Assessment of Atrial Synchrony in Paroxysmal Atrial Fibrillation and Impact of Pulmonary Vein Isolation for Atrial Dyssynchrony and Global Strain by Three-Dimensional Strain Echocardiography Yukari Kobayashi, MD, Hiroyuki Okura, MD, Yuhei Kobayashi, MD, Keisuke Okawa, MD, Kimikazu Banba, MD, Atsushi Hirohata, MD, Tomoko Tamada, MD, Kikuko Obase, MD, Akihiro Hayashida, MD, and Kiyoshi Yoshida, MD, Okayama and Kurashiki, Japan
Background: Atrial fibrillation (AF) is a risk factor for ischemic stroke and congestive heart failure. AF may cause left atrial (LA) dyssynchrony as well as electrical and mechanical remodeling. The aim of this study was to investigate LA dyssynchrony in patients with paroxysmal AF (PAF) and its recovery after pulmonary vein isolation (PVI), using a three-dimensional strain method. Methods: Thirty patients with PAF who underwent PVI were enrolled. Three-dimensional echocardiography was performed before and 3 months after PVI. Twenty subjects in whom AF had never been detected served as controls. LA dyssynchrony was quantified by the standard deviation of time to peak strain (TP-SD) from end-diastole by area tracking. Serial changes in TP-SD, LA volume, and global strain in three-dimensional echocardiography were investigated. Results: In the PAF group, TP-SD was significantly higher (9.19 6 4.98% vs 4.80 6 2.30% in controls, P < .02) and global strain significantly lower (48.2 6 20.2% vs 84.4 6 32.9% in controls, P = .0003) than in the control group. TP-SD, global strain, and LA volume all improved significantly from before to after PVI (TP-SD, from 9.19 6 4.98% to 6.31 6 2.94%, P = .005; global strain, from 48.2 6 20.2% to 58.1 6 21.2%, P = .018; LA volume index, 29.5 6 10.6 to 25.8 6 7.1 mL/m2, P = .04). Despite the improvement after PVI, TP-SD was still significantly higher and global strain lower than in controls. Conclusions: In patients with PAF, impaired LA function was documented by three-dimensional echocardiography. Despite early LA structural reverse remodeling, LA dyssynchrony was still observed 3 months after PVI. These results may affect medical therapy after successful PVI. (J Am Soc Echocardiogr 2014;27:1193-9.) Keywords: Atrial fibrillation, Left atrium, Three-dimensional echocardiography
Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice, and its prevalence is increasing with advancing age.1-3 AF is a strong risk factor not only for ischemic stroke but also for the development of congestive heart failure.4,5 In addition, AF may cause tachycardia-induced ventricular as well as atrial dysfunction, resulting in both electrophysiologic and mechanical remodeling of the atrium or left atrial (LA) enlargement.6 LA enlargement is accompanied by chronic inflammatory changes, interstitial fibrosis, and myocyte hypertrophy, which increase vulnerability to AF and further lead to LA dysfunction and thrombus forma-
From the Department of Cardiology, Sakakibara Heart Institute of Okayama, Okayama, Japan (Y.K., Yuhei. K., K.O., K.B., A.H.); Department of Cardiology, Kawasaki Medical School, Kurashiki, Japan (H.O., T.T., K.O., A.H., K.Y.). Reprint requests: Yukari Kobayashi, MD, Stanford University School of Medicine, Cardiovascular Department, 300 Pasteur Drive, Room H2170, Stanford, CA 94305 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.08.004
tion.7-9 Those changes in the atrial myocardium with fibrosis may contribute to the impairment of electrical conduction. Several studies have suggested that either noninvasive or semi-invasive methods can be used to assess LA function.10 For example, Doppler tissue imaging has been reported to be a useful method in the assessment of regional LA function.11,12 However, Doppler tissue imaging is angle dependent, which represents an important limitation. On the other hand, speckle-tracking echocardiography, which is an angle-independent echocardiographic method to assess myocardial strain, has become clinically available and enhanced our ability to evaluate the performance of the left atrium,12-16 and associations between LA strain and several clinical events or markers have been reported.17-19 Three-dimensional (3D) strain echocardiography has been developed, and its advantage for the determination of left ventricular (LV) strain and LV synchrony has been shown.20-22 Recently, its technique has been applied to left atrium as well. Mochizuki et al.23 validated the feasibility and reproducibility of 3D strain echocardiography for the determination of LA strain and synchrony, compared with two-dimensional (2D) strain echocardiography. Moreover, they reported the benefit of LA strain assessed by 3D strain 1193
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echocardiography. During ventricular systole, the atrium acts AF = Atrial fibrillation as a ‘‘reservoir,’’ and the deformation or strain obtained from the LA = Left atrial LA wall shows lengthening, LAEF = Left atrial emptying which is affected mainly by atrial fraction relaxation and stiffness.13 Time to peak strain in each segment LAVI = Left atrial volume of the left atrium is suggested to index be a potential parameter to LV = Left ventricular assess LA function. Therefore, PAF = Paroxysmal atrial atrial dyssynchrony may be asfibrillation sessed by comparing time to peak strain in each segment. PVI = Pulmonary vein isolation Recently, the standard deviation 3D = Three-dimensional of time to peak strain (TP-SD) has been used as a novel index TP-SD = Standard deviation to assess dyssynchrony in paof time to peak strain tients with AF before and after 2D = Two-dimensional defibrillation.24 At the same time, pulmonary vein isolation (PVI) has become an effective therapeutic option for drug-refractory AF,25 but there are few data on the recovery of atrial function after PVI for AF. In the present study, we assessed geometric and functional recovery, including LA dyssynchrony, of the left atrium in patients who underwent PVI for paroxysmal AF (PAF), using 3D strain speckle-tracking echocardiography.26,27 Abbreviations
METHODS We evaluated 30 patients with PAF who underwent successful PVI and maintained sinus rhythm for 3 months after PVI. They were determined as maintaining sinus rhythm according to standard 12lead electrocardiography performed at the time of echocardiography and no reports of palpitation. Standard 12-lead electrocardiography and echocardiography were performed before and 3 months after PVI in all patients. Twenty subjects who were sent to our echocardiography laboratory for screening but did not have detectable structural cardiac diseases or arrhythmias served as controls.
