Lipoprotein ‘little a’: More than a little target in the management of cardiovascular risk?

It has been 62 years since Berg¹ first described lipoprotein(a) (Lp[a]) and 32 years since a large prospective case-control study² seemingly demonstrated that Lp(a) played no contributory role in the risk for a predominantly male cohort to develop myocardial infarctions. That storyline has since flipped.

In this issue of the Journal, Al-Dalakta et al³ offer their perspective on the status of Lp(a) as a determinant of cardiovascular risk and a viable target for clinical intervention. As they discuss, there are currently several trials underway testing whether cardiovascular events will be reduced by lowering Lp(a). Results from the large prospective Lp(a)HORIZON (Assessing the Impact of Lipoprotein[a] Lowering With Pelacarsen [TQJ230] on Major Cardiovascular Events in Patients With CVD) trial⁴ should be reported soon. This study is particularly robust in that it is evaluating the additive benefit of Lp(a) reduction, using an antisense oligonucleotide, in a population of patients who are already receiving aggressive care for their cardiovascular disease.

Initially, it was thought that Lp(a) was either present or absent, but as improved quantitative assays became available, that turned out not to be the case.⁵ Everyone has circulating hepatocyte-derived Lp(a). There are different Lp(a) isoforms, each synthesized at a different rate, with the synthetic rate determining an individual’s circulating amount.⁶ It turns out that the biology of Lp(a) particles is quite interesting,⁷ and far more complex than I had realized.

Each Lp(a) particle has a low-density lipoprotein (LDL) component that is structurally similar to other LDL-containing particles. The cholesterol content of Lp(a) is included in the total amount of LDL cholesterol (LDL-C) when measured by standard laboratory assays. But since the cholesterol in Lp(a) is especially atherogenic, the varying amount of Lp(a) in different individuals with the same total LDL-C provides one explanation why the LDL-C amount alone is an imperfect determinant of cardiovascular risk.

Lp(a) is characterized by the covalent attachment of apolipoprotein(a) (apo[a]) to the apolipoprotein B of its LDL. Apo(a) dangles like a tail off the Lp(a) particle (see illustration at end of this article), conferring it with unique functional properties. The amount of circulating Lp(a) is in large part a function of the size of the particles, and the size of each Lp(a) particle is primarily determined by polymorphisms in the apo(a) gene. The most significant polymorphism is the number of repeat protein coils (kringles) coded for and translated from each of the 2 apo(a) alleles individuals inherit. The different Lp(a) molecules are termed isoforms. Each allele encodes an apo(a) isoform with a distinct number of kringles, resulting in substantial interindividual heterogeneity in isoform size and plasma Lp(a) levels.

Interestingly, apo(a) shares significant homology with plasminogen, suggesting that it originally arose from gene duplication. This plasminogen homology is biologically relevant since the Lp(a), when embedded within atherosclerotic plaque, exhibits prothrombotic activity by competing with native plasminogen and inhibiting fibrinolysis.

Lp(a) carries more atherogenic oxidized phospholipid than other LDL particles because apo(a) attracts oxidized phospholipids via high-affinity binding sites,⁸ making it the preferential plasma carrier of these proinflammatory lipids. Further amplifying its pathogenic effects, Lp(a) is selectively retained and concentrated in atherosclerotic plaque and calcified aortic valve tissue via apo(a)-mediated binding to exposed matrix proteins, including fibronectin.⁹ Once incorporated into plaque (or aortic valve tissue), Lp(a) with its oxidized phospholipid stimulates macrophage activation, cytokine release, and localized thrombosis.¹⁰

Most of the interindividual variability of circulating Lp(a) is based on its structure-driven synthetic rate, and the level in most individuals is fairly constant throughout life. But the liver and kidney are essential for Lp(a) clearance, and marked renal dysfunction leads to elevated circulating Lp(a). This elevation may be clinically relevant, potentially accounting for some of the well-recognized yet incompletely understood increased cardiovascular risk observed in patients with advanced kidney disease.^11,12

Should the Lp(a)HORIZON trial and other interventional studies be strikingly positive, this could markedly change the way we assess and manage cardiovascular risk. That would be no little change.

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