Background Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor but the underlying mechanisms responsible for its pathogenicity are poorly defined. Since Lp(a) is the prominent carrier of pro-inflammatory oxidized phospholipids (OxPL), part of its atherothrombosis might be mediated through this pathway. Methods In vivo imaging techniques MR imaging, 18F-FDG-PET/CT and SPECT/CT were used to measure subsequently atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed using FACS analysis, inflammatory stimulation assays and transendothelial migration assays. In vitro studies to the pathophysiology of Lp(a) on monocytes were performed using an in vitro model for trained immunity. Results We show that subjects with elevated Lp(a) (108 [50–195] mg/dL; n=30) have increased arterial inflammation and enhanced PBMCs trafficking to the arterial wall, compared with subjects with normal Lp(a) (7 [2–28] mg/dL; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce pro-inflammatory cytokines upon stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the pro-inflammatory response in monocytes derived from healthy controls (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apo(a). Conclusions These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease. Clinical Trial Registration URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5006 Unique Identifier: NTR5006 (VIPER study)

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Oxidative pathways in the subendothelial space activate pro-infl ammatory, immunogenic, and atherogenic processes, resulting in endothelial dysfunction, plaque growth and destabilization, platelet activation, and thrombosis, ultimately leading to clinical events ( 1 ). A variety of oxidation-specifi c epitopes (OSE) are generated during oxidative modifi cation of plaque components. These epitopes are not only expressed on modifi ed lipoproteins but also on apoptotic cells and proteins in the extracellular matrix of atherosclerotic vessels ( 2 ).Extensive experimental data exists defi ning the role of oxidation in both progression and regression of atherosclerosis. Atherosclerotic lesions of hypercholesterolemic animal models, which represent primarily early and intermediate stage atherosclerosis, contain signifi cant amounts of OSE, often in proportion to plaque burden. OSE in the vessel wall of atherosclerotic animals can also be imaged with nuclear and magnetic resonance techniques using murine and human oxidation-specifi c antibodies, such as MDA2, E06, and IK17 ( 3-5 ). Dietary interventions in hypercholesterolemic animals that promote regression result in more rapid removal of OSE than apoB, which occurs prior to plaques diminishing signifi cantly in size, and is associated with markers of plaque stabilization, such Abstract The relationships between oxidation-specifi c epitopes (OSE) and lipoprotein (a) [Lp(a)] and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophagerich areas, lipid pools, and the necrotic core, and they were most specifi cally associated with unstable and ruptured plaques. Specifi c OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic.

Objective To assess whether oxidized lipids are released downstream from obstructive plaques following percutaneous coronary and peripheral interventions using distal protection devices. Background Oxidation of lipoproteins generates multiple bioactive oxidized lipids that affect atherothrombosis and endothelial function. Direct evidence of their role during therapeutic procedures, which may result in no-reflow phenomenon, myocardial infarction and stroke, is lacking. Methods The presence of specific oxidized lipids was assessed in embolized material captured by distal protection filter devices during uncomplicated saphenous vein graft, carotid, renal, and superficial femoral artery interventions. The presence of oxidized phospholipids (OxPL) and oxidized cholesteryl esters (OxCE) was evaluated in 24 filters using liquid chromatography, tandem mass spectrometry, enzyme-linked immunosorbent assays (ELISA) and immunostaining. Results Phosphatidylcholine (PC)-containing OxPL (PC-OxPL), including PONPC [1-palmitoyl-2-(9-oxononanayl) PC], representing a major PC-OxPL molecule quantitated within plaque material, POVPC [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine] and PGPC (1-palmitoyl-2-glutaroyl-sn -glycero-3-phosphocholine) were identified in the extracted lipid portion from all vascular beds. Several species of OxCE, such as keto, hydroperoxide, hydroxy, and epoxy cholesterol ester derivatives from cholesteryl linoleate and cholesteryl arachidonate were also present. The presence of OxPL was confirmed using enzyme linked immunoassays and immunohistochemistry of captured material. Conclusion This study documents the direct release and capture of OxPL and OxCE during percutaneous interventions from multiple arterial beds in humans. Entrance of bioactive oxidized lipids into the microcirculation may mediate adverse clinical outcomes during therapeutic procedures.