Metabolic Syndrome & Pathobiology of Aortic Aneurysms

Washington University, Saint Louis MO

Investigators

Linked publications & trials

Abstract

Since the metabolic syndrome is present in about a quarter of American adults and almost half of those[unreadable] over the age of 60, it is not surprising that nearly 50% of patients with abdominal aortic aneurysms (AAAs)[unreadable] fulfill the criteria for this syndrome. However, it is surprising that essentially nothing is known about how the[unreadable] presence of this syndrome affects the clinical manifestations of AAAs.[unreadable] AAAs are a common form of vascular disease characterized by chronic aortic wall inflammation and[unreadable] connective tissue destruction, depletion of medial smooth muscle cells, and impaired connective tissue[unreadable] repair. Patients with AAAs exhibit aortic tissue production and elevated circulating levels of pro-inflammatory[unreadable] proteins that may serve as biomarkers of disease activity. Reparative biological processes, such as[unreadable] recruitment of bone marrow-derived vascular progenitor cells and neovascularization, might be capable of[unreadable] stabilizing aneurysm tissue. Many of these events are recapitulated in mouse models of AAAs. Many of the[unreadable] same pro-inflammatory proteins that circulate in patients with AAAs are also increased in people with the[unreadable] metabolic syndrome. This project will test the hypothesis that the presence of the metabolic syndrome[unreadable] adversely impacts the clinical course of people with AAAs. Several pro-inflammatory mediators affecting[unreadable] AAA biology may also be affected through signaling pathways triggered by ATM (Ataxia Telangiectasia[unreadable] Mutated) and data from Project 1 show that this protein can be activated by chloroquine. We will also test[unreadable] the hypothesis that the ATM pathway modulates inflammation to affect anuerysm formation.[unreadable] We will address the following aims:[unreadable] 1-Determine if the presence of metabolic syndrome in humans influences inflammatory markers and a[unreadable] clinically relevant outcome (persistent aneurysm expansion following endovascular aneurysm repair).[unreadable] 2-Establish if the presence of metabolic syndrome in humans influences aortic tissue recruitment and[unreadable] circulating levels of vascular progenitor cells capable of connective tissue repair.[unreadable] 3-Evaluate if ATM deficiency in mice affects the development of experimental AAAs and if ATM activation[unreadable] with chloroquine can suppress experimental AAAs.[unreadable] This project has the potential to transform the care of people with the metabolic syndrome by establishing[unreadable] the mechanisms by which this disorder may affect clinical outcomes following surgical repair of aneurysms.[unreadable]