Lp(a) expression in human aortic stenosis
Baseline patient characteristics are listed in Table 1 . The
non-stenotic/aortic insufficiency group was significantly younger than
the stenosis group (59.2±10.6 years vs 64.5±8.0 years,
p<0.0001). There were no significant differences in
preoperative cardiac risk factors nor medications. The
non-stenotic/aortic insufficiency group was significantly younger than
the stenosis group (59.2±10.6 years vs 77.4±6.2 years,
p<0.0001). Stenotic aortic valve leaflets expressed greater
Lp(a) staining (2.4/4 vs 1.7/4) concentrated in areas of fibrosis,
inflammatory infiltration and angiogenesis, compared with non-stenotic
aortic valve leaflets (p=<0.005). Lp(a) was expressed
uniformly in fibrosa , spongiosa and ventricularislayers in non-stenotic and stenotic valves (Figure 2 ).
Discussion
In this report, increased Lp(a) staining and levels was possibly
associated with significant increase in fibrosis, calcification and
inflammation of aortic valve leaflets in both mice and human aortic
valves. These findings highlight a possible important association
between Lp(a) and development of AS. Reduction of Lp(a) levels may help
in mitigating the progression of AS.
Patients with symptomatic severe AS have poor prognosis and there is a
unmet need for identification of biomarkers or medical treatment to halt
the disease progression13. Currently, there are no
biomarkers or medical therapy to stop the progression of AS and the only
salvage to cure AS is either surgical replacement or transcatheter
implantation.
Hydroxymethylglutaryl coenzyme (HMG-CoA) reductase inhibitors or statins
lower LDL cholesterol and are now a cornerstone in the treatment of
atherosclerosis. The pathogenetic similarities between atherosclerosis
and AS prompted clinical trials studying the effects of statin treatment
to slow aortic stenosis progression14. However, to
date, statin treatment has not shown clinical benefit in AS. The lack of
effect may be due to the lower efficacy of statins in decreasing Lp(a)
concentrations15. Furthermore, those patients with
elevated Lp(a) levels have a modest but significant lower LDL response
to statin therapy. Another likely reason could be poor understanding of
the underlying pathogenetic mechanisms of valvular calcification in AS.
Improved understanding of AS pathophysiology may lead to a novel
development of biomarkers or medical therapy inhibiting AS progression,
which subsequently could delay or even avoid the need for valve
replacement16.
Several genomic studies examined the role of Lp(a) and its linkage to
AS. The GWAS study showed an important link between mutations in theLPA gene with aortic stenosis (HR 1.68; 95% CI, 1.32-2.15)2. This is just an example of how genetic information
is unraveling the pathogenesis of an important human disease. The
initial GWAS in 6942 patients of white European ethnicity demonstrated
genome-wide significance between the lipoprotein(a)[Lp(a)]LPA locus (rs10455872) and the presence of aortic valve
calcification as assessed by computed tomography (OR per allele, 2.05; P
= 9.0x10−10). This association was found to hold true
in a confirmatory white European, African-American, and
Hispanic-American cohort. The authors then performed a prospective
analysis to determine that the LPA genotype was associated with
aortic stenosis (HR 1.68; 95% CI, 1.32-2.15) and aortic valve
replacement (HR 1.54; 95% CI, 1.05-2.27).
As Lp(a) is a LDL-rich cholesterol particle, possible mechanisms have
been proposed to better understand the association between high Lp(a)
and AS. First, in a similar manner to LDL role in atherosclerosis,
deposition of cholesterol may occur on the aortic valve cusps and
arterial intima leading to valve cusps thickening3.
Second mechanism suggests that Lp(a) may bind to fibrin and deliver
cholesterol to sites of tissue injury (i.e.: leaflets), thus augmenting
valve calcification17. Our study support these
mechanisms as we demonstrated increased Lp(a) staining and levels in
aortic valve cusps, more prominent in the free leaflets edges and
commissures. Further and more recent mechanism may relate to an
associated high levels of oxidized phospholipids (OxPL) with Lp(a)18.
