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Detaint D.,Hopital Bichat | Detaint D.,Center National Of Reference Pour Le Syndrome Of Marfan Et Apparentes | Michelena H.I.,Mayo Medical School | Nkomo V.T.,Mayo Medical School | And 6 more authors.
Heart | Year: 2014

Background Bicuspid aortic valve (BAV) is related to aortic dilatation, but patterns/rates are conflicting with no comparison among aneurysms of different aetiology. We sought to define ascending aorta dilatation patterns/ progression rates in BAV versus other aortopathies (Marfan syndrome (MFS), degenerative aortopathy (DA)). Design and setting Retrospective, observational study. Aortic dilatation progression was evaluated in two tertiary care centres (US and European) by repeated echocardiography ≥2 years apart in adults with BAV (n=353), matched to MFS (n=50) and DA (n=51) for gender, blood pressure, and minimum follow-up time. Results At baseline, ascending aortic dilatation was present in 87% of BAV cases: tubular ascending aorta in 60% (irrespective of BAV morphology), and Valsalva sinuses dilatation in 27% (independently linked to typical BAV morphology and male gender (p=0.0001)). After 3.6±1.2 years, the aortic dilatation rate in BAV was higher than expected for the population for all aortic levels (p=0.005) and was maximal at the tubular ascending aorta for BAV (0.42±0.6 mm/year) and DA (0.20±0.3 mm/year), and was maximal at the Valsalva sinuses for MFS (0.49±0.5 mm/year). Maximal aortic dilatation rate was similar between BAV and MFS (p>0.40) and lower in DA (p=0.02) but was heterogeneous in BAV, with 43% of BAV not progressing (vs 20% of MFS, p=0.01). Aortic dilatation rate was not proportionally related to baseline aortic size or BAV type (all models p>0.40). Conclusions In patients with BAV, tubular ascending aorta dilatation is the most common pattern and exhibits the fastest growing rate, irrespective of valve morphology and function. Dilatation of the Valsalva sinuses is less common and associated with typical BAV morphology and male gender. Aortic dilatation progresses equally fast in BAV (tubular segment) and MFS (Valsalva sinuses), but a significantly higher proportion of BAV patients does not progress at all, irrespective of BAV type. Baseline aortic diameter does not proportionally predict progression rate; systematic follow-up is therefore warranted in patients with BAV.


Regalado E.S.,University of Houston | Guo D.-C.,University of Houston | Prakash S.,University of Houston | Bensend T.A.,University of Houston | And 24 more authors.
Circulation: Cardiovascular Genetics | Year: 2015

Background - ACTA2 mutations are the major cause of familial thoracic aortic aneurysms and dissections. We sought to characterize these aortic diseases in a large case series of individuals with ACTA2 mutations. Methods and Results - Aortic disease, management, and outcome associated with the first aortic event (aortic dissection or aneurysm repair) were abstracted from the medical records of 277 individuals with 41 various ACTA2 mutations. Aortic events occurred in 48% of these individuals, with the vast majority presenting with thoracic aortic dissections (88%) associated with 25% mortality. Type A dissections were more common than type B dissections (54% versus 21%), but the median age of onset of type B dissections was significantly younger than type A dissections (27 years versus 36 years). Only 12% of aortic events were repair of ascending aortic aneurysms, which variably involved the aortic root, ascending aorta, and aortic arch. Overall, cumulative risk of an aortic event at age 85 years was 0.76 (95% confidence interval, 0.64-0.86). After adjustment for intrafamilial correlation, sex and race, mutations disrupting p.R179 and p.R258 were associated with significantly increased risk for aortic events, whereas p.R185Q and p.R118Q mutations showed significantly lower risk of aortic events compared with other mutations. Conclusions - ACTA2 mutations are associated with high risk of presentation with an acute aortic dissection. The lifetime risk for an aortic event is only 76%, suggesting that additional environmental or genetic factors play a role in expression of aortic disease in individuals with ACTA2 mutations. © 2015 American Heart Association, Inc.


