Lipoprotein(a) and Aortic Stenosis: From Genetic Risk to Emerging Therapeutic Strategies.

Aortic stenosis (AS) is the most common valvular heart disease in ageing populations and is associated with substantial morbidity and mortality. Despite advances in surgical and transcatheter valve replacement, no medical therapy has yet been shown to prevent disease onset or slow progression. Calcific AS is now recognised as an active, multifactorial process involving lipid infiltration, inflammation and osteogenic calcification of the aortic valve. Lipoprotein(a) has emerged as a key contributor to these mechanisms and is a genetically determined, lifelong cardiovascular risk factor. Lipoprotein(a) is a major carrier of oxidised phospholipids, which promote valvular inflammation and calcification. Epidemiological and Mendelian randomisation studies consistently demonstrate a strong and likely causal association between elevated lipoprotein(a) and AS. Experimental and translational data suggest that lipoprotein(a) exerts its effects early in the disease course, promoting valve inflammation and calcification before significant stenosis develops. The recent development of lipoprotein(a)-lowering therapies has renewed interest in targeting this pathway, raising the possibility that early lipoprotein(a)-lowering may modify disease progression, a hypothesis now being tested in clinical trials.