might be caused by a combination of scarring and myocardial structural recovery. † Changes in LASP could be more specific than volume reduction to detect favourable remodelling after ablation.
Methods Study population A series of 102 consecutive patients with symptomatic, drug-refractory AF in whom a cardiac magnetic resonance (CMR) study was obtained before and 6 months after PVI were included (83.6% of these patients have been included in previous studies by our group5). Exclusion criteria were age ,18 or .75 years, LA thrombus on transoesophageal echocardiography, mechanical prosthetic heart valve, and contraindications for CMR. The patients were included after written informed consent was obtained. The study protocol was approved by the hospital’s Ethics Committee.
Image acquisition Pre- and post-procedural CMR was performed by using a 1.5 Tesla scanner (Signa CV HDX-t, GE Medical Systems) and a dedicated cardiac phased-array coil. Fast spoiled gradient-echo localizer scans
Image processing All the analyses were performed as previously described,5 blinded to all clinical parameters. Only CMR data acquired before and 6 months after the first ablation procedure were analysed and included in the study. Briefly, a 3D reconstruction of LA was performed from the CMR angiography sequence by using the CARTO 3w image integration plug-in. Pulmonary veins and LA appendage were excluded at their ostia to define the LA cavity by using the mitral valve leaflets as landmarks to separate the LA from the left ventricle. The 3D LA cavity reconstruction was exported for analysis. Selfcustomized software based on MATLABw (The MathWorks) was used to automatically calculate LA volume and LASP. Left atrial sphericity evaluates the variation between the LA and the sphere that best fitted the LA shape. The average radius (AR) of such sphere is calculated as the mean of distances between all the points of the LA wall and the centre of mass. Finally, the coefficient of variation of the sphere (CVS ¼ AR standard deviation/AR) was obtained to define the LASP [(1 2 CVS) × 100].
Ablation procedure The ablation protocol has been described elsewhere.17,18 Briefly, catheters were introduced percutaneously through the right femoral vein; transseptal punctures were performed to access the LA. After transseptal access, a bolus of heparin was administered (5000 – 6000 IU, according to patient weight), followed by additional boluses to maintain an activated clotting time of 250 – 300 s. A 3D map was constructed by using an electroanatomic mapping system (CARTO, Biosense-Webster Waterloo or NAVX, St Jude Corporation) to support the creation and validation of the radiofrequency lesions. Magnetic resonance angiographic images were integrated into the navigation system to improve LA anatomical reconstruction. Continuous radiofrequency lesions were delivered to surround each ipsilateral PV. In some patients, additional ablation lines were deployed along the LA roof joining the contralateral encircling lesions and along the mitral isthmus, according to the operator’s criteria and depending on the type of AF. The endpoint was the absence or dissociation of a local electrogram inside the entire surrounded region together with exit block by pacing within the PV ostia. The endpoint of the repeated procedures was to re-isolate the PVs and achieve conduction block through the prior additional lines. In patients with documented recurrence of atypical flutter, an induction protocol (burst) was performed. Activation and entrainment maps were used to localize the circuit of the tachycardia and guide the ablation.
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probably due to scarring, whereas systolic volume only decreased after successful ablation.16 Nevertheless, there are no reports in the literature describing the RR in terms of LA shape after AF ablation. A new, shape-based marker of LA remodelling was recently described, and has demonstrated independent predictive value for AF ablation outcome.5 This new parameter compares the LA geometry and a perfect sphere and has demonstrated independent predictive value for AF ablation outcome. The proportion of patients with AF recurrence had a linear relationship with LA sphericity (LASP); the higher the LASP, the higher the probability of procedural failure.5 However, no data are available regarding the changes in LA shape after the AF ablation procedure or the clinical implications. We hypothesize that the reversibility of LA spherical deformation could be a better marker of real RR because shape should be less influenced by scarring than is volume. The purpose of the present study was to evaluate the effect of PVI on post-procedural LASP, define the concept of spherical RR, and assess the correlation between spherical and volumetric RR.
were performed in sagittal and axial views. The LA angiogram was acquired by using a breath-hold non-electrocardiogram gated twodimensional (2D) fast time-of-flight spoiled gradient-echo sequence in the axial orientation, acquired before and after an intravenous bolus of 0.4 mL/kg of gadolinium-based contrast (Omniscanw, Amersham) at a rate of 2 mL/s. An automatic bolus tracking technique in the proximal ascending aorta was used to trigger image acquisition with 2 – 7 s delay according to the heart rate, to ensure optimal visualization of the LA and PVs. The acquisition parameters were as follows: Repetition Time, 3.15 ms; echo time, 1.056 ms; flip angle, 308; bandwidth, 62.5 kHz; acquisition matrix size, 256 × 192 pixels; reconstruction matrix size, 512 × 512 pixels to yield a mean in-plane resolution of 1.4 – 1.8 mm; slice thickness, 3.2 mm with 1.6 mm overlap, reconstructed in 1.6 mm slices; and parallel imaging with an acceleration factor of 2. The pre-contrast images were automatically subtracted from the contrast images and the resulting dataset was used to create a 3D volume-rendered LA. Transthoracic echocardiography was performed to assess LA anteroposterior diameter, left ventricular dimension, and ejection fraction.
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Follow-up
was considered significant. Statistical analyses were performed by using SPSS 18.0 statistical package (SPSS) and R version 2.14.1 (the R project for statistical computing, www.r-project.org).
Patients were seen at 3, 6, and 12 months after PVI and whenever required due to the symptoms. Routine 24- or 48 h Holter monitoring was performed before each visit and the patients were also asked to communicate any episode of documented AF or symptoms suggestive of AF recurrence between scheduled visits. All the patients continued oral anticoagulation to maintain an international normalized ratio between 2.0 and 3.0 for a minimum 3-month blanking period after ablation. To manage early recurrences during the blanking period, all the patients received antiarrhythmic drugs (class IC in the absence of structural heart disease or class III otherwise). Minimum follow-up of this series was 12 months.
Results Patient characteristics In total, 102 patients were analysed [61 (59.8%) with paroxysmal AF, 31 (30.4%) with persistent AF, and 10 (9.8%) with long-standing persistent AF]. The baseline characteristics of patients with and without spherical RR are shown in Table 1. A second procedure was performed in 18 patients because of recurrent atrial arrhythmia and a third procedure in 9 of those patients (mean of 1.4 + 0.7 ablation procedures). In total, 65 patients (63.7%) received substrate ablation, mostly with an additional roofline alone (51) or in combination with other ablation sets: mitral line (10) and mitral line and CFAE ablation (2). One patient had an additional mitral line only and one had mitral line and CFAE ablation. In most cases (69.2%), additional substrate modification was performed in patients with persistent AF.
Definitions Recurrence of AF was defined as any episode of AF or flutter lasting more than 30 s recorded during follow-up after a 3-month blanking period. Spherical RR was defined as post-procedural improvement in LASP (positive D-LASP). Volumetric RR was defined as the reduction of LA volume after PVI (positive D-volume).
Statistical analysis
Clinical outcome of catheter ablation The median follow-up was 21 (range 12 –89) months. All the patients attended all the scheduled visits during at least the first year of followup. At 12-month follow-up, 60.2 and 73.0% of patients were free of arrhythmia recurrence after the first and the last PVI procedure, respectively. Atrial fibrillation was the documented arrhythmia in 70.7% of patients with recurrences, and atypical atrial flutter in 29.3%. Patients with recurrences during follow-up more often had structural heart disease (26.8 vs. 0%, P ¼ 0.002) and higher LASP (82.6 vs. 80.9%, P ¼ 0.017). There were no differences in other baseline characteristics or ablation strategy (PVI vs. PVI plus additional linear ablation).
Table 1 Baseline patient characteristics All patients (n 5 102)
Spherical RR 1 (n 5 43)
Spherical RR 2 (n 5 59)
P value
0.712
............................................................................................................................................................................... Age (years)
52.7 + 10.3
53.1 + 11.6
52.3 + 9.2
Male (%)
78%
83.7
76.3
0.373
BMI Paroxysmal AF (%)
27.1 + 3.5 59.8%
27.1 + 4.1 72.1
27.0 + 3.0 50.8
0.872 0.031*
AF period (years)a
42 (60)
48 (72)
36 (57)
0.473
Hypertension (%) SOAS (%)
35.4 17.7
32.6 15.9
41.4 10.3
0.285 0.166
Endurance sport (%)
16.5
15.8
17.6
0.529
SHD (%) Previous CVA (%)
20.3 1.3
18.6 2.4
25.4 0
0.283 0.338
LV ejection fraction (%)
57.8 + 8.9
57.4 + 9.1
58.2 + 8.7
0.652
LV end-diastolic diameter (mm) LV end-systolic diameter (mm)
52.0 + 4.4 34.3 + 5.5
52.2 + 3.9 34.1 + 5.6
51.8 + 4.8 34.5 + 5.4
0.628 0.722
LA diameter (mm)
41.4 + 5.5
41.7 + 5.3
41.1 + 4.8
0.630
LA volume (mL) LA sphericity (%)
86.4 + 25.1 81.8 + 3.4
89.5 + 22.0 81.8 + 3.1
84.2 + 27.0 81.8 + 3.5
0.290 0.987
RR, reverse remodelling; BMI, body mass index; AF, atrial fibrillation; SOAS, sleep obstructive apnoea syndrome; SHD, structural heart disease; LV, left ventricular; LA, left atrial. *Statistically significant. a Median (IQR).
