scholarly journals Excess Provisional Extracellular Matrix: A Common Factor in Bicuspid Aortic Valve Formation

2021 ◽  
Vol 8 (8) ◽  
pp. 92
Author(s):  
Christine B. Kern
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Severe Aortic Stenosis ◽  
Common Factor ◽  
Aortic Aneurysms ◽  
Molecular Characteristics ◽  
Phenotypic Characteristics ◽  
Cardiovascular Malformation ◽  
Valve Formation

A bicuspid aortic valve (BAV) is the most common cardiac malformation, found in 0.5% to 2% of the population. BAVs are present in approximately 50% of patients with severe aortic stenosis and are an independent risk factor for aortic aneurysms. Currently, there are no therapeutics to treat BAV, and the human mutations identified to date represent a relatively small number of BAV patients. However, the discovery of BAV in an increasing number of genetically modified mice is advancing our understanding of molecular pathways that contribute to BAV formation. In this study, we utilized the comparison of BAV phenotypic characteristics between murine models as a tool to advance our understanding of BAV formation. The collation of murine BAV data indicated that excess versican within the provisional extracellular matrix (P-ECM) is a common factor in BAV development. While the percentage of BAVs is low in many of the murine BAV models, the remaining mutant mice exhibit larger and more amorphous tricuspid AoVs, also with excess P-ECM compared to littermates. The identification of common molecular characteristics among murine BAV models may lead to BAV therapeutic targets and biomarkers of disease progression for this highly prevalent and heterogeneous cardiovascular malformation.

Abstract 15169: De Novo Variants of USP10 in Early Onset Bicuspid Aortic Valve Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Siddharth K Prakash ◽  
Angela T Yetman ◽  
Hector I Michelena ◽  
Malenka M Bissell ◽  
Yuli Y Kim ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Early Onset ◽  
Rare Variants ◽  
De Novo ◽  
Late Onset ◽  
Copy Number Variants ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Dissections

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) < 1%, Combined Annotation Dependent Depletion (CADD) scores > 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) > 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF<5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

Aortic diseases

ESC CardioMed ◽  
2018 ◽  
pp. 2861-2863
Author(s):  
Bernard Iung
Keyword(s):  
Aortic Valve ◽  
Aortic Dissection ◽  
Marfan Syndrome ◽  
Bicuspid Aortic Valve ◽  
Young Women ◽  
Beta Blockers ◽  
Aortic Aneurysms ◽  
Maximum Diameter ◽  
Aortic Diseases

Aortic diseases encountered in young women are mainly associated with syndromic diseases, which are often heritable, or bicuspid aortic valve. The most frequent syndromic disease is Marfan syndrome. In Marfan syndrome, the risk of aortic dissection is low during pregnancy when the maximum diameter of the ascending aorta is less than 45 mm. Dissection may affect the thoracic ascending or descending aorta. The risk of aortic dissection is low in bicuspid aortic valve when the aortic diameter is less than 50 mm. Beta blockers are recommended throughout pregnancy in Marfan syndrome and are often used in other causes of aortic aneurysms. Close echocardiographic follow-up is needed during pregnancy and after delivery.

Aortic diseases

ESC CardioMed ◽  
2018 ◽  
pp. 2861-2863
Author(s):  
Bernard Iung
Keyword(s):  
Aortic Valve ◽  
Aortic Dissection ◽  
Marfan Syndrome ◽  
Bicuspid Aortic Valve ◽  
Young Women ◽  
Beta Blockers ◽  
Aortic Aneurysms ◽  
Maximum Diameter ◽  
Aortic Diseases

Aortic diseases encountered in young women are mainly associated with syndromic diseases, which are often heritable, or bicuspid aortic valve. The most frequent syndromic disease is Marfan syndrome. In Marfan syndrome, the risk of aortic dissection is low during pregnancy when the maximum diameter of the ascending aorta is less than 45 mm. Dissection may affect the thoracic ascending or descending aorta. The risk of aortic dissection is low in bicuspid aortic valve when the aortic diameter is less than 50 mm. Beta blockers are recommended throughout pregnancy in Marfan syndrome and are often used in other causes of aortic aneurysms. Close echocardiographic follow-up is needed during pregnancy and after delivery.

Risk Factors Associated with Ascending Aortic Aneurysms and Aortic Elasticity Parameters in Children with a Bicuspid Aortic Valve

2019 ◽  
Vol 40 (5) ◽  
pp. 980-986
Author(s):  
Taliha Oner ◽  
Gokmen Akgun ◽  
Selma Oktay Ergin ◽  
Huseyin Karadag ◽  
İlker Kemal Yucel ◽  
...  
Keyword(s):  
Risk Factors ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Aneurysms ◽  
Factors Associated ◽  
Aortic Elasticity

scholarly journals Bicuspid aortic valve patients show specific epigenetic tissue signature increasing extracellular matrix destruction

2019 ◽  
Vol 29 (6) ◽  
pp. 937-943 ◽  
Author(s):  
Josephina Haunschild ◽  
Isabel N Schellinger ◽  
Sarah J Barnard ◽  
Konstantin von Aspern ◽  
Piroze Davierwala ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Epigenetic Regulation ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Aortic Tissue ◽  
Tissue Inhibitor ◽  
Tissue Samples ◽  
Increased Risk

