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Eur J Cardiothorac Surg 2004;26:1098-1103
© 2004 Elsevier Science NL

Tissue microarray detection of matrix metalloproteinases, in diseased tricuspid and bicuspid aortic valves with or without pathology of the ascending aorta

George J. Koulliasa,*, Dimitris P. Korkolisa, Pars Ravichandranb, Amanda Psyrrib, Ioannis Hatzarasa, John A. Elefteriadesa

a Section of Cardiothoracic Surgery, Yale New Haven Hospital, New Haven, CT, USA
b Department of Surgical Pathology, Yale New Haven Hospital, New Haven, CT, USA

Received 22 March 2004; received in revised form 6 July 2004; accepted 13 July 2004.

* Corresponding author. Address: 29 Argolidos Str, 145 64 Kifissia, Athens, Greece. Tel.: +30 210 6208637; fax: +30 210 8070336. (E-mail: koullias{at}hotmail.com).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: The degeneration of bicuspid aortic valve and its frequent association with ascending aortic pathology, point to a still unidentified genetic tissue defect with unknown mediators. Metalloproteinases (MMPs) are lytic enzymes that have been strongly implicated in aneurysm formation. The purpose of this study was to detect the presence of these enzymes in aortic valvular tissue in healthy and diseased aortic valves with or without the presence of synchronous ascending aortic pathology. Methods: Aortic valve specimens from 26 aortic valve replacement patients as well as 4 healthy control tricuspid aortic valves were included. 10 patients had bicuspid aortic valves, and 16 had tricuspid aortic valves. Half of our patient population had a concomitant aortic procedure for aortic pathology. The study detected MMPs 1,2 and 9 as well as their Tissue inhibitors (TIMPs) 1 and 2. MMP and TIMP detection was accomplished with the construction of a tissue micro array and immunohistochemistry. Conclusions: MMP-9 expression was significantly higher in bicuspid aortic valves compared to normal valves (P<0.05). When compared to the tricuspid valve group, MMP-9 mean value was significantly higher in bicuspid valves (P<0.05).When the entire rest of the valve group (n=4+16, i.e. control and tricuspid valve groups) was compared to the bicuspid valve group, bicuspid valves had significantly higher MMP-2, and MMP-9 (P<0.01) expression. TIMP expression also changed in diseased valves, among different patient groups. This increased proteolytic presence in bicuspid aortic valves may attribute to the observed decreased elastin and collagen content, and their resultant functional failure.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Progressive processes of different etiologies lead to gradual deterioration of the aortic valve function resulting in stenosis, regurgitation or their combination [1,2]. Recent work has shed light to the course, natural history and possible underlying causes of many of these processes [3]. Like in the case of those described as ‘degenerative’ or especially those affecting congenitally deformed valves, current thinking is that aortic valve deterioration is not a passive process related merely to hypertension, atherosclerosis or aging, but a rather chronic active process of inflammation, and valve tissue remodeling. The association of a normally functioning bicuspid or an unicommisural aortic valve with aortic dissection, and furthermore the correlation with aortic dissection after valve replacement in these patients, clearly points to a ‘genetically inferior’ aorta that coexists with a ‘genetically inferior’ bicuspid aortic valve [4]. This aorta has deteriorated mechanical properties and is prone to dilate in response to abnormal or even normal hemodynamic stresses [5]. The molecular participants and mediators leading to aortic valve pathology, malfunction and aortic wall deficiency, are essentially unknown.

Matrix metalloproteinases (MMPs) are a family of enzymes that are produced by a variety of inflammatory cells, by endothelial cells, vascular smooth muscle cells, and periadventitial connective tissue cells [6]. MMPs co-exist and react with specific tissue inhibitors of metalloproteinases (TIMPs) [7]. MMP-1, 2 and MMP-9 are of particular importance in the pathogenesis of vascular pathologies, since they degrade, native or partially degraded collagen and elastin [8–10].

In studies done in our institution as well as others, increased levels of active MMPs resulting in increased proteolysis of the aortic wall have been found in thoracic aortic aneurysms and dissections [11,12] and in patients with aortic manifestations of Marfan's syndrome [13].

In the case of diseased or degenarated congenitally deformed valves, it is conceivable that increased local MMP activity could alter their elastic and collagen component, and thus lead to structural and functional failure.

