Cardiovascular Pathology xxx (2014) xxx–xxx
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Cardiovascular Pathology
Original Article
Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal defect and patients with mitral valvular heart disease, Jae Gun Kwak a, Jeong-Wook Seo b, Sam Se Oh a, Sang Yun Lee c, Eui Keun Ham d, Woong-Han Kim e,⁎, Soo-Jin Kim f, Eun Jung Bae g, Cheoung Lim h, Chang-Ha Lee a, Cheul Lee a a
Department of Thoracic and Cardiovascular Surgery, Sejong General Hostpial, Bucheon, Republic of Korea Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea c Department of Pediatrics, Sejong General Hospital, Bucheon, Republic of Korea d Department of Pathology, Sejong General Hospital, Bucheon, Republic of Korea e Department of Thoracic and Cardiovascular Surgery, Seoul National University Children’s Hospital, Seoul, Republic of Korea f Division of Pediatric Cardiology, Department of Pediatrics, School of Medicine, Konkuk University, Seoul, Republic of Korea g Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Republic of Korea h Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 15 October 2013 Received in revised form 18 January 2014 Accepted 21 January 2014 Available online xxxx Keywords: Atrial fibrillation Congenital heart disease Septal defects Mitral regurgitation Pathology (atrium) Atrium
a b s t r a c t Background: Atrial fibrillation (AF) in adult patients with atrial septal defect (ASD) accompanies an enlarged right atrium (RA) with a less enlarged left atrium (LA), which is the opposite situation in patients with AF and mitral valvular disease. This study was to compare the histopathological change in the atrium of patients with AF of two different etiologies: ASD and mitral disease. Methods: Twenty-four patients were enrolled. Group 1 included patients with ASD (8), Group 2 included patients with ASD with AF (6), and Group 3 included patients with mitral disease with AF (10). Preoperative atrial volumes were measured. Atrial tissues were obtained during surgical procedures and stained with periodic acid-Schiff, smooth muscle actin, Sirius red, and Masson’s trichrome to detect histopathologic changes compatible with AF. The severity of histopathological changes was represented with “positivity” and “strong positivity” after analyzing digitalized images of the staining. We investigated the relationship between the degree of atrial dilatation and severity of histopathological changes according to the groups and tissues. Results: Group 2 and Group 3 patients showed a tendency toward an enlarged RA volume and enlarged LA volume, respectively, compared with each others. However, in the histopathologic analysis, “positivity” and “strong positivity” showed no significant positive correlations with the degree of atrial volume in special staining. Conclusions: A similar degree of histopathologic changes was observed in both atria in patients with AF (Group 2 and 3) regardless of the degree of dilatation of atrial volume and disease entities. Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.
1. Introduction For the past couple of decades, the Cox maze III procedure, for which lesion sets are made in both the right atrium (RA) and left atrium (LA), has been chosen as the standard surgical option for Abbreviations: AF, Atrial fibrillation; ASD, Atrial septal defect; GA, Glutaraldehyde; H&E, Hematoxylin and eosin; LA, Left atrium; MT, Masson’s Trichrome; Np, Positive pixel count; Nsp, Strongly stained positive pixel count; PAS, Periodic acid-Schiff; RA, Right atrium; SMA, Smooth muscle actin. Conflict of interest: none declared. Funding: This paper and study were performed by personal finances (Dr. Kwak). Nothing was provided by any other committees or organizations. ⁎ Corresponding author at: Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul National University, Children’s Hospital, 28 Yongon-Dong, Jongno-Gu, 110–744, Republic of Korea. Tel.: +82 2 2072 3637; fax: +82 2 3672 3637. E-mail address: [email protected] (W.-H. Kim).
treating atrial fibrillation (AF). A major cause of AF in adults is associated with left-sided valvular heart disease, especially in mitral valve stenosis or regurgitation. In a recent paper, Cox noted the effectiveness of the Cox maze III procedure for correcting various types of atrial arrhythmias, such as AF or atrial flutter, due to an enlarged LA with or without an enlarged RA [1]. However, the paper contained no comments about AF occurring with an enlarged RA in the presence of a normal or insignificantly enlarged LA. We frequently find significantly enlarged RA with a normal-sized LA in many cases of congenital heart disease, including atrial septal defect (ASD) or Ebstein’s anomaly, in adult patients. Some surgeons have treated atrial tachyarrhythmias, including AF, associated with congenital cardiac anomalies that present with an enlarged RA and nearly normal-sized LA using the RA maze procedure, and they reported tolerable surgical outcomes with this modified technique [2–4]. From the results of above previous studies, we hypothesized that patients
http://dx.doi.org/10.1016/j.carpath.2014.01.008 1054-8807/Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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J.G. Kwak et al. / Cardiovascular Pathology xxx (2014) xxx–xxx
with AF and accompanying valvular heart disease and adult patients with AF and accompanying ASD would have different atrial histopathologic findings. In this study, we tried to verify the above hypothesis via histopathologic analyses of patients’ atrial tissue. We also investigated the associations between the severity of histopathologic changes and the degree of preoperative atrial volume dilatation, which may be used as an indicator of whether to perform a RA maze in patients with ASD and AF. We expected the results of this study to provide information on whether the RA maze procedure in patients with ASD and AF can show similar effectiveness in eradicating AF and preventing its recurrence compared with an original maze procedure in the same patients.
patients in Group 3 underwent a concomitant coronary artery bypass graft surgery. Similar to Groups 1 and 2, atrial reduction plasty was performed on the patients whose atrial tissue was significantly dilated (Table 1). The resected areas of the atrial tissue were the same for all groups. For the RA reduction, we extended a usual right atriotomy (1–1.5 by 2–3 cm) for the main procedures such as ASD closure or valve repair. LA reduction plasty was performed on the area between the inferior pulmonary veins and posterior annulus of mitral valve, about 1 by 2–3 cm. This resected LA area can also be a part of the LA maze lesion sets (the mechanical barriers for arrhythmogenic circuits on the atrial tissue induced by the maze procedure) [7].
2. Materials and methods
2.4. Pathologic analysis
2.1. Patients’ grouping
All atrial tissues were immediately immersed in formalin solution after resection and embedded in a paraffin block. First, we stained the tissues with hematoxylin and eosin and selected one or two of the most severely diseased areas to create a microarray kit. One microarray kit included a 4×5 matrix, which meant that one slide contained four types of tissues (RA free wall and appendage, LA free wall and appendage) obtained from five patients. This kit could facilitate more effective staining and comparison of tissues. In patients from whom we did not obtain tissues from all four atrial areas, the spot for the missing tissue in the microarray slide was left empty (Fig. 1). Special stains used to define pathologic changes in the atrial tissue included periodic acid-Schiff (PAS, Fig. 2A), Masson’s trichrome (MT, Fig. 2C), Sirius red (Fig. 2D), and smooth muscle actin (SMA, Fig. 2B). After completing the staining procedures, the microarray slide images were digitalized for quantitative measurement of positive findings with an image analysis program (ApergioImageScope version 10.2.1.2315, Apergio Technologies, Inc, Vista, CA, USA). From the digital image analysis, we obtained the “positive pixel count (Np)”, “strongly stained positive pixel count (Nsp)”, “positivity”, which was defined as the ratio of positive pixels to the total pixel number within a single spot, and “strong positivity”, which was defined as the ratio of strong positive pixels to the total pixel number within a single spot. We compared these parameters among the three groups.
