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
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