In view of the above, we attempted to detect the immunohistochemical expression of MMPs and their tissue inhibitors in aortic valve specimens from patients with a wide range of aortic valve including those with an associated ascending aortic pathology, in an attempt to further elucidate the possible role of these lytic enzymes and their inhibitors, in congenital or acquired aortic valve tissue degeneration and resultant failure.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Patient group
Our study group consisted of 26 patients operated for aortic stenosis, insufficiency and ascending aortic aneurysm or type A dissection involving the aortic valve at Yale—New Haven Hospital between 2001 and 2002. Our study population consisted of three groups. The first group consisted of 16 patients who had tricuspid aortic valves. The second study group consisted of 10 patients who had bicuspid valves. The third study group included 13 of the above 26 patients (seven with bicuspid and six with tricuspid valves) who underwent a surgically correctable accompanying ascending aortic aneurysm or dissection (Table 1). The control group consisted of autopsy normal tricuspid aortic valve samples from four young cadavers with no evidence of any valvular, aortic, coronary, or vascular disease. These three study groups were compared between them as well as with the control group, in regards to the immunohistochemical expression of matrix metalloproteinases 1, 2 and 9 (MMPs) and their tissue inhibitors (TIMPs) 1 and 2. Full cardiopulmonary bypass (CPB), with or without deep hypothermic circulatory arrest (DHCA), was employed, depending on the type and location of the procedure performed.


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  		Table 1. Aortic valve patient groups and associated pathologies
 
2.2. Construction of aortic tissue microarray and monoclonal antibodies
Tissue microarrays are a method of harvesting small disks of tissue from a range of standard histologic sections and placing them in an array on a recipient paraffin block such that hundreds of cases can be analysed simultaneously. A valve Tissue microarray was constructed with specimens of 26 patients, using current techniques at the Yale Tissue Microarray Facility [14]. The MMP antibodies (MMP-1 OPA1-08010, MMP-2 OPA1-08023, and MMP-9 OPA1-08090, ABR Inc, Golden CO, USA) and TIMP antibodies (TIMP-1 OMA1-08510 ABR Inc Golden CO, USA and TIMP-2 AB 19078 Chemicon International Inc, Temecula CA, USA) were incubated in concentrations of 1:10–1:20 for 1h in a humidified chamber at 37°C, using antigen retrieval techniques.

2.3. Histology and immunohistochemistry
Tissue microarray slides containing the entire patient and control group were stained with hematoxylin and eosin and Giemza elastin stain. In every specimen, presence and magnitude of elastic fiber disruption, fibrosis, calcification and degree of infiltration by inflammatory cells such as macrophages and lymphocytes, were assessed.

For immunohistochemistry, as a first step, aortic tissue micro-array slides containing the entire patient and control groups in triplicate, were deparaffinised through graded xylol and alcohol solutions. Endogenous peroxidase was blocked with 3% H2O2 in a Tris-buffered saline solution and non specific binding was blocked with incubation with normal goat serum for 45min. All micro-array slides were incubated afterwards with the primary antibodies in a dilution of 1:20 for the MMPs and 1:10 for the TIMPs for 1h in a humidified chamber at 37°C. The incubation of the secondary antibody followed (Dako EnVision, peroxidase mouse; Dako, Denmark) for 45min. At the end, staining was developed with 3,3'-diaminobenzidine and hematoxylin.

2.4. Immunohistochemical Grading system
A standard semiquantitative grading system (0–4) of the intensity of the MMP-1, 2, and 9 as well as TIMP-1 and 2, immunohistochemical staining was applied blindly by two of the investigators, in all three copies of the entire patient and control group on each slide. The average of these two scores (in triplicate) was used for calculations. Grading was as follows: 0: no presence, 1, presence in <15% of cells; 2, presence in 15–50% of cells; 3, high in 50–75% of cells; and 4, intense presence in >75% of cells. The used immunohistochemical grading method, has an established value as a semiquantitative means of antigen detection in modern pathology and antigen analysis [14]. It was expressed as mean ± Standard Error of the mean (mean±SEM).

2.5. Statistical evaluation
Statistics were performed by a staff biostatistician with the simultaneous use of two commercially available biostatistical softwares, i.e. (a) "Primer of Biostatistics" by Stanton A. Glantz PhD, (McGraw-Hill Health Professions Division, 1997), and (b) STATA (STATA Corp., Stata statistical software, release 8.0. College Station, TX, USA, 2003). Data were presented either as mean or mean±SEM. Two-sample t-test was used to compare the means of every antigen in different patient groups. The Mann–Whitney rank sum test was also used since our data were ordinal. Statistical significance was set as P<0.05, to reject the null hypothesis. To find out any significant variations between individual groups p values were adjusted using the Bonferroni method.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Normal aortic valves
Normal aortic valves showed preserved leaflet architecture with no fibrosis, calcification or infiltration by inflammatory cells. Mild MMP-1, 2 and 9 was expressed in cellular and extracellular areas. TIMP-1 and 2 were also mildly expressed in areas corresponding to MMP expression (Table 2).