Between January 2010 and July 2011, 24 consecutive adult patients (N20 years of age) were enrolled in this prospective study. We divided these patients into three groups. Patients in Group 1 had simple ASD (n=8), patients in Group 2 had ASD with AF (n=6), and patients in Group 3 had mitral valvular disease with AF (n=10). 2.2. Preoperative evaluation We performed catheterization on the patients with ASD (Group 1 and 2) to evaluate the pulmonary artery resistance, pressure of right ventricle and pulmonary artery, and the reversibility of pulmonary hypertension to determine whether to close the ASD completely or partially and also to check for coronary arterial status. For patients with mitral valvular disease (Group 3), an angiographic procedure was performed by interventionists to check for coronary arterial disease. However, the pressure profiles of cardiac chambers and pulmonary artery were not measured in Group 3. The volume of the preoperative atrial chamber was measured by a cardiologist based on echocardiographic findings using a method developed by Sanfilippo et al. [5]. The anteroposterior dimension (D1) of the RA and LA was measured on the parasternal view. The mediolateral (D2) and superior-inferior (D3) dimensions of the RA and LA were measured on the apical four-chamber view. All measurements were taken along the line of the maximum diameter between the chamber walls on the respective planes. The volume of both atriums was calculated with the formula indicated for an atrium shaped as a D1 D2 D3 prolate ellipsoid Volume of the RA or LA ðmLÞ ¼ 4π 3 2 2 2 . We corrected these values for the patients’ body surface area (mL/m 2). 2.3. Operations For the patients in Group 1, we performed ASD patch closure with glutaraldehyde (GA)-fixed autologous pericardium and atrial reduction plasty with or without tricuspid valve annuloplasty according to the severity of tricuspid annulus dilatation. Atrial reduction plasty was performed on patients whose atrial chambers were significantly dilated. A LA appendectomy was performed as prophylaxis against possible thromboembolic events resulting from AF occurrence despite ASD closure in this group, as described in previous studies [6]. After resection of LA appendage, only base of LA appendage was remained. The RA appendage was resected with a triangle shape, about 1.5–2 cm of base and 1cm of height when a venous cannula was inserted into the RA appendage. Patients in Group 2 underwent ASD closure with GA-fixed autologous pericardium and a modified Cox maze III procedure. RA and LA appendage resection was performed during the Cox maze III procedure. The free wall of both atria was resected for atrial reduction plasty in patients whose atria were dilated more than normal. For the patients in Group 3, mitral valve repair or replacement and a Cox maze III procedure were concomitantly performed. Two
2.5. Statistical analysis and ethics Quantitative data are presented as the mean±standard deviation, and P b.05 was considered statistically significant. The statistical analysis and comparison of continuous variables among the groups or subgroups were performed with an independent samples t test or a Mann–Whitney U test. Pearson’s or Spearman’s correlation analysis was used to verify the correlation between the degree of RA or LA dilatation and “positivity” or “strong positivity” on the histopathologic analysis from each special staining. Statistical analysis was performed
Table 1 Operative procedures (“Cox-maze III” procedure, which was concomitantly performed in all patients in Groups 2 and 3, was not described in this table) Group 1 (n=8)
Group 2 (n=6)
Group 3 (n=10)
ASD closure+TVP 4 ASD fenestrated closure+TVP 4 MVR+TVP ASD closure only 4 ASD fenestrated closure 1 MVP+TVP ASD closure+TVP 1 MVP+CABG MVR+AVR+TVP MVP+TVP+CABG MVR+AVR+TVP +CABG
4 2 1 1 1 1
AVR, aortic valve replacement; CABG, coronary artery bypass graft; MVP, mitral valve repair; MVR, mitral valve replacement; TVP, tricuspid valve repair (including annuloplasty).
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Fig. 1. Examples of microscopic findings of each staining. We can magnify these digitalized images at most 20 times. The original size of each spot was about 3mm in diameter. Each column means individual patients. About the rows, from top to bottom, each row means left atrial auricle, left atrial free wall, right atrial auricle and right atrial wall. Therefore, in these panels, we did not obtain the left atrial auricle tissue of the forth patient. (A: Hematoxylin and eosin staining, B: Periodic acid-Schiff staining, C: Masson’s trichrome staining, D: Sirius red staining, E: Smooth muscle actin staining.)
using SPSS 18.0 for Windows (SPSS Inc, Chicago, IL, USA). The hospital ethics committee in Sejong General Hospital reviewed and approved this study (study approval number: SJH2010-050). Informed consent regarding the postoperative histopathologic study and data collection with analysis was obtained from all patients and their families. 3. Results 3.1. Preoperative patient characteristics The mean age of all patients was 49.9±13.5years. A preoperative catheterization study was performed in 12 patients; all belonged to Groups 1 and 2. More than a mild degree of pulmonary hypertension was observed in patients from these two groups (mean main pulmonary artery pressure: 28.2±12.2 mm Hg in Group 1, 33.4±13.1 mm Hg in Group 2). No statistical differences in catheterization data were noted between the patients in Groups 1 and 2. The types of AF in this study included the persistent type (three patients in Group 2 and two patients in Group 3) and the permanent type (three patients in Group 2 and eight patients in Group 3). Only one patient with AF was able to be treated by cardioversion before operation in Group 2; the others had intractable AF. The mitral valve diseases in Group 3 patients originated from rheumatic change (n=6) or degenerative change (n=4) including leaflet prolapse, annular dilatation, and also fibrotic change. All the patients with rheumatic change on their mitral valve showed stenosis (mitral stenoinsufficiency in five patients, pure mitral stenosis in 1 patient.), all patients (n=4) with degenerative change on mitral valve showed only regurgitation. The Group 1 patients were older than those in Group 2 by about 10 years, and the Group 3 patients were older than the Group 2 patients by about 6 years; however, these differences did not reach statistical significance. The preoperative LA volume was 86.4±62.1 ml, and the LA volume index was 52.6±36.9 ml/m 2. The preoperative RA volume was 87.3±36.8 ml, and the RA volume index was 55.5±24.1 ml/m 2.
Table 2 shows the preoperative characteristics for each group. Among the patients with ASD, patients in Group 2 had a larger preoperative RA and LA volume and volume index than patients in Group 1, but the differences did not reach statistical significance. In the comparison between patients with AF and mitral valvular disease and ASD, the RA volume and volume index were larger in Group 2 patients than in Group 3 patients. The LA volume and volume index were significantly larger in Group 3 than in Group 2 (Table 2). We also compared the LA and RA volume index in the same group. The RA volume was significantly enlarged compared with the LA volume in Groups 1 and 2, and the LA volume was also significantly enlarged compared with the RA volume in Group 3 (Table 3). 3.2. Histopathologic results We initially assumed that the atrial free wall and auricle would show different extents of histopathologic change, because the degree of atrial tissue dilation might differ according to the location in the atrium [8]. However, after analyzing the digital staining images, we found no significant difference in the positive pixel count or the positivity of the atrial auricle and atrial free wall of either atrium in all types of stains. Therefore, we considered the atrial appendage and atrial free wall to be the same atrial tissue during analysis of the histopathologic data. In Group 3, we found no statistical difference in the positivity of both atrial tissues between patients with degenerative mitral valve disease and rheumatic mitral valve disease in all staining. In addition, the morphological changes of atrial cells, such as the degree of myocyte hypertrophy, intimal sclerosis, fat or inflammatory cell infiltration into epicardial tissue, interstitial fibrosis, or thickness of the intima, muscle layer, and epicardium, showed similar features between these two subgroups in Group 3. From these results, we were able to consider two mitral valvular disease entities (degenerative or rheumatic origin of the mitral valve) to be one mitral valve disease for analysis of the entire data set.
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Fig. 2. Comparison of positivity and Strong positivity in each group, using periodic acid-Schiff stain (A), smooth muscle actin stain (B), Masson’s trichrome stain (C) and Sirius red stain (D). (P value astride two bars indicates statistical significance between those two groups).
