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Lp(a) - Lipoprotein a

Lp(a) or Lipoprotein (a): A comprehensive review

October 18, 2024 | Dr Reza Moazzeni

Lipoprotein(a) – A Critical Factor in Cardiovascular Risk Assessment

Lipoprotein(a) [Lp(a)] is a significant independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. Initially discovered in 1963 by Kåre Berg, its clinical relevance has only recently gained substantial recognition. This heightened attention is due to a growing body of epidemiological data and genetic studies linking Lp(a) levels to cardiovascular risk [1]. The awareness of Lp(a) is transitioning from specialist knowledge to widespread clinical adoption, with evidence supporting its role in not only ASCVD but also conditions like aortic stenosis and even childhood ischemic strokes.

What is Lp(a)?

Lipoprotein(a) is a complex lipoprotein particle made up of an LDL-like core bound to apolipoprotein(a) [apo(a)]. Unlike LDL, which is a product of very-low-density lipoprotein (VLDL) metabolism, Lp(a) is synthesized and secreted directly by hepatocytes [2]. Research continues to explore how Lp(a) is assembled and cleared from the body, with questions remaining about its metabolism.

Epidemiology and Genetic Determinants:

Recent large-scale population studies, such as those from the UK Biobank, demonstrate the widespread impact of elevated Lp(a) levels:

      • About 20% of the global population has Lp(a) levels exceeding 50 mg/dL or 125 nmol/L, a threshold linked to increased cardiovascular risk [3].
      • Lp(a) concentrations are primarily determined by genetics, with over 90% of the variation attributable to the LPA gene locus [4].
      • The relationship between Lp(a) levels and ASCVD risk is continuous and linear, meaning risk persists even at levels previously deemed “normal” [5].

Clinical Significance and Risk Assessment:

Including Lp(a) in cardiovascular risk assessments can improve existing strategies:

      • Lp(a) enhances risk prediction beyond traditional risk factors and scoring systems [6].
      • Elevated Lp(a) levels can help explain residual cardiovascular risk in patients whose LDL cholesterol (LDL-C) is already well-controlled [7].
      • New clinical guidelines, including those from the NLA and the European Atherosclerosis Society, now recommend at least one lifetime Lp(a) test for all adults, especially in those with a family history of ASCVD.
      • Relative Atherogenicity of Lipoprotein(a) and Low-Density Lipoprotein Particles: LDL particles are much more abundant and are responsible for the majority of the ASCVD risk; however, on a per-particle basis, an Lp(a) particle is 6-fold more atherogenic than an LDL particle. (Elias Björnson, Jan Borén, et. al. JACC. 2024)

Therapeutic Landscape and Future Directions:

Though traditional lipid-lowering therapies like statins have little effect on Lp(a), new treatments are on the horizon:

      • Lipoprotein apheresis has been shown to lower Lp(a) levels and reduce cardiovascular events in high-risk patients [9].
      • Novel therapies, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are in advanced clinical trials, with reductions in Lp(a) exceeding 80% [10].
      • Ongoing Phase 3 randomized controlled trials (RCTs) like Lp(a)HORIZON are set to report results soon, potentially establishing whether lowering Lp(a) will reduce cardiovascular outcomes in secondary prevention.

The Journey of Lipoprotein(a) Discovery

The discovery of Lipoprotein(a) [Lp(a)] dates back to 1963, when Norwegian physician Kåre Berg identified it as a distinct antigen in human plasma. During his research on low-density lipoproteins (LDL), Berg immunized rabbits with human LDL and observed an unexpected precipitin band in about 30% of human sera samples, which he called “Lp(a)” [12]. This discovery was pivotal in recognizing Lp(a) as a genetically determined lipoprotein.

Key Early Findings:

      • Lp(a) was identified as a heritable trait with significant inter-individual variability.
      • Early studies hinted at the unique structural components that distinguish Lp(a) from other lipoproteins.

Structural Elucidation and Biochemical Characterization:

Over the next two decades, research provided greater clarity on Lp(a)’s structure and composition:

        • 1972: Esko Kostner and colleagues purified Lp(a), noting its structural similarity to LDL but with additional protein components [13].
        • 1987: Researchers discovered that apolipoprotein(a) [apo(a)] has a structural homology to plasminogen, suggesting potential roles in both atherosclerosis and thrombosis [14].

Genetic Insights and Population Studies:

By the 1990s and 2000s, significant advances were made in understanding the genetics of Lp(a):

      • 1992: The cloning and sequencing of the LPA gene explained the genetic basis of apo(a) size polymorphism [15].
      • 1997: The discovery of the kringle IV-2 repeat polymorphism in the LPA gene shed light on the genetic regulation of Lp(a) levels, which vary widely across populations.
      • Large-scale population studies cemented Lp(a) as an independent risk factor for cardiovascular disease [16].

Modern Era: From Risk Factor to Therapeutic Target:

The 21st century marked a renaissance in Lp(a) research, with several critical findings:

      • 2009: Genome-wide association studies (GWAS) definitively linked LPA gene variants to coronary heart disease risk [17].
      • 2010s: Mendelian randomization studies provided robust evidence for Lp(a)’s causal role in atherosclerotic cardiovascular disease (ASCVD) [18].
      • 2012: Lp(a) was also implicated in aortic valve stenosis, expanding the scope of its clinical significance beyond coronary artery disease [19].
      • 2016-Present: Ongoing development of targeted Lp(a)-lowering therapies, such as antisense oligonucleotides and small interfering RNAs, represents a potential breakthrough in cardiovascular risk management [20].

The journey of Lp(a) discovery highlights its evolution from an obscure genetic variant to a recognized cardiovascular risk factor and therapeutic target. This progression underscores the value of sustained scientific exploration and collaboration across genetics, biochemistry, and clinical research to improve cardiovascular outcomes.

