Correspondence:
Bobby Yanagawa MD, PhD, FRCSC Program Director, Division of Cardiac Surgery, University of Toronto Assistant Professor, Division of Cardiac Surgery, St. Michael’s Hospital  30 Bond Street, 8th Floor, Bond Wing Toronto, ON M5B 1W8 Canada Tel: 416 864 5706 Fax: 416 864 5031 Email: yanagawab@smh.ca
Conflict of Interests: None
Manuscript word count : 2704
Abbreviations and acronyms : AS, aortic stenosis; Lp(a),lipoprotein(a)
Abstract
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.
Introduction:
Aortic stenosis (AS) is the most common valvular heart disease in developed countries, for which the only definitive treatment is either surgical treatment or transcatheter aortic valve replacement1. Despite the growing burden of AS, there are no targeted medical to reduce the need for aortic valve replacement (AVR). This could be in part due to the poor understanding of the pathogenesis for AS. Recently, there is a growing interest and evidence on the role of Lp(a) in AS development or progression. Genetic studies showed an important link between certain genes and the development of AS. Using a Mendelian randomization study design, the landmark, genome-wide association study by Thanassoulis et al reported an important link between mutations in the lipoprotein (a) (Lp[a]) gene in the dysregulation of lipid metabolism and fibrinolysis in AS (HR 1.68; 95% CI, 1.32-2.15) 2. This discovery clearly demonstrated that genetic variants of Lp(a) are strongly linked with aortic valve calcium and clinical AS.
Lp(a) is a low-density plasma lipoprotein complex that consist of cholesterol- rich LDL particle with one molecule of apolipoprotein B100 and an additional protein, apolipoprotein (a), attached via disulphide bond3,4. Case control and Mendelian randomization studies have linked high Lp(a) plasma concentration with cardiovascular disease 5,6,7. However, there exists variations in serum concentrations of Lp(a), which is primarily under genetic control driven in part by variable number of kringle (K) IV type 2 repeats (KIV-2) and single nucleotide polymorphisms in the LPA gene itself 8.
Studies in Lp(a)-transgenic mice models have demonstrated that apo(a) is retained in atheromas and suggest that it promotes fatty streak formation 9. In this report we report an evidence of association of Lp(a) and AS in experimental mice model and human aortic valves.
Material and Methods