To exclude bias by AF types on histopathologic changes in atrial tissue, we analyzed and compared histopathologic characteristics of atrial tissues of the patients with persistent AF and those with permanent AF in Groups 2 and 3, respectively. In Group 2, three patients had persistent AF and three patients had permanent AF, and in all stains, no statistical difference in positivity was noted between these two subtypes of AF in both atrial tissues. Group 3 included two patients with persistent AF and eight patients with permanent AF, and they also showed no difference in positivity in pathological analyses. Morphologic changes in atrial tissue also showed similar degrees of histopathological changes among these subtypes in each group. PAS staining, in contrast to our expectation, showed that positivity in the LA, not in the enlarged RA, was statistically higher in Group 1
than in Group 2 (0.83±0.04 for Group 1 vs. 0.78±0.07 for Group 2, P= .009). Strong positivity was also significantly higher in Group 1 than in Group 2 in the LA. Positivity of the LA was not significantly different between Groups 2 and 3, but strong positivity of the LA was significantly higher in Group 3 than in Group 2 (0.01±0.012 in Group 2 vs. 0.03±0.024 in Group 3, p=.006). For the RA, positivity in Group 2 and 3 was not significantly different, but strong positivity was significantly higher in Group 3 than in Group 2 despite a smaller RA (Fig. 1A). SMA staining showed no significantly different histopathologic findings in either of the atrial tissue types from Groups 1 and 2. The positivity of both atrial tissues was higher for Group 3 than Group 2, but only the difference for the RA tissue was statistically significant
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Fig 2. (continued)
(0.09±0.13 for Group 2 vs. 0.10±0.04 for Group 3, RA, P=.011, Fig. 1-B). MT staining demonstrated that positivity was significantly higher in the RA in Group 1 than in Group 2 (0.74±0.10 vs. 0.64±0.20, P= .041). In the LA, histopathologic analysis showed that positivity of Group 2 was significantly higher than that in Group 3 (0.75±0.10 vs. 0.60±0.17, P=.008) despite the fact that the LA in Group 3 was significantly dilated compared with that in Group 2 (29.7±16.9 vs. 92.0±23.2 mL/m 2, pb.001). Strong positivity was also higher in Group 2 than in Group 3 in the LA (0.38±0.127 in Group 2 vs. 0.18±0.136 in Group 3, P=0.002, Fig. 1-C). Sirius red staining showed no difference among groups or atrial tissues in terms of the positive pixel count or positivity (Fig. 1D). All the data were shown in Table 4. We confirmed the above results with Spearman’s correlation analysis between the degree of atrial volume index and the severity of
histopathologic change using special stains of both atrial tissues. No statistical correlations were observed between the degree of RA volume index and the severity of histopathologic change of RA tissues in all stains. In terms of the LA volume index and positivity or strong positivity of LA tissue, the positivity and strong positivity of MT staining showed a significant correlation with the LA volume index; however, in contrast to our expectations, it was a negative correlation coefficient (Table 5). 3.3. Clinical results Overall follow-up duration was 30.0±11.4months (range: 6.75– 45.5months). No operative mortality was observed, and there was one late death in Group 2 that occurred 13 months after the first operation due to progressive right ventricular failure and accompanying
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Table 2 Preoperative patient characteristics between the paired groups (Group 1 vs. group2 and Group 2 vs. Group 3)
Age (years) Body weight (kg) Atrial volume index (mL/m2)
LA RA LA+RA
Group 1
Group 2
P value
Group 2
Group 3
P value
40.3±12.2 56.7±10.3 25.1±6.6 53.9±10.4 79.0±11.2
52.4±16.0 51.7±12.2 29.7±16.9 65.6±26.7 92.3±39.5
.157 .262 .852 .278 .287
52.4±16.0 51.7±12.2 29.7±16.9 65.6±26.7 92.3±39.5
58.2±6.8 65.1±11.9 92.0±39.5 49.2±30.6 141.1±43.0
.588 .077 b .001 .368 .056
Preop, preoperative.
Klebsiella pneumonia. Two patients in Group 3 required permanent pacemaker implantation after anti-arrhythmic operation due to complete atrioventricular block and sick sinus syndrome, respectively. AF recurred in three patients (1 from Group 2 and 2 from Group 3) after anti-arrhythmic surgery. Atrial flutter occurred in one patient who had not shown any arrhythmia prior to surgery; that was restored after cardioversion. Except for one patient who died, all patients showed New York Heart Association (NYHA) functional class 1 at their last follow-up. Due to the small number of patients, it was impossible to analyze the association between the severity of pathologic changes and recurrence of AF. 4. Discussion AF can occur due to various conditions such as chronic mitral valve disease, electrolyte imbalance during the immediate postoperative period, or accompanying congenital heart diseases. Among them, chronic mitral valve disease is one of the most common prior conditions of AF and is associated with a dilated LA [9]. Chronic mitral valve disease also induces congestive heart failure, and congestive heart failure is also commonly associated with AF. Some biopsy and autopsy studies from patients with AF associated with congestive heart failure showed structural abnormalities including an the increased amount of atrial fibrosis, cellular hypertrophy, degeneration and interstitial fibrosis [10,11]. These structural abnormalities seem more marked in the LA than in the RA [12–14]. For this reason, most antiarrhythmic surgeries or interventional therapies for AF have been developed with particular focus on the treatment of left-sided valvular disease and dilated LA. The Cox maze III procedure, which is considered to be a standard surgical option for treating AF, includes RA and LA lesion sets; however, many surgeons and physicians have developed modified forms of this procedure to obtain similar surgical outcomes with simpler and less invasive techniques, such as a mini-maze using robotic instruments, pulmonary vein isolation, or LA maze with surgical or interventional approaches [15–17]. However, few studies have examined AF associated with congenital heart disease. Stulak et al. used only the RA maze procedure to treat atrial arrhythmias, including AF, that developed in conjunction with congenital cardiac diseases, such as Ebstein’s anomaly and ASD, and they reported excellent surgical outcomes from their procedure [2]. This group suggested that preoperative dilated right atrial volume is one of the indicators for application of a RA maze in treatment of these conditions. In terms of the histopathologic changes in the RA in patients with AF associated with ASD, Morton et al. revealed that ASD results in chronic right heart volume overloading, which induces RA stretching remodeling [18]. We expected the RA in patients with AF and ASD Table 3 Comparison of RA volume index and LA volume index in the same group
Group 1 Group 2 Group 3
RA volume index (mL/m2)
LA volume index (mL/m2)
P value
53.9±10.4 65.6±26.7 49.2±30.6
25.1±6.6 29.7±16.9 92.0±39.5
b .001 .008 .003
might be larger than that of patients with mitral valve disease. We also anticipated that the LA in patients with AF and mitral valvular disease would be larger than that in patients with ASD and AF. During the progression of atrial dilatation, histopathological changes such as fibrosis, degenerative, or inflammatory changes of muscle fibers are expected to occur in atrial tissue [19]. Therefore, we hypothesized that dilated atrial tissue might show more significant histopathologic changes, which are also thought to be an important factor in or results of AF development [20–22]. If these hypotheses were true, then the degree of preoperative atrial volume could be one of the factors for determining whether only a RA maze can be used to treat AF accompanied by ASD, because the LA volume of these patients is not usually significantly enlarged. As expected, the mean atrial volume of patients with AF and ASD was larger than that of patients with ASD without AF, especially in the RA, although this difference did not reach statistical significance. The volume of the LA was significantly larger and the RA volume was smaller in patients with AF and mitral valvular disease than in patients with AF and ASD in this study. Therefore, we could assume that RA dilation was not strongly associated with AF occurrence in patients with mitral valve disease. However, the histopathologic changes we observed were not correlated with the degree of atrial dilatation. For example, PAS staining, which is mainly used to detect glycogen in tissue, did not demonstrate significant differences in positivity and strong positivity between RA tissue in patients with ASD without AF and in those having ASD with AF, although atrial tissue reportedly undergoes cellular structure remodeling, which is associated with sarcomere replacement by glycogen in cases of chronic AF [20]. Although a longer follow-up duration is needed for Group 1 patients, we could also assume that the histopathologic changes may have already occurred in the atrial tissue of these patients based on these results. Strong positivity in Group 3 patients, whose RA volume was much smaller than that of Group 2, was higher than that of Group 2. These results also show that histopathologic changes were not correlated with the degree of atrial dilatation. Regarding SMA staining, Driesen et al. reported that SMA staining Table 4 Results of pathologic analysis (bold and italic indicate that there is statistical significance between the paired groups) Staining
