Fig. 4.

Working hypothesis. Schematic overview of our working hypothesis regarding similarities and differences in aortic wall pathology between bicuspid aortic valve (BAV), tricuspid aortic valve (TAV), and Marfan syndrome (MFS). According to our hypothesis, the ascending aortic wall can be classified as being either mature or less well differentiated. Patients with a TAV have a differentiated/mature vascular wall [differentiated vascular smooth muscle cells (VSMCs) and lamin A/C] in which cardiovascular aging (increased expression of progerin with increased apoptosis, atherosclerosis, and inflammation) accompanies degeneration with features of cytolytic necrosis (CN). This progressive aortic wall pathology in TAV thus leads to a weakened aortic media causing complications as aortic dilation and dissection. In BAV and MFS, weakness of the aorta is however caused by immaturity of the aortic wall (deficient differentiated VSMCs and lamin A/C expression) instead of aging. Fibrillin-1, pivotal for structural stability of the vessel wall, is produced by VSMCs. Immaturity of the vessel thus leads to a quantitative decrease of fibrillin-1 in both BAV and MFS. In MFS, additionally, the FBN1 (fibrillin-1) mutation leads to VSMC apoptosis through an increased signaling of angiotensin II receptors (AT2 receptor). CN, caused by VSMC apoptosis, in combination with the immature state of the aortic media renders the vascular wall extremely weak, most probably presenting a different pathogenesis of aortic dissection in MFS as compared to the TAV