Stepwise increase of angiopoietin-2 serum levels is related to haemodynamic and functional impairment in stable chronic heart failure

Background: A reciprocal link between inflammation, oxidative/nitrosative stress, and endothelial dysfunction has been postulated in chronic heart failure (CHF). The endothelial repair mechanisms involved remain to be determined. Our aim was to investigate whether there are detectable signs of ongoing angiogenesis in serum of CHF patients and to evaluate the correlation with indexes of haemodynamic and functional impairment. Methods and results: Enzyme-linked immunosorbent assay tests were used to quantify angiogenin, angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, Tie-2, and brain natriuretic peptide in serum of 87 patients with CHF of increasing severity according to New York Heart Association (NYHA; class I, n=8; II, n=45; and III, n=34) and in 14 healthy subjects matched for age and sex. Angiogenin, angiopoietin-2, and Tie-2 were significantly increased in CHF of increasing severity (Kruskal Wallis: p=0.0004, p < 0.0001, and p=0.017, respectively). Angiopoietin-2 was inversely correlated with the 6-min walking test (r=0.65, p < 0.0001), peak oxygen consumption (VO2max; r=-0.57, p=0.0002), and deceleration time (r=-0.61, p < 0.0001). Multiple regression analysis showed that angiopoietin-2 was mainly associated with VO2max (p=0.018). The angiopoietin-2 area under the receiver operating characteristic curve for CHF diagnosis was 0.94 (95% CI 0.88-0.99; p < 0.001). Conclusions: These data demonstrate that angiopoietin-2 and selected serum markers of angiogenesis progressively increase with haemodynamic and functional decline in CHF.