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Spherical and volumetric RR were assessed only for the first ablation procedure. The recurrence rate was analysed for the first and any repeated procedure. Continuous data are expressed as mean + SD, median, and interquartile range (IQR) or number (percentage) as appropriate. The x 2 test was used to compare proportions between the groups. Student’s t and Mann – Whitney U tests were used to compare continuous variables between groups according to normality assumptions. Univariate and multivariate analyses were performed to explore the association between predictors and RR after a first procedure. Variables were included in the multivariate analysis by using a backward stepwise procedure with criteria of P , 0.05 for inclusion and P . 0.10 for removal from the model. A P value of ≤0.05
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Spherical reverse remodelling after PVI
Reverse remodelling findings
P ¼ ns) (Figure 1). A significantly greater proportion of patients with paroxysmal AF had spherical RR, compared with those with persistent AF (50.8 vs. 29.3%, P ¼ 0.03) (Figure 1). Patients with persistent AF showed post-procedural worsening of LASP (81.9 vs. 82.9%, P ¼ 0.018) (Table 2 and Figure 2). There was no significant difference
Spherical RR was present in 42.2% of patients, with mean LASP reduction (D-LASP) of 1.97 + 1.67%. Patients with no recurrence showed a trend towards a higher proportion of spherical RR compared with those with recurrences (46.2 vs. 32.4%, respectively;
Spherical reverse remodelling
Volumetric reverse remodelling
Female Male
P = ns
P = ns
HT Non-HT
P = ns
P = ns
SHD Non-SHD
P = ns
P = ns
Persistent AF Paroxysmal AF
P = 0.031
P = ns
PVI only PVI + Substrate
P = ns
P = ns
Recurrence No recurrence
P = ns
P = ns
20
30
40
50
60
70
80
20
30
40
50
60
70
80
Figure 1 Proportion of patients presenting spherical (left panel) and volumetric (right panel) reverse remodeling at 6-month follow-up.
Table 2 Comparison of pre-procedural and post-procedural LASP and LA volume in subgroups LA volume
........................................... Pre
P value
Post
LA sphericity
......................................
Pre
Post
81.9 + 3.1
82.2 + 3.9
P value
............................................................................................................................................................................... All patients
85.3 + 23.7
78.0 + 24.9
0.001*
0.273
Sex Female
80.8 + 24.8
78.5 + 26.9
0.663
82.5 + 3.7
82.7 + 4.9
0.639
Male
87.8 + 25.1
77.5 + 23.6
,0.001*
81.6 + 3.3
81.8 + 3.7
0.457
Hypertension Yes No
91.7 + 24.0
85.4 + 24.7
0.065
82.2 + 3.4
82.5 + 4.0
0.497
86.4 + 25.1
77.7 + 24.1
,0.001*
81.8 + 3.4
82.0 + 4.0
0.379
SOAS Yes
95.4 + 23.7
89.0 + 28.6
0.190
82.5 + 2.5
82.2 + 3.1
0.502
No
85.0 + 25.2
76.1 + 22.9
,0.001*
81.8 + 3.2
82.1 + 4.0
0.269
SHD Yes
101.2 + 25.7
91.3 + 24.5
0.003*
83.5 + 3.1
83.7 + 3.9
0.794
No
82.1 + 23.3
73.8 + 22.7
,0.001*
81.3 + 3.2
81.5 + 3.9
0.396
AF type Paroxysmal
81.6 + 21.1
73.4 + 22.9
,0.001*
81.6 + 3.7
81.5 + 4.3
0.601
Persistent
93.6 + 28.8
84.2 + 24.8
0.007*
81.9 + 2.8
82.9 + 3.4
0.041*
Roofline Yes
86.4 + 24.1
78.5 + 25.6
0.001*
81.8 + 3.0
82.1 + 3.8
0.425
No
78.6 + 20.8
74.4 + 20.5
0.429
82.2 + 3.8
82.9 + 4.6
0.247
Recurrence Yes No
89.3 + 30.5
79.0 + 27.3
0.010*
82.4 + 3.7
82.6 + 4.1
0.622
83.0 + 18.7
75.8 + 18.4
0.004*
81.7 + 2.7
81.9 + 3.8
0.532
LA, left atrial; AF, atrial fibrillation; SOAS, sleep obstructive apnoea syndrome; SHD, structural heart disease. *Statistically significant.
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HT, hypertension; SHD, structural heart disease; PVI, pulmonary vein isolation; Substrate, additional substrate modification.
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in the proportion of patients with additional linear ablation between patients with and without spherical RR (60.5 vs. 66.1%; P ¼ 0.353). Volumetric RR was present in 68.6% of patients, with a mean volume reduction (D-volume) of 18.2 + 11.8 mL. A significant reduction of the mean volume was observed in the study population after a first PVI procedure (86.4 + 25.1 vs. 77.7 + 24.2, P , 0.001). Significant reduction of LA volume was found only in patients in whom a roofline was deployed (8.1 + 19.7 vs. 4.6 + 16.7 mL without roofline) (Table 2). Left atrial size reduction was not
associated with procedural outcome (62.1% in patients with successful ablation vs. 62.9% of patients with procedural failure; P ¼ ns, Figure 1). Moderate but significant positive correlation was observed between pre-procedural LA volume and D-volume (r ¼ 0.4180, P , 0.001), with greater reduction in patients with larger LA, regardless of procedural outcome (Figure 3). In the overall population, D-volume and D-LASP showed a weak correlation (r ¼ 0.212; P ¼ 0.033). However, in the analysis of
Patient 2
Before ablation
Patient 1
After ablation
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Figure 2 Upper panel: Right lateral and superior view of pre-procedural LA reconstruction. Lower panel: same projections of post-procedural LA reconstruction. Case 1 (left) shows an example of worsening of LASP (D-LASP 26.05%) but volumetric RR (D-volume 12.9 mL) in a patient with persistent AF. Case 2 (right) presented spherical and volumetric RR with substantial improvement in LASP (D-LASP 6.21%) and volume decrease (D-volume 8.4 mL) after ablation of paroxysmal AF.
No recurrence
B
R = 0.418, P < 0.001 140 Left atrial volume
Left atrial volume
200
150
100
50
120 100 80
50.00
R = 0.496, P = 0.003
150
100
40
40 –50.00 –25.00 0 25.00 D-Left atrial volume
200
50
60
0
Recurrence
C
R = 0.473, P < 0.001
Left atrial volume
All patients
A
–60.00 –40.00 –20.00 0 20.00 40.00 D-Left atrial volume
–50.00 –25.00 0 25.00 D-Left atrial volume
50.00
Figure 3 Dot plots showing the lineal correlation between pre-procedural left atrial volume and post-procedural left atrial volume changes (D-volume) in the overall population (A), in patients with successful ablation (B), and patients with recurrence (C ).
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Spherical reverse remodelling after PVI
All patients
A
No recurrence
B
0
–5.00
5.00
0
R = 0.176, P = 0.33
8.00 D-Left atrial sphericity
D-Left atrial sphericity
D-Left atrial sphericity
5.00
Recurrence
C
R = 0.206, P = 0.14
R = 0.212, P = 0.033
–5.00
6.00 4.00 2.00 0 –2.00 –4.00
–50.00 –25.00 0 25.00 50.00 D-Left atrial volume
–60.00 –40.00 –20.00 0 20.00 40.00 D-Left atrial volume
–50.00 –25.00 0 25.00 D-Left atrial volume
50.00
Figure 4 Dot plots showing the lineal correlation between the change in left atrial sphericity (D-LASP) and left atrial volume (D-volume) in the overall population (A), in patients with successful ablation (B), and patients with recurrence (C).
Table 3 Univariate and multivariate analysis for prediction of RR Spherical RR
.......................................................
Volumetric RR
.....................................................