Group 1
Periodic acid-Schiff
0.81±0.03 0.80±0.05 0.02±0.019 0.01±0.014 0.83±0.04 0.78±0.07 0.03±0.043 0.01±0.012 0.77±0.00 0.99±0.01 0.05±0,034 0.06±0.089 0.94±0.17 0.99±0.01 0.04±0.055 0.06±0.030 0.15±0.16 0.09±0.13 0.03±0.028 0.02 ± 0.017 0.14±0.10 0.08 ± 0.07 0.03±0.020 0.03±0.017 0.74±0.10 0.64±0.20 0.27±0.108 0.26±0.111 0.73±0.10 0.75±0.10 0.31±0. 155 0.38±0.127
RA Positivity Strong positivity LA Positivity Strong positivity Sirius red RA Positivity Strong positivity LA Positivity Strong positivity Smooth muscle RA Positivity actin Strong positivity LA Positivity Strong positivity Masson’s RA Positivity trichrome Strong positivity LA Positivity Strong positivity
Group 2
Group 3 0.78±0.06 0.02±0.021 0.80±0.05 0.03±0.024 0.98±0.07 0.04±0.018 0.99±0.00 0.05±0.042 0.10±0.04 0.03±0.013 0.12±0.09 0.04±0.029 0.71±0.12 0.21±0.141 0.60±0.17 0.18±0.136
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Table 5 Correlation between atrial volume index and positivity and strong positivity LAA
PAS
Atrial volume index
MT
Atrial volume index
SMA
Atrial volume index
Sirius red
Atrial volume index
Correlation P value Correlation P value Correlation P value Correlation P value
coefficient coefficient coefficient coefficient
LAW
RAA
RAW
Posi
Str.Posi
Posi
Str.Posi
Str.Posi
Str.Posi
Posi
Str.Posi
0.305 .191 −0.496 .026 0.012 .960 0.390 .089
0.224 .342 −0.447 .048 0.400 .081 0.090 .705
−0.158 .494 −0.095 .681 0.309 .173 0.218 .343
0.331 .143 −0.370 .099 0.249 .276 −0.309 .174
0.147 .513 −0.159 .797 0.343 .118 0.207 .355
0.089 .695 0.058 .762 0.127 .573 −0.211 .347
0.291 .167 0.065 .680 0.133 .535 −0.047 .829
0.089 .680 −0.089 .118 0.030 .891 −0.098 .648
MT, Masson’s trichrome stain; LAA, Left atrial auricle; LAW, Left atrial free wall; PAS, Periodic Acid-Schiff stain; Posi, positivity; RAA, Right atrial auricle; RAW, Right atrial free wall; SMA, smooth muscle actin stain; Str Posi, Strong positivity.
showed that expression of alpha SMA in a chronic AF goat model was elevated [21]. In our SMA staining, positivity and strong positivity were also higher in Group 3 than in Group 2 patients in both atria regardless of the atrial volume index. Although it did not reach statistical significance, patients in Group 1 showed higher positivity and strong positivity than patients in Group 2 in both atria, which suggested that SMA was already present in the patients with ASD prior to AF occurring. This result also suggests that closer observation might be needed for late-occurring AF after correction of ASD in Group 1. MT staining, which is used to detect collagen fibers or muscle tissue, showed significantly higher levels of strong Positivity and positivity in Group 2 than in Group 3. The volume of the LA in Group 2 patients was significantly smaller than that in Group 3 patients, but significant fibrotic change had already occurred in nondilated LA tissue. If we consider these histopathologic results, performing only a RA maze in these patients would be somewhat dangerous in terms of preventing AF recurrence. Sirius red staining, which is useful to stain for collagen fibers, showed no difference between the atrial tissues or between the groups. This result also suggests that no correlation exists between the degree of atrial volume dilatation and the severity of atrial histopathologic change, similar to the results of the previous staining study. Xiao et al. revealed that atrial fibrosis increased in patients with rheumatic mitral valve disease accompanied by AF [23]. They analyzed RA specimens in their study, and various histopathologic changes in RA tissue increased gradually in patients with AF compared with normal patients. Although they only mentioned the size of the LA, we assumed that the RA size of that study was not large. Their study indirectly supported our results in that similar histopathologic changes occurred in both atria regardless of the degree of atrial dilatation because they studied RA tissue in a general population of patients with AF associated with mitral valvular disease. Castonguay et al. also revealed that right atrial tissue also showed significant histopathological changes as well as left atrial tissue in patients with AF, even though the main pathologic changes showed little bit different each other [19]. Our results might be also indirectly supported by a dog study that was performed by Ryu et al. [24]. In their activation mapping study involving a dog model of congestive heart failure, they found two distinct foci in both atria with different frequencies and fibrillatory conduction. Although their dog model did not exactly reflect a lone right heart problem, their study showed that AF can affect both atria. Although they did not include many patients (11 patients with hemodynamically significant ASDs (Qp:QsN1.5:1), Roberts-Thomson et al. revealed that ASDs are also associated with chronic LA stretch, which results in remodeling of the LA, such as enlargement, loss of myocardium and electrical scars [25]. Walker et al. reported that an enlarged RA in patients with ASD induced RV enlargement, which resulted in paradoxical ventricular septal movement and finally distorted the LV diastolic filling function. Lin suggested that these prolonged abnormal interventricular actions
might lead to electro-pathological remodeling in the LA, which may eventually result in AF [26]. In our study, three patients with recurrence of AF were observed during the follow-up period. Because of the small number of patients, we were unable to carry out statistical analyses between the severity of histopathologic change and AF recurrence. Simple comparison between the mean values of the histopathological changes in each group and the histopathologic change in each patient with recurrence did not seem to show significant differences. However, we expect that a further study including a larger number of patients would reveal the differences in the severity of histopathological changes between patients with and without recurrence. Our study had some limitations. First, the number of the patients was not large, which made our statistical analyses and comprehension of results difficult. However, we were able to find definite and consistent tendencies based on all of the results of histopathological data. Second, an unavoidable limitation was imposed regarding the biopsy study in that we obtained only part of the tissue, not the entire tissue. Because we could not find significantly different histopathological results between the atrial free wall and auricle, we decided to consider these “two different tissues” as “two different areas from the same atrial tissue.” As a result, we obtained, at most, two biopsy tissues from one atrium, i.e., four biopsy tissues from one patient. We had hoped that this might somewhat overcome the limitation of the biopsy study. In conclusion, our pathological analyses demonstrated the following results. First, the severity of histopathologic change in atrial tissues of patients with chronic AF did not show a meaningful correlation with the degree of atrial dilation. The histopathological changes in atrial tissues progressed regardless of the degree of atrial dilatation. Second, similar histopathological changes occurred in the LA of the patients with ASD and AF compared with those with mitral valvular disease and AF despite the fact that the degree of LA dilatation was not significant. Therefore, when we consider a histopathological viewpoint only, a RA maze alone may not be enough to eradicate AF in patients with ASD, despite the fact that their LA is not significantly enlarged. Acknowledgments The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/KjJyBV. References [1] Cox JL. The longstanding, persistent confusion surrounding surgery for atrial fibrillation. J Thorac Cardiovasc Surg 2010;139:1374–86. [2] Stulak JM, Dearani JA, Puga FJ, Zehr KJ, Schaff HV, Danielson GK. Right-sided maze procedure for atrial tachyarrhythmias in congenital heart disease. Ann Thorac Surg 2006;81:1780–4 [discussion 4–5]. [3] Theodoro DA, Danielson GK, Porter CJ, Warnes CA. Right-sided maze procedure for right atrial arrhythmias in congenital heart disease. Ann Thorac Surg 1998;65: 149–53 [discussion 53–4].