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endocardial contour of the left atrium was traced manually on an end-diastolic cavitary frame, and after defining the thickness of the region to be considered, the software automatically tracked the atrial wall on subsequent frames. Adequate tracking can be verified and corrected by adjusting the region of interest or the contour (Figure 1). The software automatically divided the LA wall into the following 16 segments: four segments at the roof, six segments in the middle, and six segments in the basal part (Figure 1D). While retaining the entire left atrium, depth and sector width were decreased as much as possible to improve the temporal and spatial resolution of the image, resulting in a volume rate of 36.4 6 6.2 volumes/sec in this study. LA dyssynchrony was quantified using the 3D strain speckletracking method. We analyzed area tracking, which is deformation data of the endocardial surface.28 For each segment, LA wall lengthening (positive strain value) is observed during LV systole (Figure 2). A curve plotting the average of the 16 segments’ strain curves was also automatically generated, referred to as global strain, which is an index of the amount of LA deformation. Global strain was originally established and reported to refer to the average of the each strain value obtained from 16 LV segments throughout the entire cardiac cycle. Global strain is automatically calculated and displayed as a global strain curve by the software in the echocardiographic machine, and similar to global LV strain, LA global strain was derived from the continual averaging of all segmental strain values over time and was automatically calculated and displayed. On the other hand, the averaged peak strain is the average of each peak strain value in all segments. Whereas global strain is influenced by dyssynchrony because it is the average of strain values at the same time, peak strain is not influenced by the timing of their peaks, because peak strain values have nothing to do with the time at which they appear. Time to peak strain was defined as the time from end-diastole (the R wave on the electrocardiogram) to maximal positive deformation or peak strain (Figure 2). As an index of LA dyssynchrony, TP-SD of the area tracking was computed and expressed as a percentage of the R-R0 interval, as reported previously.23,24 Higher grades of dyssynchrony were recognized as larger values of TP-SD. All echocardiographic studies were performed by an experienced cardiologist who was blinded to the patients’ clinical information. Ten subjects, including patients and controls, were randomly selected to test intra- and interobserver variability for strain and TP-SD. Their data were analyzed again 2 to 4 weeks after the first analysis by the same investigator and by a second independent investigator.
Echocardiography All echocardiographic studies were performed using a commercially available echocardiographic system (Artida; Toshiba Medical Systems, Tochigi, Japan) and a dedicated software package (Ultra Extend; Toshiba Medical Systems) with a 2.5-MHz variable-frequency harmonic phased-array transducer. Standard echocardiographic views, including apical four- and twochamber views, with the patient in the left lateral recumbent position, were obtained in 2D and color tissue Doppler modes. Mitral inflow velocities were recorded by standard pulsed-wave Doppler at the tips of the mitral valve leaflets in an apical four-chamber view. In addition to that, we evaluated LV ejection fraction, derived by using the modified Simpson’s method. All patients underwent 3D echocardiography from the apical approach to evaluate LA volume and strain analysis. After the entire left atrium was acquired, 3D data were sent to the dedicated software for subsequent offline analysis. Three-dimensional speckle-tracking analysis was done as reported previously.20,23 In brief, the
Statistical Analysis All analyses were performed using SPSS version 21 (SPSS, Inc, Chicago, IL). All continuous variables are expressed as mean 6 SD. The Shapiro-Wilk test was used to assess the distribution of continuous variables. Comparisons between two sets of continuous variables were performed using either t tests or Mann-Whitney U tests, as appropriate. Comparisons between two sets of categorical variables were done using either c2 tests or Fisher’s exact tests, as appropriate. Comparisons of continuous variables before and after PVI were performed using either paired t test or Wilcoxon signed rank sum tests, as appropriate. Medications before and after PVI were analyzed using the McNemar test. Intra- and interobserver variability were assessed in 10 randomly selected subjects, as stated previously. Intraclass correlation coefficients and the absolute difference between two paired measurements divided by the mean of the repeated observation were calculated. P values < .05 were considered significant.
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Figure 1 Three-dimensional tracking approach. After the LA endocardial contour was traced (yellow dotted line) and the epicardial contour was set (green dotted line), the software automatically tracked the atrial wall, allowing real-time adjustments and in-motion verification. (A) Apical four-chamber view, (B) apical view orthogonal to plane A, (C1) the basal portion of the left atrium, (C2) the middle portion, (C3) the roof portion, and (D) the scheme of 16 segments. RESULTS Baseline characteristics are shown in Table 1. There was no significant difference between the PAF group and the control group, except for a higher incidence of hypertension in the PAF group. In the PAF group, the average duration of PAF was 3.8 years. We were able to obtain optimal 2D echocardiographic images as well as 3D images, including speckle-tracking waveforms, from all study patients both before and after PVI. The mean 3D volume rate was 36.4 volumes/sec, which was considerably higher than that of a previous study (>15 volumes/sec). Comparisons of the baseline echocardiographic parameters between the PAF group (before PVI) and the control group are shown in Table 2. TP-SD, LA volume index (LAVI), and the E/e0 ratio (medial) were significantly larger, and global strain, peak strain, LA emptying fraction (LAEF), and medial e0 were significantly smaller in the PAF group (before PVI) than in the control group (Table 2). PVI was successfully performed in all patients, and no major complications occurred in the follow-up period. Procedural details are as follows: PVI only in 15 patients (50%), PVI and cavotricuspid isthmus line ablation in eight patients (27%), PVI and superior vena cava line ablation in four patients (13%), PVI and roof line ablation in one patient (3%), PVI and superior vena cava/cavotricuspid isthmus line ablation in one patient (3%), and Box isolation and superior vena cava line ablation in one patient (3%). There was no significant difference in medication before and after PVI (Table 3). Echocardiography demonstrated that LAVI decreased and LAEF increased significantly during 3-month follow-up. By 3D speckle-tracking echocardiography performed 3 months after PVI, TP-SD decreased significantly (from 9.19 6 4.98% to 6.31 6 2.94%, P = .005), global strain increased significantly (from 48.2 6 20.2% to 58.1 6 21.2%, P = .018), and peak strain increased (52.6 6 21.2% to 59.2 6 20.2%, P = .073), respectively. The
representative case is shown in Figure 3. In this figure, 3D speckletracking curves showed significant LA dyssynchrony before PVI. Three months after PVI, time to peak LA strain of each curve became similar, suggesting a reduction in LA dyssynchrony. Likewise, LAVI was decreased significantly and global strain and LAEF were significantly increased after PVI (Table 2). However, significant differences in TP-SD, global strain, and LAEF still remained between patients after PVI and the control group, whereas there was no significant difference in LAVI. We did not find any specific patterns in the time to peak strain data among the different LA segments. Interobserver and Intraobserver Variability For interobserver variability, the absolute differences between two paired measurements divided by the mean of the repeated observation in TP and strain values were 4.9 6 6.4% and 13.3 6 25.8%, and intraclass correlation coefficients were 0.692 (P < .001) and 0.638 (P = .001), respectively. For intraobserver variability, the absolute differences between two paired measurements divided by the mean of the repeated observation in TP and strain values were 6.2 6 6.5% and 16.6 6 11.0%, and intraclass correlation coefficients were 0.783 (P < .01) and 0.754 (P < .01), respectively.
