Distinct association of VEGF-C and VEGF-D with prognosis in patients with chronic heart failure: the PREHOSP-CHF study
Authors: Iguchi M , Wada H , Shinozaki T , Suzuki M , Ajiro Y , Matsuda M , Koike A , Koizumi T , Shimizu M , Ono Y , Takenaka T , Kotani K , Abe M , Akao M , Hasegawa K ,   PREHOSP-CHF investigators
Published: October 2021

Abstract

Background
The lymphatic system has been suggested to play an important role in cardiovascular (CV) diseases including heart failure (HF). Vascular endothelial growth factor C (VEGF-C) and VEGF-D are key regulators of lymphoangiogenesis.

Purpose
To investigate the association of VEGF-C and VEGF-D with prognosis in patients with chronic HF (CHF).

Methods
The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in CHF. A total of 1,024 patients (mean age, 75.5±12.6 years; male, 58.7%) admitted to acute decompensated HF were included in the analyses. The primary outcome was MACE defined as a composite of CV death or HF hospitalization. The secondary outcomes were all-cause death, CV death, and HF hospitalizations. Serum levels of VEGF-C and VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitive C reactive protein (hs-CRP), VEGF, and soluble VEGF receptor-2 (sVEGFR-2) were measured at the time of discharge. Patients were followed-up over two years.

Results
Median [interquartile range] of VEGF-C and VEGF-D levels were 4821 [3633–6131] pg/ml and 404 [296–559] pg/ml, respectively. In multivariate stepwise regression analysis, independent determinants of VEGF-C levels were younger age, female gender, absence of prior HF hospitalization, chronic kidney disease, and anemia, lower ejection fraction, lower NT-proBNP levels, higher VEGF levels, and higher sVEGFR-2 levels, while those of VEGF-D levels were lower body mass index, presence of diabetes and atrial fibrillation, and higher NT-proBNP levels. During the follow-up, a total of 209 (20.4%) all-cause deaths, 112 (10.9%) CV deaths, and 309 (30.2%) HF hospitalizations occurred. After adjusting for established risk factors and CV biomarkers, VEGF-C levels were significantly and inversely associated with the incidence of MACE and non-CV death (Fig.1, model 4). On the other hand, VEGF-D levels were significantly and positively associated with the incidence of HF hospitalization (Fig. 1, model 4). When we divided the patients into 4 groups based on the median of VEGF-C and VEGF-D levels, patients with low VEGF-C and high VEGF-D showed significantly higher incidence of MACE, all-cause death, CV death, and HF hospitalization compared to those with high VEGF-C and low VEGF-D (Fig. 2).

Conclusions
Among patients with CHF, VEGF-C and VEGF-D had different characteristic and association with the incidence of adverse events. VEGF-C levels were inversely associated with the incidence of MACE and non-CV death, and VEGF-D levels were positively associated with the incidence of HF hospitalization. These results suggests different effects of VEGF-C and VEGF-D in CHF. Combination of VEGF-C and VEGF-D enables us to make good risk stratification in patients with CHF.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Clinical Research from the National Hospital Organization Figure 1Figure 2