Elevated plasma WIF-1 levels are associated with worse prognosis in heart failure with pulmonary hypertension

Abstract

Aims: Heart failure (HF) is a progressive condition that is becoming more prevalent in the ageing population. Pulmonary hypertension is a common complicating factor in HF and negatively impacts survival. Plasma biomarkers are a potential method for determining the prognosis of patients with left heart failure with pulmonary hypertension (LHF-PH). We aimed to analyse the prognostic capability of 33 proteins related to, among other pathways, inflammation, coagulation, and Wnt signalling in LHF-PH.

Methods: Plasma levels of 33 proteins were analysed using proximity extension assay from the plasma of 20 controls and 67 LHF-PH patients, whereof 19 underwent heart transplantation (HT). Haemodynamics in the patients were assessed using right heart catheterization.

Results: Eleven proteins had elevated plasma levels in LHF-PH compared with controls (P < 0.01), which decreased towards the controls' levels after HT (P < 0.01). Survival analysis of these proteins showed that elevated plasma levels of growth hormone, programmed cell death 1 ligand 2, tissue factor pathway inhibitor 2, and Wnt inhibitory factor 1 (WIF-1) were associated with worse transplantation-free survival in LHF-PH (P < 0.05). When adjusted for age, sex and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels using multivariable cox regressions, only WIF-1 remained prognostic [hazard ratio (95% confidence interval)] [1.013 (1.001-1.024)]. WIF-1 levels in LHF-PH patients also correlated with the mean right atrial pressure (r_s = 0.42; P < 0.01), stroke volume index (r_s = 0.41; P < 0.01), cardiac index (r_s = -0.42; P < 0.01), left ventricular stroke work index (r_s = -0.41; P < 0.01), and NT-proBNP (r_s = 0.63; P < 0.01).

Conclusions: The present study demonstrated that LHF-PH patients have higher plasma WIF-1 levels than healthy controls, suggesting that plasma WIF-1 may be a potential future prognostic biomarker in LHF-PH. Its prognostic capability could be further refined by including it in a multi-marker panel. Further studies are needed to establish the potential role of WIF-1 in LHF-PH pathophysiology in larger cohorts to determine its clinical applicability.

Keywords: Biomarkers; Coagulation proteins; Haemodynamics; PD-L2; TFPI-2; WIF1.