Kessler K.,University Paris Diderot | Kessler K.,French Institute of Health and Medical Research | Borges L.F.,University of Sao Paulo | Borges L.F.,Federal University of Minas Gerais | And 5 more authors.
Cardiovascular Research | Year: 2014

Aims Human thoracic aneurysm of the ascending aorta (TAA) is a chronic disease characterized by dilatation of the aortic wall, which can progress to vessel dissection and rupture. TAA has several aetiologies, but all forms present common features, including tissue remodelling. Here, we determined and characterized the angiogenic process associated with TAA and its relation with wall remodelling. Methods and results Immunostaining for blood vessels showed an increased density of microvessels originating from the adventitia in the external medial layer of TAA compared with healthy aortas. Proteomic array analysis of 55 angiogenic factors in medial and adventitial layers showed different expression profiles in both tissue compartments between aneurysmal and healthy aortas. Quantification by ELISA confirmed that all forms of TAA contained higher levels of several pro- and anti-angiogenic factors, including angiopoietin-1 and -2, fibroblast growth factor-acidic, and thrombospondin-1, than that of healthy aortas. However, all groups showed comparable levels of vascular endothelial growth factor-A. Quantitative RT-PCR demonstrated that angiopoietins were overexpressed in TAA media. Immunostaining and electron microscopy revealed that neovessels had defective endothelial junctions and poor mural cell coverage. This incomplete structure was associated with the accumulation of plasminogen and albumin in the media of TAA. Conclusion We describe, for the first time, leaky neovessel formation in TAA media in association with an imbalance of angiogenic factor levels. Although the initiating mechanisms of neo-angiogenesis in TAA and the potential aetiology-related differences remain to be determined, our results suggest that neo-angiogenesis could participate in TAA wall remodelling and weakening through deposition of blood-borne zymogens. © 2014 Published on behalf of the European Society of Cardiology.


PubMed | Center National Of Reference Pour Le Syndrome Of Marfan Et Apparentes, University of Sao Paulo and University Paris Diderot
Type: Journal Article | Journal: Cardiovascular research | Year: 2014

Human thoracic aneurysm of the ascending aorta (TAA) is a chronic disease characterized by dilatation of the aortic wall, which can progress to vessel dissection and rupture. TAA has several aetiologies, but all forms present common features, including tissue remodelling. Here, we determined and characterized the angiogenic process associated with TAA and its relation with wall remodelling.Immunostaining for blood vessels showed an increased density of microvessels originating from the adventitia in the external medial layer of TAA compared with healthy aortas. Proteomic array analysis of 55 angiogenic factors in medial and adventitial layers showed different expression profiles in both tissue compartments between aneurysmal and healthy aortas. Quantification by ELISA confirmed that all forms of TAA contained higher levels of several pro- and anti-angiogenic factors, including angiopoietin-1 and -2, fibroblast growth factor-acidic, and thrombospondin-1, than that of healthy aortas. However, all groups showed comparable levels of vascular endothelial growth factor-A. Quantitative RT-PCR demonstrated that angiopoietins were overexpressed in TAA media. Immunostaining and electron microscopy revealed that neovessels had defective endothelial junctions and poor mural cell coverage. This incomplete structure was associated with the accumulation of plasminogen and albumin in the media of TAA.We describe, for the first time, leaky neovessel formation in TAA media in association with an imbalance of angiogenic factor levels. Although the initiating mechanisms of neo-angiogenesis in TAA and the potential aetiology-related differences remain to be determined, our results suggest that neo-angiogenesis could participate in TAA wall remodelling and weakening through deposition of blood-borne zymogens.


Guo D.-C.,University of Texas Health Science Center at Houston | Gong L.,University of Texas Health Science Center at Houston | Regalado E.S.,University of Texas Health Science Center at Houston | Santos-Cortez R.L.,Baylor College of Medicine | And 19 more authors.
American Journal of Human Genetics | Year: 2015

