Abstract
Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein with a strong genetic regulation. Up to 90% of the concentrations are explained by a single gene, the LPA gene. The concentrations show a several-hundred-fold interindividual variability ranging from less than 0.1mg/dL to more than 300mg/dL. Lp(a) plasma concentrations above 30mg/dL and even more above 50mg/dL are associated with an increased risk for cardiovascular disease including myocardial infarction, stroke, aortic valve stenosis, heart failure, peripheral arterial disease, and all-cause mortality. Since concentrations above 50mg/dL are observed in roughly 20% of the Caucasian population and in an even higher frequency in African-American and Asian-Indian ethnicities, it can be assumed that Lp(a) is one of the most important genetically determined risk factors for cardiovascular disease.Carriers of genetic variants that are associated with high Lp(a) concentrations have a markedly increased risk for cardiovascular events. Studies that used these genetic variants as a genetic instrument to support a causal role for Lp(a) as a cardiovascular risk factor are called Mendelian randomization studies. The principle of this type of studies has been introduced and tested for the first time ever with Lp(a) and its genetic determinants.There are currently no approved pharmacologic therapies that specifically target Lp(a) concentrations. However, some therapies that target primarily LDL cholesterol have also an influence on Lp(a) concentrations. These are mainly PCSK9 inhibitors that lower LDL cholesterol by 60% and Lp(a) by 25-30%. Furthermore, lipoprotein apheresis lowers both, Lp(a) and LDL cholesterol, by about 60-70%. Some sophisticated study designs and statistical analyses provided support that lowering Lp(a) by these therapies also lowers cardiovascular events on top of the effect caused by lowering LDL cholesterol, although this was not the main target of the therapy. Currently, new therapies targeting RNA such as antisense oligonucleotides (ASO) or small interfering RNA (siRNA) against apolipoprotein(a), the main protein of the Lp(a) particle, are under examination and lower Lp(a) concentrations up to 90%. Since these therapies specifically lower Lp(a) concentrations without influencing other lipoproteins, they will serve the last piece of the puzzle whether a decrease of Lp(a) results also in a decrease of cardiovascular events.
Highlights
Lipoprotein(a) [Lp(a)] is one of the strongest genetically determined risk factors for cardiovascular disease (CVD) (Kronenberg and Utermann 2013)
The evidence is quite strong that high Lp(a) concentrations are associated with an increasing risk for cardiovascular disease (Kronenberg and Utermann 2013; Cegla et al 2019)
A sufficient study size and number of endpoints is in this context a prerequisite since the finding of an association with all-cause mortality is mainly driven by death in the wider context of CVD
Summary
Lipoprotein(a) [Lp(a)] is one of the strongest genetically determined risk factors for cardiovascular disease (CVD) (Kronenberg and Utermann 2013). In a further investigation they examined whether patients with cardiovascular disease and elevated Lp(a) concentrations experience anti-inflammatory effects following large reductions of Lp(a) by apo(a) antisense therapy They observed in a first step that circulating monocytes of healthy individuals and patients, both having high Lp(a) concentrations, are characterized by a markedly pro-inflammatory gene expression profile with several pathways of the innate immune system being upregulated. In an intervention with apo(a) antisense therapy the authors showed that the resulting 47% lowering of Lp(a) concentrations was capable of reversing the pro-inflammatory gene expression signature to levels close to that of controls with normal Lp(a) concentrations This was accompanied with a 22% functional reduction in transendothelial migration capacity of monocytes ex vivo (Fig. 2c) (Stiekema et al 2020; Coassin and Kronenberg 2020). It might very well be that some of these variants explain the large ethnic and interindividual differences in Lp(a) concentrations
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