© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Structural correlate of atrial fibrillation in human patients
aDepartment of Experimental Cardiology, Max-Planck Institute, Benekestrasse 2, D-61231 Bad Nauheim, Germany
bDepartment of Cardiac Surgery, Kerckhoff Clinic, Bad Nauheim, Germany
* Corresponding author. Tel.: +49-6032-705-402; fax: +49-6032-705-419 skostin{at}kerckhoff.mpg.de
Received 25 September 2001; accepted 18 January 2002
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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Objective: We tested the hypothesis that structural remodeling of cellular connections, alterations in the expression of connexins (Cx), and an increase in fibrosis represent anatomic substrates of atrial fibrillation (AF). Methods: In 31 patients with AF undergoing a Maze procedure and 22 patients in sinus rhythm (SR), biopsies were taken intraoperatively from the right atrial (RA) free wall and appendages and investigated with immunoconfocal and electron microscopy. Results: All patients with AF exhibited a concomitant lateralization of gap junctional proteins Cx43 and Cx40, and N-cadherin (the major mechanical junction protein), instead of being confined to the intercalated discs, as observed in SR. These results were confirmed by quantitative immunoconfocal analysis and electron microscopy. Among diverse junctional proteins, in AF, Cx40 was markedly heterogenous in distribution. As compared with the SR group, Cx43 was significantly decreased in AF by 57% in RA appendages and by 56% in RA free wall. Cx40 was reduced by 54% in appendages, but had a tendency to be increased in the RA free wall. Collagen I was significantly higher in AF than in SR by 48% in RA appendages and by 69% in the RA free wall tissues. Conclusions: The structural correlate of AF comprises extensive concomitant remodeling of mechanical and electrical junctions, reduction of Cx43, heterogenous distribution of Cx40 in terms of different amounts of Cx40 in different RA tissues or in spatially adjacent regions of atrial myocardium. These changes, together with augmentation of fibrosis, may underlie localized conduction abnormalities and contribute to initiation and self-perpetuation of re-entry pathways and AF.
KEYWORDS Arrhythmia (mechanisms); Gap junctions; Remodeling; Fibrosis; Supraventr. arrhythmia
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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Atrial fibrillation (AF) is the most common cardiac arrhythmia and numerous experimental and clinical studies showed that whatever the initial cause and triggers, AF causes alterations in atrial electrical properties. This process called electrical remodeling [1–3] comprises alterations in ion channel gene expression (for review see Refs. [4–6]) leading to changes in action potential duration, effective refractory periods and conduction velocity which facilitates the appearance of multiple re-entrant wavelets that is a final common pathway for AF [6,7]. However, it is likely that self-perpetuation of AF and the progressive trend of this arrhythmia to become persistent, and finally the establishment of points of no return to sinus rhythm (SR) in permanent AF may also involve structural changes. Recent experimental studies have shown that in AF cardiomyocytes undergo dramatic structural changes including cellular hypertrophy, disintegration of the contractile apparatus, accumulation of glycogen, changes in mitochondrial size and shape [8–12]. In addition to these complex changes, atrial myocytes in human AF showed signs of degeneration and apoptosis [13–16]. All these studies suggest the involvement of a second factor in the pathogenesis of AF [17], that is the structural remodeling.
Among different structural components of the atrial myocardium, central to the determinants of passive conduction of atrial impulse are the intercellular junctions, the size and packing geometry of individual myocytes, and the composition of the extracellular matrix [7,18]. Intercellular coupling between myocytes is provided by gap junctional channels composed of connexins (Cx) [19–21]. In the adult normal atrium, gap junctions are closely associated with the junctions responsible for cell-to-cell adhesion and mechanical coupling, the fascia adherens junctions and the desmosomes [22]. Although the evidence that gap junctions undergo a significant remodeling in experimental and clinical AF has recently emerged [23–27], no investigation has previously been undertaken to determine whether gap junctional remodeling is associated with the remodeling of adherens junctions in this type of arrhythmia. To test the hypothesis that AF involves remodeling not only of electrical, but also of mechanical junctions, the present study set out to compare the patterns of distribution and expression of proteins forming gap junctions (Cx43 and Cx40), fascia adherens (N-cadherin and vinculin), and desmosomes (desmoplakin) in the atrial myocardium of patients with AF and in patients in SR. In addition, we determined the extent of interstitial fibrosis as a potential anatomic substrate of AF.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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2.1 Patients
Before cardiac surgery, two investigators (ZS and SH) assessed the clinical characteristics of patients as described previously [28]. The study group included 31 patients with a mean duration of AF of more than 1 year (mean 6.2±5.3 years) who underwent a mini-Maze procedure. The surgical procedure has been described in detail previously [28]. The AF patients were matched for left ventricular function, right and left atrial sizes with 22 patients in normal SR. Clinical data are summarized in Table 1. The institutional Ethical Committee approved the study, and all patients gave written informed consent.
