Transthoracic echocardiographic backscatter-based assessment of left atrial remodeling involving left atrial and ventricular fibrosis in patients with atrial fibrillation

International Journal of Cardiology 176 (2014) 1064–1066

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Letter to the Editor

Transthoracic echocardiographic backscatter-based assessment of left atrial remodeling involving left atrial and ventricular fibrosis in patients with atrial fibrillation Naoko Sasaki, Yasuo Okumura ⁎, Ichiro Watanabe, Koichi Nagashima, Kazumasa Sonoda, Rikitake Kogawa, Keiko Takahashi, Kazuki Iso, Kimie Ohkubo, Toshiko Nakai, Takafumi Hiro, Atsushi Hirayama Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

a r t i c l e

i n f o

Article history: Received 29 May 2014 Accepted 26 July 2014 Available online 2 August 2014 Keywords: Atrial fibrosis Ventricular fibrosis Integrated backscatter Atrial fibrillation Catheter ablation

Left atrial (LA) fibrosis is a hallmark of atrial structural remodeling [1–3] and is related to recurrence after atrial fibrillation (AF) ablation, but the relationship to left ventricle (LV) fibrosis [4–6] remains unknown. Echocardiography-derived integrated backscatter (IBS) can noninvasively quantify myocardial fibrosis. Therefore, we used IBS to investigate whether a relationship exists between the LA and LV fibroses in AF and its impact on the post-ablation results. We studied 113 patients (mean age, 58.6 ± 9.7 years; 56 paroxysmal AF) who underwent their first catheter ablation of AF between September 2010 and January 2014 at Nihon University Itabashi Hospital. The exclusion criteria were: any valvular heart disease (moderate to severe state), LV contraction abnormality, LV hypertrophy, idiopathic cardiomyopathy, chronic pulmonary disease or thyroid disease. Randomly-selected patient records from our institution's echocardiographic database from May to August 2013, of 21 age- and sexmatched patients with no evidence of AF or heart disease, were accessed for the control data. All subjects signed a written informed consent, which was approved by the Institutional Review Board of Nihon University Itabashi Hospital.

⁎ Corresponding author at: 30-1 Ohyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan. Tel.: +81 3 3972 8111; fax: +81 3 3972 1098. E-mail address: [email protected] (Y. Okumura).

http://dx.doi.org/10.1016/j.ijcard.2014.07.138 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Comprehensive transthoracic echocardiography was performed in the AF patients 1 day before the ablation and in the control patients at the time of their outpatient clinic visit(s) using an ultrasound system with a 3.5-MHz transducer (GE Healthcare UK Ltd., Buckinghamshire, UK) [7]. The two-dimensional (2D) data in the parasternal short- and long-axis views were stored in a cine-loop format with an adjustment in the gain settings and depth [7]. The calibrated IBS, which is based on 2D gray-scale images, is a measure of the myocardial ultrasound reflectivity and can be used to estimate myocardial fibrosis. IBS is expressed in decibels (dB); normal myocardium has intermediate ultrasound reflectivity, but this may increase as the fibrotic content increases and the IBS values are near 0 dB. The IBS values were determined at the middle portion of the posterior LA in the parasternal long-axis view and the anterior and posterior walls of the LV sectioned at the papillary muscle in the parasternal short-axis view at 80–120 frames/s in a fixed 2 × 3-mm region using an off-line analysis (EchoPAC BT 11, GE Healthcare UK). To calibrate the IBS values of the myocardium, the IBS of the corresponded-pericardium was subtracted from the IBS for each myocardial element (Fig. 1). All measurements were performed by sonographers and cardiologists with no knowledge of the patients' background. As previously described [8], AF patients underwent an extensive ipsilateral pulmonary vein isolation (PVI) using an irrigated-tip catheter and three-dimensional mapping system. The endpoint of the ablation was a complete PVI with entrance and exit blocks and an LA ablation if AF was not terminated after the PVI. AF recurrence was defined as AF lasting more than 30 s after a 2-month post-ablation blanking period. Statistical analyses were performed using JMP 10 software. Unpaired t-test, Mann-Whitney U test or chi-square test was used to evaluate the significant differences between the two groups. We performed one-way ANOVA with a post-hoc Tukey honest significant difference test to analyze the continuous variables between the three groups. Multivariate Cox regression model was used to determine the predictors of post-ablation AF recurrence. P b 0.05 was considered significant. Table 1 shows the clinical characteristics of the enrolled subjects. The patients with AF had a significantly higher prevalence of heart failure, and use of beta-blockers and antiarrhythmic agents. The patients with persistent AF had a greater LA and a lower LV ejection fraction (LVEF) than the patients in the other two groups (P b 0.05). In