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Contents lists available at ScienceDirect
Cardiovascular Pathology
Original Article
Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal defect and patients with mitral valvular heart disease, Jae Gun Kwak a, Jeong-Wook Seo b, Sam Se Oh a, Sang Yun Lee c, Eui Keun Ham d, Woong-Han Kim e,⁎, Soo-Jin Kim f, Eun Jung Bae g, Cheoung Lim h, Chang-Ha Lee a, Cheul Lee a a
Department of Thoracic and Cardiovascular Surgery, Sejong General Hostpial, Bucheon, Republic of Korea Department of Pathology, Seoul National University Hospital, Seoul, Republic of Korea c Department of Pediatrics, Sejong General Hospital, Bucheon, Republic of Korea d Department of Pathology, Sejong General Hospital, Bucheon, Republic of Korea e Department of Thoracic and Cardiovascular Surgery, Seoul National University Children’s Hospital, Seoul, Republic of Korea f Division of Pediatric Cardiology, Department of Pediatrics, School of Medicine, Konkuk University, Seoul, Republic of Korea g Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, Republic of Korea h Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 15 October 2013 Received in revised form 18 January 2014 Accepted 21 January 2014 Available online xxxx Keywords: Atrial fibrillation Congenital heart disease Septal defects Mitral regurgitation Pathology (atrium) Atrium
a b s t r a c t Background: Atrial fibrillation (AF) in adult patients with atrial septal defect (ASD) accompanies an enlarged right atrium (RA) with a less enlarged left atrium (LA), which is the opposite situation in patients with AF and mitral valvular disease. This study was to compare the histopathological change in the atrium of patients with AF of two different etiologies: ASD and mitral disease. Methods: Twenty-four patients were enrolled. Group 1 included patients with ASD (8), Group 2 included patients with ASD with AF (6), and Group 3 included patients with mitral disease with AF (10). Preoperative atrial volumes were measured. Atrial tissues were obtained during surgical procedures and stained with periodic acid-Schiff, smooth muscle actin, Sirius red, and Masson’s trichrome to detect histopathologic changes compatible with AF. The severity of histopathological changes was represented with “positivity” and “strong positivity” after analyzing digitalized images of the staining. We investigated the relationship between the degree of atrial dilatation and severity of histopathological changes according to the groups and tissues. Results: Group 2 and Group 3 patients showed a tendency toward an enlarged RA volume and enlarged LA volume, respectively, compared with each others. However, in the histopathologic analysis, “positivity” and “strong positivity” showed no significant positive correlations with the degree of atrial volume in special staining. Conclusions: A similar degree of histopathologic changes was observed in both atria in patients with AF (Group 2 and 3) regardless of the degree of dilatation of atrial volume and disease entities. Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.
1. Introduction For the past couple of decades, the Cox maze III procedure, for which lesion sets are made in both the right atrium (RA) and left atrium (LA), has been chosen as the standard surgical option for Abbreviations: AF, Atrial fibrillation; ASD, Atrial septal defect; GA, Glutaraldehyde; H&E, Hematoxylin and eosin; LA, Left atrium; MT, Masson’s Trichrome; Np, Positive pixel count; Nsp, Strongly stained positive pixel count; PAS, Periodic acid-Schiff; RA, Right atrium; SMA, Smooth muscle actin. Conflict of interest: none declared. Funding: This paper and study were performed by personal finances (Dr. Kwak). Nothing was provided by any other committees or organizations. ⁎ Corresponding author at: Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul National University, Children’s Hospital, 28 Yongon-Dong, Jongno-Gu, 110–744, Republic of Korea. Tel.: +82 2 2072 3637; fax: +82 2 3672 3637. E-mail address: [email protected] (W.-H. Kim).
treating atrial fibrillation (AF). A major cause of AF in adults is associated with left-sided valvular heart disease, especially in mitral valve stenosis or regurgitation. In a recent paper, Cox noted the effectiveness of the Cox maze III procedure for correcting various types of atrial arrhythmias, such as AF or atrial flutter, due to an enlarged LA with or without an enlarged RA [1]. However, the paper contained no comments about AF occurring with an enlarged RA in the presence of a normal or insignificantly enlarged LA. We frequently find significantly enlarged RA with a normal-sized LA in many cases of congenital heart disease, including atrial septal defect (ASD) or Ebstein’s anomaly, in adult patients. Some surgeons have treated atrial tachyarrhythmias, including AF, associated with congenital cardiac anomalies that present with an enlarged RA and nearly normal-sized LA using the RA maze procedure, and they reported tolerable surgical outcomes with this modified technique [2–4]. From the results of above previous studies, we hypothesized that patients
http://dx.doi.org/10.1016/j.carpath.2014.01.008 1054-8807/Crown Copyright © 2014 Published by Elsevier Inc. All rights reserved.
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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with AF and accompanying valvular heart disease and adult patients with AF and accompanying ASD would have different atrial histopathologic findings. In this study, we tried to verify the above hypothesis via histopathologic analyses of patients’ atrial tissue. We also investigated the associations between the severity of histopathologic changes and the degree of preoperative atrial volume dilatation, which may be used as an indicator of whether to perform a RA maze in patients with ASD and AF. We expected the results of this study to provide information on whether the RA maze procedure in patients with ASD and AF can show similar effectiveness in eradicating AF and preventing its recurrence compared with an original maze procedure in the same patients.
patients in Group 3 underwent a concomitant coronary artery bypass graft surgery. Similar to Groups 1 and 2, atrial reduction plasty was performed on the patients whose atrial tissue was significantly dilated (Table 1). The resected areas of the atrial tissue were the same for all groups. For the RA reduction, we extended a usual right atriotomy (1–1.5 by 2–3 cm) for the main procedures such as ASD closure or valve repair. LA reduction plasty was performed on the area between the inferior pulmonary veins and posterior annulus of mitral valve, about 1 by 2–3 cm. This resected LA area can also be a part of the LA maze lesion sets (the mechanical barriers for arrhythmogenic circuits on the atrial tissue induced by the maze procedure) [7].
2. Materials and methods
2.4. Pathologic analysis
2.1. Patients’ grouping
All atrial tissues were immediately immersed in formalin solution after resection and embedded in a paraffin block. First, we stained the tissues with hematoxylin and eosin and selected one or two of the most severely diseased areas to create a microarray kit. One microarray kit included a 4×5 matrix, which meant that one slide contained four types of tissues (RA free wall and appendage, LA free wall and appendage) obtained from five patients. This kit could facilitate more effective staining and comparison of tissues. In patients from whom we did not obtain tissues from all four atrial areas, the spot for the missing tissue in the microarray slide was left empty (Fig. 1). Special stains used to define pathologic changes in the atrial tissue included periodic acid-Schiff (PAS, Fig. 2A), Masson’s trichrome (MT, Fig. 2C), Sirius red (Fig. 2D), and smooth muscle actin (SMA, Fig. 2B). After completing the staining procedures, the microarray slide images were digitalized for quantitative measurement of positive findings with an image analysis program (ApergioImageScope version 10.2.1.2315, Apergio Technologies, Inc, Vista, CA, USA). From the digital image analysis, we obtained the “positive pixel count (Np)”, “strongly stained positive pixel count (Nsp)”, “positivity”, which was defined as the ratio of positive pixels to the total pixel number within a single spot, and “strong positivity”, which was defined as the ratio of strong positive pixels to the total pixel number within a single spot. We compared these parameters among the three groups.
