Epigenetically Programmed Inflammation in Aortic Valve Stenosis: The Role of Trained Immunity

All articles of this category (opens in new window) Background: Aortic valve stenosis (AVS) is a progressive disease with no pharmacological treatment to prevent its deterioration. Recent evidence suggests that trained immunity, a persistent hyperactivation of innate immune cells, plays a key role in chronic inflammation and valvular calcification. This study investigated how trained immunity contributes to VIC-mediated calcification and explored sex-specific immune responses in aged aortic valves. Methods: Human monocytes were stimulated with oxidized lipids and hyperglycemia-mimicking conditions to induce trained immunity. After a resting phase, cytokine secretion, epigenetic profiling, and metabolic activity were assessed. Trained monocytes were co-cultured with human VICs, and calcification was quantified. ATAC-seq and ChIP-seq identified chromatin accessibility changes and trained-immunity-specific enhancers, while RNA-seq characterized gene expression. For immune-driven calcification in aging, aortic valves and monocytes were isolated from aged male and female mice. Echocardiography, histology, and scRNA-seq analyzed valvular structure, calcification, and immune cell populations. Monocytes from aged mice were co-cultured with VICs to determine calcification potential. Results: Trained human monocytes displayed a persistent hyperinflammatory phenotype, with significantly increased IL-6, TNF-α, and IL-1β secretion. Epigenetic analysis revealed sustained inflammatory gene activation, promoting chronic immune activation. When co-cultured with VICs, trained monocytes significantly enhanced calcification, with higher ALP activity and upregulation of RUNX2 and BMP2 compared to control. In aged mice, echocardiography demonstrated structural valve deterioration, with increased leaflet thickening and reduced cusp mobility. Histological staining confirmed enhanced calcification and immune infiltration, particularly in aged male mice. scRNA-seq of aortic valve immune cells revealed a distinct pro-inflammatory signature, with expansion of T-cell subsets. Aged male monocytes exhibited a stronger pro-calcific phenotype than female monocytes, directly accelerating VIC calcification in co-culture assays. Conclusion: These findings establish trained immunity as a key driver of VIC-mediated calcification in AVS, with a distinct sex-dependent effect. Aged male monocytes exhibit a stronger pro-calcific phenotype, accelerating VIC calcification and valve degeneration. Targeting trained immunity may offer a novel therapeutic approach to slow A vs. progression and mitigate immune-driven valve pathology. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany