Abstract Body: Intermittent statin adherence has been shown to worsen cardiovascular outcomes compared to individuals who are adherent to their statin treatment. Oxidized phospholipids (OxPL) derived from LDL play a crucial role in pre-clinical models in the development and progression of atherosclerosis, and are thought to have similar effects clinically. The natural antibody E06, binding to OxPL, has been shown to diminish macrophage (Mφ) uptake of OxLDL in vitro and decrease atherosclerosis progression in vivo. In prior work using a model of plasma cholesterol cycling (high-low-high), resulting in atherosclerotic plaque Progression (P), Regression (PR), and re-Progression (PRP), we observed accelerated plaque inflammation in the PRP group relative to mice with non-cycling high cholesterol. We hypothesized that OxPL promotes accelerated inflammation after regression in the plaques of cholesterol-cycled mice via trained immunity, and that the E06 antibody will mitigate this in PRP. To test this, we utilized transgenic "E06 mice" that secrete from liver a single-chain variable fragment of E06 on the Ldlr^−/− background. Both E06 and Ldlr^-/- mice were subjected to an initial high cholesterol diet and divided into the cholesterol cycling groups: P, PR and PRP (n>10/group). Plaque regression was induced by ApoB-ASO injections, which significantly lower cholesterol levels by inhibiting hepatic ApoB production. Ldlr^-/- mice in the PRP group exhibited accelerated plaque inflammation post-regression as assessed by Mφ (CD68+ cells) accumulation in aortic roots. While the accumulation of Mφs in Ldlr^-/- mice was 50% higher in PRP vs. PR, there was no significant change of Mφs in the E06 mice (P=0.0003). Peripheral blood exhibited a reduction of total monocytes in the PRP group of E06 mice compared to Ldlr^-/- mice. Evidence of effects of the E06 antibody on trained innate immunity was obtained by ex vivo stimulation of bone marrow monocytes with LPS, which demonstrated higher IL-6 levels in the supernatant of cells from Ldlr^-/- mice vs E06 mice in the PRP group (n=5-6, 79.6±10.5 vs. 50.8±37.4 ng/mL, P=0.03). In progress is single-cell RNA sequencing of plaque cells from E06 and Ldlr^-/- mice, which should be available by the time of this meeting. In summary, this work provides insight into the increased risk of cardiovascular disease in individuals with intermittent adherence to statins and highlights the importance of neutralizing OxPL during the resultant cholesterol cycling.