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J Thorac Cardiovasc Surg 2003;126:401-407
© 2003 The American Association for Thoracic Surgery

Surgery for acquired cardiovascular disease

Obstruction of St Jude medical valves in the aortic position: histology and immunohistochemistry of pannus

Hideki Teshima, MDa,*, Nobuhiko Hayashida, MDa, Hirohisa Yano, MDa, Masaru Nishimi, MDa, Eiki Tayama, MDa, Shuji Fukunaga, MDa, Hidetoshi Akashi, MDa, Takemi Kawara, MDa, Shigeaki Aoyagi, MDa

a From the Departments of Surgery and Pathology, Kurume University, School of Medicine, Kurume, Japan

Received for publication November 12, 2002; revisions received January 21, 2003; revisions received April 1, 2003; accepted for publication April 8, 2003.

* Address for reprints: Hideki Teshima, MD, Department of Surgery, Kurume University, School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan
tesshi{at}med.kurume-u.ac.jp


   Abstract
Top
 Abstract
Materials and methods
 Results
 Discussion
 Conclusions
 References
 
OBJECTIVE: This study aims to reveal the morphological, histological, and immunohistochemical mechanism of pannus formation using resected pannus tissue from patients with prosthetic valve dysfunction.

METHOD: Eleven patients with prosthetic valve (St Jude Medical valve) dysfunction in the aortic position who underwent reoperation were studied. We used specimens of resected pannus for histological staining (hematoxylin and eosin, Grocott’s, azan, elastica van Gieson) and immunohistochemical staining (transforming growth factor-beta, transforming growth factor-beta receptor 1, {alpha}-smooth muscle actin, desmin, epithelial membrane antigen, CD34, factor VIII, CD68KP1, matrix metalloproteinase-1, matrix metalloproteinase-3, and matrix metalloproteinase-9).

RESULTS: Pannus without thrombus was observed at the periannulus of the left ventricular septal side; it extended into the pivot guard, interfering with the movement of the straight edge of the leaflet. The histological staining demonstrated that the specimens were mainly constituted with collagen and elastic fibrous tissue accompanied by endothelial cells, chronic inflammatory cells infiltration, and myofibroblasts. The immunohistochemical findings showed significant expression of transforming growth factor-beta, transforming growth factor-beta receptor 1, CD34, and factor VIII in the endothelial cells of the lumen layer; strong transforming growth factor-beta receptor 1, {alpha}-smooth muscle actin, desmin, and epithelial membrane antigen in the myofibroblasts of the media layer; and transforming growth factor-beta, transforming growth factor-beta receptor 1, and CD68KP1 in macrophages of the stump lesion.

CONCLUSIONS: Pannus appeared to originate in the neointima in the periannulus of the left ventricular septum. The structure of the pannus consisted of myofibroblasts and an extracellular matrix such as collagen fiber. The pannus formation after prosthetic valve replacement may be associated with a process of periannular tissue healing via the expression of transforming growth factor-beta.

Key Words: 35


Top: Yano, Kawara, TayamaBottom: Hayashida, Teshima, Aoyagi


Prosthetic valve dysfunction (PVD) due to thrombus and pannus formation is an infrequent but serious complication. In particular, patients with complete obstruction of the prosthetic valve may develop acute hemodynamic deterioration, a life-threatening condition.1

Several clinical and histological studies have reported an occurrence of pannus formation in patients who received prosthetic valve replacement2-6 and mitral valve repair.7 The mechanisms of pannus formation in children have been reported to be associated with endocardial fibroelastosis8 and pseudoxanthoma elasticum.9 The operative findings demonstrated a narrowing of the orifice of the aortic prosthetic valve due to pannus overgrowth arising from the periannular tissue and an obstruction of leaflet movement.1,3-7,10

The cause of pannus is generally recognized as a bioreaction to the prostheses2,3,7; however, the detailed mechanism of its formation has not yet been fully demonstrated. Because PVD due to pannus formation is infrequent and asymptomatic,3-5 effective diagnostic and therapeutic methods to manage this complication have not been established. Although reoperations are necessary for cases with marked deterioration of prosthetic valve function, postoperative mortality has been reported to be high.5,6 Therefore, further basic studies are essential for the prevention, diagnosis, and treatment of pannus formation. The aim of the present study is to elucidate the morphological, histological, and immunohistochemical mechanisms of pannus formation using resected pannus tissue from patients with PVD.


