title: Longitudinal Association Between Endothelial Dysfunction, Inflammation, and Clotting Biomarkers With Subclinical Atherosclerosis in Type 1 Diabetes: An Evaluation of the DCCT/EDIC Cohort.
abstract: 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.
  
  
  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: acute-phase 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.
authors: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC Ralph H. Johnson VA Medical Center, Charleston, SC huntke@musc.edu.
authors: Kelly J
authors: KJ
authors: Hunt
authors: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.
authors: Nathaniel L
authors: NL
authors: Baker
authors: The Biostatistics Center, The George Washington University, Washington, DC.
authors: Patricia A
authors: PA
authors: Cleary
authors: Ralph H. Johnson VA Medical Center, Charleston, SC Department of Medicine and Laboratory Services, Medical University of South Carolina, Charleston, SC.
authors: Richard
authors: R
authors: Klein
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC.
authors: Gabriel
authors: G
authors: Virella
authors: Ralph H. Johnson VA Medical Center, Charleston, SC Department of Medicine and Laboratory Services, Medical University of South Carolina, Charleston, SC.
authors: Maria F
authors: MF
authors: Lopes-Virella
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism*; D001777:Blood Coagulation / Q000502:physiology; D002097:C-Reactive Protein / Q000378:metabolism; D059168:Carotid Intima-Media Thickness; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000175:diagnosis* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000097:blood / Q000175:diagnosis* / Q000503:physiopathology; D018450:Disease Progression; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019040:E-Selectin; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D002097:C-Reactive Protein