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Objective: High cholesterol levels in circulating immune complexes (IC), surrogate markers of modified LDL, are associated with increased carotid intima-media thickness (IMT) and cardiovascular events in type 1 diabetes. Different modifications of LDL are involved in IC formation, but which of these are predictive of vascular events is not known. Therefore, we measured oxidized LDL (oxLDL), advanced glycation end products-modified LDL (AGE-LDL), and malondialdehyde-modified LDL (MDA-LDL) in IC and determined their relationship with increased carotid IMT and compared the strength of the association with that observed with conventional risk factors.Research Design and Methods: Levels of oxLDL, AGE-LDL, and MDA-LDL were measured in circulating IC isolated from sera of 479 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort, collected at baseline. Internal and common carotid IMT were measured 8 and 14 years later by DCCT/EDIC.Results: OxLDL, AGE-LDL, and MDA-LDL levels in circulating IC were significantly correlated with diabetes duration, BMI, and lipid and blood pressure, but not with age. Multivariate logistic regression models indicated that individuals in the highest versus lowest quartile of oxLDL and AGE-LDL in IC had a 6.11-fold [confidence interval (CI) 2.51-14.8] and a 6.4-fold (CI 2.53-16.2) increase in the odds of having high carotid IMT, respectively, after adjusting for conventional risk factors. Parallel analyses resulted in odds ratios of 2.62 (CI 1.24, 5.55) for LDL-C, 1.45 (CI 0.69, 3.03) for diastolic blood pressure, and 2.33 (CI 1.09, 4.99) for A1C.Conclusions: OxLDL and AGE-LDL in circulating IC were significantly associated with progression and increased levels of carotid IMT in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Oxidized LDL (oxLDL) and oxLDL antibodies form immune complexes (IC) that reflect essential components in the development of atherosclerosis: dyslipidemia, oxidative stress and induction of a pro-inflammatory humoral immune response. We measured oxLDL in IC (oxLDL-IC) isolated from patients with type 1 diabetes to assess the relationship between oxLDL-IC and coronary artery calcification (CAC). Methods: OxLDL was measured in IC isolated from baseline samples from a subgroup of 476 patients of the Diabetes Control and Complications Trial (DCCT). CAC was determined by computed tomography (CT) 11–20 years later. Multivariable log-binomial regression models were used to estimate the risk ratios associated with having a high CAC score with an increase of 1 standard deviation (SD) of the natural logarithm of oxLDL-IC. Results: Multivariable regression models indicate that a 1 SD increase in the levels of oxLDL-IC was associated with a 37% increase in the risk of having high CAC score (RR=1.36; 95% CI: 1.12–1.67) at follow-up after adjustment for DCCT treatment group, retinopathy/AER groups, gender and CT scanning site as well as baseline age, diabetes duration and HbA1C %. Further adjustment for smoking status, blood pressure and LDL resulted in a risk ratio of 1.23 (95% CI: 1.01–1.50) which remained statistically significant indicating that baseline oxLDL-IC is independently associated with the development of CAC. Discussion: Increased levels of oxLDL-IC are associated with the development of coronary calcification. This observation reinforces previously published clinical and experimental data demonstrating that oxLD-IC has pro-inflammatory and proatherogenic properties. [Copyright &y& Elsevier]

We investigated the hypothesis that modified lipoproteins trigger an immune response leading to the production of autoantibodies and subsequently to the formation of atherogenic immune complexes (IC). We recruited 20 type 2 diabetic patients with macrovascular disease, 14 nondiabetic patients with coronary artery disease (CAD), and 34 healthy control subjects matched for age, sex, and race. Serum antibodies to oxidized and glycated LDL did not differ significantly among the 3 groups. Serum IC contained variable, but not statistically different, amounts of IgG, IgM, and IgA. In contrast, the content of cholesterol in IC isolated from diabetic patients was significantly higher than that in IC isolated from control subjects, and the content of apolipoprotein (apo)-B was significantly higher than that in IC isolated from control subjects and patients with CAD. Cholesteryl ester accumulation in human monocyte-derived macrophages incubated with IC, a measure of the atherogenic potential of IC, was significantly higher in macrophages incubated with red blood cell-adsorbed IC isolated from diabetic patients compared with IC isolated from control subjects (P < 0.03) or from patients with CAD (P < 0.04) and was strongly correlated with the content of apoB (r = 0.68, P < 0.001) and cholesterol (r = 0.61, P < 0.001) in IC. LDL from diabetic patients was more susceptible to oxidation in vitro, was significantly smaller, and contained significantly less alpha-tocopherol than LDL isolated from subjects in the other groups. In addition, the n-3 polyunsaturated fatty acid content of phospholipids and cholesteryl esters in LDL isolated from diabetic patients was significantly increased (P < 0.05) compared with that from patients with CAD or from control subjects. We postulate that LDL size, susceptibility to oxidation, and lipid fatty acid composition may play a critical role in the production of antibodies to oxidized LDL and consequently in the formation of LDL-containing IC in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]