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2.2 Tissue preparation
Tissue samples were taken intraoperatively from right atrial (RA) appendages and free wall tissues and either immediately frozen in liquid nitrogen for immunohistochemistry or immersed in 3% glutaraldehyde buffered with 0.1 mol/l Na cacodylate for electron microscopy.
2.3 Immunofluorescent labeling
Before immunolabeling, tissue characterization and orientation was recorded by hematoxylin–eosin staining. Frozen sections, 10 µm thick, were fixed for 10 min with 4% paraformaldehyde and then incubated with the primary antibodies: monoclonal (clone 1E9, Biotrend) and polyclonal anti-Cx43 (Zymed), polyclonal anti-Cx40 (Biotrend), monoclonal (clone GC-4, Sigma) and polyclonal anti-N-cadherin (Sigma), monoclonal anti-vinculin (clone hVIN-1, Sigma), monoclonal anti-desmoplakin (clone DP 1&2-2.15, Boehringer), monoclonal anti-dystrophin (clone MANDYS8, Sigma) and monoclonal anti-collagen I (clone COL-I, Sigma). Anti-mouse or anti-rabbit IgG-conjugated with Cy2 or Cy3 (Biotrend) were used as detection systems. The nuclei were stained with TOTO-3 (Molecular Probes). F-actin was fluorescently stained using FITC or TRITC-conjugated phalloidin (Sigma).
2.4 Confocal microscopy
The samples were examined with a confocal scanning laser microscope, Leica TCS NT, equipped with argon/krypton and helium/neon lasers. Confocal images were obtained using different Leica objectives and three confocal detectors for reflected fluorescence and one confocal detector for transmitted light. Each recorded image was taken using multi-channel scanning and consisted of 1024x1024 pixels. Series of confocal optical sections were taken through the depth of the tissue sample at 0.5- to 1-µm intervals. In order to improve image quality and to obtain a high signal/noise ratio each image from the series was signal-averaged. After data acquisition, the images were transferred to a Silicon Graphics Indy workstation (Silicon Graphics) for image restoration and reconstruction using Imaris®, the multichannel image processing software (Bitplane, Zürich, Switzerland). The principles of this method have been previously described [29,30].
2.5 Quantitative analysis
For quantitative analysis, all sections from all patients were immunolabeled simultaneously using identical dilutions of primary and secondary antibodies and other reagents. Sections were scanned under identical parameters of imaging, zoom, pinholes, objective, and laser power.
2.5.1 Quantification of junctional proteins in longitudinal sections
The quantity of the gap junctional proteins Cx40 and Cx43 was determined in tissue sections concomitantly immunolabeled for the membrane-associated proteins dystrophin and vinculin. The quantity of N-cadherin was determined in sections labeled for F-actin. Before quantification, all tissue sections were briefly inspected to ensure that the image collected demonstrates a full range of the fluorescence intensity from 0 to 255 intensity levels and were kept constant for recording of data in all measurements. Quantification of Cx43 and Cx40 was performed blindly, having on the screen only one channel showing vinculin or dystrophin labeling. The values of myocyte area were obtained immediately based on clearly delineated cell borders by dystrophin or vinculin labeling. From each cell, several histograms of connexin fluorescence intensity were obtained. The first histogram represented the total fluorescence intensity of connexin per cell area, and the following histograms represented connexin signal intensity that was not associated with transverse boundaries of the cell, i.e. with the intercalated discs. The histograms were converted into Macintosh Excel data for calculation of the connexin signal. A pixel intensity threshold of 50 from 0–255 gray scale was used for either Cx43 or Cx40 quantification. Per each patient, 112±11 atrial myocytes with clearly defined cellular borders were investigated for connexin expression and 75±9 myocytes for the N-cadherin signal.