Between January 2010 and July 2011, 24 consecutive adult patients (N20 years of age) were enrolled in this prospective study. We divided these patients into three groups. Patients in Group 1 had simple ASD (n=8), patients in Group 2 had ASD with AF (n=6), and patients in Group 3 had mitral valvular disease with AF (n=10). 2.2. Preoperative evaluation We performed catheterization on the patients with ASD (Group 1 and 2) to evaluate the pulmonary artery resistance, pressure of right ventricle and pulmonary artery, and the reversibility of pulmonary hypertension to determine whether to close the ASD completely or partially and also to check for coronary arterial status. For patients with mitral valvular disease (Group 3), an angiographic procedure was performed by interventionists to check for coronary arterial disease. However, the pressure profiles of cardiac chambers and pulmonary artery were not measured in Group 3. The volume of the preoperative atrial chamber was measured by a cardiologist based on echocardiographic findings using a method developed by Sanfilippo et al. [5]. The anteroposterior dimension (D1) of the RA and LA was measured on the parasternal view. The mediolateral (D2) and superior-inferior (D3) dimensions of the RA and LA were measured on the apical four-chamber view. All measurements were taken along the line of the maximum diameter between the chamber walls on the respective planes. The volume of both atriums was calculated with the formula indicated for an atrium shaped as a D1 D2 D3 prolate ellipsoid Volume of the RA or LA ðmLÞ ¼ 4π 3 2 2 2 . We corrected these values for the patients’ body surface area (mL/m 2). 2.3. Operations For the patients in Group 1, we performed ASD patch closure with glutaraldehyde (GA)-fixed autologous pericardium and atrial reduction plasty with or without tricuspid valve annuloplasty according to the severity of tricuspid annulus dilatation. Atrial reduction plasty was performed on patients whose atrial chambers were significantly dilated. A LA appendectomy was performed as prophylaxis against possible thromboembolic events resulting from AF occurrence despite ASD closure in this group, as described in previous studies [6]. After resection of LA appendage, only base of LA appendage was remained. The RA appendage was resected with a triangle shape, about 1.5–2 cm of base and 1cm of height when a venous cannula was inserted into the RA appendage. Patients in Group 2 underwent ASD closure with GA-fixed autologous pericardium and a modified Cox maze III procedure. RA and LA appendage resection was performed during the Cox maze III procedure. The free wall of both atria was resected for atrial reduction plasty in patients whose atria were dilated more than normal. For the patients in Group 3, mitral valve repair or replacement and a Cox maze III procedure were concomitantly performed. Two
2.5. Statistical analysis and ethics Quantitative data are presented as the mean±standard deviation, and P b.05 was considered statistically significant. The statistical analysis and comparison of continuous variables among the groups or subgroups were performed with an independent samples t test or a Mann–Whitney U test. Pearson’s or Spearman’s correlation analysis was used to verify the correlation between the degree of RA or LA dilatation and “positivity” or “strong positivity” on the histopathologic analysis from each special staining. Statistical analysis was performed
Table 1 Operative procedures (“Cox-maze III” procedure, which was concomitantly performed in all patients in Groups 2 and 3, was not described in this table) Group 1 (n=8)
Group 2 (n=6)
Group 3 (n=10)
ASD closure+TVP 4 ASD fenestrated closure+TVP 4 MVR+TVP ASD closure only 4 ASD fenestrated closure 1 MVP+TVP ASD closure+TVP 1 MVP+CABG MVR+AVR+TVP MVP+TVP+CABG MVR+AVR+TVP +CABG
4 2 1 1 1 1
AVR, aortic valve replacement; CABG, coronary artery bypass graft; MVP, mitral valve repair; MVR, mitral valve replacement; TVP, tricuspid valve repair (including annuloplasty).
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Fig. 1. Examples of microscopic findings of each staining. We can magnify these digitalized images at most 20 times. The original size of each spot was about 3mm in diameter. Each column means individual patients. About the rows, from top to bottom, each row means left atrial auricle, left atrial free wall, right atrial auricle and right atrial wall. Therefore, in these panels, we did not obtain the left atrial auricle tissue of the forth patient. (A: Hematoxylin and eosin staining, B: Periodic acid-Schiff staining, C: Masson’s trichrome staining, D: Sirius red staining, E: Smooth muscle actin staining.)
using SPSS 18.0 for Windows (SPSS Inc, Chicago, IL, USA). The hospital ethics committee in Sejong General Hospital reviewed and approved this study (study approval number: SJH2010-050). Informed consent regarding the postoperative histopathologic study and data collection with analysis was obtained from all patients and their families. 3. Results 3.1. Preoperative patient characteristics The mean age of all patients was 49.9±13.5years. A preoperative catheterization study was performed in 12 patients; all belonged to Groups 1 and 2. More than a mild degree of pulmonary hypertension was observed in patients from these two groups (mean main pulmonary artery pressure: 28.2±12.2 mm Hg in Group 1, 33.4±13.1 mm Hg in Group 2). No statistical differences in catheterization data were noted between the patients in Groups 1 and 2. The types of AF in this study included the persistent type (three patients in Group 2 and two patients in Group 3) and the permanent type (three patients in Group 2 and eight patients in Group 3). Only one patient with AF was able to be treated by cardioversion before operation in Group 2; the others had intractable AF. The mitral valve diseases in Group 3 patients originated from rheumatic change (n=6) or degenerative change (n=4) including leaflet prolapse, annular dilatation, and also fibrotic change. All the patients with rheumatic change on their mitral valve showed stenosis (mitral stenoinsufficiency in five patients, pure mitral stenosis in 1 patient.), all patients (n=4) with degenerative change on mitral valve showed only regurgitation. The Group 1 patients were older than those in Group 2 by about 10 years, and the Group 3 patients were older than the Group 2 patients by about 6 years; however, these differences did not reach statistical significance. The preoperative LA volume was 86.4±62.1 ml, and the LA volume index was 52.6±36.9 ml/m 2. The preoperative RA volume was 87.3±36.8 ml, and the RA volume index was 55.5±24.1 ml/m 2.
Table 2 shows the preoperative characteristics for each group. Among the patients with ASD, patients in Group 2 had a larger preoperative RA and LA volume and volume index than patients in Group 1, but the differences did not reach statistical significance. In the comparison between patients with AF and mitral valvular disease and ASD, the RA volume and volume index were larger in Group 2 patients than in Group 3 patients. The LA volume and volume index were significantly larger in Group 3 than in Group 2 (Table 2). We also compared the LA and RA volume index in the same group. The RA volume was significantly enlarged compared with the LA volume in Groups 1 and 2, and the LA volume was also significantly enlarged compared with the RA volume in Group 3 (Table 3). 3.2. Histopathologic results We initially assumed that the atrial free wall and auricle would show different extents of histopathologic change, because the degree of atrial tissue dilation might differ according to the location in the atrium [8]. However, after analyzing the digital staining images, we found no significant difference in the positive pixel count or the positivity of the atrial auricle and atrial free wall of either atrium in all types of stains. Therefore, we considered the atrial appendage and atrial free wall to be the same atrial tissue during analysis of the histopathologic data. In Group 3, we found no statistical difference in the positivity of both atrial tissues between patients with degenerative mitral valve disease and rheumatic mitral valve disease in all staining. In addition, the morphological changes of atrial cells, such as the degree of myocyte hypertrophy, intimal sclerosis, fat or inflammatory cell infiltration into epicardial tissue, interstitial fibrosis, or thickness of the intima, muscle layer, and epicardium, showed similar features between these two subgroups in Group 3. From these results, we were able to consider two mitral valvular disease entities (degenerative or rheumatic origin of the mitral valve) to be one mitral valve disease for analysis of the entire data set.
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Fig. 2. Comparison of positivity and Strong positivity in each group, using periodic acid-Schiff stain (A), smooth muscle actin stain (B), Masson’s trichrome stain (C) and Sirius red stain (D). (P value astride two bars indicates statistical significance between those two groups).
