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Lipoprotein(a)
Lipoprotein(a)
Lipoprotein(a)
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Not to be confused with members of the apolipoprotein A subgroup, including APOA1, APOA2, APOA4 and APOA5.

LPA
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesLPA, AK38, APOA, LP, Lipoprotein(a), Lp(a)
External IDsHomoloGene: 87856; GeneCards: LPA; OMA:LPA - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4018

n/a

Ensembl

ENSG00000198670

n/a

UniProt

P08519

n/a

RefSeq (mRNA)

NM_005577

n/a

RefSeq (protein)

n/a

n/a

Location (UCSC)Chr 6: 160.53 – 160.66 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.[3][4][5][6]

Lipoprotein(a) was discovered in 1963 by Kåre Berg.[7] The human gene encoding apolipoprotein(a) was successfully cloned in 1987.[8]

Structure

[edit]

Lipoprotein(a) [Lp(a)] consists of an LDL-like particle and the specific apolipoprotein(a), which is bound covalently to the apoB contained in the outer shell of the particle. Lp(a) plasma concentrations are highly heritable[9][10] and mainly controlled by the LPA gene[11] located on chromosome 6q25.3–q26.[12] Apo(a) proteins vary in size due to a size polymorphism [KIV-2 VNTR], which is caused by a variable number of kringle IV repeats in the LPA gene.[13] This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to more than 50 kringle IV repeats (each of the variable kringle IV consists of 114 amino acids).[8][14] These variable apo(a) sizes are known as "apo(a) isoforms".

There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration.[15] One theory explaining this correlation involves different rates of protein synthesis. Specifically, the larger the isoform, the more apo(a) precursor protein accumulates intracellularly in the endoplasmic reticulum. Lp(a) is not fully synthesised until the precursor protein is released from the cell, so the slower production rate for the larger isoforms limits the plasma concentration.[16][17]

Populations

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Lp(a) concentrations can vary by more than one thousand between individuals, from <0.2 to >200 mg/dL. Scientists have found that this range of concentrations has been observed in all populations studied. The mean and median concentrations differ among world populations. Most prominently, there is a two to threefold higher mean Lp(a) plasma concentration in populations of African descent compared to Asian, Oceanic, or European populations.[18][19] The general inverse correlation between apo(a) isoform size and Lp(a) plasma concentration is observed in all populations.[15] However, it was also discovered that mean Lp(a) associated with certain apo(a) isoforms varies between populations.[citation needed]

In addition to size effects, mutations in the LPA promoter may lead to a decreased apo(a) production.[20]

The Atherosclerosis Risk in Communities (ARIC) Study is a community-based cohort from 4 geographically diverse US communities. The ARIC Study found that the proportion of Atherosclerotic Cardiovascular Disease cases potentially attributable to elevated Lp(a) was 10.2% among Black adults compared with 4.7% among white adults. The population-attributable fraction ratio for Black adults compared with white adults was 2.30. Because the hazard ratios for ASCVD associated with higher Lp(a) did not significantly differ between races, the ARIC study concluded that these differences appeared to be driven largely by racial differences in the distribution of Lp(a) levels.[21]

Function and pathology

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Lp(a) is assembled at the hepatocyte cell membrane surface, which is similar to typical LDL particles. However, there are other possible locations of assembly. The particles mainly exist in plasma.[22][23][24][25]

Lp(a) contributes to the process of atherogenesis. The structure of apolipoprotein(a) is similar to plasminogen and tPA (tissue plasminogen activator), and it competes with plasminogen for its binding site, leading to reduced fibrinolysis.[26][27] Also, because Lp(a) stimulates secretion of PAI-1, it leads to thrombogenesis.[28][3][29] It also may enhance coagulation by inhibiting the function of tissue factor pathway inhibitor.[30]

Moreover, Lp(a) carries atherosclerosis-causing cholesterol and binds atherogenic pro-inflammatory oxidised phospholipids as a preferential carrier of oxidised phospholipids in human plasma,[31] which attracts inflammatory cells to vessel walls and leads to smooth muscle cell proliferation.[32][33][34] Moreover, Lp(a) also is hypothesised to be involved in wound healing and tissue repair by interacting with components of the vascular wall and extracellular matrix.[35][36] Apo(a), a distinct feature of the Lp(a) particle, binds to immobilized fibronectin and endows Lp(a) with the serine-proteinase-type proteolytic activity.[37]

Nonetheless, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy.[citation needed] Thus, plasma Lp(a) is not vital, at least under normal environmental conditions.[citation needed] Since apo(a)/Lp(a) appeared rather recently in mammalian evolution — only old world monkeys and humans have been shown to harbour Lp(a) — its function might not be vital, but just evolutionarily advantageous under certain environmental conditions, e.g., in case of exposure to certain infectious diseases.[20]

Catabolism and clearance

[edit]

The half-life of Lp(a) in circulation is approximately three to four days.[23] The mechanism and sites of Lp(a) catabolism are largely unknown. The LDL receptor has been reported as a receptor for Lp(a) clearance, but is not a major pathway of Lp(a) metabolism under normal or hypercholesterolemic conditions.[29][38][39] The kidney has been identified as playing a role in Lp(a) clearance from plasma.[40]

Disease

[edit]

High Lp(a) in blood correlates with coronary heart disease (CHD), cardiovascular disease (CVD), atherosclerosis, thrombosis, and stroke.[41] However, the association between Lp(a) levels and stroke is not as strong as that between Lp(a) and cardiovascular disease.[3] Lp(a) concentrations may be affected by disease states (for example, kidney failure or autoinflammatory conditions), but are only slightly affected by diet, exercise, and other environmental factors.[citation needed]

Most commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Results using statin medications have been mixed in most trials, although a meta-analysis published in 2012 suggests that atorvastatin may be of benefit.[42]

