Vascular endothelial factor C and D in patients with heart failure with preserved, mildly reduced, and reduced ejection fraction: the PREHOSP-CHF study

Abstract

Abstract Background The lymphatic system has been suggested to play an important role in cardiovascular diseases including heart failure (HF). Vascular endothelial growth factor C (VEGF-C) and D (VEGF-D) are key regulators of lymphangiogenesis, and we recently reported the association of low VEGF-C with the risk of all-cause death and high VEGF-D with the risk of HF hospitalization in patients with HF. Purpose To investigate the association of VEGF-C and VEGF-D with prognosis in patients with HF with preserved ejection fraction (EF) (HFpEF: EF≥50%), mildly reduced EF (HFmrEF: EF, 40–49%), and reduced EF (HFrEF: EF<40%). 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-C and 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, were measured at the time of discharge. Patients were followed-up over two years. Results The numbers of HFpEF, HFmrEF, and HFrEF were 429 (41.9%), 186 (18.2%), and 409 (39.9%), respectively. HFpEF patients were older, more likely to be female, and had more hypertension, atrial fibrillation, and anemia, but less coronary artery disease. NT-proBNP and hs-cTnI levels increased with decreasing EF. VEGF-C levels decreased with increasing EF (median [interquartile range]: HFpEF, 4508 [3318–5919] pg/ml; HFmrEF, 4719 [3663–6203] pg/ml; HFrEF, 5023 [3804–6382] pg/ml), whereas VEGF-D levels were comparable among the three EF groups (HFpEF, 404.6 [293.1–560.3] pg/ml; HFmrEF, 386.0 [298.5–556.3] pg/ml; HFrEF, 414.2 [296.1–557.3] pg/ml). In multivariate stepwise logistic regression analyses, anemia and high NT-proBNP were independently associated with low VEGF-C levels, and high NT-proBNP was independently associated with high VEGF-D levels, across all the EF groups. During the follow-up, incidences of all-cause death and HF hospitalizations were similar among the three EF groups (log-rank P=0.6 for all-cause death, and log-rank P=0.3 for HF hospitalization). On multivariate Cox proportional hazard analyses including established risk factors and cardiovascular biomarkers, VEGF-C levels tended to be inversely associated with the incidence of all-cause death in patients with HFpEF and HFrEF (Figure). On the contrary, VEGF-D levels were significantly and positively associated with the incidence of HF hospitalization in patients with HFpEF, and tended to be positively associated with it in patients with HFmrEF and HFrEF (Figure). Conclusions Low VEGF-C was associated with the risk of all-cause death in patients with HFpEF and HFrEF, while high VEGF-D was associated with the risk of HF hospitalization especially in HFpEF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Grant-in-Aid for Clinical Research from the National Hospital Organization