Genetics and Epidemiology of Lipoprotein(a)

Lipoprotein(a) [Lp(a)] levels are primarily governed by genetic factors, with heritability estimates ranging between 70-90% [30]. The LPA gene, located on chromosome 6q26-27, is the key genetic determinant of Lp(a) concentrations, making genetics the dominant factor in understanding Lp(a) variability across individuals and populations.

LPA Gene Structure and Variants:

The LPA gene encodes apolipoprotein(a) [apo(a)], the distinctive protein component of Lp(a). A critical feature of the LPA gene is the kringle IV type 2 (KIV-2) copy number variant (CNV), which ranges from 3 to over 40 copies and leads to apo(a) isoforms of varying sizes [31].

      • Smaller apo(a) isoforms (fewer KIV-2 repeats) are associated with higher Lp(a) levels and greater cardiovascular risk [32].
      • Single nucleotide polymorphisms (SNPs), such as rs10455872 and rs3798220 in the LPA promoter region, also contribute to Lp(a) concentration, accounting for up to 36% of the variation in Lp(a) levels, independent of the KIV-2 CNV [33, 34].

Population Distribution of Lp(a) Levels:

Lp(a) levels display a highly skewed distribution across populations, with a long right tail toward higher concentrations:

      • In Caucasians, the median Lp(a) level is approximately 12 mg/dL, with around 20% of individuals having levels greater than 50 mg/dL [35].
      • This skewed distribution, however, varies significantly across different ethnic groups.

Ethnic and Racial Variations in Lp(a) Concentrations:

Substantial differences in Lp(a) levels exist between racial and ethnic groups, driven primarily by genetic factors:

      • African Americans generally have 2-3 times higher median Lp(a) levels compared to Caucasians [36].
      • South Asians tend to exhibit higher Lp(a) levels than Caucasians, while East Asians typically have lower levels [37, 38].
      • The prevalence of small apo(a) isoforms, which are more common in African populations, accounts for much of the elevated Lp(a) levels in these groups [39].
      • Certain LPA gene variants linked to high Lp(a) concentrations are more frequent in specific populations, explaining much of the interethnic variability [40].

Heritability and Familial Patterns:

The strong genetic control of Lp(a) levels leads to distinct familial patterns:

      • First-degree relatives of individuals with high Lp(a) (above the 95th percentile) have a 1.8-fold increased risk of elevated Lp(a) levels [41].
      • Autosomal codominant inheritance of LPA gene variants results in a wide range of Lp(a) levels within families [42].
      • Unlike other lipoproteins like LDL cholesterol, which are influenced by multiple genes, Lp(a) levels are predominantly determined by a single gene (LPA), simplifying its genetic architecture and making it a compelling candidate for genetic testing and personalized risk assessment [43].

Gene-Environment Interactions:

While genetics are the predominant determinant of Lp(a) levels, environmental factors can have a modest effect:

      • Acute phase reactions and inflammation may transiently raise Lp(a) levels [44].
      • Hormonal influences, such as estrogen and testosterone, also play a role in modulating Lp(a) concentrations [45].
      • Certain dietary factors and lifestyle changes may affect Lp(a) levels, but these effects are minor when compared to the genetic component [46].

Lipoprotein(a): Structure and Function

Definition and Basic Structure of Lp(a)

Lipoprotein(a) [Lp(a)] is a complex macromolecule found in human plasma. It consists of a lipid-rich core, primarily composed of cholesteryl esters and triglycerides, surrounded by a shell of phospholipids and apolipoproteins. The key structural feature that distinguishes Lp(a) from other lipoproteins is the presence of apolipoprotein(a) [apo(a)], which is covalently bound to apolipoprotein B-100 (apoB-100) via a single disulfide bond [24, 28†source].

Key Structural Components:

      • Lipid core: Primarily cholesteryl esters and triglycerides
      • Phospholipid monolayer
      • ApoB-100: Present as one molecule per Lp(a) particle
      • Apo(a): The defining protein of Lp(a)

The Unique Apolipoprotein(a) Component

Apo(a) is a large glycoprotein that differentiates Lp(a) from all other lipoproteins. Structurally, apo(a) shares a high degree of sequence identity with the fibrinolytic zymogen plasminogen, leading to its potential roles in thrombosis and atherosclerosis [28†source].

Kringle Domains:

      • Apo(a) contains multiple kringle IV (KIV) domains, with 10 distinct subtypes (KIV1 to KIV10).
      • The KIV2 domain exhibits size polymorphism, ranging from 3 to more than 40 copies, which directly influences the molecular weight of Lp(a) particles [31].
      • Apo(a) also has a single kringle V (KV) domain and a protease-like domain that is structurally similar to plasminogen but enzymatically inactive [29].
      • The size polymorphism of apo(a) results in Lp(a) particles of varying molecular weights (300-800 kDa), and there is an inverse correlation between apo(a) size and plasma Lp(a) concentrations [25].

Clarification: Lp(a) is Not Just LDL with an Extra Protein

Although Lp(a) and LDL share certain structural features, they are distinct particles. Unlike LDL, which is formed from the metabolism of very-low-density lipoprotein (VLDL), Lp(a) is synthesized and secreted as a complete particle by the liver [28†source]. Key differences include:

      • Protein Composition:
        Lp(a) contains both apoB-100 and apo(a), while LDL contains only apoB-100.
      • Size and Density:
        Lp(a) particles are larger and denser than LDL particles due to the presence of apo(a).
      • Metabolic Pathways:
        Lp(a) has distinct clearance mechanisms and half-lives compared to LDL [26].

Synthesis and Secretion by the Liver

A key characteristic of Lp(a) is that it is synthesized directly by hepatocytes in the liver, in contrast to LDL, which forms in the bloodstream through VLDL metabolism.

Assembly Process:

      • ApoB-100 is synthesized and lipidated in the endoplasmic reticulum.
      • Apo(a) is synthesized separately and undergoes extensive post-translational modifications.
      • The two proteins then associate and form a covalent bond either in the extracellular space or at the cell surface [28†source].

Cholesterol Content in Lp(a) vs LDL Particles

      • LDL particles: Cholesterol comprises 42-55% of LDL particle mass, primarily in the form of cholesteryl esters [29].
      • Lp(a) particles: Cholesterol accounts for only 30-45% of Lp(a) particle mass, partly due to the presence of apo(a). Consequently, Lp(a) particles carry less cholesterol than LDL particles, and traditional lipid panels often overestimate the cholesterol content in Lp(a) [29].

Pathophysiology of Lipoprotein(a) in Cardiovascular Disease

Lipoprotein(a) [Lp(a)] plays a multifaceted role in cardiovascular disease (CVD), contributing through both atherogenic and pro-thrombotic mechanisms, with important implications for arterial and valvular diseases.

Atherogenic Effects

Cholesterol Deposition and Intimal Retention:

Lp(a) particles penetrate the arterial intima and bind to extracellular matrix components. Their long residence time in the vessel wall, facilitated by apolipoprotein(a) [apo(a)], promotes cholesterol deposition, contributing to plaque growth, particularly at sites of arterial injury​.

Foam Cell Formation and Inflammation:

Macrophage uptake of oxidized Lp(a) particles promotes foam cell formation. Additionally, Lp(a) enhances the production of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, accelerating atherogenesis.

Incorporation of Microthrombi at Sites of Arterial Injury:

At sites of minor arterial injury—including areas of turbulent flow—microthrombi may form and become incorporated into the arterial wall. This process not only contributes to arterial stenosis but also plays a role in the pathogenesis of aortic valve stenosis, where Lp(a)-mediated microthrombi deposition accelerates calcification.

Pro-thrombotic Effects

Inhibition of Fibrinolysis:

Lp(a) competes with plasminogen for binding to fibrin, reducing fibrinolysis and promoting thrombus growth. This is particularly important at sites of plaque rupture, where thrombosis is enhanced.

Promotion of Platelet Aggregation and Thrombosis:

Lp(a) enhances platelet aggregation, particularly in the presence of subthreshold agonists, which further promotes thrombosis.

Lp(a) and Calcific Aortic Valve Disease (CAVD)

Elevated Lp(a) levels are associated with calcific aortic valve disease (CAVD). The presence of oxidized phospholipids carried by Lp(a) triggers osteogenic differentiation in valvular cells, promoting calcification. Additionally, microthrombi deposition in areas with turbulent and high-velocity flow, such as the aortic valve, contributes to the process.

Synergistic Effects with Other Risk Factors

Lp(a) may exert synergistic effects with other cardiovascular risk factors. For example, the combination of elevated Lp(a) and LDL cholesterol levels significantly heightens the risk of coronary heart disease [66]. In patients with familial hypercholesterolemia, elevated Lp(a) further increases cardiovascular risk [67].

Lp(a) Screening Recommendations

Recent guidelines emphasize the importance of incorporating Lipoprotein(a) [Lp(a)] screening into cardiovascular risk assessments due to its well-established role as an independent risk factor for both atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD).

Routine Screening:

Measurement of Lp(a) in all adults at least once during their lifetime is considered reasonable for cardiovascular risk assessment (Class of Recommendation [COR] I, Level of Evidence [LOE] B-NR) [188]. Lp(a) levels are primarily genetically determined, remaining stable over time, making this single measurement sufficient for most individuals.

Clinical Scenarios Where Lp(a) Testing is Particularly Valuable

Several clinical scenarios warrant special consideration for Lp(a) testing:

    • Premature ASCVD: Lp(a) testing can help explain the etiology and guide management in patients with early-onset cardiovascular disease [78].
    • Familial Hypercholesterolemia (FH): Elevated Lp(a) is common in FH patients and further increases their cardiovascular risk [79].
    • Recurrent ASCVD Events Despite Optimal Therapy: Lp(a) may explain residual risk in patients with well-controlled traditional risk factors [80].
    • Calcific Aortic Valve Disease: Given the strong association between Lp(a) and aortic valve calcification, testing may be valuable in patients with or at risk for aortic stenosis [81].
    • Borderline or Intermediate ASCVD Risk: Lp(a) measurement can help refine risk assessment and guide preventive interventions [82].

Risk Classification by Lp(a) Levels:

    • Lp(a) levels ≥125 nmol/L (≥50 mg/dL) are associated with high risk of cardiovascular events, such as myocardial infarction and stroke.
    • Levels <75 nmol/L (<30 mg/dL) are considered low risk.
    • Levels between 75 and 125 nmol/L (30–50 mg/dL) indicate intermediate risk [188].
      These thresholds are helpful for refining cardiovascular risk assessment alongside traditional risk factors like LDL cholesterol.

Selective Screening in High-Risk Children:

Selective screening for Lp(a) is recommended for children at high risk, particularly those with:

    • Familial hypercholesterolemia (FH),
    • A family history of premature ASCVD,
    • First-degree relatives with elevated Lp(a) [188].

Early identification of elevated Lp(a) levels in these populations can guide proactive risk management strategies.

Measurement and Laboratory Considerations

Methods for Measuring Lp(a)

Accurate measurement of Lp(a) is essential for cardiovascular risk assessment and management:

Immunochemical Assays:

Immunochemical assays, calibrated against the World Health Organization (WHO)/International Federation of Clinical Chemistry and Laboratory Medicine (IFCCLM) reference material, are the recommended method for Lp(a) measurement [71]. These assays must be insensitive to apo(a) isoform size to avoid underestimating Lp(a) levels in individuals with smaller isoforms [87].

Mass Spectrometry-Based Methods:

Although mass spectrometry-based methods offer more precise Lp(a) quantification, they are not yet widely available in routine clinical practice [88].

Standardization Issues and Efforts

The variability in apo(a) isoform sizes presents challenges in developing a universal standard for Lp(a) measurement:

Apo(a) Size Heterogeneity:

The size variability in apo(a) isoforms complicates Lp(a) measurement standardization [89]. While global standardization efforts by the IFCCLM are ongoing, full alignment across labs has yet to be achieved [71].

Current Methods:

In the interim, assays using a 5-point calibrator are considered sufficient for assessing Lp(a)-related cardiovascular risk [90].

Interpreting Lp(a) Test Results

Proper interpretation of Lp(a) results is key to making informed clinical decisions:

Preferred Units:

Lp(a) levels should ideally be reported in nmol/L, although mg/dL can be used if nmol/L values are unavailable. This helps to standardize results and reflect particle number more accurately [71].

Conversion Challenges:

Due to variability in apo(a) isoform sizes, the use of a fixed conversion factor between mg/dL and nmol/L is not recommended [71].

Frequency of Testing and Monitoring

Given that Lp(a) levels are primarily genetically determined, a single lifetime measurement is sufficient for most individuals [91]. However, repeat testing may be required in certain situations, such as:

Intermediate Risk Levels:

Patients with intermediate Lp(a) levels may benefit from repeat testing to better assess long-term risk [92].

Changes in Health Status:

Conditions such as renal disease or menopause may affect Lp(a) levels, warranting periodic monitoring [92].

Therapy Monitoring:

For individuals receiving Lp(a)-lowering therapies, more frequent testing may be necessary to track treatment efficacy [93].

Considerations for Lp(a)-C and LDL-C Calculations

Recent studies have raised concerns about traditional methods used to adjust for Lp(a)-associated cholesterol:

Correction Factor Issues:

The previously proposed correction factor for Lp(a)-C in LDL-C calculations has been found to be inaccurate, potentially leading to undertreatment of patients. Its use is no longer recommended [71].

New Formula Proposals:

A newer formula using molar concentrations of Lp(a) for LDL-C correction is currently under investigation but has not yet been validated for routine clinical use [94].

Emerging Technologies and Future Directions

Several new developments in Lp(a) measurement are under investigation, with the potential to improve clinical utility and accessibility:

Novel Assays:

New assays targeting specific regions of apo(a) may provide more accurate Lp(a) quantification [95].

Genetic Risk Scores:

Genetic risk scores based on LPA gene variants are being studied for identifying high-risk individuals, but they currently do not add significant value beyond Lp(a) concentration measurement [96].

Point-of-Care Testing:

The development of point-of-care testing for Lp(a) could increase access to testing, especially in primary care settings, and help improve cardiovascular risk stratification [97].

Lp(a) Particle Concentration (nmol/L) vs. Mass Concentration (mg/dL)

The preference for reporting Lp(a) in nmol/L rather than mg/dL is based on key considerations:

Apo(a) Size Heterogeneity:

The apo(a) component of Lp(a) varies in size due to the number of kringle IV type 2 (KIV2) repeats [98]. This variability affects mass concentration (mg/dL) but not molar concentration (nmol/L).

Relationship to Particle Number:

nmol/L directly reflects the number of Lp(a) particles, which is more relevant to cardiovascular risk than mass concentration (mg/dL) [99].

Consistency Across Isoforms:

Reporting in nmol/L provides a more consistent measure across apo(a) isoforms compared to mg/dL, which can overestimate risk in patients with larger Lp(a) particles [100].

Clinical Relevance:

The number of Lp(a) particles (nmol/L) is believed to correlate more closely with cardiovascular risk than the mass of Lp(a) (mg/dL) [101].

Standardization Efforts:

The use of nmol/L aligns with global efforts to standardize Lp(a) measurement, as it is less affected by the variability in apo(a) isoform sizes [71].

Assay Development:

New assays targeting stable regions of apo(a) common across all isoforms are being developed to provide more accurate particle number representation [102].

Management Strategies and Emerging Therapies for Elevated Lipoprotein(a)

Current Management Approaches

Lifestyle Modifications:

Heart-healthy diet, regular exercise, and smoking cessation are essential lifestyle interventions for all patients with elevated Lp(a) [103].

LDL-C Management:

Aggressive reduction of LDL cholesterol (LDL-C) remains the cornerstone of managing patients with elevated Lp(a), even though LDL-C-lowering therapies do not directly target Lp(a) [71].

Lipid-Lowering Therapies:

Statins have minimal to no effect on Lp(a) levels, and they may even cause a slight increase. However, statins significantly reduce cardiovascular risk regardless of Lp(a) levels. PCSK9 inhibitors lower Lp(a) by 20-30%, and niacin can reduce Lp(a) by 20-30%, although niacin is no longer recommended due to the lack of demonstrated cardiovascular benefit [104-106].

Lipoprotein Apheresis:

Apheresis is FDA-approved for high-risk patients with familial hypercholesterolemia (FH) and documented cardiovascular disease who have elevated Lp(a) levels (≥60 mg/dL or ~150 nmol/L) and LDL-C ≥100 mg/dL despite maximally tolerated therapy. Apheresis can lower both Lp(a) and LDL-C by 60-70%, with a time-averaged Lp(a) reduction of 30-35% [107-108].

Aspirin:

In patients with genetically elevated Lp(a), aspirin may reduce cardiovascular events, though it does not affect Lp(a) levels directly. A risk-benefit discussion on aspirin use is recommended for primary prevention patients with elevated Lp(a) [109].