Niacin (Vitamin B3) has been shown to reduce the levels of Lp(a) significantly in individuals with high levels of low-molecular weight Lp(a).[43][44]

High Lp(a) correlates with early atherosclerosis independently of other cardiac risk factors, including LDL. In patients with advanced cardiovascular disease, Lp(a) indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains very similar to plasminogen (PLG). Lp(a) accumulates in the vessel wall and inhibits the binding of PLG to the cell surface, reducing plasmin generation, which increases clotting. This inhibition of PLG by Lp(a) also promotes the proliferation of smooth muscle cells. These unique features of Lp(a) suggest that Lp(a) causes generation of clots and atherosclerosis.[45]

Diagnostic testing

[edit]

Numerous studies confirming a strong correlation between elevated Lp(a) and heart disease have led to the consensus that Lp(a) is an important independent predictor of cardiovascular disease.[46][3] Animal studies have shown that Lp(a) may directly contribute to atherosclerotic damage by increasing plaque size, inflammation, instability, and smooth muscle cell growth.[47] Genetic data also support the theory that Lp(a) causes cardiovascular disease.[4]

The European Atherosclerosis Society recommends that patients with a moderate or high risk of cardiovascular disease should have their Lp(a) levels checked. Any patient with one of the following risk factors should be screened:

  • premature cardiovascular disease
  • Familial hypercholesterolaemia
  • family history of premature cardiovascular disease
  • family history of elevated Lp(a)
  • recurrent cardiovascular disease despite statin treatment
  • ≥3% ten-year risk of fatal cardiovascular disease according to the European guidelines
  • ≥10% ten-year risk of fatal and/or non-fatal cardiovascular disease according to the U.S. guidelines[3]

If the level is elevated, treatment should be initiated to bring the level below 50 mg/dL. In addition, the patient's other cardiovascular risk factors (including LDL levels) should be managed optimally.[3] Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter as well.[48][49]

Prior studies of the relationship between Lp(a) and ethnicity have shown inconsistent results. Lp(a) levels seem to differ in different populations. For example, in some African populations, Lp(a) levels are higher on average than in other groups, so that using a risk threshold of 30 mg/dl could classify over 50% of the individuals as higher risk.[50][51][52][53] Some part of this complexity may be related to the different genetic factors involved in determining Lp(a) levels. One recent study showed that in different ethnic groups, different genetic alterations were associated with increased Lp(a) levels.[54]

More recent data suggest that prior studies were underpowered. The Atherosclerosis Risk in Communities (ARIC) Study followed 3467 African Americans and 9851 whites for 20 years. The researchers found that an elevated Lp(a) conferred the same risk in each group. African Americans had roughly three times the level of Lp(a); however, Lp(a) also predicted an increased risk of stroke.[55]

Approximate levels of risk are indicated by the results below, although at present, there are various methods by which to measure Lp(a). A standardized international reference material has been developed and is accepted by the WHO Expert Committee on Biological Standardization and the International Federation of Clinical Chemistry and Laboratory Medicine. Although further standardization is still needed, the development of a reference material is an important step toward standardizing results.[56][57]

Lipoprotein(a) — Lp(a)[58]

Desirable: <14 mg/dL (<35 nmol/L)
Borderline risk: 14–30 mg/dL (35–75 nmol/L)
High risk: 31–50 mg/dL (75–125 nmol/L)
Very high risk: >50 mg/dL (>125 nmol/L)

Lp(a) appears with different isoforms (per kringle repeats) of apolipoprotein; 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different isoforms. Lighter Lp(a) are also associated with disease. Thus, a test with simple quantitative results may not provide a complete assessment of risk.[59]

The US FDA has given the Tina-quant® lipoprotein Lp(a) RxDx assay from Roche a Breakthrough Device Designation. The assay is designed to identify patients who may benefit from therapies aimed at decreasing Lp(a) levels.[60]

Treatment

[edit]

The current simplest treatment for elevated Lp(a) is to take 1–3 grams of niacin daily, typically in an extended-release form. Niacin therapy may reduce Lp(a) levels by 20–30%.[61] However more recent research suggests that the inflammatory effects of the breakdown products of excess niacin lead to an increase in risk of major adverse cardiovascular event.[62]

A meta-analysis suggested that atorvastatin may lower Lp(a) levels.[42] In severe cases, such as familial hypercholesterolemia or treatment-resistant hypercholesterolemia, LDL apheresis may dramatically reduce Lp(a). The goal of the treatment is to reduce levels to below 50 mg/dL. Cost is prohibitively high.[3]

A meta-analysis of six clinical trials confirmed that flaxseed supplementation modestly lowers Lp(a) levels.[63]

Testosterone is known to reduce Lp(a) levels.[64] Testosterone replacement therapy also appears to be associated with lower Lp(a) levels.[64][65] Estrogen replacement therapy in post-menopausal women will reduce Lp(a).[66] Raloxifene has not been shown to reduce Lp(a), while tamoxifen has.[67]

L-carnitine may also reduce Lp(a) levels. A systematic review and meta-analysis found a significant reduction with oral but not intravenous carnitine.[68] Other medications that are in various stages of development include thyromimetics, cholesterol-ester-transfer protein (CETP inhibitors), anti-sense oligonucleopeptides and small interfering RNAs (such as Pelacarsen and Olpasiran),[69] and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.[65][70]

The American Academy of Pediatrics now recommends that all children between the ages of nine and eleven years old be screened for hyperlipidemia. Lp(a) levels should be considered in children with a family history of early heart disease or high blood cholesterol levels. However, there have not been enough studies to determine which therapies might be beneficial.[71]

Clinical trials

[edit]

Several investigational new drugs that lower Lp(a) levels are currently being evaluated in clinical trials for the treatment of cardiovascular disease.[72]

