4D FLOW MRI IDENTIFIES REGIONS OF MORE SEVERE AORTOPATHY IN THE HUMAN BICUSPID AORTA

Abstract

Patients with congenital bicuspid aortic valves (BAV) are prone to progressive enlargement of the ascending aorta (aortopathy), characterized by medial elastin fiber degradation. We previously demonstrated that non-invasive hemodynamic assessment of regional wall shear stress (WSS) using 4D flow MRI can identify tissue regions with more severe elastin degeneration. The specificity of these observations to regions of high WSS is unclear. In this study, we extend these observations and examined molecular mediators of ECM homeostasis and histopathology in aortic tissue from BAV patients in the context of differential regional hemodynamics. Aortic tissue from regions of normal and elevated WSS (from mean aortic diameter 4.6±0.3 cm; range: 4.0-5.2 cm) was collected from BAV patients (N=17) undergoing ascending aortic surgery and who received pre-operative 4D flow MRI. To determine regions of “normal” and “elevated” WSS, WSS heatmaps of each aorta were constructed relative to the 95% confidence interval for normal physiological WSS values of a tricuspid aortic valve population. Tissue was evaluated for elastin fiber content and architecture (fiber thickness and fiber-to-fiber distance). Mediators of ECM degradation (TGFβ-1, MMPs and TIMPs) were assessed in areas of normal and elevated WSS. MMP-2 concentration was positively correlated with TIMP-2 concentration in all tissues (r=0.744; p<0.0001) independent of regional WSS. However, in samples from regions of elevated WSS, TGFβ-1 concentrations negatively correlated with the amount of elastin fibers (r=-0.548; p=0.053) and concentration of MMP-2 positively correlated with elastin fiber-to-fiber distance (r=0.539; p=0.026). Importantly, no correlations between mediators of ECM degradation and metrics of elastin fiber degradation were observed in adjacent tissue regions subjected to normal WSS. ECM dysregulation in the BAV aorta correlated with aortopathy in areas of elevated WSS but not in adjacent areas of normal WSS. These data further implicate WSS and regional hemodynamics in the expression of human bicuspid aortopathy. 4D flow MRI may be a promising non-invasive imaging tool to guide patient-specific resection strategies given the observed specificity of elevated WSS to predict tissue regions with more severe aortopathy.