2.5.2 Quantification of vinculin in transverse sections
Five to 10 fields (size 250x250 µm) of transversally sectioned atrial tissue and labeled for vinculin were investigated per each patient. The images were analyzed using NIH image software. According to vinculin labeling, cross-sectioned myocytes were classified as unlabeled, when vinculin was present only at the lateral sarcolemma, or as labeled, when apart from membrane labeling, distinct areas of adherens junction were clearly identified. The latter area was measured and expressed as percent of positive label per total myocyte cross-sectional area. In dependence of the area of vinculin labeling, the myocytes were divided into four groups: positive labeling less than 25%, 25–50%, 50–75%, and more than 75% of the total myocyte cross-sectional area (see Fig. 5). In each patient, 464±28 myocytes were analyzed.
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2.5.3 Quantification of Cx40 heterogeneity
For quantification of Cx40 heterogeneity we used double labeled tissue sections for Cx40 with homogenously expressed proteins (N-cadherin, vinculin, as examples). Selected fields (from 5 to 10 per each patient) were acquired from each section at x16 magnification to allow for a montage. If the resolution was not appropriate to detect microscopic areas of diminished Cx40, then higher magnification was used. The images were transferred to a Macintosh computer and the montages were established using Adobe® Photoshop® 5.5 software. Thereafter, images were thresholded at 50 of the pixel intensity for Cx40 signal using NIH image software. After the total tissue area was determined, the images were inspected using high zoom to clearly delineate the areas of diminished Cx40 reactivity. The area of Cx40 heterogeneity was measured and expressed as a percent per entire montage area.
2.5.4 Quantification of fibrosis
For each patient, 50 to 70 fields (size 150x150 µm) were analyzed for the quantity of collagen I. Endomysial fibrosis (between individual myocytes) was calculated as percent of collagen I per tissue area. Perimysial collagen I was not included in the quantification of fibrosis.
2.6 Electron microscopy
Small tissue samples were embedded in Epon following routine procedures. Ultra-thin sections were stained with uranyl acetate and lead citrate and viewed and photographed in a Philips CM 10 electron microscope.
2.7 Statistical analysis
Results are reported as means±S.D. Differences between group means were analyzed using the two-way unpaired t-test or the Mann–Whitney U-test for two group comparisons. For multiple comparisons we used ANOVA on ranks, followed by analysis with the Bonferroni t-test. Differences between groups were considered significant at P<0.05.
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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3.1 Intercellular junctions in AF
3.1.1 Immunoconfocal assessment of intercellular junctions
In longitudinally sectioned RA myocytes from patients in SR, Cx43 gap junctions are mainly located at the cell termini as short transverse lines representing intercalated discs, with little side-to-side interconnections (Fig. 1A and C). These data are in close agreement with those previously described for normal adult atrial myocardium in different animal species [22,24,25,30,31] and in man [26,27,32,33]. In AF, the pattern of Cx43 labeling was found to be highly disturbed with extensive lateral deposition of the label, instead of being confined to the intercalated discs. This pattern was consistently observed in either RA appendages (Fig. 1B) or RA free walls (Fig. 1D). In order to quantify the extent of lateralization of Cx43 gap junctions we performed double labeling for Cx43 and membrane-associated proteins, dystrophin and vinculin. Representative micrographs of Cx43 and dystrophin labeling in the SR and AF groups are shown in Fig. 1E and F. Quantitative analysis revealed that in patients in SR, from the total amount of Cx43 per myocyte, 15±3% and 10.9±2.75% of the label was confined to the lateral sarcolemma in RA appendages and free wall myocytes, respectively. In contrast, in the AF group, lateral Cx43 labeling was, respectively, 3.1- and 3.9-fold higher in RA appendages (45.2±3%) and free wall myocytes (39.3±4.8%).
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Fig. 2 compares the patterns of Cx40 labeling between SR and AF groups in RA appendages and free walls. Similar to Cx43 labeling, Cx40 in SR patients was mainly confined to the sites of apparent intercellular apposition, whereas fibrillating atrial myocardium exhibited a striking remodeling of Cx40 distribution along the lateral cell borders. To quantitatively determine the degree of lateralization of Cx40 we performed double labeling for Cx40 with either dystrophin or vinculin. Representative micrographs of Cx40 and vinculin labeling in the SR and AF groups are shown in Fig. 2E and F. Quantitative analysis showed that in patients in SR, 14.2±3% and 9.4±2.35% of the Cx40 label was found at the lateral sarcolemma in myocytes of RA appendages and free wall, respectively. In the AF group, both values were statistically different (41.2±5.3% and 43.3±4.2% in myocytes from appendages and free wall, respectively).
