TGF-beta pathway and inflammatory biomarkers across HFpEF and PAH patients
C Janssen Telders, E N Toth, T Neumann, C Becher, J Van Wezenbeek, A Llucia-Valldeperas, L Celant, T Dekker, J W Duitman, H J Bogaard, M J Goumans, M L Handoko, F S De ManAbstract
Background
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with limited effective treatment options. Emerging evidence implicates the transforming growth factor-beta (TGF-β) superfamily in vascular and fibrotic remodeling across cardiovascular diseases. The recent success of sotatercept, an activin ligand trap, in pulmonary arterial hypertension (PAH) highlights the therapeutic potential of targeting this pathway. However, the role of the TGF-β superfamily in HFpEF remains poorly defined.
Purpose
To determine whether circulating TGF-β superfamily members and inflammatory cytokines differ among individuals with HFpEF, PAH, and healthy controls.
Methods
This study retrospectively included HFpEF and PAH-patients from two independent cohorts and healthy controls. All patients underwent diagnostic right heart catheterization. HFpEF was defined by a post-capillary wedge pressure (PCWP) ≥15mmHg at rest and/or ≥25mmHg at maximal exercise. PAH was defined by a mean pulmonary artery pressure (mPAP) ≥20 mmHg, a pulmonary artery wedge pressure (PAWP) ≤15mmHg, and a pulmonary vascular resistance (PVR) ≥2WU. Blood samples were retrieved from all participants. Circulating concentrations of TGF-β superfamily members were measured by ELISA, and inflammatory markers were quantified using multiplex Luminex assays.
Results
The study population comprised 62 HFpEF patients, 57 PAH patients, and 21 healthy controls. Compared with PAH, HFpEF patients were older, more often female, had a higher BMI, and higher NYHA functional class. Circulating TGF-β superfamily profiles differed markedly between groups (Figure). Activin A levels were highest in HFpEF, intermediate in PAH, and lowest in controls (p<0.001). Follistatin and follistatin-like 3 (FSTL3) were significantly elevated in HFpEF compared with both groups (p<0.001), whereas inhibin A was significantly reduced in HFpEF (p<0.001). No differences were observed for activin B or C. In parallel, HFpEF patients exhibited a distinct pro-inflammatory phenotype, with broadly elevated circulating cytokines compared with both PAH patients and controls.
Discussion
Our findings indicate that HFpEF is associated with a distinct and selective alteration in circulating TGF-β superfamily signaling, characterized by enhanced activin-related signaling. This ligand profile is consistent with a relative shift toward SMAD2/3-biased signaling, favoring pro-fibrotic and pro-inflammatory processes. The concurrent presence of a broad pro-inflammatory cytokine signature further supports a maladaptive systemic milieu in HFpEF. Together, these data suggest that dysregulated TGF-β–mediated signaling may contribute to the pathophysiology of HFpEF. Moreover, given the recent therapeutic success of sotatercept in PAH—where overlapping alterations in circulating TGF-β superfamily ligands are observed—its potential role in HFpEF warrants further investigation.FigureFor image description, please refer to the figure legend and surrounding text.