title: Impact of soluble TWEAK and CD163/TWEAK ratio on long-term cardiovascular mortality in patients with peripheral arterial disease.
abstract: OBJECTIVE
  Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has recently been introduced as a potential mediator of cardiovascular disease. We examined the associations between sTWEAK, its scavenger receptor sCD163, sCD163/sTWEAK ratio and risk for long-term all-cause and cardiovascular mortality in patients with lower-extremity peripheral arterial disease (PAD).
  
  
  METHODS
  sTWEAK and sCD163 serum levels were measured retrospectively in a cohort of 295 patients with symptomatic PAD followed for 6.1±2.1 years. The endpoints were defined as all-cause or cardiovascular death. The relationship between sTWEAK, sCD163 levels, sCD163/sTWEAK ratio, and times to fatal outcome was examined by Cox proportional hazards analysis.
  
  
  RESULTS
  sTWEAK levels were significantly lower (672 (IQR 515; 872)pg/ml vs. 814 (IQR 673; 957)pg/ml, p < 0.0001), and sCD163/sTWEAK ratio significantly higher (0.91 (IQR 0.63; 1.37) vs. 0.77 (IQR 0.55; 1.12), p = 0.008) in patients with critical limb ischemia (CLI) on admission as compared with those with intermittent claudication (IC). During follow-up, 80 (27%) patients died, hereof 33 (11.5%) of cardiovascular causes. Cox regression analysis revealed that an increase of 100 pg/ml of baseline sTWEAK were associated with a decreased risk for all cause [adjusted hazard ratio (HR) 0.89 (95%CI (0.80-0.99)), p = 0.043] and cardiovascular mortality [adjusted HR 0.83 (95% CI (0.69-0.99)), p = 0.038]. The patients with lower sTWEAK concentrations had a higher risk for cardiovascular death being more than two times as great as patients in the two upper tertiles (adjusted HR 2.2, 95% CI (1.06-4.87), p = 0.035). Similarly, the risk of cardiovascular death was 3-fold increased for patients in the upper tertile of sCD163/sTWEAK ratio as comparing with the patients in two lower tertiles (adjusted HR 3.04, 95% CI (1.44-6.43), p = 0.004). The model including sCD163/sTWEAK ratio have shown a significant improvement in accuracy of cardiovascular death prediction (the area under ROC curve 0.79 (0.72-0.86) vs. 0.84 (0.78-0.90), p = 0.019).
  
  
  CONCLUSIONS
  Decreased sTWEAK concentration, and increased sCD163/sTWEAK ratio were significantly and independently associated with long-term cardiovascular mortality in patients with lower-extremity PAD.
authors.affiliation: Vascular Research Unit, Department of Vascular Surgery, Viborg Hospital, Heibergs Allé 4, DK-8800 Viborg, Denmark. Grazina.urbonaviciene@sun.au.dk
authors.forename: Grazina
authors.initials: G
authors.lastname: Urbonaviciene
authors.forename: Jose L
authors.initials: JL
authors.lastname: Martin-Ventura
authors.forename: Jes S
authors.initials: JS
authors.lastname: Lindholt
authors.forename: Sigitas
authors.initials: S
authors.lastname: Urbonavicius
authors.forename: Juan A
authors.initials: JA
authors.lastname: Moreno
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Luis M
authors.initials: LM
authors.lastname: Blanco-Colio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000097:blood*; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000209:etiology / Q000401:mortality*; D016009:Chi-Square Distribution; D000074049:Cytokine TWEAK; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006801:Humans; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000150:complications / Q000401:mortality*; D016016:Proportional Hazards Models; D011956:Receptors, Cell Surface / Q000097:blood*; D012044:Regression Analysis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000097:blood*; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D000098902:CD163 Antigen; D000074049:Cytokine TWEAK; D011956:Receptors, Cell Surface; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors