Lipoprotein (a) is an Upstream Mediator of Aortic Stenosis

Background: A landmark genome-wide association study has linked mutations in the plasma lipoprotein complex lipoprotein(a) [Lp(a)] and aortic stenosis. We attempted to determine whether Lp(a) is a key upstream mediator of aortic stenosis. Methods: Male, Lp(a) transgenic (N=10) and control mice (N=10) were fed a high cholesterol diet for 6 weeks, then hearts were sectioned for histological analysis. Human stenosis (N=8) and non-stenotic (N=7) aortic valve leaflets were obtained intraoperatively and submitted for histologic and immunohistochemical analyses. All histological sections were semi-quantitatively graded in a blinded manner (0-3/3+ units). Results: Aortic valves from Lp(a) transgenic mice fed a high-cholesterol diet demonstrated significant aortic valve changes including fibrosis (2.0/4 vs 0.5/4), calcification (1.9.4 vs 0.1/4) units, angiogenesis (1.1/4 vs 0.3/4) and inflammatory infiltration (1.0 vs 0.1/4) compared with control aortic valves (all p<0.001). Human stenotic aortic valve leaflets expressed greater Lp(a) (2.4/4 vs 1.7/4) in areas of fibrosis, inflammatory infiltration and angiogenesis, compared with non-stenotic aortic valve leaflets (p=<0.005) Conclusion: Our proof-of-concept studies offer evidence for a potential causative role of Lp(a) as a trigger of aortic stenosis. Further work is needed to confirm these results. Therapeutic strategies targeting Lp(a) levels may serve as a novel strategy to limit progressive calcification in aortic stenosis.