title: Prevalence of subclinical atherosclerosis is increased in systemic sclerosis and is associated with serum proteins: a cross-sectional, controlled study of carotid ultrasound.
abstract: OBJECTIVE
  SSc is associated with an increased prevalence of atherosclerosis (ATS). This study assessed the prevalence of subclinical ATS as measured by carotid US and explored serum proteins to identify potential biomarkers of SSc-ATS.
  
  
  METHODS
  Forty-six SSc female patients and 46 age- and ethnicity-matched controls underwent carotid US to assess the presence of plaque and carotid intima media thickness (CIMT). Abstracted data included demographics, ATS risk factors and serum measurements [cholesterol, proinflammatory high-density lipoprotein (piHDL), CRP, lipoproteins]. Serum cytokines/proteins analyses included circulating type I IFN activity by quantifying IFN-inducible genes, soluble junctional adhesion molecule A (sJAM-A) and 100 serum proteins by using a microplate-based multiplex platform. Proteins significant at P < 0.05 on bivariate analyses for the presence of plaque were used to develop a composite measure.
  
  
  RESULTS
  Patients with SSc had more plaque (45.6% vs 19.5%, P = 0.01) but similar CIMT compared with controls. Multiplex analysis detected significant associations between serum proteins of inflammation, vasculopathy and fibrosis with ATS in SSc, including IL-2, IL-6, CRP, keratinocyte growth factor, intercellular adhesion molecule 1, endoglin, plasminogen activator inhibitor 1 and insulin-like growth factor binding protein 3 associated with carotid plaque. Myeloid progenitor inhibitory factor 1, serum amyloid A, thrombomodulin, N-terminal pro-brain natriuretic peptide (BNP), and Clara cell secretory protein 16 kD correlated with CIMT. The median composite score for the plaque group was 6 and for the no plaque group it was 2 (P < 0.0001).
  
  
  CONCLUSIONS
  Patients with SSc have a higher prevalence of carotid plaque than matched controls, and patients with SSc-plaque vs patients without plaque have elevated serum proteins implicated in both vasculopathy and fibrosis. Further studies are needed to evaluate the role of these proteins in SSc compared with healthy controls.
authors.affiliation: Division of Rheumatology/Department of Internal Medicine, University of Michigan Scleroderma Program, Suite 7C27, 300 North Ingalls Street, SPC 5422, Ann Arbor, MI 48109, USA. khannad@med.umich.edu.
authors.forename: Elena
authors.initials: E
authors.lastname: Schiopu
authors.forename: Karen M
authors.initials: KM
authors.lastname: Au
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McMahon
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
authors.forename: Anagha
authors.initials: A
authors.lastname: Divekar
authors.forename: Ram R
authors.initials: RR
authors.lastname: Singh
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Furst
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Clements
authors.forename: Nagesh
authors.initials: N
authors.lastname: Ragvendra
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.forename: Paul
authors.initials: P
authors.lastname: Maranian
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood; D058070:Asymptomatic Diseases; D015415:Biomarkers; D002097:C-Reactive Protein / Q000378:metabolism; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002340:Carotid Artery Diseases / Q000097:blood / Q000150:complications* / Q000000981:diagnostic imaging; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D019742:Chemokines, CC / Q000097:blood; D003430:Cross-Sectional Studies; D000071063:Endoglin; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000097:blood; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000150:complications* / Q000000981:diagnostic imaging; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011956:Receptors, Cell Surface / Q000097:blood; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000097:blood / Q000150:complications* / Q000000981:diagnostic imaging; D000685:Serum Amyloid A Protein; D018180:Thrombomodulin / Q000097:blood; D014598:Uteroglobin / Q000097:blood
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C105504:CCL23 protein, human; D019742:Chemokines, CC; C064206:ENG protein, human; D000071063:Endoglin; C496453:FGF7 protein, human; C573420:ICAM1 protein, human; C515497:IGFBP3 protein, human; C508594:IL2 protein, human; C508600:IL6 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D007376:Interleukin-2; D015850:Interleukin-6; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D000685:Serum Amyloid A Protein; C546931:THBD protein, human; D018180:Thrombomodulin; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D051523:Fibroblast Growth Factor 7; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein; D014598:Uteroglobin
keywords: atherosclerosis; carotid intima media thickness; endothelial dysfunction; serum proteins; systemic sclerosis; type I interferon