Up to 20% of individuals who have thoracic aortic aneurysms or acute aortic dissections but who do not have syndromic features have a family history of thoracic aortic disease. Significant genetic heterogeneity is established for this familial condition. Whole-genome linkage analysis and exome sequencing of distant relatives from a large family with autosomal-dominant inheritance of thoracic aortic aneurysms variably associated with the bicuspid aortic valve was used for identification of additional genes predisposing individuals to this condition. A rare variant, c.1031A>C (p.Glu344Ala), was identified in MAT2A, which encodes methionine adenosyltransferase II alpha (MAT IIα). This variant segregated with disease in the family, and Sanger sequencing of DNA from affected probands from unrelated families with thoracic aortic disease identified another MAT2A rare variant, c.1067G>A (p.Arg356His). Evidence that these variants predispose individuals to thoracic aortic aneurysms and dissections includes the following: there is a paucity of rare variants in MAT2A in the population; amino acids Glu344 and Arg356 are conserved from humans to zebrafish; and substitutions of these amino acids in MAT Iα are found in individuals with hypermethioninemia. Structural analysis suggested that p.Glu344Ala and p.Arg356His disrupt MAT IIα enzyme function. Knockdown of mat2aa in zebrafish via morpholino oligomers disrupted cardiovascular development. Co-transfected wild-type human MAT2A mRNA rescued defects of zebrafish cardiovascular development at significantly higher levels than mRNA edited to express either the Glu344 or Arg356 mutants, providing further evidence that the p.Glu344Ala and p.Arg356His substitutions impair MAT IIα function. The data presented here support the conclusion that rare genetic variants in MAT2A predispose individuals to thoracic aortic disease. © 2015 The American Society of Human Genetics.


Stheneur C.,Center National Of Reference Pour Le Syndrome Of Marfan Et Apparentes | Tubach F.,AP HP | Tubach F.,University Paris Diderot | Jouneaux M.,AP HP | And 12 more authors.
Genetics in Medicine | Year: 2014

Purpose:Because diagnosis of Marfan syndrome is difficult during infancy, we used a large cohort of children to describe the evolution of the Marfan syndrome phenotype with age.Methods:Two hundred and fifty-nine children carrying an FBN1 gene mutation and fulfilling Ghent criteria were compared with 474 non-Marfan syndrome children.Results:Prevalence of skeletal features changed with aging: prevalence of pectus deformity increased from 43% at 0-6 years to 62% at 15-17 years, wrist signs increased from 28 to 67%, and scoliosis increased from 16 to 59%. Hypermobility decreased from 67 to 47% and pes planus decreased from 73 to 65%. Striae increased from 2 to 84%. Prevalence of ectopia lentis remained stable, varying from 66 to 72%, similar to aortic root dilatation (varying from 75 to 80%). Aortic root dilatation remained stable during follow-up in this population receiving β-blocker therapy. When comparing Marfan syndrome children with non-Marfan syndrome children, height appeared to be a simple and discriminant criterion when it was >3.3 SD above the mean. Ectopia lentis and aortic dilatation were both similarly discriminating.Conclusion:Ectopia lentis and aortic dilatation are the best-discriminating features, but height remains a simple discriminating variable for general practitioners when >3.3 SD above the mean. Mean aortic dilatation remains stable in infancy when children receive a β-blocker. © American College of Medical Genetics and Genomics.


Gomez D.,French Institute of Health and Medical Research | Kessler K.,French Institute of Health and Medical Research | Borges L.F.,French Institute of Health and Medical Research | Borges L.F.,Federal University of Minas Gerais | And 12 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Objective-Tissue activation of proteolysis is involved in acute intramural rupture (dissections, acute ascending aortic dissection) and in progressive dilation (aneurysms, thoracic aneurysm of the ascending aorta) of human ascending aorta. The translational aim of this study was to characterize the regulation of antiproteolytic serpin expression in normal, aneurysmal, and dissecting aorta. Approach and Results-We explored expression of protease nexin-1 (PN-1) and plasminogen activator inhibitor-1 and their regulation by the Smad2 signaling pathway in human tissue and cultured vascular smooth muscle cells (VSMCs) of aneurysms (thoracic aneurysm of the ascending aorta; n=46) and acute dissections (acute ascending aortic dissection; n=10) of the ascending aorta compared with healthy aortas (n=10). Both PN-1 and plasminogen activator inhibitor-1 mRNA and proteins were overexpressed in medial tissue extracts and primary VSMC cultures from thoracic aneurysm of the ascending aorta compared with acute ascending aortic dissection and controls. Transforming growth factor-β induced increased PN-1 expression in control but not in aneurysmal VSMCs. PN-1 and plasminogen activator inhibitor-1 overexpression by aneurysmal VSMCs was associated with increased Smad2 binding on their promoters and, functionally, resulted in VSMC self-protection from plasmin-induced detachment and death. This phenomenon was restricted to aneurysms and not observed in acute dissections. Conclusions-These results demonstrate that epigenetically regulated PN-1 overexpression promotes development of an antiproteolytic VSMC phenotype and might favor progressive aneurysmal dilation, whereas absence of this counter-regulation in dissections would lead to acute wall rupture. © 2013 American Heart Association, Inc.