N. Sasaki et al. / International Journal of Cardiology 176 (2014) 1064–1066

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Fig. 1. Measurements of the integrated backscatter of the LA and LV. (A) In the parasternal long-axis view, the IBS of the pericardium (red line) and LA (yellow line) is shown. (B) In the short axis view of the LV at the papillary muscle level, the IBS of the pericardium (red line), anterior LV (yellow line) and posterior LV (blue line) is shown. To calibrate the IBS values of the myocardium, the IBS of the pericardium is subtracted from the IBS for each myocardial element. LA = left atrium; LV = left ventricle; IBS = integrated backscatter.

Table 1 Clinical characteristics and echocardiographic variables in the three study groups. Characteristic

Control (n = 21)

Paroxysmal AF (n = 56)

Persistent AF (n = 57)

P value

Age, years Sex, male AF duration, months Body mass index, kg/m2 Comorbidity Hypertension Diabetes mellitus Ischemic heart disease Dyslipidemia Heart failure Medications Class I antiarrhythmic drug Class III antiarrhythmic drug ARB or ACE inhibitor Beta-blocker Calcium channel blocker Statin Echocardiography LAD, mm LAV, mL/m2 LV diastolic dimension, mm IVS thickness, mm PW thickness, mm LVEF, % LVEDV, mL/m2 E/Aa E/E′ (septal) E/E′ (lateral)

60.8 ± 9.6 17 (81) 23.4 ± 3.0

59.4 ± 9.3 49 (88) 36 (14–59) 23.6 ± 4.1

57.8 ± 10.2 46 (81) 49 (22–85) 23.7 ± 3.4

0.4216 0.5837 0.0888 0.9525

9 (43) 2 (10) 1 (5)

29 (53) 3 (5) 3 (5)

36 (63) 5 (9) 0 (0)

0.2364 0.7456 0.2103

3 (14) 0 (0)

8 (15) 15 (27)⁎

3 (5) 18 (32)⁎

0.2432 0.0142

0 (0)

24 (44)⁎⁎

28 (49)⁎⁎

0.0003

0 (0)

13 (24)⁎⁎

26 (44)⁎⁎,†

0.0002

9 (43) 1 (5) 2 (10)

20 (36) 24 (44)⁎⁎ 13 (24)

28 (47) 27 (47)⁎⁎ 15 (26)

0.4975 0.0019 0.2809

3 (14)

7 (13)

3 (5)

0.3098

34.3 ± 6.0 37.2 ± 5.6 41.0 ± 6.0⁎⁎,†† b0.0001 29.2 ± 10.7 41.6 ± 16.0⁎ 54.1 ± 22.1⁎⁎,†† b0.0001 47.7 ± 4.1 48.9 ± 5.8 50.2 ± 6.0 0.2052 9.2 ± 1.3 9.5 ± 1.5 70.2 ± 4.7 90 ± 11 1.0 ± 0.3 10.7 ± 3.7 8.1 ± 3.5

9.5 ± 1.7 9.5 ± 1.4 66.5 ± 9.0 93 ± 23 1.3 ± 0.6 10.5 ± 5.1 6.8 ± 2.5

9.5 ± 1.7 9.8 ± 1.4 64.0 ± 7.0⁎⁎ 96 ± 21 1.1 ± 0.4 11.0 ± 5.2 8.6 ± 6.0

0.7051 0.4096 0.0064 0.4372 0.1166 0.8710 0.1158

Values are mean ± SD, median (interquartile range), or n (%). For comparisons across the 3 groups, ANOVA was used for the parametric variables, and post-hoc analysis was performed with Tukey honest significance test. AF = atrial fibrillation; ARB = angiotensin receptor blocker; ACE = angiotensin-converting enzyme; LAD = left atrial dimension; LAV = left atrial volume; IVS = interventricular septum; PW = posterior wall; LVEF = left ventricular ejection fraction; LVEDV = left ventricular end-diastolic volume. The bolds indicates the signficant differences (P b 0.05) between the groups. a Abandoned in 16 paroxysmal AF patients and 43 persistent AF patients because of the presence of AF rhythm at the time of evaluation. ⁎ P b 0.05 vs. value in the control patients. ⁎⁎ P b 0.01 vs. value in the control patients. † P b 0.05 vs. value in the paroxysmal AF patients. †† P b 0.01 vs. value in the paroxysmal AF patients.

