Marfan syndrome and mitral valve prolapse

Weyman, Arthur E.; Scherrer‐Crosbie, Marielle

doi:10.1172/jci23701

Cited by 42 publications

(8 citation statements)

References 32 publications

(40 reference statements)

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“…In the mouse model studied in this report, enhanced TGF-β-mediated signals were a consequence of fibrillin-1 deficiency. As pointed out by Weyman and Scherrer-Crosbie [4], such abnormalities have not been demonstrated in sporadic MVP patients or families with the disorder. Other discrepancies of this model with the clinical presentation of MVP include adult onset compared with onset in infancy in Marfan syndrome, and homogeneous valve involvement with extensive valvular interstitial cell proliferation in the latter [3].…”

Section: Discussionmentioning

confidence: 98%

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Cardiac transgenic matrix metalloproteinase-2 expression induces myxomatous valve degeneration: a potential model of mitral valve prolapse disease

Mahimkar

Nguyen

Mann

et al. 2009

Cardiovascular Pathology

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Introduction Myxomatous mitral valve “degeneration” with prolapse (MVP) is the most frequent form of nonischemic mitral valve disease. In myxomatous valves, interstitial cells express extracellular matrix-degrading enzymes and it has been postulated that matrix metalloproteinases (MMPs) contribute to these changes. Methods We generated mice with cardiac-specific expression of constitutively active MMP-2 under the control of the α-myosin heavy chain promoter. Results These mice are normal at 4–6 months of age; at 12–14 months the mitral valves and chordae tendineae exhibit severe myxomatous change with echocardiographic MVP. Myxomatous change was also evident to a lesser extent in the aortic valves. Myxomatous changes were heterogeneous and limited to the left side of the heart with major disorganization of collagen bundles within the lamina fibrosa. Alcian blue/PAS-stained valves revealed massive accumulation of acidic glycosoaminoglycans within the lamina spongiosa, consistent with valvular interstitial cell differentiation to a chondrocytic phenotype. Cells with the histologic features of hypertrophied chondrocytes were found within the chordae tendineae and the tips of the mitral papillary muscles. Conclusion This report demonstrates that increased activity of a single enzyme, MMP-2, within a transgenic context reproduces many of the features of the human MVP syndrome. The cardiac-specific MMP-2 transgenic mouse potentially provides a unique experimental platform for the evaluation of nonsurgical therapies based on the underlying pathophysiology of this disease. Published by Elsevier Inc.

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Section: Discussionmentioning

confidence: 98%

“…While inherited connective tissue disorders, such as Marfan syndrome, have provided potential mechanistic insights into the pathogenesis of this disorder, the majority of MVP cases are sporadic. Furthermore, the murine fibrillin-1 knockout model of Marfan syndrome bears only a partial resemblance to human MVP [3,4]. …”

Section: Introductionmentioning

confidence: 99%

Cardiac transgenic matrix metalloproteinase-2 expression induces myxomatous valve degeneration: a potential model of mitral valve prolapse disease

Mahimkar

Nguyen

Mann

et al. 2009

Cardiovascular Pathology

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“…These findings align closely with our results, which suggest that the functional consequence of valve thickening, reduced fiber alignment, and abnormal matrix deposition ultimately leads to a reduction in tissue stiffness. Upon substantial remodeling, the functional consequence of MV leaflets can ultimately result in prolapse and regurgitation [36] . Although several studies have reported disparate prevalence of MV prolapse among individuals with MFS, the biomechanical remodeling within the MV is substantial [37] .…”

Section: Discussionmentioning

confidence: 99%

Multi-Scale Biomechanical Remodeling in Aging and Genetic Mutant Murine Mitral Valve Leaflets: Insights into Marfan Syndrome

et al. 2012

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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.

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“…However, all the selected MVP patients had only posterior MVP. It is known that two-thirds of MVP patients present the posterior prolapse, while the remaining third show anterior or bileaflet prolapse [ 22 , 23 ]. Considering this, to obtain a model able to discriminate MVP from healthy subjects, in primary screening, we must use a population with not only posterior but also anterior and bileaflet prolapse.…”

Section: Discussionmentioning

confidence: 99%

Identification of Patients Affected by Mitral Valve Prolapse with Severe Regurgitation: A Multivariable Regression Model

Songia

Porro

Chiesa

et al. 2017

Oxidative Medicine and Cellular Longevity

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Background. Mitral valve prolapse (MVP) is the most common cause of severe mitral regurgitation. Besides echocardiography, up to now there are no reliable biomarkers available for the identification of this pathology. We aim to generate a predictive model, based on circulating biomarkers, able to identify MVP patients with the highest accuracy. Methods. We analysed 43 patients who underwent mitral valve repair due to MVP and compared to 29 matched controls. We assessed the oxidative stress status measuring the oxidized and the reduced form of glutathione by liquid chromatography-tandem mass spectrometry method. Osteoprotegerin (OPG) plasma levels were measured by an enzyme-linked immunosorbent assay. The combination of these biochemical variables was used to implement several logistic regression models. Results. Oxidative stress levels and OPG concentrations were significantly higher in patients compared to control subjects (0.116 ± 0.007 versus 0.053 ± 0.013 and 1748 ± 100.2 versus 1109 ± 45.3 pg/mL, respectively; p < 0.0001). The best regression model was able to correctly classify 62 samples out of 72 with accuracy in terms of area under the curve of 0.92. Conclusions. To the best of our knowledge, this is the first study to show a strong association between OPG and oxidative stress status in patients affected by MVP with severe regurgitation.

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Marfan syndrome and mitral valve prolapse

Cited by 42 publications

References 32 publications

Cardiac transgenic matrix metalloproteinase-2 expression induces myxomatous valve degeneration: a potential model of mitral valve prolapse disease

Cardiac transgenic matrix metalloproteinase-2 expression induces myxomatous valve degeneration: a potential model of mitral valve prolapse disease

Multi-Scale Biomechanical Remodeling in Aging and Genetic Mutant Murine Mitral Valve Leaflets: Insights into Marfan Syndrome

Identification of Patients Affected by Mitral Valve Prolapse with Severe Regurgitation: A Multivariable Regression Model

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