DISCUSSION To the best of our knowledge, this is the first attempt to assess the impact of PVI on the recovery of LA function using 3D echocardiography. The main findings of our study are that (1) 3D echocardiography is feasible to evaluate LA wall deformation before and after PVI, (2) LA dyssynchrony and reduced global LA strain were observed in patients
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Table 1 Clinical characteristics Control
Before PVI
Variable
(n = 20)
(n = 30)
P
Age (y) Men Hypertension Dyslipidemia Diabetes mellitus eGFR (mL/min/1.73 m2)
57 6 18 11 (55%) 9 (45%) 4 (20%) 1 (5%) 95.0 6 25.2
64 6 10 22 (71%) 23 (74%) 11 (35%) 3 (10%) 79.3 6 23.8
.09 .88 .02 .30 .53 .08
eGFR, Estimated glomerular filtration rate. Data are expressed as mean 6 SD or as number (percentage).
Table 2 Comparison of echocardiographic characteristics
Variable
Figure 2 Derived strain curves. Time to peak (TP) was defined as the time from end-diastole (the R wave on the electrocardiogram) to maximal time positive deformation marked with circle of the curve. TP-SD was calculated as the standard deviation of TP and expressed as a percentage of the R-R0 interval. Higher grades of dyssynchrony were identified by larger values of TP-SD. with PAF, and (3) LA dyssynchrony and reduced global LA strain improve 3 months after PVI. Assessment of LA Function Patients with histories of PAF have been reported to have decreased global LA longitudinal strain, possibly due to the structural remodeling process, which conduces to electrical dissociation between muscle bundles and to local conduction heterogeneities that facilitate the initiation and perpetuation of AF. Although how reduced LA strain affects patients is unclear, considering that there was no significant difference in LAVI between post-PVI patients and controls but global strain was still significantly lower after PVI, LA strain may imply LA function more than LA volume. Moreover, it has been reported that LA strain during LV systole indicates LA reservoir function.12,13 Therefore, lower strain values possibly suggest deteriorated LA reservoir function. In our study, LA strain assessed by 3D speckletracking echocardiography was decreased in patients with PAF, which is concordant with the results of previous studies using 2D speckletracking.29,30 An advantage of 3D speckle-tracking is that it provides more spatial information on the entire cardiac chambers and more accurate measures of the LA cavity.25,26 Mochizuki et al. showed that LA strain and dyssynchrony assessed by 3D speckle-tracking were
Control
Before PVI
After PVI
(n = 20)
(n = 30)
(n = 30)
HR (beats/min) 60.0 6 10.6 66.6 6 12.9 63.3 6 9.3 Left atrium 20.7 6 6.9 29.5 6 10.6* 25.8 6 7.1† LAVI (mL/m2) LAEF (%) 56.9 6 9.9 40.2 6 10.6* 47.1 6 10.8†‡ TP-SD (%) 4.80 6 2.30 9.19 6 4.98* 6.31 6 2.94†‡ Global strain (%) 84.4 6 32.9 48.2 6 20.2* 58.1 6 21.2†‡ Peak strain (%) 88.5 6 31.1 52.6 6 21.2* 59.2 6 20.2‡ Left ventricle LVEDV (mL) 100.4 6 27.7 108.1 6 23.4 105.0 6 16.6 LVESV (mL) 39.5 6 19.5 35.8 6 9.5 36.2 6 7.5 Stroke volume (mL) 63.2 6 12.6 72.3 6 16.7 68.8 6 13.2 LVEF (%) 65.5 6 3.2 67.4 6 5.1 66.6 6 4.3 E (m/sec) 0.70 6 0.19 0.72 6 0.19 0.78 6 0.21 A (m/sec) 0.71 6 0.21 0.79 6 0.23 0.68 6 0.23 E/A ratio 1.13 6 0.57 0.94 6 0.32 1.23 6 0.35† 0 Medial e (cm/sec) 8.92 6 3.11 6.66 6 1.75* 7.05 6 2.02‡ 0 Medial a (cm/sec) 9.99 6 1.24 9.73 6 2.04* 8.22 6 2.33‡ 0 E/e ratio 8.34 6 2.41 11.22 6 3.95* 11.9 6 4.02‡ LVEF, LV ejection fraction. Data are expressed as mean 6 SD. *P < .05, control versus before PVI. † P < .05, before PVI versus after PVI. ‡ P < .05, control versus after PVI.
