elastin and Mitral-Valve-Insufficiency

Mitral valve degeneration is a key component of the pathophysiology of Marfan syndrome. The biomechanical consequences of aging and genetic mutation in mitral valves are poorly understood because of limited tools to study this in mouse models. Our aim was to determine the global biomechanical and local cell-matrix deformation relationships in the aging and Marfan related Fbn1 mutated murine mitral valve. To conduct this investigation, a novel stretching apparatus and gripping method was implemented to directly quantify both global tissue biomechanics and local cellular deformation and matrix fiber realignment in murine mitral valves. Excised mitral valve leaflets from wild-type and Fbn1 mutant mice from 2 weeks to 10 months in age were tested in circumferential orientation under continuous laser optical imaging. Mouse mitral valves stiffen with age, correlating with increases in collagen fraction and matrix fiber alignment. Fbn1 mutation resulted in significantly more compliant valves (modulus 1.34 ± 0.12 vs. 2.51 ± 0.31 MPa, respectively, P<.01) at 4 months, corresponding with an increase in proportion of GAGs and decrease in elastin fraction. Local cellular deformation and fiber alignment change linearly with global tissue stretch, and these slopes become more extreme with aging. In comparison, Fbn1 mutated valves have decoupled cellular deformation and fiber alignment with tissue stretch. Taken together, quantitative understanding of multi-scale murine planar tissue biomechanics is essential for establishing consequences of aging and genetic mutations. Decoupling of local cell-matrix deformation kinematics with global tissue stretch may be an important mechanism of normal and pathological biomechanical remodeling in valves.

Topics: Aging; Animals; Biomechanical Phenomena; Elastin; Extracellular Matrix; Fibrillin-1; Fibrillins; Marfan Syndrome; Mice; Mice, Inbred C57BL; Microfilament Proteins; Microscopy, Confocal; Mitral Valve; Mitral Valve Insufficiency; Mutation; Tensile Strength

Although chronic mitral regurgitation results in adverse left ventricular remodeling, its effect on the mitral valve leaflets per se is unknown. In a chronic ovine model, we tested whether isolated mitral regurgitation alone was sufficient to remodel the anterior mitral leaflet.. Twenty-nine sheep were randomized to either control (CTRL, n=11) or experimental (HOLE, n=18) groups. In HOLE, a 2.8- to 4.8-mm diameter hole was punched in the middle scallop of the posterior mitral leaflet to create "pure" mitral regurgitation. At 12 weeks, the anterior mitral leaflet was analyzed immunohistochemically to assess markers of collagen and elastin synthesis as well as matrix metalloproteinases and proteoglycans. A semiquantitative grading scale for characteristics such as intensity and delineation of stain between layers was used to quantify differences between HOLE and CTRL specimens across the heterogeneous leaflet structure. At 12 weeks, mitral regurgitation grade was greater in HOLE versus CTRL (3.0+/-0.8 versus 0.4+/-0.4, P<0.001). In HOLE anterior mitral leaflet, saffron-staining collagen (Movat) decreased, consistent with an increase in matrix metalloproteases throughout the leaflet. Type III collagen expression was increased in the midleaflet and free edge and expression of prolyl-4-hydroxylase (indicating collagen synthesis) was increased in the spongiosa layer. The proteoglycan decorin, also involved in collagen fibrillogenesis, was increased compared with CTRL (all P

Topics: Animals; Biomarkers; Collagen; Decorin; Echocardiography; Elastin; Extracellular Matrix; Extracellular Matrix Proteins; Immunohistochemistry; Matrix Metalloproteinases; Mitral Valve; Mitral Valve Insufficiency; Procollagen-Proline Dioxygenase; Proteoglycans; Sheep; Staining and Labeling; Up-Regulation

