Severe Aortopathy is Specific to Regions of Elevated WSS in the Human Bicuspid Aorta
David G Guzzardi, Alex J Barker, Pim van Ooij, Sean Kang, S Chris Malaisrie, Jyothy J Puthumana, Darrell D Belke, Holly EM Mewhort, Daniyil A Svystonyuk, Subodh Verma, Jeremy Collins, James Carr, Robert O Bonow, Michael Markl, James D Thomas, Patrick M McCarthy & Paul WM Fedak
OBJECTIVE: Bicuspid aortic valve (BAV) disease predisposes patients to medial elastic fiber degeneration, weakening and aneurysm formation of the ascending aorta, collectively known as bicuspid aortopathy. Although previous work has demonstrated severe aortopathy in aortic wall subjected to elevated wall shear stress (WSS), whether these changes are specific to these regions of elevated WSS is unclear. This study builds on previous work by comparing tissue from multiple regions of normal WSS throughout the human BAV aorta to regions of elevated WSS as determined by 4D flow MRI.
METHODS: Aortic tissue (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. Regions of “normal” and “elevated” WSS were generated 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), and mediators of extracellular matrix degradation (TGFβ-1, MMPs and TIMPs). Multiple regions of normal WSS were averaged within each aorta and compared to regions of elevated WSS.
RESULTS: Mean elastin fiber content (p=0.0036) and thickness (p=0.0001) were significantly decreased, and TGFβ-1 concentrations increased (p=0.064) in regions of elevated WSS compared to an average of all regions of normal WSS in the same aortas. Importantly, TGFβ-1 concentrations negatively correlated to elastic fiber content only in regions of elevated WSS (r=-0.562; p=0.024) and not in adjacent tissue regions subjected to normal WSS.
CONCLUSIONS: For the first time, we show that the aortopathy (elastic fiber degeneration and molecular mediators) in BAV aortas is specific to regions of elevated WSS compared to multiple regions of normal WSS in the same BAV aortas. Importantly, these results extend the observation that non-invasive hemodynamic mapping using 4D flow MRI may be a useful tool in designing patient-specific resection strategies, and further implicate hemodynamics in the expression of human bicuspid aortopathy.