To exclude bias by AF types on histopathologic changes in atrial tissue, we analyzed and compared histopathologic characteristics of atrial tissues of the patients with persistent AF and those with permanent AF in Groups 2 and 3, respectively. In Group 2, three patients had persistent AF and three patients had permanent AF, and in all stains, no statistical difference in positivity was noted between these two subtypes of AF in both atrial tissues. Group 3 included two patients with persistent AF and eight patients with permanent AF, and they also showed no difference in positivity in pathological analyses. Morphologic changes in atrial tissue also showed similar degrees of histopathological changes among these subtypes in each group. PAS staining, in contrast to our expectation, showed that positivity in the LA, not in the enlarged RA, was statistically higher in Group 1
than in Group 2 (0.83±0.04 for Group 1 vs. 0.78±0.07 for Group 2, P= .009). Strong positivity was also significantly higher in Group 1 than in Group 2 in the LA. Positivity of the LA was not significantly different between Groups 2 and 3, but strong positivity of the LA was significantly higher in Group 3 than in Group 2 (0.01±0.012 in Group 2 vs. 0.03±0.024 in Group 3, p=.006). For the RA, positivity in Group 2 and 3 was not significantly different, but strong positivity was significantly higher in Group 3 than in Group 2 despite a smaller RA (Fig. 1A). SMA staining showed no significantly different histopathologic findings in either of the atrial tissue types from Groups 1 and 2. The positivity of both atrial tissues was higher for Group 3 than Group 2, but only the difference for the RA tissue was statistically significant
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Fig 2. (continued)
(0.09±0.13 for Group 2 vs. 0.10±0.04 for Group 3, RA, P=.011, Fig. 1-B). MT staining demonstrated that positivity was significantly higher in the RA in Group 1 than in Group 2 (0.74±0.10 vs. 0.64±0.20, P= .041). In the LA, histopathologic analysis showed that positivity of Group 2 was significantly higher than that in Group 3 (0.75±0.10 vs. 0.60±0.17, P=.008) despite the fact that the LA in Group 3 was significantly dilated compared with that in Group 2 (29.7±16.9 vs. 92.0±23.2 mL/m 2, pb.001). Strong positivity was also higher in Group 2 than in Group 3 in the LA (0.38±0.127 in Group 2 vs. 0.18±0.136 in Group 3, P=0.002, Fig. 1-C). Sirius red staining showed no difference among groups or atrial tissues in terms of the positive pixel count or positivity (Fig. 1D). All the data were shown in Table 4. We confirmed the above results with Spearman’s correlation analysis between the degree of atrial volume index and the severity of
histopathologic change using special stains of both atrial tissues. No statistical correlations were observed between the degree of RA volume index and the severity of histopathologic change of RA tissues in all stains. In terms of the LA volume index and positivity or strong positivity of LA tissue, the positivity and strong positivity of MT staining showed a significant correlation with the LA volume index; however, in contrast to our expectations, it was a negative correlation coefficient (Table 5). 3.3. Clinical results Overall follow-up duration was 30.0±11.4months (range: 6.75– 45.5months). No operative mortality was observed, and there was one late death in Group 2 that occurred 13 months after the first operation due to progressive right ventricular failure and accompanying
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
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Table 2 Preoperative patient characteristics between the paired groups (Group 1 vs. group2 and Group 2 vs. Group 3)
Age (years) Body weight (kg) Atrial volume index (mL/m2)
LA RA LA+RA
Group 1
Group 2
P value
Group 2
Group 3
P value
40.3±12.2 56.7±10.3 25.1±6.6 53.9±10.4 79.0±11.2
52.4±16.0 51.7±12.2 29.7±16.9 65.6±26.7 92.3±39.5
.157 .262 .852 .278 .287
52.4±16.0 51.7±12.2 29.7±16.9 65.6±26.7 92.3±39.5
58.2±6.8 65.1±11.9 92.0±39.5 49.2±30.6 141.1±43.0
.588 .077 b .001 .368 .056
Preop, preoperative.
Klebsiella pneumonia. Two patients in Group 3 required permanent pacemaker implantation after anti-arrhythmic operation due to complete atrioventricular block and sick sinus syndrome, respectively. AF recurred in three patients (1 from Group 2 and 2 from Group 3) after anti-arrhythmic surgery. Atrial flutter occurred in one patient who had not shown any arrhythmia prior to surgery; that was restored after cardioversion. Except for one patient who died, all patients showed New York Heart Association (NYHA) functional class 1 at their last follow-up. Due to the small number of patients, it was impossible to analyze the association between the severity of pathologic changes and recurrence of AF. 4. Discussion AF can occur due to various conditions such as chronic mitral valve disease, electrolyte imbalance during the immediate postoperative period, or accompanying congenital heart diseases. Among them, chronic mitral valve disease is one of the most common prior conditions of AF and is associated with a dilated LA [9]. Chronic mitral valve disease also induces congestive heart failure, and congestive heart failure is also commonly associated with AF. Some biopsy and autopsy studies from patients with AF associated with congestive heart failure showed structural abnormalities including an the increased amount of atrial fibrosis, cellular hypertrophy, degeneration and interstitial fibrosis [10,11]. These structural abnormalities seem more marked in the LA than in the RA [12–14]. For this reason, most antiarrhythmic surgeries or interventional therapies for AF have been developed with particular focus on the treatment of left-sided valvular disease and dilated LA. The Cox maze III procedure, which is considered to be a standard surgical option for treating AF, includes RA and LA lesion sets; however, many surgeons and physicians have developed modified forms of this procedure to obtain similar surgical outcomes with simpler and less invasive techniques, such as a mini-maze using robotic instruments, pulmonary vein isolation, or LA maze with surgical or interventional approaches [15–17]. However, few studies have examined AF associated with congenital heart disease. Stulak et al. used only the RA maze procedure to treat atrial arrhythmias, including AF, that developed in conjunction with congenital cardiac diseases, such as Ebstein’s anomaly and ASD, and they reported excellent surgical outcomes from their procedure [2]. This group suggested that preoperative dilated right atrial volume is one of the indicators for application of a RA maze in treatment of these conditions. In terms of the histopathologic changes in the RA in patients with AF associated with ASD, Morton et al. revealed that ASD results in chronic right heart volume overloading, which induces RA stretching remodeling [18]. We expected the RA in patients with AF and ASD Table 3 Comparison of RA volume index and LA volume index in the same group
Group 1 Group 2 Group 3
RA volume index (mL/m2)
LA volume index (mL/m2)
P value
53.9±10.4 65.6±26.7 49.2±30.6
25.1±6.6 29.7±16.9 92.0±39.5
b .001 .008 .003
might be larger than that of patients with mitral valve disease. We also anticipated that the LA in patients with AF and mitral valvular disease would be larger than that in patients with ASD and AF. During the progression of atrial dilatation, histopathological changes such as fibrosis, degenerative, or inflammatory changes of muscle fibers are expected to occur in atrial tissue [19]. Therefore, we hypothesized that dilated atrial tissue might show more significant histopathologic changes, which are also thought to be an important factor in or results of AF development [20–22]. If these hypotheses were true, then the degree of preoperative atrial volume could be one of the factors for determining whether only a RA maze can be used to treat AF accompanied by ASD, because the LA volume of these patients is not usually significantly enlarged. As expected, the mean atrial volume of patients with AF and ASD was larger than that of patients with ASD without AF, especially in the RA, although this difference did not reach statistical significance. The volume of the LA was significantly larger and the RA volume was smaller in patients with AF and mitral valvular disease than in patients with AF and ASD in this study. Therefore, we could assume that RA dilation was not strongly associated with AF occurrence in patients with mitral valve disease. However, the histopathologic changes we observed were not correlated with the degree of atrial dilatation. For example, PAS staining, which is mainly used to detect glycogen in tissue, did not demonstrate significant differences in positivity and strong positivity between RA tissue in patients with ASD without AF and in those having ASD with AF, although atrial tissue reportedly undergoes cellular structure remodeling, which is associated with sarcomere replacement by glycogen in cases of chronic AF [20]. Although a longer follow-up duration is needed for Group 1 patients, we could also assume that the histopathologic changes may have already occurred in the atrial tissue of these patients based on these results. Strong positivity in Group 3 patients, whose RA volume was much smaller than that of Group 2, was higher than that of Group 2. These results also show that histopathologic changes were not correlated with the degree of atrial dilatation. Regarding SMA staining, Driesen et al. reported that SMA staining Table 4 Results of pathologic analysis (bold and italic indicate that there is statistical significance between the paired groups) Staining