feasible, reproducible, and beneficial compared with those by 2D speckle-tracking for identifying patients with PAF.23 In addition to the studies described above, a previous study using 2D speckle-tracking demonstrated the improved mechanical properties of the left atrium by the recovery of LA mechanical synchrony (i.e., the reduction of dispersed atrial regional deformation as reflected by the decrease in TP-SD24), so we further assessed LA functional conditions by not only LA strain but also TP-SD using 3D echocardiography. In our present study, TP-SD was expressed as a percentage of the R-R0 interval. Because time to peak strain can be influenced by heart rate, we corrected TP-SD by the R-R0 interval, as was done by the previous investigators. In the PAF group, baseline LA global strain and peak strain were significantly lower and TP-SD was significantly higher than in the control group, suggesting that LA reservoir function is impaired in
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Table 3 Comparison of medications before and after PVI Before PVI
After PVI
Medication
(n = 30)
(n = 30)
P
Sodium channel blockers b-blockers Calcium channel blockers ACE inhibitors/ARBs Digitalis
15 (50%) 7 (23%) 12 (40%) 8 (27%) 2 (1%)
9 (30%) 8 (27%) 12 (40%) 7 (23%) 2 (1%)
.10 1.00 1.00 1.00 1.00
ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blockers.
patients with PAF. On the other hand, increased LAVI in patients with PAF may suggest the presence of LA remodeling. Efficacy of PVI in Patients with PAF Our study revealed that PVI improved LA remodeling, increased LAEF and global strain, and ameliorated LA dyssynchrony. However, there still remained LA dyssynchrony and impaired global strain between the control group and 3 months after PVI. This may suggest that LA compliance was still impaired despite early LA reverse remodeling, although no statistically significant difference in LAVI between post-PVI patients and the control group, may be derived from the small number of participants in this study. Whether these 3D echocardiographic indices will be normalized during longer term (>3 months) follow-up is still uncertain, therefore, extended followup study is needed. Interestingly, although peak systolic strain (LA wall lengthening) did not change significantly, global LA strain and LAEF were increased after PVI. These results may suggest that the improvement of LA dyssynchrony influenced the improvement of global LA strain. Therefore, TP-SD may be used as a surrogate marker of LA function. Clinical Implications In this study, we were able to detect the impairment of LA function in patients with PAF by TP-SD and the impact of PVI on LA functional recovery by 3D strain echocardiography. Several studies have reported that LA strain can be used as an accurate measurement of LA reservoir function. Moreover, reduction of LA strain has been shown to correlate with the progression of LA wall fibrosis in patients with AF assessed by magnetic resonance imaging.31 We assume that the progression of LA fibrosis prevents the left atrium from uniformly relaxing, leading to LA dyssynchrony during LA diastole. Therefore, TP-SD can possibly become a surrogate marker of LA fibrosis progression. Recently, a preprocedural degree of LA fibrosis assessed by magnetic resonance imaging has been demonstrated to be associated with the recurrence of AF after PVI.32 In that study, the authors demonstrated that patients with advanced fibrosis showed higher recurrence of arrhythmia after PVI. Also, Hammerstingl et al. showed that 2D speckle-tracking echocardiography predicts recurrence after successful AF,32 and Schneider et al. reported improvement of Doppler-derived LA strain and strain rate after successful PVI.33 Together with these previous reports, the assessment of LA function with strain values and TP-SD will possibly enable us to predict the effectiveness of PVI and the recurrence of AF. Furthermore, these parameters may be useful to determine the discontinuation of antiarrhythmic or anticoagulation therapy. LV dyssynchrony is a
Figure 3 Representative cases of strain in (A) a control subject, (B) a patient with PAF before PVI, and (C) the same patient after PVI. The patient with PAF showed higher TP-SD. After PVI, improvement of TP-SD was observed.
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well-known cause of decreased cardiac output. Similarly, LA dyssynchrony may also affect both LA filling and ejection, because LA contraction will not be fully synchronized in patients with larger TP-SD. Thus, LA dyssynchrony may be associated with impaired LV filling and increased LV filling pressure. It is possible that improved LA dyssynchrony by PVI may result in improved LV filling and reduce the chance of congestive heart failure. Considering this, LA dyssynchrony could be a target for therapy, similar to LV dyssynchrony. Limitations First, we did not measure pulmonary capillary wedge pressure, though previous studies have shown that the ratio of invasively measured pulmonary capillary wedge pressure to LA systolic strain can be used as an index of LA stiffness.34,35 Second, we applied the current 3D speckle-tracking analysis software designed for LV analysis to LA strain analysis. Dedicated software for LA analysis is needed. Third, the mechanism of LA dyssynchrony is still uncertain based only on our present results. Therefore, further studies are needed to clarify pathophysiology under LA dyssynchrony in patients with PAF. Fourth, we could not compare our results with failed PVI patients, because of the high success rate of this procedure. In our study, various different ablation procedures were used. Although the difference in the procedure might affect the results, the impact of the each procedure could not be investigated, because of small sample size. We only compared patients who underwent PVI only (n = 15) and those who underwent PVI plus any additional procedures (n=15), but we did not find any differences in the serial changes in LA dyssynchrony (data not shown). Fifth, LA volume values at the beginning and the end of the reservoir function period were not obtained in this study. These values might have provided serial changes in each component of LA function and thus clarified if there were different response in each component to the LA isolation. Finally, this study was a small, single-center study with relatively short follow-up period. Further larger scale, multicenter studies with longer follow-up periods are needed to confirm our results.
CONCLUSIONS Three-dimensional speckle-tracking is feasible to describe LA deformation. In patients with PAF, LA enlargement, reduced LA peak strain, global strain, and LA dyssynchrony were documented by 3D echocardiography. Although LA dyssynchrony and global strain improved to some extent after successful PVI, they were still within the pathologic range.
ACKNOWLEDGMENT The authors express appreciation to Shuichiro Fukuda, MT (Sakakibara Heart Institute of Okayama), for his echocardiographic work and evaluation.
