Lipoprotein(a) and calcific aortic stenosis: from inherited risk marker to therapeutic target.

Background: Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease in older adults and remains a condition for which valve replacement is the only established disease-modifying treatment. Converging genetic, epidemiological, imaging and mechanistic evidence supports an active disease process involving lipid deposition, inflammation, extracellular matrix remodeling, osteogenic differentiation and progressive mineralization. Lipoprotein(a) [Lp(a)] has emerged as an inherited risk factor of particular interest because it links apolipoprotein(a), apolipoprotein B, oxidized phospholipids (OxPL), autotaxin (ATX)-lysophosphatidic acid signaling and valvular calcification. Objective: To review the evidence connecting Lp(a) with the initiation and progression of CAVS, distinguish levels of evidence and plausible mediators, and discuss the current and future clinical implications of Lp(a) measurement and Lp(a)-lowering therapy in aortic valve disease. Methods: A narrative review was performed using PubMed/MEDLINE, major cardiovascular guidelines, consensus statements and reference lists of key articles. Searches were updated to June 2026 and prioritized genetic studies, Mendelian randomization analyses, prospective cohorts, imaging studies, tissue and mechanistic studies, systematic reviews, randomized trials and early-phase pharmacological studies relevant to Lp(a), oxidized phospholipids and CAVS. Results: Genetic and Mendelian randomization studies support a likely causal contribution of the LPA locus and lifelong exposure to apoB-containing lipoproteins to aortic valve calcification and incident CAVS. Clinical and imaging studies associate higher Lp(a) concentrations with prevalent valve calcification, incident aortic stenosis and, in selected cohorts, faster haemodynamic progression. Mechanistically, Lp(a)-associated particles and lipid mediators have been detected in valve tissue, and OxPL, autotaxin-derived lysophosphatidic acid and related inflammatory pathways can promote valve interstitial cell osteogenic transformation. However, evidence for progression is heterogeneous, and established calcific disease is also shaped by baseline calcium burden, valve anatomy, renal-mineral pathways, inflammation, fibrosis and mechanical stress. Existing statin-based and mineral-targeted therapies have not slowed established CAVS, while potent Lp(a)-lowering agents can markedly reduce Lp(a) but still lack definitive valvular outcome data. Conclusions: Lp(a) should be considered a cardiovascular risk enhancer and a plausible causal contributor to calcific aortic valve disease, especially during earlier lipid-inflammatory and microcalcific phases. Measuring Lp(a) at least once in adulthood is supported by contemporary lipid guidance and may be particularly informative in premature CAVS, family clustering, coexisting premature atherosclerotic cardiovascular disease or unexplained rapid progression. Whether pharmacological Lp(a) lowering can prevent CAVS or slow progression remains an important but unproven translational question.