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Cardiovascular diseases (CVDs) are the leading cause of death globally, attributed to a complex etiology involving metabolic, genetic, and protein-related factors. Lipoprotein(a) (Lp(a)), identified as a genetic risk factor, exhibits elevated levels linked to an increased risk of cardiovascular diseases. The lipoprotein(a) kringle domains have recently been identified as a potential target for the treatment of CVDs, in this study we utilized a fragment-based drug design approach to design a novel, potent, and safe inhibitor for lipoprotein(a) kringle domain. With the use of fragment library (61,600 fragments) screening, combined with analyses such as MM/GBSA, molecular dynamics simulation (MD), and principal component analysis, we successfully identified molecules effective against the kringle domains of Lipoprotein(a). The hybridization process (Breed) of the best fragments generated a novel 249 hybrid molecules, among them 77 exhibiting superior binding affinity (≤ -7 kcal/mol) compared to control AZ-02 (-6.9 kcal/mol), Importantly, the top ten molecules displayed high similarity to the control AZ-02. Among the top ten molecules, BR1 exhibited the best docking energy (-11.85 kcal/mol ), and higher stability within the protein LBS site, demonstrating the capability to counteract the pathophysiological effects of lipoprotein(a) [Lp(a)]. Additionally, principal component analysis (PCA) highlighted a similar trend of motion during the binding of BR1 and the control compound (AZ-02), limiting protein mobility and reducing conformational space. Moreover, ADMET analysis indicated favorable drug-like properties, with BR1 showing minimal violations of Lipinski's rules. Overall, the identified compounds hold promise as potential therapeutics, addressing a critical need in cardiovascular medicine. Further preclinical and clinical evaluations are needed to validate their efficacy and safety, potentially ushering in a new era of targeted therapies for CVDs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a)) 1,2 . Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K IV ) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3-7 ). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K IV 7-8. We identify compounds that bind to apo(a) K IV 7-8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329-which is already in phase 2 studies-as a potent and specific orally administered agent for reducing the levels of Lp(a)., (© 2024. The Author(s).)

Background: Lipoprotein (a) [Lp(a)] serum levels are highly genetically determined and promote atherogenesis. High Lp(a) levels are associated with increased cardiovascular morbidity. Serum Lp(a) levels have recently been associated with large artery atherosclerosis (LAA) stroke. We aimed to externally validate this association in an independent cohort., Methods: This study stems from the prospective multicentre CoRisk study (CoPeptin for Risk Stratification in Acute Stroke patients [NCT00878813]), conducted at the University Hospital Bern, Switzerland, between 2009 and 2011, in which Lp(a) plasma levels were measured within the first 24 hours after stroke onset. We assessed the association of Lp(a) with LAA stroke using multivariable logistic regression and performed interaction analyses to identify potential effect modifiers., Results: Of 743 patients with ischaemic stroke, 105 (14%) had LAA stroke aetiology. Lp(a) levels were higher for LAA stroke than non-LAA stroke patients (23.0 nmol/l vs 16.3 nmol/l, p = 0.01). Multivariable regression revealed an independent association of log10and#xA0;Lp(a) with LAA stroke aetiology (aOR 1.47 [95% CI 1.03and#x2013;2.09], p = 0.03). The interaction analyses showed that Lp(a) was not associated with LAA stroke aetiology among patients with diabetes., Conclusions: In a well-characterised cohort of patients with ischaemic stroke, we validated the association of higher Lp(a) levels with LAA stroke aetiology, independent of traditional cardiovascular risk factors. These findings may inform randomised clinical trials investigating the effect of Lp(a) lowering agents on cardiovascular outcomes. The CoRisk (CoPeptin for Risk Stratification in Acute Patients) study is registered on ClinicalTrials.gov., Registration Number: NCT00878813.

