Abstract 4369915: Direct Vascular Endothelial Assessment Highlights the Pleotropic Anti-Inflammatory Properties of Statin Therapy: Findings from the American Heart Association Cardiometabolic Health Strategically Focused Research Network

Background: Statins are central to cardiovascular (CV) prevention, primarily for their lipid-lowering effects, but may also offer anti-inflammatory benefits. This study compared the impact of statins versus ezetimibe on the vascular endothelium in patients receiving background PCSK9 inhibitor (PCSK9i) therapy. Methods: CHORD (CHOlesterol lowering and Residual Risk in Diabetes) is a prospective clinical study of LLT with the PCSK9i, Repatha 140mg, plus either atorvastatin 80mg (statin) or ezetimibe 10mg daily for 1 month to evaluate mechanisms of CV disease. Participants with an LDL-C > 100 mg/dL and with or without type 2 diabetes were enrolled. In a subset of participants, endothelial cell (EC) harvesting was performed at baseline and follow-up by inserting a J-wire through an angiocatheter into the brachial vein. ECs were isolated with magnetic beads directed against CD146, and transcript expression assessed using next-generation RNA sequencing. Results: We performed EC harvesting at baseline and follow-up in those that received PCSK9i + ezetimibe (n=16, median age 47 years, 69% male, LDL-C 133 mg/dL, hsCRP 1.1 mg/L) or PCSK9i + statin (n=24, median age 44 years, 50% male, LDL-C 143 mg/dL, hsCRP 1.1 mg/L). After 1 month of LLT, LDL-C and hsCRP decreased by 80% and 6%, respectively, in the statin group (P<0.05 for each). In the ezetimibe group, LDL-C decreased by 70% (p<0.01) with no reduction in hsCRP. In those that received PCSK9i + statin, EC RNA sequencing revealed 1858 genes upregulated and 1102 genes downregulated (nominal p-value < 0.05), while in those given PCSK9i + ezetimibe, 1804 genes were upregulated, and 1073 genes were downregulated (nominal p-value < 0.05). Overall, LLT improved EC health and senescence-related pathways while decreasing EC-related inflammation (Figure). Comparatively, in the PCSK9i + statin vs. PCSK9i + ezetimibe group, many more pathways were impacted, including upregulated EC migration and proliferation, nitric oxide, and glycosaminoglycan metabolism, while downregulated pathways included IL-6, TNF, MIP-1, CD40, Th17, IL-23, and reactive oxygen species signaling (Figure). Conclusion: We demonstrate that on a background of PCSK9 inhibitor therapy, statins provide greater improvements to EC health and anti-inflammatory effects, supporting their benefits beyond LDL-C reduction.