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Ann Thorac Surg 1997;63:1012-1017
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Immunohistochemical Abnormalities of Fibrillin in Cardiovascular Tissues in Marfan's Syndrome

Division of Cardiac Surgery and Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Accepted for publication October 24, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Molecular defects in the glycoprotein fibrillin are believed to be responsible for impaired structural integrity of cardiovascular, skeletal, and ocular tissues in Marfan's syndrome (MFS). Traditionally, excellent results have been achieved with the Bentall composite graft repair of aneurysms of the ascending aorta in MFS. However, because of the potential complications associated with prosthetic valves, there is growing interest in techniques that preserve the native aortic valve.

Methods. Between May 1994 and February 1995, 15 patients with a history of concomitant or remote aortic root aneurysms or dissection underwent operation for valvular heart disease. Specimens of aortic valve, ascending aortic wall, and mitral valve were obtained specifically to observe differences in fibrillin content and architecture between patients with (n = 9) and without (n = 6) MFS. In addition, control specimens of aortic valve, aortic wall, and mitral valve were obtained from 4 patients with isolated valvular or coronary artery disease but no evidence of connective tissue disorders or other aortic pathologic conditions. Fibrillin immunostaining using indirect immunofluorescence was used. Specimens were coded and graded by a blinded observer to determine quantity, homogeneity, and fragmentation of fibrillin.

Results. Observed fibrillin abnormalities in MFS and control patients were limited to the midportion (elastin-associated microfibrils) of the aortic valve, aortic wall, and mitral valve tissues. Fibrillin abnormalities of aortic valve, aortic wall, and mitral valve tissues were seen in all patients with MFS and were most severe in those older than 20 years. Similar fibrillin abnormalities of aortic valve and aortic wall specimens were observed in control patients more than 60 years old.

Conclusions. Even in the setting of a normal-appearing aortic valve, the current rationale for widespread use of valve-sparing repairs of aortic root aneurysms in patients with MFS and patients older than 60 years should be carefully reexamined in light of these findings.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Marfan's syndrome (MFS), one of the most common heritable connective tissue disorders, is caused by mutations in the fibrillin gene locus on chromosome 15 [1–3]. The glycoprotein fibrillin is a major component of 10-nm microfibrils in the extracellular matrix [4, 5]. These multiprotein microfibrils serve as an essential anchoring scaffold for elastin networks [6, 7]. Molecular defects in fibrillin are believed to be responsible for impaired structural integrity of cardiovascular, skeletal, and ocular tissues in MFS.

Cardiovascular complications are the leading causes of premature mortality in MFS [8]. Progressive aneurysmal dilatation of the ascending aorta results in aortic valve incompetence with left ventricular failure and markedly increases the risk of fatal aortic dissection [9]. Over the past several decades, the morbidity and the mortality caused by the cardiovascular sequelae of MFS have dramatically decreased because of the combination of close medical follow-up, long-term use of ß-adrenergic blocking agents, and prophylactic aortic root replacement [10]. Traditionally, excellent results have been achieved with the modified Bentall composite graft repair for the surgical management of ascending aortic aneurysms [11–13]. However, because of potential complications associated with prosthetic valves, there is growing interest in techniques that preserve the native aortic valve [14, 15]. Guidelines for candidacy for these valve-sparing techniques have not been clearly defined. Normal appearance on gross inspection of the aortic valve is frequently the only criterion used for selection of a valve-conservation procedure over standard valve replacement.

The purpose of this study was to evaluate the architecture of fibrillin in cardiovascular tissue of patients with MFS. Evidence of major abnormalities in the structural integrity of the aortic valve in patients with annuloaortic ectasia may preclude the application of valve-sparing techniques in these individuals.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We performed a single-blinded protocol consisting of 19 consecutive patients undergoing a cardiac operation for aortic aneurysmal or valvular disease at the Johns Hopkins Hospital between May 1994 and February 1995. Nine patients had been diagnosed with MFS (8 male and 1 female), and 10 patients served as controls (8 male and 2 female). All MFS patients (mean age, 36.2 years; range, 16 to 52 years) satisfied the diagnostic criteria defined by the International Nosology of Heritable Disorders of Connective Tissue [16], and all were followed by the Department of Medical Genetics at the Johns Hopkins Hospital. Control patients (mean age, 53.6 years; range, 40 to 71 years) had no personal or family history of any heritable connective tissue disorders and none of the physical stigmata of MFS.