Elevated lipoprotein(a) [Lp(a)] levels are independently associated with atherosclerotic cardiovascular disease, although this association is less explored in postmenopausal women. The main objective of this systematic review was to analyze the association between elevated Lp(a) levels and cardiovascular outcomes in posmenopausal women. Studies that evaluated this association were searched in the current literature. Ten studies including 157.690 women were considered eligible for this study. In total, 4 prospective cohorts, 3 cross-sectional studies, 2 nested case-control studies, and one post-hoc analysis from a randomized clinical trial were analyzed. The included studies showed different results regarding the association between Lp(a) levels and cardiovascular outcomes: a positive association (4 studies), no association (2 studies), or different results depending on the subgroups or outcomes evaluated (4 studies). The results were robust when evaluating coronary events. The reduction in coronary events attributed to a hormone replacement therapy-associated decrease in Lp(a) levels was controversial., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Growing studies show that lipoprotein (a) [Lp(a)] is related to calcified aortic valve diseases in general population, while the relationship between Lp(a) and aortic valve calcification (AVC) in patients with new-onset acute myocardial infarction (AMI) remains unclear. Therefore, this study was to evaluate the correlation between Lp(a) and AVC in patients with new-onset AMI., Methods: This cross-sectional study included 410 patients with new-onset AMI who were hospitalised in Zhongda Hospital affiliated to Southeast University from January 1, 2020 to December 31, 2021. Multivariable logistic regression, subgroup analysis, generalised additive model, threshold and saturation effect and receiver operator characteristic (ROC) curve were used to explore the association between Lp(a) and AVC., Results: Patients with AVC had higher levels of Lp(a) than those without AVC. Multivariable logistic regression analysis showed that higher Lp(a) was still associated with higher risk of AVC after adjusting for confounding factors, and this correlation was robust in most subgroups and sensitivity analyses ( p  < 0.05). Additionally, the generalised additive model showed that there was a nonlinear correlation between Lp(a) and AVC (P for nonlinearity = 0.037). Threshold and saturation effect analysis indicated that when Lp(a) < 840 mg/L, it was positively correlated with the prevalence of AVC ( p  < 0.05), but when Lp(a) ≥ 840 mg/L, this correlation no longer existed. Besides, ROC curve analysis demonstrated that Lp(a) had a good diagnostic performance for AVC., Conclusion: Lp(a) was independently associated with the prevalence of AVC in patients with new-onset AMI.

Methods: Three hundred thirty-nine patients (230 men, 109 women) treated with lipoprotein apheresis in Saxony, Germany, in 2018 are described in terms of age, lipid pattern, risk factors, cardiovascular events, medication, and number of new admissions since 2014, and the data are compared with figures from 2010 to 2013., Results: Patients were treated by 45.5 physicians in 16 lipoprotein apheresis centers. With about 10 patients per 100 000 inhabitants, the number of patients treated with lipoprotein apheresis in Saxony is twice as high as in Germany as a whole. The median treatment time was 3 years. Almost all patients had hypertension; type 2 diabetes mellitus was seen significantly more often in patients with low Lipoprotein(a). Cardiovascular events occurred in almost all patients before initiation of lipoprotein apheresis, under apheresis therapy the cardiovascular events rate was very low in this high-risk group. For some cardiovascular regions even no events could be observed., Conclusions: The importance of lipoprotein apheresis in Saxony had been increasing from 2010 to 2018., (© 2022 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis and Japanese Society for Apheresis.)

Objective: We evaluated the safety and efficacy of lipoprotein apheresis (LA) in patients with familial hypercholesterolemia (FH) who can't reach low-density lipoprotein cholesterol(LDL-C) target goals with the maximal tolerated dose of lipid-lowering agents. Methods: This was a retrospective cross-sectional study. Between February 2015 and November 2019, patients with FH who were admitted in Fuwai hospital and treated with LA were consecutively enrolled. Based on intensive lipid-lowering agents, these patients received LA by double filtration plasma pheresis (DFPP) method. The changes of lipid levels such as LDL-C and lipoprotein(a)[Lp(a)] were compared before and after LA treatment, and the changes of immunoglobulin (Ig) concentration and LA-related adverse effects were also discussed. Results: A total of 115 patients with FH were enrolled in this study, of which 8 cases were homozygous FH and 107 cases were heterozygous FH. The age was (43.9±12.2) years and there were 75 (65.2%) males, and 108 (93.8%) with coronary artery disease. For pre-and immediately after LA treatment, the LDL-C was (5.20±2.94) mmol/L vs. (1.83±1.08) mmol/L, Lp(a) concentration was 428.70(177.00, 829.50)mg/L vs. 148.90(75.90, 317.00) mg/L ( P <0.001), with a decrease of 64.2% and 59.8% respectively. The levels of IgG and IgA measured 1 day after LA treatment were both in the normal range and IgM concentration was below the reference value, the reductions of which were 15.1%, 25.0% and 58.7% respectively ( P <0.001). Six patients had mild symptoms of nausea, hypotension dyspnea and palpitation, the symptoms were relieved by symptomatic treatment. Conclusion: For patients with FH who do not achieve LDL-C target goal with the maximal tolerated lipid-lowering agents, especially those with elevated Lp(a) levels, LA, which can significantly further reduce LDL-C and Lp(a) levels, is an effective and safe option.

