Abstract 4370745: Aggressive Lipid Lowering Differentially Impacts the Vascular Endothelium in Diabetic vs Healthy Individuals. Findings from the American Heart Association Cardiometabolic Health Strategically Focused Research Network

Background: Vascular endothelial cell (EC) damage and subsequent cardiovascular (CV) events occur in patients with type 2 diabetes (T2D) despite aggressive medical therapy. This study investigated the key vascular EC pathways in T2D vs controls at baseline and after aggressive lipid lowering therapy (LLT) to improve our mechanistic understanding of CV risk reduction strategies in T2D. Methods: CHORD (CHOlesterol lowering and Residual Risk in Diabetes) is a clinical trial of LLT with PCSK9 inhibitor plus high-intensity statin or ezetimibe for 1-month to evaluate mechanisms of CV risk in T2D and non-T2D (controls) free of clinical CV disease with an LDL-C > 100 mg/dL. In a subset of participants, 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 in 15 participants with DM (median age 55 years, 60% male, HbA1c 6.7%, LDL-C 131 mg/dL) and 25 controls (median age 37 years, 56% male, HbA1c 5.2%, LDL-C 142 mg/dL). After adjustment for age and sex, EC RNA sequencing in T2D (vs controls) demonstrated 1126 upregulated and 204 downregulated genes (nominal p<0.05) with dysregulated pathways in T2D (vs controls) involved in lipid metabolic process, apoptosis, interferon signaling, and leukocyte vascular adhesion. After lipid-lowering (LDL-C decreased by 70% in both T2D and controls), 839 genes were upregulated, and 1271 genes were downregulated (nominal p<0.05) with upregulated EC pathways related to EC health, nitric oxide, and IL-10 signaling. Downregulated EC pathways after LLT included interferon production, inflammasome signaling and NFkB production (Figure). When compared to controls, T2D showed preferential reduction in endothelial inflammatory pathways yet upregulation in those related to platelet activation and hemostasis (Figure). Following LLT, the dysregulated pathways between T2D and controls at baseline (lipid process, apoptosis, interferon signaling, leukocyte vascular adhesion) were no longer significantly different between groups. Conclusion: While individuals with and without T2D derive improvement in vascular endothelial function, aggressive lipid lowering appears to have a more robust anti-inflammatory impact in T2D yet no impact on those related to hemostasis.