Elastic and collagenous networks in vascular diseases.
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Supravalvular aortic stenosis (SVAS), Marfan syndrome (MFS) and Ehlers-Danlos syndrome type IV (EDS IV) are three clinical entities characterized by vascular abnormalities that result from mutations of structural components of the extracellular matrix (ECM). Analyses of naturally occurring human mutations and of artificially generated deficiencies in the mouse have provided insights into the pathogenesis of these heritable disorders of the connective tissue. SVAS is associated with haploinsufficiency of elastin, one of the two major components of the elastic fibers. SVAS is characterized by narrowing of the arterial lumen due to the failure of regulation of cellular proliferation and matrix deposition. Mutations in fibrillin 1 are the cause of dissecting aneurysm leading to rupture of the ascending aorta. Fibrillin-1 is the building block of the microfibrils that span the entire thickness of the aortic wall and are a major component of the elastic fibers that reside in the medial layer. The vascular hallmark of EDS IV is rupture of large vessels. The phenotype is caused by mutations in type III collagen. The mutations ultimately affect the overall architecture of the collagenous network and the biomechanical properties of the adventitial layer of the vessel wall. Altogether, these genotype-phenotype correlations document the diversified contributions of distinct extracellular macroaggregates to the assembly and function of the vascular matrix. (+info)
Hypoplastic left heart syndrome.
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Hypoplastic left heart syndrome may be accurately diagnosed during fetal life. Prenatal diagnosis provides the opportunity for parents to make an informed choice about their options, including surgery, nonintervention postnatally or termination of pregnancy. Short to medium term survival continues to improve for a condition that was previously invariably lethal. There continues to be a significant mortality and morbidity associated with hypoplastic left heart syndrome, and the long-term prognosis is unknown. Knowledge of the condition prior to birth means that babies who are to undergo surgery present in optimal condition for such interventions. Parents who have had an affected fetus or child should be offered detailed fetal echocardiography to exclude a recurrence in subsequent pregnancies. (+info)
Elastin: mutational spectrum in supravalvular aortic stenosis.
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Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams syndrome. SVAS is caused by translocations, gross deletions and point mutations that disrupt the elastin gene (ELN) on 7q11.23. Functional hemizygosity for elastin is known to be the cause of SVAS in patients with gross chromosomal abnormalities involving ELN. However, the pathogenic mechanisms of point mutations are less clear. One hundred patients with diagnosed SVAS and normal karyotypes were screened for mutations in the elastin gene to further elucidate the molecular pathology of the disorder. Mutations associated with the vascular disease were detected in 35 patients, and included nonsense, frameshift, translation initiation and splice site mutations. The four missense mutations identified are the first of this type to be associated with SVAS. Here we describe the spectrum of mutations occurring in familial and sporadic SVAS and attempt to define the mutational mechanisms involved in SVAS. SVAS shows variable penetrance within families but the progressive nature of the disorder in some cases, makes identification of the molecular lesions important for future preventative treatments. (+info)
Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome.
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To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion. (+info)
Supravalvular aortic stenosis and peripheral pulmonary stenosis coexisting with a straight thoracic spine.
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Supravalvular aortic stenosis (SVAS) is recognized in cases of Williams syndrome and in sporadic cases not associated with other features of the syndrome. It is also well recognized as associated with peripheral pulmonary stenosis (PPS). A male patient was diagnosed as having PPS at the age of 1 year and 8 months, and was found at the age of 18 years to have SVAS. Cardiac catheterization showed that he had a localized type of SVAS and regression of the PPS. Chest X-ray showed that he did not have the normal thoracic curvature. His 19-year-old sister had also been diagnosed with PPS, and his 43-year-old mother was known to have a harsh systolic cardiac murmur of unknown etiology. Cardiac magnetic resonance imaging showed a localized type of SVAS in his mother also, though not in his sister, both of whom had a somewhat straight thoracic spine, most noticeably in the mother, though not to the degree observed in the patient. This case appears to be familial, though it is not clear whether this skeletal abnormality is an unknown phenotypic feature of this cardiovascular disease. (+info)
Williams syndrome associated with complete atrioventricular septal defect.
