VEGF-D plasma levels and VEGFD genetic variants are independently associated with outcomes in patients with cardiovascular disease.

AIMS: The vascular endothelial growth factor (VEGF) family is involved in pathophysiological mechanisms underlying cardio vascular (CV) diseases. The aim of this study was to investigate the associations between circulating VEGF ligands and/or soluble receptors and CV outcome in patients with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS).

METHODS AND RESULTS: Levels of VEGF biomarkers, including bFGF, Flt-1, KDR (VEGFR2), PlGF, Tie-2, VEGF-A, VEGF-C, and VEGF-D, were measured in the PLATO ACS cohort (n = 2,091, discovery cohort). Subsequently, VEGF-D was also measured in the STABILITY CCS cohort (n = 4,015, confirmation cohort) to verify associations with CV outcomes. Associations between plasma VEGF-D and outcomes were analyzed by multiple Cox regression models with hazard ratios (HR [95% CI]) comparing the upper versus the lower quartile of VEGF-D. GWAS of VEGF-D in PLATO identified SNPs that were used as genetic instruments in Mendelian randomization (MR) meta-analyses versus clinical endpoints. GWAS and MR was performed in patients with ACS from PLATO (n = 10,013) and FRISC-II (n = 2,952), and with CCS from the STABILITY trial (n = 10,786). VEGF-D, KDR, Flt-1, and PlGF showed significant association with CV outcomes. VEGF-D was most strongly associated with CV death (p = 3.73e-05, HR 1.892 [1.419, 2.522]). Genome wide significant associations with VEGF-D levels were identified at the VEGFD locus on chromosome Xp22. MR analyses of the combined top ranked SNPs (GWAS p-values; rs192812042, p = 5.82e-20; rs234500, p = 1.97e-14) demonstrated a significant effect on CV mortality (p = 0.0257, HR 1.81 [1.07, 3.04] per increase of one unit in log VEGF-D).

CONCLUSION: This is the first large-scale cohort study to demonstrate that both VEGF-D plasma levels and VEGFD genetic variants are independently associated with CV outcomes in patients with ACS and CCS. Measurements of VEGF-D levels and/or VEGFD genetic variants may provide incremental prognostic information in patients with ACS and CCS.