title: Extracellular vesicle-derived CD14 is independently associated with the extent of cardiovascular disease burden in patients with manifest vascular disease.
abstract: BACKGROUND
  In patients with established cardiovascular disease, high levels of the extracellular vesicle (EV)-derived proteins cystatin C, CD14, and α2-antiplasmin predict recurrent cardiovascular events. We examined whether these proteins are associated with the extent of vascular disease.
  
  
  METHODS
  In 1062 patients from the SMART (Secondary Manifestations in ARTerial disease) study, EVs were isolated from plasma at baseline. Cystatin C, CD14, and α2-antiplasmin were measured in these vesicles using a multiplex assay. The extent of vascular disease burden was determined by a sum score that incorporates history and current presence of clinically manifest coronary, cerebrovascular, peripheral arterial, and abdominal aneurysm disease, and parameters of atherosclerosis that were assessed during the SMART screening protocol (ankle-brachial index, common carotid intima-media thickness, carotid stenosis, and aorta diameter). The relation between EV protein levels and extent of vascular disease was evaluated using ordinal multivariable regression models.
  
  
  RESULTS
  EV-derived CD14 was significantly associated with the number of affected vascular territories (OR 2.4, 95% CI 1.4-4.1) as represented by the sum score, independently of cardiovascular risk factors. Cystatin C and α2-antiplasmin EV levels did not show an independent association with vascular disease extent. When investigating parameters of the sum score separately, we did not observe a strong association between any of the EV-derived proteins and the markers of atherosclerosis.
  
  
  CONCLUSIONS
  EV-derived CD14 levels are strongly correlated to the extent of vascular disease, but not specifically to markers that reflect atherosclerosis burden, in patients with manifest cardiovascular disease.
authors.affiliation: University Medical Center, Utrecht, The Netherlands Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands jvrijenh@umcutrecht.nl.
authors.forename: Joyce E P
authors.initials: JE
authors.lastname: Vrijenhoek
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Frans L
authors.initials: FL
authors.lastname: Moll
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: de Borst
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Michiel L
authors.initials: ML
authors.lastname: Bots
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Louise
authors.initials: L
authors.lastname: Catanzariti
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Sander M
authors.initials: SM
authors.lastname: van de Weg
authors.affiliation: University Medical Center, Utrecht, The Netherlands Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands National University Hospital, Singapore.
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Frank L J
authors.initials: FL
authors.lastname: Visseren
authors.affiliation: University Medical Center, Utrecht, The Netherlands.
authors.forename: Hester M Den
authors.initials: HM
authors.lastname: Ruijter
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis*; D003430:Cross-Sectional Studies; D055316:Cystatin C / Q000097:blood; D000067128:Extracellular Vesicles / Q000737:chemistry*; D005260:Female; D006801:Humans; D016014:Linear Models; D018950:Lipopolysaccharide Receptors / Q000097:blood*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D011237:Predictive Value of Tests; D012307:Risk Factors; D012720:Severity of Illness Index; D000979:alpha-2-Antiplasmin / Q000032:analysis
chemical_list: D015415:Biomarkers; C525030:CST3 protein, human; D055316:Cystatin C; D018950:Lipopolysaccharide Receptors; D000979:alpha-2-Antiplasmin
keywords: Atherosclerosis; biomarkers; peripheral vascular diseases; protein