Abstract 12898: Serum Vascular Endothelial Growth Factor-C Levels are Inversely Associated With Major Adverse Cardiovascular Events in Patients With Arteriosclerotic Obliterans

Abstract

Background: Vascular endothelial growth factor-C (VEGF-C), a homologue of VEGF family, plays a key role in lymphangiogenesis. Recently, we demonstrated that VEGF-C is closely associated with dyslipidemia and atherosclerosis. However, the relationship between serum VEGF-C levels and cardiovascular events in patients with atherosclerotic disease is unknown. Methods and Results: We performed a prospective cohort study involving a total of 209 patients with arteriosclerotic obliterans (ASO) (age, 73±8 y [SD]; male, 75%; hypertension, 88%; diabetes, 69%; dyslipidemia, 72%; history of smoking, 76%; Fontaine class, 2.1±0.8). Serum levels of VEGF-C, VEGF-A and high-sensitivity C-reactive protein (hsCRP) were determined employing specific enzyme-linked immunosorbent assays. The primary outcome was major adverse cardiac events (MACEs) defined as all-cause mortality, hospitalization due to acute coronary syndrome, stroke, congestive heart failure, aortic disease, and coronary/peripheral revascularization. Patients were followed up over a 4 year period. The median follow-up was 484 (IQR, 220-955) days. During the follow-up period, MACEs developed in a total of 86 patients (41.1 %). Patients were divided into two groups based on the median of each biomarker. In Kaplan-Meier analyses, low-VEGF-C (P=0.014, by log-rank test), but not high-hsCRP or high-VEGF-A, was significantly associated with MACEs. Multivariate Cox proportional hazard analyses revealed that serum levels of VEGF-C (hazard ratio [HR], 0.79 [per 1-SD increase]; 95% confidence interval [CI], 0.63-0.99; P=0.04), but not hsCRP or VEGF-A, were inversely and significantly associated with MACEs after adjustment for age, gender, and established risk factors. Finally, we performed stepwise Cox proportional hazard analysis including data on age, gender, established risk factors, Fontaine class and serum levels of hsCRP, VEGF-A and VEGF-C. Notably, Fontaine class (HR, 1.4; 95% CI, 1.1-1.8; P=0.002) and the VEGF-C level (HR [per 1-SD increase], 0.80; 95% CI, 0.64-0.99; P=0.045), but not other parameters, were independent predictors of MACEs. Conclusions: A low VEGF-C value may serve as a predictive marker of cardiovascular events in patients with ASO.