OR (95% CI)
P value
OR (95% CI)
P value
1.004 (0.962–1.048) 1.414 (0.64–4.310)
0.863 0.542
1.006 (0.963– 1.052) 2.362 (0.793– 7.035)
0.777 0.123
............................................................................................................................................................................... Age Male Hypertension
0.676 (0.262–1.748)
0.420
0.843 (0.326– 2.183)
0.725
SOAS
2.133 (0.662–6.877)
0.205
0.730 (0.226– 2.363)
0.600
Paroxysmal AF SHD
3.409 (1.274–9.121) 0.568 (0.177–1.827)
0.015* 0.343
0.754 (0.298– 1.909] 0.958 (0.308– 2.981)
0.552 0.941
LV ejection fraction
0.958 (0.904–1.015)
0.144
0.994 (0.939– 1.052)
0.824
LA sphericity LA diameter
0.960 (0.830–1.111) 1.026 (0.948–1.109)
0.586 0.525
0.974 (0.839– 1.131) 1.023 (0.945– 1.108)
0.731 0.572
LA volume
1.012 (0.992–1.031)
0.241
1.033 (1.008– 1.058)
0.008*
Roofline Recurrence
2.105 (0.514–8.628) 0.931 (0.345–2.509)
0.301 0.887
1.528 (0.422– 5.532) 0.781 (0.283– 2.160)
0.519 0.634
5.820 (1.757–19.280) 1.025 (0.997–1.054)
0.004* 0.079
1.062 (1.026– 1.099)
0.001*
Multivariate Paroxysmal AF LA volume
RR, reverse remodelling; SOAS, sleep obstructive apnoea syndrome; AF, atrial fibrillation; SHD, structural heart disease; LV, left ventricular; LA, left atrial. *Statistically significant.
subgroups with recurrence and no recurrence there was no correlation (Figure 4). A high proportion of patients with spherical RR also had LAvolume reduction (79.1%). However, only 48.6% of patients with LA size decrease also had spherical RR.
and multivariate analysis [OR 5.820 (1.757–19.280), P ¼ 0.004], showing independent predictive value. For pre-procedural prediction of volumetric RR, only LA volume demonstrated predictive value in both univariate [OR 1.033 (1.008 –1.058), P ¼ 0.008] and multivariate analysis [OR 1.062 (1.026 –1.099), P ¼ 0.001].
Prediction of reverse remodelling To identify the pre-procedural predictors of RR after AF ablation, we performed univariate and multivariate regression, adjusted by LA volume, LASP, AF type, AF recurrence, and hypertension (Table 3). Paroxysmal AF was identified as the only predictor for spherical RR in both univariate [odds ratio (OR) 3.409 (1.274 –9.121), P ¼ 0.015]
Discussion The present study had three main findings: (i) PVI led to spherical RR in a smaller proportion of patients, compared with volumetric RR; (ii) patients without recurrences were more likely to achieve spherical
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Univariate
846 RR; and (iii) patients with paroxysmal AF had a higher probability of achieving spherical RR.
Shape and volume after pulmonary vein isolation: scarring or reverse remodelling?
AF, after creation of ablation lines. Finally, a recent study in lone AF patients by Teh et al.25 showed that the abnormal atrial substrate did not reverse even after successful catheter ablation, although a significant size decrease was observed. In the present study, higher pre-procedural LA volume was correlated with greater decrease in size, according to the previous data,15 probably due to a higher retraction capacity of dilated atria (Figure 3). Moreover, pre-procedural LA volume had independent predictive value for volumetric RR. This could be more a reflection of scarrelated retraction than of RR. Another important finding of our study is that up to 52% of patients presenting volume reduction did not exhibit spherical RR. In these patients, we would suggest scar-related LA retraction as the main mechanism of LA size reduction. On the other hand, up to 80% of patients with spherical RR also had volumetric RR, which suggests that real structural RR occurs when both spherical and volumetric RR are present. In conclusion, the present study strongly suggests that real RR after PVI might be assessed in a better manner by a combination of improved LA geometry, demonstrated by changes in LASP, and LA volume reduction. While volume changes alone are associated with scarring, additional improvement in LASP appears to be a better and more specific marker of good result and myocardial recovery.
Clinical implications The presence of chronic AF increases the risk of congestive heart failure and mortality. Previous studies have demonstrated that up to 30% of paroxysmal AF will evolve to chronic AF during followup.28 Some evidence has been published showing the ‘protective’ effect of catheter ablation on the progression of the disease and the incidence of heart failure and hospitalizations.29,30 A recent publication by Jongnarangsin et al.31 reported a progression rate of paroxysmal-to-persistent AF of 0.6% per year after PVI, compared with 9% in pharmacologically treated patients. Paroxysmal AF was associated with improved LA remodelling outcomes in this case series. Therefore, we hypothesize that a PVIbased rhythm control strategy early in the course of the atrial disease (paroxysmal) may improve spherical RR, prevent the progression of structural remodelling, and thus guard against AF-related complications.
Conclusion Pulmonary vein isolation leads to spherical RR in a substantial proportion of patients, and in a higher proportion of patients with paroxysmal AF. Reverse remodelling may be caused by a combination of scarring and myocardial structural recovery. Changes in LASP might be more specific than volume reduction to detect favourable remodelling.
Acknowledgements The authors want to thank Neus Portella and Elaine M. Lilly, PhD, for editorial assistance. Conflict of interest: none declared.
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The effect of catheter ablation of AF on LA size has been previously described,16,19 – 22 showing a reduction of both LA diameter and volume. This process has been called atrial RR. In the most detailed analysis, however, diastolic LA volume decreased in all the patients, probably due to scarring, whereas systolic volume only decreased after successful ablation.16 To the best of our knowledge, this is the first study evaluating the changes in LA shape after PVI, which contributes new insights about the atrial RR process. LASP was recently described as a shape-based marker of structural LA remodelling in patients with AF.5 This parameter compares LA geometry with a perfect sphere and seems to offer a more subtle index to measure the abnormal remodelling process. A more spherical LA was observed in patients with persistent AF and structural cardiomyopathy. A spherical atrium was associated with worse clinical outcome after ablation. Moreover, LASP independently predicted AF recurrences during follow-up. However, to date, there is no information regarding the effect of PVI in terms of geometrical RR (spherical RR). In the present study, we observed some degree of improvement in LASP in nearly 42% of this series, with a significantly greater proportion occurring in patients with paroxysmal (72%) vs. persistent (28%) AF. According to the previous studies, this finding supports a better RR outcome in patients with early-stage atrial remodelling.23,24 On the other hand, a progression of spherical remodelling was observed in patients with persistent AF, suggesting that PVI had no effect on RR when the disease is in an advanced stage (Figure 2).25 In the present study, there was a trend towards a higher proportion of spherical RR in patients with successful ablation (46%) compared with those who had recurrences (32%); no differences in volumetric RR were observed. Reduction of arrhythmia burden after PVI in patients with recurrences might possibly lead to a certain degree of myocardial recovery, which would explain the lack of significant differences based on ablation success. This hypothesis could not be tested in the present series because arrhythmia burden was not assessed. Contradictory results have been reported regarding PVI effect on LA size. Some studies have shown RR only after a successful procedure,9 – 11 suggesting that the restoration of sinus rhythm leads to structural RR. In other reports13,15 and our own series, volume reduction was independent of clinical outcome. Moreover, we observed significant reduction of LA size, independent of recurrences, when a roofline was deployed, compared with patients without it. We might hypothesize that scar-induced atrial retraction, not necessarily related to success, explains the observed reduction in LA size. Wylie et al.26 describe a strong correlation between scar size, assessed by magnetic resonance imaging, and LA size and Richter et al.14 report an association between higher levels of matrix metalloproteinase-9 and transforming growth factor-b1, markers of tissue healing, and greater decrease in LA size. An experimental model in dogs with and without AF by Avitall et al.27 showed a reduction of LA size, even below the baseline LA volume of dogs without
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Spherical reverse remodelling after PVI
Funding This work was supported by the Ministerio de Ciencia e Innovacio´n, Instituto de Salud Carlos III, Madrid, Spain (Fondo Investigacio´n Sanitaria PI1102003, REDSINCOR RD06/0003/008 and Red HERACLES RD06/ 0009) and Fondo Europeo de Desarrollo Regional (FEDER), European Union.
