Key result
Severe AVS is associated with epigenetic reprogramming of NFAT signalling in circulating T cells, including hypomethylation of NFATC1 and NFATC3 and induction of downstream target genes like Interferon g (5-fold, P<0.0001).
Why the study?
Circulating immune cells experience high shear stress during calcific AVS progression, but the underlying mechanism whereby mechanical shear stress reprograms these cells remains undefined.
Cross-Sectional (n=48)
Hemodynamic shear stress in severe aortic stenosis may trigger epigenetic reprogramming of NFAT signaling in circulating T cells, promoting inflammation and valve degeneration.
Background Calcific aortic valve stenosis (AVS) is an active inflammatory disease characterized by progressive fibro-calcific remodelling and thickening of the aortic leaflets. Due to AVS progression circulating immune cells experience high shear stress (HSS), which is known to influence immune cell response. However, the underlying mechanism whereby mechanical sheer stress reprograms circulating immune cells remains undefined. Aim In this study, we uncover an HSS-induced epigenetic axis of gene regulatory signature among circulating T cell in patients with AVS. Methods Peripheral blood was obtained from 14 healthy subjects and 34 patients with severe AVS before bioprosthetic trans-aortic valvular replacement. Circulating T cells were isolated using negative selection using magnetic cell separation, from which DNA was isolated for DNA methylation analysis using Infinium Methylation EPIC Bead Chip Array. Results DNA methylation analysis via Methylation EPIC BeadChip array revealed 102,942 differentially methylated CpG sites (DMPs, P < 0.01%, |D methylation| > 10%) in AVS samples found primarily within promoter regions. Unsupervised analysis identified clustering of samples based on the presence of AVS, with gene-set enrichment analysis of DMPs revealing "Cardiac Hypertrophy" (4.5% enrichment, P = 0.0001) as the most disproportionately enriched pathway, wherein hypomethylation of genes encoding proinflammatory NFAT signalling intermediates were noted to be primarily contributory, including NFATC1 (0.6-fold, P = 0.01) and NFATC3 (0.43-fold, P = 0.01). Circulating T cells obtained from patients suffering from severe AVS exhibit induction of NFAT downstream target genes Cyclin D1 (1.9-fold, P < 0.001), Interleukin 2 (2.3-fold, P < 0.05), Interferon g (5-fold, P < 0.0001), and TNFa (2.4-fold, P < 0.0001). Conclusion Taken together, these observations support that hemodynamic shear stresses trigger the epigenetic reprogramming of NFAT signalling within circulating T cells, which may in-turn promote the accelerated degeneration of aortic valvular calcification.
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Zhang et al. (2025) conducted a cross-sectional in Severe aortic valvular stenosis (n=48). Severe AVS (high shear stress exposure) vs. Healthy subjects was evaluated on Differentially methylated CpG sites (DMPs) and gene expression in circulating T cells. Severe AVS is associated with epigenetic reprogramming of NFAT signalling in circulating T cells, including hypomethylation of NFATC1 and NFATC3 and induction of downstream target genes like Interferon g (5-fold, P<0.0001).
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