The Hemodynamic Theory of Bicuspid Aortic Valve Disease

The bicuspid aortic valve (BAV) is the most common congenital cardiovascular defect affecting 1-2% of the population. A normal aortic valve consists of three leaflets and is often referred to as the tricuspid aortic valve (TAV). The BAV exists in several different morphogenic phenotypes, resulting in two aortic valve leaflets instead of three and is known as the type-I BAV. While the BAV anatomy may not intrinsically hamper valvular function, it is associated with a spectrum of secondary valvulopathy and aortopathy such as calcific aortic valve disease (CAVD) and aortic dilation. The abnormal mechanical stresses imposed by the BAV on its leaflets and on the aortic wall could trigger cell-mediated processes, leading ultimately to valvular calcification and aortic medial degeneration. Despite increasing evidence for this hemodynamic etiology, the demonstration of the involvement of mechanical abnormalities in the pathogenesis of BAV disease requires the investigation of causality between the blood flow environment imposed on the leaflets and the aortic wall and the local biology, which has been lacking to date.

The hypothesis of this dissertation is that is that abnormal wall shear stress (WSS) generated on the fused BAV leaflet or the endothelium of the proximal and mid sections of the ascending aorta (AA) downstream of various type-I BAVs will promote acute expression of biomarkers associated with valvular inflammation and remodeling and vascular remodeling, respectively. Therefore, the objective of this study is to determine the biological response of AV and AA tissue to BAV flow environments.

AV tissue was exposed to the WSS environments of non-coronary and fused BAV leaflets. AA tissue was exposed to WSS from the convexity and concavity downstream of a BAV and WSS from the proximal and mid sections of the convexity downstream of three type-I BAV morphotypes. The acute remodeling and inflammation responses were measured in terms of expression of matrix metalloproteinases (MMP-2 and MMP-9), pro-inflammatory cytokines (TGF-β1 and BMP-4) and cellular adhesion molecules (ICAM-1 and VCAM-1).

This study found that AV tissue responds in a time-dependent manner to BAV leaflet WSS, with acute inflammatory and remodeling expression and activity within 24 hours that begins to decrease after 48 hours, except in the case of pro-inflammatory cytokine BMP-4 and cellular adhesion molecule VCAM-1. Endothelial activation through VCAM-1 peaks at 48 hours after conditioning under the fused BAV leaflet WSS environment. BMP-4 inhibition on leaflet tissue conditioned under the WSS environment from the fused BAV leaflet significantly reduces the inflammatory response through suppression of VCAM-1 expression.

In the AA, remodeling is asymmetric, with WSS from the convexity, and not the concavity, inducing a significant remodeling response after 48 hours. The specific WSS environment linked to the BAV morphotype and location also affects the remodeling response of AA tissue, with overall higher MMP-9 expression in the proximal AA and higher MMP-2 expression in the mid AA. All three morphotypes were linked with significantly elevated remodeling indices relative to TAV conditioned tissue and fresh controls.

In summary, evidence for the causative effects of BAV hemodynamics on secondary valvulopathy and aortopathy is emerging. While those complications may still be promoted by some genetic predispositions, it is likely that their pathogenesis is also driven by synergies between the local mechanical stress abnormalities and the local biology of the leaflets and ascending aortic wall.