To quantitate the pathologic features of carcinoid plaques in a relatively large number of surgical specimens from a single institution.. Medical records, operative reports, and surgical specimens were reviewed from all patients with carcinoid heart disease who underwent cardiac valvular surgery at Mayo Clinic, Rochester, Minn, between 1980 and 2000.. The study group included 75 patients (45 men, 30 women) who ranged in age from 26 to 78 years (mean, 59 years). From these 75 patients, 139 valves had been excised surgically (73 tricuspid, 55 pulmonary, 6 mitral, 5 aortic). Pure regurgitation was the most common dysfunctional state of the tricuspid valve (80% [60/75]), mitral valve (97% [32/33]), and aortic valve (96% [23/24]). The pulmonary valve was more often both stenotic and insufficient (52% [37/71]) than purely regurgitant (30% [21/71]). In all cases, valve dysfunction was attributed to the presence of carcinoid plaques, which caused both thickening and retraction. Thickening was the result of both cellular proliferation and deposition of extracellular matrix. Proliferation of myofibroblasts was observed in all plaques and was mild in 49% (68/139) and moderate or severe in 51% (71/139). Extracellular matrix included collagen (in 99% of the 139 valves), myxoid ground substance (98% [136/139]), and elastin (20% [28/139]). Carcinoid plaques were also involved by neovascularization (94% [131/139]), chronic inflammation (94% [131/139]), and mast cell infiltration (64% [89/139]). Severe thickening was attributable primarily to collagen deposition in tricuspid valves and to myofibroblast proliferation and myxoid matrix in pulmonary valves.. Among patients undergoing valvular surgery for carcinoid heart disease, tricuspid and pulmonary valves represented 92% of the excised valves (128/ 139). Although numerous cellular and extracellular features were common to the carcinoid plaques, variability in their relative expression produced appreciable differences in the histologic appearance among the plaques.

Topics: Adult; Aged; Aortic Valve Insufficiency; Carcinoid Heart Disease; Collagen; Elastin; Female; Fibroblasts; Hemodynamics; Humans; Hyperplasia; Inflammation; Male; Mast Cells; Middle Aged; Mitral Valve Insufficiency; Neovascularization, Pathologic; Pulmonary Valve Insufficiency; Retrospective Studies; Severity of Illness Index; Tricuspid Valve Insufficiency

Topics: Adrenergic beta-Antagonists; Aortic Aneurysm; Aortic Dissection; Aortic Valve Insufficiency; Elastin; Fibrillins; Genetic Counseling; Humans; Marfan Syndrome; Microfilament Proteins; Mitral Valve Insufficiency; Myofibrils; Patient Care Team; Phenotype

Human mitral valves (32 floppy and 17 rheumatic) obtained at surgery were analysed and compared with 35 normal (autopsy) valves. Total amounts of collagen, proteoglycan and elastin were increased approx. 3-fold in floppy and rheumatic valves. The water content of rheumatic cusps was lower than normal. The most significant changes in floppy valves were the 59% increase in mean value of the proteoglycan content, a large increase in the ease of extractability of proteoglycans from 26.7 to 57.2% of the total and a 62% increase in mean value of the elastin content in the anterior cusps. Normal human mitral valve cusps contained a mean proportion of 29.3 (and chordae 26.6) type III collagen (as % of total types III + I collagen), the values increasing significantly to 33.2 and 36.3% respectively in chronic rheumatic disease. The ratio observed in floppy valves depended on the extent of secondary surface fibrosis, which could be demonstrated histologically; in valve cusps with considerable secondary fibrosis, the percentage of type III increased significantly (to 34.4%), whereas it decreased significantly (to 25.2%) when fibrosis was negligible. It is concluded that the ratio of collagen types in floppy valves reflects the extent of secondary fibrosis rather than the pathogenesis of the disrupted collagen in the central core of the valve.

Topics: Amino Acids; Collagen; Elastin; Glycosaminoglycans; Hexuronic Acids; Humans; Hydroxyproline; Mitral Valve; Mitral Valve Insufficiency; Procollagen; Proteoglycans; Rheumatic Heart Disease

Topics: Adult; Amino Acids; Aorta, Thoracic; Aortic Valve; Aortic Valve Insufficiency; Collagen; Deafness; Elastin; Humans; Lipids; Male; Mitral Valve Insufficiency; Myocardium; Nose Deformities, Acquired; Phospholipids; Polychondritis, Relapsing