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The Expression Of Key Genes s Associated With the Induction of Abdominal Aortic Aneurysm (AAA) During Peak Periods of Cellular Activity in a Porcine Aneurysm Model

Robert L Hynecek, Brian G DeRubertis, Soo J Rhee, K Craig Kent, Peter L Faries ∙ Weill Medical College of Cornell University, New York, NY

Objective: Small animal models are useful for the investigation of gene expression characteristics that accompany abdominal aortic aneurysm (AAA) formation, but are impractical for the study of endovascular interventions. A porcine model of AAA that combines enzymatic extracellular matrix degradation and balloon dilation to simulate accelerated AAA formation is utilized. Nuclear imaging is used to identify peak cell activity following aneurysm induction, and gene expression characteristics that correspond to aneurysm formation within this period are characterized using microarray analysis. Methods: AAAs were created in 8 Yorkshire swine (25-35kg). Aortas were dilated using balloon angioplasty (12-14mm) and enzyme infusion with 50ml of collagenase (8000u) and elastase (500u). Positron emission tomography computed tomography (PET/CT) was performed on five days (1, 3, 7, 14, and 28) on each of the swine. 10 mCi of 18-fluorodeoxyglucose (FDG) was injected intravenously and uptake was quantified within the AAA and a surgically exposed sham segment of aorta using radioactive decay density within an ellipsoid volume of interest (VOI). The remaining 3 swine were sacrificed 7 days after the procedure. RNA was isolated from porcine aortas and normal suprarenal abdominal aorta for each time point. cDNA generated from the samples was hybridized to porcine gene chip arrays (20,201 genes), and changes in gene expression were analyzed. Results: FDG uptake within VOIs enclosing porcine AAA relative to sham aortic segments demonstrated peak activity on day 7 (32.7%±22.3%), which was significantly higher (p=0.001) than day 1 (-2.8%±17.9%), and day 28 (1.2%±22.9%). Key matrix metalloproteinases (MMPs) increased from baseline (MMP3 21.0x, MMP1 15.4x). Key tissue inhibitors of metalloproteinase (TIMP) levels were downregulated (TIMP4 x/2.9, TIMP3 x/2.1). Conclusions: PET/CT demonstrates that enzyme perfusion and aortic dilation induce cellular activity that peaks at the seventh postoperative day. MMPs and TIMPs associated with AAA pathological pathways were upregulated and downregulated respectively at this time point. Gene products associated with the propagation of aneurysms can more clearly describe AAA formation in this model and provide methods for the evaluation of endovascular treatment strategies.