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Ann Thorac Surg 2010;89:38-43. doi:10.1016/j.athoracsur.2009.10.008
© 2010 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Capillary Supply to the Sinus Node in Subjects with Long-Term Atrial Fibrillation

Aquilino Hurlé, MD, PhDa,*, Damián Sánchez-Quintana, MD, PhDb, Siew Y. Ho, MD, PhDc, Eduardo Bernabeu, MDa, Margarita Murillo, BSb, Vicente Climent, MD, PhDb

a Department of Cardiac Surgery, Hospital General Universitario de Alicante, Alicante, Spain
b Department of Human Anatomy, University of Extremadura, School of Medicine, Badajoz, Spain
c National Heart and Lung Institute, Imperial College, London, United Kingdom

Accepted for publication October 6, 2009.

* Address correspondence to Dr Hurlé, Servicio de Cirugía Cardiaca, Hospital General Universitario de Alicante, Alicante, 03010, Spain (Email: hurle_aqu{at}gva.es).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Atrial ischemia, and sinus node ischemia in particular, may be involved in the pathogenesis of atrial fibrillation. In this study we compared the sinus node blood capillary content in normal hearts in sinus rhythm and in pathologic hearts with chronic atrial fibrillation and we analyzed the ultrastructural features of such capillaries.

Methods: Sinus node biopsy specimens were obtained from 16 patients in chronic atrial fibrillation undergoing open heart surgery. Control sinus node specimens of normal hearts were obtained at autopsy from 7 subjects. Specimens were processed for immunohistochemical, light microscopy and transmission electron microscopy analysis and compared grossly and with morphometric techniques.

Results: The proportion of sinus node tissue corresponding to capillaries, defined as blood vessel density (or BVD), was estimated as 1.06 ± 1.47% for the atrial fibrillation group versus 2.12 ± 2.0% for controls (p < 0001). Internal capillary diameter averaged 21.6 µm in the atrial fibrillation group and 24.2 µm in controls (p = 0.175), whereas external diameter averaged 32.2 µm in the atrial fibrillation group and 38.9 µm in controls (p = 0.052). Ultrastructural analysis demonstrated scarce and interrupted myoendocardial bridges and abnormal deposits of elastic fibers under the endothelial basal membrane at the level of precapillary sphincters and metaarterioles of atrial fibrillation specimens.

Conclusions: There is a significant reduction in the amount of capillaries in the sinus node of hearts in chronic atrial fibrillation. Our findings would support a potential association between sinus node tissue ischemia and chronic atrial fibrillation.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
A number of descriptive and embryologic studies have been conducted on the sinus node (SN) of men and other mammals, mainly concerning its structure, distribution, innervation, and development [1–4]. There are also several publications detailing the gross anatomy of the SN and its blood supply [1, 2, 4, 5], as well as the density of its capillary and precapillary network [6, 7].

Blood supply to human SN comes from the SN artery, which characteristically has a variable origin. Venous drainage from the SN is by small Thebesian venules, directly into the right atrium adjacent to the node [1, 2, 5]. The SN artery supplies the SN itself as well as its surrounding atrial myocardium, and it constitutes an essential component of the anastomotic circulation as it connects with most other atrial arteries. Sinus node microvascularization is characterized by the presence of an irregular plexus of precapillary arterioles and capillaries that are more densely arranged than in the adjacent atrial tissue [6, 8].

We recently reported on the histologic changes taking place in the SN of patients with long-standing atrial fibrillation (AF) [9]. To our knowledge, there have been no previous studies comparing the SN blood supply to normal hearts in sinus rhythm and that of hearts in AF. A study of such kind would be of relevance because, as will be discussed later, atrial ischemia, and SN ischemia in particular, could be involved in the pathogenesis of AF [10]. In this comparative prospective study we quantified the SN blood capillary content and analyzed the ultrastructural appearance of such capillaries in both normal hearts in sinus rhythm and in pathologic hearts in AF.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
It was essential to ensure that SN undergoing biopsy would have no adverse consequences whatsoever in any participant. Strict patient selection criteria were, therefore, established in order to ensure that no one with even a small chance of reverting to sinus rhythm by any medical, interventional, or surgical means could possibly be included. Thus, these inclusion criteria were the following: (1) documented ongoing permanent AF for 10 years or more; and (2) a left atrial transverse diameter greater than 60 mm, as measured by means of transthoracic echocardiography.

