Vascular endothelial growth factors A and D as independent prognostic factors in acute coronary syndrome patients

Introduction Acute coronary syndrome (ACS) often results from atherosclerotic plaque rupture, causing thrombotic coronary occlusion and myocardial ischaemia. The VEGF family promotes post-ischaemic repair via angiogenesis and vascular homeostasis. VEGF-A, upregulated by hypoxia (HIF-1α), inflammation, and stress, acts via VEGFR-1/2 to drive beneficial neovascularization but also increases permeability, potentially contributing to maladaptive remodelling. VEGF-D supports angiogenesis (VEGFR-2) and lymphangiogenesis (VEGFR-3), with emerging yet limited clinical relevance in ACS. Purpose Vascular endothelial growth factor (VEGF)-A and VEGF-D have distinct roles in angiogenesis and lymphangiogenesis. We investigated their associations with cardiac recovery and prognosis in the acute and sub-acute period after an acute coronary syndrome (ACS). Methods We measured baseline plasma VEGF-A and VEGF-D within 24 hours of admission in a prospective cohort of 525 ACS patients and repeated the measurements six weeks later in a follow-up subgroup (n = 117). Incident major adverse cardiovascular events (MACE), heart failure (HF) and all-cause mortality were followed via national registries. Echocardiography was performed at 1-year post-ACS in the follow-up subgroup. Results During a median follow-up of 25.8–39.5 months, 87 patients experienced MACE, 41 were hospitalised for HF, and 63 died. In Cox regression analyses adjusted for clinical parameters, baseline VEGF-A was independently associated with incident MACE (HR per 1-SD increase 1.46, 95 % CI 1.14–1.89, p = 0.030), HF (HR 1.74, 95% CI 1.18–2.58, p = 0.006), and mortality (HR 1.33, 95% CI 1.004–1.77, p = 0.047). Baseline VEGF-D showed no associations with the outcomes. In contrast, follow-up VEGF-D was associated with HF independently of all considered confounders (HR 2.22 per 1-SD increase, 95 % CI 1.07–4.58, p = 0.032). Baseline VEGF-A was identified as the strongest independent predictive biomarker at baseline for all outcomes and follow-up VEGF-D was the strongest biomarker for HF, in Cox proportional regression models including TnT and NT-proBNP. In ROC analyses, addition of baseline VEGF-A and follow-up VEGF-D to clinical parameters improved outcome discrimination. In the follow-up subgroup, higher baseline VEGF-A and higher six-week VEGF-D were correlated with lower LVEF at 1-year, supporting the associations between biomarkers and HF. Further, among the 44 patients discharged with an LVEF >50% and no prevalent HF, elevated baseline VEGF-A independently predicted LVEF decline (defined as >5% absolute decrease) (OR 2.65 per 1-SD increase, 95 % CI 1.06–6.64, p = 0.038). Conclusion VEGF-A and VEGF-D have distinct and complementary predictive values in the acute and sub-acute periods post-ACS. Our study identifies baseline VEGF-A as a strong independent predictor of negative prognosis and follow-up VEGF-D as a potential candidate biomarker to identify patients at high risk for HF.