4D-FLOW MRI MAPPING OF REGIONAL AORTIC WALL SHEAR STRESS IMPLICATES HEMODYNAMICS IN HUMAN BICUSPID AORTOPATHY

Abstract

BACKGROUND: Patients with congenital bicuspid aortic valves (BAV) are predisposed to progressive dilatation of the ascending aorta (“bicuspid aortopathy”). A possible inherited/genetic etiology has led to aggressive surgical resection strategies to remove fragile tissue prone to complications. We recently demonstrated patterns of altered wall shear stresses (WSS) in the BAV aorta. These observations suggest regional hemodynamics may trigger local aortic extracellular matrix (ECM) degeneration leading to aortopathy. If validated, a more patient-specific and targeted resection strategy based on preoperative regional hemodynamic assessments may be warranted. For the first time, we correlated regional aortic tissue pathology with local hemodynamics using 4D-MRI in BAVpatients undergoing ascending aortic resection. METHODS AND RESULTS: BAV patients (N1⁄411) referred for ascending aortic resection received preoperative 4D-MRI. Regional WSS differences within each patient’s aorta relative to a normal tricuspid aortic valve control population for “elevated” (>1.96 SD) and “normal” WSS were defined. Paired aortic wall samples were collected during surgical resection from the predefined “elevated” and “normal” WSS regions. Aortic tissue was examined for histologic abnormalities consistent with BAV aortopathy (cystic medial necrosis, ECM fragmentation and mucopolyssacharide deposition) and molecular mediators of ECM regulation (TGFb-1, MMP, TIMP). All BAV patients studied had adjacent aortic regions with elevated and normal areas of WSS suggesting hemodynamic heterogeneity. Within the same patients’ aorta, aortic media subjected to elevated WSS demonstrated increased mucopolyssacharide composition (Figure 1C, white arrows) and elastin fragmentation (Figure 1D, black arrows) as compared to adjacent areas with normal WSS. Multiplex protein analyses revealed a 1.49-fold ( 0.71SD) increase in the profibrotic transforming growth factor b-1 (TGFb-1) in elevated WSS regions as compared to normal (P1⁄40.045). Mean fold increases in ECM-proteases MMP-1 (1.62 0.84; P1⁄40.057), MMP-2 (1.49 1.00; P1⁄40.18), MMP-3 (1.23 0.36; P1⁄40.18), MMP-7 (1.57 0.75; P1⁄40.067), and TIMP-2 (1.26 0.33; P1⁄40.038) were observed in aortic wall subjected to elevated WSS regions as compared to normal WSS regions within the same patients’ ascending aorta. CONCLUSION: In the BAV aorta, regional WSS corresponds with local histological abnormalities and ECM dysregulation. These novel data strongly implicate local hemodynamics as a mediator of BAV aortopathy. With further validation, 4DMRI could be used to guide personalized resection strategies for patients with BAV aortopathy.