Background: Elevated plasma Lp(a) (lipoprotein(a)) levels are associated with increased risk for atherosclerotic cardiovascular disease and aortic valve stenosis. However, the cell biology of Lp(a) biosynthesis remains poorly understood, with the locations of the noncovalent and covalent steps of Lp(a) assembly unclear and the nature of the apoB-containing particle destined for Lp(a) unknown. We, therefore, asked if apo(a) and apoB interact noncovalently within hepatocytes and if this impacts Lp(a) biosynthesis., Methods: Using human hepatocellular carcinoma cells expressing 17K (17 kringle) apo(a), or a 17KΔLBS7,8 variant with a reduced ability to bind noncovalently to apoB, we performed coimmunoprecipitation, coimmunofluorescence, and proximity ligation assays to document intracellular apo(a):apoB interactions. We used a pulse-chase metabolic labeling approach to measure apo(a) and apoB secretion rates., Results: Noncovalent complexes containing apo(a)/apoB are present in lysates from cells expressing 17K but not 17KΔLBS7,8, whereas covalent apo(a)/apoB complexes are absent from lysates. 17K and apoB colocalized intracellularly, overlapping with staining for markers of endoplasmic reticulum trans-Golgi, and early endosomes, and less so with lysosomes. The 17KΔLBS7,8 had lower colocalization with apoB. Proximity ligation assays directly documented intracellular 17K/apoB interactions, which were dramatically reduced for 17KΔLBS7,8. Treatment of cells with PCSK9 (proprotein convertase subtilisin/kexin type 9) enhanced, and lomitapide reduced, apo(a) secretion in a manner dependent on the noncovalent interaction between apo(a) and apoB. Apo(a) secretion was also reduced by siRNA-mediated knockdown of APOB ., Conclusions: Our findings explain the coupling of apo(a) and Lp(a)-apoB production observed in human metabolic studies using stable isotopes as well as the ability of agents that inhibit apoB biosynthesis to lower Lp(a) levels.

LIPOPROTEIN(a) : NSFA CONSENSUS Lipoprotein(a), first described in 1963, consists of a low-density lipoprotein (LDL) associated with apolipoprotein(a) [apo(a)] which has a structural similarity with plasminogen but does not have fi-brinolytic activity. This complex structure determines the prothrom¬botic and antifibrinolytic action of high concentrations of Lp(a) and promotes the progression of atherosclerosis. Lp(a) has a propensity to remain in the arterial intima and to deposit its load of choleste¬rol and oxidized phospholipids at the sites of plaque formation. Lp(a) is characterized by a dramatically wide range of plasma concentrations (from 0.01 to > 3g/L, or from 2.5nmol/L to > 750nmol/L) that are mainly influenced by genetic factors and not by age, gender or lifestyle. The increase in its circulating concen¬tration is related to the increase in atherothrombotic risk. In this context, Lp(a) assays, although currently insufficiently standardized, are of considerable interest not only for cardiovascular risk strati¬fication in high-risk subjects, but also for the clinical follow-up of patients treated with new lipid-lowering therapies likely to signifi¬cantly reduce its circulating concentration, PCSK9 inhibitors, an¬ti-apo(a) antisense oligonucleotide «ONAS» and, ultimately, to improve the management of subjects at high cardiovascular risk., Competing Interests: E. Anglés-Cano déclare n’avoir aucun lien d’intérêts. V. Durlach déclare avoir participé à des essais cliniques pour Amgen, Sanofi, Bioprojet, à des conférences, colloques ou actions de formation pour Amgen, Sanofi, Servier, MSD et Preuves et Pratiques ; avoir été pris en charge à l’occasion de déplacements pour congrès, par Servier, Amgen, Sanofi, Novo Nordisk.

