Abstract
Background
Diabetes is a risk factor for coronary heart disease (CHD), but further risk stratification in patients with diabetes is necessary to improve the prediction and prevention of cardiovascular events and deaths. 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 CHD. VEGF-D signaling has been used as a therapeutic target of human diseases such as lymphangioleiomyomatosis and refractory angina. Furthermore, in clinical settings, the VEGF-D level is already established as a diagnostic biomarker for lymphangioleiomyomatosis. However, the prognostic value of VEGF-D in suspected or known CHD patients with diabetes is unknown.
Methods
Serum VEGF-D levels were measured in 1,087 suspected or known CHD patients with diabetes 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, 147 patients died from any cause, 47 died from cardiovascular disease, and 94 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, 1.34; 95% confidence interval [CI], 1.21–1.47), cardiovascular death (HR, 1.40; 95% CI, 1.18–1.62), and MACE (HR, 1.22; 95% CI, 1.07–1.40). 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], 0.258; 95% CI, 0.088–0.429; P=0.003; integrated discrimination improvement [IDI], 0.013; 95% CI, 0.002–0.024; P=0.022), but not that of cardiovascular death (NRI, 0.046; 95% CI, −0.245–0.336; P=0.759; IDI, 0.013; 95% CI, −0.005–0.031; P=0.146) or MACE (NRI, 0.064; 95% CI, −0.146–0.274; P=0.552; IDI, 0.001; 95% CI, −0.002–0.004; P=0.557).
Conclusions
In suspected or known CHD patients with diabetes undergoing elective coronary angiography, elevated VEGF-D levels may predict all-cause 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
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