UNRAVELLING AETIOLOGY AND RISK FACTORS IN PATIENTS WITH A BICUSPID AORTIC VALVES

The bicuspid aortic valve is generally considered to be a result of a congenital fusion of two out of three leaflets. We found that the non-coronary leaflet develops from the same embryonic structure that also gives rise to the right coronary leaflet. A BAV type 2 can be considered as the result of an improper separation rather than an abnormal fusion of two separately developed leaflets, which is an essential different starting point for our research to explore the genetic and signalling pathways of BAV genesis. We also have found in a bicuspid aortic model (NOS3 knock out) that 2 out 3 contributing extracardiac cell populations (neural crest and second heart field) are disturbed in their contribution to both the aortic valvular leaflets and the aorta wall. This results in BAV and abnormal elastin production in the ascending aortic wall from its initial formation in the embryo onwards. Hemodynamics seems to play a more modest role in the formation of the aorta aneurysm than one has generally considered up till now. To study the role of haemodynamics in EMT during valve formation and calcification we made use of the ex vivo miniature tissue culture system. In cultured mouse adult hearts, we found that by changing flow, the response of valve endothelial cells is altered. By culturing valves of mice with a genetic endothelial lineage trace, we could show that when exposed to high physiological flow, the endothelial cell phenotype and lining is maintained. Interestingly, by adding calcification inducing factors such as B-glycerolphosphate, dexamethasone or Bone Morphogenetic Proteins, we were able to induce valvular calcification in the cultured adult mouse hearts. We further studied the role of haemodynamics in the pathology of BAV by immunoshistochemical analysis of aortic material. We observed that at the non-jet side of the aorta the endothelial cells showed a significantly increased inflammation (P50+), endothelial-to-mesenchymal-transition (SNAI1+) and trend towards increased proliferation in BAV patients. Our results show an increased endothelial activity at the inner curvature of the ascending aorta/aortic arch with oscillatory flow in BAV patients. In human aortic samples from BAV patients, we have identified that the protein FHL2 is increased in the dilated aorta compared with the non-dilated aorta. FHL2 is an interesting biomarker as it has been described to reduce smooth muscle cell contractility. Our observed increase in FHL2 expression in the dilated aorta could therefore be related to an increase in synthetic SMCs, causing the breakdown of the elastic lamellae and destabilization of the aorta. We investigated women with Turner syndrome using advanced imaging technology to study structural abnormalities. We focused on partial abnormal pulmonary venous return and found that 25% of the women indeed had this abnormality, a much higher prevalence than expected. In addition, we discovered structural abnormalities in the aortic arch, large arteries and coronary arteries. This last finding is completely new. We also investigated the aorta flow with 4D MRI in patients with BAV and demonstrated the feasibility of this technique to estimate regurgitation and showed good correlation with echocardiography. Of patients with coarctation, approximately 50% to 75% have a bicuspid aortic valve. We found that coarctation stent treatment in Turner patients is associated with a higher risk than normal. Finally, we investigated the risk of dissection and found a lower risk than expected. Aortic stenosis is the most frequent complication of bicuspid aortic valve and the main reason for valve surgery during lifetime. Different options for valve replacement are available and we investigated the outcomes for the different options in children and adults. Then an information portal was developed according to the systematic International Patient Decision Aid Standards (IPDAS) development process. First, we conducted comprehensive surveys and interviews among patients (N=63), caregivers of pediatric patients (N=10) and physicians (N=32) to assess the current state of patient information and explore their preferences and needs, to determine the focus for the development of the information portal. We found that patient knowledge and numeracy is limited, reliable information is scarce, physicians inform patients selectively and patient involvement is suboptimal. Then we tested the impact of the information portal on the subjective quality of life. We found no effect, however, when studying the results in more detail we found that 50% of the patients never visited the website and that in the patients who did visit the website there was a clear positive effect on the quality of life. We discovered a new gene mutation on SMAD6 in patients with a bicuspid aortic valve that is associated with aortic aneurysm. Also we discovered TBX20 as a contributing gene. Finally, loss-of-function mutations in the X-linked biglycan gene were found to cause a severe syndromic form of thoracic aortic aneurysms and dissections.

1. http://publications.europa.eu/resource/authority/data-theme/HEAL

1. http://id.loc.gov/vocabulary/iso639-1/en

1. http://data.europa.eu/eli/reg/2025/327/oj

collection type: Disease specific,Hospital,Image collection,Longitudinal,Non-Human,Rare disease collection | disease: Congenital insufficiency of aortic valve | data categories: Biological samples,Imaging data,Medical records | materials: DNA,Plasma,Serum | omics: Genomics | imaging: Y | sex: Female,Male