Ultrasound Imaging of Tissue Remodeling in Murine Models of Vascular Disease and Repair
thesisposted on 03.12.2021, 14:32 by Alycia Gabrielle BermanAlycia Gabrielle Berman
An abdominal aortic aneurysm (AAA) is a pathological dilation of the abdominal aorta, as defined by a 50% increase in diameter or a diameter greater than 3 cm. While typically asymptomatic, there is a risk that the AAA will rupture, causing massive hemorrhaging and high mortality rates. Thus, once detected, the clinician must choose between surveillance and elective surgical repair. The first option carries the risk of rupture; the second risks complications and graft failure. Currently, clinical metrics of rupture risk are dependent on diameter and growth rate. However, a number of studies have indicated that, although rupture risk does increase with increased diameter, there are also a large number of patients with aneurysms for which the diameter criteria is insufficient. There remains a strong need to 1) determine better estimates of rupture risk in order to accurately assess the need for surgery and 2) improve surgical treatment to reduce perioperative risk.
Herein, we use ultrasound in mice to address these two prevalent uncertainties in aneurysm development and treatment. First, we further develop a murine aneurysm model that forms large aneurysms with distal thrombus. To increase the applicability of the model, we modulate aneurysm growth by altering elastase concentration and lysyl oxidase inhibition. We show that initial elastase concentration impacts aneurysm size, which is driven in part by a change in the degree of initial degradation of the aortic wall. We also demonstrate that lysyl oxidase inhibition (via BAPN) remains necessary for expansion even after the initial aneurysm formation and that removal of the lysyl oxidase inhibitor effectively stops growth in this model. As a final point, we show that female mice develop larger aneurysms than the males using this model. Then, with the aim of improving surgical treatment options, we explore the patency of various design parameters involved in tissue-engineered vascular grafts. To do so, we assess the allowable parameter design space of murine textile arterial grafts, so as to lead to better selection of key design components. Overall, the findings in this thesis demonstrate the applicability of ultrasound in small animals to improve aneurysm diagnostic and treatment options.