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  		Table 2. MMP and TIMP immunohistochemical grade and their statistical comparisons
 
3.2. Tricuspid aortic valves
Extensive leaflet architectural disruption was observed in 100% of the 16 diseased tricuspid valves. This consisted of areas of extensive fibrosis, leaflet thickening, calcification with variable inflammatory cell infiltration and isolated cases of commissural fusion in cases of aortic stenosis. In cases aortic valves associated with regurgitation, in addition to the above findings, cicatricial shortening as well as rolling and fibrosis of the free leaflet edge was observed. MMPs and TIMPs were present in fibroblasts, extracellular matrix, lymphocytes and macrophages surrounding areas of calcification. Nevertheless, their expression, was not significantly higher compared to normal aortic valves (P>0.05 for all antigens), (Fig. 1, Table 2).



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  		Fig. 1. Mean immunohistochemical grade values for all examined MMPs and TIMPs in normal tricuspid valves (NAVs), diseased bicuspid aortic valves (BAVs), and diseased tricuspid aortic valves (TAVs).

 
3.3. Bicuspid aortic valves
Diffuse leaflet architectural disruption and multiple degrees of inflammatory cell infiltration was observed in 100% of the 10 bicuspid aortic valves. In cases of aortic stenosis, extensive calcifications were detected. In cases of aortic regurgitation, redundancy was seen as well as destructive and regenerating changes in cases of endocarditis. MMP-1, 2 and 9 as well as TIMP-1 and 2 were detected in 100% of these valves (Fig. 2). Of special interest was the finding that MMP-2 and 9 (which are lysing elastin) immunoreactivity was found in elastic fibers (Fig. 3). When compared to normal valves, MMP-9 expression was significantly higher in bicuspid aortic valves (2.6±0.16 vs. 1.5±0, P<0.05) (Table 2). When compared to the tricuspid valve group, MMP-9 mean immunohistochemical value was significantly higher in bicuspid valves (P<0.05). When the entire rest of the valve group (n=4+16, i.e. control and tricuspid valve groups) was compared to the bicuspid valve group, bicuspid valves showed significantly higher MMP-2 (1.0±0.14 vs. 0.6±0.13, P<0.01), and MMP-9 (2.6±0.16 vs. 1.8±0.09, P<0.01) expression (Table 2).



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  		Fig. 2. Mean immunohistochemical grade values for all examined MMPs and TIMPs, in bicuspid aortic valves (BAVs) and all other valves.

 


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  		Fig. 3. Increased MMP-9 immunohistochemical expression in a bicuspid aortic valve with myxomatous degeneration. MMP-9 is strongly expressed in fragmented elastic fibers (white arrows) and in inflammatory cells (gray arrows) (x120).

 
3.4. Aortic valves associated with aortic pathology
A total of 13 patients had synchronous, associated, surgically corrected ascending aortic pathology (Table 1). Seven of these patients had bicuspid valves and the remaining six, tricuspid valves. MMP and TIMP expression in this group was not different from the one in those valves not associated with ascending aortic disease (P>0.05 at all comparisons), but MMP-9 expression was significantly higher than the control group (2.3±0.13 vs. 1.5±0.22, P<0.05). Furthermore, MMP-9 expression in the bicuspid valve subgroup was significantly higher that the corresponding tricuspid group (2.57±0.2 vs. 2.0±0, P<0.05) among these patients.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
It is becoming increasingly evident, that gradual deterioration and failure of the aortic valve in many cases, seems to be an active process involving environmental and genetic links in valve remodeling and tissue strength, and not a merely an age, hypertension or infection related degenerative process. This seems to be especially true in the case of nonrheumatic aortic stenosis [3], or calcific aortic stenosis of a congenitally abnormal aortic valve. This holds true particularly due to its synchronous or metachronous association with annuloaortic ectasia and Type A dissection [4]. The same seems to be valid in the case of congenital aortic valve-related aortic regurgitation or the floppy aortic valve in which anuloaortic ectasia, aortic cystic medial necrosis or mitral valve prolapse may also occur [2].

In the above cases, tissues seem to be more prone to dilation and redundancy, even in normal blood pressure range [4]. Of interest is the study of Bauer and colleagues who demonstrated that, patients with a bicuspid aortic valve without aneurysmal aortas, had thinner elastic lamellae and in greater distance between them, than patients with a tricuspid aortic valve [15]. Furthermore, there appear to be different subgroups of young adults with bicuspid aortic valves, who present with dilatation either at different levels of the aortic root, or the ascending aorta, later in life [16].

MMP-2 and 9, have a profound proteolytic activity towards Type IV collagen and elastin and have been detected with increased activity, in numerous studies in abdominal aortic aneurysms [8,9]. Studies done at our institution have shown an increased MMP presence as well as an increased proteolytic equilibrium in thoracic aortic aneurysms and dissections [11,12]. MMPs with the exception of MMP-9 and TIMPs have been previously found to be expressed in normal heart valves [17]. In studies performed on aortic valve samples of eight cases of subacute endocarditis and thirteen cases of degenerative disease, and in a limited sample of nonrheumatic aortic stenosis, showed increased local production of MMP-2 and 9 [3,18].