References
15. Muller H, Noble S, Keller PF, Sigaud P, Gentil P, Lerch R et al. Biatrial anatomical reverse remodelling after radiofrequency catheter ablation for atrial fibrillation: evidence from real-time three-dimensional echocardiography. Europace 2008;10: 1073 –8. 16. Perea RJ, Tamborero D, Mont L, De Caralt TM, Ortiz JT, Berruezo A et al. Left atrial contractility is preserved after successful circumferential pulmonary vein ablation in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2008;19:374 – 9. 17. Tamborero D, Mont L, Berruezo A, Matiello M, Benito B, Sitges M et al. Left atrial posterior wall isolation does not improve the outcome of circumferential pulmonary vein ablation for atrial fibrillation: a prospective randomized study. Circ Arrhythm Electrophysiol 2009;2:35 –40. 18. Tamborero D, Mont L, Berruezo A, Guasch E, Rios J, Nadal M et al. Circumferential pulmonary vein ablation: does use of a circular mapping catheter improve results? A prospective randomized study. Heart Rhythm 2010;7:612 –8. 19. Hof IE, Velthuis BK, Chaldoupi SM, Wittkampf FH, van Driel VJ, van der Heijden JF et al. Pulmonary vein antrum isolation leads to a significant decrease of left atrial size. Europace 2011;13:371 –5. 20. Reant P, Lafitte S, Jais P, Serri K, Weerasooriya R, Hocini M et al. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation 2005;112:2896 –903. 21. Tops LF, Bax JJ, Zeppenfeld K, Jongbloed MR, van der Wall EE, Schalij MJ. Effect of radiofrequency catheter ablation for atrial fibrillation on left atrial cavity size. Am J Cardiol 2006;97:1220 –2. 22. Delgado V, Vidal B, Sitges M, Tamborero D, Mont L, Berruezo A et al. Fate of left atrial function as determined by real-time three-dimensional echocardiography study after radiofrequency catheter ablation for the treatment of atrial fibrillation. Am J Cardiol 2008;101:1285 –90. 23. Tops LF, Delgado V, Bertini M, Marsan NA, Den Uijl DW, Trines SA et al. Left atrial strain predicts reverse remodeling after catheter ablation for atrial fibrillation. J Am Coll Cardiol 2011;57:324 – 31. 24. Kuppahally SS, Akoum N, Badger TJ, Burgon NS, Haslam T, Kholmovski E et al. Echocardiographic left atrial reverse remodeling after catheter ablation of atrial fibrillation is predicted by preablation delayed enhancement of left atrium by magnetic resonance imaging. Am Heart J 2010;160:877 –84. 25. Teh AW, Kistler PM, Lee G, Medi C, Heck PM, Spence SJ et al. Long-term effects of catheter ablation for lone atrial fibrillation: progressive atrial electroanatomic substrate remodeling despite successful ablation. Heart Rhythm 2012;9: 473 –80. 26. Wylie JV Jr, Peters DC, Essebag V, Manning WJ, Josephson ME, Hauser TH. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm 2008;5: 656 –62. 27. Avitall B, Urbonas A, Urboniene D, Millard S, Helms R. Time course of left atrial mechanical recovery after linear lesions: normal sinus rhythm versus a chronic atrial fibrillation dog model. J Cardiovasc Electrophysiol 2000;11:1397 –406. 28. Nieuwlaat R, Prins MH, Le Heuzey JY, Vardas PE, Aliot E, Santini M et al. Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: followup of the euro heart survey on atrial fibrillation. Eur Heart J 2008;29:1181 –9. 29. Ouyang F, Tilz R, Chun J, Schmidt B, Wissner E, Zerm T et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation 2010;122:2368 –77. 30. Tanner H, Makowski K, Roten L, Seiler J, Schwick N, Muller C et al. Catheter ablation of atrial fibrillation as first-line therapy—a single-centre experience. Europace 2011; 13:646–53. 31. Jongnarangsin K, Suwanagool A, Chugh A, Crawford T, Good E, Pelosi F Jr et al. Effect of catheter ablation on progression of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:9– 14.
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1. Mont L, Tamborero D, Elosua R, Molina I, Coll-Vinent B, Sitges M et al. Physical activity, height, and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals. Europace 2008;10:15 –20. 2. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89: 724 –30. 3. Tsao HM, Yu WC, Cheng HC, Wu MH, Tai CT, Lin WS et al. Pulmonary vein dilation in patients with atrial fibrillation: detection by magnetic resonance imaging. J Cardiovasc Electrophysiol 2001;12:809 –13. 4. Nedios S, Tang M, Roser M, Solowjowa N, Gerds-Li JH, Fleck E et al. Characteristic changes of volume and three-dimensional structure of the left atrium in different forms of atrial fibrillation: predictive value after ablative treatment. J Interv Card Electrophysiol 2011;32:87 –94. 5. Bisbal F, Guiu E, Calvo N, Marin D, Berruezo A, Arbelo E et al. Left atrial sphericity: a new method to assess atrial remodeling. Impact on the outcome of atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013;24:752 –9. 6. DeMaria AN, Lies JE, King JF, Miller RR, Amsterdam EA, Mason DT. Echographic assessment of atrial transport, mitral movement, and ventricular performance following electroversion of supraventricular arrhythmias. Circulation 1975;51:273–82. 7. 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. 8. Arbelo E, Brugada J, Hindricks G, Maggioni A, Tavazzi L, Vardas P et al. ESCEURObservational Research Programme: the Atrial Fibrillation Ablation Pilot Study, conducted by the European Heart Rhythm Association. Europace 2012;14: 1094– 103. 9. Beukema WP, Elvan A, Sie HT, Misier AR, Wellens HJ. Successful radiofrequency ablation in patients with previous atrial fibrillation results in a significant decrease in left atrial size. Circulation 2005;112:2089 –95. 10. Marsan NA, Maffessanti F, Tamborini G, Gripari P, Caiani E, Fusini L et al. Left atrial reverse remodeling and functional improvement after mitral valve repair in degenerative mitral regurgitation: a real-time 3-dimensional echocardiography study. Am Heart J 2011;161:314 –21. 11. Jahnke C, Fischer J, Gerds-Li JH, Gebker R, Manka R, Fleck E et al. Serial monitoring of reverse left-atrial remodeling after pulmonary vein isolation in patients with atrial fibrillation: a magnetic resonance imaging study. Int J Cardiol 2011;153:42 –6. 12. Montserrat S, Sitges M, Calvo N, Silva E, Tamborero D, Vidal B et al. Effect of repeated radiofrequency catheter ablation on left atrial function for the treatment of atrial fibrillation. Am J Cardiol 2011;108:1741 –6. 13. Jayam V, Dong J, Vasamreddy C, Lickfett L, Kato R, Dickfeld T et al. Atrial volume reduction following catheter ablation of atrial fibrillation and relation to reduction in pulmonary vein size: an evaluation using magnetic resonance angiography. J Interv Card Electrophysiol 2005;13:107–14. 14. Richter B, Gwechenberger M, Socas A, Zorn G, Albinni S, Marx M et al. Time course of markers of tissue repair after ablation of atrial fibrillation and their relation to left atrial structural changes and clinical ablation outcome. Int J Cardiol 2011;152:231 –6.
847
Europace (2014) 16, 840–847 doi:10.1093/europace/eut385
Ablation for atrial fibrillation
Reversal of spherical remodelling of the left atrium after pulmonary vein isolation: incidence and predictors Felipe Bisbal 1,2, Esther Guiu 1,2, Pilar Cabanas 1, Naiara Calvo1, Antonio Berruezo 1,2, Jose´ Marı´a Tolosana 1,2, Elena Arbelo 1,2, Ba´rbara Vidal 1,2, Teresa Marı´a de Caralt 1,2, Marta Sitges 1,2, Josep Brugada 1,2, and Lluı´s Mont 1,2* 1 Unitat de Fibril.lacio´ Auricular (UFA), Hospital Clı´nic, Universitat de Barcelona, 08036 Barcelona, Catalonia, Spain; and 2Institut d’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Catalonia, Spain
Received 4 June 2013; accepted after revision 13 November 2013; online publish-ahead-of-print 2 January 2014
Aims
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Atrial fibrillation † Catheter ablation † Remodelling † Spherical reverse remodelling † Atrial volume † Magnetic resonance
Introduction Atrial fibrillation (AF) is a well-established cause of left atrial (LA) remodelling, characterized not only by chamber enlargement,1 – 4 but also by geometrical changes including spherical deformation.5 In 1975, de Maria et al.6 showed that restoration of sinus rhythm leads to decreased LA size. Since then, extensive data have been published describing this ‘reverse remodelling’ (RR) process.