Drug Modality Mechanism Dosing / administration Clinical trial Trial endpoints
Pelacarsen Antisense oligonucleotide Targets LPA mRNA Subcutaneous injection once monthly Phase 3 – Lp(a) HORIZON[73] Time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularization requiring hospitalization
Olpasiran siRNA (GalNAc-conjugated) " Subcutaneous injection every 12 weeks Phase 3 – OCEAN(a)-Outcomes[74] Time to first occurrence of coronary heart-disease death, myocardial infarction, or urgent coronary revascularization
Zerlasiran siRNA " Subcutaneous injection; dosing under study (e.g., every 16–24 weeks) Phase 2 – ALPACAR-360[75] Placebo-adjusted, time-averaged percent change in Lp(a) from baseline through ~36 weeks
Lepodisiran siRNA (extended-duration) " Infrequent subcutaneous dosing (under study) Phase 2[76] Placebo-adjusted, time-averaged percent change in serum Lp(a) from day 60 to day 180
Muvalaplin Oral small-molecule Inhibits Lp(a) assembly Oral, once daily in trials Phase 2 – KRAKEN[77] Percent change in Lp(a) from baseline at 12 weeks

Interactions

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Lp(a) has been shown to interact with calnexin,[78][79] fibronectin,[37] and fibrinogen beta chain.[80]

See also

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References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Lipoprotein(a)

View on Grokipedia
from Grokipedia
Lipoprotein(a), abbreviated as Lp(a), is a genetically inherited lipoprotein particle primarily synthesized in the liver, consisting of a (LDL)-like core covalently linked to (a) [apo(a)], which renders it an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), including , , , and . Structurally, Lp(a) comprises B-100 (apoB-100), the primary protein of LDL, bound via a bridge to apo(a), a that exhibits structural homology to plasminogen but lacks its fibrinolytic activity, potentially promoting and inhibiting . This assembly occurs intracellularly in hepatocytes, with plasma levels largely determined by hepatic production rather than , and minor clearance through the kidneys. The apo(a) component features multiple kringle IV type 2 (KIV-2) repeats, with the number of repeats (typically 3–40) inversely correlating with Lp(a) concentration: fewer repeats result in smaller isoforms and higher circulating levels due to increased secretion efficiency. Genetically, Lp(a) levels are predominantly controlled by the LPA gene on , with heritability exceeding 90%, making it stable throughout an individual's lifetime and unaffected by most factors, including dietary influences such as red meat consumption. Prevalence varies by , with elevated levels more common in individuals of African descent (approximately 40–50% with levels >30 mg/dL) compared to those of European (~20%) or Asian (~10%) ancestry, and it often co-occurs with , amplifying risk. In pathophysiology, elevated Lp(a) contributes to ASCVD through pro-atherogenic, pro-inflammatory, pro-thrombotic, and anti-fibrinolytic mechanisms, including oxidized phospholipid enrichment that drives formation, vascular , and plaque instability. Individuals with the highest Lp(a) levels face up to a 31% increased risk of overall CVD and a 42% greater likelihood of atherosclerotic events. Higher Lp(a) levels act as a causal risk factor for continuously elevated risk of both incident and recurrent atherosclerotic cardiovascular disease. High Lp(a) levels are associated with significantly increased risk of early secondary cardiovascular events in patients with prior multiple CVDs. Higher Lp(a) levels show a linear association with increased long-term ASCVD risk, including in individuals with diabetes. Levels above 50 mg/dL (or 125 nmol/L) are associated with a 2- to 3-fold increased risk of and , independent of LDL cholesterol, with even higher risks when combined with other factors like or . Measurement of Lp(a) involves immunoassays such as or turbidimetric methods on non-fasting serum or plasma, with results reported in mg/dL (mass) or nmol/L (particle number) to account for isoform variability; the latter is preferred for accuracy, as recommended by the International Federation of . Screening is recommended once in a lifetime for all adults per 2024 National Lipid Association guidelines, and for adults with family history of premature ASCVD or elevated LDL per guidelines. Optimal levels are below 30 mg/dL (<75 nmol/L), with no specific thresholds universally defined but high-risk categories starting at 50 mg/dL. Currently, no FDA-approved therapies specifically target Lp(a), though lipoprotein apheresis can reduce levels by 50–75% in severe cases, and adjunctive agents like PCSK9 inhibitors (e.g., evolocumab) lower it by 20–30%, while niacin achieves 20–40% reductions. Emerging treatments, including antisense oligonucleotides (e.g., pelacarsen) and small interfering RNA therapies (e.g., olpasiran), have shown promise in phase 3 trials for 80–90% reductions, with approvals expected in 2026 or later. Management emphasizes aggressive control of other modifiable risk factors, such as LDL cholesterol and blood pressure, to mitigate overall cardiovascular burden.