   Materials and methods
Top
 Abstract
 Materials and methods
Results
 Discussion
 Conclusions
 References
 
Patients
Of 615 patients who underwent aortic valve replacement (AVR) with a St Jude Medical (SJM) valve (St Jude Medical, Inc, St Paul, Minn) at the Kurume University School of Medicine between 1980 and 1999, 12 cases (11 patients) undergoing reoperations for PVD in the aortic position were diagnosed by cineradiography and Doppler echocardiography.10 The incidence of PVD in the aortic position due to pannus formation was 1.95% (12/615) during this period. Among these patients, 11 resected specimens were used in the present study. There were 3 male and 7 female patients, whose ages ranged from 49 to 69 years of age (mean 63.9 ± 5.8 years) at the time of reoperation. The period between the prior operation and reoperation ranged from 22 to 170 months (mean 83 ± 52 months). The primary valve lesions were aortic stenosis in 6 cases and aortic regurgitation in 5. Two cases had re-AVR and 2 had AVR and mitral valve replacement. The prothrombin time-international normalized ratio (PT-INR) at the time of diagnosis of PVD ranged from 1.43 to 2.05 (mean 1.70 ± 0.16). Preoperatively, 8 patients were classified as New York Heart Association functional class II and 3 were classified as class III.

The diagnosis of PVD was based on the results of cineradiography and Doppler echocardiography, as described previously.10 The opening angles ranged from 36° to 86° (mean 53 ± 18°), calculated as the distance between the 2 leaflets in the fully open position. The peak pressure gradients by Doppler echocardiography ranged from 29.7 to 86.0 mm Hg (mean 50.1 ± 17.1 mm Hg) calculated with a modified Bernoulli equation (p = PV2 x 4, where p is the pressure gradient and PV is the maximal velocity in meters per second).

Reoperations were performed through a repeat median sternotomy. The standard cardiopulmonary bypass was established with the aortic and both vena caval cannulations, and systemic hypothermia was maintained at 28°C. The operative procedure consisted of re-AVR in 9 cases, aortic root replacement with a composite graft in 1, and pannus resection in 1.

Pannus formation was classified by the categories reported by Vitale and colleagues.3 The morphologic patterns of the pannus were classified as either concentric (ie, with regular, circular ingrowth tissue over the prosthesis) or eccentric (ie, with irregular, noncircular pannus over localized, protruding edges of the prosthesis). These morphologic locations were classified by their positions (left ventricular, aortoventricular, or aortic). The association of thrombi with pannus and their positions on the prosthetic surfaces were also assessed.

Immunohistochemistry
Resected pannus tissue samples obtained during surgery were fixed in 10% buffered formalin immediately. All tissues were embedded in paraffin within 48 hours of formalin fixation and cut at 4-µm intervals according to the standard protocol11-15 just before staining. Histological staining was performed using hematoxylin and eosin (HE), Grocott’s, azan, and elastica van Gieson stains. Immunohistochemistry was conducted using Histofine rabbit or goat streptavidin-biotin peroxidase kits (SAB-PO (M) or (G), Nichirei Corporation, Tokyo, Japan). Antibodies for immunohistochemical staining were as follows: transforming growth factor-beta (TGF-ß), transforming growth factor-beta receptor type 1 (TGF-ß-R1), CD34 (endothelial cell marker), CD68KP1, matrix metalloproteinase (MMP)-1, MMP-3, MMP-9 (Novocastra Laboratories, Ltd, Newcastle, UK); {alpha}-smooth muscle actin ({alpha}-SMA), desmin, epithelial membrane antigen (EMA), factor VIII (Immunon, Pittsburgh, Pa). The effectiveness of serial immunohistochemical sections was confirmed by the expression of each positive control section. Negative control sections were processed in an identical manner by substitution of primary antibody with normal mouse immunoglobulin 1. Peroxidase reaction was developed by using 3,3'-diaminobenzidine/H2O2 substrate solution.11-14