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34. 35.
parameters are reduced in patients with atrial fibrillation (results from the MAGYAR-Path study). Echocardiography 2013;30:1078-83. Cameli M, Lisi M, Righini FM, Focardi M, Alfieri O, Mondillo S. Left atrial speckle tracking analysis in patients with mitral insufficiency and history of paroxysmal atrial fibrillation. Int J Cardiovasc Imaging 2012;28:1663-70. Kirchhof P, Bax J, Blomstrom-Lundquist C, Calkins H, Camm AJ, Cappato R, et al. Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNETEHRA consensus conference ‘‘Research Perspectives in AF’’. Eur Heart J 2009;30:2969-77. Kuppahally SS, Akoum N, Burgon NS, Badger TJ, Kholmovski EG, Vijayakumar S, et al. Left atrial strain and strain rate in patients with paroxysmal and persistent atrial fibrillation: relationship to left atrial structural remodeling detected by delayed-enhancement MRI. Circ Cardiovasc Imaging 2010;3:231-9. Hammerstingl C, Schwekendiek M, Momcilovic D, Schueler R, Sinning JM, Schrickel JW, et al. Left atrial deformation imaging with ultrasound based two-dimensional speckle-tracking predicts the rate of recurrence of paroxysmal and persistent atrial fibrillation after successful ablation procedures. J Cardiovasc Electrophysiol 2012;23:247-55. Schneider C, Malisius R, Krause K, Lampe F, Bahlmann E, Boczor S, et al. Strain rate imaging for functional quantification of the left atrium: atrial deformation predicts the maintenance of sinus rhythm after catheter ablation of atrial fibrillation. Eur Heart J 2008;29:1397-409. Kurt M, Wang J, Torre-Amione G, Nagueh SF. Left atrial function in diastolic heart failure. Circ Cardiovasc Imaging 2009;2:10-5. Hoit BD, Walsh RA. Regional atrial distensibility. Am J Physiol 1992;262: H1356-60.
Background: Atrial fibrillation (AF) is a risk factor for ischemic stroke and congestive heart failure. AF may cause left atrial (LA) dyssynchrony as well as electrical and mechanical remodeling. The aim of this study was to investigate LA dyssynchrony in patients with paroxysmal AF (PAF) and its recovery after pulmonary vein isolation (PVI), using a three-dimensional strain method. Methods: Thirty patients with PAF who underwent PVI were enrolled. Three-dimensional echocardiography was performed before and 3 months after PVI. Twenty subjects in whom AF had never been detected served as controls. LA dyssynchrony was quantified by the standard deviation of time to peak strain (TP-SD) from end-diastole by area tracking. Serial changes in TP-SD, LA volume, and global strain in three-dimensional echocardiography were investigated. Results: In the PAF group, TP-SD was significantly higher (9.19 6 4.98% vs 4.80 6 2.30% in controls, P < .02) and global strain significantly lower (48.2 6 20.2% vs 84.4 6 32.9% in controls, P = .0003) than in the control group. TP-SD, global strain, and LA volume all improved significantly from before to after PVI (TP-SD, from 9.19 6 4.98% to 6.31 6 2.94%, P = .005; global strain, from 48.2 6 20.2% to 58.1 6 21.2%, P = .018; LA volume index, 29.5 6 10.6 to 25.8 6 7.1 mL/m2, P = .04). Despite the improvement after PVI, TP-SD was still significantly higher and global strain lower than in controls. Conclusions: In patients with PAF, impaired LA function was documented by three-dimensional echocardiography. Despite early LA structural reverse remodeling, LA dyssynchrony was still observed 3 months after PVI. These results may affect medical therapy after successful PVI. (J Am Soc Echocardiogr 2014;27:1193-9.) Keywords: Atrial fibrillation, Left atrium, Three-dimensional echocardiography
Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice, and its prevalence is increasing with advancing age.1-3 AF is a strong risk factor not only for ischemic stroke but also for the development of congestive heart failure.4,5 In addition, AF may cause tachycardia-induced ventricular as well as atrial dysfunction, resulting in both electrophysiologic and mechanical remodeling of the atrium or left atrial (LA) enlargement.6 LA enlargement is accompanied by chronic inflammatory changes, interstitial fibrosis, and myocyte hypertrophy, which increase vulnerability to AF and further lead to LA dysfunction and thrombus forma-
From the Department of Cardiology, Sakakibara Heart Institute of Okayama, Okayama, Japan (Y.K., Yuhei. K., K.O., K.B., A.H.); Department of Cardiology, Kawasaki Medical School, Kurashiki, Japan (H.O., T.T., K.O., A.H., K.Y.). Reprint requests: Yukari Kobayashi, MD, Stanford University School of Medicine, Cardiovascular Department, 300 Pasteur Drive, Room H2170, Stanford, CA 94305 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.08.004
tion.7-9 Those changes in the atrial myocardium with fibrosis may contribute to the impairment of electrical conduction. Several studies have suggested that either noninvasive or semi-invasive methods can be used to assess LA function.10 For example, Doppler tissue imaging has been reported to be a useful method in the assessment of regional LA function.11,12 However, Doppler tissue imaging is angle dependent, which represents an important limitation. On the other hand, speckle-tracking echocardiography, which is an angle-independent echocardiographic method to assess myocardial strain, has become clinically available and enhanced our ability to evaluate the performance of the left atrium,12-16 and associations between LA strain and several clinical events or markers have been reported.17-19 Three-dimensional (3D) strain echocardiography has been developed, and its advantage for the determination of left ventricular (LV) strain and LV synchrony has been shown.20-22 Recently, its technique has been applied to left atrium as well. Mochizuki et al.23 validated the feasibility and reproducibility of 3D strain echocardiography for the determination of LA strain and synchrony, compared with two-dimensional (2D) strain echocardiography. Moreover, they reported the benefit of LA strain assessed by 3D strain 1193
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echocardiography. During ventricular systole, the atrium acts AF = Atrial fibrillation as a ‘‘reservoir,’’ and the deformation or strain obtained from the LA = Left atrial LA wall shows lengthening, LAEF = Left atrial emptying which is affected mainly by atrial fraction relaxation and stiffness.13 Time to peak strain in each segment LAVI = Left atrial volume of the left atrium is suggested to index be a potential parameter to LV = Left ventricular assess LA function. Therefore, PAF = Paroxysmal atrial atrial dyssynchrony may be asfibrillation sessed by comparing time to peak strain in each segment. PVI = Pulmonary vein isolation Recently, the standard deviation 3D = Three-dimensional of time to peak strain (TP-SD) has been used as a novel index TP-SD = Standard deviation to assess dyssynchrony in paof time to peak strain tients with AF before and after 2D = Two-dimensional defibrillation.24 At the same time, pulmonary vein isolation (PVI) has become an effective therapeutic option for drug-refractory AF,25 but there are few data on the recovery of atrial function after PVI for AF. In the present study, we assessed geometric and functional recovery, including LA dyssynchrony, of the left atrium in patients who underwent PVI for paroxysmal AF (PAF), using 3D strain speckle-tracking echocardiography.26,27 Abbreviations
METHODS We evaluated 30 patients with PAF who underwent successful PVI and maintained sinus rhythm for 3 months after PVI. They were determined as maintaining sinus rhythm according to standard 12lead electrocardiography performed at the time of echocardiography and no reports of palpitation. Standard 12-lead electrocardiography and echocardiography were performed before and 3 months after PVI in all patients. Twenty subjects who were sent to our echocardiography laboratory for screening but did not have detectable structural cardiac diseases or arrhythmias served as controls.
