P1645Vascular endothelial growth factor-D and mortality in suspected or known coronary heart disease patients with a history of heart failure: a subanalysis of the ANOX study

Abstract

Abstract Background Vascular endothelial growth factor-D (VEGF-D) is a secreted glycoprotein that can act as lymphangiogenic and angiogenic growth factors through binding to its specific receptors, VEGFR-3 (Flt-4) and VEGFR-2 (KDR/Flk-1). VEGF-D signaling via VEGFR-3 plays an important role in lipoprotein metabolisms which may contribute to coronary heart disease (CHD). Recent studies suggest that VEGF-D appears to be a biomarker of pulmonary congestion and heart failure in both dyspnea patients and the general population. However, the prognostic value of VEGF-D in suspected or known CHD patients with a history of heart failure is unknown. Methods Serum VEGF-D levels were measured in 253 suspected or known CHD patients with a history of heart failure undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Results During the follow-up, 54 patients died from any cause, 24 died from cardiovascular disease, and 35 developed MACE. After adjustment for established risk factors, VEGF-D levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.44; 95% confidence interval [CI], 1.18–1.75), cardiovascular death (HR, 1.73; 95% CI, 1.32–2.25), and MACE (HR, 1.49; 95% CI, 1.14–1.89). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of VEGF-D levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.471; 95% CI, 0.176–0.766; P=0.002; integrated discrimination improvement [IDI], 0.036; 95% CI, 0.008–0.064; P=0.011) and cardiovascular death (NRI, 0.722; 95% CI, 0.326–1.118; P<0.001; IDI, 0.063; 95% CI, 0.005–0.122; P=0.033), but not that of MACE (NRI, 0.453; 95% CI, 0.100–0.805; P=0.012; IDI, 0.028; 95% CI, −0.007–0.063; P=0.116). Conclusions In suspected or known CHD patients with a history of heart failure undergoing elective coronary angiography, elevated VEGF-D levels may predict all-cause and cardiovascular mortality independent of established risk factors and cardiovascular biomarkers. Acknowledgement/Funding The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.