Lipidomic remodeling is associated with hemodynamic severity in calcific aortic valve stenosis

Calcific aortic valve stenosis (CAVS) is characterized by progressive leaflet calcification driven in part by lipid dysregulation, yet the metabolic pathways underlying disease advancement remain poorly understood. LC/MS-based lipidomics was performed on aortic valve tissue from 99 patients undergoing surgical replacement and on plasma from an independent cohort of 107 individuals (58 severe AS; 49 controls). Unsupervised k-means clustering defined lipid-based phenotypes that were compared with echocardiographic markers of severity. Plasma-tissue concordance was assessed in an overlap subset (n = 17), and the discriminatory performance of plasma lipids was examined using ROC analysis. Tissue lipidomics identified three molecular clusters associated with differing hemodynamic profiles. The most pronounced metabolic remodeling was observed between cluster 3 and the other clusters, which exhibited higher hemodynamic burden, and was marked by increases in diacylglycerols (DG), alkyl lysophosphatidylcholines [LPC(O)], and dihexosylceramides (Hex2Cer). DG and LPC(O) species also showed strong associations with valve stiffness and calcification burden. In plasma, several DG species were positively associated with AS status, whereas selected triglycerides demonstrated inverse associations. In exploratory ROC analyses, TG 52:4 and TG 54:4 showed discriminatory potential (AUC 0.831 and 0.880, respectively). These triglycerides also demonstrated strong plasma-tissue concordance (r > 0.7). Comprehensive lipidomic profiling reveals early, pathway-specific lipid remodeling that parallels clinical severity in CAVS. DG and LPC(O) species associate with valvular stiffening, while circulating TG 52:4 and TG 54:4 emerge as candidate noninvasive biomarkers requiring independent validation.NEW & NOTEWORTHY Our study delivers the largest lipidomic analysis of human aortic valves, revealing early metabolic shifts, especially in diacylglycerols and alkyl-lysophosphatidylcholines that closely track hemodynamic severity. By integrating valve tissue and plasma profiles, we identify triglycerides TG 52:4 and TG 54:4 as promising noninvasive candidate biomarkers. These findings clarify lipid-driven mechanisms of calcific aortic stenosis and highlight new opportunities for earlier detection and risk stratification.