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We investigated whether the composition of modified forms of LDL in circulating immune complexes (LDL-ICs) was associated with cardiovascular disease (CVD) outcomes, including any CVD, major adverse cardiac and cerebrovascular events (MACCE), myocardial infarction (MI), and coronary artery disease, in type 1 diabetes (T1D). Our results demonstrate that the baseline levels of oxidized LDL (oxLDL), MDA-modified LDL (MDA-LDL), and advanced glycosylation-modified LDL (AGE-LDL) in circulating ICs were associated with the four CVD outcomes in unadjusted models, and adjustment by age and mean HbA1c only resulted in minimal reduction of these associations. After adjustments were made for other cardiovascular risk factors, particularly LDL cholesterol, oxLDL-IC and MDA-LDL-IC remained independently associated with the risk of CVD, and oxLDL-IC was independently associated with the risk of MACCE and MI. In the majority of cases, the baseline levels of modified LDL-IC (measured many years before the occurrence of any CVD event) were associated with the risk of CVD over a 25-year period even after adjustment for other risk factors (including LDL cholesterol). Therefore, modified LDL biomarkers may help identify patients with T1D at high risk for MACCE and CVD events very early in the evolution of the disease, before other signals of disease are apparent. [ABSTRACT FROM AUTHOR]

Objective: To determine whether biomarkers of inflammation and endothelial dysfunction are associated with the development of kidney dysfunction and the time frame of their association.Research Design and Methods: Biomarkers were measured at four time points during 28 years of treatment and follow-up in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. In addition to traditional biomarkers of inflammation (C-reactive protein and fibrinogen), we measured interleukin-6 (IL-6) and soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1/2), markers of endothelial dysfunction (soluble intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin [sE-selectin]), and fibrinolysis (total and active plasminogen activator inhibitor-1 [PAI-1]). Renal outcomes were defined as progression to incident chronic kidney disease (stage 3 or more severe) or macroalbuminuria (albumin excretion rate ≥300 mg/24 h). Prospective multivariate event-time analyses were used to determine the association of each biomarker with each subsequent event within prespecified intervals (3-year and 10-year windows).Results: Multivariate event-time models indicated that several markers of inflammation (sTNFR-1/2), endothelial dysfunction (sE-selectin), and clotting/fibrinolysis (fibrinogen and PAI-1) are significantly associated with subsequent development of kidney dysfunction. Although some markers showed variations in the associations between the follow-up windows examined, the results indicate that biomarkers (sTNFR-1/2, sE-selectin, PAI-1, and fibrinogen) are associated with progression to chronic kidney disease in both the 3-year and the 10-year windows.Conclusions: Plasma markers of inflammation, endothelial dysfunction, and clotting/fibrinolysis are associated with progression to kidney dysfunction in type 1 diabetes during both short-term and long-term follow-up. [ABSTRACT FROM AUTHOR]

OBJECTIVE There is considerable interest in identifying biomarkers that predict high risk for the development of macrovascular complications in patients with diabetes. Therefore, the longitudinal association between subclinical atherosclerosis as measured by internal carotid artery intima-media thickness (IMT) and acute-phase reactants, cytokines/adipokines, thrombosis, and adhesion molecules was examined. RESEARCH DESIGN AND METHODS Biomarkers were measured at four time points over 20 years in 886 DCCT/EDIC participants with type 1 diabetes. Four composite scores were created by combining z scores generated from within the data set of individual biomarkers: acutephase reactants (fibrinogen, C-reactive protein), thrombosis (fibrinogen, active and total plasminogen activator inhibitor [PAI]-1), cytokines/adipokines (tumor necrosis factor receptor-1 and -2, active and total PAI-1, IL-6), and endothelial dysfunction (soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble E-selectin). Internal carotid IMT was measured at EDIC years 1, 6, and 12, with elevated IMT defined at each time point as being in the upper quintile of its distribution. RESULTS Logistic regression models indicate that while individual biomarkers were not predictive of or associated with subclinical atherosclerosis, composite scores of acute-phase reactants (odds ratio [OR] 2.78 [95% CI 1.42, 5.42]), thrombolytic factors (OR 2.83 [95% CI 1.45, 5.52]), and cytokines/adipokines (OR 2.83 [95% CI 1.48, 5.41])measured at our final time point EDIC years 8-11 were associated with higher levels of atherosclerosis at EDIC year 12, but findings were not consistent at early time points. The endothelial dysfunction score was not appreciably predictive of or associated with subclinical atherosclerosis at any of the time points measured. CONCLUSIONS The pathophysiologic relationship between higher biomarker levels and progression of subclinical atherosclerosis remains unclear. [ABSTRACT FROM AUTHOR]

We have previously shown that high levels of oxidized LDL and AGE-LDL in circulating IC are strong predictors of atherosclerosis progression in 518 subjects with type 1 diabetes from the DCCT/EDIC cohort. In this study we investigated whether oxLDL, MDA-LDL and AGE-LDL in circulating IC measured in the same subjects at DCCT baseline were associated with acute CVD events. Three overlapping CVD outcomes were considered: any CVD events, major adverse cardiac and cerebrovascular events (MACE) and myocardial infarction (MI). Cox proportional hazards models assessed the association between IC biomarker values and the subsequent risk of CVD, using inverse probability weighting to obtain results representative of the full DCCT/EDIC cohort. Results: Levels of AGE-LDL, oxLDL and MDA-LDL in circulating IC, measured at baseline (Table) were significantly associated with the 3 CVD outcomes in unadjusted models and were minimally attenuated after adjustment for age and mean HbA1c. After adjustments for conventional CVD risk factors, including LDL-Chol, high levels of oxLDL-IC and MDA-LDL-IC remained independently associated with increased subsequent risk of any CVD, and higher oxLDL-IC with increased risk of MACE and MI events. Conclusions: High levels of oxLDL-IC measured more than one decade prior to the occurrence of CVD events identified patients at high risk, even after adjustment by LDL-C and conventional CVD risk factors. Disclosure: M.F. Lopes-Virella: None. I. Bebu: None. K.J. Hunt: None. G. Virella: None. N.L. Baker: None. B. Braffett: None. J. Lachin: Board Member; Self; Tolerion, Inc. Funding: National Institute of Diabetes and Digestive and Kidney Diseases [ABSTRACT FROM AUTHOR]

A response from the authors of the article "Baseline Markers of Inflammation Are Associated With Progression to Macroalbuminuria in Type 1 Diabetic Subjects" in the 2013 issue is presented.