Sixteen consecutive patients (10 female, mean age 66 years) in chronic AF satisfying the above criteria, undergoing elective surgery for heart valve disease, were included in this study (AF group). Relevant clinical data for this group of patients is summarized in Table 1. Informed written consent for the study and biopsies was obtained from all 16 participants and the study was reviewed and approved by the Ethics Committee.


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  		Table 1 Patients' Clinical Data
 
In each patient, a 4-mm transmural punch biopsy specimen was obtained from the anterolateral junction between the superior caval vein and the terminal crest of the right atrium, where the SN has been reported to be located [1–4]. A preliminary overall histologic examination of all tissue specimens was conducted and reported recently [9].

Also, control biopsy specimens of the same area of the heart were obtained postmortem from 7 subjects (4 female, mean age 62 years) who were previously in sinus rhythm and died from noncardiac causes (ie, trauma or neoplastic disease).

Light Microscopy
Biopsy specimens from both groups were fixed immediately in 10% neutral buffered formalin solution for 24 to 48 hours. These samples were then dehydrated and embedded in paraffin for histologic and immunohistochemical analysis. From each sample, transmural 7-µm-thick sections were cut and stained with Masson's trichrome. Immunohistochemical staining was performed in an automated immunostainer by means of a CD31 (JC70A) clone antibody (Dako, Glostrup, Denmark) with tissue pretreatment; paraffin-wet heat antigen retrieval and dilution 1:200.

Transmission Electron Microscopy (TEM)
Ultrastructural examination was conducted in all 16 AF and 7 control specimens. For this purpose, smaller fragments (2 mm approximately) were cut from biopsy samples prior to formalin fixation. These were fixed in 1.0% paraformaldehyde/1.5% glutaraldehyde in 0.05 M cacodylate buffer (pH 7.4) for 2 hours at 4°C, post-fixed in 1% osmium tetroxide, and dehydrated and embedded in Durcupan (Fluka A.G., Buchs, Switzerland). Semithin 1 µm sections were stained with Toluidine Blue 0 (Sigma-Aldrich, Cedex, France) and thin sections of selected fields were examined in a Jeol JEM-1010 electron microscope (Jeol Ltd, Tokyo, Japan), after staining with uranyl acetate and lead citrate.

Morphometry
Nodal tissue morphometric evaluation was performed on CD31 and Masson's trichrome-labeled tissue sections from AF and control specimens. In Masson's trichrome-stained specimens, images in which blood capillaries could be identified were selected (in order to ensure accuracy, only those structures with a compatible histologic appearance and red blood cell content demonstrated in their lumens were considered as true blood vessels). Digital photographs, with a 512 x 512 pixel resolution, were taken from these slides for histologic analysis.

The proportion of capillaries in each selected specimen was estimated with the aid of a grid of 11 vertical and horizontal lines, providing 121 intersection points. The total number of these intersection points was defined as 100%. The proportion of tissue corresponding to blood capillaries in each specimen was expressed as blood vessel density (BVD), which was defined as the percentage of intersection points overlying blood vessels within the tissue extension limited by the grid.

Those capillaries with a round profile (ie, cut in transverse plane) at the intersection points were measured for two widest diameters: (1) the internal diameter (diameter between the ends of the endothelial cells) was measured in images obtained from CD31; and (2) the external diameter (including the tunica adventitia) was measured in images of Masson's trichrome. It should be noted at this point that these capillary vessels were not prepared under controlled pressure because the specimens were fixed by immersion rather than by vascular perfusion. Nevertheless, vessel diameters were comparable as tissues from both groups were treated in the same manner.

Statistical analysis was carried out with an SPSS 11 (SPSS Inc, Chicago, IL) computer package. Continuous variables from AF and control groups were expressed as mean values ± standard deviation and compared with nonparametric tests. A p value of less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
There were no significant differences in terms of age and sex between the AF group and the control group. The etiology of heart valve disease in the AF group was rheumatic in 14 patients and degenerative in the remaining 2.

In 5 of the AF specimens, apart from epicardial and endocardial connective tissue and epicardial fat, only a dense connective matrix, without vessels, could be demonstrated within the atrial wall. These specimens were excluded for quantification purposes in order to avoid bias.

Light Microscopy
Masson's trichrome and CD 31-stained tissue samples showed the typical features of nodal tissue in chronic AF when compared with controls (Fig 1). The AF specimens displayed myocardial cell degeneration, progressive loss of nodal cells, a significantly higher proportion of connective tissue matrix, and an evident decrease in blood vessel content when compared with controls [9] (Fig 1).