Immunohistochemical staining was performed for smooth muscle cells (SMCs), including myofibroblasts, which were specified with {alpha}-SMA.13,15,16,17 The synthetic and contractile SMC phenotypes were specified with desmin.18 EMA was specified by immunohistochemical staining in epithelial cells, squamous cells, plasma cells, and myofibroblasts. Immunohistochemical staining was performed for macrophages, including foreign body giant cells, which were specified with CD68KP1.19 Immunohistochemical staining was performed for endothelial cells, which were specified with CD34 and factor VIII. TGF-ß, TGF-ß-R1,14,15,17,20,21 and MMPs16,22 were specified by immunohistochemical staining in the cytokine secreted by macrophages, leukocytes, fibroblasts, and myofibroblasts.

An assessment of each immunohistochemical staining was performed by our pathologists. The results were expressed semi-quantitatively as follows: "+" represents a proportion of one third or less of positively stained cells; "++" represents a proportion of two thirds, and "+++" represents a proportion of more than two thirds of positively stained cells.15


   Results
Top
 Abstract
 Materials and methods
 Results
Discussion
 Conclusions
 References
 
Operative findings did not reveal structural malfunctions in all SJM valves. All pannus formation was observed at the septum of the left ventricle. The pannus extended into the pivot guard from the sewing cuff and had 2 linear prints (Figure 1, A; black arrows), interfering with the movement of the straight edge of the leaflet in the pivot guard.



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  		Figure 1. A, The pannus showed two linear prints (indicated by black arrows). B, The histological finding of pannus allowed for the classification of three unique layers: lumen (L), internal medial layer (IM), and external medial layer (EM), at 50x magnification with HE staining.

 
As for morphologic location, 8 cases had pannus on the left ventricular side and 3 cases on the aortoventricular side. Six cases had concentric morphologic patterns and 5 cases had eccentric patterns. Thrombi associated with pannus formation were observed in 2 cases. The thrombi were located on the aortoventricular and aortic side in the leaflet surface and hinge, and were extended from pannus.

Histological analyses showed that pannus tissue was comprised of the following 3 distinctive layers and a lesion (Figure 1, B): a lumen layer (L) in the surface of pannus, an internal medial layer (IM), an external medial layer (EM), and a stump lesion located between the autologous annular tissue and the prosthetic valve (Figures 2, D; 3, B; and 4, D).



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  		Figure 2. A, Endothelial cells in the lumen layer. B, Collagen and elastic fibrous tissue in the external media were observed. C, Myofibroblasts in the internal media. D, Chronic inflammatory cell infiltration was observed in the stump lesions. The lumen layer is shown at the top of the figure. Magnification x200 (A), x200 (B), x200 (C), and x100 (D).

 
The specimens consisted of the endothelial cells in the lamina layer (Figure 2, A), chronic inflammatory cell infiltration (neutrophils, lymphocytes, plasma cells, macrophages, foreign body giant cells, and mast cells), pleomorphic spindle cells such as myofibroblasts, and capillary vessels (Figures 1, B; 2, A, C, and D). Neither malignant cells, calcifications, nor cavitations were found in the pannus specimens. Bacteria and fungi were also not found in the pannus specimens with HE and Grocott’s staining.

The internal media layer showed proliferation of spindle cells arranged in whorled pattern and edematous or myxomatous stromal change (Figure 2, C). However, hyalinized collagen fibers were observed in the external media layer (Figure 2, B).

The infiltration of chronic inflammatory cells, such as macrophages and foreign body giant cells, was observed around the sewing cuff in the stump lesions. However, overgrowth of spindle cells such as myofibroblasts was rarely observed in the lesions (Figure 2, D).

TGF-ß was expressed in the endothelial cells of the lumen layer and in the chronic inflammatory cells, including macrophages and foreign body giant cells of the stump lesion (Figure 3, A, B). However, TGF-ß was not expressed in the pleomorphic spindle cells of the media layer.



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  		Figure 3. A, Expression of TGF-ß was observed in endothelial cells. B, Expression of TGF-ß was observed in macrophages and foreign body giant cells of the stump lesion (* ). C, D, TGF-ß-R1 was significantly expressed in the endothelial cells of the lumen layer and in myofibroblasts, macrophages, and foreign body giant cells in most of the pannus specimens. The lumen layer is shown at the top of the figure. Magnification x200 (A), x100 (B), x100 (C), and x200 (D).