Tissue Specimens
Biopsy specimens were obtained from material normally excised during various therapeutic cardiovascular procedures. This material consisted of tissue from aortic valves (6 patients with and 6 without MFS), ascending aortic walls (7 with and 6 without MFS), and mitral valves (3 with and 1 without MFS). The specimens were transported in Michel's medium, embedded in OCT medium (Tissue Tek, Miles Lab, Elkhart, IN), snap frozen in liquid nitrogen, and stored at -20°C before sectioning.

A coding system ensured that the analyses would be performed without knowledge of the clinical diagnosis. After this single-blinded protocol, all specimens were read by a member of the Division of Dermatoimmunology without prior knowledge of the clinical diagnosis or the age of the patient from whom the specimen was derived.

Immunofluorescence Techniques
For indirect immunofluorescence, the biopsy material embedded in OCT medium was sectioned to 5 µm (2800 Frigocut N; Reichert-Jung) and mounted on albumin-coated slides. These were then washed twice with phosphate-buffered saline solution and incubated at room temperature with fibrillin murine monoclonal antibody (Ab 69) for 30 to 50 minutes. Ab 69 was provided by the Division of Pediatric Cardiology at the Johns Hopkins Hospital and was used in previous studies by Sakai and colleagues [4, 5]. After two 10-minute washes, the sections were incubated for 30 minutes with fluorochrome-conjugated antimouse immunoglobulin G antiserum as a secondary antibody. We initially used fluorescein isothiocyanate–conjugated antiserum but found ourselves unable to differentiate its emissions from the autofluorescence of elastic and collagen fibers. Therefore, goat antimouse immunoglobulin G conjugated with Texas Red sulfonyl chloride at a concentration of 0.014 mg/mL was used for most studies. Slides were again washed twice with phosphate-buffered saline solution and mounted using mounting medium (Permafluor/Lipshaw) with the addition of an antifading agent (DABCO/Sigma; 2 mol/L glycine, pH 10). All specimens were examined under an Olympus BH2-RFCA microscope equipped with epifluorescent illumination. Two different barrier filters allowed the visualization of fluorescein isothyocyanate Texas Red sulfonyl chloride on the same sections, with maximal emissions at about 550 nm and 640 nm, respectively. Photographs were taken with an Olympus C-35AD camera with exposures lasting 15 to 35 seconds. A tungsten film (Ektachrome 64T, Eastman Kodak, Rochester, NY) was used.

To check for the possibility of antigen masking, air-dried cryosections were digested with elastase (Worthington) 0.0001% in 0.067 mol/L Tris-HCl (pH 8.8) for 20 minutes at room temperature. Higher concentrations of elastase were found to disrupt the histologic architecture.

Evaluation of Fibrillin Architecture
Specimens of cardiovascular tissue were examined by a blinded observer. The architecture of the fibrillin in the samples of cardiovascular tissue was graded by both quantitative and qualitative criteria. After all observations per patient were combined, a global assessment of the immunohistochemical findings was done. Evaluation of the fibrillin architecture was accomplished as follows:

1. Quantitative criterion
   1. Estimation of density of fibrillin staining
      1. Grading scale
         • 1 = Large areas of markedly reduced fibrillin density
           
         • 2 = Confluent staining with some areas of sparse fibrillin staining
           
         • 3 = Confluent and even distribution of fibrillin throughout specimen
           
         
         
      
      
   
   
2. Qualitative criteria
   1. Presence or absence of fragmentation of fibrillin
      1. Grading scale
         1. 1 = Smooth, wavy uninterrupted fibers
            
         2. 2 = Partial fragmentation of longer fibers
            
         3. 3 = Extensive and almost complete fragmentation of all fibers
            
         
         
      
      
   2. Homogeneity of fibrillin deposition on elastic fibers
      1. Grading scale
         1. 1 = Abnormal globular change in fibrillin coating of fibers
            
         2. 2 = Smooth, normal coating of fibers
            
         
         
      
      
   
   
3. Global assessment
   1. Normal
      
   2. Borderline abnormal
      
   3. Abnormal
      
   
   

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
In patients from whom samples were taken from the different sampling sites, the final immunohistologic diagnoses were consistent among all of each patient's specimens. There was no significant difference noted in the characteristics of the fibrillin immunostaining after treatment of any of the samples with elastase.

