Enhanced Biochemical Monitoring for Aortic Aneurysm Disease

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PROJECT SUMMARY Aortic Aneurysm (AA) represents a major cause of morbidity and mortality in the United States and continues to be a difficult management problem for cardiovascular surgeons. This disease weakens the vessel wall and leads to dilation that can progress to rupture in the absence of symptoms. At present, the diagnosis of aneurysm disease is highly dependent on costly, advanced imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). There are no point-of-care plasma biomarker assays currently available that either screen for AAs or follow disease progression to inform optimal timing for surgical intervention. To develop novel assays capable of diagnosing, locating, tracking, and assessing diameter (or risk) of AAs: We have assembled an extensive clinical plasma biorepository and selected instruments that are quantitative, scalable, reproducible, and able to be automated. Using this repository, as well as newly collected blood samples, we will test the hypothesis that quantification of aneurysm biomarkers enables enhanced biochemical monitoring for AA. In aneurysm tissue enhanced proteolysis results in pathological remodeling and progressive dilation. This breakdown of normally long-lasting matrix molecules, such as elastin and collagen, emphasizes the involvement of Matrix Metalloproteinases (MMPs), and their endogenous regulators, the Tissue Inhibitors of Matrix Metalloproteinases (TIMPs). These enzymes degrade all components of the vessel wall and are attributed to the development and progression of aneurysm disease. MicroRNAs represent a class of small non-coding RNA that regulate translation and a subset are secreted by aortic cells during progression of AA. Extracellular Vesicles (EVs) have been identified as critical mediators of cell-to-cell communication and extracellular matrix remodeling. EVs contain multiple MMPs, TIMPs, microRNAs, and the transforming growth factor (TGF)-ß, all which influence signaling pathways and contribute to degradation of the vascular wall. Experiments conducted by this laboratory show that when an aneurysm presents, a unique set of these circulating molecules also emerge. These signature profiles are different among AA location, subtype, and size. Accordingly, experiments and testing will demonstrate the following three aims. First, AA can be identified in plasma by profiling the MMP:TIMP ratio because it provides a unique metric of proteolytic activity within the aortic wall. Second, that the subset of microRNAs secreted from aortic cells under stress is correlated linearly to aortic diameter and pathological progression of AA. Third, circulating Extracellular Vesicle (EV) size, structure, and composition is altered in patients with AA subtypes and profiling them constitutes a diagnostic assay. Even if one aim should fail as a diagnostic assay, another can take its place; nevertheless, this study will provide mechanistic data and insight into upstream pathways involved in AA progression. Combined, this study will advance the development of a standardized screening assay for early diagnosis and risk stratification to mitigate life-threatening aortic complications.