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endocardial contour of the left atrium was traced manually on an end-diastolic cavitary frame, and after defining the thickness of the region to be considered, the software automatically tracked the atrial wall on subsequent frames. Adequate tracking can be verified and corrected by adjusting the region of interest or the contour (Figure 1). The software automatically divided the LA wall into the following 16 segments: four segments at the roof, six segments in the middle, and six segments in the basal part (Figure 1D). While retaining the entire left atrium, depth and sector width were decreased as much as possible to improve the temporal and spatial resolution of the image, resulting in a volume rate of 36.4 6 6.2 volumes/sec in this study. LA dyssynchrony was quantified using the 3D strain speckletracking method. We analyzed area tracking, which is deformation data of the endocardial surface.28 For each segment, LA wall lengthening (positive strain value) is observed during LV systole (Figure 2). A curve plotting the average of the 16 segments’ strain curves was also automatically generated, referred to as global strain, which is an index of the amount of LA deformation. Global strain was originally established and reported to refer to the average of the each strain value obtained from 16 LV segments throughout the entire cardiac cycle. Global strain is automatically calculated and displayed as a global strain curve by the software in the echocardiographic machine, and similar to global LV strain, LA global strain was derived from the continual averaging of all segmental strain values over time and was automatically calculated and displayed. On the other hand, the averaged peak strain is the average of each peak strain value in all segments. Whereas global strain is influenced by dyssynchrony because it is the average of strain values at the same time, peak strain is not influenced by the timing of their peaks, because peak strain values have nothing to do with the time at which they appear. Time to peak strain was defined as the time from end-diastole (the R wave on the electrocardiogram) to maximal positive deformation or peak strain (Figure 2). As an index of LA dyssynchrony, TP-SD of the area tracking was computed and expressed as a percentage of the R-R0 interval, as reported previously.23,24 Higher grades of dyssynchrony were recognized as larger values of TP-SD. All echocardiographic studies were performed by an experienced cardiologist who was blinded to the patients’ clinical information. Ten subjects, including patients and controls, were randomly selected to test intra- and interobserver variability for strain and TP-SD. Their data were analyzed again 2 to 4 weeks after the first analysis by the same investigator and by a second independent investigator.
Echocardiography All echocardiographic studies were performed using a commercially available echocardiographic system (Artida; Toshiba Medical Systems, Tochigi, Japan) and a dedicated software package (Ultra Extend; Toshiba Medical Systems) with a 2.5-MHz variable-frequency harmonic phased-array transducer. Standard echocardiographic views, including apical four- and twochamber views, with the patient in the left lateral recumbent position, were obtained in 2D and color tissue Doppler modes. Mitral inflow velocities were recorded by standard pulsed-wave Doppler at the tips of the mitral valve leaflets in an apical four-chamber view. In addition to that, we evaluated LV ejection fraction, derived by using the modified Simpson’s method. All patients underwent 3D echocardiography from the apical approach to evaluate LA volume and strain analysis. After the entire left atrium was acquired, 3D data were sent to the dedicated software for subsequent offline analysis. Three-dimensional speckle-tracking analysis was done as reported previously.20,23 In brief, the
Statistical Analysis All analyses were performed using SPSS version 21 (SPSS, Inc, Chicago, IL). All continuous variables are expressed as mean 6 SD. The Shapiro-Wilk test was used to assess the distribution of continuous variables. Comparisons between two sets of continuous variables were performed using either t tests or Mann-Whitney U tests, as appropriate. Comparisons between two sets of categorical variables were done using either c2 tests or Fisher’s exact tests, as appropriate. Comparisons of continuous variables before and after PVI were performed using either paired t test or Wilcoxon signed rank sum tests, as appropriate. Medications before and after PVI were analyzed using the McNemar test. Intra- and interobserver variability were assessed in 10 randomly selected subjects, as stated previously. Intraclass correlation coefficients and the absolute difference between two paired measurements divided by the mean of the repeated observation were calculated. P values < .05 were considered significant.