Control Group
Ten patients undergoing a cardiac operation during the period of study served as controls. These patients had no prior clinical diagnosis or family history of MFS and exhibited none of the physical stigmata consistent with MFS. Indirect immunofluorescence of the aortic roots, aortic valves, and mitral valves for fibrillin (Ab 69) revealed a characteristic and reproducible pattern (Tables 1, 2).

AORTIC AND MITRAL VALVES.
A staining pattern similar to that seen in the aortic subendothelium was present along the entire valvular subendocardium in all seven valves examined (six aortic and one mitral). A fine meshwork of fibrillin was present in the valvular core and was considered normal. This array was present in the mitral valve specimen as well as in four of the aortic valve specimens (patient mean age, 50.3 years; range, 42 to 59 years) (Fig 1). Of the remaining two aortic valve specimens, one was classified as borderline abnormal and the other as clearly abnormal; these specimens were from the same 2 patients (aged 68 and 71 years) whose aortic roots were classified as borderline abnormal and as clearly abnormal.

View larger version (150K): [in this window] [in a new window]   Fig 1. . Immunofluorescent Texas red sulfanyl chloride staining of fibrillin in human aortic valve leaflet: normal leaflet from patient without Marfan's syndrome. (Original magnification, x400.)

AORTIC AND MITRAL VALVES.
The subendocardial pattern of fibrillin staining for both valves was identical to the pattern seen in the control group. Of the six aortic valve cores evaluated, four specimens (patient mean age, 45.25 years; range, 38 to 52 years) were regarded as clearly abnormal (Fig 2) and the remaining two specimens (patient ages, 19 and 20 years), as borderline abnormal (Fig 3). This group showed a pattern similar to aortic valves from the control group diagnosed as borderline abnormal. Of the three mitral valve specimens, two (patient ages, 45 and 51 years) were classified as clearly abnormal, and the other (patient age, 16 years) was considered borderline abnormal. Again, no abnormalities in subendothelial and subendocardial (non–elastin-associated microfibrils) fibrillin patterns were observed.

View larger version (143K): [in this window] [in a new window]   Fig 2. . Immunofluorescent Texas red sulfanyl chloride staining of fibrillin in human aortic valve leaflet: leaflet from patient with Marfan's syndrome shows severe fragmentation of fibrillin and markedly reduced quantity and homogeneity of these elastin-associated microfibrils. (Original magnification, x400.)

View larger version (131K): [in this window] [in a new window]   Fig 3. . Immunofluorescent Texas red sulfanyl chloride staining of fibrillin in human aortic valve leaflet: leaflet from patient with Marfan's syndrome shows moderate fragmentation of fibrillin. (Original magnification, x400.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Recent biochemical and genetic linkage studies [2, 3] have demonstrated that the molecular defects responsible for MFS arise from mutations in the fibrillin gene locus on chromosome 15 (fibrillin-1). Fibrillin-1, a 350-kD glycoprotein, is an integral structural component of 10-nm noncollagenous microfibrils of the extracellular matrix found in most tissues [4]. More than 30 mutations have been discovered in the fibrillin gene locus in MFS, and this may account for the clinical pleiotropism characteristic of the syndrome. These mutations correlate with alternations in the synthesis, intracellular processing, and microfibril assembly of fibrillin-1 [17–19].

Elastic tissues, such as the media of the aorta, have an abundance of elastic fibers composed of an amorphous core of elastin surrounded by a mantle of microfibrils known as elastin-associated microfibrils [6, 7]. The microfibrils serve as an anchoring scaffold in the construction of the elastin network. Mutants in fibrillin are now believed to result in structural deficits in the extracellular matrix that lead to the clinical findings characterizing MFS. Abnormalities in the expression of fibrillin messenger ribonucleic acid and in fibrillin immunostaining patterns in skin and cutaneous fibroblast culture of patients with MFS have been reported [20]. Similar work has been conducted on cultured aortic smooth muscle cells of bovine Marfan strains [21], but the absence of data regarding in vivo evaluation of human cardiovascular tissue prompted this study.

