Sex Differences in the Association between Vascular Endothelial Growth Factor D and Mortality in Patients With Suspected or Known Coronary Artery Disease: The ANOX Study

Background: Vascular endothelial growth factor D (VEGF-D) is a secreted glycoprotein that can promote lymphangiogenesis and angiogenesis. We previously demonstrated that serum levels of VEGF-D are associated with all-cause mortality in patients with suspected or known coronary artery disease (CAD). However, sex differences in the associations of VEGF-D with all-cause and cause-specific mortality in those patients are unclear. Methods: Serum levels of VEGF-D were measured in 2,418 patients (1,624 men and 794 women) with suspected or known CAD. The outcomes were all-cause death, cardiovascular (CV) death, non-CV death, cancer death, and other non-CV death. Patients were followed up over a 6-year period. Results: During the follow-up, 391 men and 145 women died of any cause, 120 men and 46 women died of CV diseases, 241 men and 85 women died of non-CV diseases, 102 men and 26 women died of cancer, and 139 men and 59 women died of other non-CV diseases. After adjustment for potential clinical confounders and established CV biomarkers (i.e., N-terminal pro-brain natriuretic peptide, high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein), log-transformed (Ln-) VEGF-D levels were significantly associated with all-cause death (adjusted hazard ratio [aHR] for 1-SD increase, 1.42; 95% confidence interval [CI], 1.10–1.86), non-CV death (aHR, 1.60; 95% CI, 1.15–2.28), and other non-CV death (aHR, 2.00; 95% CI, 1.31–3.09), but not with CV death (aHR, 1.21; 95% CI, 0.75–2.05) or cancer death (aHR, 1.15; 95% CI, 0.71–2.14), in women; and not significantly associated with all-cause death (aHR, 0.94; 95% CI, 0.83–1.06), CV death (aHR, 0.92; 95% CI, 0.73–1.17), non-CV death (aHR, 0.91; 95% CI, 0.78–1.05), cancer death (aHR, 0.89; 95% CI, 0.71–1.12), or other non-CV death (aHR, 0.90; 95% CI, 0.74–1.08), in men. The addition of Ln-VEGF-D to the model with potential clinical confounders and established CV biomarkers significantly improved the prediction of all-cause death (continuous net reclassification improvement, 0.184; 95% CI, 0.005–0.362; P=0.045; integrated discrimination improvement, 0.012; 95% CI, 0.003–0.022; P=0.012), but not that of CV death, non-CV death, cancer death, or other non-CV death, in women, while Ln-VEGF-D did not significantly improve the prediction of any outcomes in men. Conclusions: In patients with suspected or known CAD, serum levels of VEGF-D significantly predicted all-cause mortality in women, but not in men.