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Figure 1 Three-dimensional tracking approach. After the LA endocardial contour was traced (yellow dotted line) and the epicardial contour was set (green dotted line), the software automatically tracked the atrial wall, allowing real-time adjustments and in-motion verification. (A) Apical four-chamber view, (B) apical view orthogonal to plane A, (C1) the basal portion of the left atrium, (C2) the middle portion, (C3) the roof portion, and (D) the scheme of 16 segments. RESULTS Baseline characteristics are shown in Table 1. There was no significant difference between the PAF group and the control group, except for a higher incidence of hypertension in the PAF group. In the PAF group, the average duration of PAF was 3.8 years. We were able to obtain optimal 2D echocardiographic images as well as 3D images, including speckle-tracking waveforms, from all study patients both before and after PVI. The mean 3D volume rate was 36.4 volumes/sec, which was considerably higher than that of a previous study (>15 volumes/sec). Comparisons of the baseline echocardiographic parameters between the PAF group (before PVI) and the control group are shown in Table 2. TP-SD, LA volume index (LAVI), and the E/e0 ratio (medial) were significantly larger, and global strain, peak strain, LA emptying fraction (LAEF), and medial e0 were significantly smaller in the PAF group (before PVI) than in the control group (Table 2). PVI was successfully performed in all patients, and no major complications occurred in the follow-up period. Procedural details are as follows: PVI only in 15 patients (50%), PVI and cavotricuspid isthmus line ablation in eight patients (27%), PVI and superior vena cava line ablation in four patients (13%), PVI and roof line ablation in one patient (3%), PVI and superior vena cava/cavotricuspid isthmus line ablation in one patient (3%), and Box isolation and superior vena cava line ablation in one patient (3%). There was no significant difference in medication before and after PVI (Table 3). Echocardiography demonstrated that LAVI decreased and LAEF increased significantly during 3-month follow-up. By 3D speckle-tracking echocardiography performed 3 months after PVI, TP-SD decreased significantly (from 9.19 6 4.98% to 6.31 6 2.94%, P = .005), global strain increased significantly (from 48.2 6 20.2% to 58.1 6 21.2%, P = .018), and peak strain increased (52.6 6 21.2% to 59.2 6 20.2%, P = .073), respectively. The
representative case is shown in Figure 3. In this figure, 3D speckletracking curves showed significant LA dyssynchrony before PVI. Three months after PVI, time to peak LA strain of each curve became similar, suggesting a reduction in LA dyssynchrony. Likewise, LAVI was decreased significantly and global strain and LAEF were significantly increased after PVI (Table 2). However, significant differences in TP-SD, global strain, and LAEF still remained between patients after PVI and the control group, whereas there was no significant difference in LAVI. We did not find any specific patterns in the time to peak strain data among the different LA segments. Interobserver and Intraobserver Variability For interobserver variability, the absolute differences between two paired measurements divided by the mean of the repeated observation in TP and strain values were 4.9 6 6.4% and 13.3 6 25.8%, and intraclass correlation coefficients were 0.692 (P < .001) and 0.638 (P = .001), respectively. For intraobserver variability, the absolute differences between two paired measurements divided by the mean of the repeated observation in TP and strain values were 6.2 6 6.5% and 16.6 6 11.0%, and intraclass correlation coefficients were 0.783 (P < .01) and 0.754 (P < .01), respectively.
DISCUSSION To the best of our knowledge, this is the first attempt to assess the impact of PVI on the recovery of LA function using 3D echocardiography. The main findings of our study are that (1) 3D echocardiography is feasible to evaluate LA wall deformation before and after PVI, (2) LA dyssynchrony and reduced global LA strain were observed in patients
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Table 1 Clinical characteristics Control
Before PVI
Variable
(n = 20)
(n = 30)
P
Age (y) Men Hypertension Dyslipidemia Diabetes mellitus eGFR (mL/min/1.73 m2)
57 6 18 11 (55%) 9 (45%) 4 (20%) 1 (5%) 95.0 6 25.2
64 6 10 22 (71%) 23 (74%) 11 (35%) 3 (10%) 79.3 6 23.8
.09 .88 .02 .30 .53 .08
eGFR, Estimated glomerular filtration rate. Data are expressed as mean 6 SD or as number (percentage).
Table 2 Comparison of echocardiographic characteristics
Variable
Figure 2 Derived strain curves. Time to peak (TP) was defined as the time from end-diastole (the R wave on the electrocardiogram) to maximal time positive deformation marked with circle of the curve. TP-SD was calculated as the standard deviation of TP and expressed as a percentage of the R-R0 interval. Higher grades of dyssynchrony were identified by larger values of TP-SD. with PAF, and (3) LA dyssynchrony and reduced global LA strain improve 3 months after PVI. Assessment of LA Function Patients with histories of PAF have been reported to have decreased global LA longitudinal strain, possibly due to the structural remodeling process, which conduces to electrical dissociation between muscle bundles and to local conduction heterogeneities that facilitate the initiation and perpetuation of AF. Although how reduced LA strain affects patients is unclear, considering that there was no significant difference in LAVI between post-PVI patients and controls but global strain was still significantly lower after PVI, LA strain may imply LA function more than LA volume. Moreover, it has been reported that LA strain during LV systole indicates LA reservoir function.12,13 Therefore, lower strain values possibly suggest deteriorated LA reservoir function. In our study, LA strain assessed by 3D speckletracking echocardiography was decreased in patients with PAF, which is concordant with the results of previous studies using 2D speckletracking.29,30 An advantage of 3D speckle-tracking is that it provides more spatial information on the entire cardiac chambers and more accurate measures of the LA cavity.25,26 Mochizuki et al. showed that LA strain and dyssynchrony assessed by 3D speckle-tracking were
Control
Before PVI
After PVI
(n = 20)
(n = 30)
(n = 30)
HR (beats/min) 60.0 6 10.6 66.6 6 12.9 63.3 6 9.3 Left atrium 20.7 6 6.9 29.5 6 10.6* 25.8 6 7.1† LAVI (mL/m2) LAEF (%) 56.9 6 9.9 40.2 6 10.6* 47.1 6 10.8†‡ TP-SD (%) 4.80 6 2.30 9.19 6 4.98* 6.31 6 2.94†‡ Global strain (%) 84.4 6 32.9 48.2 6 20.2* 58.1 6 21.2†‡ Peak strain (%) 88.5 6 31.1 52.6 6 21.2* 59.2 6 20.2‡ Left ventricle LVEDV (mL) 100.4 6 27.7 108.1 6 23.4 105.0 6 16.6 LVESV (mL) 39.5 6 19.5 35.8 6 9.5 36.2 6 7.5 Stroke volume (mL) 63.2 6 12.6 72.3 6 16.7 68.8 6 13.2 LVEF (%) 65.5 6 3.2 67.4 6 5.1 66.6 6 4.3 E (m/sec) 0.70 6 0.19 0.72 6 0.19 0.78 6 0.21 A (m/sec) 0.71 6 0.21 0.79 6 0.23 0.68 6 0.23 E/A ratio 1.13 6 0.57 0.94 6 0.32 1.23 6 0.35† 0 Medial e (cm/sec) 8.92 6 3.11 6.66 6 1.75* 7.05 6 2.02‡ 0 Medial a (cm/sec) 9.99 6 1.24 9.73 6 2.04* 8.22 6 2.33‡ 0 E/e ratio 8.34 6 2.41 11.22 6 3.95* 11.9 6 4.02‡ LVEF, LV ejection fraction. Data are expressed as mean 6 SD. *P < .05, control versus before PVI. † P < .05, before PVI versus after PVI. ‡ P < .05, control versus after PVI.
