Focus on lipoprotein(a): The time is now

Abstract

Low-density lipoprotein cholesterol (LDL-C) is the most important risk factor for atherosclerotic cardiovascular disease (ASCVD), but some individuals who meet the LDL-C treatment goal still have a residual risk of ASCVD [1]. Numerous clinical studies and meta-analyses have shown that high lipoprotein (a) (Lp(a)) concentration is a continuous, independent, and moderately significant risk factor for ASCVD, and that this association is not dependent on LDL-C or non-HDL-C levels or other risk factors [2].

Lp(a) was first introduced to the scientific world by the Norwegian physician and geneticist Kare Berg in 1963 [3]. Lp(a) closely resembles LDL in terms of its protein and lipid composition, containing one molecule of apolipoprotein B (apoB) wrapped around a core of cholesterol esters and triglycerides with a surface of phospholipids and unesterified cholesterol particles. Lp(a) also contains a highly glycosylated protein called apo(a). This protein forms a covalent bond with apoB-100 via a single disulfide bond, which distinguishes Lp(a) from LDL.

Despite the fact that the structure of Lp(a) is similar to that of LDL, Lp(a) with a unique apo(a) is more atherogenic than LDL, and it is an attractive target for blood lipid intervention. The expert panel of the Beijing Heart Society has extended the systematic knowledge regarding Lp(a) beyond integrating the current global knowledge of Lp(a) and summarizing the evidence from Chinese populations. The scientific statement from Beijing Heart Society suggests key points for managing Lp(a) in Chinese populations for reference in clinical practice [4].

Lp(a) concentrations vary greatly among different races and geographic regions. In the Chinese population, Lp(a) concentrations have a skewed distribution with a median concentration of 5.6–8.0 mg/dL, which is slightly lower than that in Caucasians (9.0–17.0 mg/dL) but much lower than that in African Americans (33 mg/dL). Lp(a) concentrations are heritable, with total heritability of 68%–98%. The LPA gene (MIM 152200; ENSG00000198670) located on chromosome 6q27 encodes apo(a), and copy number variations in KIV-2 within the gene can range from 2 to 40 copies, which can explain 70%–90% of plasma Lp(a) concentrations [5].

In addition, single-nucleotide polymorphisms on the LPA gene are also associated with Lp(a) concentrations. The variant rs10455872 located in intron 25 and rs3798220 in the protease-like domain show the strongest correlation with Lp(a) concentrations, accounting for 22% of the variation in Lp(a) concentrations. However, these two single-nucleotide polymorphisms have not been found to be associated with Lp(a) concentrations in South Asian and Chinese populations [6]. In Chinese populations, rs7770628 and rs73596816 are the single-nucleotide polymorphisms most significantly associated with the severity of coronary heart disease in Chinese patients [7]. Notably, the concentration of Lp(a) is not solely determined by classical genetic factors; it is also affected by other factors including age, hormonal concentrations, and renal function.

A large amount of evidence from human genetic, epidemiological, and Mendelian randomization studies have shown that elevated Lp(a) concentrations are an independent risk factor for various cardiovascular diseases (CVDs), such as coronary artery disease, cerebral ischemic stroke, and calcific aortic valve stenosis (CAVS).

Evidence from the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial showed that the risk of major adverse cardiovascular events was almost double in individuals with Lp(a) concentrations ≥50 mg/dL, despite LDL-C concentrations ≥1.62 mmol/L. In the Chinese population, a retrospective analysis (CCSSSCC database) of 1522 patients with acute myocardial infarction and 1691 control individuals (LDL-C concentrations <2.6 mmol/L) without coronary artery disease was performed. This study showed that the risk of the initial onset of acute myocardial infarction in patients with Lp(a) concentrations in the second, third, fourth, and fifth quintiles was significantly higher than that in the first quintile.

Evidence based on a large-scale observational trial and Mendelian randomization study of hundreds of thousands of people showed that there was a positive correlation between Lp(a) concentrations and ischemic stroke resulting from aortic occlusion. A prospective study from the Chinese population showed that the risk of ischemic stroke increased if Lp(a) concentrations were >38.2 mg/dL.

The Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) study showed that increased Lp(a) concentrations accelerated the progression of CAVS. Evidence from a prospective Chinese cohort suggested that Lp(a) concentrations might be helpful in the risk stratification of patients with CAVS. Furthermore, elevated Lp(a) concentrations are an enhanced risk factor for CVD in patients with familial hypercholesterolemia and type 2 diabetes mellitus. In patients with CVD and type 2 diabetes mellitus, the risk of CVD associated with Lp(a) might be further increased.

