Mol Biol Rep. 2026 Oct 29;53(1):1855. doi: 10.1007/s11033-026-13036-7.
ABSTRACT
Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease in the Western countries and carries significant morbidity and mortality, yet no pharmacological therapy has demonstrated efficacy in modifying its natural history. Once regarded as a passive degenerative process, CAVD is now recognized as an actively regulated disease driven by endothelial dysfunction, chronic inflammation, dysregulated mineral metabolism, and cellular senescence, which collectively drive progressive fibrotic remodeling and calcification of the valve leaflets through both dystrophic and osteogenic mechanisms. This review examines the pharmacological strategies that have been investigated or are currently under evaluation to slow CAVD progression, encompassing lipid-lowering agents, renin-angiotensin system inhibitors, bone resorption inhibitors, vitamin K supplementation, and nitric oxide pathway modulators. Despite strong biological rationale and encouraging observational or preclinical data, each of these approaches has thus far failed to demonstrate consistent disease, modifying efficacy in prospective randomized trials, reflecting the complexity of CAVD pathophysiology and the historical lack of mechanistic precision in patient selection and trial design. Emerging evidence suggests that cellular senescence may represent a unifying and potentially actionable therapeutic target, bridging endothelial dysfunction, chronic inflammation, and active calcification within a single pathophysiological framework. Preclinical studies demonstrate that senolytic clearance of senescent cells reduces calcification in atherosclerosic and hypercholesterolemic vascular models provide a compelling rationale for extending this approach to valvular targets.
PMID:42965583 | DOI:10.1007/s11033-026-13036-7