Pulmonary vein isolation (PVI) is now a routine procedure for the treatment of drug-refractory symptomatic AF.7,8 Several studies evaluating the effect of PVI on LA size have been conducted in the past decade by using different image techniques. Some reported a significant decrease in LA volume after PVI only in patients without recurrences,9 – 12 whereas others observed a decrease regardless of the clinical outcome.13 – 15 A previous study by our group showed that maximal LA volume decreased in all the patients,
* Corresponding author. Arrhythmia Section, Cardiology Department, Thorax Institute, Hospital Clinic, C/Villarroel 170, 08036 Barcelona, Spain. Tel: +34 93 2275551; fax: +34 93 4513045, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
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Pulmonary vein isolation (PVI) induces left atrial (LA) volume reduction, known as reverse remodelling (RR). The related changes in LA shape have not yet been evaluated. Left atrial sphericity (LASP) is a new shape-based marker of remodelling that compares LA geometry and a perfect sphere and is a powerful predictor of PVI success. We aimed to evaluate the effect of PVI on LASP and describe the concept of spherical and volumetric RR. ..................................................................................................................................................................................... Methods Left atrial sphericity and volume were automatically obtained with self-customized software using a magnetic resonance and results imaging-based three-dimensional reconstruction of LA. Reverse remodelling was defined as improvement in LASP (spherical RR) or volume reduction (volumetric RR). In a series of 102 patients, spherical and volumetric RR was observed in 42.2 and 69%, respectively. Patients with paroxysmal atrial fibrillation (AF) had higher probability to present spherical RR as compared with patients with persistent AF (50.8 vs. 29.3%, P ¼ 0.03). Patients with persistent AF showed significant post-procedural worsening of LASP (81.9 vs. 82.9%, P ¼ 0.04). Patients with no recurrence showed a trend towards a higher proportion of spherical RR compared with those with recurrences (46.2 vs. 32.4%, respectively); no differences were observed in volumetric RR (62.1 vs. 62.9%, respectively). Paroxysmal AF was the only independent predictor of spherical RR. ..................................................................................................................................................................................... Conclusion Pulmonary vein isolation leads to spherical RR in a substantial proportion of patients, and in higher proportion of patients with paroxysmal AF. Reverse remodelling may be caused by a combination of scarring and myocardial structural recovery. Changes in LASP might be more specific than volume reduction to detect favourable remodelling.
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What’s new? † Left atrial sphericity (LASP) is a new method to evaluate and quantify the structural remodelling associated with atrial fibrillation (AF). † Left atrial sphericity has independent predictive value for AF recurrence after catheter ablation. † The present study is the first evaluating the effect of catheter ablation on LASP, defining the concept of spherical reverse remodelling, and correlating the changes in left atrial shape with changes in volume. † Atrial fibrillation ablation improves atrial geometry in a substantial proportion of patients, and a higher proportion of patients with paroxysmal AF. † Post-ablation reverse remodelling might be caused by a combination of scarring and myocardial structural recovery. † Changes in LASP could be more specific than volume reduction to detect favourable remodelling after ablation.
Methods Study population A series of 102 consecutive patients with symptomatic, drug-refractory AF in whom a cardiac magnetic resonance (CMR) study was obtained before and 6 months after PVI were included (83.6% of these patients have been included in previous studies by our group5). Exclusion criteria were age ,18 or .75 years, LA thrombus on transoesophageal echocardiography, mechanical prosthetic heart valve, and contraindications for CMR. The patients were included after written informed consent was obtained. The study protocol was approved by the hospital’s Ethics Committee.
Image acquisition Pre- and post-procedural CMR was performed by using a 1.5 Tesla scanner (Signa CV HDX-t, GE Medical Systems) and a dedicated cardiac phased-array coil. Fast spoiled gradient-echo localizer scans
Image processing All the analyses were performed as previously described,5 blinded to all clinical parameters. Only CMR data acquired before and 6 months after the first ablation procedure were analysed and included in the study. Briefly, a 3D reconstruction of LA was performed from the CMR angiography sequence by using the CARTO 3w image integration plug-in. Pulmonary veins and LA appendage were excluded at their ostia to define the LA cavity by using the mitral valve leaflets as landmarks to separate the LA from the left ventricle. The 3D LA cavity reconstruction was exported for analysis. Selfcustomized software based on MATLABw (The MathWorks) was used to automatically calculate LA volume and LASP. Left atrial sphericity evaluates the variation between the LA and the sphere that best fitted the LA shape. The average radius (AR) of such sphere is calculated as the mean of distances between all the points of the LA wall and the centre of mass. Finally, the coefficient of variation of the sphere (CVS ¼ AR standard deviation/AR) was obtained to define the LASP [(1 2 CVS) × 100].
Ablation procedure The ablation protocol has been described elsewhere.17,18 Briefly, catheters were introduced percutaneously through the right femoral vein; transseptal punctures were performed to access the LA. After transseptal access, a bolus of heparin was administered (5000 – 6000 IU, according to patient weight), followed by additional boluses to maintain an activated clotting time of 250 – 300 s. A 3D map was constructed by using an electroanatomic mapping system (CARTO, Biosense-Webster Waterloo or NAVX, St Jude Corporation) to support the creation and validation of the radiofrequency lesions. Magnetic resonance angiographic images were integrated into the navigation system to improve LA anatomical reconstruction. Continuous radiofrequency lesions were delivered to surround each ipsilateral PV. In some patients, additional ablation lines were deployed along the LA roof joining the contralateral encircling lesions and along the mitral isthmus, according to the operator’s criteria and depending on the type of AF. The endpoint was the absence or dissociation of a local electrogram inside the entire surrounded region together with exit block by pacing within the PV ostia. The endpoint of the repeated procedures was to re-isolate the PVs and achieve conduction block through the prior additional lines. In patients with documented recurrence of atypical flutter, an induction protocol (burst) was performed. Activation and entrainment maps were used to localize the circuit of the tachycardia and guide the ablation.
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probably due to scarring, whereas systolic volume only decreased after successful ablation.16 Nevertheless, there are no reports in the literature describing the RR in terms of LA shape after AF ablation. A new, shape-based marker of LA remodelling was recently described, and has demonstrated independent predictive value for AF ablation outcome.5 This new parameter compares the LA geometry and a perfect sphere and has demonstrated independent predictive value for AF ablation outcome. The proportion of patients with AF recurrence had a linear relationship with LA sphericity (LASP); the higher the LASP, the higher the probability of procedural failure.5 However, no data are available regarding the changes in LA shape after the AF ablation procedure or the clinical implications. We hypothesize that the reversibility of LA spherical deformation could be a better marker of real RR because shape should be less influenced by scarring than is volume. The purpose of the present study was to evaluate the effect of PVI on post-procedural LASP, define the concept of spherical RR, and assess the correlation between spherical and volumetric RR.
were performed in sagittal and axial views. The LA angiogram was acquired by using a breath-hold non-electrocardiogram gated twodimensional (2D) fast time-of-flight spoiled gradient-echo sequence in the axial orientation, acquired before and after an intravenous bolus of 0.4 mL/kg of gadolinium-based contrast (Omniscanw, Amersham) at a rate of 2 mL/s. An automatic bolus tracking technique in the proximal ascending aorta was used to trigger image acquisition with 2 – 7 s delay according to the heart rate, to ensure optimal visualization of the LA and PVs. The acquisition parameters were as follows: Repetition Time, 3.15 ms; echo time, 1.056 ms; flip angle, 308; bandwidth, 62.5 kHz; acquisition matrix size, 256 × 192 pixels; reconstruction matrix size, 512 × 512 pixels to yield a mean in-plane resolution of 1.4 – 1.8 mm; slice thickness, 3.2 mm with 1.6 mm overlap, reconstructed in 1.6 mm slices; and parallel imaging with an acceleration factor of 2. The pre-contrast images were automatically subtracted from the contrast images and the resulting dataset was used to create a 3D volume-rendered LA. Transthoracic echocardiography was performed to assess LA anteroposterior diameter, left ventricular dimension, and ejection fraction.
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Follow-up
was considered significant. Statistical analyses were performed by using SPSS 18.0 statistical package (SPSS) and R version 2.14.1 (the R project for statistical computing, www.r-project.org).
Patients were seen at 3, 6, and 12 months after PVI and whenever required due to the symptoms. Routine 24- or 48 h Holter monitoring was performed before each visit and the patients were also asked to communicate any episode of documented AF or symptoms suggestive of AF recurrence between scheduled visits. All the patients continued oral anticoagulation to maintain an international normalized ratio between 2.0 and 3.0 for a minimum 3-month blanking period after ablation. To manage early recurrences during the blanking period, all the patients received antiarrhythmic drugs (class IC in the absence of structural heart disease or class III otherwise). Minimum follow-up of this series was 12 months.
Results Patient characteristics In total, 102 patients were analysed [61 (59.8%) with paroxysmal AF, 31 (30.4%) with persistent AF, and 10 (9.8%) with long-standing persistent AF]. The baseline characteristics of patients with and without spherical RR are shown in Table 1. A second procedure was performed in 18 patients because of recurrent atrial arrhythmia and a third procedure in 9 of those patients (mean of 1.4 + 0.7 ablation procedures). In total, 65 patients (63.7%) received substrate ablation, mostly with an additional roofline alone (51) or in combination with other ablation sets: mitral line (10) and mitral line and CFAE ablation (2). One patient had an additional mitral line only and one had mitral line and CFAE ablation. In most cases (69.2%), additional substrate modification was performed in patients with persistent AF.
Definitions Recurrence of AF was defined as any episode of AF or flutter lasting more than 30 s recorded during follow-up after a 3-month blanking period. Spherical RR was defined as post-procedural improvement in LASP (positive D-LASP). Volumetric RR was defined as the reduction of LA volume after PVI (positive D-volume).