Jondeau G.,French Institute of Health and Medical Research | Boileau C.,Center National Of Reference Pour Le Syndrome Of Marfan Et Apparentes
Current Opinion in Cardiology | Year: 2014

Purpose of review A lot of new data have been obtained in familial thoracic aortic aneurysms, including description of new entities and better understanding of pathophysiology. The aim of this review is to put them in perspective. Recent findings The new data have been collected, put together, and allowed a new classification scheme to be proposed by the Montalcino Aortic Consortium on the basis of the role of proteins coded by the culprit gene (either protein of the extracellular matrix or protein of the transforming growth factor-beta pathway, or protein of the contractile apparatus of the smooth muscle cell). These groups of diseases include aortic aneurysm, but the extent of extra-aortic vascular risk and the presence of extra-aortic (skeletal, ophthalmologic, neurological, or immunological) features vary according to the gene involved. This understanding also sheds light on the therapeutic benefits that can be foreseen for new molecules, or old molecules used in a newer way. Summary Classification of familial forms of thoracic aortic aneurysm should allow a better understanding of these diseases and therefore standardization of initial evaluation of the patients (vascular evaluation limited or not to the aorta, and extravascular evaluation, including or not skeleton, eyes, neurology, digestive tract, and immunological diseases) and individualization of therapy (adapted to both the genotype and the phenotype).


PubMed | Center National Of Reference Pour Le Syndrome Of Marfan Et Apparentes
Type: Journal Article | Journal: Heart (British Cardiac Society) | Year: 2011

Marfan syndrome has changed over the last few years: new diagnostic criteria have been proposed, new clinical entities recognised and life expectancy increased. The role of fibrillin 1, which was initially thought to be mainly structural, has been shown to also be functional. The altered transforming growth factor pathway is better understood, the importance of epigenetic factors has been demonstrated and recent data suggest that many of the observations made in Marfan syndrome can actually be made in thoracic aortic aneurysm from diverse aetiologies. Besides transforming growth factor , the role of metalloproteinase, the fibrinolytic/coagulation system, is being suggested in the progression of the disease. A relationship between the type of fibrillin 1 (FBN1) gene mutation and the mechanism for the disease (haplo-insufficiency vs negative dominance), as well as some genotype/phenotype correlations, has been observed, although the main challenge of recognising gene modifiers has yet to explain tremendous variability despite similar mutation. This progress has led to new hopes for tomorrows therapies, some of which are being tested in clinics, whereas others are still in the field of animal models. Here we review some of the new data obtained in the understanding of the pathophysiology and genetics of this disease.


PubMed | French Institute of Health and Medical Research, AP HP, University Paris Diderot, Center National Of Reference Pour Le Syndrome Of Marfan Et Apparentes and University of Versailles
Type: Journal Article | Journal: Genetics in medicine : official journal of the American College of Medical Genetics | Year: 2014

Because diagnosis of Marfan syndrome is difficult during infancy, we used a large cohort of children to describe the evolution of the Marfan syndrome phenotype with age.Two hundred and fifty-nine children carrying an FBN1 gene mutation and fulfilling Ghent criteria were compared with 474 non-Marfan syndrome children.Prevalence of skeletal features changed with aging: prevalence of pectus deformity increased from 43% at 0-6 years to 62% at 15-17 years, wrist signs increased from 28 to 67%, and scoliosis increased from 16 to 59%. Hypermobility decreased from 67 to 47% and pes planus decreased from 73 to 65%. Striae increased from 2 to 84%. Prevalence of ectopia lentis remained stable, varying from 66 to 72%, similar to aortic root dilatation (varying from 75 to 80%). Aortic root dilatation remained stable during follow-up in this population receiving -blocker therapy. When comparing Marfan syndrome children with non-Marfan syndrome children, height appeared to be a simple and discriminant criterion when it was >3.3 SD above the mean. Ectopia lentis and aortic dilatation were both similarly discriminating.Ectopia lentis and aortic dilatation are the best-discriminating features, but height remains a simple discriminating variable for general practitioners when >3.3 SD above the mean. Mean aortic dilatation remains stable in infancy when children receive a -blocker.

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