Background-This study was performed to assess whether oxidized low-density lipoprotein (OxLDL) levels are elevated after percutaneous coronary intervention (PCI). Methods and Results-Patients (nϭ141) with stable angina pectoris undergoing PCI had serial venous blood samples drawn before PCI, after PCI, and at 6 and 24 hours, 3 days, 1 week, and 1, 3, and 6 months. Plasma levels of OxLDL-E06, a measure of oxidized phospholipid (OxPL) content on apolipoprotein B-100 detected by antibody E06, lipoprotein(a) [Lp(a)], autoantibodies to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL), and apolipoprotein B-100 -immune complexes (apoB-IC) were measured. OxLDL-E06 and Lp(a) levels significantly increased immediately after PCI by 36% (PϽ0.0001) and 64% (PϽ0.0001), respectively, and returned to baseline by 6 hours. In vitro immunoprecipitation of Lp(a) from selected plasma samples showed that almost all of the OxPL detected by E06 was bound to Lp(a) at all time points, except in the post-PCI sample, suggesting independent release and subsequent reassociation of OxPL with Lp(a) by 6 hours. Strong correlations were noted between OxLDL-E06 and Lp(a) (rϭ0.68, PϽ0.0001). MDA-LDL and Cu-OxLDL autoantibodies decreased, whereas apoB-IC levels increased after PCI, but both returned to baseline by 6 hours. Subsequently, IgM autoantibodies increased and peaked at 1 month and then returned to baseline, whereas IgG autoantibodies increased steadily over 6 months. Conclusions-PCI results in acute plasma increases of Lp(a) and OxPL and results in short-term and long-term immunologic responses to OxLDL. OxPL that are released or generated during PCI are transferred to Lp(a), suggesting that Lp(a) may contribute acutely to a protective innate immune response. In settings of enhanced oxidative stress and chronically elevated Lp(a) levels, the atherogenicity of Lp(a) may stem from its capacity as a carrier of proinflammatory oxidation byproducts.
Abstract-To determine whether labeled antibodies against oxidized LDL (OxLDL) offer advantages for quantifying atherosclerosis, we compared in vivo aortic uptake of 125 I-labeled MDA2, a monoclonal antibody against malondialdehyde-lysine epitopes), atherosclerotic surface area, and aortic weight in Watanabe heritable hyperlipidemic and New Zealand White rabbits and in low density lipoprotein receptor-deficient (LDLR Ϫ/Ϫ ) and apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Absolute and specific uptakes of 125 I-MDA2 were significantly greater in plaque than in normal aortas. Uptake of 125 I-MDA2 significantly correlated with aortic weight and percent atherosclerotic surface area in rabbits and mice. To assess whether 125 I-MDA2 uptake reflects changes in lesion content of OxLDL, in a separate study, extensive atherosclerosis was induced in 4 groups of LDLR Ϫ/Ϫ mice by feeding them a high fat/cholesterol diet for 6 months. A baseline group was euthanized at this time. The remaining groups were fed "regression" diets (chow or chowϩ1% vitamin Eϩ0.05% vitamin C) or the high fat/cholesterol diet for 6 more months. When atherosclerosis was measured as percent surface area or aortic weight, there was strong progression in the high fat/cholesterol group, moderate progression in the chow group, and no progression in the chowϩvitamin Eϩvitamin C group compared with the baseline group. The 125 I-MDA2 method also yielded a significant increase in atherosclerosis in the high fat/cholesterol group but significant decreases in the chow and chowϩvitamin Eϩvitamin C groups. Immunocytochemistry showed fewer oxidation-specific epitopes in lesions from the chow and chowϩvitamin Eϩvitamin C groups. Thus, the uptake of 125 I-MDA2 correlates well with traditional measures of atherosclerosis but also reflects reduced plaque OxLDL content after hypocholesterolemic intervention.
Objective-Labeled oxidation-specific antibodies (Ox-AB) detect, quantify, and noninvasively image lipid-rich atherosclerotic lesions. However, it is unknown whether Ox-AB detect plaque stabilization. Methods and Results-The aortic uptake of intravenously injected 125 I-MDA2 (Ox-AB to malondialdehyde [MDA]-lowdensity lipoprotein [LDL]) was quantitated in: (1) LDL receptorϪ/Ϫ mice with established atherosclerosis continued on Western diet (Progression) or switched to chow (Regression) or chowϩvitamins E and C (Regression-VIT) for 6 months; and (2) Watanabe rabbits (3-to 57-months old) with naturally evolved atherosclerotic lesions. In mice, the Progression group had more extensive atherosclerosis, higher 125 I-MDA2 uptake, high concordance of Sudan (lipid)-staining and 125 I-MDA2 uptake, and stronger oxidized LDL (OxLDL) and macrophage immunostaining than both Regression groups. In contrast, the Regression groups showed Sudan-positive lesions with focally diminished 125 I-MDA2 uptake, which coincided with reduced OxLDL and macrophages but more smooth muscle cells (SMCs) and collagen. In rabbits, areas of increased 125 I-MDA2 uptake were associated with high Sudan concordance and strong immunostaining for OxLDL and macrophages. Interestingly, advanced lesions with focally diminished 125 I-MDA2 uptake showed stronger immunostaining for SMCs and collagen, particularly at the fibrous cap. Several invasive and noninvasive techniques are being intensively evaluated for detection of such plaques. 5 OxLDL and oxidation-specific epitopes, which are relatively accessible targets, particularly when present in the form of large extracellular deposits in the lipid core, 6 -8 are rational targets for imaging and may serve as markers of plaque vulnerability. Conclusion-Ox-AB See page 2203We have shown previously that intravenously injected, radiolabeled oxidation-specific antibodies (Ox-AB), such as the murine monoclonal antibody (MAB) MDA2, which detects malondialdehyde (MDA)-lysine epitopes, have a strong and specific predilection for atherosclerotic lesions but not normal arteries. 9,10 Aortic uptake of 125 I-MDA2 is enhanced in lipid-rich lesions and reduced in lesions of LDL receptorϪ/Ϫ (LDLRϪ/Ϫ) mice on dietary/antioxidant diets. 10 99m Tc-labeled MDA2 noninvasively images atherosclerotic lesions in live animals. 9 However, it is unknown whether plaque uptake of radiolabeled Ox-AB may reflect the changes that occur when plaques become more stable, a property that would potentially enhance the utility of this imaging approach in patients at risk for plaque rupture. The present study therefore assessed the rela-
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