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Fig. 3 shows another peculiar feature of structural alterations in AF—spatial remodeling of fascia adherens junction and its major transmembrane protein, N-cadherin. Similar to connexin labeling in the SR group, N-cadherin in RA appendages and the free wall is localized mainly at the myocyte cell termini with some lateral labeling occasionally observed. In marked contrast, fibrillating atria showed a striking rearrangement of N-cadherin at the lateral sarcolemma. Similar results were observed by immunostaining of desmosomes for desmoplakin (data not shown).
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For a comprehensive characterization of the junctional organization it is absolutely necessary to investigate the pattern of junction distribution in transverse sections. Because the intercalated discs are not arranged perfectly at the same level, some myocytes in transverse sections are not labeled. However, if the intercalated disc is located in a scanning plane, then some of the myocytes show abundant labeling of different junctional proteins including Cx43 (Fig. 4A), N-cadherin (Fig. 4C) and vinculin (Fig. 4E). Because of the disruption of the intercalated disc structures and lateralization of gap junctions as observed in longitudinal sections of fibrillating atria, in transverse sections it was rather difficult to find typical intercalated discs containing an entire population of gap junctions (Fig. 4B), or large areas of N-cadherin (Fig. 4D) and vinculin labeling (Fig. 4F) as observed in atria in SR.
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To address quantitatively the changing pattern of adherens junctions induced by AF we have performed a morphometric analysis of vinculin labeling in atrial myocytes sectioned in a transverse plane. The rationale of using vinculin labeling resides in the properties of anti-vinculin antibody to clearly delineate peripheral sarcolemma as well as the fascia adherens junction (Fig. 4E and F). Double labeling for vinculin with N-cadherin revealed identical areas of adherens junctions with both antibodies (data not shown). Quantitative results given in Fig. 5 show that regardless of the RA tissue examined, approximately half of the cross-sectioned myocytes in both groups of patients were unlabeled. However, there was a marked difference between SR and AF in the frequency distribution of the area of labeled myocytes. Thus, in appendages from patients in SR the histograms of labeled myocytes were skewed toward the larger areas of labeling such that 29.3±2.2% from the total number of myocytes or 57.5±4.7% from the total number of labeled myocytes showed areas of positive labeling comprising more than 50% of the total cross-sectional cell area. In fibrillating appendages, this population of myocytes was significantly less and constituted 15.3±3.5% from the total myocytes or 30.5±5.8% from the total labeled myocytes. These differences were even more pronounced in the RA free wall myocytes so that in the AF group the majority of labeled myocytes (75.7±2.5%) showed an area less than 50% from cross-sectional cell area, whereas in the SR group these myocytes comprised only 25.4±5.5%. These data indicate that remodeling of adhesive junctions severely affects the morphology of the intercalated discs by disrupting and fragmenting these structures. In addition to these changes, the percent of cross-sectioned myocytes displaying lateral contacts was, respectively, 4- and 5.35-fold higher in the RA appendage and free wall in patients with AF as compared with those tissues in the SR group.
3.1.2 Associated remodeling of adhesive connections and gap junctions in AF
In order to determine whether AF is associated with concomitant remodeling of all types of intercellular junctions, we performed double labeling for different cell junctional proteins. Fig. 6 shows confocal images of RA sections from patients with AF demonstrating that lateralization of Cx43 label is mirrored by that of Cx40 (Fig. 6A–C). Accordingly, the redistribution of the N-cadherin signal from the intercalated discs to the lateral cell borders was found to be very similar with that of Cx40 (Fig. 6D–F). Further evidence for a closely associated spatial redistribution of diverse junctional proteins in patients with AF was obtained when RA tissues were sectioned in a transverse plane and double labeled for desmoplakin and Cx43 or Cx40. As can be ascertained from Fig. 6G and H, in AF, when all of these junctional proteins were viewed en-face, they were organized as crest-like or linear structures, instead of forming ovoid structures representing typical face-on viewed intercalated discs as observed in the SR group (for comparison see Fig. 4C and E). These data indicate that AF in human patients is characterized by a concomitant and congruent remodeling of the major proteins forming electrical and mechanical junctions.