Figure 1
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  		Fig 1. Sinus node histologic sections. (A) and (B) Masson's trichrome staining. (C) and (D) CD 31 endothelial antigen immunohistochemical staining (vessel walls stained in brown). (A) and (C) are specimens from control group and (B) and (D) from atrial fibrillation (AF) group. Note fewer and thinner capillaries in AF specimens; scale bar 15 µm. (CV = capillary vessels.)

 
Morphometric and Quantitative Analysis
A total of 165 BVD measurements were made from the remaining 11 AF specimens and 70 BVD measurements were made from controls. Average estimated BVD was 1.06 ± 1.47% (range, 0 to 6.61%) for the AF group and 2.12 ± 2.0% (range, 0 to 7.43%) for the control group. The BVD difference between both groups was highly significant (p < 0.00001).

Forty vessels were measured in both AF and control groups for internal and external diameters, yielding a total of 160 diameter measurements. Mean estimated internal diameter value was 21.60 ± 7.69 µm (range, 10.80 to 48.10 µm) for AF and 24.20 ± 8.60 µm (range, 8.52 to 46.17 µm) for controls (p = 0.175). External diameter values averaged 32.18 ± 6.94 µm (range, 22.80 to 52.49 µm) for the AF group and 37.90 ± 12.40 µm (range, 21.15 to 76.89 µm) for controls (p = 0.052).

Ultrastructural Analysis
The TEM analysis of controls suffered minor alterations, such as clumping of nuclear chromatin or mitochondrial shape changes, in some specimens due to the time elapsed between death and tissue fixation. Apart from these, control specimens displayed nodal cells distributed in a mass of supporting collagen. These were small and round cells, with an empty appearing cytoplasm, containing only sparse myofibrils and small mitochondria, surrounding a large central nucleus (Fig 2A). All stages of transition could be identified from nodal cells to ordinary working atrial myocardial cells. Transitional cells had increasing numbers of myofibrils and mitochondria, while the cytoplasm became more electron dense. Working myocardial myocytes displayed intercalated discs (Figure 2B) as opposed to nodal cells, which lacked such structures (Fig 2A, square) and contained only scattered desmosomes. Well arranged cristae were identified in working myocardial cell mitochondria (Fig 2C). Pinocytic vesicles invaginating from plasma membranes were observed in nodal cells in greater quantities than in transitional or working myocardial cells. However, no major nodal cell pinocytic vesicle differences could be demonstrated between AF and control specimens (Fig 2D, square).


Figure 2
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  		Fig 2. Sinus node transmission electron microscopy images illustrating the main differences between atrial fibrillation (AF) and normal control nodal tissue. (A), (B), and (C) Control specimens. (D), (E), and (F) The AF specimens. All three types of myocardial cells are demonstrated in (A) and (D): nodal cells (Nc), working myocytes (Wm), and transitional cells (Tc). The inset in (A) shows simple cellular boundaries between two nodal and transitional cells. The inset in (D) shows invaginated plasma membranes forming many pinocytic vesicles (arrows) in a nodal cell. (E) shows the altered cell adhesion zone with a disrupted intercalated disk (Id) between two adjacent myocytes (My) and (F) shows mitochondrial disruption. Scale bars: 1 µm for (A) and (D) and 500 nanometers for (B), (C), (E), and (F). (Mi = mitochondria.)

 
Myocardial tissue degenerative changes in long-standing AF hearts included loss of nodal, transitional, and working myocardial cells. The remaining cell population revealed other cellular alterations, such as increased cell volume with large vacuolar areas, severe alterations of cell adhesion at the level of intercalated discs (Fig 2E), mitochondrial disruption (Fig 2F), and segmental loss of perinuclear membrane.

The endothelial layer of continuous capillaries displayed much more abundant vacuoles of pinocytosis in control specimens than in AF specimens (Fig 3A, square). Alterations in the AF vascular nodal territory were observed mainly in precapillary sphincters and metaarterioles (Fig 3B). These included vessel diameter reduction and an abnormal gross deposit of elastic fibers and amorphous substance between the endothelial cell basement membrane and the smooth muscle cell basement membrane. Myoendocardial bridges were also scarce or incomplete in these vessels. In most AF specimens, endothelial cells were not in contact with the muscular layer of the vessel (Fig 3B). Continuous capillaries occasionally displayed other alterations related to pathologic cardiac vessels (Fig 3C), and we were also able to identify areas of interrupted and thickened basement membrane, which appeared to be in continuity with neighboring collagen (Fig 3D).


