Available online 11 February 2023, 101746

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High levels of lipoprotein(a) [Lp(a)] are causal for development of atherosclerotic cardiovascular disease and highly regulated by genetics. Levels are higher in Blacks compared to Whites, and in women compared to men. Lp(a)’s main protein components are apolipoprotein (apo) (a) and apoB100, the latter being the main component of Low-Density Lipoprotein (LDL) particles. Studies have identified Lp(a) particles to be associated with inflammatory, coagulation and wound healing pathways. Lack of validated and accepted assays to measure Lp(a), risk cutoff levels, guidelines for diagnosis, and targeted therapies have added challenges to the field. Scientific efforts are ongoing to address these, including studies evaluating the cardiovascular benefits of decreasing Lp(a) levels with targeted apo(a) lowering treatments. This review will provide an overview of evidence-based effects of high Lp(a) on disease presentation, highlight available guidelines and discuss promising therapies in development. We will conclude with current clinical information and future research needs in the field.

Section snippetsWhat is Lipoprotein (a)?

Lipoprotein (a) [Lp(a)] is a plasma lipid particle containing two main apolipoproteins: apolipoprotein B100 [apoB] and apolipoprotein(a) [apo(a)] [1]. It was first discovered by Kare Berg in 1963 [2]. Current evidence supports that the assembly of the Lp(a) particle occurs within the liver, including the binding of apo(a) to apoB via a single disulfide bond [3]. Most individuals produce two isoforms of apo(a), as determined by the number of Kringle-IV type 2 (KIV-2) repeats in the particle,

Metabolic Regulation of Circulating Lipoprotein(a) Levels: Synthesis, Production and Clearance

The levels of circulating plasma proteins are regulated by their production and clearance and the specific pathways responsible for Lp(a) processing are still being investigated [8]. The production of Lp(a) has been shown to be highly affected by the size of KIV-2 repeats and the self-reported race/ethnicity [9], [10]. It has been shown that levels of Lp(a) are higher in Blacks and Hispanics compare to Whites. Additionally, results from studies using Low-Density Lipoprotein Cholesterol (LDL-C)

Lipoprotein(a): Genetics and Clinical Perspective

Lp(a) levels are primarily genetically regulated [17]. The size of the apo(a) is determined by the KIV-2 copy number and is inversely related to the Lp(a) plasma levels. This copy number variance may account for the large variability (19% to 69%) of interindividual Lp(a) levels [18]. Genetic relationships with APOE ε2 allele have been linked to a small decrease (0.5%) in levels of Lp(a) [19]. Lastly, the work of various investigators [20], [21], [*22], and most recent publications from Dr.

Lp(a) and ASCVD and Aortic Valve Stenosis

Lp(a) particles have been identified in human atheroma dissections [40], [41], indicating that the molecule is involved in atherogenic mechanisms. In addition, genetic studies have provided convincing evidence that LPA is associated causally with coronary heart disease (CHD) and the development of aortic stenosis [*22], [42], [43], [44], [45]. There is data supporting an association between high Lp(a) levels with myocardial infarction [46], [47], [48], aortic valve disease [49], [50], stroke

Lipoprotein(a) Links to Inflammatory Pathways

Inflammatory pathways have been linked to the development and outcomes of ASCVD. Importantly, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) for the first time provided conclusive evidence that inflammation enhances cardiovascular disease (CVD) in humans [60]. Interleukins (IL-6 and IL-18), markers of the inflammatory state, are associated with CVD risk in humans [61], [62], [63], and use of Tocilizumab, an IL-6 antagonist, resulted in decreased serum Lp(a) concentrations

Measuring Lp(a) in Patients: How and When?

Despite the lack of international or national standardized assays, the data on Lp(a)’s causal link to ASCVD and multiple national statements and international guidelines have encouraged clinicians to measure Lp(a) levels at least once in a lifetime [53]. Although temporal variabilities in Lp(a) levels have been reported during a lifetime [70], these are not significant for individuals to be classified as having high levels in one measurement, and later in life finding these levels to be low

What to Do When Lp(a) is High?

The current guidelines on management of Lp(a) levels suggest lowering all other risk factors [*53], [76]. In the published statement on Lp(a) from the American Heart Association (AHA), authors have provided user friendly tables to assess risk, these can aid clinicians to assess additional cardiovascular risk factors, including Lp(a) levels when/if available [53]. Some therapies that lower apoB and LDL-C also decrease Lp(a) modestly, such as niacin, CETP inhibitors, ApoB antisense. PSCK9

Drugs in Development that Lower Lp(a)

Over the last 5 years there has been an increased interest in understanding Lp(a) disease presentation and its link to development of ASCVD. This has been driven by the investments being made in novel therapies that target apo(a) synthesis, using small interfering RNA (siRNA) and antisense technology in the liver and thereby lowering the production of Lp(a) [53]. Completed studies in these programs observed reductions in Lp(a) plasma levels between 71% and 97% with olpasiran, a N

Summary

This review described Lp(a), discussed the role of genetics and other factors that affect Lp(a) levels, and its role in cardiovascular disease with the emphasis on clinical implications. There is strong scientific support for measuring Lp(a) in every individual at least once in adulthood and some suggest measuring it twice. Obtaining a thorough medical history in every patient will ensure correct follow up and personalized advise from treating physicians. It is clear that in individuals with

Acknowledgement

All the presented text and figures have been developed by the study authors.

Funding and Conflicts of Interest

There are no conflicts from the authors for the work presented. The authors receive funding from NIH-NHLBI (R01HL139759, T32HL007343) and industry studies (Amgen, Inc; Kaneka) examining the role of lipid lowering therapies on lipid metabolic factors.

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