https://doi.org/10.1007/s00392-025-02625-4
1Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland; 2Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg Department of Molecular and Clinical Medicine Gothenburg, Schweden; 3Deutsches Herzzentrum der Charite (DHZC) Klinik für Kardiologie, Angiologie und Intensivmedizin Berlin, Deutschland
Emerging research has highlighted the substantial impact of gut microbiota and their metabolites on cardiovascular diseases (CVDs), such as coronary artery disease and heart failure (HF). One such metabolite, imidazole propionate (ImP), derived from microbial histidine metabolism, has been associated with insulin resistance and type 2 diabetes. Recent studies suggest that ImP may also contribute to HF progression. However, the exact molecular mechanism through which ImP impairs cardiac function remains unknown. Here, we analyzed the link between ImP blood levels and HF severity in a patient cohort and examined its effects on cardiac fibrosis and HF progression using both in vitro and in vivo models.
Methods and results:
In our clinical study of 831 patients with cardiac dysfunction, elevated plasma ImP levels were associated with reduced left ventricular ejection fraction (LVEF) and more severe HF symptoms, as classified by the New York Heart Association (NYHA) stages III and IV, indicating a potential link between higher ImP concentrations and increased HF severity. C57BL/6J mice administered ImP over eight weeks exhibited significant declines in LVEF and stroke volume compared to control mice. In vitro, human cardiac fibroblasts (HCFs) exposed to ImP for 24 h showed dose-dependent increases in cell proliferation, assessed by BrdU incorporation assay, and upregulation of pro-fibrotic markers, including collagen type I alpha 1 (COL1A1) and α-smooth muscle actin (αSMA), on protein levels. These pro-fibrotic effects were significantly reduced with co-treatment of the anti-fibrotic drug pirfenidone (PFD), a known p38γ inhibitor. Supporting this, mice with a genetic knockout for p38γ treated with ImP preserved cardiac function with LVEF comparable to those in control mice, indicating that p38γ activation is a critical mediator in ImP-induced cardiac dysfunction.
Conclusion:
Collectively, these studies suggest that ImP contributes to cardiac remodeling and HF progression by enhancing cardiac fibroblast proliferation and fibrosis through p38γ activation. Targeting ImP production or its signaling pathways could represent a promising therapeutic strategy to prevent and treat HF development.