Statistical analysis
Clinical outcome of catheter ablation The median follow-up was 21 (range 12 –89) months. All the patients attended all the scheduled visits during at least the first year of followup. At 12-month follow-up, 60.2 and 73.0% of patients were free of arrhythmia recurrence after the first and the last PVI procedure, respectively. Atrial fibrillation was the documented arrhythmia in 70.7% of patients with recurrences, and atypical atrial flutter in 29.3%. Patients with recurrences during follow-up more often had structural heart disease (26.8 vs. 0%, P ¼ 0.002) and higher LASP (82.6 vs. 80.9%, P ¼ 0.017). There were no differences in other baseline characteristics or ablation strategy (PVI vs. PVI plus additional linear ablation).
Table 1 Baseline patient characteristics All patients (n 5 102)
Spherical RR 1 (n 5 43)
Spherical RR 2 (n 5 59)
P value
0.712
............................................................................................................................................................................... Age (years)
52.7 + 10.3
53.1 + 11.6
52.3 + 9.2
Male (%)
78%
83.7
76.3
0.373
BMI Paroxysmal AF (%)
27.1 + 3.5 59.8%
27.1 + 4.1 72.1
27.0 + 3.0 50.8
0.872 0.031*
AF period (years)a
42 (60)
48 (72)
36 (57)
0.473
Hypertension (%) SOAS (%)
35.4 17.7
32.6 15.9
41.4 10.3
0.285 0.166
Endurance sport (%)
16.5
15.8
17.6
0.529
SHD (%) Previous CVA (%)
20.3 1.3
18.6 2.4
25.4 0
0.283 0.338
LV ejection fraction (%)
57.8 + 8.9
57.4 + 9.1
58.2 + 8.7
0.652
LV end-diastolic diameter (mm) LV end-systolic diameter (mm)
52.0 + 4.4 34.3 + 5.5
52.2 + 3.9 34.1 + 5.6
51.8 + 4.8 34.5 + 5.4
0.628 0.722
LA diameter (mm)
41.4 + 5.5
41.7 + 5.3
41.1 + 4.8
0.630
LA volume (mL) LA sphericity (%)
86.4 + 25.1 81.8 + 3.4
89.5 + 22.0 81.8 + 3.1
84.2 + 27.0 81.8 + 3.5
0.290 0.987
RR, reverse remodelling; BMI, body mass index; AF, atrial fibrillation; SOAS, sleep obstructive apnoea syndrome; SHD, structural heart disease; LV, left ventricular; LA, left atrial. *Statistically significant. a Median (IQR).
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Spherical and volumetric RR were assessed only for the first ablation procedure. The recurrence rate was analysed for the first and any repeated procedure. Continuous data are expressed as mean + SD, median, and interquartile range (IQR) or number (percentage) as appropriate. The x 2 test was used to compare proportions between the groups. Student’s t and Mann – Whitney U tests were used to compare continuous variables between groups according to normality assumptions. Univariate and multivariate analyses were performed to explore the association between predictors and RR after a first procedure. Variables were included in the multivariate analysis by using a backward stepwise procedure with criteria of P , 0.05 for inclusion and P . 0.10 for removal from the model. A P value of ≤0.05
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Reverse remodelling findings
P ¼ ns) (Figure 1). A significantly greater proportion of patients with paroxysmal AF had spherical RR, compared with those with persistent AF (50.8 vs. 29.3%, P ¼ 0.03) (Figure 1). Patients with persistent AF showed post-procedural worsening of LASP (81.9 vs. 82.9%, P ¼ 0.018) (Table 2 and Figure 2). There was no significant difference
Spherical RR was present in 42.2% of patients, with mean LASP reduction (D-LASP) of 1.97 + 1.67%. Patients with no recurrence showed a trend towards a higher proportion of spherical RR compared with those with recurrences (46.2 vs. 32.4%, respectively;
Spherical reverse remodelling
Volumetric reverse remodelling
Female Male
P = ns
P = ns
HT Non-HT
P = ns
P = ns
SHD Non-SHD
P = ns
P = ns
Persistent AF Paroxysmal AF
P = 0.031
P = ns
PVI only PVI + Substrate
P = ns
P = ns
Recurrence No recurrence
P = ns
P = ns
20
30
40
50
60
70
80
20
30
40
50
60
70
80
Figure 1 Proportion of patients presenting spherical (left panel) and volumetric (right panel) reverse remodeling at 6-month follow-up.
Table 2 Comparison of pre-procedural and post-procedural LASP and LA volume in subgroups LA volume
........................................... Pre
P value
Post
LA sphericity
......................................
Pre
Post
81.9 + 3.1
82.2 + 3.9
P value
............................................................................................................................................................................... All patients
85.3 + 23.7
78.0 + 24.9
0.001*
0.273
Sex Female
80.8 + 24.8
78.5 + 26.9
0.663
82.5 + 3.7
82.7 + 4.9
0.639
Male
87.8 + 25.1
77.5 + 23.6
,0.001*
81.6 + 3.3
81.8 + 3.7
0.457
Hypertension Yes No
91.7 + 24.0
85.4 + 24.7
0.065
82.2 + 3.4
82.5 + 4.0
0.497
86.4 + 25.1
77.7 + 24.1
,0.001*
81.8 + 3.4
82.0 + 4.0
0.379
SOAS Yes
95.4 + 23.7
89.0 + 28.6
0.190
82.5 + 2.5
82.2 + 3.1
0.502
No
85.0 + 25.2
76.1 + 22.9
,0.001*
81.8 + 3.2
82.1 + 4.0
0.269
SHD Yes
101.2 + 25.7
91.3 + 24.5
0.003*
83.5 + 3.1
83.7 + 3.9
0.794
No
82.1 + 23.3
73.8 + 22.7
,0.001*
81.3 + 3.2
81.5 + 3.9
0.396
AF type Paroxysmal
81.6 + 21.1
73.4 + 22.9
,0.001*
81.6 + 3.7
81.5 + 4.3
0.601
Persistent
93.6 + 28.8
84.2 + 24.8
0.007*
81.9 + 2.8
82.9 + 3.4
0.041*
Roofline Yes
86.4 + 24.1
78.5 + 25.6
0.001*
81.8 + 3.0
82.1 + 3.8
0.425
No
78.6 + 20.8
74.4 + 20.5
0.429
82.2 + 3.8
82.9 + 4.6
0.247
Recurrence Yes No
89.3 + 30.5
79.0 + 27.3
0.010*
82.4 + 3.7
82.6 + 4.1
0.622
83.0 + 18.7
75.8 + 18.4
0.004*
81.7 + 2.7
81.9 + 3.8
0.532
LA, left atrial; AF, atrial fibrillation; SOAS, sleep obstructive apnoea syndrome; SHD, structural heart disease. *Statistically significant.
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HT, hypertension; SHD, structural heart disease; PVI, pulmonary vein isolation; Substrate, additional substrate modification.
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in the proportion of patients with additional linear ablation between patients with and without spherical RR (60.5 vs. 66.1%; P ¼ 0.353). Volumetric RR was present in 68.6% of patients, with a mean volume reduction (D-volume) of 18.2 + 11.8 mL. A significant reduction of the mean volume was observed in the study population after a first PVI procedure (86.4 + 25.1 vs. 77.7 + 24.2, P , 0.001). Significant reduction of LA volume was found only in patients in whom a roofline was deployed (8.1 + 19.7 vs. 4.6 + 16.7 mL without roofline) (Table 2). Left atrial size reduction was not
associated with procedural outcome (62.1% in patients with successful ablation vs. 62.9% of patients with procedural failure; P ¼ ns, Figure 1). Moderate but significant positive correlation was observed between pre-procedural LA volume and D-volume (r ¼ 0.4180, P , 0.001), with greater reduction in patients with larger LA, regardless of procedural outcome (Figure 3). In the overall population, D-volume and D-LASP showed a weak correlation (r ¼ 0.212; P ¼ 0.033). However, in the analysis of
Patient 2
Before ablation
Patient 1
After ablation
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Figure 2 Upper panel: Right lateral and superior view of pre-procedural LA reconstruction. Lower panel: same projections of post-procedural LA reconstruction. Case 1 (left) shows an example of worsening of LASP (D-LASP 26.05%) but volumetric RR (D-volume 12.9 mL) in a patient with persistent AF. Case 2 (right) presented spherical and volumetric RR with substantial improvement in LASP (D-LASP 6.21%) and volume decrease (D-volume 8.4 mL) after ablation of paroxysmal AF.
