For patients with BAV, increased aortic valve-mediated WSS is significantly associated with elastic fiber thinning, particularly with aortic valve stenosis and in earlier stages of aortopathy. Elastic fiber thinning correlates with impaired tissue biomechanics. These novel findings further implicate valve-mediated hemodynamics in the progression of BAV aortopathy.

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The gold standard treatment for full thickness injuries of the skin is autologous split-thickness skin grafting. This involves harvesting the epidermis and superficial dermis from healthy skin and transplanting it onto the prepared wound bed. The donor site regenerates spontaneously, but the appendages and cellular components from the dermal layer are excluded from the graft. As a result, the new tissue is inferior; the healed graft site is dry/itchy, has decreased elasticity, increased fragility, and altered sensory function. Because this dermal layer is composed of collagen and other extracellular matrix proteins, the aim was to characterize the changes in the dermal collagen after split thickness grafting that could contribute to a deficit in functionality. This will serve as a baseline for future studies designed to improve skin function using pharmacological or cell-based therapies for skin repair. A xenograft model whereby human split-thickness grafts were implanted into full-thickness defects on immunocompromised (athymic Nu/Nu) mice was used. The grafts were harvested 4 and 8 weeks later. The collagen microstructure was assessed with second harmonic generation with dual-photon microscopy and light polarization analysis. Collagen fiber stiffness and engagement stretch were estimated by fitting the results of biaxial mechanical tensile tests to a histo-mechanical constitutive model. The stiffness of the collagen fibril-proteoglycan complex increased from 682 ± 226 kPa/sr to 1016 ± 324 kPa/sr between 4 and 8 weeks postgrafting. At the microstructural level there were significant decreases in both thickness of collagen fibers (3.60 ± 0.34 μm vs. 2.10 ± 0.27 μm) and waviness ratio (2.04 ± 0.17 vs. 1.43 ± 0.08) of the collagen fibers postgrafting. The decrease of the macroscopic engagement stretch from 1.19 ± 0.11 to 1.09 ± 0.08 over time postgrafting mirrored the decrease in waviness measured at the microscopic level. This suggested that the integrity of the collagen fibers was compromised and contributed to the functional deficit of the skin postgrafting.

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Introduction: A suspected genetic cause for bicuspid aortic valve (BAV) aortopathy has led to aggressive resection strategies. Using 4D flow MRI, we documented increased regional wall shear stress (WSS) in BAV patients. Local hemodynamics may exacerbate extracellular matrix (ECM) degradation leading to disease progression. If validated, preoperative regional hemodynamic assessment could be used to guide more targeted patient-specific aortic resection. For the first time, we correlated regional WSS with aortic tissue remodeling in BAV patients. Methods & Results: BAV patients (N=11) undergoing ascending aortic resection received preoperative 4D flow MRI with regional WSS differences mapped. Paired aortic wall samples (from same-patient with elevated WSS paired to normal WSS regions) were collected during surgery and compared using histology (pentachrome), biomechanics (biaxial mechanical testing), and ECM regulation (protein expression). Patient mean age: 49±18 years; mean aortic diameter: 4.6±0.7cm (range: 3.6 - 6.3cm); 55% had R+L fusion pattern; 36% had severe aortic stenosis. All patients had heterogeneous WSS patterns with regions of elevated WSS adjacent to those of normal WSS. By histology, regions of increased WSS showed greater medial elastin fragmentation, fibrosis, and cystic medial necrosis compared to adjacent areas of normal WSS. Regions of increased WSS showed increased elastic modulus (fold change±SD: 1.53±0.68; P=0.06, N=5) and collagen stiffness (1.37±0.49; P=0.07, N=5) compared to normal WSS regions suggesting altered distensibility. Multiplex protein analyses of ECM regulatory molecules revealed an increase in transforming growth factor β-1 (1.49±0.71, P=0.02), MMP-1 (1.62±0.84; P=0.01), MMP-2 (1.49±1.00; P=0.06), MMP-3 (1.23±0.36; P=0.02), MMP-7 (1.57±0.75; P=0.02), and TIMP-2 (1.26±0.33; P=0.01) in elevated WSS regions suggesting ECM dysregulation consistent with aortic remodeling. Conclusions: In BAV aorta, regional WSS corresponds with local histologic abnormalities, altered biomechanics, and ECM dysregulation. These novel data strongly implicate local hemodynamics as a mediator of BAV aortopathy. With further validation, 4D flow MRI could be used to guide personalized resection strategies.