Interrogation Of Endothelial Permeability In Aortic Aneurysm And Dissection Using Nanoparticle Contrast- enhanced Computed Tomography

Background: Aortic pathologies, such as aortic aneurysm and dissection (AAD), are characterized by enhanced endothelial permeability and dysfunction. Non-invasive monitoring of changes in endothelial permeability could enable early detection and prediction of AAD progression. Herein, we investigated nanoparticle contrast-enhanced computed tomography (nCECT) to probe endothelial permeability changes in a mouse model of sporadic AAD. Methods: In vivo studies were performed in a mouse model of AAD challenged with high fat diet (5 weeks) and angiotensin II infusion (last one week). The effects of nanoparticle contrast agent (NPCA) size (80, 150, and 250 nm) and dose (300, 600, and 1200 mg I/kg) on detecting endothelial permeability changes were studied. In vivo and ex vivo nCECT imaging were performed 4 days post-contrast and findings were compared with gross and histologic examination. A subset of mice was followed-up with longitudinal nCECT up to 6 months. Results: nCECT showed a higher incidence of aortic injury associated with enhanced endothelial permeability compared to gross examination findings. The absolute improvements in detection rates were 21%, 17% and 16% for 80 nm, 150 nm, 250 nm NPCA respectively (Figure 1B). Sensitivity of nCECT for detection of aortic injury improved with increasing NPCA dose compared to gross exam (-17% at 300 mg I/kg to 14% at 1200 mg I/kg, Figure 1C). Follow-up nCECT at 6 months did not show significant increase in wall signal enhancement compared to baseline (Figure 2), suggesting resolution of inflammation and endothelial dysfunction, and progressive repair and remodeling of aortic wall which were confirmed by the microscopic analysis. Conclusion: nCECT detected enhanced endothelial permeability before pathological changes were evident on gross examination in a mouse model of sporadic AAD. Furthermore, this approach enabled non-invasive monitoring of changes in endothelial permeability at sites of aortic degeneration.