The scientific statement from Beijing Heart Society recommends that the general population need to have Lp(a) concentrations measured at least once in their lifetime to identify individuals (Lp(a) concentrations >180 mg/dL [>430 nmol/L]) with a high lifetime risk of ASCVD, which is approximately equivalent to the risk associated with heterozygous familial hypercholesterolemia. This recommendation is consistent with the 2019 European Guidelines for the Management of Dyslipidemia.

Based on the large amount of evidence between Lp(a) concentrations and CVD, the measurement of Lp(a) is recommended for the following five types of populations: (a) populations considered having an extremely high risk of ASCVD; (b) individuals with a family history of premature ASCVD (men <55 years, women <65 years); (c) individuals with lineal relatives who have Lp(a) concentrations ≥90 mg/dL (200 nmol/L); (d) those with familial hypercholesterolemia or other types of hereditary dyslipidemia; and (e) patients with CAVS.

Lp(a) cutoff values for an increased cardiovascular risk are inconsistent according to guidelines and consensuses in different countries, but 50 mg/dL is frequently recommended as the cutoff value. After evaluating the published evidence from the Chinese population, the expert panel of the Beijing Heart Society recommended an Lp(a) cutoff value of 30 mg/dL for increased cardiovascular risk in China.

Two primary principles of managing Lp(a) concentrations include lowering the overall ASCVD risk and controlling all associated types of dyslipidemia. Although lifestyle interventions cannot directly reduce Lp(a) concentrations, controlling common risk factors for patients with elevated Lp(a) levels is beneficial. There have been few studies in China regarding interventions for Lp(a) concentrations. Clinical trials in other countries have suggested that lowering LDL-C concentrations by statin therapy helps reduce the CVD risk induced by increased Lp(a) concentrations. Notably, in some studies, Lp(a) concentrations were mildly increased during statin therapy. Whether this approach can benefit patients is unknown. PCSK9 inhibitors, which are strong LDL-C-lowering drugs, can reduce Lp(a) lowering by approximately 20%–30%. Such a reduction in Lp(a) concentrations may not significantly change the decrease in cardiovascular events related to high Lp(a) concentrations. Therefore, PCSK9 inhibitors for lowering Lp(a) concentrations as the primary goal in the Chinese population is not recommended. Niacin therapy has a limited effect in reducing the degree of Lp(a) concentrations (23%) and its clinical benefits are not clear; therefore, it is not recommended. Lipoprotein apheresis can greatly reduce various blood lipid concentrations (Lp(a) by 50%–70%), but it is not recommended by Chinese experts as a routine treatment owing to safety and cost concerns.

RNA-targeting therapy may effectively reduce Lp(a) concentrations. Phase I and II clinical trials have shown that antisense oligonucleotides targeting liver lipoprotein apheresis RNA can lower Lp(a) concentrations by >80%. An ongoing phase III clinical trial will determine whether such a large decrease can significantly reduce the CVD risk in patients with increased Lp(a) concentrations.

For the first time, the clinical expert statement is concerned with laboratory methods of blood lipids. The standardization of Lp(a) assays will affect the clinical determination of high-risk patients and the determination of therapeutic target values. The variation in the copy number of KIV2 in apo(a) is the main reason for the polymorphism of Lp(a) and the main obstacle for the lack of standardization. The fundamental solution to this problem is to use monoclonal antibodies that are insensitive to apo(a) isoforms and do not cross-react with fibrinogen, and to trace the assay to the World Health Organization/International Federation of Clinical Chemistry and Laboratory Medicine standard reference material 2B. Mass concentration assay is not the best method to determine Lp(a) concentrations owing to the high polymorphism in Lp(a) size and density. The molar concentration detection method, which indicates the number of Lp(a) particles, is the preferred method to eliminate Lp(a) polymorphisms. A conversion factor cannot be used to convert between these two methods because the conversion relation is non-uniform at different concentrations. Although this statement indicates that reporting results as mass concentration or molar concentration is acceptable based on the status quo, molar concentration is recommended.

The role of Lp(a) in CVD is well known, and it is the most important enhancer of ASCVD risk after LDL-C. The expected development of novel RNA-targeted drugs has also increased clinical attention to Lp(a) to an unprecedented level. Therefore, the cutoff point for Lp(a) concentrations indicating a risk of ASCVD in the Chinese population and the standardization of laboratory tests are future focuses of research.

Ya-hui Lin: Project administration (equal); Writing–original draft (lead); Writing–review & editing (lead). Qiong Yang: Conceptualization (equal); Writing–original draft (equal). Zhou Zhou: Funding acquisition (lead); Writing–review & editing (equal).

The authors declare no conflict of interest.

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