No recurrence
B
R = 0.418, P < 0.001 140 Left atrial volume
Left atrial volume
200
150
100
50
120 100 80
50.00
R = 0.496, P = 0.003
150
100
40
40 –50.00 –25.00 0 25.00 D-Left atrial volume
200
50
60
0
Recurrence
C
R = 0.473, P < 0.001
Left atrial volume
All patients
A
–60.00 –40.00 –20.00 0 20.00 40.00 D-Left atrial volume
–50.00 –25.00 0 25.00 D-Left atrial volume
50.00
Figure 3 Dot plots showing the lineal correlation between pre-procedural left atrial volume and post-procedural left atrial volume changes (D-volume) in the overall population (A), in patients with successful ablation (B), and patients with recurrence (C ).
845
Spherical reverse remodelling after PVI
All patients
A
No recurrence
B
0
–5.00
5.00
0
R = 0.176, P = 0.33
8.00 D-Left atrial sphericity
D-Left atrial sphericity
D-Left atrial sphericity
5.00
Recurrence
C
R = 0.206, P = 0.14
R = 0.212, P = 0.033
–5.00
6.00 4.00 2.00 0 –2.00 –4.00
–50.00 –25.00 0 25.00 50.00 D-Left atrial volume
–60.00 –40.00 –20.00 0 20.00 40.00 D-Left atrial volume
–50.00 –25.00 0 25.00 D-Left atrial volume
50.00
Figure 4 Dot plots showing the lineal correlation between the change in left atrial sphericity (D-LASP) and left atrial volume (D-volume) in the overall population (A), in patients with successful ablation (B), and patients with recurrence (C).
Table 3 Univariate and multivariate analysis for prediction of RR Spherical RR
.......................................................
Volumetric RR
.....................................................
OR (95% CI)
P value
OR (95% CI)
P value
1.004 (0.962–1.048) 1.414 (0.64–4.310)
0.863 0.542
1.006 (0.963– 1.052) 2.362 (0.793– 7.035)
0.777 0.123
............................................................................................................................................................................... Age Male Hypertension
0.676 (0.262–1.748)
0.420
0.843 (0.326– 2.183)
0.725
SOAS
2.133 (0.662–6.877)
0.205
0.730 (0.226– 2.363)
0.600
Paroxysmal AF SHD
3.409 (1.274–9.121) 0.568 (0.177–1.827)
0.015* 0.343
0.754 (0.298– 1.909] 0.958 (0.308– 2.981)
0.552 0.941
LV ejection fraction
0.958 (0.904–1.015)
0.144
0.994 (0.939– 1.052)
0.824
LA sphericity LA diameter
0.960 (0.830–1.111) 1.026 (0.948–1.109)
0.586 0.525
0.974 (0.839– 1.131) 1.023 (0.945– 1.108)
0.731 0.572
LA volume
1.012 (0.992–1.031)
0.241
1.033 (1.008– 1.058)
0.008*
Roofline Recurrence
2.105 (0.514–8.628) 0.931 (0.345–2.509)
0.301 0.887
1.528 (0.422– 5.532) 0.781 (0.283– 2.160)
0.519 0.634
5.820 (1.757–19.280) 1.025 (0.997–1.054)
0.004* 0.079
1.062 (1.026– 1.099)
0.001*
Multivariate Paroxysmal AF LA volume
RR, reverse remodelling; SOAS, sleep obstructive apnoea syndrome; AF, atrial fibrillation; SHD, structural heart disease; LV, left ventricular; LA, left atrial. *Statistically significant.
subgroups with recurrence and no recurrence there was no correlation (Figure 4). A high proportion of patients with spherical RR also had LAvolume reduction (79.1%). However, only 48.6% of patients with LA size decrease also had spherical RR.
and multivariate analysis [OR 5.820 (1.757–19.280), P ¼ 0.004], showing independent predictive value. For pre-procedural prediction of volumetric RR, only LA volume demonstrated predictive value in both univariate [OR 1.033 (1.008 –1.058), P ¼ 0.008] and multivariate analysis [OR 1.062 (1.026 –1.099), P ¼ 0.001].
Prediction of reverse remodelling To identify the pre-procedural predictors of RR after AF ablation, we performed univariate and multivariate regression, adjusted by LA volume, LASP, AF type, AF recurrence, and hypertension (Table 3). Paroxysmal AF was identified as the only predictor for spherical RR in both univariate [odds ratio (OR) 3.409 (1.274 –9.121), P ¼ 0.015]
Discussion The present study had three main findings: (i) PVI led to spherical RR in a smaller proportion of patients, compared with volumetric RR; (ii) patients without recurrences were more likely to achieve spherical
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Univariate
846 RR; and (iii) patients with paroxysmal AF had a higher probability of achieving spherical RR.
Shape and volume after pulmonary vein isolation: scarring or reverse remodelling?
AF, after creation of ablation lines. Finally, a recent study in lone AF patients by Teh et al.25 showed that the abnormal atrial substrate did not reverse even after successful catheter ablation, although a significant size decrease was observed. In the present study, higher pre-procedural LA volume was correlated with greater decrease in size, according to the previous data,15 probably due to a higher retraction capacity of dilated atria (Figure 3). Moreover, pre-procedural LA volume had independent predictive value for volumetric RR. This could be more a reflection of scarrelated retraction than of RR. Another important finding of our study is that up to 52% of patients presenting volume reduction did not exhibit spherical RR. In these patients, we would suggest scar-related LA retraction as the main mechanism of LA size reduction. On the other hand, up to 80% of patients with spherical RR also had volumetric RR, which suggests that real structural RR occurs when both spherical and volumetric RR are present. In conclusion, the present study strongly suggests that real RR after PVI might be assessed in a better manner by a combination of improved LA geometry, demonstrated by changes in LASP, and LA volume reduction. While volume changes alone are associated with scarring, additional improvement in LASP appears to be a better and more specific marker of good result and myocardial recovery.
Clinical implications The presence of chronic AF increases the risk of congestive heart failure and mortality. Previous studies have demonstrated that up to 30% of paroxysmal AF will evolve to chronic AF during followup.28 Some evidence has been published showing the ‘protective’ effect of catheter ablation on the progression of the disease and the incidence of heart failure and hospitalizations.29,30 A recent publication by Jongnarangsin et al.31 reported a progression rate of paroxysmal-to-persistent AF of 0.6% per year after PVI, compared with 9% in pharmacologically treated patients. Paroxysmal AF was associated with improved LA remodelling outcomes in this case series. Therefore, we hypothesize that a PVIbased rhythm control strategy early in the course of the atrial disease (paroxysmal) may improve spherical RR, prevent the progression of structural remodelling, and thus guard against AF-related complications.
Conclusion Pulmonary vein isolation leads to spherical RR in a substantial proportion of patients, and in a higher proportion of patients with paroxysmal AF. Reverse remodelling may be caused by a combination of scarring and myocardial structural recovery. Changes in LASP might be more specific than volume reduction to detect favourable remodelling.
Acknowledgements The authors want to thank Neus Portella and Elaine M. Lilly, PhD, for editorial assistance. Conflict of interest: none declared.
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The effect of catheter ablation of AF on LA size has been previously described,16,19 – 22 showing a reduction of both LA diameter and volume. This process has been called atrial RR. In the most detailed analysis, however, diastolic LA volume decreased in all the patients, probably due to scarring, whereas systolic volume only decreased after successful ablation.16 To the best of our knowledge, this is the first study evaluating the changes in LA shape after PVI, which contributes new insights about the atrial RR process. LASP was recently described as a shape-based marker of structural LA remodelling in patients with AF.5 This parameter compares LA geometry with a perfect sphere and seems to offer a more subtle index to measure the abnormal remodelling process. A more spherical LA was observed in patients with persistent AF and structural cardiomyopathy. A spherical atrium was associated with worse clinical outcome after ablation. Moreover, LASP independently predicted AF recurrences during follow-up. However, to date, there is no information regarding the effect of PVI in terms of geometrical RR (spherical RR). In the present study, we observed some degree of improvement in LASP in nearly 42% of this series, with a significantly greater proportion occurring in patients with paroxysmal (72%) vs. persistent (28%) AF. According to the previous studies, this finding supports a better RR outcome in patients with early-stage atrial remodelling.23,24 On the other hand, a progression of spherical remodelling was observed in patients with persistent AF, suggesting that PVI had no effect on RR when the disease is in an advanced stage (Figure 2).25 In the present study, there was a trend towards a higher proportion of spherical RR in patients with successful ablation (46%) compared with those who had recurrences (32%); no differences in volumetric RR were observed. Reduction of arrhythmia burden after PVI in patients with recurrences might possibly lead to a certain degree of myocardial recovery, which would explain the lack of significant differences based on ablation success. This hypothesis could not be tested in the present series because arrhythmia burden was not assessed. Contradictory results have been reported regarding PVI effect on LA size. Some studies have shown RR only after a successful procedure,9 – 11 suggesting that the restoration of sinus rhythm leads to structural RR. In other reports13,15 and our own series, volume reduction was independent of clinical outcome. Moreover, we observed significant reduction of LA size, independent of recurrences, when a roofline was deployed, compared with patients without it. We might hypothesize that scar-induced atrial retraction, not necessarily related to success, explains the observed reduction in LA size. Wylie et al.26 describe a strong correlation between scar size, assessed by magnetic resonance imaging, and LA size and Richter et al.14 report an association between higher levels of matrix metalloproteinase-9 and transforming growth factor-b1, markers of tissue healing, and greater decrease in LA size. An experimental model in dogs with and without AF by Avitall et al.27 showed a reduction of LA size, even below the baseline LA volume of dogs without
F. Bisbal et al.
Spherical reverse remodelling after PVI
Funding This work was supported by the Ministerio de Ciencia e Innovacio´n, Instituto de Salud Carlos III, Madrid, Spain (Fondo Investigacio´n Sanitaria PI1102003, REDSINCOR RD06/0003/008 and Red HERACLES RD06/ 0009) and Fondo Europeo de Desarrollo Regional (FEDER), European Union.