Structure and Genetics

Composition and Molecular Structure

Lipoprotein(a) [Lp(a)] is a lipoprotein particle structurally similar to low-density lipoprotein (LDL), consisting of a core LDL-like moiety containing apolipoprotein B-100 (apoB-100) covalently bound to one molecule of apolipoprotein(a) [apo(a)] through a disulfide bond. This 1:1 molar ratio of apoB-100 to apo(a) distinguishes Lp(a) from LDL, which lacks the apo(a) component. Apo(a) is a large glycoprotein synthesized primarily in the liver and homologous to plasminogen, featuring a complex domain structure that includes a signal peptide, multiple kringle IV (KIV) domains (types 1 through 10), a kringle V (KV) domain, and a catalytically inactive protease-like domain. The KIV domains are triple-loop structures stabilized by internal disulfide bonds, with KIV types 3 through 10 present as single copies, KIV-1 duplicated once, and KIV-2 exhibiting high variability in copy number (typically 3 to >40 repeats), which determines apo(a) isoform ranging from approximately 300 to 800 . This heterogeneity in KIV-2 repeats leads to substantial variation in overall Lp(a) , with diameters typically spanning 20–30 nm as observed by and . The lipid core of Lp(a) mirrors that of LDL, comprising a spherical interior rich in cholesteryl esters and triglycerides, surrounded by a surface monolayer of phospholipids, free , and the protein components. Apo(a) extends from or wraps around this core, potentially altering particle conformation. Biochemically, Lp(a) exhibits higher sialic acid content than LDL, primarily due to extensive on apo(a), which contributes to its anionic properties and stability. Additionally, Lp(a) demonstrates greater resistance to oxidative modification compared to LDL, attributed to the protective effects of apo(a) domains that bind oxidized phospholipids and limit further peroxidation. The covalent linkage forming Lp(a) occurs via a disulfide bond between a unique residue (Cys4057) in the KIV-9 domain of apo(a) and 3734 (Cys3734) in the flexible linker region of apoB-100, following initial non-covalent interactions mediated by lysine-binding sites in apo(a) KIV-7 and KIV-8 domains. This specific bonding site ensures stable assembly of the particle in the after .

Genetic Basis and Population Variations

The genetic basis of lipoprotein(a) (Lp(a)) is primarily determined by the LPA gene, located on 6q25.3–q27, which encodes the apolipoprotein(a) (apo(a)) protein. This gene exhibits significant structural variability due to copy number variations (CNVs) in the kringle IV type 2 (KIV-2) repeats, where fewer repeats correspond to smaller apo(a) isoforms and inversely correlate with higher plasma Lp(a) levels. These CNVs account for a substantial portion of the variability in Lp(a) concentrations, with the number of KIV-2 repeats ranging from 3 to over 40 across individuals. Lp(a) inheritance follows a codominant pattern, with plasma levels demonstrating high estimated at 90–95%. Specific single polymorphisms (SNPs) within the LPA , such as rs10455872 and rs3798220, are strongly associated with elevated Lp(a) levels, as these variants promote smaller apo(a) isoforms and reduced hepatic clearance. Genome-wide association studies (GWAS) have identified additional genetic modifiers outside the LPA locus, including the SORT1 on chromosome 1p13.3, which influences Lp(a) concentrations independently through effects on secretion and processing. Population variations in Lp(a) levels reflect ethnic differences in LPA gene alleles and KIV-2 CNV frequencies, leading to a global of elevated Lp(a) (>50 mg/dL) in approximately 20–30% of individuals. Levels are highest among people of African descent, with up to 50–70% exhibiting concentrations above this threshold due to a higher frequency of low-KIV-2 repeat alleles. In contrast, East Asians show lower (10–20%), attributed to more large apo(a) isoforms, while Europeans display intermediate levels around 20–25%; South Asians also experience elevated rates (∼25%), often linked to smaller isoforms that confer increased risk for ischemic .

Physiology and Metabolism

Biosynthesis and Assembly

Lipoprotein(a) [Lp(a)] is synthesized primarily in hepatocytes within the liver, where apolipoprotein(a) [apo(a)] is produced as a large glycoprotein through translation of the LPA gene. Apo(a) undergoes extensive post-translational modifications, including N-linked glycosylation, which is essential for its proper folding and secretion. This process occurs independently of apolipoprotein B-100 (apoB-100), the structural protein of low-density lipoprotein (LDL), which is assembled into nascent LDL particles in the endoplasmic reticulum (ER) of hepatocytes. Once secreted, apo(a) forms a covalent disulfide bond with apoB-100 on the surface of LDL particles to assemble mature Lp(a). The assembly of Lp(a) proceeds via both intracellular and extracellular pathways, with the rate-limiting step being the of apo(a) from . Intracellularly, apo(a) and apoB-100 can associate noncovalently within the ER or Golgi apparatus before , while extracellular disulfide bonding predominantly occurs at the hepatocyte plasma membrane. This two-step mechanism ensures efficient particle formation, though the exact proportion of intracellular versus extracellular assembly varies with apo(a) isoform size. No significant Lp(a) synthesis occurs outside the liver, confirming as the exclusive site of production. Daily hepatic production rates of Lp(a) typically range from 10 to 30 mg in individuals with average plasma levels, directly contributing to the circulating pool while maintaining steady-state concentrations. Regulation of Lp(a) biosynthesis is predominantly transcriptional, governed by promoter elements in the LPA gene that control apo(a) expression levels. Variability in apo(a) isoform size, determined by the number of IV type 2 (KIV-2) repeats, inversely affects synthesis rates: shorter isoforms with fewer KIV-2 repeats (e.g., <22 repeats) are synthesized and secreted more rapidly than longer ones, leading to higher plasma Lp(a) concentrations for the former. Recent studies have highlighted the role of ER stress in modulating apo(a) folding and secretion efficiency; unresolved protein misfolding in the ER can trigger the unfolded protein response, reducing apo(a) output and thus Lp(a) assembly. These regulatory mechanisms underscore the genetic dominance in Lp(a) production, with over 90% of plasma levels determined by LPA variants.

