PROJECT SUMMARY / ABSTRACT Abdominal aortic aneurysm (AAA) is a life-threatening condition in which progressive dilatation of the infrarenal aorta leads to rupture. With ~2.3 million prevalent cases in the United States, AAA afflicts ~4% of the population ≥ 65 years of age and is responsible for ~41,000 deaths annually. No medical therapies exist that prevent AAA, AAA growth, rupture, or aneurysm-related death. The only efficacious intervention is surgery. Genome-wide association studies (GWAS) and preliminary pharmacogenetic causal inference studies from AAA GWAS demonstrate that both LDL-C lowering and PCSK9 inhibition are protective of AAA. The greatest therapeutic opportunities for pharmacological treatment of AAA lie in prevention of aneurysm expansion in individuals with small AAA. Despite our team's robust evidence linking LDL-C and PCSK9 to the development of AAA, their causal role in AAA growth remains unknown and the data to support conducting a large-scale efficacy trial is lacking. This project will leverage two orthogonal approaches to generate data that supports the role of LDL-C in AAA growth and that intensive LDL-C lowering with PCSK9 inhibitors will protect against aneurysm expansion. First, we will perform a multi-ancestry meta-analysis of GWAS of AAA growth rate and leverage these data to conduct genetic causal inference experiments interrogating the role of PCSK9 and LDL-c in AAA expansion. Second, we will conduct a quadruple-blind, randomized, placebo-controlled mechanistic clinical trial to test the effect of intensive short-term LDL-C lowering with PCSK9 inhibition on inflammation in the aneurysmal aortic wall; the primary outcome will be the production of the inflammatory cytokine interleukin 6 (IL-6) monocytes/macrophages in the aortic wall as measured by single nucleus RNA sequencing and confirmed by bulk RNA sequencing tissue- based immunofluorescence. Key secondary outcomes include: 1) matrix metalloproteinase 9 (MMP-9) production and activity; 2) relative numbers, cell type distribution, and inflammatory state of infiltrating immune cells; and 3) the relative number and proliferative/contractile state of aortic smooth muscle cells in the aortic wall. Successfully completing the proposed research will establish causal evidence linking LDL-C and AAA growth, and the ability to modulate this with PCSK9 inhibition. It will provide human mechanistic evidence that PCSK9 inhibitors induce anti-inflammatory changes in aneurysmal aortic wall that protect from aneurysm expansion. These data will provide the justification for a future large-scale randomized controlled trial to assess the efficacy of PCSK9 inhibitors to treat AAA.