Objective: Lipoprotein (a) [Lp(a)] is an LDL-like particle constituted by lipids, apolipoprotein B100 and apolipoprotein (a) [apo(a)], a multidomain glycoprotein whose molecular mass is dependent on the genetically encoded number of Kringle IV type 2 (KIV-2) repeats. Because Lp(a) isoforms have been associated with cardiovascular risk (CVR), we have investigated if their interfacial properties can contribute to distinguish between low and high-risk groups and thus be used as a new CVR indicator., Methods: Four Lp(a) variants, each carrying a different apo(a) isoform (K20, K24, K25, and K29), were purified from plasma of homozygous donors and their interfacial properties characterized using ellipsometry and surface pressure techniques., Results: Ellipsometry measurements revealed that these isoforms had a similar propensity to form adsorbed layers at hydrophobic-hydrophilic interfaces, but surface pressure enabled to clearly separate them into two groups: K20 and K24 on one side, and K25 and K29 on the other side., Conclusion: Though K24 and K25 differ only by a single KIV-2 domain, their sharp difference in surface pressure suggests a critical threshold between the two Lp(a) forms, providing insights into the use of condensed matter approaches to monitor CVR. Our findings may represent a new laboratory window to assist medical decisions and to develop precision medicine treatments, practices, and products for CVR, which can be extended to other cardiovascular disease conditions., (© 2021 by the Association of Clinical Scientists, Inc.)

Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Despite high-intensity lipid-lowering therapy, there is a residual risk of cardiovascular events that could be associated with lipoprotein(a) (Lp(a)). It has been shown that there is an association between elevated Lp(a) level and cardiovascular outcomes in patients with coronary heart disease. Data about the role of Lp(a) in the development of cardiovascular events after peripheral revascularization are scarce., Purpose: To evaluate the relationship of Lp(a) level with cardiovascular outcomes after revascularization of carotid and lower limbs arteries., Methods: The study included 258 patients (209 men, mean age 67 years) with severe carotid and/or lower extremity artery disease, who underwent successful elective peripheral revascularization. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the composite of primary endpoint and repeated revascularization., Results: For 36-month follow-up, 29 (11%) primary and 128 (50%) secondary endpoints were registered. There was a greater risk of primary (21 (8%) vs. 8 (3%); hazard ratio (HR), 3.0; 95% confidence interval (CI) 1.5-6.3; p < 0.01) and secondary endpoints (83 (32%) vs. 45 (17%), HR, 2.8; 95% CI 2.0-4.0; p < 0.01) in patients with elevated Lp(a) level (≥30 mg/dL) compared to patients with Lp(a) < 30 mg/dL. Multivariable-adjusted Cox regression analysis revealed that Lp(a) was independently associated with the incidence of cardiovascular outcomes., Conclusions: Patients with peripheral artery diseases have a high risk of cardiovascular events. Lp(a) level above 30 mg/dL is significantly and independently associated with cardiovascular events during 3-year follow-up after revascularization of carotid and lower limbs arteries.

