Plasma tumour necrosis factor-alpha-related proteins in prognosis of heart failure with pulmonary hypertension

Abstract

Aims: Patients with heart failure (HF) exhibit poor prognosis, which is further deteriorated by pulmonary hypertension (PH), with negative impact on morbidity and mortality. As PH due to left HF (LHF-PH) is among the most common causes of PH, there is an urge according to the 2021 European Society of Cardiology HF guidelines to find new biomarkers that aid in prognostication of this patient cohort. Given the role of tumour necrosis factor-alpha (TNF-α) in HF progression, we aimed to investigate the prognostic value of plasma proteins related to TNF-α in patients with LHF-PH, in relation to haemodynamic changes following heart transplantation (HT).

Methods and results: Twenty TNF-α-related plasma proteins were analysed using proximity extension assay in healthy controls (n = 20) and patients with LHF-PH (n = 67), before and 1 year after HT (n = 19). Plasma levels were compared between the groups, and the prognostic values were determined using Kaplan-Meier and Cox regression analyses. Plasma levels of lymphotoxin-beta receptor (LTBR), TNF receptor superfamily member 6B (TNFRSF6B), and TNF-related apoptosis-inducing ligand receptors 1 and 2 (TRAIL-R1 and TRAIL-R2, respectively) were higher in LHF-PH pre-HT vs. controls (P < 0.0001), as well as higher in pre-HT vs. post-HT (P < 0.001). The elevated pre-HT levels of LTBR, TNFRSF6B, TRAIL-R1, and TRAIL-R2 decreased towards the levels of healthy controls after HT. Higher preoperative levels of LTBR, TNFRSF6B, TRAIL-R1, and TRAIL-R2 in LHF-PH were associated with worse survival rates (P < 0.002). In multivariate Cox regression models, each adjusted for age and sex, LTBR, TNFRSF6B, TRAIL-R1, and TRAIL-R2 predicted mortality (P < 0.002) [hazard ratio (95% confidence interval): 1.12 (1.04-1.19), 1.01 (1.004-1.02), 1.28 (1.14-1.42), and 1.03 (1.02-1.04), respectively].

Conclusions: Elevated pre-HT plasma levels of the TNF-α-related proteins LTBR, TNFRSF6B, TRAIL-R1, and TRAIL-R2 in LHF-PH decreased 1 year after HT, displaying a normalization pattern towards the levels of the healthy controls. These proteins were also prognostic, where higher levels were associated with worse survival rates in LHF-PH, providing new insight in their potential role as prognostic biomarkers. Larger studies are warranted to validate our findings and to investigate their possible pathobiological mechanisms in LHF-PH.

Keywords: Biomarkers; Cardiovascular diseases; Haemodynamics; Multi-marker panel; Pulmonary hypertension; Survival.

Figure 1

Overview of study set‐up. The present study started with 20 plasma proteins. Initial testing with the Mann–Whitney U tests and the Wilcoxon signed rank tests was applied on the LHF‐PH group (n = 67). In the end, four proteins predicted mortality and higher levels were associated with worse survival rates. AUC, area under the curve; HT, heart transplantation; LHF‐PH, left‐sided heart failure with pulmonary hypertension; LTBR, lymphotoxin‐beta receptor; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; ROC, receiver operating characteristic; TNFRSF6B, TNF receptor superfamily member 6B; TNF‐α, tumour necrosis factor‐alpha; TRAIL‐R, TNF‐related apoptosis‐inducing ligand receptor.

Figure 2

(A–D) Plasma levels of four proteins in controls, patients with pulmonary hypertension due to left heart failure (LHF‐PH), pre‐heart transplantation (HT), and post‐HT. Lymphotoxin‐beta receptor (LTBR), tumour necrosis factor (TNF) receptor superfamily member 6B (TNFRSF6B), and TNF‐related apoptosis‐inducing ligand receptors 1 (TRAIL‐R1) and 2 (TRAIL‐R2) were all higher in LHF‐PH compared with controls and lower in post‐HT compared with pre‐HT (P < 0.01; false discovery rate at 1%). The high protein levels displayed a normalization pattern post‐HT towards levels of the healthy controls. (E–H) Kaplan–Meier survival curves of patients with protein levels below and above the thresholds attained by receiver operating characteristic analyses. Patients with LTBR, TNFRSF6B, TRAIL‐R1, or TRAIL‐R2 levels above the respective threshold had worse survival rates compared with patients with values below the threshold. Event = death (n = 23). AU, arbitrary units. *P < 0.01, **P < 0.001, ***P < 0.0001.