title: Markers of inflammation and endothelial dysfunction are associated with incident cardiovascular disease, all-cause mortality, and progression of coronary calcification in type 2 diabetic patients with microalbuminuria.
abstract: BACKGROUND
  We evaluated markers of inflammation and endothelial dysfunction and their associations with incident cardiovascular disease (CVD), all-cause mortality and progression of coronary artery calcium (CAC) in patients with type 2 diabetes (T2D) and microalbuminuria but without known coronary artery disease (CAD).
  
  
  METHODS
  Prospective study including 200 patients receiving multifactorial treatment. Markers of inflammation (TNF-ɑ, sICAM-1, sICAM-3, hsCRP, SAA, IL-1β, IL-6, IL-8) and endothelial dysfunction (thrombomodulin, sVCAM-1, sICAM-1, sICAM-3, sE-selectin, sP-selectin) were measured at baseline. Adjustment included traditional CVD risk factors, and full adjustment additionally NT-proBNP and CAC. The "SQRT method" assessed CAC progression after 5.8years, and cut-point was an annualised difference >2.5.
  
  
  RESULTS
  Occurrence of CVD (n=40) and all-cause mortality (n=26) was traced after 6.1years. In adjusted and fully adjusted Cox models, TNF-ɑ was a determinant of CVD and all-cause mortality (p≤0.007). Further, in adjusted and fully adjusted logistic regression, TNF-ɑ was related to CAC progression (p≤0.042). Of the other biomarkers, sICAM-3 and thrombomodulin were also associated with both endpoints (p≤0.046), IL-1β with CVD endpoints (p=0.021), and sVCAM-1 and sICAM-1 with all-cause mortality (p≤0.005). Higher composite z-scores including all markers of inflammation and endothelial dysfunction were associated with CVD and all-cause mortality (p≤0.008).
  
  
  CONCLUSIONS
  In patients with T2D and microalbuminuria without known CAD and receiving multifactorial treatment, biomarkers of inflammation and endothelial dysfunction were independently associated with CVD, all-cause mortality and CAC progression. Especially TNF-ɑ was a robust determinant, even after adjusting for NT-proBNP and CAC.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark. Electronic address: bjos@steno.dk.
authors.forename: Bernt Johan
authors.initials: BJ
authors.lastname: von Scholten
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Reinhard
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Tine Willum
authors.initials: TW
authors.lastname: Hansen
authors.affiliation: Department of Internal Medicine and Cardiovascular Research Institute (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Department of Internal Medicine and Cardiovascular Research Institute (CARIM), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: Stehouwer
authors.affiliation: Rigshospitalet, Copenhagen, Denmark; University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: The Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter Karl
authors.initials: PK
authors.lastname: Jacobsen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark; University of Copenhagen, Copenhagen, Denmark; Aarhus University, Aarhus, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000097:blood / Q000150:complications / Q000401:mortality / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood*; D002318:Cardiovascular Diseases / Q000097:blood / Q000150:complications / Q000453:epidemiology* / Q000503:physiopathology; D002423:Cause of Death; D003327:Coronary Disease / Q000097:blood / Q000150:complications / Q000453:epidemiology* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000401:mortality* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000097:blood / Q000401:mortality; D003928:Diabetic Nephropathies / Q000097:blood / Q000150:complications / Q000401:mortality* / Q000503:physiopathology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000097:blood* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D061205:Vascular Calcification / Q000097:blood / Q000150:complications / Q000453:epidemiology* / Q000473:pathology
chemical_list: D015415:Biomarkers
keywords: Cardiovascular disease; Coronary artery calcium score; Markers of inflammation; Microalbuminuria; TNF-alpha; Type 2 diabetes