Abstract OBJECTIVES Patients with a bicuspid aortic valve (BAV) have an increased risk for developing thoracic aortic aneurysm, which is characterized by the destruction of the elastic media of the aortic wall. Several important enzymes have been characterized to play key roles in extracellular matrix homeostasis, namely matrix metalloproteinases (MMPs). In this study, we investigated MMP-2 levels and their epigenetic regulation via the miR-29 family. METHODS Aortic tissue samples from 58 patients were collected during cardiac surgery, of which 30 presented with a BAV and 28 with a tricuspid aortic valve. Polymerase chain reaction, western blot analysis and immunohistochemistry were performed to analyse MMP-2. In addition, enzyme-linked immunosorbent assay measurements were carried out to investigate both MMP-2 and tissue inhibitor of metalloproteinase-2 levels. To examine the epigenetic regulation of aortic extracellular matrix homeostasis, we furthermore studied the expression levels of miR-29 via qRT-PCR. RESULTS Patients with a BAV were significantly younger at the time of surgery, presented significantly less frequently with arterial hypertension and displayed more often with an additional valvular disease. On a molecular level, we found that MMP-2 is increased on gene and protein level in BAV patients. Tissue inhibitor of metalloproteinase-2 levels do not differ between the groups. Interestingly, we also found that only miR-29A is significantly downregulated in BAVs. CONCLUSIONS Our findings highlight the importance of MMP-2 in the context of extracellular matrix destruction in BAV patients. We present new evidence that miR-29A is a crucial epigenetic regulator of these pathomechanistic processes and might hold promise for future translational research.

scholarly journals Bicuspid Aortic Valve Disease and Ascending Aortic Aneurysms: Gaps in Knowledge

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Katie L. Losenno ◽  
Robert L. Goodman ◽  
Michael W. A. Chu
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Disease ◽  
Aortic Aneurysms ◽  
Valve Disease ◽  
Cardiac Anomaly ◽  
Aortic Dilatation ◽  
Congenital Cardiac Anomaly ◽  
Valvular Stenosis ◽  
Ongoing Surveillance

The bicuspid aortic valve is the most common congenital cardiac anomaly in developed nations. The abnormal bicuspid morphology of the aortic valve results in valvular dysfunction and subsequent hemodynamic derangements. However, the clinical presentation of bicuspid aortic valve disease remains quite heterogeneous with patients presenting from infancy to late adulthood with variable degrees of valvular stenosis and insufficiency and associated abnormalities including aortic coarctation, hypoplastic left heart structures, and ascending aortic dilatation. Emerging evidence suggests that the heterogeneous presentation of bicuspid aortic valve phenotypes may be a more complex matter related to congenital, genetic, and/or connective tissue abnormalities. Optimal management of patients with BAV disease and associated ascending aortic aneurysms often requires a thoughtful approach, carefully assessing various risk factors of the aortic valve and the aorta and discerning individual indications for ongoing surveillance, medical management, and operative intervention. We review current concepts of anatomic classification, pathophysiology, natural history, and clinical management of bicuspid aortic valve disease with associated ascending aortic aneurysms.

scholarly journals VASCULARIZATION PATTERN OF ASCENDING AORTIC ANEURYSMS ASSOCIATED TO BICUSPID AORTIC VALVE

2015 ◽  
Vol 65 (10) ◽  
pp. A2107
Author(s):  
Victoria Cañadas Godoy ◽  
Isidre Vilacosta ◽  
Paloma Aragoncillo ◽  
Luis Maroto ◽  
Cristina Fernandez ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Aneurysms

The Value of Circulating Biomarkers in Bicuspid Aortic Valve-Associated Aortopathy

2016 ◽  
Vol 66 (04) ◽  
pp. 278-286 ◽  
Author(s):  
Shiho Naito ◽  
Mathias Hillebrand ◽  
Alexander Bernhardt ◽  
Annika Jagodzinski ◽  
Lenard Conradi ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Risk Stratification ◽  
Bicuspid Aortic Valve ◽  
Aortic Aneurysms ◽  
Conventional Imaging ◽  
Circulating Biomarkers ◽  
Screening Process ◽  
Cross Sectional ◽  
Thoracic Aortic Aneurysms ◽  
Definition Of

AbstractTraditional risk stratification model of bicuspid aortic valve (BAV) aortopathy is based on measurement of maximal cross-sectional aortic diameter, definition of proximal aortic shape, and aortic stiffness/elasticity parameters. However, conventional imaging-based criteria are unable to provide reliable information regarding the risk stratification in BAV aortopathy, especially considering the heterogeneous nature of BAV disease. Given those limitations of conventional imaging, there is a growing clinical interest to use circulating biomarkers in the screening process for thoracic aortic aneurysms as well as in the risk-assessment algorithms. We aimed to systematically review currently available biomarkers, which may be of value to predict the natural evolution of aortopathy in individuals with BAV.

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