Background: Lipoprotein(a) [Lp(a)] is a pro-atherogenic and pro-thrombotic LDL-like particle recognized as an independent risk factor for cardiovascular disease (CVD). The cholesterol within Lp(a) (Lp(a)-C) contributes to the reported LDL-cholesterol (LDL-C) concentration by nearly all available methods. Accurate LDL-C measurements are critical for identification of genetic dyslipidemias such as familial hypercholesterolemia (FH). FH diagnostic criteria, such as the Dutch Lipid Clinic Network (DLCN) criteria, utilize LDL-C concentration cut-offs to assess the likelihood of FH. Therefore, failure to adjust for Lp(a)-C can impact accurate FH diagnosis and classification, appropriate follow-up testing and treatments, and interpretation of cholesterol-lowering treatment efficacy., Objective: In this study, we use direct Lp(a)-C measurements to assess the potential misclassification of FH from contributions of Lp(a)-C to reported LDL-C in patient samples submitted for advanced lipoprotein profiling., Methods: A total of 31,215 samples submitted for lipoprotein profiling were included. LDL-C was measured by beta quantification or calculated by one of three equations. Lp(a)-C was measured by quantitative lipoprotein electrophoresis. DLCN LDL-C cut-offs were applied to LDL-C results before and after accounting for Lp(a)-C contribution., Results: Lp(a)-C was detected in 8665 (28%) samples. A total of 940 subjects were reclassified to a lower DLCN LDL-C categories; this represents 3% of the total patient series or 11% of subjects with measurable Lp(a)-C., Conclusion: Lp(a)-C is present in a significant portion of samples submitted for advanced lipid testing and could cause patient misclassification when using FH diagnostic criteria. These misclassifications could trigger inappropriate follow-up, treatment, and cascade testing for suspected FH., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Elevated circulating concentrations of lipoprotein(a) [Lp(a)] is strongly associated with increased risk of atherosclerotic cardiovascular disease (CVD) and degenerative aortic stenosis. This relationship was first observed in prospective observational studies, and the causal relationship was confirmed in genetic studies. Everybody should have their Lp(a) concentration measured once in their lifetime. CVD risk is elevated when Lp(a) concentrations are high i.e. > 50 mg/dL (≥100 mmol/L). Extremely high Lp(a) levels >180 mg/dL (≥430 mmol/L) are associated with CVD risk similar to that conferred by familial hypercholesterolemia. Elevated Lp(a) level was previously treated with niacin, which exerts a potent Lp(a)-lowering effect. However, niacin is currently not recommended because, despite the improvement in lipid profile, no improvements on clinical outcomes have been observed. Furthermore, niacin use has been associated with severe adverse effects. Post hoc analyses of clinical trials with proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors have shown that these drugs exert clinical benefits by lowering Lp(a), independent of their potent reduction of low-density lipoprotein cholesterol (LDL-C). It is not yet known whether PCSK9 inhibitors will be of clinical use in patients with elevated Lp(a). Apheresis is a very effective approach to Lp(a) reduction, which reduces CVD risk but is invasive and time-consuming and is thus reserved for patients with very high Lp(a) levels and progressive CVD. Studies are ongoing on the practical application of genetic approaches to therapy, including antisense oligonucleotides against apolipoprotein(a) and small interfering RNA (siRNA) technology, to reduce the synthesis of Lp(a)., Competing Interests: Declaration of competing interest Dr Cybulska has served as a consultant for Amgen and Sanofi-Aventis; Dr Kłosiewicz-Latoszek has served as a consultant for Amgen and Sanofi; Dr Penson owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, LinkMedical,Napp and Sanofi; Dr Banach has received research grant(s)/support from Sanofi and Valeant, and has served as a consultant for Abbott/Mylan, Abbott Vascular, Amgen, KRKA, MSD, Novo Nordisk, Polpharma, Polfarmex, Regeneron, Sanofi-Aventis, Servier, Valeant, Daichii Sankyo, Esperion, Lilly, and Resverlogix., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate the interaction effects between lipoprotein (a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) on first incident acute myocardial infarction (AMI) among Chinese Han population., Methods: 1522 cases and 1691 controls were retrospectively analyzed. All subjects were grouped by Lp(a) or LDL-C level., Results: Compared with reference group (LDL-C < 2.6 mmol/L and in the 1st quintile of Lp(a)), multivariable-adjusted analysis revealed that OR(95%CI) of first incident AMI for higher LDL-C alone is 2.66(1.78-3.98); that ORs(95%CI) for higher Lp(a) alone are 1.51(1.07-2.15), 1.84(1.28-2.64), 1.86(1.30-2.67) and 2.66(1.88-3.76) across the Lp(a) quintiles; and that ORs(95%CI) for both higher LDL-C and higher Lp(a) are 3.95(2.64-5.92), 3.20(2.21-4.64), 5.64(3.80-8.36) and 7.48(4.90-11.44) which were greater than the sum of the risks of both alone across the Lp(a) quintiles. Relative excess risks due to interaction were 1.78(95% CI, 0.12-3.44, P = 0.036) and 3.01(0.58-5.44, P = 0.015) at the 4th and 5th quintile of Lp(a), confirming the presence of additive interaction between Lp(a) and LDL-C on initial AMI., Conclusions: Lp(a) interacts with LDL-C in first incident AMI on additive scale in Chinese Han population. The risk of initial AMI from exposure of elevated Lp(a) combined with elevated LDL-C is much greater than the sum of the risks from that of both alone., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Cardiovascular (CV) diseases account for most worldwide mortality, and a higher level of lipoprotein (Lp)-(a) is recognized as a prevalent contributing risk factor. However, there is no consensus regarding nutritional strategies for lowering Lp(a) concentration. Thus, the purposes of this literature review were to: (1) critically examine data concerning the effects of dietetic interventions and nutraceutical agents on Lp(a) level; and (2) review the feasibility and utility of their clinical use., Methods: A literature search was conducted for studies published between August 2018 and March 2019. The search was performed using the Cochrane, Medline, and Web of Science databases. In order to expand the research, there were no delimitations on the type or year of the studies. A total of 1932 articles were identified using this search procedure. After duplicates were eliminated, 740 abstracts of articles written in English were screened to identify those of highest relevance. In the final tally, a total of 152 full-text articles were included in this review., Findings: Several foods and decreases in saturated fat and ethanol intake, especially red wine intake, may lower Lp(a) concentration, but limits are necessary. Coffee and tea intake may decrease Lp(a) level; further investigation is crucial before they can be considered potent Lp(a)-lowering agents. Among supplementation strategies, only l-carnitine and coenzyme Q10 are promising clinical candidates to lower Lp(a) level. Since both l-carnitine and coenzyme Q10 supplementation are commonly used for CV support, they deserve further exploration regarding clinical applicability. In contrast, despite potential CV benefits, current research fails to justify use of higher intakes of vitamin C, soy isoflavones, garlic, and ω-3 for decreasing Lp(a) concentration., Implications: Definitive long-term clinical trials are needed to confirm the effects of dietetic interventions and nutraceutical agents on Lp(a) concentration when anticipating improved CV outcomes., (Copyright © 2019. Published by Elsevier Inc.)