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3.1.3 Ultrastructural assessment of intercellular junctions
We used electron microscopy to characterize intercellular junctions at higher resolution. Representative electron micrographs of RA appendages in patients with AF and SR are shown in Fig. 7. As can be seen, atrial myocytes in SR are connected mainly at the true end of the cell via intercalated discs (Fig. 7A). In contrast, in AF, atrial myocytes are extensively interconnected side-by-side (Fig. 7B). While some typical plicate segments could be found, most adhesive junctions were strewn in longitudinally orientated arrays along the lateral sarcolemma in parallel with myofibrils. Fig. 8 compares the patterns of intercalated discs in RA free wall myocytes in patients in SR and in patients with AF. In patients in SR, intercalated discs in longitudinal sections are organized more frequently as simple straight structures or less frequently as a ‘stairs’ across the myofibrils (Fig. 8A and B). In contrast, in patients with AF, intercalated disc structures are strewn longitudinally, running in parallel with myofibrils (Fig. 8D and E). This difference between groups is reflected in the ultrastructural organization of the intercalated discs seen in transverse sections such that transversally sectioned myocytes in patients in SR contained numerous finger-like plicate projections (Fig. 8C), whereas in patients with AF, it was rather difficult to find typical intercalated discs containing numerous plicate segments (Fig. 8F). These findings provide additional evidence for dramatic remodeling of intercalated disc structures induced by AF and thus confirms immunoconfocal findings.
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3.2 Heterogenous distribution of Cx40 in AF
Early immunohistochemical studies of atrial myocardium in a goat model of AF have shown that this type of arrhythmia is associated with a heterogenous distribution of Cx40 [24,25]. To determine whether this also occurs in AF in human patients, the distribution pattern of labeling intensities of Cx40 was compared in double labeling experiments with that of Cx43 and that of the proteins forming adherens type of junctions. Fig. 9 shows examples of a homogenous distribution of desmoplakin (panels A and C) and Cx43 labeling (panels D and F), which contrasted with heterogenously distributed Cx40 labeling (panels B and E) in spatially adjacent myocytes of the RA appendage in patients with AF. In order to ensure that diminished Cx40 expression is not related to fiber orientation, we performed double labeling for Cx40 with the membrane-associated proteins dystrophin and vinculin. Fig. 10A–C shows that longitudinally sectioned myocytes from the RA free wall display a uniform distribution of dystrophin that markedly contrasted with a heterogenous distribution of Cx40. Similar results were observed by double immunolabeling for Cx40 and vinculin (Fig. 10D–F). The heterogeneity of Cx40 label in terms of the scarcity and reduced Cx40 signal was found to affect more frequently small microscopic areas (100–500 µm in size), but large myocardial areas (up to several millimetres) could be observed as well. A representative example of such a large area of diminished Cx40 contrasting with a uniform distribution of N-cadherin signal is shown in Fig. 11. Quantitative analysis revealed that Cx40 heterogeneity in patients with AF affected 17.9±5.7% of the RA appendage and 13.5±4.9% of the RA free wall myocardium. In patients in SR, heterogeneity of Cx40 could be observed as well, however it affected a significantly smaller area of the RA appendages (4.4±1.8%) and RA free wall tissue (2.75±1.9%).
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Taken together, these results indicate that from diverse mechanical and electrical junctional proteins, only Cx40 was found in AF to be heterogenously distributed so that fibrillating atria showed focal regions in which Cx40 appeared to be diminished, but not Cx43, N-cadherin or desmoplakin.
3.3 Connective tissue in AF
Another important structural parameter that may influence the pattern of impulse conduction is interstitial fibrosis. Fig. 12 displays confocal micrographs of RA appendages and free wall tissues comparing the amount of collagen I and the packing geometry of myocytes stained for F-actin in SR patients with the AF group. It is obvious that in patients with AF, the degree of fibrosis is highly augmented and tends to separate myocytes from each other.
