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

Abstract

AimsPatients 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 resultsTwenty 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].ConclusionsElevated 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.

Editors' highlight picks from 2023 in ESC heart failure

“…Preclinical and translational investigations frequently aim at the molecular drivers of HF pathogenesis. Accordingly, interactions between metabolic, microvascular, inflammatory, and haemodynamic parameters are analysed to reveal fine details of myocardial dysfunction in HF phenotypes with distinct aetiologies ranging from Takotsubo cardiomyopathy 49 through severe functional mitral regurgitation, 50 HF complicated by pulmonary hypertension, 51 and HF patients with coronary artery disease (CAD) 52,53 to peripartum cardiomyopathy. 54 Recognition of genetic variants co-segregating with congenital heart disease (CHD) is instrumental for early prenatal diagnosis.…”