Lipoprotein(a) [Lp(a)], discovered in 1963, has been associated with atherosclerotic cardiovascular disease (ASCVD) independent of other traditional risk factors, including LDL cholesterol. Lp(a) is an apolipoprotein B (apoB)-containing lipoprotein, which contains an LDL-like particle. Unlike LDL, which is a primary therapeutic target to decrease ASCVD, current guidelines recommend measuring Lp(a) for risk assessments because there is no clear evidence demonstrating the clinical benefit of decreasing Lp(a) using classical drugs such as niacin. However, recent Mendelian randomization studies indicate that Lp(a) causally correlates with ASCVD. In addition, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for apo(a), have exhibited efficacy in decreasing Lp(a) substantially, invigorating a discussion whether Lp(a) could be a novel therapeutic target for further ASCVD risk reduction. This review aims to provide current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings.

Lipoprotein (a) [Lp(a)] concentrations are among the strongest genetic risk factors for cardiovascular disease and present pronounced interethnic and interindividual differences. Approximately 90% of Lp(a) variance is controlled by the LPA gene, which contains a 5.6-kb-large copy number variation [kringle IV type 2 (KIV-2) repeat] that generates >40 protein isoforms. Variants within the KIV-2 region are not called in common sequencing projects, leaving up to 70% of the LPA coding region currently unaddressed. To completely assess the variability in LPA , we developed a sequencing strategy for this region and report here the first map of genetic variation in the KIV-2 region, a comprehensively evaluated ultradeep sequencing protocol, and an easy-to-use variant analysis pipeline. We sequenced 123 Central-European individuals and reanalyzed public data of 2,504 individuals from 26 populations. We found 14 different loss-of-function and splice-site mutations, as well as >100, partially even common, missense variants. Some coding variants were frequent in one population but absent in others. This provides novel candidates to explain the large ethnic and individual differences in Lp(a) concentrations. Importantly, our approach and pipeline are also applicable to other similar copy number variable regions, allowing access to regions that are not captured by common genome sequencing., (Copyright © 2019 Coassin et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.)

