Impact of soluble TWEAK and CD163/TWEAK ratio on long-term cardiovascular mortality in patients with peripheral arterial disease

Aim: 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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.