Aortic valve stenosis promotes pathological shear stress-dependent epigenomic dysregulation in circulating T cells.

BackgroundCalcific aortic valve stenosis (AVS) is the most prevalent valvular heart disease in Western adults, yet no disease-modifying therapy exists. High shear stress (HSS) generated by progressive valvular obstruction drives endothelial injury and immune-mediated inflammation, but the contribution of circulating T cells to AVS pathogenesis remains poorly defined. ObjectivesWe tested whether chronic HSS corresponds with epigenomic reprogramming of peripheral T cells proportionate with hemodynamic severity to yield a clinically informative proxy of disease. MethodsA prospective cohort of 70 participants was recruited for peripheral blood sampling, including 34 with severe symptomatic AVS (aortic valve area <1.0 cm2, mean gradient [≥]40 mmHg) scheduled for transcatheter aortic valve implantation and 36 age- and sex-matched controls. Peripheral T cells were isolated and profiled by genome-wide CpG methylation (Illumina MethylationEPIC) and RNA-sequencing. To test whether HSS directly activates inflammatory signaling, Jurkat T cells were exposed to 20 dyn/cm2 HSS via parallel-plate microfluidic chamber and concomitant CD3/CD28 stimulation, followed by assessment of NFAT nuclear translocation and NFAT target gene expression. ResultsUnsupervised clustering of the 5,000 most-variable CpG loci resolved an epigenomic axis segregating AVS from control T cells (PC1, 15.8% variance explained; P = 3.9x10-6). Multivariable-adjusted analysis identified 3,950 differentially methylated positions (1,889 hyper-, 2,061 hypo-methylated), enriched in promoter-associated CpG islands implicating aortic valve morphogenesis (P = 6.0 x 10-10) and cell-cell adhesion pathways (P = 9.5 x 10-5). Multi-omics factor analysis isolated a latent factor that independently associated with AVS (adjusted P = 1.8x10-3; AUC = 0.79), enriched for chemokine receptor binding and TNF-family signaling, and correlated with canonical HSS-responsive transcripts, consistent with a T cell-mediated shear stress activation. An 18-CpG elastic-net methylation risk score discriminated AVS from controls (AUC = 0.89) and independently predicted hemodynamic severity ({beta} = 7.05 mmHg/SD, 95% CI 2.31-11.79). HSS augmented NFAT nuclear translocation in CD3/CD28-activated Jurkat T cells and induced NFAT-responsive inflammatory transcripts. ConclusionsSevere AVS is associated with promoter-enriched epigenomic remodeling of circulating T cells that converges on hemodynamic stress-dependent inflammatory programs. An 18-CpG methylation risk score outperforms clinical covariates and tracks hemodynamic severity, establishing peripheral T cell DNA methylation as a molecular corollary of AVS.