Abstract Body: Background: Cardiac fibrosis is a key pathological feature of heart failure and other cardiovascular diseases, contributing to ventricular stiffening and dysfunction. Growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, has been implicated in attenuating fibrosis by modulating inflammatory responses. However, its precise mechanisms in ventricular fibrosis remain unclear.

Hypothesis: In this study, we investigate whether exogenous GDF11 supplementation accelerates NF-κB-mediated inflammatory activation and resolution, ultimately reducing ventricular fibrosis in an angiotensin II (AngII)-induced fibrosis model. We hypothesized that GDF11 promotes early activation of NF-κB target genes and suppresses fibroblast activation, leading to improved ventricular remodeling.

Methods and Results: Using a mouse model of AngII-induced ventricular fibrosis, we administered recombinant GDF11 (rGDF11) and analyzed inflammatory and fibrotic responses at 3, 7, 14, and 28 days post-pump implantation (ppi). Our results show that rGDF11 treatment induced earlier NF-κB phosphorylation and target gene expression (IL-1β, IL-6, TNF-α) at 3 days ppi compared to 7 days in controls, followed by a more rapid resolution of inflammation. This was associated with a significantly reduced collagen deposition dynamic as evidenced by Masson's trichrome staining at 7, 14, and 28 days ppi. While the literature suggests that GDF11 may influence macrophage polarisation dynamics, further investigation is required to confirm this mechanism in our model.

Conclusions and Perspectives: These findings suggest that GDF11 plays a role in modulating NF-κB-driven inflammation and fibrosis resolution, thereby attenuating excessive fibrotic remodeling. This study highlights the therapeutic potential of GDF11 in targeting inflammatory dynamics to reduce ventricular fibrosis, providing a novel approach to the treatment of heart failure.