Abnormalities in the fibrillin immunostaining characteristics in the aortic wall of patients with MFS were localized primarily to the central portion of the media, a region rich in elastin autofluorescence. Both qualitative and quantitative changes were noted in fibrillin staining. This coincident appearance of both elastin and fibrillin is highly suggestive of the presence of elastin-associated microfibrils. That these staining characteristics were unchanged after treatment with elastase rules out the possibility that antigen masking is responsible for these results. The site of these abnormalities largely coincided with both the plane of aortic dissection in patients with MFS and the region of pathology found in cystic medial necrosis. These findings suggest the possibility that microfibrils, in addition to or as a result of serving as scaffolds for assembly and interaction with other extracellular components of the connective tissue matrix, also contribute to the tensile strength of cardiovascular tissue.

Diffuse abnormal fibrillin staining was present throughout the structure of the aortic and mitral valves of patients with MFS. Not only were there large areas of markedly reduced fibrillin density, but the remaining fibers were partially or completely fragmented. In light of the role of fibrillin in the maintenance of tissue structural integrity, these defects in valvular fibrillin are particularly concerning when one considers the recent trend toward valve-sparing procedures in the surgical management of MFS.

As premature death in MFS often results from aortic dissection [8], these patients eventually undergo elective replacement of the aortic root to prevent the untoward sequelae of progressive aneurysmal dilatation of the ascending aorta. Traditionally, concurrent replacement of the aortic valve at the time of aortic aneurysm repair (ie, the Bentall composite graft procedure) has been the operative technique of choice [11]. Perioperative mortality rates with this procedure are less than 5%, and long-term results have been excellent [12, 13]. Nevertheless, the use of prosthetic valves commits the patient to lifelong anticoagulation and is associated with additional morbidity including thromboembolic events, anticoagulant-related hemorrhage, endocarditis, and hemolysis.

To eliminate the potential sequelae associated with prosthetic valves, some groups [14, 15] have advocated valve-conservation techniques (ie, David reimplantation and Yacoub remodeling procedures) in cases of MFS where intraoperative inspection reveals a grossly normal aortic valve. The findings of our study, however, suggest that even if the leaflets are thin and pliable on gross examination, there may be major defects in structural integrity because of the mutant fibrillin protein that likely will adversely affect long-term durability of the valve. Furthermore, replacement of the dynamic ascending aorta and sinuses of Valsalva with a noncompliant prosthetic tube graft may result in additional stress on the native aortic valve that will accelerate leaflet degeneration.

Despite the limited number of patients and the unavailability of precise age-matched controls, the results of this preliminary study provide the basis for further investigation of the role of mutant fibrillin in the pathogenesis of cardiovascular lesions in MFS. It also provides immunohistologic evidence of structural deficits in the aortic valves of patients with MFS and supports the clinical apprehension of some groups that valve-conservation techniques in MFS may increase the risk of late reoperation for aortic valve replacement [22, 23]. Further, the abnormalities noted in the aortic valve of elderly patients who do not have MFS may argue against routine preservation of the native valve in this population.

The effects of aging were evident in both the MFS and the control groups. Several patients in the MFS group were classified as only borderline abnormal on the basis of specimens from the aortic roots and aortic valves. These patients were the youngest in their group, and besides young age, they possessed no other clinical findings differentiating them from the remaining MFS patients. In the control group, some patients were classified as borderline abnormal or clearly abnormal on the basis of immunohistochemical abnormalities in fibrillin in their tissue samples. These patients were the oldest in the control group. These findings are consistent with the previously described gradual decrease in aortic and cutaneous immunoreactive microfibrils that is associated with aging [24]. The pathophysiologic significance of these findings is unclear.

In summary, patients with MFS demonstrate major abnormalities in the fibrillin architecture of the aortic valve, ascending aortic wall, and mitral valve. Patients without MFS who are older than 60 years demonstrate derangements in aortic valve and ascending aortic wall fibrillin similar to those seen in patients with MFS. Because fibrillin plays an important role in the structural integrity of connective tissue, the widespread application of valve-sparing techniques as alternatives for the management of aortic root aneurysms in patients with MFS and patients more than 60 years old without MFS should be carefully reexamined.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This research was partially supported by funds from the Dana and Albert Brocolli Center for Aortic Diseases.

We thank Drs Reed E. Dietz and Lynn Y. Sakai for providing the monoclonal antibodies. We also are indebted to the Division of Medical Genetics of the Johns Hopkins University for supplying clinical information regarding the MFS group and to Paula Bonitz for expert technical assistance.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Fleischer, The Johns Hopkins Hospital, 600 N Wolfe St, Blalock 618, Baltimore, MD 21287-4618.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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