Aortic valve disease: Exploring methods, models, and mechanisms

This thesis covers several aspects of aortic valve disease. In the first part, we use histopathological studies to gain insight into the varied background and pathogenesis of aortic valve disease. We show that changes in blood flow during left ventricular assist device support cause aortic valve interstitial cell (VIC) proliferation and phenotypical activation that may be associated with altered miRNA-143 expression, and lead to an increased influx of M2 macrophages. Radiation-associated aortic valve stenosis is frequently seen as a late sequela after thoracic radiotherapy. We show that high-dose radiation at young age results in premature fibrotic aortic valve stenosis and emphasize the importance of field reduction and lowering radiation dose. In the second part, we investigate cell culture models for in vitro VIC research. We show that major steps can still be made in terms of standardization and implementation of biologically relevant culture environments to improve translation of in vitro findings and accelerate research on aortic valve pathogenesis, drug discovery, and regeneration. We propose a novel matrix-free 3D cell culture platform that is able to produce large numbers of stable and viable VIC co-culture spheroids with high reproducibility and biological relevance. Ultimately, we evaluate decellularized porcine small intestinal submucosa as a pulmonary valved conduit in sheep and lamb and underline the importance of xenogeneic antigen masking and the host inflammatory response to the graft. Added are several case reports on rare valve diseases and complications after valve replacement