Figure 3
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  		Fig 3. Transmission electron microscopy micrographs of four vessels. (A) Control group. (B), (C), and (D) Atrial fibrillation group. The vessels shown in (A), (C), and (D) are continuous capillaries. Note large pinocytotic vesicles (Pv) in the endothelial layer (El) of capillary (A), which is magnified in the inset. (B) Precapillary sphincter-metaarteriole with a disrupted smooth muscle layer (Ml), a thick layer of elastic fibers (Ef), and interrupted myoendothelial bridges (arrows). Note the large nuclei (N) protruding into the lumen (L) of the vessel. There is a small thrombus (T) in (C). The outer contour in this capillary vessel shows images corresponding, probably, to fragments of a neighboring pericyte (Pr). (D) Thickened basement membrane (Bm) in continuity to collagen fibers (Co). Scale bar = 1 µm. (Er = erythrocytes.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The ultimate causes for chronic AF are not yet well understood. However, a potential association between atrial ischemia and AF can be suspected from histologic observations. In a previous study, we described the structural changes within the SN of patients with chronic AF that included progressive tissue fibrosis, with myocardial cell degeneration and loss [9]. These features have also been reported to occur in the working atrial wall of subjects in chronic AF [10] and analogous histologic findings can be observed in the ventricular myocardium as the result of an ischemic insult to the heart [11].

Some clinical observations would also support a relationship between atrial ischemia and AF. Atrial ischemia is known to play an important role in the genesis of supraventricular tachyarrhythmias secondary to acute myocardial infarction [12]. Open heart surgery [13, 14], coronary artery inflammatory disease [15], and, also, conditions leading to hypoxemia, such as obstructive pulmonary disease [16] or pneumonia [17], are associated to a higher incidence of AF. Range and colleagues [18] reported a significant impairment of myocardial perfusion in male patients suffering from idiopathic persistent AF, demonstrated by means of positron emission tomography scanning, and Skalidis and colleagues [19] described isolated atrial myocardial perfusion abnormalities in patients with lone recurrent AF by measuring peak coronary blood flow velocity.

It is also possible to find some other factors that could relate ischemia to fibrosis and AF. There are evidences that increasing fibrosis and structural alterations take place in the aging SN [20] and the incidence of AF is known to be in direct relationship with old age [21]. Also, systemic hypertension, included among the cardiovascular causes in the pathophysiology of the AF [21], has been reported to increase angiotensin II, which appears to be related to cardiac fibroblast involvement [22].

Previous morphologic studies, focused likewise on left atrial capillary densities of subjects in chronic AF, demonstrated a significantly reduced amount of capillaries as well as increased interstitial fibrosis in the myocardium surrounding the pulmonary vein ostia [23], an area that has been reported to be the most important location for AF triggers [24].

As far as we know, there are no reports in the literature comparing (structurally and [or] ultrastructurally) the SN blood capillary network between normal individuals and subjects in AF. In our study, even after discarding the specimens with no blood vessel content, we were still able to demonstrate a 50% blood capillary reduction in the SN of AF patients when compared with that of normal subjects in sinus rhythm, although such capillaries were not significantly thinner in AF specimens. The true relevance of this finding is uncertain but such a considerable capillary reduction should lead, theoretically at least, to a substantial decrease in blood supply to the SN of patients in AF, a fact that is likely to contribute to the pathophysiologic mechanisms responsible for this arrhythmia.

We were also able to discover ultrastructural changes affecting both the elastic fiber layer and the myoendocardial bridges in SN tissues from AF patients. These abnormalities could impair intercellular communications and, consequently, affect the transport of nutrients to nodal tissue.

Thus, the data obtained in our study on SN capillarity should be added to the growing pool of clinical, experimental, and morphologic evidence suggesting a potential association between atrial tissue ischemia, SN tissue included, and AF. The question then, as expressed by Haigney [25] in his editorial, would be to determine what comes first, AF or a reduced resting myocardial blood flow. In other words, further studies are necessary to ascertain whether atrial tissue ischemia is a cause or, simply, a consequence of AF.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by the Consejería de Infraestructuras y Desarrollo Tecnológico, Junta de Extremadura (PRI 06B186) and CNIC-13, Translational, Spain to V.C. and D.S.Q.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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Invited Commentary
Stefano Benussi and Ottavio Alfieri
Ann. Thorac. Surg. 2010 89: 43. [Extract] [Full Text] [PDF]



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