Normal Physiological Roles

Lipoprotein(a) (Lp(a)) serves as the preferential carrier of oxidized phospholipids (OxPL) in human plasma, potentially facilitating their delivery to tissues for signaling purposes in normal physiology. This transport function may contribute to lipid homeostasis by modulating inflammatory responses through OxPL, which act as damage-associated molecular patterns recognized by the immune system. Although not directly involved in classical reverse cholesterol transport like HDL, Lp(a)'s association with OxPL suggests a complementary role in lipid modification and cellular communication under healthy conditions. Due to the structural homology between apolipoprotein(a) (apo(a)) and plasminogen, Lp(a) is hypothesized to play a role in wound healing and tissue repair by exerting anti-fibrinolytic activity. This homology enables apo(a) to bind fibrin and endothelial cells, inhibiting plasminogen activation and thereby stabilizing clots during injury to promote repair. Lp(a) accumulates at sites of vascular injury, enhancing monocyte chemotaxis and supporting tissue remodeling without excessive fibrinolysis. From an evolutionary standpoint, Lp(a) likely conferred ancestral benefits in wound healing and vascular repair, emerging in primates as a mechanism to deliver lipids and modulate hemostasis during trauma. Low levels of Lp(a) exhibit neutral or protective effects, as evidenced by an inverse association with hemorrhagic stroke risk, suggesting a balancing role in hemostasis that prevents excessive bleeding. Evidence from animal models for overt normal physiological functions remains limited; transgenic mice overexpressing human Lp(a) primarily highlight its liver-specific expression but do not demonstrate clear non-pathological benefits, with studies often focusing on disease contexts instead.

Catabolism and Clearance

The primary clearance of lipoprotein(a) [Lp(a)] occurs through hepatic uptake, involving various scavenger receptors, including SR-B1 and members of the LDL receptor-related protein family such as LRP1, with the role of the low-density lipoprotein receptor (LDLR) being debated. However, this process is less efficient compared to that of low-density lipoprotein (LDL), as the apolipoprotein(a) [apo(a)] component sterically hinders the interaction of the underlying apolipoprotein B-100 (apoB-100) with LDLR, reducing binding affinity and overall receptor-mediated endocytosis. Additional pathways involve plasminogen receptors on hepatocytes and endothelial cells, which recognize the kringle domains of apo(a), further contributing to catabolism, though the relative contributions of these receptors remain under investigation. The fractional catabolic rate (FCR) of Lp(a) is notably slower than that of LDL, typically ranging from 0.10 to 0.35 pools per day versus 0.3 to 0.5 pools per day for LDL, resulting in a plasma half-life of approximately 3 to 4 days for Lp(a) compared to 2 to 3 days for LDL; this prolonged circulation promotes plasma accumulation, particularly in individuals with elevated production rates. Metabolic turnover studies employing stable isotopic labeling with deuterated amino acids have demonstrated that roughly 70% of Lp(a) catabolism occurs in the liver, with the remainder involving extrahepatic sites; these studies also reveal size-dependent clearance, where larger apo(a) isoforms (with more kringle IV repeats) exhibit slower FCR due to reduced receptor interactions, independent of production differences. Genetic variations in apo(a) isoform size, as detailed in structural genetics, further modulate this clearance efficiency in a limited manner. Renal involvement in Lp(a) clearance is minor, involving glomerular filtration of free or fragmented apo(a) forms, with subsequent excretion of apo(a) fragments in urine accounting for only 1% to 3% of total apo(a) turnover in healthy individuals. This pathway is significantly impaired in chronic kidney disease, where reduced glomerular function leads to diminished fractional catabolic rates (e.g., 0.164 versus 0.246 pools per day in hemodialysis patients compared to controls) and elevated plasma Lp(a) levels. Additionally, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition enhances Lp(a) uptake by increasing hepatic LDLR availability, though the effect is modest (15% to 30% reduction) due to inherent binding limitations.

Pathophysiology and Disease Associations

Pro-Atherogenic and Pro-Thrombotic Mechanisms

Lipoprotein(a) [Lp(a)] promotes atherogenesis by facilitating the infiltration of lipoproteins into the arterial intima, where it accumulates more readily than low-density lipoprotein (LDL) due to the apo(a) component's affinity for vascular proteoglycans and integrins in the vessel wall. This enhanced retention distinguishes Lp(a) from LDL and contributes to subendothelial deposition, initiating plaque formation. Once in the intima, Lp(a) undergoes oxidative modification, generating oxidized phospholipids that are avidly taken up by macrophages, leading to foam cell formation and lipid-laden plaques. The apo(a) moiety further exacerbates atherogenesis by binding oxidized phospholipids, which enhances monocyte recruitment and adhesion to the endothelium via upregulation of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). This process amplifies inflammatory cell infiltration into the vessel wall, perpetuating the atherosclerotic lesion. In addition to its pro-atherogenic effects, Lp(a) exhibits prothrombotic effects through its kringle structures, which enhance thrombus formation on ruptured plaques, while its interaction with platelet-activating factor acetylhydrolase may modulate platelet activation. Lp(a) also promotes platelet aggregation independent of this interaction. Lp(a) drives vascular inflammation by inducing endothelial cells to upregulate pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which accelerate plaque instability and rupture. These cytokines foster a pro-inflammatory milieu that recruits additional immune cells and promotes matrix degradation in the arterial wall. Epidemiological data indicate that each 50 mg/dL increase in Lp(a) concentration elevates cardiovascular disease (CVD) risk by approximately 20%, independent of LDL cholesterol levels. This risk association underscores the additive pathogenic role of Lp(a) in atherosclerosis and thrombosis.