 
TGF-ß-R1 (Figure 3, C, D), {alpha}-SMA (Figure 4, A, B), desmin, and EMA were significantly expressed in the spindle cells. TGF-ß-R1 was detected in the endothelial cells of the lumen layer and in the macrophages and foreign body giant cells in most of the pannus specimens. These spindle cells were identified as myofibroblasts based on their immunohistochemical patterns.



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  		Figure 4. A, B, The expression of {alpha}-SMA was observed in the endothelial cells of the lumen layer and the myofibroblasts. C, Factor VIII expressed in the endothelial cells of the lumen layer. D, CD68KP1 expressed in macrophages and foreign body giant cell of the stump lesion around the sewing cuff (* ). The lumen layer is shown at the top of the figure. Magnification x100 (A), x100 (B), x100 (C), and x200 (D).

 
CD34 and factor VIII (Figure 4, C) were expressed in the endothelial cells of the lumen layer. CD68KP1 was expressed in macrophages and foreign body giant cells of the stump lesion around the sewing cuff (Figure 4, D). MMPs (MMP-1, MMP-3, and MMP-9) were not expressed in all specimens. These results are summarized in Table 1. The staining ratio of immunohistochemical staining (except MMP-1, -3, and -9) semi-quantitatively ranged from 73% (8/11) to 100% (11/11). All MMP-1, -3, and -9 staining was negative.


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  		TABLE 1. Results of immunohistochemistry

 

   Discussion
Top
 Abstract
 Materials and methods
 Results
 Discussion
Conclusions
 References
 
This study examined whether chronic inflammatory reactions and periannular wound healing after AVR contribute to neointimal response (ie, pannus overgrowth). In the present study we found that pannus was observed at the septum of the left ventricle and it extended into the pivot guard, interfering with the movement of the straight edge of the leaflet. Proliferation of myofibroblasts was observed frequently between the lumen layer and the internal media layer of pannus tissue. The inflammatory reaction was mainly composed of chronic inflammatory cell infiltration (neutrophils, lymphocytes, plasma cells, macrophages, foreign body giant cells, and mast cells). This inflammatory reaction was also observed around the sewing cuff at the stump lesion. Pannus consisted mostly of collagen and elastic fibrous tissue, suggesting pannus formation resulted from an accumulation of a generated extracellular matrix. Strong TGF-ß-R1 expression could be identified in myofibroblasts that were specified with {alpha}-SMA. These findings suggested pannus formation is due to persistent neointimal development by protracted chronic inflammatory response, which provokes proliferation of myofibroblasts and extracellular matrix without fresh thrombus formation.

The results of our study coincided with those of earlier histological studies conducted by Schoen2 and Vitale and colleagues.3 Recent clinical and histological studies have shown that pannus formation was also observed around the prosthetic ring after mitral valve repair.7 Our previous studies10,23 demonstrated that asymptomatic PVD in the aortic position was more frequent than we expected and that the cause may be related to periannular pannus formation.1 Therefore, these studies suggested that overgrowth of periannular pannus may be associated with persistent inflammation caused by the prosthesis.

All patients receiving prosthetic valve replacement have a risk of periannular intimal thickening. However, pannus formation is an infrequent complication. We thus hypothesized that the development of pannus overgrowth during the follow-up period is related to other factors. Therefore, we examined the expression of growth factor for neointimal thickening and the expression of inhibiting factor for extracellular matrix (such as collagenase), based on the hypothesis of coronary restenosis by Schwartz and colleagues.13

