Lymphangiogenic factors and all-cause and cause-specific mortality and impact of chronic kidney disease on them in patients with suspected or known coronary artery disease: The EXCEED-J Study

Background The lymphangiogenic factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, are secreted glycoproteins that exhibit structural homology, but have differential receptor binding and regulatory mechanisms. We have demonstrated that serum levels of VEGF-C are inversely, and those of VEGF-D are positively associated with all-cause mortality in patients with suspected or known coronary artery disease (CAD). However, these associations need to be confirmed in other cohort studies, and the associations of VEGF-C and VEGF-D with cause-specific mortality, and impact of chronic kidney disease (CKD) on these associations are unknown. Methods Serum levels of VEGF-C and VEGF-D were measured in 3,255 patients with suspected or known CAD enrolled in the EXCEED-J Study. The outcomes were all-cause death, cardiovascular (CV) death, cancer death, and other non-CV death. Patients were followed up for 6 years. Results During the follow-up, 518 (15.9%) deaths occurred, including 169 (5.2%) CV deaths, 117 (3.6%) cancer deaths, 170 (5.2%) other non-CV deaths, and 60 (1.8%) undetermined deaths. After adjustment for clinical confounders and CV biomarkers, VEGF-C levels were significantly and inversely associated with all-cause death (hazard ratio [HR] for 1-SD increase, 0.88; 95% confidence interval [CI], 0.79–0.97) and other non-CV death (HR, 0.79; 95% CI, 0.66–0.95) in the entire cohort, and all-cause death (HR, 0.86; 95% CI, 0.75–0.98) and other non-CV death (HR, 0.76; 95% CI, 0.60–0.95) in patients with CKD, but not significantly associated with any outcomes in patients without CKD; whereas log-transformed (Ln-) VEGF-D levels were significantly associated with all-cause death (HR, 1.20; 95% CI, 1.09–1.32), cancer death (HR, 1.29; 95% CI, 1.05–1.58), and other non-CV death (HR, 1.23; 95% CI, 1.04–1.45) in the entire cohort, all-cause death (HR, 1.13; 95% CI, 1.00–1.27) in patients with CKD, and all-cause death (HR, 1.26; 95% CI, 1.08–1.47) and cancer death (HR, 1.44; 95% CI, 1.08–1.91) in patients without CKD. Among the outcomes significantly associated with VEGF-C or Ln-VEGF-D above, the addition of VEGF-C to the model with clinical confounders and CV biomarkers further improved the prediction of all-cause death in the entire cohort, and the addition of Ln-VEGF-D further improved the prediction of all-cause death in the entire cohort, and all-cause death and cancer death in patients without CKD (P<0.05 for both continuous net reclassification improvement and integrated discrimination improvement for all comparisons). The addition of either VEGF-C or Ln-VEGF-D did not further improve the prediction of any outcomes in patients with CKD. Conclusions The VEGF-C level independently and inversely predicted all-cause mortality, and the VEGF-D level independently predicted all-cause and cancer mortality in patients with suspected or known CAD. These predictive abilities of lymphangiogenic factors were attenuated in the presence of CKD.