Potential involvement of S100A8/S100A9 and neutrophil extracellular traps in rheumatic heart disease valvular injury

Rheumatic heart disease (RHD) causes immune-mediated valvular inflammation and fibrosis, but the contribution of neutrophil extracellular traps (NETs) remains unclear. We integrated mitral valve transcriptomics with histological, molecular and echocardiographic assessments in a rat RHD model. Transcriptomic analysis included four rats per group; each subsequent experiment included three rats per group. RHD valves showed inflammatory infiltration, collagen remodeling and increased S100A8/S100A9 expression, alongside enhanced myeloperoxidase (MPO) and citrullinated histone H3 (citH3) staining. S100A8/A9 and MPO showed partial local colocalization, whereas the measured echocardiographic parameters did not differ significantly between groups at the terminal assessment. Exploratory screening using nominal P < 0.05 and |log₂ fold change| > 1 identified 89 genes, nine of which overlapped a NET-related gene set. These included S100A8 and S100A9, with nominal P values of 0.009565 and 0.002586 and Benjamini–Hochberg-adjusted P values of 0.419214 and 0.297275, respectively. The combined findings support a possible contribution of S100A8/S100A9-associated NET responses to valvular inflammation and remodeling. However, the exploratory transcriptomic evidence, small experimental groups and absence of functional perturbation leave the proposed causal pathway in RHD unconfirmed.