INTRODUCTION

Lipoprotein(a) (Lp(a)) is a particle similar to low-density lipoprotein (LDL) cholesterol, first identified in 1963. Its levels are primarily determined by genetics, and there are significant racial variations in serum concentrations [1,2]. Numerous epidemiological studies have provided evidence of its association with an increased risk of cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS) in individuals with high concentrations of Lp(a). Additionally, genetic research supports a strong correlation between genetically determined high levels of Lp(a) and increased risks of CVD and CAVS.

Recent guidelines recommend using Lp(a) levels to predict lifetime CVD risk, given that Lp(a) levels are genetically determined and generally not reduced by standard lipid-lowering medications. However, controversies exist regarding the universal cutoffs for predicting high CVD risk and the discrepancies in Lp(a) measurement methods [1]. Furthermore, it remains unclear whether Lp(a) should be used as an adjunct or as a substitute for traditional risk factors in predicting CVD risk.

In this article, I will focus on summarizing the current evidence and knowledge regarding the predictive capacity of Lp(a) as a prognostic marker for future CVD and CAVS.

CURRENT KNOWLEDGE AND CHALLENGES WHEN CONSIDERING Lp(a) AS THE PROGNOSTIC MARKER OF CVD

Lp(a) is an LDL-like particle consisting of triglycerides and cholesterol esters encased within an outer membrane of phospholipids and free cholesterol. Its protein component includes a single copy of apolipoprotein B-100 (apoB) linked to a single apolipoprotein(a) (apo(a)) particle through both covalent and noncovalent bonds [3].

Lp(a) is known to contribute to the development of atherosclerosis through vascular inflammation, atherogenesis, calcification, and thrombosis [4]. It penetrates the intima, undergoes oxidation, and leads to an increase in reactive oxygen species. The oxidized LDL is then absorbed by macrophages, which transform into foam cells and facilitate the formation of atherosclerotic plaques. Through these various mechanisms, Lp(a) promotes the development of atherosclerotic CVD.

Lp(a) is synthesized by the LPA gene, which encodes for two kringle domains, KIV-KV [4]. KIV is subdivided into 10 subtypes (KIV₁–KIV₁₀), and the expansion of KIV-2 leads to a range of variations, resulting in anywhere from 1 to over 40 identical copies. This expansion results in heterogeneous apo(a) isoform sizes, which compromises the accuracy of antibody-mediated immunoassays used to measure the true Lp(a) burden [3]. Since each Lp(a) molecule consists of one mole of apo(a) and one mole of apoB, regardless of the apo(a) size, measuring the molar concentration of Lp(a) may not accurately reflect the actual Lp(a) burden. Consequently, the International Federation of Clinical Chemistry, in collaboration with multiple associations, has recommended measuring Lp(a) in nanomoles per liter and has developed a reference material for this measurement.

Lp(a) levels are genetically determined and remain stable throughout an individual's lifetime. The challenges in establishing a global risk cutoff for Lp(a) include the following: (1) lack of uniformity in measurement units and methods; (2) racial variations in the values measured across different studies; and (3) inconsistency in the values reported by various studies. Even though numerous studies have indicated racial differences in Lp(a) levels, recent guidelines specify when to measure Lp(a) and establish treatment thresholds [5]. For instance, the 2018 American College of Cardiology/American Heart Association Cholesterol Guidelines state that Lp(a) levels ≥125 nmol/L should be considered a risk-enhancing factor for atherosclerotic CVD [6].

CLINICAL STUDIES THAT LINK Lp(a) LEVELS TO HIGH CVD RISK

The key clinical study demonstrating the association between Lp(a) and the risk for CVD is evidenced by data from a prospective study of the Danish general population, known as the Copenhagen City Heart Study (CCHS) [7]. This study followed 9,330 participants from the CCHS who had their baseline Lp(a) levels measured and had no prior history of CVD. Over a 10-year period, 498 participants developed myocardial infarction (MI). In women, the risk for MI significantly increased with rising Lp(a) levels, moving from the second to the fifth quintiles compared to the 1st quintile. Notably, women in the fifth quintile group (≥120 mg/dL) experienced a 3.6-fold increased risk for MI. A similar pattern of risk was observed in men based on their Lp(a) levels. The authors concluded that there is a stepwise increase in MI risk associated with higher levels of Lp(a), with no evidence of a threshold effect.

