Novel pharmacological targets for the treatment of aortic stenosis

Calcific aortic stenosis (AS) is the most prevalent valvular lesion requiring intervention worldwide and is associated with substantial morbidity and mortality. Despite its growing global burden, no pharmacological therapy has been proven to prevent the onset or slow the progression of AS, leaving valve replacement as the only definitive treatment for severe disease. Increasing evidence has shifted our understanding of AS from a passive degenerative process to an active inflammatory and fibro-calcific disease involving lipid infiltration, immune cell activation, and osteogenic transformation of valvular interstitial cells. Among the implicated factors, lipoprotein(a) [Lp(a)] has emerged as a key causal driver of aortic valve calcification and AS. This review summarizes our current understanding of AS pathophysiology and highlights the role of Mendelian randomization in identifying therapeutic targets. We review prior pharmacological strategies, including statins, anti-hypertensives, and anti-resorptive therapies, that have failed to modify disease progression in randomized trials. We then discuss emerging therapeutic approaches targeting molecular pathways implicated in AS, with a focus on Lp(a)-lowering strategies. Novel RNA-based therapies, including antisense oligonucleotides and small interfering RNAs targeting the LPA gene (such as pelacarsen, olpasiran, lepodisiran, and zerlasiran), have demonstrated substantial reductions in circulating Lp(a) concentrations, and are currently being evaluated in large clinical trials. Additional investigational approaches, including PCSK9 inhibition, anti-inflammatory therapies, metabolic interventions, and modulators of nitric oxide signalling, are also reviewed. Finally, we highlight recent genomic and proteomic studies that are uncovering new biological pathways and potential therapeutic targets in AS. Together, these advances suggest that targeted molecular therapies, particularly those aimed at lowering Lp(a), may represent a promising pharmacologic approach for influencing the natural history of calcific AS, potentially offering new options in the management of this common and often debilitating disease. Key words: Aortic stenosis, Lipoprotein(a), Mendelian randomization, RNA-targeted therapies, Proteomics.