Group 1
Periodic acid-Schiff
0.81±0.03 0.80±0.05 0.02±0.019 0.01±0.014 0.83±0.04 0.78±0.07 0.03±0.043 0.01±0.012 0.77±0.00 0.99±0.01 0.05±0,034 0.06±0.089 0.94±0.17 0.99±0.01 0.04±0.055 0.06±0.030 0.15±0.16 0.09±0.13 0.03±0.028 0.02 ± 0.017 0.14±0.10 0.08 ± 0.07 0.03±0.020 0.03±0.017 0.74±0.10 0.64±0.20 0.27±0.108 0.26±0.111 0.73±0.10 0.75±0.10 0.31±0. 155 0.38±0.127
RA Positivity Strong positivity LA Positivity Strong positivity Sirius red RA Positivity Strong positivity LA Positivity Strong positivity Smooth muscle RA Positivity actin Strong positivity LA Positivity Strong positivity Masson’s RA Positivity trichrome Strong positivity LA Positivity Strong positivity
Group 2
Group 3 0.78±0.06 0.02±0.021 0.80±0.05 0.03±0.024 0.98±0.07 0.04±0.018 0.99±0.00 0.05±0.042 0.10±0.04 0.03±0.013 0.12±0.09 0.04±0.029 0.71±0.12 0.21±0.141 0.60±0.17 0.18±0.136
Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
J.G. Kwak et al. / Cardiovascular Pathology xxx (2014) xxx–xxx
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Table 5 Correlation between atrial volume index and positivity and strong positivity LAA
PAS
Atrial volume index
MT
Atrial volume index
SMA
Atrial volume index
Sirius red
Atrial volume index
Correlation P value Correlation P value Correlation P value Correlation P value
coefficient coefficient coefficient coefficient
LAW
RAA
RAW
Posi
Str.Posi
Posi
Str.Posi
Str.Posi
Str.Posi
Posi
Str.Posi
0.305 .191 −0.496 .026 0.012 .960 0.390 .089
0.224 .342 −0.447 .048 0.400 .081 0.090 .705
−0.158 .494 −0.095 .681 0.309 .173 0.218 .343
0.331 .143 −0.370 .099 0.249 .276 −0.309 .174
0.147 .513 −0.159 .797 0.343 .118 0.207 .355
0.089 .695 0.058 .762 0.127 .573 −0.211 .347
0.291 .167 0.065 .680 0.133 .535 −0.047 .829
0.089 .680 −0.089 .118 0.030 .891 −0.098 .648
MT, Masson’s trichrome stain; LAA, Left atrial auricle; LAW, Left atrial free wall; PAS, Periodic Acid-Schiff stain; Posi, positivity; RAA, Right atrial auricle; RAW, Right atrial free wall; SMA, smooth muscle actin stain; Str Posi, Strong positivity.
showed that expression of alpha SMA in a chronic AF goat model was elevated [21]. In our SMA staining, positivity and strong positivity were also higher in Group 3 than in Group 2 patients in both atria regardless of the atrial volume index. Although it did not reach statistical significance, patients in Group 1 showed higher positivity and strong positivity than patients in Group 2 in both atria, which suggested that SMA was already present in the patients with ASD prior to AF occurring. This result also suggests that closer observation might be needed for late-occurring AF after correction of ASD in Group 1. MT staining, which is used to detect collagen fibers or muscle tissue, showed significantly higher levels of strong Positivity and positivity in Group 2 than in Group 3. The volume of the LA in Group 2 patients was significantly smaller than that in Group 3 patients, but significant fibrotic change had already occurred in nondilated LA tissue. If we consider these histopathologic results, performing only a RA maze in these patients would be somewhat dangerous in terms of preventing AF recurrence. Sirius red staining, which is useful to stain for collagen fibers, showed no difference between the atrial tissues or between the groups. This result also suggests that no correlation exists between the degree of atrial volume dilatation and the severity of atrial histopathologic change, similar to the results of the previous staining study. Xiao et al. revealed that atrial fibrosis increased in patients with rheumatic mitral valve disease accompanied by AF [23]. They analyzed RA specimens in their study, and various histopathologic changes in RA tissue increased gradually in patients with AF compared with normal patients. Although they only mentioned the size of the LA, we assumed that the RA size of that study was not large. Their study indirectly supported our results in that similar histopathologic changes occurred in both atria regardless of the degree of atrial dilatation because they studied RA tissue in a general population of patients with AF associated with mitral valvular disease. Castonguay et al. also revealed that right atrial tissue also showed significant histopathological changes as well as left atrial tissue in patients with AF, even though the main pathologic changes showed little bit different each other [19]. Our results might be also indirectly supported by a dog study that was performed by Ryu et al. [24]. In their activation mapping study involving a dog model of congestive heart failure, they found two distinct foci in both atria with different frequencies and fibrillatory conduction. Although their dog model did not exactly reflect a lone right heart problem, their study showed that AF can affect both atria. Although they did not include many patients (11 patients with hemodynamically significant ASDs (Qp:QsN1.5:1), Roberts-Thomson et al. revealed that ASDs are also associated with chronic LA stretch, which results in remodeling of the LA, such as enlargement, loss of myocardium and electrical scars [25]. Walker et al. reported that an enlarged RA in patients with ASD induced RV enlargement, which resulted in paradoxical ventricular septal movement and finally distorted the LV diastolic filling function. Lin suggested that these prolonged abnormal interventricular actions
might lead to electro-pathological remodeling in the LA, which may eventually result in AF [26]. In our study, three patients with recurrence of AF were observed during the follow-up period. Because of the small number of patients, we were unable to carry out statistical analyses between the severity of histopathologic change and AF recurrence. Simple comparison between the mean values of the histopathological changes in each group and the histopathologic change in each patient with recurrence did not seem to show significant differences. However, we expect that a further study including a larger number of patients would reveal the differences in the severity of histopathological changes between patients with and without recurrence. Our study had some limitations. First, the number of the patients was not large, which made our statistical analyses and comprehension of results difficult. However, we were able to find definite and consistent tendencies based on all of the results of histopathological data. Second, an unavoidable limitation was imposed regarding the biopsy study in that we obtained only part of the tissue, not the entire tissue. Because we could not find significantly different histopathological results between the atrial free wall and auricle, we decided to consider these “two different tissues” as “two different areas from the same atrial tissue.” As a result, we obtained, at most, two biopsy tissues from one atrium, i.e., four biopsy tissues from one patient. We had hoped that this might somewhat overcome the limitation of the biopsy study. In conclusion, our pathological analyses demonstrated the following results. First, the severity of histopathologic change in atrial tissues of patients with chronic AF did not show a meaningful correlation with the degree of atrial dilation. The histopathological changes in atrial tissues progressed regardless of the degree of atrial dilatation. Second, similar histopathological changes occurred in the LA of the patients with ASD and AF compared with those with mitral valvular disease and AF despite the fact that the degree of LA dilatation was not significant. Therefore, when we consider a histopathological viewpoint only, a RA maze alone may not be enough to eradicate AF in patients with ASD, despite the fact that their LA is not significantly enlarged. Acknowledgments The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/KjJyBV. References [1] Cox JL. The longstanding, persistent confusion surrounding surgery for atrial fibrillation. J Thorac Cardiovasc Surg 2010;139:1374–86. [2] Stulak JM, Dearani JA, Puga FJ, Zehr KJ, Schaff HV, Danielson GK. Right-sided maze procedure for atrial tachyarrhythmias in congenital heart disease. Ann Thorac Surg 2006;81:1780–4 [discussion 4–5]. [3] Theodoro DA, Danielson GK, Porter CJ, Warnes CA. Right-sided maze procedure for right atrial arrhythmias in congenital heart disease. Ann Thorac Surg 1998;65: 149–53 [discussion 53–4].
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Please cite this article as: Kwak JG, et al, Histopathologic analysis of atrial tissue in patients with atrial fibrillation: comparison between patients with atrial septal def..., Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.01.008
