Ann Thorac Surg 2004;77:532-536
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
Fibrillin and other matrix proteins in mitral valve prolapse syndrome
Joseph F. Nasuti, MDa,
Paul J. Zhang, MDa,
Michael D. Feldman, MD, PhDa,
Terri Pasha, BSa,
Jasvir S. Khurana, MDa,
Joseph H. Gorman, III, MDa,
Robert C. Gorman, MDa,
Jagat Narula, MD, PhDb,
Navneet Narula, MDa*
a Hospital of University of Pennsylvania,Philadelphia, PA, USA
b Hahneman University Hospital, Philadelphia, Pennsylvania, USA
Accepted for publication August 6, 2003.
* Address reprint requests to Dr Narula, Department of Pathology and Laboratory Medicine, Anatomic Pathology Section, University of Pennsylvania Medical Center, 3400 Spruce St, 6 Founders Pavilion, Philadelphia, PA19104, USA
e-mail: nnarula{at}mail.med.upenn.edu
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Abstract
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BACKGROUND: Unlike myxomatous degeneration in Marfan syndrome, which has been reported to result from a mutation in the gene that codes for the extracellular structural protein fibrillin, no specific molecular abnormality has been documented to be the underlying cause of myxomatous degeneration in mitral valve prolapse syndrome (MVPS). The present study examined the distribution of fibrillin and other extracellular matrix proteins in patients with isolated MVPS.
METHODS: Mitral valve leaflets from 7 MVPS patients and 5 rheumatic heart disease (RHD) patients were characterized immunohistochemically for fibrillin, elastin, collagen I, and collagen III distribution, and compared with five normal mitral valves.
RESULTS: In normal mitral valve leaflets immunostaining for fibrillin, elastin, collagen I, and collagen III revealed a fibrillary and laminar pattern in the atrialis and the spongiosa. In addition, both the collagens were present in the ventricularis, and the coarse bundles in the fibrosa exhibited alternating bandlike collagen I immunoreactivity. The staining patterns of fibrillin, elastin, and collagens I and III revealed distinctly different distribution in MVPS relative to the normal and RHD leaflets. MVPS leaflets in areas of myxoid degeneration displayed a more diffuse, weaker, and nonlaminar pattern of staining for fibrillin. Similar, but less severe abnormality of elastin, collagen I, and collagen III was also observed. Unlike diffuse abnormality in MVPS, the disruption of extracellular proteins in RHD only occurred at the site of the inflammatory damage, but the overall architecture was preserved.
CONCLUSIONS: The results of the current study suggest a primary role for abnormal fibrillin and other matrix proteins in producing myxoid degeneration of mitral valve leaflets in MVPS.
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Introduction
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Myxomatous degeneration is a relatively common finding in surgically resected mitral valve leaflets. Clinically, this histologic finding is associated with mitral valve prolapse or floppy mitral valve syndrome. Morphologically, myxomatous degeneration has been characterized by expansion of the spongiosa of the valve leaflet with an amorphous, finely granular, and faintly basophilic material [1]. It has been well documented that the myxomatous degeneration observed in mitral valve prolapse syndrome (MVPS) is identical to the gross and histologic changes seen in Marfan's syndrome [2–4]. In addition, echocardiographic, skeletal, and anthropometric similarities have also been reported between primary mitral valve prolapse and Marfan syndrome [5]. On histopathologic characterization, extracellular matrix proteins in chordae from patients with MVPS has revealed clumps of electron dense material comprising collagen I, collagen III, and fibronectin, and may represent stress and strain on the valvular support structures leading to collagen degeneration [6]. In the myxomatous valves, activated myofibroblasts express upregulation of catabolic enzymes, but interstitial collagen mRNA is not altered [7].