In a study involving 126,634 participants from 36 prospective studies within the Emerging Risk Factors Collaboration, identified through electronic database searches, researchers analyzed the associations between baseline Lp(a) levels and the risk of coronary heart disease (CHD), stroke, and nonvascular mortality [8]. The analysis revealed a broadly continuous relationship between Lp(a) levels and CHD risk. The risk ratios for CHD and stroke per one standard deviation increase in Lp(a) levels were 1.16 and 1.11, respectively, after adjusting for confounding variables. The authors concluded that there is a continuous, independent association between Lp(a) levels and the risks of CHD and stroke in these study populations.

In another study involving 460,506 middle-aged participants from the UK Biobank database, a linear relationship between Lp(a) and atherosclerotic CVD was observed over a median follow-up period of 11.2 years [9]. Although there were significant differences in Lp(a) concentrations according to race, the risk associated with a 50 nmol/L increase in Lp(a) appeared similar across ethnic groups (e.g., a 1.11-fold increased risk for White participants per 50 nmol/L increase).

Another interesting aspect of Lp(a) in relation to CVD is its strong genetic determination. A study involving 40,486 participants from three studies of White individuals—the CCHS, Copenhagen General Population Study (CGPS), and Copenhagen Ischemic Heart Disease Study—recorded Lp(a) levels, Lp(a) KIV-2 size polymorphism genotypes, and MIs [10]. Across all studies, the number of KIV-2 repeats was inversely correlated with Lp(a) levels, and Lp(a) levels were significantly correlated with an increased risk of MI. The findings suggest that genetically elevated Lp(a) levels are associated with a higher risk of MI. Another study examined the relationship between 48,742 single-nucleotide polymorphisms in 2,100 candidate genes and 3,145 case subjects with CHD, alongside 3,352 control subjects [11]. This study identified two common variants in the LPA locus associated with increased Lp(a) levels, fewer KIV-2 repeats, and a heightened risk for CHD. This further supports the notion that Lp(a) levels and CHD risk are genetically linked.

Lp(a) AND CAVS

High Lp(a) levels are considered a strong independent risk factor for AVS. The potential mechanisms through which Lp(a) influences the progression of CAVS include increased endothelial permeability, endothelial adhesion, microthrombi formation, enhanced cell proliferation, inflammatory mediators, osteoblastic differentiation, calcium deposition, and hydroxyapatite formation in aortic valves [12].

Accumulating evidence from clinical trials suggests an association between high Lp(a) levels and an increased risk of CAVS. One study, which combined data from two prospective general population studies, CCHS and CGPS, followed 77,680 Danish participants for up to 20 years. The study found that elevated Lp(a) levels were associated with an increased risk of AVS in a concentration-dependent manner [13]. Subsequent studies have reported similar findings [14,15]. Interestingly, a secondary analysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial revealed that increasing Lp(a) levels, but not LDL cholesterol levels, were associated with a higher risk of subsequent AVS events [16]. A recent systematic review of 21 studies provided convincing evidence of a potential causal association between high Lp(a) and AVS [12].

CONCLUSIONS

Although statins reduce cardiovascular risk by approximately 30% to 40% from baseline, a residual cardiovascular risk of around 40% remains, indicating the need for additional surrogate markers to further reduce cardiovascular risk [17]. Lp(a) is emerging as a novel marker that accounts for this residual cardiovascular risk and is genetically determined. Epidemiological and genetic studies have demonstrated a significant association between elevated Lp(a) levels and increased risk of atherosclerotic CVD and AVS, independent of LDL cholesterol levels. Further research is necessary before Lp(a) can be recommended as a target for reducing atherosclerotic CVD risk.

ARTICLE INFORMATION

Conflicts of interest

The author has no conflicts of interest to declare.

Funding

The author received no financial support for this study.

REFERENCES

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References

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