comparison to the control values, the calibrated IBS values of the LA increased in the paroxysmal AF patients and further increased in the persistent AF patients (−16.1 ± 2.7 vs. −13.7 ± 3.6 vs. −11.8 ± 4.5 dB, respectively, P b 0.0001). These findings held true for the calibrated IBS values of the anterior LV and posterior LV (Fig. 2). During the 13.8 (8.7–19.9)-month follow-up, AF recurred in 17 (30.4%) paroxysmal and 34 (59.6%) persistent AF patients. Although no predictors of recurrence were found in the paroxysmal AF group, recurrence among the persistent AF patients was associated with LA enlargement (P = 0.0357), and a high calibrated IBS of the LA (P = 0.0332) and LV anterior walls (P = 0.0236) (Table 2). Multivariate analysis showed that the IBS of the LA was the only independent predictor of post-ablation recurrence in patients with persistent AF (hazard ratio for + 1-dB change, 1.07; 95% confidence interval 1.01– 1.04; P= 0.0334). The depicted fibrotic changes differed between the controls and AF patients, and there was a steady increase in the fibrotic changes of the LA and LV in the AF patients. Importantly, the calibrated IBS of both the LA and LV was significantly associated with the presence of AF. The myocardial IBS reflects the collagen content of the myocardial tissue [4–6]. Thus, our results imply that fibrotic changes occur not only in the LA, but also in the LV with progressive structural atrial remodeling associated with AF. Interestingly, the AF recurrence in the persistent AF group was associated with the calibrated IBS not only of the LA, but also of the LV, by univariate analysis, but the calibrated IBS of the LA was the only predictor of AF recurrence after multivariate analysis. This suggests that AFinduced LA remodeling was linked to LV remodeling, and the persistence of AF may lead to structural remodeling in the LA much more than in the LV, which may explain the results shown in the multivariate analysis. No association between LA remodeling and AF recurrence was shown in our paroxysmal AF group, indicating the fact that most patients with recurrent paroxysmal AF had a conduction recurrence across disconnected lesions rather than progressive atrial remodeling [2]. In conclusion, although fibrosis is present in both the LA and LV in AF patients, LA fibrosis is the only useful predictor of post-ablation recurrence, and only in patients with persistent AF.

Conflict of interest None.

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Fig. 2. Comparison of the calibrated IBS values of the LA and LV. The calibrated IBS of the LA (A), anterior LV (B) and posterior LV (C) in the control (gray circles), paroxysmal atrial fibrillation (AF) (black circles) and persistent AF (white circles) patients is shown. The IBS values of the LA and LV are increased in the paroxysmal and persistent AF patients (in comparison to the values in the control patients), with a greater increase in the persistent AF patients. The abbreviations are as in Fig. 1.

References [1] Cappato R, Negroni S, Pecora D, et al. Prospective assessment of late conduction recurrence across radiofrequency lesions producing electrical disconnection at the pulmonary vein ostium in patients with atrial fibrillation. Circulation 2003;108:1599–604. [2] Kubota T, Kawasaki M, Takasugi N, et al. Evaluation of left atrial degeneration for the prediction of atrial fibrillation: usefulness of integrated backscatter transesophageal echocardiography. JACC Cardiovasc Imaging 2009;2:1039–47. [3] Wang GD, Shen LH, Wang L, Li HW, Zhang YC, Chen H. Relationship between integrated backscatter and atrial fibrosis in patients with and without atrial fibrillation who are undergoing coronary bypass surgery. Clin Cardiol 2009;32:56–61. [4] Picano E, Pelosi G, Marzilli M, et al. In vivo quantitative ultrasonic evaluation of myocardial fibrosis in humans. Circulation 1990;81:58–64. [5] Ciulla M, Paliotti R, Hess DB, et al. Echocardiographic patterns of myocardial fibrosis in hypertensive patients: endomyocardial biopsy versus ultrasonic tissue characterization. J Am Soc Echocardiogr 1997;10:657–64.

