BACKGROUND AND AIMS: We have recently reported that monocytes can undergo functional and transcriptional reprogramming towards a long-term pro-inflammatory phenotype after brief in vitro exposure to atherogenic stimuli such as oxidized LDL. This process is termed 'trained immunity', and is mediated by epigenetic remodeling and a metabolic switch towards increased aerobic glycolysis. We hypothesize that trained immunity contributes to atherogenesis. Therefore, we investigated the inflammatory phenotype and epigenetic remodeling of monocytes from patients with and without established atherosclerosis. METHODS: Monocytes were isolated from 20 patients with severe symptomatic coronary atherosclerosis (total plaque score >4 on coronary computed tomography angiography) and 17 patients with asymptomatic carotid atherosclerosis and matched controls for both groups. Ex vivo stimulation, RNA analysis and chromatin immunoprecipitation were performed. RESULTS: Monocytes from patients with symptomatic atherosclerosis have a higher production of pro-inflammatory cytokines upon LPS stimulation than healthy controls (TNFalpha 499 +/- 102 vs. 267 +/- 45 pg/ml, p = 0.01). This was associated with lower histone 3 lysine 4 trimethylation (H3K4me3) (19% vs. 33%, p = 0.002), and lower H3K27me3 (0.005% vs. 0.8%, p