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Aortic stenosis is a growing worldwide health burden with no approved therapies beyond surgical or transcatheter valve replacement procedures. Calcification of aortic valve leaflets is a major contributor to aortic stenosis, subsequent heart failure and ultimately death. A small number of genetic contributors to valvular calcification have been identified, with elevated lipoprotein(a) (Lp(a)) being one of the strongest risk factors for calcific aortic valve disease (CAVD).1 Despite >1 billion people globally having elevated Lp(a) (>30 to 50 mg/dL or >75 to 125 nmol/L),2 the normal physiological function of Lp(a) and how Lp(a) mechanistically promotes CAVD progression have not been established. As such, identifying the roles that Lp(a) plays in human disease is a major unmet medical need with far-reaching therapeutic potential. In their Heart paper, Capoulade et al3 assessed Lp(a) complexes with apolipoproteins and oxidised phospholipids (OxPLs) in patients from the Aortic Stenosis Progression Observation: Measuring Effects of Rousvastatin trial. This new clinical report demonstrates the novel finding that complexes of Lp(a) with apolipoprotein CIII (apoCIII) are associated with accelerated CAVD progression, in addition to validating4 the association of apolipoprotein(a) (apo(a))-OxPL complexes with accelerated CAVD progression.
Lp(a) is a low-density lipoprotein-like particle with apo(a) covalently bound to apolipoprotein B (apoB) on the particle surface (figure 1). Unlike low-density lipoprotein, apo(a) levels are only modestly altered by diet, and it is likely that apo(a) impairs the uptake of Lp(a) via receptors that bind apoB. This lack of association to diet and the complexing of molecules with Lp(a) presents therapeutic challenges as well as opportunities. Firm evidence supports the finding that statins increase receptor-mediated uptake of low-density lipoprotein, but there is no clear evidence that statins reduce Lp(a) or work as an effective therapy for cardiovascular calcification and aortic stenosis.5 This suggests mechanistic differences between low-density lipoprotein and Lp(a) metabolism, along with the conundrum of how circulating Lp(a) interacts with and mediates its effects in cardiovascular cells. One possibility is receptor-mediated uptake of Lp(a) or molecules complexed with Lp(a),6 another is receptor-independent uptake, and a third possibility is metabolism of Lp(a) particles trapped in the extracellular matrix releasing molecules that interact with cardiovascular cells (figure 1). Supporting the latter, autotaxin, an enzyme that produces lysophosphatidic acid from lysophosphatidylcholine in Lp(a) trapped in the extracellular matrix, promotes valvular calcification via inflammation and has been reported to be increased in CAVD.7 In contrast, Capoulade et al3 did not find an association of autotaxin on Lp(a) or apoB with increased progression of aortic stenosis. The reason for this discrepancy is not clear, but some potential reasons could include that the present study assessed autotaxin mass but not activity, and only autotaxin on Lp(a) and apoB but not total plasma levels. Further work is critically needed to define how Lp(a) interacts with valve cells that are responsible for the production of calcification in the extracellular matrix. Lp(a) can be directly targeted via antisense oligonucleotides, a very promising and selective therapeutic approach for Lp(a)-associated diseases. However, better defining Lp(a) uptake and metabolism mechanisms in the valve might lead to the development of small-molecule therapies that could be more accessible to a broader patient population due to comparatively lower costs for small-molecule drugs.
Many proteins are found on Lp(a) particles, including apoCIII, a finding that was verified by Capoulade et al3 using proteomics. Unlike apo(a) or apoB, which occur in a 1:1 ratio, apoCIII was found to be likely carried as multiple copies on a subset of Lp(a) particles. This raises the intriguing but unproven hypothesis that apoCIII complexed with Lp(a) could be responsible for inducing molecular mechanisms leading to accelerated CAVD. ApoCIII promotes cardiovascular inflammation,8 but whether apoCIII directly induces valvular calcification and the mechanisms by which it could do so was not assessed by Capoulade et al3 or in other published reports. Like apo(a), apoCIII can interfere with apoB binding to cell surface receptors; as such, it is tempting to speculate that the subset of Lp(a) complexed with apoCIII may have altered metabolism and uptake. In addition to apoCIII complexing with Lp(a), apo(a) and apoB complex with OxPLs, which have been previously associated with increased CAVD progression.4 OxPLs promote cardiovascular disease via inflammation, including valvular calcification that was inhibited in a hypercholesterolaemic mouse model by the E06 antibody, which impairs uptake of oxidised lipids.9 Taken together, the findings of Capoulade et al3 and others4 9 support the untested potential of indirectly targeting Lp(a)-mediated CAVD with antibodies, including E06 that interact with oxidised lipids.
In summary, the findings of Capoulade et al3 raise the potential for some combination of elevated Lp(a) and Lp(a) complexes with apolipoproteins or OxPLs to serve as biomarkers for individuals with increased CAVD risk. Clinical studies assessing the effectiveness of Lp(a) or apoCIII antisense oligonucleotides, EO6 antibodies or other means of targeting these apolipoproteins and oxidised lipids could be the next major therapeutic step to identify non-surgical interventions for CAVD, particularly in the high-risk population of patients with elevated Lp(a).
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Footnotes
MAR and EA are joint senior authors.
Contributors MAR wrote the manuscript and EA edited and critically revised the manuscript.
Funding This work is supported by National Institutes of Health grants R01HL136431, R01HL14917 and R01HL147095.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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