Unlike myxomatous degeneration in Marfan syndrome, which has been demonstrated to result from a mutation in the gene that codes for the extracellular structural protein fibrillin, no such specific abnormality has been documented in the underlying cause of myxomatous degeneration in MVPS [8]. Yet the role of fibrillin in maintaining the structural integrity of connective tissue matrices by binding other matrix proteins, such as elastin and collagens I and III, makes an abnormality of fibrillin a likely culprit in producing myxomatous degeneration of mitral valve leaflets in patients with MVPS [9–11]. Although an excellent characterization of elastic fibers and other connective tissue components in MVPS has been reported [12], we hypothesized that abnormality in fibrillin may be responsible for the pathogenesis of MVPS. Therefore, we investigated immunohistologic distribution of fibrillin in abnormal valve leaflets from patients with MVPS relative to normal controls and other acquired disease processes, such as rheumatic heart disease (RHD).
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Material and methods
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Diseased valve leaflets were obtained during mitral valve replacement surgery from 7 patients with MVPS and from 5 patients with RHD. Normal mitral valve tissue samples were harvested at autopsy from five cadavers without valvular heart disease. The samples were submitted to the surgical pathology laboratory at the Hospital of the University of Pennsylvania for gross and histopathologic evaluation between January 1, 1999 and December 31, 2001. The specimens were fixed in neutral buffered 10% formalin. The mitral valve tissue specimens were cut in the long axis of the cusp, at right angles to the atrioventricular insertion of the valve. The tissue blocks were routinely processed and paraffin embedded, and 5-µ sections were made from each block. The tissue sections were stained with hematoxylin and eosin. Immunohistochemical characterization was performed with the following antibodies: fibrillin (Neo-Markers, Fremont, CA; mouse monoclonal diluted 1:50), elastin (Sigma, St. Louis, MO; mouse monoclonal diluted 1:50), collagen I (cell culture supernatant, pure), and collagen III (Gibco-BRL, Gaithersburg, MD; rabbit polyclonal, diluted 1:500). The staining was performed with an automated immunohistochemical instrument (Ventana Medical Systems, Tucson, AZ) using the avidin-biotin complex method, with DAB as a chromogen. The qualitative staining patterns for each of the four proteins were recorded and compared between the normal, rheumatic, and floppy mitral valve leaflets.
Clinical information for each of the 17 patients was obtained from medical records. The 7 MVPS patients consisted of three men and four women ranging in age from 37 to 78 years old (mean 57 years old). The 5 RHD patients included two men and three women with a mean age of 61 years old (age range 43 to 76 years old). The 5 patients in whom normal mitral valve tissue was harvested at autopsy consisted of two men and three women ranging in age from 41 to 72 years old (mean age 60 years old).
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Results
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Collagens I and III were characterized by an undulating, fibrillary, laminar pattern distribution in the atrialis and spongiosa, and the ventricularis of the normal mitral valve leaflets (Fig 1). The coarse bundles in the fibrosa also exhibited alternating bandlike collagen I immunoreactivity. Fibrillin and elastin immunostaining revealed a similar fibrillary and laminar pattern that was essentially limited to the atrialis and the spongiosa in normal mitral valve leaflets.
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Fig 1. Immunohistochemical staining of a normal mitral valve leaflet. Note the fibrillary, laminar staining patterns for (A) collagen I and (B) collagen III are strongest in the atrialis and spongiosa of the valve leaflet. Immunostaining of (C) fibrillin and (D) elastin reveals similar fibrillary laminar pattern, which is essentially limited to the atrialis and spongiosa. (a = atrial surface; v = ventricular surface.)
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In the RHD valves the zonal architecture of the valve and the distribution of the matrix proteins were still maintained in areas that lacked fibrosis and neovascularization. The intensity of the extracellular proteins was normal in the morphologically normal areas. However, there was an overall increase in staining intensity for elastin, collagen I, and collagen III in all layers of the postinflammatory areas of the valve. Fibrillin immunostaining was increased particularly in areas of fibrosis (Fig 2).
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Fig 2. Immunohistochemical staining of a diseased mitral valve leaflet from a rheumatic heart disease patient. There is an overall increase in staining intensity for (A) collagen I, (B) collagen III, and (D) elastin in all layers of the valve. However the zonal architecture of the valve is still maintained. (C) Fibrillin immunostaining is increased particularly in areas of fibrosis and is revealed in the figure. (a = atrial surface; v = ventricular surface.)