Several biochemical growth factors have been shown to be implicated in the rapid formation of neointimal hyperplasia.14,17 Of these, TGF-ß was reported to be involved in extracellular matrix production and SMC migration and proliferation.14,17,20 An increase in TGF-ß1 expression may provoke a differentiation signal to trigger adventitial fibroblasts to become myofibroblasts, which causes arterial remodeling via their mechanical and synthetic properties as seen in coronary restenosis after percutaneous coronary intervention.17 Several studies24-26 have shown that fibrogenesis and organ remodeling may occur via the expression of TGF-ß within the neointima of implant devices or in the anastomotic site in patients receiving allogenic vessel grafting, artificial vessel grafting, ventricular assist devices, or coronary artery bypass grafting. Therefore, the neointimal hyperplasia via the TGF-ß expression may also be implicated in pannus formation. On the other hand, no expression of MMP-1, -3, or -9 (which were used because these factors are classified into collagenases, gelatinases membrane-type MMPs, and stromelysins based on their individual in vitro substrate specificity and they inhibit neointima development) was found in this study. Therefore, it is unlikely that matrix remodeling by MMP-1, -3, and -9 caused the development of pannus tissue. Consequently, these results suggest that excessive pannus overgrowth is related to the proliferation of myofibroblasts and extracellular matrix, stimulated by TGF-ß. However, the various MMPs are complex and different in their functions and activities, especially activity of MMP-2 and -9, which inhibits smooth muscle cell migration found in dense fibrous tissue in the arterial wall.16 We are planning to perform a prospective study with immunoblotting and MMP zymogram to be certain that MMPs do not play a significant role in pannus formation.

Some coexisting factors, such as prosthetic valve design, biocompatibility, surgical techniques, prosthetic valve size in cases of smaller annuli, blood flow turbulence, shear stress, and inadequate anticoagulation, may also contribute to pannus formation.3,27,28 In particular, we are concerned about the design of pivot guard systems in the SJM valve. The SJM valve has a characteristic pivot system, a so-called "low-profile structure." The clearance between the edge of the pivot guard and the straight edge of the leaflet is considerably narrow in the fully open position. Therefore, pannus tissue easily extended into the pivot guard and interfered with the leaflet motion.1,23 Moreover, because pannus in this study was observed in the anterior septum of the left ventricle in all patients, the contact between the edge of the pivot guard and the septum may also contribute to this complication. Other factors, such as local hemodynamics and shear stress in the vicinity of the pivot guard, may also be associated with thrombus formation and neointimal hyperplasia. In the present study, however, the association between these factors and pannus formation was not investigated and the precise mechanisms remain to be elucidated.

Inadequate anticoagulation in patients with prosthetic valves was considered a risk factor not only for thrombosed valves but also for pannus formation. Schwartz and colleagues13 hypothesized that coronary restenosis is attributable to excessive neointimal formation accompanied by myofibroblasts and inflammatory cells. According to their hypothesis, although excessive neointimal hyperplasia induces the tumorous growth of myofibroblasts and SMC, thrombosis plays an important role in the restenotic neointimal formation that causes restenosis.13 The PT-INR levels as indices of anticoagulation therapy for patients with prosthetic valves are maintained at a slightly lower range in Japan than those in North American and European countries because of particular concerns about bleeding complications.29 Because thrombus can be a primary cause of pannus formation,21,30 further studies are required to assert whether the lower PT-INR levels observed in this study cause pannus overgrowth.

Study limitations
We intended to reveal whether the pannus formation was due to a form of normal healing or abnormal growth of neointima as we examined the pannus without a comparison to control autologous tissues. We plan to undertake a prospective study in which pannus and control tissue are examined to reveal the detailed mechanism of pannus formation, with better understanding of the precise role of the local inflammatory response in the vicinity of the sewing cuff. Moreover, further prospective and quantitative studies involving more PVD cases with analyses of the composition and organization of the matrix components, protein synthesis, and genetic information are required.


   Conclusions
Top
 Abstract
 Materials and methods
 Results
 Discussion
 Conclusions
References
 
Pannus appeared to originate in the neointima in the periannulus of the left ventricular septum. The structure of pannus consisted of myofibroblasts and extracellular matrix. The pannus formation after prosthetic valve replacement may be associated with a process of periannular tissue healing via the expression of TGF-ß.


   Acknowledgments
 
We wish to thank Ms Misato Shiraishi for expert technical help in this study.


   Footnotes
 
This work was supported in part by a Grant-in-Aid for Scientific Research, Japan Society for the Promotion of Science (grant nos. C-14571290 and C-13671416).


   References
Top
 Abstract
 Materials and methods
 Results
 Discussion
 Conclusions
 References
 

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