Association of Vascular endothelial factor D with pulmonary hypertension in heart failure: the PREHOSP-CHF Study

Abstract Background Pulmonary hypertension (PH) complicated with heart failure (HF) is associated with increased morbidity and mortality. Vascular endothelial growth factor D (VEGF-D), one of key regulators of lymphangiogenesis, was reported to be higher in HF patients with pulmonary congestion on chest X-ray. Furthermore, we previously reported that HF patients with high VEGF-D had higher incidence of major adverse cardiovascular events (MACE), defined as cardiovascular death or heart failure hospitalization. Purpose To investigate the association of VEGF-D with pulmonary hypertension in patients with HF. Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in HF. A total of 1,024 patients (mean age 75.5±12.6 years; 58.7% male) admitted to acute decompensated HF were included in the analyses. Serum levels of VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitivity C reactive protein (hs-CRP), were measured at the time of discharge. PH was assessed by tricuspid regurgitation velocity (TRV) in echocardiography. Patients were followed-up over two years. Results Data on PH was obtained in 932 patients. Of these, 44 (4.7%) and 223 (23.9%) patients showed PH (TRV>3.4 m/s) and borderline PH (TRV>2.8 m/s), respectively. Patients with PH/borderline PH were significantly older and had lower body mass index. Prevalence of prior HF hospitalization, HF with preserved ejection fraction, atrial fibrillation, anemia, and chronic kidney disease were higher in patients with PH/borderline PH. Levels of NT-proBNP and VEGF-D, but not hs-cTnI or hs-CRP, were higher in patients with PH/borderline PH (Figure). Levels of NT-proBNP and VEGF-D had weak but significant correlation with TRV (NT-proBNP, R2=0.04, P<0.001; VEGF-D, R2=0.05, P<0.001). After adjustment for these factors, VEGF-D levels were significantly correlated with TRV (β, 3.29; SEM, 0.85, P<0.001). During the follow-up, 12 in PH, 34 in borderline PH, and 53 in no PH patients developed MACE. Unadjusted Hazard ratios [95% confidence intervals] for MACE compared to no PH were 2.44 [1.58-3.60] in PH, and 1.62 [1.26-2.05] in borderline PH. When we divided each PH group into two groups based on the median of VEGF-D levels of each group (no PH, 387 pg/ml; borderline PH, 479 pg/ml; PH, 549 pg/ml), patients with high VEGF-D showed significantly higher incidence of MACE in no PH (unadjusted hazard ratio, 1,70; 95% confidence intervals, 1.29-2.26), and tended to show high incidence of MACE in borderline PH group (unadjusted hazard ratio, 1,39; 95% confidence intervals, 0.93-2.09) and PH group (unadjusted hazard ratio, 1,83; 95% confidence intervals, 0.84-4.18). Conclusions VEGF-D levels were independently associated with PH in patients with HF, and might serve as a predictive biomarker for PH, as well as prognostic biomarker for MACE among patients with HF.