In contrast to others [17], in the present study we showed that MMP-9 is expressed in normal aortic valves. This finding, most possibly represents the normally existing tissue homeostatic equilibrium. We reconfirmed in a more sizable patient sample of patients that, all cases of diseased aortic valves demonstrate considerable MMP and TIMP immunohistochemical presence. Furthermore, in agreement with a previous observation, elastolytic MMP-2 and 9 were localized in areas of intense elastin presence [18].

We demonstrated for the first time that bicuspid valves as a group, express immunohistochemically higher MMP-9 values than normal aortic valves (P<0.05). Bicuspid valve leaflets express always higher MMP-2 and 9 values than the rest of the valve group (P<0.05). Furthermore, compared to tricuspid aortic valves alone, the bicuspid valve group expresses significantly higher MMP-9 and lower TIMP-1 values at all times (P<0.05). In addition, both bicuspid and tricuspid diseased valves, demonstrate 62 and 88% elevations in MMP-9/TIMP-1 ratio, respectively, compared to normal aortic valves. This ratio has been atypically used in the literature as a proteolysis indicator [18].

Bicuspid aortic valves associated with ascending aortic disease, also express higher MMP-9 values than their tricuspid counterparts. As a group although, the MMP-TIMP presence in valves with concominant aortic disease, is not different from the valve group not associated with aortic pathology. This finding needs further clarification and study in larger samples, for conclusions to be safely drawn. Data on MMP and TIMP expression in the aortic wall of these patients demonstrated statistically increased MMP-9 and MMP-9/TIMP-1 ratio compared to normal ascending aortas of cadavers with no vascular or cardiac pathology [11].

This increased MMP-9 presence implies increased probability of proteolysis and elastolysis of the leaflet tissue. It is possible that this newly demonstrated increased proteolytic activity within the bicuspid valve leaflets, could be one of the reasons that this valve morphology is defective and leads chronically to failure.

The potential clinical implication of the finding of increased MMP presence of this study is that substances acting as matrix metalloproteinase inhibitors may potentially have a positive impact in slowing the degeneration of bicuspid aortic valves. These MMP inhibiting agents such as the tetracyclines, and statins are under investigation in relation to their role in abdominal aortic aneurysm, saphenous vein graft disease and neoplasm growth inhibition.

In conclusion, bicuspid aortic valves have increased MMP-9 expression, compared to either normal or diseased tricuspid aortic valves. Our results suggest clearly that increased MMP-9 presence in bicuspid aortic valves may be one of the causes of increased elastin and collagen degradation with resultant decrease of the lamellar number and density seen in morphologic studies [15]. Consequently, MMP-9-related proteolysis—as evidenced immunohistochemically in this study by the increased expression of MMP-9 and the decreased expression of its inhibitor, TIMP-1-may take active part in the valvular tissue remodeling in degenerative aortic dysfunction, especially in the deterioration of bicuspid aortic valves. The association of the bicuspid valve with the presence of annular or ascending aortic dilatation seems also to relate to the increased coexisting local MMP activity in the area of the annulus and the ascending aorta seen in other studies [11,12].

Further quantitative determinations of these indications of this increased proteolytic state and reversed enzymatic equilibrium within the bicuspid aortic valve leaflets are needed.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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  9. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter TB. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002;110:625-632.[CrossRef][Medline]
  10. Dollery C, McEwan J, Henney A. Matrix metalloproteinases and cardiovascular disease. Circ Res 1995;77:863-869.[Free Full Text]
  11. Koullias GJ, Ravichandran P, Korkolis DP, Rimm DL, Elefteriades JA. Increased tissue microarray MMP expression favors proteolysis in thoracic aortic aneurysms and dissections. Ann Thorac Surg 2004in press.
  12. Lesauskaite V, Tanganelli P, Sassi C, Neri E, Diciolla F, Ivanoviene L, Epistolato MC, Lalinga AV, Alessandrini C, Spina D, et al. Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: morphology, immunoreactivity for osteopontin, Matrix metalloproteinases, and their inhibitors. Hum Pathol 2001;32:1003-1011.[CrossRef][Medline]
  13. Segura AM, Rafael LBS, Horiba K, Stetler-Stevenson WG, McAllister HA, Willerson JT, Ferrans VJ. Immunohistochemistry of matrix metalloproteinases and their inhibitors in thoracic aortic aneurysms and aortic valves of patients with Marfan syndrome. Circulation 1998;98(19s):331II-337II.
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