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3.4 Quantitative analysis of junctional proteins and fibrosis
Quantitative analysis showed significant differences between groups in the amount of Cx43 or Cx40 per myocyte area and in the percentage of RA myocardium occupied by collagen I (Fig. 13). As compared with the SR group, Cx43 was significantly decreased in AF by 57.3% in RA appendages and by 56.6% in the RA free wall. Cx40 was reduced by 53.9% in appendages, but had a trend to be increased by 16% in the RA free wall. In patients in SR, RA appendages contained 5.4±1.07% of collagen I. This value was increased by 48.6% in fibrillating RA appendages. In patients in SR, RA free wall tissue contained 3.8±0.9% of collagen I, whereas in AF, this value was significantly increased by 69.3%. There were no changes between groups in the quantity of N-cadherin per cell area.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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4.1 Remodeling of intercellular junctions in AF
The present study demonstrates that chronic permanent AF in human patients is consistently associated with distinct changes in the distribution pattern of junctions forming the atrial intercalated disc: fascia adherens, the desmosomes and gap junctions. In SR patients, the major constituent proteins of these junctions—N-cadherin, desmoplakin, and the connexins, respectively—were found to be predominantly confined to the transverse boundaries of atrial myocytes. In contrast, in patients with AF, this pattern appeared grossly disrupted with redistribution of N-cadherin, desmoplakin and connexin labeling from the cell termini to the lateral borders. Quantitative immunoconfocal analysis and electron microscopy confirmed the changing pattern of junctional contacts in AF. This pattern was found to affect large areas of fibrillating RA tissues and therefore can be interpreted as a hallmark of structural remodeling inherent to AF. Given that chronic AF is a reentrant arrhythmia [5,7,34], the link between the structural remodeling of intercellular junctions and AF is also supported by the fact that similar disruptions and disarrangements of intercellular junctions have consistently been described in other types of reentry arrhythmias such as those associated with healed myocardial infarcts [35–37], cardiomyopathies [38,39] or myocardial hypertrophy (reviewed in Refs. [19–21,40,41]).
Our observations of a concomitant redistribution of cell adhesion junctions and gap junctions in fibrillating human atrial tissues are consistent with the hypothesis that the spatial rearrangement of gap junctions is determined by the extent to which mechanical junctions provide enough membrane apposition to allow insertion of new gap junctional channels [29,42]. Studies in ventricular myocytes in vivo [43,44] or in vitro [45] have shown that specific mechanisms that initiate structural remodeling of intercellular junctions involve activation of multiple signal pathways triggered by chemical or humoral mediators such as cAMP and angiotensin II (reviewed in Refs. [20,41]). However, the question of whether concomitant changes in different types of cell-to-cell junctions, as we described in AF, are regulated by a common signaling pathway or whether atrial myocytes may respond in a similar way as ventricular myocytes awaits further substantiation. Recent findings of a threefold increase of the atrial angiotensin-converting enzyme in patients with chronic AF suggests a potential role of the angiotensin system in junctional remodeling in this arrhythmia [46]. An interesting hypothesis of the mechanism of myocyte junctional remodeling in AF has emerged from studies carried out in a goat model of lone AF which showed that atrial myocytes during the induction of persistent AF reactivate a fetal program of gene expression and a fetal pattern of myocyte junctions [8,9,11,14]. In accordance with these findings, remodeling of intercellular junctions observed in the present study in patients with AF could thus be envisaged as a step-wise reversal of the normal myocyte differentiation pathway. Further studies are needed to demonstrate whether dramatic junctional remodeling as observed in human AF involves similar developmental mechanisms of the process of reverse maturation of myocyte interconnections [22,47].
4.2 Gap junctions and connexins in AF
Growing evidence suggests that three-dimensional distribution of gap junctions and the quantity of their constituent connexin isoforms are critical determinants of normal and abnormal impulse conduction in different regions of the heart, including the atrial myocardium [30–32,48]. Thus, in the atrium of the dog an increase in Cx43 protein has been found after prolonged rapid pacing [23], whereas in a similar goat model of AF [24,25], the amount of Cx43 mRNA and protein remained unchanged. In the present study we found reduced levels of Cx43 in patients with AF implying a role of Cx43 in the pathogenesis of human AF. Although studies carried out in Cx43-deficient mice have shown that reduction of Cx43 by 50% has no effect on atrial conduction [48], the existence of species differences may limit extrapolation of data from non-human species to the human atrial tissue [32].