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Williams syndrome is a genetic disorder associated with characteristic facies, supravalvar aortic stenosis, peripheral pulmonary stenosis, mental retardation, hypertension, premature aging of skin, and congenital cardiac defects. Many cardiac defects such as bicuspid aortic valve, mitral valve regurgitation, coarctation of the aorta, and ventricular or atrial septal defects are linked to the syndrome. Complete atrioventricular septal defect has rarely been associated with Williams syndrome and only one necropsy case has been reported in the literature. The long term follow up of Williams syndrome associated with complete atrioventricular septal defect is reported. During a 10 year follow up period, the pressure gradient in the ascending aorta did not increase despite narrowing of the ascending aorta as identified on an aortogram. (+info)
Follow-up study of morphology and cardiac function in rats undergoing induction of supravalvular aortic stenosis.
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OBJECTIVE: To characterize the follow-up of an experimental model of left ventricular hypertrophy (LVH) induced by supravalvular ascending aortic stenosis in young rats. METHODS: Wistar rats were submitted to thoracotomy and aortic stenosis was created by placing a clip on the ascending aorta (AoS group, n=12). Age-matched control animals underwent a sham operation (C group, n=12). Cardiac function was analysed by echocardiograms performed 6, 12, and 21 weeks after aortic banding. Myocardial morphological features and myocardial hydroxyproline concentration (HOP) were evaluated 2, 6, 12, and 21 weeks after surgery in additional animals. RESULTS: Aortic banding promoted early concentric LVH and a progressive increase in HOP. Under light microscopy, we observed myocyte hypertrophy and wall thickening of the intramural branches of the coronary arteries due to medial hypertrophy. Cardiac function was supranormal after 6 weeks (percentage of fractional shortening - EAo6: 70.3 +/- 10.8; C6: 61.3 +/- 5.4; p<0.05), and depressed in the last period. Diastolic dysfunction was detected after 12 weeks (ratio of early-to-late filling velocity - EAo12: 4.20 +/- 3.25; C12: 1.61 +/- 0.16; p<0.05). CONCLUSION: Ascending aortic stenosis promotes concentric LVH with myocardial fibrosis and minimal histological changes. According to the period of evaluation, cardiac function may be improved, normal, or depressed. The model is suitable and useful for studies on pathophysiology and treatment of the different phases of cardiac hypertrophy. (+info)
Williams-Beuren syndrome in the Hong Kong Chinese population: retrospective study.
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OBJECTIVE: To estimate the incidence and document the clinical characteristics of Williams-Beuren syndrome in the Hong Kong Chinese population. DESIGN: Cytogenetic analysis and retrospective study. SETTING: Clinical Genetic Service, Department of Health, Hong Kong. PATIENTS: Forty-one Chinese patients with Williams-Beuren syndrome. MAIN OUTCOME MEASURES: From 1 January 1995 to 30 June 2002, fluorescence in situ hybridisation was used to confirm diagnoses in 41 cases of Williams-Beuren syndrome by detecting chromosome 7q microdeletion. Case records were reviewed, the incidence of the condition in the local population was estimated, and the main clinical characteristics were determined. RESULTS: The minimal incidence of Williams-Beuren syndrome in this locality was estimated to be approximately 1 per 23500 live births. Common dysmorphic facial features included periorbital fullness (83%), full lips (80%), a long philtrum (51%), a flat nasal bridge (41%), and abnormal teeth (37%). No patients had a stellate iris. The majority (82%) had at least one documented cardiac anomaly; among these patients, peripheral pulmonary stenosis was diagnosed in 61% and supravalvular aortic stenosis in 45%. Nearly all (93%) of the study group exhibited developmental delay. CONCLUSION: As in the West, patients with Williams-Beuren syndrome in the Hong Kong Chinese population display craniofacial dysmorphism, cardiovascular anomalies, and mental deficiency. Supravalvular aortic stenosis-the cardiac defect most commonly associated with Williams-Beuren syndrome in western countries-is less common than peripheral pulmonary stenosis in this region. Studies involving periodic cardiovascular evaluation are needed to confirm if this difference is significant. (+info)