[6] Di Bello V, Giorgi D, Talini E, et al. Incremental value of ultrasonic tissue characterization (backscatter) in the evaluation of left ventricular myocardial structure and mechanics in essential arterial hypertension. Circulation 2003;107:74–80. [7] Lang RM, Bierig M, Devereux RB, et al. Chamber Quantification Writing Group; American Society of Echocardiography's Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [8] Okumura Y, Watanabe I, Kofune M, et al. Impact of biomarkers of inflammation and extracellular matrix turnover on the outcome of atrial fibrillation. J Cardiovasc Electrophysiol 2011;22:987–93.

Table 2 Predictors of AF recurrence in patients with paroxysmal AF and persistent AF. Factor

Age, years Sex, male AF duration, months BMI, kg/m2 Hypertension Heart failure Class I antiarrhythmic drugs Class III antiarrhythmic drugs ARB or ACE inhibitor Beta-blockers Calcium channel blockers AF termination by PVI LAD, mm LAV, mL/m2 LV diastolic dimension, mm IVS thickness, mm PW thickness, mm LVEF, % LVEDV, mL/m2 E/A § E/E′ (septal) E/E′ (lateral) cIBS of LA, dB cIBS of LV anterior, dB cIBS of LV posterior, dB

Paroxysmal AF (n = 56)

Persistent AF (n = 57)

No recur n = 39

Recur n = 17

P value

No recur n = 23

Recur n = 34

P value

60.1 ± 9.2 34 (87) 32 (13–60) 22.9 ± 3.7 19 (49) 12 (31) 16 (41) 11 (28) 12 (31) 15 (38) 8 (21) 30 (79) 36.7 ± 6.2 40.2 ± 17.0 48.5 ± 5.4 9.5 ± 1.8 9.5 ± 1.6 66.5 ± 8.6 93.1 ± 21.6 1.3 ± 0.6 10.2 ± 4.9 7.0 ± 2.7 −13.7 ± 3.7 −20.4 ± 5.4 −20.0 ± 5.3

57.9 ± 9.5 15 (88) 37 (18–59) 25.0 ± 4.6 10 (59) 3 (18) 8 (47) 2 (12) 8 (47) 9 (53) 5 (29) 13 (76) 38.1 ± 3.9 44.9 ± 13.5 49.9 ± 6.6 9.4 ± 1.2 9.5 ± 1.1 66.6 ± 10.0 93.5 ± 25.2 1.3 ± 0.7 11.2 ± 5.5 6.6 ± 1.8 −13.9 ± 3.5 −20.6 ± 5.3 −20.3 ± 4.8

0.4099 0.9125 0.3183 0.0823 0.5447 0.2837 0.7321 0.1657 0.2701 0.3520 0.5001 0.8372 0.4028 0.3246 0.4304 0.8393 0.9994 0.9876 0.9526 0.8765 0.5190 0.6159 0.8793 0.8873 0.8305

57.6 ± 9.3 19 (83) 49 (12–73) 23.1 ± 3.6 12 (52) 8 (35) 9 (39) 7 (30) 10 (43) 8 (35) 7 (30) 9 (39) 39.8 ± 5.4 47.3 ± 15.9 49.5 ± 6.4 9.5 ± 1.5 9.7 ± 1.4 66.1 ± 6.8 97.2 ± 23.9 1.0 ± 0.3 9.9 ± 3.5 7.4 ± 3.0 −13.3 ± 5.3 −19.5 ± 5.4 −19.9 ± 4.2

57.9 ± 10.9 27 (79) 49 (23–99) 24.0 ± 3.3 24 (70) 10 (29) 19 (56) 19 (56) 17 (50) 19 (56) 8 (24) 8 (24) 42.0 ± 6.4 60.3 ± 25.7 50.6 ± 5.8 9.6 ± 1.9 9.9 ± 1.5 62.6 ± 6.7 95.4 ± 18.3 1.2 ± 0.5 12.0 ± 5.4 9.4 ± 7.2 −10.8 ± 3.6 −16.4 ± 4.4 −17.9 ± 5.1

0.9094 0.7641 0.6424 0.2967 0.1574 0.6694 0.2145 0.0584 0.6285 0.1145 0.5613 0.2066 0.1892 0.0357 0.4993 0.8329 0.6983 0.0728 0.7545 0.3362 0.1218 0.0776 0.0332 0.0236 0.1205

Values are the mean ± SD or n (%). PVI = pulmonary vein isolation. The other abbreviations are as in Tables 1 and 2.