Management in Special Populations

Familial Hypercholesterolemia (FH):

Patients with FH commonly have elevated Lp(a), significantly compounding their cardiovascular risk. In these cases, more aggressive LDL-C lowering with therapies like PCSK9 inhibitors may be necessary [71].

Children and Adolescents:

In children with elevated Lp(a)—especially those with FH or a family history of premature ASCVD—early identification and management of other risk factors are essential. Statins may be considered for high-risk pediatric patients [111].

Emerging Therapies

Antisense Oligonucleotides (ASOs):

Pelacarsen has demonstrated reductions in Lp(a) levels of >80% and is currently being investigated in phase 3 trials to determine its impact on cardiovascular outcomes [112].

Small Interfering RNAs (siRNAs):

Olpasiran and other siRNAs have shown nearly 100% reductions in Lp(a) levels in early-phase trials, with ongoing phase 3 studies assessing their clinical benefit [113-114].

Small Molecules:

Muvalaplin, an oral small molecule, interferes with the interaction between apo(a) and apoB, showing promising reductions in Lp(a) levels in early trials [126-127].

Long-term Safety and Future Directions

Safety Concerns:

Although ASOs and siRNAs show significant promise, their long-term safety profiles are still under investigation. Ongoing large-scale trials will clarify potential adverse effects and the long-term impact of Lp(a)-lowering therapies on cardiovascular events [139].

Future Approaches:

Large clinical trials are evaluating whether lowering Lp(a) will translate into meaningful reductions in cardiovascular events. Personalized therapies, potentially combining genetic risk scores with Lp(a)-lowering treatments, may become standard for high-risk patients. Combination therapies targeting both LDL-C and Lp(a) are also likely to emerge for comprehensive lipid management in high-risk populations [115-117].

Special Patient Populations and Clinical Considerations for Elevated Lipoprotein(a)

Primary Prevention

Refining Risk Assessment:
In adults aged 40-75 years with intermediate ASCVD risk, Lp(a) levels ≥50 mg/dL (≥125 nmol/L) are considered risk-enhancing factors, potentially supporting the initiation or intensification of statin therapy [140-141].

Secondary Prevention

Residual Risk in ASCVD:
Elevated Lp(a) remains a significant contributor to residual cardiovascular risk in patients with established ASCVD, even those on optimal therapy. More aggressive LDL-C lowering may be necessary in these patients [143-145].

Familial Hypercholesterolemia (FH)

Increased Risk:
Up to 30-50% of patients with FH have elevated Lp(a), compounding their cardiovascular risk. Lp(a) measurement is recommended in all FH patients to better stratify risk and guide more aggressive treatment, including potential consideration of apheresis in select cases [146-148].

Pediatric Considerations

Early Screening and Management:
Selective screening for Lp(a) is recommended in high-risk children, particularly those with FH or a strong family history of premature ASCVD. Early identification allows for long-term management strategies focusing on reducing other risk factors [149-151].

Women’s Cardiovascular Health

Impact of Hormonal Changes:
Lp(a) levels can rise during pregnancy and after menopause. Some studies suggest that elevated Lp(a) may pose a greater risk of ASCVD in women than in men, although hormone replacement therapy (HRT) is not recommended for lowering Lp(a) due to other cardiovascular risks [152-154].

Chronic Kidney Disease (CKD)

Lp(a) Elevations in CKD:
Lp(a) levels tend to increase as kidney function declines and contribute to the elevated cardiovascular risk in patients with chronic kidney disease (CKD). Dialysis does not effectively lower Lp(a) levels, and further increases are often seen in hemodialysis patients [155-157].

Ethnic and Racial Considerations

Variation in Lp(a) Levels:
African Americans tend to have higher average Lp(a) levels than Caucasians, but when adjusted for Lp(a) concentration, cardiovascular risk appears to be similar across ethnicities. Genetic variants affecting Lp(a) levels vary across populations [158-160].

Acute Coronary Syndromes (ACS)

Prognostic Implications:
Elevated Lp(a) is associated with an increased risk of recurrent events following ACS. Measurement of Lp(a) during or soon after an ACS event may provide valuable prognostic information. Ongoing studies are investigating whether Lp(a)-lowering therapies can improve outcomes in the post-ACS setting [161-163].

Future Directions and Unanswered Questions in Lipoprotein(a) Research

Impact of Lp(a)-Lowering on Cardiovascular Events

Despite significant advancements in understanding Lipoprotein(a) [Lp(a)] as a major cardiovascular risk factor, several critical questions remain unanswered. While Lp(a) has been recognized as a key contributor to atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD), the translation of these findings into effective clinical practice is still evolving. Emerging therapies like antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) hold great promise, but many areas require further investigation. A pivotal question is whether lowering Lp(a) levels will result in a significant reduction in cardiovascular events. While current clinical trials aim to provide clarity, the extent of risk reduction associated with Lp(a)-specific therapies remains uncertain. Additionally, understanding the optimal level of Lp(a) reduction necessary to achieve a tangible clinical benefit is crucial for establishing therapeutic targets and treatment thresholds.

Role of Lp(a)-Lowering in Primary Prevention

The role of Lp(a)-lowering therapies in primary prevention also remains largely unexplored. Current research primarily focuses on secondary prevention in patients with established cardiovascular disease, leaving a gap in understanding how interventions might benefit individuals with elevated Lp(a) but no diagnosed ASCVD. Identifying the right populations for early intervention could change the landscape of preventive cardiovascular care.

Mechanistic Insights into Lp(a) Biology

Mechanistically, several aspects of Lp(a) biology and its contributions to disease remain under investigation. The specific pathways by which Lp(a) promotes atherosclerosis and thrombosis are still not fully understood, particularly in relation to the unique structural properties of apo(a). Furthermore, Lp(a)’s role in the progression of aortic valve calcification raises additional questions about how interventions might slow or prevent aortic valve stenosis.

