Enhanced Biochemical Monitoring for Aortic Aneurysm Disease

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.

Grant Number: 5R01HL169390-03
NIH Institute/Center: NIH
Principal Investigator: Adam Akerman