Inflammatory and hormonal crosstalk linking rheumatic fever to chronic valvular heart disease

Rheumatic heart disease (RHD) is a chronic, immune-mediated valvular disorder triggered by Group A β-hemolytic streptococcal infection. Persistent inflammation and immune-mediated tissue injury are central features of disease progression, whereas the roles of hormonal and metabolic regulatory pathways remain less well defined. Emerging evidence suggests that inflammatory signaling may intersect with hormonal and metabolic pathways during the transition from rheumatic fever to chronic valvular disease. Pro-inflammatory mediators have been associated with immune activation and extracellular matrix remodeling, with potential involvement of pathways such as nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and the NOD-like receptor protein 3 inflammasome. Chronic inflammation may also be accompanied by altered neuroendocrine anti-inflammatory feedback, including changes in glucocorticoid receptor signaling and hypothalamic-pituitary-adrenal axis regulation. In addition, sex hormones, thyroid hormones, and metabolic hormones may be linked to immune-cell differentiation, endothelial function, and valvular cell phenotypes, suggesting a possible inflammatory-endocrine regulatory loop that remains insufficiently validated in RHD-specific studies. These relationships may provide a context for understanding valvular interstitial cell activation, endothelial dysfunction, endothelial-mesenchymal transition, metabolic reprogramming, energy imbalance, fibrosis, and calcification, but direct causal evidence remains limited. Future dual-target strategies addressing both inflammatory and hormonal signaling may provide a theoretical framework for individualized intervention; however, their efficacy and safety require rigorous RHD-specific validation. This review summarizes current evidence and discusses the inflammatory-hormonal network as a hypothesis-generating framework for understanding chronic rheumatic valvular remodeling.