From biomechanical mechanisms to clinical reasoning: Deciphering mechanobiological drivers of aortic valve...

Calcific aortic valve disease (CAVD) is a degenerative cardiovascular disorder characterized by progressive valvular thickening and calcification, ultimately leading to aortic stenosis, heart failure, and high mortality. Despite associations with hyperlipidemia, inflammation, and bicuspid aortic valve (BAV) malformation, no targeted pharmacotherapies exist, indicating unaddressed core pathogenic mechanisms. The aortic valve is composed of valvular interstitial cells (VICs) and endothelial cells (VECs) which are constantly exposed to hemodynamic forces, with progressive extracellular matrix (ECM) stiffening during CAVD-two mechanobiological pillars closely linked to pathogenesis. This article synthesizes current mechanobiology research on CAVD and bridges biomechanical insights with clinical practice to dissect precision interventions. Clinical and experimental evidence confirms abnormal hemodynamics (e.g., oscillatory shear stress, elevated blood pressure) and increased ECM stiffness drive CAVD by modulating VIC phenotypic transition (osteogenic differentiation, myofibroblastic transformation), VEC dysfunction (epithelial-mesenchymal transition, inflammation), and ECM remodeling/apoptosis. These effects are mediated by chemical pathways (Transforming growth factor-β1(TGF-β1), YAP, Notch1/Runt-related transcription factor 2 (Runx2), Wnt/β-catenin) and cytoskeleton/nucleoskeleton-dependent mechanotransduction (integrin-linker of the nucleoskeleton and cytoskeleton (LINC) complex-chromatin cascade). Current research uses bioreactors and stiffness-tunable gels but faces challenges of unstandardized parameters, decoupled mechanical cues, and limited clinical specimens. Derived insights enable mechanomedicine innovations: novel drug targets, physical therapies (ultrasound/light-mediated ECM modulation), personalized surgical planning (computational fluid dynamics-guided valvuloplasty), optimized bioprosthetic valves, and early diagnosis (valvular elastography). Overcoming interdisciplinary barriers and standardizing methods will accelerate translation of mechanobiological findings into precision clinical strategies, addressing CAVD patients' unmet needs.