Aortic valve stenosis in 2026: from emerging mechanisms to clinical drug development.

Calcific aortic valve stenosis (AS) is the most prevalent valvular heart disease in high-income countries, affecting 9.4 million persons globally. While surgical and transcatheter aortic valve replacement have transformed outcomes, they address end-stage disease rather than the underlying pathobiology. The development of pharmacological therapies to slow or halt AS progression would represent a paradigm shift in disease management. Recent advances have substantially expanded our understanding of AS pathogenesis. Large-scale genome-wide association studies have identified over 260 risk loci, with the LPA locus confirming lipoprotein(a) as the most robustly validated genetic risk factor. Single-cell transcriptomics have revealed unexpected cellular heterogeneity and novel mechanisms including macrophage-to-mesenchymal transition. Emerging insights into metabolic reprogramming, epigenetic regulation, innate immunity and clonal hematopoiesis have identified multiple therapeutic targets. Despite these pathophysiological advances, no pharmacological therapy has yet demonstrated efficacy in adequately powered randomized trials. Statin therapy and skeletal bone metabolism-targeted agents have proven ineffective previously and multiple mechanistically diverse approaches are now under investigation. The most promising developments center on lipoprotein(a) reduction with antisense oligonucleotides, with the first dedicated AS trial ongoing. Additional strategies include PCSK9 inhibition, supplementation of omega-3 fatty acids, treatment with colchicine, soluble guanylate cyclase activation with ataciguat, and DPP-4 inhibition. Success in any of these trials would represent the first disease-modifying therapy for AS, with potential to delay valve replacement, preserve myocardial function, and improve outcomes for millions of patients worldwide.