Correspondence:
Bobby Yanagawa MD, PhD, FRCSC
Program Director, Division of Cardiac Surgery, University of Toronto
Assistant Professor, Division of Cardiac Surgery, St. Michael’s
HospitalÂ
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