Non-Cardiovascular Roles of Lp(a)

Beyond cardiovascular risk, Lp(a)’s potential non-cardiovascular roles—such as its involvement in wound healing and angiogenesis—are underexplored. Understanding these broader biological functions could provide new insights into Lp(a)’s influence on overall health and offer novel therapeutic opportunities.

Conclusion

In conclusion, while tremendous strides have been made in Lp(a) research, critical questions about its clinical relevance, therapeutic thresholds, and mechanistic roles remain. Answering these questions will be key to shaping the future of Lp(a) management, enabling more precise and effective strategies for reducing cardiovascular risk in affected individuals.

References and further reading

  1. Wilson DP, et al. J Clin Lipidol. 2022;16:e77-e95.
  2. Patel AP, et al. Arterioscler Thromb Vasc Biol. 2021;41:465-474.
  3. Welsh P, et al. Eur J Prev Cardiol. 2022;28:1991-2000.
  4. Mehta A, et al. Atherosclerosis. 2022;349:42-52.
  5. Wong N.D., et al. J Am Coll Cardiol. In press.
  6. Virani SS, et al. Circulation. 2012;125:241-249.
  7. Guan W, et al. Arterioscler Thromb Vasc Biol. 2015;35:996-1001.
  8. Pare G, et al. Circulation. 2019;139:1472-1482.
  9. Kronenberg F, et al. Eur Heart J. 2022;43:3925-3946.
  10. Trinder M, et al. JAMA Cardiol. 2020;6:1-9.
  11. Perrot N, et al. JAMA Cardiol. 2019;4:620-627.
  12. Thomas PE, et al. J Am Coll Cardiol. 2023;82:2265-2276.
  13. Arsenault BJ, et al. JAMA Netw Open. 2020;3:e200129.
  14. Cao YX, et al. Thromb Haemost. 2021;121:1161-1168.
  15. Larsson SC, et al. Circulation. 2020;141:1826-1828.
  16. Thomas PE, et al. Eur Heart J. 2023;44:1449-1460.
  17. Willeit P, et al. Lancet. 2018;392:1311-1320.
  18. Khera AV, et al. Circulation. 2014;129:635-642.
  19. O’Donoghue ML, et al. Circulation. 2019;139:1483-1492.
  20. Reyes-Soffer G, et al. Arterioscler Thromb Vasc Biol. 2022;42:e48-e60.
  21. Finneran P, et al. J Am Heart Assoc. 2021;10:e017470.
  22. Orfanos P, et al. Eur J Cardiovasc Nurs. 2023;22.
  23. Safarova MS, Kullo IJ. Atherosclerosis. 2022;361:30-31.
  24. Malick WA, et al. J Am Coll Cardiol. 2023;81:1633-1645.
  25. Swerdlow DI, et al. Cardiovasc Res. 2022;118:1218-1231.
  26. Safarova MS, Moriarty PM. Curr Atheroscler Rep. 2023;25:391-404.
  27. Moriarty PM, et al. J Clin Apher. 2017;32:574-578.
  28. Sultan SM, et al. Int J Stroke. 2014;9:79-87.
  29. Kenet G, et al. Circulation. 2010;121:1838-1847.
  30. Nowak-Gottl U, et al. Blood. 1999;94:3678-3682.
  31. Sträter R, et al. Stroke. 2001;32:2554-2558.
  32. Strandkjaer N, et al. J Clin Endocrinol Metab. 2022;107:324-335.
  33. de Boer LM, et al. Atherosclerosis. 2022;349:227-232.
  34. Sagris M, et al. Cardiovasc Res. 2022;118:2281-2292.
  35. Raitakari O, et al. Circulation. 2023;147:23-31.
  36. Khoury M, Clarke SL. Circulation. 2023;147:32-34.
  37. Marcovina SM, Albers JJ. J Lipid Res. 2016;57:526-537.
  38. Szarek M, et al. Circulation. 2024;149:192-203.
  39. Marcovina SM, Shapiro MD. J Am Coll Cardiol. 2022;79:629-631.
  40. Yeang C, et al. J Lipid Res. 2021;62:100053.
  41. Zheng W, et al. J Am Heart Assoc. 2022;11:e023136.
  42. Rosenson RS, et al. Cardiovasc Drugs Ther. 2022.
  43. Mukamel RE, et al. Science. 2021;373:1499-1505.
  44. Dron JS, et al. Circ Genom Precis Med. 2021;14:e003182.
  45. Arnett DK, et al. J Am Coll Cardiol. 2019;74:1376-1414.
  46. Pearson GJ, et al. Can J Cardiol. 2021;37:1129-1150.
  47. Khan SS, et al. Circulation. 2023;148:1982-2004.
  48. Trinder M, et al. J Am Coll Cardiol. 2022;79:617-628.
  49. Deshotels MR, et al. J Am Heart Assoc. 2022;11:e026762.
  50. Enkhmaa B, Berglund L. Atherosclerosis. 2022;349:53-62.
  51. Michos ED, et al. Mayo Clin Proc. 2017;92:1831-1841.
  52. Mehta A, et al. J Am Coll Cardiol. 2022;79:757-768.
  53. Jackson CL, et al. J Clin Lipidol. 2023;17:538-548.
  54. Perrot N, et al. Atherosclerosis. 2017;256:47-52.
  55. Wilkinson MJ, et al. J Am Heart Assoc. 2023;12:e028892.
  56. Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681.
  57. de Boer LM, et al. Atherosclerosis. 2022;349:215-226.