References
15. Muller H, Noble S, Keller PF, Sigaud P, Gentil P, Lerch R et al. Biatrial anatomical reverse remodelling after radiofrequency catheter ablation for atrial fibrillation: evidence from real-time three-dimensional echocardiography. Europace 2008;10: 1073 –8. 16. Perea RJ, Tamborero D, Mont L, De Caralt TM, Ortiz JT, Berruezo A et al. Left atrial contractility is preserved after successful circumferential pulmonary vein ablation in patients with atrial fibrillation. J Cardiovasc Electrophysiol 2008;19:374 – 9. 17. Tamborero D, Mont L, Berruezo A, Matiello M, Benito B, Sitges M et al. Left atrial posterior wall isolation does not improve the outcome of circumferential pulmonary vein ablation for atrial fibrillation: a prospective randomized study. Circ Arrhythm Electrophysiol 2009;2:35 –40. 18. Tamborero D, Mont L, Berruezo A, Guasch E, Rios J, Nadal M et al. Circumferential pulmonary vein ablation: does use of a circular mapping catheter improve results? A prospective randomized study. Heart Rhythm 2010;7:612 –8. 19. Hof IE, Velthuis BK, Chaldoupi SM, Wittkampf FH, van Driel VJ, van der Heijden JF et al. Pulmonary vein antrum isolation leads to a significant decrease of left atrial size. Europace 2011;13:371 –5. 20. Reant P, Lafitte S, Jais P, Serri K, Weerasooriya R, Hocini M et al. Reverse remodeling of the left cardiac chambers after catheter ablation after 1 year in a series of patients with isolated atrial fibrillation. Circulation 2005;112:2896 –903. 21. Tops LF, Bax JJ, Zeppenfeld K, Jongbloed MR, van der Wall EE, Schalij MJ. Effect of radiofrequency catheter ablation for atrial fibrillation on left atrial cavity size. Am J Cardiol 2006;97:1220 –2. 22. Delgado V, Vidal B, Sitges M, Tamborero D, Mont L, Berruezo A et al. Fate of left atrial function as determined by real-time three-dimensional echocardiography study after radiofrequency catheter ablation for the treatment of atrial fibrillation. Am J Cardiol 2008;101:1285 –90. 23. Tops LF, Delgado V, Bertini M, Marsan NA, Den Uijl DW, Trines SA et al. Left atrial strain predicts reverse remodeling after catheter ablation for atrial fibrillation. J Am Coll Cardiol 2011;57:324 – 31. 24. Kuppahally SS, Akoum N, Badger TJ, Burgon NS, Haslam T, Kholmovski E et al. Echocardiographic left atrial reverse remodeling after catheter ablation of atrial fibrillation is predicted by preablation delayed enhancement of left atrium by magnetic resonance imaging. Am Heart J 2010;160:877 –84. 25. Teh AW, Kistler PM, Lee G, Medi C, Heck PM, Spence SJ et al. Long-term effects of catheter ablation for lone atrial fibrillation: progressive atrial electroanatomic substrate remodeling despite successful ablation. Heart Rhythm 2012;9: 473 –80. 26. Wylie JV Jr, Peters DC, Essebag V, Manning WJ, Josephson ME, Hauser TH. Left atrial function and scar after catheter ablation of atrial fibrillation. Heart Rhythm 2008;5: 656 –62. 27. Avitall B, Urbonas A, Urboniene D, Millard S, Helms R. Time course of left atrial mechanical recovery after linear lesions: normal sinus rhythm versus a chronic atrial fibrillation dog model. J Cardiovasc Electrophysiol 2000;11:1397 –406. 28. Nieuwlaat R, Prins MH, Le Heuzey JY, Vardas PE, Aliot E, Santini M et al. Prognosis, disease progression, and treatment of atrial fibrillation patients during 1 year: followup of the euro heart survey on atrial fibrillation. Eur Heart J 2008;29:1181 –9. 29. Ouyang F, Tilz R, Chun J, Schmidt B, Wissner E, Zerm T et al. Long-term results of catheter ablation in paroxysmal atrial fibrillation: lessons from a 5-year follow-up. Circulation 2010;122:2368 –77. 30. Tanner H, Makowski K, Roten L, Seiler J, Schwick N, Muller C et al. Catheter ablation of atrial fibrillation as first-line therapy—a single-centre experience. Europace 2011; 13:646–53. 31. Jongnarangsin K, Suwanagool A, Chugh A, Crawford T, Good E, Pelosi F Jr et al. Effect of catheter ablation on progression of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 2012;23:9– 14.
Downloaded from by guest on February 28, 2016
1. Mont L, Tamborero D, Elosua R, Molina I, Coll-Vinent B, Sitges M et al. Physical activity, height, and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals. Europace 2008;10:15 –20. 2. Vaziri SM, Larson MG, Benjamin EJ, Levy D. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89: 724 –30. 3. Tsao HM, Yu WC, Cheng HC, Wu MH, Tai CT, Lin WS et al. Pulmonary vein dilation in patients with atrial fibrillation: detection by magnetic resonance imaging. J Cardiovasc Electrophysiol 2001;12:809 –13. 4. Nedios S, Tang M, Roser M, Solowjowa N, Gerds-Li JH, Fleck E et al. Characteristic changes of volume and three-dimensional structure of the left atrium in different forms of atrial fibrillation: predictive value after ablative treatment. J Interv Card Electrophysiol 2011;32:87 –94. 5. Bisbal F, Guiu E, Calvo N, Marin D, Berruezo A, Arbelo E et al. Left atrial sphericity: a new method to assess atrial remodeling. Impact on the outcome of atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013;24:752 –9. 6. DeMaria AN, Lies JE, King JF, Miller RR, Amsterdam EA, Mason DT. Echographic assessment of atrial transport, mitral movement, and ventricular performance following electroversion of supraventricular arrhythmias. Circulation 1975;51:273–82. 7. 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. 8. Arbelo E, Brugada J, Hindricks G, Maggioni A, Tavazzi L, Vardas P et al. ESCEURObservational Research Programme: the Atrial Fibrillation Ablation Pilot Study, conducted by the European Heart Rhythm Association. Europace 2012;14: 1094– 103. 9. Beukema WP, Elvan A, Sie HT, Misier AR, Wellens HJ. Successful radiofrequency ablation in patients with previous atrial fibrillation results in a significant decrease in left atrial size. Circulation 2005;112:2089 –95. 10. Marsan NA, Maffessanti F, Tamborini G, Gripari P, Caiani E, Fusini L et al. Left atrial reverse remodeling and functional improvement after mitral valve repair in degenerative mitral regurgitation: a real-time 3-dimensional echocardiography study. Am Heart J 2011;161:314 –21. 11. Jahnke C, Fischer J, Gerds-Li JH, Gebker R, Manka R, Fleck E et al. Serial monitoring of reverse left-atrial remodeling after pulmonary vein isolation in patients with atrial fibrillation: a magnetic resonance imaging study. Int J Cardiol 2011;153:42 –6. 12. Montserrat S, Sitges M, Calvo N, Silva E, Tamborero D, Vidal B et al. Effect of repeated radiofrequency catheter ablation on left atrial function for the treatment of atrial fibrillation. Am J Cardiol 2011;108:1741 –6. 13. Jayam V, Dong J, Vasamreddy C, Lickfett L, Kato R, Dickfeld T et al. Atrial volume reduction following catheter ablation of atrial fibrillation and relation to reduction in pulmonary vein size: an evaluation using magnetic resonance angiography. J Interv Card Electrophysiol 2005;13:107–14. 14. Richter B, Gwechenberger M, Socas A, Zorn G, Albinni S, Marx M et al. Time course of markers of tissue repair after ablation of atrial fibrillation and their relation to left atrial structural changes and clinical ablation outcome. Int J Cardiol 2011;152:231 –6.
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