Associated Diseases and Risks

Elevated levels of lipoprotein(a) [Lp(a)] are strongly associated with increased risk of atherosclerotic cardiovascular diseases (ASCVD), including myocardial infarction, ischemic stroke, and peripheral artery disease. Meta-analyses of prospective studies have demonstrated a dose-dependent relationship, with Lp(a) concentrations exceeding 100 mg/dL conferring a 2- to 3-fold higher risk of these events compared to lower levels, independent of other lipid parameters. Individuals with the highest Lp(a) levels face up to a 31% increased risk of overall CVD and a 42% greater likelihood of atherosclerotic events. Higher Lp(a) levels show a linear association with increased long-term ASCVD risk, including in individuals with diabetes. This risk is additive to traditional factors such as low-density lipoprotein cholesterol, as evidenced by pooled data from statin trials showing heightened hazard ratios when both Lp(a) and LDL-C are elevated. In patients with ischemic heart disease, elevated Lp(a) predicts adverse cardiovascular outcomes, including recurrent events; higher Lp(a) levels act as a causal risk factor for continuously elevated risk of both incident and recurrent ASCVD, and are associated with significantly increased risk of early secondary cardiovascular events in patients with prior multiple CVDs. Importantly, elevated Lp(a) confers increased cardiovascular risk even in individuals with normal carotid ultrasound and normal echocardiography. As a genetically determined independent causal risk factor for ASCVD, including myocardial infarction and stroke, Lp(a) acts through pro-atherogenic, pro-thrombotic, and pro-inflammatory mechanisms. Normal imaging indicates the absence of detectable subclinical atherosclerosis or structural abnormalities at the time of assessment but does not eliminate the lifelong risk from elevated Lp(a), which persists independently of carotid plaque presence or intima-media thickness. Lp(a) also accelerates valvular heart disease, particularly calcific , by promoting valvular calcification and inflammation. Prospective cohort studies indicate that individuals with Lp(a) >100 mg/dL face a significantly higher incidence of severe degenerative , with faster hemodynamic progression and increased need for valve intervention. This association holds across populations, with genetic and proteomic analyses linking Lp(a) to macrocalcification and adverse valvular outcomes. Beyond cardiovascular conditions, elevated Lp(a) is implicated in the progression of (CKD), where it contributes to renal function decline through inflammatory and atherogenic pathways. Mendelian randomization analyses support a causal role, showing modest but significant effects of genetically elevated Lp(a) on CKD incidence and progression. Associations extend to recurrent miscarriages, particularly in women with prothrombotic profiles, where higher Lp(a) levels correlate with unexplained losses due to its antifibrinolytic properties. Additionally, Lp(a) predicts the development of non-alcoholic (NAFLD) in population-based cohorts, with elevated levels linked to hepatic and severity, though some studies note inverse correlations in advanced disease stages. Epidemiological evidence from Mendelian randomization studies robustly confirms the causality of Lp(a) in ASCVD, demonstrating that lifelong exposure to high Lp(a) increases coronary heart disease and risk proportionally to plasma levels. Recent cohort analyses, including 2024 data, suggest potential links to through vascular mechanisms, such as cerebral small vessel disease burden in affected patients, though direct associations with incidence remain inconsistent across studies. For risk stratification, Lp(a) measurement enhances traditional models like the by improving discrimination and reclassification of ASCVD risk, particularly in intermediate-risk individuals. Its impact is amplified in , where co-elevation with Lp(a) doubles premature cardiovascular event rates compared to LDL-C elevation alone, underscoring the need for targeted assessment in this population.

Diagnosis

Laboratory Testing Methods

The primary methods for measuring lipoprotein(a) (Lp(a)) in clinical laboratories are immunoturbidimetric and nephelometric immunoassays, which detect apo(a) epitopes on the Lp(a) particle while minimizing interference from apoB-100 on the underlying LDL-like particle. These assays rely on antigen-antibody reactions to quantify Lp(a) concentration, with immunoturbidimetry measuring light scattering due to aggregate formation and nephelometry assessing scattered light intensity. For accurate reporting, Lp(a) concentrations are preferably expressed in nmol/L, which provides isoform-independent measurements by counting particle numbers rather than mass, unlike mg/dL units that can vary with apo(a) size heterogeneity. A rough conversion factor of approximately 2.5 is sometimes applied from mg/dL to nmol/L, but direct conversion is discouraged due to variability and isoform effects. Lp(a) levels remain stable in non-fasting samples, allowing measurement without dietary restrictions, though recent meals should be avoided to prevent minor triglyceride-related interferences. For optimal reproducibility, plasma samples should be stored at -80°C immediately after collection, as prolonged storage at higher temperatures can lead to degradation. Traditional immunoassays often underestimate Lp(a) in individuals with large apo(a) isoforms, as these methods may target epitopes in the variable IV type 2 repeats, leading to lower signal for larger particles. To address this, guidelines since recommend using ISO 15189-accredited assays traceable to the WHO/IFCC secondary reference material for standardized, isoform-insensitive calibration. In research settings, mass spectrometry-based approaches enable precise, isoform-independent quantification of Lp(a) by targeting specific peptides in apo(a), offering higher specificity beyond antibody-dependent methods for concentration measurement.