Lp(a) a is a major carrier of oxidized phospholipids (OxPL) and is
established risk factor for AS population and genetic
studies19. Recently, Zheng and colleagues reported an
association between Lp(a), OxPL and increased risk of valve replacement
and mortality (n=145, HR; 1.85, 95% CI: 1.13- 3.08;p=0.014) compared to
patients with lower levels of Lp(a)18. These robust
findings reaffirm the importance of circulating lipids in the
pathogenesis and bring to light the importance of Lp(a) in this common
but poorly understood disorder. Furthermore, Capoulade and colleagues
showed a significant relationship between the elevated levels of Lp(a)
and AS progression. In their secondary analysis of the ASTRONOMER trial
(effects of Rosuvastatin on aortic stenosis progression), a linear
association was found between plasma levels of Lp(a) (odds ratio
[OR] per 10-mg/dL increase, 1.10; 95% CI, 1.03-1.19; p = 0.006),
OxPL-apoB (OR per 1-nM increase, 1.06; 95% CI, 1.01-1.12; p = .02) and
faster progression of AS 20. Such data provide insight
and light for future medical therapy targeting Lp(a) levels.
Our results along with other recent published data, provide a rationale
and hope to develop novel therapeutic medical strategies to tackle the
progression of AS.
Limitations:
Our study has several limitations that are mainly driven by the small
sample size in our cohort. First, small size of human and animal
participants which may have affected the results seen. However, in
conjunction with other larger published data18,20,21,
our results could explain the mechanism of Lp(a) role in developing AS.
Second, given the small sample size, we were not able to look for
possible predictors of elevated Lp(a) in AS patients or the mice model.
Third, we did not investigate if cusp morphology could play a role in
increasing levels of Lp(a) and ultimately developing AS.
Conclusion:
The evidence supporting an association between Lp(a) and AS is growing.
We provide an experimental and human evidence of Lp(a) association with
aortic stenosis. This amplifies the need for larger studies addressing
such an association. As such, future aortic stenosis studies should
consider targeting Lp(a) levels for possible AS medical treatment.
Authors Contribution:
Ahmad Makhdoum1,MD, MSc: drafting and analysis of the
manuscript:
Yasuhiro Kotani2,MD,PhD:Design and analysis of the
manuscript.
Ryuichi Morishita3,MD,PhD: Design and analysis and
methodology.
Rei Otsu3,MD: Experiments.
Yoshiaki Taniyama3,MD, PhD: Experiments and design.
Amine Mazine1,MD, MSc: Drafting the manuscript.
Hon Sing Leong4, PhD: Design and analysis.
Subodh Verma1,MD, PhD: Drafting and revising the
manuscript.
Bobby Yanagawa1,MD, PhD: Revising and drafting the
manuscript
References
1. Iung B. A prospective survey of patients with valvular heart disease
in Europe: The Euro Heart Survey on Valvular Heart Disease.European Heart Journal . 2003;24(13):1231-1243.
doi:10.1016/S0195-668X(03)00201-X.
2. Thanassoulis G, Campbell CY, Owens DS, et al. Genetic Associations
with Valvular Calcification and Aortic Stenosis. New England
Journal of Medicine . 2013;368(6):503-512. doi:10.1056/NEJMoa1109034.
3. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a
cardiovascular risk factor: current status. European Heart
Journal . 2010;31(23):2844-2853.
4. Catapano AL, De Backer G, Graham I, et al. ESC/EAS Guidelines for the
management of dyslipidaemias: The Task Force for the management of
dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). European Heart Journal .
2011;32(14):1769-1818.
5. Afshar M, Thanassoulis G. Lipoprotein(a). Current Opinion in
Lipidology . 2017;28(2):170-176. doi:10.1097/MOL.0000000000000392.
6. Clarke R, Peden JF, Hopewell JC, et al. Genetic Variants Associated
with Lp(a) Lipoprotein Level and Coronary Disease. New England
Journal of Medicine . 2009;361(26):2518-2528. doi:10.1056/NEJMoa0902604.