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On the other hand, the pattern of immunohistochemical staining for distribution of elastin, collagen I, and collagen III in the floppy mitral valve leaflets exhibited diffuse and disorganized staining pattern with lack of the zonal restriction of these proteins seen in the normal valves. In the floppy valves fibrillin immunoreactivity was more intense than the normal valves without the normal zonal restriction. In the spongiosa the staining was revealed as a coarse, wavy, cordlike, or nodular pattern. The myxomatous areas indicated elastin and collagens, and lacked staining for fibrillin (Fig 3).
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Fig 3. Immunohistochemical staining of mitral valve leaflet from a mitral valve prolapse syndrome patient with severe myxoid degeneration. Immunohistochemical staining for (A) collagen I, (B) collagen III, (C) fibrillin, and (D) elastin exhibit weak, diffuse, and disorganized staining patterns with lack of zonal restriction seen in normal and rheumatic valves. (a = atrial surface; v = ventricular surface.)
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Comment
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Mitral valve prolapse syndrome is a common condition affecting 5% to 10% of the United States population [13]. Although most patients with mitral valve prolapse are asymptomatic, approximately 3% develop serious complications. These complications include infective endocarditis, mitral insufficiency, embolic stroke, embolic systemic infarct, and atrial and ventricular arrhythmias, all of which occur at a greater rate than in the general population [14–17]. The complications of mitral valve prolapse may necessitate surgical removal where the pathologic finding is commonly myxomatous degeneration.
Myxomatous degeneration is morphologically identical to the changes seen in Marfan syndrome [1, 2]. The defect in Marfan's syndrome has been mapped to chromosome 15 (15q21.1). This mutation produces a defective fibrillin molecule resulting from a substitution of a vital cysteine producing an altered protein structure [8]. This alteration produces a diminished adhesiveness for other extracellular matrix proteins, such as collagen and elastin. In addition, evidence for defective fibrillin synthesis, secretion, and incorporation into the extracellular matrix has been observed in Marfan's syndrome and related disorders [18, 19]. The results of our study suggest that the myxoid degeneration in MVPS may also be a result of altered protein matrix architecture that commonly contributes to maintaining the structural integrity of the valve leaflets. Comparison of the normal and myxoid mitral valve leaflets revealed a consistent pattern of decreased immunostaining of fibrillin in the area of myxoid change. The decrease in fibrillin staining also correlated with the disorganization in the staining pattern of elastin, and collagens I and III. Studies of genetic connective tissue disorders indicate that a fibrillin-elastin covalent bond is particularly important in creating an extracellular protein matrix [20, 21]. Our results suggest that a defect in fibrillin may contribute to the development of myxomatous degeneration in MVPS. Unlike Marfan syndrome, no genetic abnormality is known to be associated with myxomatous degeneration in MVPS, and it is likely that some acquired posttranslational defect may be contributory. The data suggests that extracellular matrix phenotype in mitral valve consistent with Marfan syndrome, but in the absence of other genotypic characteristics of Marfan syndrome, could represent a "forme fruste" of the genetic syndrome. The onus will be on investigators to demonstrate if these changes progress with time, age, or stress connected with the abnormal valve motion. Such investigation would also be able to address whether earlier surgical intervention (and decreased stress) may retard a posttranslational defect.
Conclusions
There seems to be a role of abnormal fibrillin distribution in myxomatous degeneration of the mitral valve in patients with MVPS. This is in contrast to acquired disease of the valves (such as RHD) wherein basic architecture of extracellular matrix proteins remains unaltered and these proteins are disrupted only at the sites of inflammatory damage, possibly secondary to reparative process.
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References
|
|---|
- Davies M.J., Moore B.P., Braimbridge M.V. The floppy mitral valve: study of incidence, pathology, and complications in surgical, necropsy, and forensic material. Br Heart J 1978;40:468-481.[Free Full Text]
- Glesby M.J., Pyeritz R.E. Association of mitral valve prolapse and systemic abnormalities of connective tissue: a phenotypic continium. JAMA 1989;262:523-528.[Abstract/Free Full Text]
- Melissari M., Giordano G., Crafa P., Martella E.M., Ricci R. Mitral valve prolapse in a case of Marfan syndrome with congenital cardiac disease, chronic obstructive pulmonary disease and schizopherna. Pathologica 1995;87:78-81.[Medline]
- Kawai S., Okada R. Pathologic aspects of mitral valve prolapse syndrome. J Cardiography 1986;11(Suppl):19-34.