Interpretation and Screening Guidelines

Interpretation of lipoprotein(a) [Lp(a)] levels focuses on their role as an independent risk factor for (ASCVD), with measurements typically reported in mg/dL or nmol/L units. Levels below 30 mg/dL (75 nmol/L) are associated with low , 30-50 mg/dL (75-125 nmol/L) indicate intermediate or borderline , and values exceeding 50 mg/dL (125 nmol/L) denote high for ASCVD events such as and . Currently, no specific therapeutic targets exist for Lp(a), but elevated levels serve as a risk-enhancing factor in ASCVD risk calculators, prompting intensified lifestyle and lipid-lowering interventions. Risk grading incorporates lifelong exposure to elevated Lp(a), particularly relevant for young adults, where sustained levels ≥30 mg/dL from youth approximately double the likelihood of developing adult ASCVD compared to lower exposures. For family-based , cascade screening is advised when an exceeds 50 mg/dL (125 nmol/L), with enhanced detection rates if the threshold is set at >100 mg/dL (≈250 nmol/L), identifying additional at-risk relatives efficiently. Major guidelines emphasize targeted yet broad screening to optimize CVD prevention. The 2022 European Atherosclerosis Society (EAS) consensus recommends Lp(a) measurement at least once in every adult's lifetime, with cascade screening prioritized in families with (FH), personal or family history of premature ASCVD, or documented very high Lp(a). The (AHA) identifies Lp(a) ≥50 mg/dL (≥125 nmol/L) as a key risk enhancer, advising testing in high-risk populations including those with FH or strong family history of early CVD, aligning with 2024 updates promoting integration into routine risk evaluation. Lp(a) interpretation must account for confounders, as levels are predominantly genetically determined but exhibit variations by demographics. influences concentrations, with women generally showing higher levels than men, especially after age 50 (e.g., 27 mg/dL higher on average in women aged 50-89). also plays a role, with markedly elevated mean levels in individuals of African descent (often >50 mg/dL) and South Asians compared to Whites or Hispanics, though no standardized ethnicity-adjusted cutoffs are currently endorsed. Age has limited effect post-childhood, with stability typical after age 20, though slight increases may occur in some cohorts. Cost-effectiveness analyses support Lp(a) screening as a viable component of CVD prevention, particularly following data from post-2023 outcome trials demonstrating risk reclassification benefits. Modeling across multiple countries shows that primary prevention screening is cost-saving from both healthcare and societal viewpoints, yielding up to 1,167 per person in the through reduced events and optimized therapy allocation. These findings underscore the strategy's efficiency, especially in high-prevalence settings, with test costs comparable to standard panels (≈25-100 ).

Treatment and Management

Current Therapeutic Approaches

Current therapeutic approaches for elevated lipoprotein(a) [Lp(a)] primarily emphasize indirect risk reduction through of other cardiovascular factors, as direct Lp(a)-lowering options remain limited. These strategies aim to mitigate the pro-atherogenic and pro-thrombotic effects of high Lp(a) by targeting overall profiles and modifiable factors. Lifestyle interventions have a limited direct impact on Lp(a) levels, which are largely genetically determined. and may achieve modest reductions of 5-10% in some individuals, particularly those with baseline levels above 20 mg/dL, though results are inconsistent across studies. does not alter Lp(a) concentrations but significantly reduces associated cardiovascular risks by improving endothelial function and overall profiles. Among pharmacotherapies, niacin at doses of 1-2 g/day can lower Lp(a) by 20-25%, as demonstrated in randomized controlled trials and meta-analyses, but its use is often limited by side effects including flushing, gastrointestinal upset, and elevated liver enzymes. PCSK9 inhibitors, such as evolocumab and alirocumab, reduce Lp(a) by 20-30% through enhanced hepatic clearance of apolipoprotein B-containing lipoproteins, with reductions of up to 31% observed in long-term trials like FOURIER. Statins do not directly lower Lp(a) and may increase levels by 10-20%, potentially due to reduced LDL receptor activity; nevertheless, they are strongly recommended for aggressive LDL cholesterol control to address the compounded cardiovascular risk in high Lp(a) patients. Lipoprotein apheresis, specifically LDL-apheresis, provides the most substantial acute reduction, removing 50-75% of circulating Lp(a) per session by extracorporeal filtration of apolipoprotein B particles; it is reserved for select patients with severe and persistently high Lp(a) despite maximal , typically administered weekly to maintain lower average levels and reduce cardiovascular events. The 2025 focused update of the ESC/EAS guidelines for dyslipidaemias classifies Lp(a) levels above 50 mg/dL (≈105 nmol/L) as a cardiovascular risk-enhancing factor and prioritizes intensive LDL lowering—targeting reductions of at least 50% in very high-risk patients—to manage overall atherogenic risk in those with elevated Lp(a).

Emerging Therapies and Future Directions

Antisense oligonucleotides (ASOs) represent a promising class of emerging therapies for reducing lipoprotein(a) [Lp(a)] levels by specifically targeting the LPA gene. Pelacarsen (IONIS/APO(a)-LRx), developed by Ionis Pharmaceuticals and Novartis, is an investigational second-generation ASO that inhibits apo(a) synthesis in the liver through binding to LPA mRNA, leading to its degradation. In phase 2 trials, subcutaneous administration of pelacarsen at doses of 80 mg monthly achieved up to 80% reduction in Lp(a) concentrations, with effects independent of LPA genetic variants or isoform size. The ongoing phase 3 Lp(a)HORIZON trial (NCT04023552), involving over 8,000 patients with established cardiovascular disease and elevated Lp(a), is evaluating whether pelacarsen reduces major adverse cardiovascular events, with topline results anticipated in the first half of 2026. Small interfering RNA (siRNA) therapies offer another targeted approach, leveraging RNA interference to silence LPA gene expression with potentially longer-lasting effects. Olpasiran (AMG 890), from Amgen, is administered subcutaneously and has demonstrated profound Lp(a) lowering in clinical studies, with doses of 75 mg or higher every 12 weeks reducing levels by more than 95% and sustaining approximately 40-50% reductions even off-treatment. The phase 3 OCEAN(a)-Outcomes trial (NCT05581303), enrolling nearly 7,300 participants with atherosclerotic cardiovascular disease and Lp(a) ≥200 nmol/L, is assessing olpasiran's impact on major adverse cardiovascular events, with primary completion expected in 2026. Other siRNA candidates, such as lepodisiran (Eli Lilly) and zerlasiran (Silence Therapeutics), have shown substantial reductions (up to 94% for lepodisiran in phase 2 as of March 2025) and are advancing in clinical development. Gene editing technologies, particularly /Cas9-based methods, are in for permanent Lp(a) reduction by targeting the LPA promoter or gene directly in hepatocytes. For instance, investigational therapies like STX-1200 utilize -CasX to knock out LPA expression, showing potent silencing in preclinical models without off-target effects. These approaches aim for one-time administration via nanoparticles, potentially offering durable benefits, though clinical translation remains years away due to safety and delivery challenges. Beyond nucleic acid-based therapies, enhancements in lipoprotein and early-stage monoclonal antibodies targeting apo(a) are under exploration. Advances in protocols, such as more efficient selective removal systems, have improved Lp(a) clearance by up to 75% per session, with long-term use demonstrating reduced progression of in high-risk patients. Looking ahead, successful outcomes from ongoing phase 3 trials could lead to FDA approvals for Lp(a)-specific therapies like pelacarsen and olpasiran by 2026-2027, potentially transforming management of elevated Lp(a) as a causal cardiovascular risk factor. However, challenges including high development costs, subcutaneous dosing requirements, and equitable access in diverse populations must be addressed to realize widespread clinical impact.

