Gannon, O. J.; Rahtes, A.; Bonin, J.; Salfate del Rio, I.; Partridge, J.; Khan, S.; Nobles, A.; Covert, G.; Bahr, A.; Ramos, R. B.; MacNamara, K. C.; Fredman, G.

While cholesterol lowering remains the cornerstone therapy for atherosclerosis and prevention of major adverse cardiovascular events, 33-50% of individuals on lipid-lowering therapy continue to exhibit elevated inflammation. Middle age (MA) represents a critical window for disease acceleration, underscoring a need to better understand non-resolving inflammation in this time frame. We rendered young (2 months) and MA mice (10 months) hypercholesterolemic with an AAV8-PCSK9 virus and fed a western diet (WD). Following 20 weeks on a WD, mice were switched to chow for 6 weeks to mimic lipid-lowering therapy. We found that MA atherosclerotic mice had increased plaque necrosis with increased circulating and bone marrow PMN compared to young mice. Upon lipid lowering, unlike in young mice, MA mice had increased necrosis, and reduced remodeling as well as increased circulating white blood cells and bone marrow hematopoietic stem cell progenitors (HSPCs). Circulating neutrophils correlated with necrosis in MA mice whereas young mice exhibited no correlation. Lipid lowered MA atherosclerotic mice had bone marrow HSPCs and neutrophils that exhibited a more activated phenotype relative to young. Elevated neutrophil-endothelial contacts were observed in the hippocampal vasculature of MA lipid lowered mice. While lipid lowering restrains atheroprogression in young, it is inadequate in MA, failing to reduce systemic inflammation and indicating the need for complementary therapies during this time frame.