7. Kamstrup PR. Genetically Elevated Lipoprotein(a) and Increased Risk
of Myocardial Infarction. J Am Med Assoc . 2009;301(22):2331-2339.
doi:10.1001/jama.2009.801.
8. Berglund L, Ramakrishnan R. Lipoprotein(a). Arterioscler Thromb
Vasc Biol . 2004;24(12):2219-2226.
doi:10.1161/01.ATV.0000144010.55563.63.
9. Schneider M, Witztum JL, Young SG, et al. High-level lipoprotein
[a] expression in transgenic mice: evidence for oxidized
phospholipids in lipoprotein [a] but not in low density
lipoproteins. Journal of Lipid Research . 2005;46(4):769-778.
doi:10.1194/jlr.M400467-JLR200.
10. Morishita R, Yamada S, Yamamoto K, et al. Novel therapeutic strategy
for atherosclerosis: ribozyme oligonucleotides against apolipoprotein(a)
selectively inhibit apolipoprotein(a) but not plasminogen gene
expression. Circulation . 1998;98(18):1898-1904.
doi:10.1161/01.cir.98.18.1898.
11. Lawn RM, Wade DP, Hammer RE, Chiesa G, Verstuyft JG, Rubin EM.
Atherogenesis in transgenic mice expressing human apolipoprotein( a ).Nature . 1992;360(6405):670-672. doi:10.1038/360670a0.
12. Callow MJ, Verstuyft J, Tangirala R, Palinski W, Rubin EM.
Atherogenesis in transgenic mice with human apolipoprotein B and
lipoprotein (a). J Clin Invest . 1995;96(3):1639-1646.
doi:10.1172/JCI118203.
13. Czarny MJ, Resar JR. Diagnosis and Management of Valvular Aortic
Stenosis. Clin Med Insights Cardiol . 2015;8s1:CMC.S15716.
doi:10.4137/CMC.S15716.
14. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J, ASTRONOMER Investigators.
Effect of Lipid lowering with rosuvastatin on progression of aortic
stenosis: results of the aortic stenosis progression observation:
measuring effects of rosuvastatin (ASTRONOMER) trial.Circulation . 2010;121(2):306-314.
doi:10.1161/CIRCULATIONAHA.109.900027.
15. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic
valve disease. Nature . 2005;437(7056):270-274.
doi:10.1038/nature03940.
16. Zhao Y, Nicoll R, He YH, Henein MY. The effect of statins therapy in
aortic stenosis: Meta-analysis comparison data of RCTs and
observationals. Data Brief . 2016;7:357-361.
doi:10.1016/j.dib.2016.02.045.
17. Nordestgaard BG, Langsted A. How Does Elevated Lipoprotein(a)
Cause Aortic Valve Stenosis? JAC . 2015;66(11):1247-1249.
18. Zheng KH, Tsimikas S, Pawade T, et al. Lipoprotein(a) and Oxidized
Phospholipids Promote Valve Calcification in Patients With
Aortic Stenosis. JAC . 2019;73(17):2150-2162.
doi:10.1016/j.jacc.2019.01.070.
19. Kamstrup PR, Hung M-Y, Witztum JL, Tsimikas S, Nordestgaard BG.
Oxidized Phospholipids and Risk of Calcific Aortic Valve Disease: The
Copenhagen General Population Study. Arterioscler Thromb Vasc
Biol . 2017;37(8):1570-1578. doi:10.1161/ATVBAHA.116.308761.
20. Capoulade R, Yeang C, Chan KL, Pibarot P, Tsimikas S. Association of
Mild to Moderate Aortic Valve Stenosis Progression With Higher
Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a
Randomized Clinical Trial. JAMA Cardiol . 2018;3(12):1212-1217.
doi:10.1001/jamacardio.2018.3798.
21. Cairns BJ, Coffey S, Travis RC, et al. A Replicated, Genome-Wide
Significant Association of Aortic Stenosis With a Genetic Variant for
Lipoprotein(a). Circulation . 2017;135(12):1181-1183.
doi:10.1161/CIRCULATIONAHA.116.026103.
Table