Interactions and Modifiers

Interactions with Other Lipoproteins and Lipids

Lipoprotein(a) [Lp(a)] shares the apoB-100 protein with (LDL), enabling both to bind to the low-density lipoprotein receptor (LDLR) for hepatic clearance, though Lp(a) exhibits lower binding affinity. This shared pathway results in receptor competition, particularly in conditions like (FH), where defective LDLR function impairs clearance of both particles, leading to their concurrent elevation in plasma. On an equimolar basis, Lp(a) demonstrates greater atherogenicity than LDL due to its additional pro-inflammatory and pro-thrombotic components, amplifying vascular risk beyond simple competition effects. Lp(a) displays an inverse correlation with high-density lipoprotein (HDL) levels, where reduced HDL exacerbates the cardiovascular risks associated with elevated Lp(a). This relationship stems from HDL's role in reverse , which facilitates the removal of excess from peripheral tissues; impaired HDL function limits this protective mechanism, allowing Lp(a)-mediated lipid accumulation to persist and intensify endothelial damage. A distinctive feature of Lp(a) is its preferential carriage of oxidized phospholipids (OxPL), carrying substantially more OxPL per particle than LDL, which promotes through inflammatory signaling. These OxPL, primarily associated with the apo(a) component, are transferred from oxidized LDL to Lp(a) in a selective manner, enhancing the particle's ability to elicit proinflammatory responses in vascular cells and contributing to plaque instability. Unlike LDL, where OxPL content is minimal, Lp(a)'s elevated load directly correlates with heightened and barrier disruption. In , Lp(a) often co-elevates with triglyceride-rich lipoproteins (TRLs), such as (VLDL) and remnants, which share overlapping metabolic pathways and amplify thrombotic potential. This coexistence arises from dysregulated and increased TRL production, incorporating Lp(a) into triglyceride-enriched fractions that exhibit prolonged circulation and enhanced platelet activation. The combined presence heightens risk by synergizing Lp(a)'s properties with TRL-induced hypercoagulability. Recent 2024 studies highlight additive interactions between Lp(a) and remnant —derived from TRL —in promoting plaque burden, where combined elevations independently correlate with increased coronary and carotid plaque severity beyond individual effects. For instance, in population cohorts, higher Lp(a) alongside remnant levels was associated with greater plaque volume and instability, underscoring their synergistic role in atherogenesis. These findings emphasize the need to consider remnant in for Lp(a)-related .

Genetic and Environmental Modifiers

Lipoprotein(a) [Lp(a)] levels are primarily determined by genetic variants in the LPA gene, but secondary genetic and environmental factors can modulate expression and circulating concentrations. While core LPA polymorphisms account for over 90% of variance, emerging evidence from pilot studies suggests that epigenetic alterations such as patterns in the LPA promoter region, influenced by factors like and diet, may contribute to additional variability in Lp(a) levels. Environmental influences on Lp(a) include dietary saturated fatty acid (SFA) intake, where reductions in SFA consumption—typically by 7-8% of energy—have been associated with modest increases in plasma Lp(a) concentrations, averaging 5-6% across meta-analyses of controlled trials. This counterintuitive effect contrasts with the beneficial reduction in LDL cholesterol from low-SFA diets and may relate to altered hepatic apolipoprotein(a) synthesis. Overall, Lp(a) levels exhibit minimal dietary influence, including from red meat consumption—a source rich in saturated fats—as they are primarily genetically determined with only modest modulatory effects from diet. In vitro studies suggest that vitamin C may downregulate apo(a) expression via epigenetic mechanisms, but clinical evidence for Lp(a) reduction in humans, particularly in deficiency states, is limited. Hormonal changes significantly affect Lp(a) in both sexes. In women, the menopausal transition elevates Lp(a) levels by approximately 20-30%, attributable to estrogen withdrawal and its impact on hepatic production, with levels stabilizing higher postmenopause unless mitigated by therapy. Testosterone administration in men generally lowers Lp(a) levels, with reductions of 20-37% reported in several studies, though effects may vary by dosage, duration, and individual factors. Comorbid conditions like chronic inflammation, as seen in , upregulate hepatic Lp(a) synthesis through cytokine-mediated pathways such as IL-6 signaling, resulting in higher plasma levels compared to healthy controls and correlating with disease activity markers like . Renal impairment similarly disrupts Lp(a) clearance, with patients exhibiting roughly 50% reduced catabolic rates due to diminished receptor-mediated uptake, leading to accumulated circulating Lp(a) independent of genetic factors. Pharmacological interventions beyond primary lipid therapies can modify Lp(a). Estrogen replacement therapy in postmenopausal women lowers Lp(a) by 15-25%, primarily through enhanced hepatic clearance and reduced synthesis, with oral formulations showing greater efficacy than routes due to first-pass liver effects. Fibrates exert variable impacts on Lp(a), with meta-analyses indicating modest reductions of 10-20% in some patients via peroxisome proliferator-activated receptor-alpha activation, though effects differ by type and baseline levels, occasionally showing no change or slight increases.

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