  58. Awad K, et al. Drugs. 2018;78:453-462.
  59. Sahebkar A, et al. Sci Rep. 2018;8:17887.
  60. Ridker PM, et al. J Clin Lipidol. 2023;17:297-302.
  61. Wright RS, et al. J Am Coll Cardiol. 2021;77:1182-1193.
  62. Ray KK, et al. Eur Heart J. 2022;43:5047-5057.
  63. Bittner VA, et al. J Am Coll Cardiol. 2020;75:133-144.
  64. Sahebkar A, et al. Metabolism. 2016;65:1664-1678.
  65. Coronary Drug Project Research Group. JAMA. 1975;231:360-381.
  66. Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255.
  67. AIM-HIGH Investigators. N Engl J Med. 2011;365:2255-2267.
  68. HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371:203-212.
  69. Chasman DI, et al. Atherosclerosis. 2009;203:371-376.
  70. Lacaze P, et al. J Am Coll Cardiol. 2022;80:1287-1298.
  71. Koschinsky ML, et al. J Clin Lipidol. 2024; [In press].
  72. Tsimikas S, et al. J Am Coll Cardiol. 2021;77:1576-1589.
  73. O’Donoghue ML, et al. N Engl J Med. 2022;387:1855-1864.
  74. ClinicalTrials.gov. NCT04023552.
  75. ClinicalTrials.gov. NCT05030428.
  76. Nissen SE, et al. JAMA. 2022;327:1679-1687.
  77. Nissen SE, et al. JAMA. 2023;330:2075-2083.
  78. Sosnowska B, et al. Pharmaceuticals (Basel). 2022:15.
  79. Nicholls SJ, et al. JAMA. 2023;330:1042-1053.
  80. Bhatia HS, et al. J Am Heart Assoc. 2023;12:e031255.
  81. Varvel S, et al. Arterioscler Thromb Vasc Biol. 2016;36:2239-2245.
  82. Kelsey MD, et al. Am J Prev Cardiol. 2023;14:100478.
  83. Stürzebecher PE, et al. Atherosclerosis. 2023;367:24-33.
  84. Ma GS, et al. Angiology. 2019;70:332-336.
  85. Bhatia HS, et al. Atherosclerosis. 2022;349:144-150.
  86. Wilkinson MJ, et al. Angiology. 2017;68:795-798.
  87. Reyes-Soffer G., et al. Am J Prev Cardiol. In press.
  88. Marcovina SM, Albers JJ. J Lipid Res. 2016;57:526-537.
  89. Yeang C, et al. J Lipid Res. 2021;62:100054.
  90. Tsimikas S, et al. J Am Coll Cardiol. 2018;71:177-192.
  91. Wilson DP, et al. J Clin Lipidol. 2019;13:374-392.
  92. Langsted A, et al. Eur Heart J. 2019;40:2760-2770.
  93. Kronenberg F. Clin Exp Nephrol. 2014;18:234-237.
  94. Tsimikas S, et al. N Engl J Med. 2020;382:244-255.
  95. Yeang C, et al. J Lipid Res. 2021;62:100053.
  96. Scipione CA, Koschinsky ML. Curr Opin Lipidol. 2018;29:369-377.
  97. Trinder M, et al. JAMA Cardiol. 2021;6:287-295.
  98. Moriarty PM, et al. Arterioscler Thromb Vasc Biol. 2017;37:580-588.
  99. Marcovina SM, Albers JJ. J Lipid Res. 2016;57:526-537.
  100. Tsimikas S. J Am Coll Cardiol. 2017;69:692-711.
  101. Kronenberg F, Utermann G. J Intern Med. 2013;273:6-30.
  102. Willeit P, et al. Lancet. 2018;392:1311-1320.
  103. Grundy SM, et al. J Am Coll Cardiol. 2019;73:e285-e350.
  104. Willeit P, et al. Lancet. 2018;392:1311-1320.
  105. O’Donoghue ML, et al. Circulation. 2019;139:1483-1492.
  106. HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371:203-212.
  107. Moriarty PM, et al. Eur Heart J. 2016;37:3588-3595.
  108. Roeseler E, et al. Arterioscler Thromb Vasc Biol. 2016;36:2019-2027.
  109. Chasman DI, et al. Atherosclerosis. 2009;203:371-376.
  110. Alonso R, et al. J Am Coll Cardiol. 2014;63:1982-1989.
  111. Goldberg AC, et al. J Clin Lipidol. 2011;5:S1-S8.
  112. Tsimikas S, et al. N Engl J Med. 2020;382:244-255.
  113. Koren MJ, et al. Nat Med. 2022;28:96-103.
  114. Viney NJ, et al. Lancet. 2016;388:2239-2253.
  115. Tsimikas S, et al. J Am Coll Cardiol. 2020;76:261-273.
  116. Trinder M, et al. JAMA Cardiol. 2021;6:287-295.
  117. Bittner VA, et al. J Am Coll Cardiol. 2020;75:133-144.
  118. Viney NJ, et al. Lancet. 2016;388:2239-2253.
  119. Tsimikas S, et al. N Engl J Med. 2020;382:244-255.
  120. Tsimikas S, et al. J Am Coll Cardiol. 2021;77:1576-1589.
  121. Koren MJ, et al. Nat Med. 2022;28:96-103.
  122. O’Donoghue ML, et al. N Engl J Med. 2022;387:1855-1864.
  123. ClinicalTrials.gov. NCT05030428.
  124. Nissen SE, et al. JAMA. 2022;327:1679-1687.
  125. Tsimikas S. Curr Opin Lipidol. 2018;29:459-466.
  126. Nicholls SJ, et al. JAMA. 2023;330:1042-1053.
  127. Bittner V, et al. Eur Heart J. 2023;44:3531-3533.
  128. O’Donoghue ML, et al. Circulation. 2019;139:1483-1492.