feasible, reproducible, and beneficial compared with those by 2D speckle-tracking for identifying patients with PAF.23 In addition to the studies described above, a previous study using 2D speckle-tracking demonstrated the improved mechanical properties of the left atrium by the recovery of LA mechanical synchrony (i.e., the reduction of dispersed atrial regional deformation as reflected by the decrease in TP-SD24), so we further assessed LA functional conditions by not only LA strain but also TP-SD using 3D echocardiography. In our present study, TP-SD was expressed as a percentage of the R-R0 interval. Because time to peak strain can be influenced by heart rate, we corrected TP-SD by the R-R0 interval, as was done by the previous investigators. In the PAF group, baseline LA global strain and peak strain were significantly lower and TP-SD was significantly higher than in the control group, suggesting that LA reservoir function is impaired in
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Table 3 Comparison of medications before and after PVI Before PVI
After PVI
Medication
(n = 30)
(n = 30)
P
Sodium channel blockers b-blockers Calcium channel blockers ACE inhibitors/ARBs Digitalis
15 (50%) 7 (23%) 12 (40%) 8 (27%) 2 (1%)
9 (30%) 8 (27%) 12 (40%) 7 (23%) 2 (1%)
.10 1.00 1.00 1.00 1.00
ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blockers.
patients with PAF. On the other hand, increased LAVI in patients with PAF may suggest the presence of LA remodeling. Efficacy of PVI in Patients with PAF Our study revealed that PVI improved LA remodeling, increased LAEF and global strain, and ameliorated LA dyssynchrony. However, there still remained LA dyssynchrony and impaired global strain between the control group and 3 months after PVI. This may suggest that LA compliance was still impaired despite early LA reverse remodeling, although no statistically significant difference in LAVI between post-PVI patients and the control group, may be derived from the small number of participants in this study. Whether these 3D echocardiographic indices will be normalized during longer term (>3 months) follow-up is still uncertain, therefore, extended followup study is needed. Interestingly, although peak systolic strain (LA wall lengthening) did not change significantly, global LA strain and LAEF were increased after PVI. These results may suggest that the improvement of LA dyssynchrony influenced the improvement of global LA strain. Therefore, TP-SD may be used as a surrogate marker of LA function. Clinical Implications In this study, we were able to detect the impairment of LA function in patients with PAF by TP-SD and the impact of PVI on LA functional recovery by 3D strain echocardiography. Several studies have reported that LA strain can be used as an accurate measurement of LA reservoir function. Moreover, reduction of LA strain has been shown to correlate with the progression of LA wall fibrosis in patients with AF assessed by magnetic resonance imaging.31 We assume that the progression of LA fibrosis prevents the left atrium from uniformly relaxing, leading to LA dyssynchrony during LA diastole. Therefore, TP-SD can possibly become a surrogate marker of LA fibrosis progression. Recently, a preprocedural degree of LA fibrosis assessed by magnetic resonance imaging has been demonstrated to be associated with the recurrence of AF after PVI.32 In that study, the authors demonstrated that patients with advanced fibrosis showed higher recurrence of arrhythmia after PVI. Also, Hammerstingl et al. showed that 2D speckle-tracking echocardiography predicts recurrence after successful AF,32 and Schneider et al. reported improvement of Doppler-derived LA strain and strain rate after successful PVI.33 Together with these previous reports, the assessment of LA function with strain values and TP-SD will possibly enable us to predict the effectiveness of PVI and the recurrence of AF. Furthermore, these parameters may be useful to determine the discontinuation of antiarrhythmic or anticoagulation therapy. LV dyssynchrony is a
Figure 3 Representative cases of strain in (A) a control subject, (B) a patient with PAF before PVI, and (C) the same patient after PVI. The patient with PAF showed higher TP-SD. After PVI, improvement of TP-SD was observed.
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well-known cause of decreased cardiac output. Similarly, LA dyssynchrony may also affect both LA filling and ejection, because LA contraction will not be fully synchronized in patients with larger TP-SD. Thus, LA dyssynchrony may be associated with impaired LV filling and increased LV filling pressure. It is possible that improved LA dyssynchrony by PVI may result in improved LV filling and reduce the chance of congestive heart failure. Considering this, LA dyssynchrony could be a target for therapy, similar to LV dyssynchrony. Limitations First, we did not measure pulmonary capillary wedge pressure, though previous studies have shown that the ratio of invasively measured pulmonary capillary wedge pressure to LA systolic strain can be used as an index of LA stiffness.34,35 Second, we applied the current 3D speckle-tracking analysis software designed for LV analysis to LA strain analysis. Dedicated software for LA analysis is needed. Third, the mechanism of LA dyssynchrony is still uncertain based only on our present results. Therefore, further studies are needed to clarify pathophysiology under LA dyssynchrony in patients with PAF. Fourth, we could not compare our results with failed PVI patients, because of the high success rate of this procedure. In our study, various different ablation procedures were used. Although the difference in the procedure might affect the results, the impact of the each procedure could not be investigated, because of small sample size. We only compared patients who underwent PVI only (n = 15) and those who underwent PVI plus any additional procedures (n=15), but we did not find any differences in the serial changes in LA dyssynchrony (data not shown). Fifth, LA volume values at the beginning and the end of the reservoir function period were not obtained in this study. These values might have provided serial changes in each component of LA function and thus clarified if there were different response in each component to the LA isolation. Finally, this study was a small, single-center study with relatively short follow-up period. Further larger scale, multicenter studies with longer follow-up periods are needed to confirm our results.
CONCLUSIONS Three-dimensional speckle-tracking is feasible to describe LA deformation. In patients with PAF, LA enlargement, reduced LA peak strain, global strain, and LA dyssynchrony were documented by 3D echocardiography. Although LA dyssynchrony and global strain improved to some extent after successful PVI, they were still within the pathologic range.
ACKNOWLEDGMENT The authors express appreciation to Shuichiro Fukuda, MT (Sakakibara Heart Institute of Okayama), for his echocardiographic work and evaluation.
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