Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-β, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-β signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1-deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-β activation and signaling. In addition, TGF-β antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-β-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease. IntroductionMarfan syndrome (MFS) is a common, autosomal-dominant, systemic disorder of connective tissue, with an estimated prevalence of 1 in 5,000-10,000 individuals (1). It is caused by mutations in FBN1, the gene encoding fibrillin-1 (2), the principal component of extracellular matrix microfibrils. Clinical manifestations of MFS include skeletal deformities, ocular lens dislocation, lung pathology, and cardiac complications, such as aortic dissection and mitral valve prolapse (MVP) and dysfunction. Mitral valve disease is the leading indication for surgery and cause of death in young children with MFS, and there are currently no known or proposed medical therapies for prophylactic treatment of valve disease. While infants presenting with the most severe and rapidly progressive form of MFS can show mitral valve dysfunction at birth, manifestations are highly variable in the classic form of MFS, and myxomatous changes are not easily quantified using noninvasive imaging modalities, precluding a precise understanding of the natural history of disease. To our knowledge, neither recapitulation nor mechanistic exploration of mitral valve pathology in mouse models of MFS has previously been documented.

Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-β, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-β signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1-deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-β activation and signaling. In addition, TGF-β antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-β-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease. IntroductionMarfan syndrome (MFS) is a common, autosomal-dominant, systemic disorder of connective tissue, with an estimated prevalence of 1 in 5,000-10,000 individuals (1). It is caused by mutations in FBN1, the gene encoding fibrillin-1 (2), the principal component of extracellular matrix microfibrils. Clinical manifestations of MFS include skeletal deformities, ocular lens dislocation, lung pathology, and cardiac complications, such as aortic dissection and mitral valve prolapse (MVP) and dysfunction. Mitral valve disease is the leading indication for surgery and cause of death in young children with MFS, and there are currently no known or proposed medical therapies for prophylactic treatment of valve disease. While infants presenting with the most severe and rapidly progressive form of MFS can show mitral valve dysfunction at birth, manifestations are highly variable in the classic form of MFS, and myxomatous changes are not easily quantified using noninvasive imaging modalities, precluding a precise understanding of the natural history of disease. To our knowledge, neither recapitulation nor mechanistic exploration of mitral valve pathology in mouse models of MFS has previously been documented.

Serum FSH concentrations are not invariably elevated in recently post-menopausal women and use of FSH as a determinant for postmenopausal status in clinical trials should be used with caution. Notwithstanding their higher free oestradiol index, women found to have an abnormally low basal FSH had evidence of poor prolactin, FSH and LH but not TSH responses to pituitary stimulation. This may represent either a degree of subclinical pituitary failure of a variant of normal. The low levels of gonadotrophin activity did not affect bone mineral density.