  129. Bittner VA, et al. J Am Coll Cardiol. 2020;75:133-144.
  130. Ray KK, et al. N Engl J Med. 2020;382:1507-1519.
  131. Crosby J, et al. N Engl J Med. 2014;371:22-31.
  132. Chadwick AC, Musunuru K. Curr Cardiol Rep. 2017;19:22.
  133. Bergmark C, et al. J Lipid Res. 2008;49:2230-2239.
  134. Raal FJ, et al. J Lipid Res. 2016;57:1086-1096.
  135. Tsimikas S, et al. J Am Coll Cardiol. 2020;76:261-273.
  136. Burgess S, et al. JAMA Cardiol. 2018;3:619-627.
  137. Tsimikas S, et al. J Am Coll Cardiol. 2018;71:177-192.
  138. Nordestgaard BG, Langsted A. J Lipid Res. 2016;57:1953-1975.
  139. Tsimikas S. J Am Coll Cardiol. 2017;69:692-711.
  140. Grundy SM, et al. J Am Coll Cardiol. 2019;73:e285-e350.
  141. Wilson DP, et al. J Clin Lipidol. 2019;13:374-392.
  142. Kamstrup PR, et al. J Am Coll Cardiol. 2013;61:1146-1156.
  143. O’Donoghue ML, et al. J Am Coll Cardiol. 2014;63:520-527.
  144. Tsimikas S, et al. N Engl J Med. 2020;382:244-255.
  145. Bittner VA, et al. J Am Coll Cardiol. 2020;75:133-144.
  146. Langsted A, et al. Lancet Diabetes Endocrinol. 2016;4:577-587.
  147. Cuchel M, et al. Eur Heart J. 2014;35:2146-2157.
  148. Moriarty PM, et al. Eur Heart J. 2016;37:3588-3595.
  149. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics. 2011;128 Suppl 5:S213-S256.
  150. Zachariah JP, et al. Pediatr Cardiol. 2012;33:1230-1235.
  151. Goldberg AC, et al. J Clin Lipidol. 2011;5:S1-S8.
  152. Anagnostis P, et al. Maturitas. 2015;81:62-68.
  153. Pare G, et al. Circulation. 2019;139:1472-1482.
  154. Rossouw JE, et al. JAMA. 2002;288:321-333.
  155. Kronenberg F, et al. J Am Soc Nephrol. 2000;11:105-115.
  156. Kronenberg F, et al. Kidney Int Suppl. 2003;(84):S113-S116.
  157. Hopewell JC, et al. J Lipid Res. 2018;59:577-585.
  158. Guan W, et al. Arterioscler Thromb Vasc Biol. 2015;35:996-1001.
  159. Paré G, et al. Circulation. 2019;139:1472-1482.
  160. Kraft HG, et al. Eur J Hum Genet. 1996;4:74-87.
  161. Schwartz GG, et al. JAMA Cardiol. 2018;3:164-168.
  162. Zewinger S, et al. Lancet Diabetes Endocrinol. 2017;5:534-543.
  163. O’Donoghue ML, et al. J Am Coll Cardiol. 2014;63:520-527.
  164. Tsimikas S, et al. N Engl J Med. 2020;382:244-255.
  165. Burgess S, et al. JAMA Cardiol. 2018;3:619-627.
  166. Willeit P, et al. Lancet. 2018;392:1311-1320.
  167. Trinder M, et al. JAMA Cardiol. 2021;6:287-295.
  168. Varvel SA, et al. Arterioscler Thromb Vasc Biol. 2016;36:2239-2245.
  169. Pare G, et al. Circulation. 2019;139:1472-1482.
  170. Scipione CA, et al. J Lipid Res. 2015;56:2273-2285.
  171. Zheng KH, et al. J Am Coll Cardiol. 2019;73:2150-2162.
  172. Hoover-Plow J, Huang M. Metabolism. 2013;62:479-491.
  173. van der Valk FM, et al. Circulation. 2016;134:611-624.
  174. Ray KK, et al. Atherosclerosis. 2019;288:194-202.
  175. Viney NJ, et al. Lancet. 2016;388:2239-2253.
  176. Saleheen D, et al. Lancet Diabetes Endocrinol. 2017;5:524-533.
  177. Verbeek R, et al. J Am Coll Cardiol. 2017;69:1513-1515.
  178. Ellis KL, et al. J Am Coll Cardiol. 2019;73:1029-1039.
  179. Warden BA, et al. Crit Pathw Cardiol. 2019;18:37-42.
  180. Tsimikas S, et al. J Am Coll Cardiol. 2018;71:177-192.
  181. Wilson DP, et al. J Clin Lipidol. 2019;13:374-392.
  182. Marcovina SM, Albers JJ. J Lipid Res. 2016;57:526-537.
  183. Boffa MB, Koschinsky ML. Nat Rev Cardiol. 2019;16:305-318.
  184. Alaa AM, et al. PLoS One. 2019;14:e0213653.
  185. Andermann A, et al. Bull World Health Organ. 2008;86:317-319.
  186. Ferdinand KC, et al. Am J Prev Cardiol. 2020;2:100038.
  187. Cohn J, et al. Pediatrics. 2021;147:e2020034546.
  188. Koschinsky ML, et al. J Clin Lipidol. 2024; [In press].
  189. Nordestgaard BG, Langsted A. J Lipid Res. 2016;57:1953-1975.
  190. Tsimikas S. J Am Coll Cardiol. 2017;69:692-711.
  191. Wilson DP, et al. J Clin Lipidol. 2019;13:374-392.
  192. Marcovina SM, Albers JJ. J Lipid Res. 2016;57:526-537.
  193. Grundy SM, et al. J Am Coll Cardiol. 2019;73:e285-e350.
  194. Tsimikas S, et al. N Engl J Med. 2020;382:244-255.
  195. Kronenberg F, Utermann G. J Intern Med. 2013;273:6-30.
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