Our data showing a decreased level of Cx40 per myocyte in RA appendages are in good agreement with those obtained in a goat model of AF [24,25] and with earlier observations of reduced Cx40 protein in patients that were undergoing a Maze operation [49]. A recent publication by Polontchouk et al. [26] showed an increased Cx40 in RA appendages in patients with AF. The discrepancy between this study and our data may be explained by the fact that Cx40 heterogeneity was not documented in AF patients included in that study. Another recent publication by Dupont et al. [27] also showed increased Cx40 protein in RA appendages in human patients susceptible to postoperative AF. The discrepancy between this study and ours may be explained by different mechanisms of the development of postoperative AF and long-standing permanent AF in our patients. On the other hand, Dupont et al. observed a heterogenous Cx40 distribution in both control and AF, which was confirmed in the present study. However, we found statistically larger areas of Cx40 heterogeneity in AF patients than in the SR group that may partially explain the discrepancy of data. Moreover our data of diminished Cx40 expression in RA appendages concurs with those obtained in a goat model of chronic AF, which also showed a marked Cx40 heterogeneity (
25% of the atrial area), that was associated with decreased Cx40 protein [24].
Increased degrees of Cx40 heterogeneity in terms of different amounts of Cx40 in different RA tissues or in spatially adjacent regions of atrial tissue observed in our patients with AF could potentially lead to a non-uniform pattern of wave-front propagation. Importantly, a recent study of a murine model of heterogenous gap junction channel expression [50] provided evidence by directly linking the heterogenous pattern of gap junction distribution not only to conduction defects but also to contractile dysfunction which is a common observation in AF [51]. The heterogeneity of atrial Cx40 distribution was first observed by van der Velden et al. [24] in a goat model of chronic AF. These findings were further quantitatively confirmed by the same group in a similar model and the most important observation was that heterogenously distributed Cx40 gap junctions became visible immediately after the initiation of atrial burst pacing and correlated with the stabilization of AF [25]. Taken together, all these experimental and clinical observations, as well as studies carried out in Cx40 knock-out mice [52], suggest that altered Cx40 distribution and expression (either increased or decreased) is one of the major factors of electrical and morphological remodeling in AF.
4.3 Interstitial fibrosis and AF
It has long been recognized that microscopic changes in coupling due to interstitial fibrosis result in spatial non-uniformities of the propagation that can contribute to local conduction block and reentry even in small regions of the atrial tissue [18]. In line with this evidence, our present findings of advanced interstitial fibrosis in human AF would predict an impairment of atrial conduction at the microscopic level and the formation of stable local sources for microreentry and AF. Moreover, interstitial fibrosis may render the atrial myocardium discontinuous resulting in a branching architecture that was recently demonstrated to form a substrate for very slow conduction [53]. On the other hand, increased interstitial fibrosis may cause a rearrangement of atrial myocyte connections and therefore may also account for the widespread, generalized process of junctional remodeling consistently observed in our patients with AF. Given the known role of the angiotensin system in the progression of myocardial fibrosis [54] and in promoting cellular junctional remodeling [44], the results of the present study suggest that angiotensin-converting enzyme inhibition and angiotensin II receptor blockade may not only prevent but also reverse junctional remodeling and atrial fibrosis, thereby creating more homogenous mechanoelectrical coupling.
4.4 Limitations of the study
The present study does not clarify whether structural remodeling of intercellular connections and gap junctions precedes, coincides or follows electrical remodeling or whether the described structural remodeling of atrial myocardium is a primary cause of AF. To address these questions, a larger study including patients with lone AF will be needed. Nevertheless, several structural features of human AF, including gap junctional remodeling, heterogeneity of Cx40 label and interstitial fibrosis, resemble those observed in different animal models of AF [10,24,25] or in patients with lone AF [13], suggesting that these changes are indeed responsible for the maintenance of AF.
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5. Conclusions |
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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The structural correlate of chronic AF in human patients comprises extensive concomitant remodeling of the intercellular junctions responsible for mechanical and electrical coupling between atrial myocytes, reduction of Cx43 per cell, and heterogenous distribution of Cx40. These changes together with augmentation of fibrosis may underlie localized conduction abnormalities and contribute to initiation and self-perpetuation of reentry pathways and AF.
Time for primary review 27 days.
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TopAbstract1. Introduction2. Methods3. Results4. Discussion5. ConclusionsReferences |
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