- Roman M.J., Devereux R.B., Kramer-Fox R., Spitzer M.C. Comparison of cardiovascular and skeletal features of primary mitral valve prolapse and Marfan syndrome. Am J Cardol 1989;63:317-321.
- Akhtar S., Meek K.M., James V. Immunolocalization of elastin, collagen type I and III, fibronectin, and vitronectin in extracellular matrix components of normal and myxomatous mitral heart valve chordae tendinae. Cardiovasc Pathol 1999;8:203-211.[Medline]
- Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen F. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 2001;104:2525–38
- Tsipouras P., Del Mastro R., Sarfarazi M., Lee B., Vitale E., Steinmann B. Genetic linkage of the Marfan syndrome, ectopia lentis and congenital contractual arachnodactyly to the fibrillin genes 15 and 5. The international Marfan syndrome collaborative study. N Eng J Med 1992;326:905-909.[Abstract]
- Mecham R.P., Broekelman T., Davis E.C., Gibson M.A., Brown-Augsburger P. Elastic fibre assembly: macromolecular interactions. Ciba Found Symp 1995;192:172-184.[Medline]
- Kielty C.M., Whittaker S.P., Grant M.E., Shuttleworth C.A. Attachment of human vascular smooth muscle cells to intact microfibrillar assembles of collagen VI and fibrillin. J Cell Sci 1992;103:445-451.[Abstract]
- Keene D.R., Jordan C.D., Reinhart D.P., et al. Fibrillin-1 in human cartilage: development expression and formation of special banded fibers. J Histochem Cytochem 1997;45:1069-1082.[Abstract/Free Full Text]
- Tamura K., Fakuda Y., Ishizaki M., Masuda Y., Yamanaka N., Ferrans V.J. Abnormalities in elastic fibers and other connective tissue components of floppy mitral valve. Am Heart J 1995;129:1149-1158.[Medline]
- Markiewicz W., Stoner J., London E., Hunt S.A., Popp R.L. Mitral valve prolapse in one hundred presumably healthy young females. Circulation 1976;53:464-473.[Abstract/Free Full Text]
- Boudoulas H., Kolibach A., Baker P., King B., Wooley C.F. Mitral valve prolapse and the mitral valve prolapse syndrome. A diagnostic classification and pathogenesis of symptoms. Am Heart J 1989;118:797-818.
- Devereux R.B., Kramer-Fox R., Kingsfield P. Mitral valve prolaspe. Causes, clinical manifestations and management. Ann Intern Med 1989;111:305-317.
- Clemens J.D., Horwitz R.I., Jaffe C.C., Feinstein A.R., Stanton B.F. A controlled evaluation of the risk of bacterial endocarditis in persons with mitral valve prolapse syndrome. N Engl J Med 1982;307:776-781.[Abstract]
- MacMahon S.W., Roberts J.K., Kramer-Fox R., Zucker D.M., Roberts R.B., Devereux R.B. Mitral valve prolapse and infective endocarditis. Am Heart J 1987;113:1291-1298.[Medline]
- Milewicz D.M., Pyeritz R.E., Crawford E.S., Byers P.H. Defective synthesis, secretion and extracellular matrix formation of fibrillin by cultured dermal fibroblasts. J Clin Invest 1992;89:79-86.
- Godfrey M. From fluorescence to the gene: the skin in Marfan syndrome. J Invest Dermatol 1994;103:58S-62S.[Medline]
- Perejda A.J., Abraham P.A., Carnes W.H. Marfan syndrome: structual biochemical and mechanical studies of the aortic media. J Lab Clin Med 1985;106:367-383.
- Sakia L.Y., Keene D.R., Engvall E. A new 350-kD glycoprotein is a component of extracelluar microfibrils. J Cell Biol 1986;103:2499-2509.[Abstract/Free Full Text]
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Abstract
Introduction