Lipoprotein(a), or Lp(a), is a major risk factor for atherothrombotic events along with low-density lipoprotein cholesterol and, inversely, high-density lipoprotein cholesterol. Lp(a) also contributes to the progression of calcific aortic stenosis and to the rare occurrence of arterial thrombotic strokes without atherosclerosis in children and younger women. Much has been learned about the inheritance of Lp(a) levels and the relationship between apolipoprotein(a) structure and function. Recent work suggests an intriguing interaction between oxidized phospholipids on Lp(a) and inflammatory interleukin-1 genotypes. New pharmaceutical approaches with antisense and RNA interference technology may achieve up to 90% lowering of Lp(a). This Roundtable includes practical considerations for clinically measuring and responding to Lp(a) levels., (Copyright © 2018. Published by Elsevier Inc.)

Background: Lipoprotein(a) [Lp(a)] is reported as Lp(a) particle mass (mg/dL) or molar concentration of apolipoprotein(a) [apo(a)] (nmol/L), which is considered the gold standard. Values are often converted from one measurement to the other but the validity of this is unknown., Objectives: To quantify the relationship between Lp(a) molar concentration and Lp(a) mass in the context of various Lp(a) level thresholds and apo(a) isoform size., Methods: In all samples, Lp(a) levels in molar concentration and apo(a) isoform size were determined at the Northwest Lipid Metabolism and Diabetes Research Laboratories (NLMDRL). Lp(a) mass levels were determined at the University of California, San Diego (UCSD) (1635 samples), by 5 commercially available assays: Denka 1 and Denka 2 (each 80 samples), 2 turbidimetric assays (2545 and 2673 samples, respectively), and an enzyme-linked immunosorbent assay (2605 samples). The ratios between Lp(a) molar concentration and mass (eg, nmol/L/mg/dL) were calculated and related to apo(a) isoform size., Results: The mean (SD) ratios for NLMDRL/UCSD, NLMDRL/Denka1, and NLMDRL/Denka2 were 2.42 (1.25), 1.64 (0.18), and 2.02 (0.22), respectively. The ratios for NLMDRL/UCSD, NLMDRL/Denka1, and NLMDRL/Denka2 increased by Lp(a) cutoffs, with ratios of 1.82, 1.52, and 1.87, respectively, for Lp(a) < 75 nmol/L and 2.80, 1.89, and 2.24, respectively, for Lp(a) > 125 nmol/L. For the commercial turbidimetric assays and enzyme-linked immunosorbent assay, the ratios ranged from <1 to >5., Conclusions: Lp(a) molar/mass ratios are threshold, method, and isoform dependent. A single conversion factor between assays is not appropriate. These data support the transition of Lp(a) mass assays to molar concentration to improve diagnostic and clinical interpretation of Lp(a)-mediated risk., (Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Lipoprotein(a) Lp(a) is a cholesterol-rich, LDL-like particle that is independently associated with an increased risk for ischemic heart disease, atherosclerosis, thrombosis, and stroke. Genetic variation in the Lp(a) locus and some other genes related to Lp(a) synthesis and metabolism play a critical role in regulating plasma Lp(a) levels. The pathophysiological potential of Lp(a) is related to proatherogenic and prothrombotic effects on the vasculature. Different molecular mechanisms underlying the atherothrombotic potential of Lp(a), free apolipoprotein(a), and oxidized-Lp(a) have been proposed. However, plasma Lp(a) assay is complicated by problems associated with quantification and standardization owing to the polymorphic nature of this lipoprotein. This review has focused on the physicochemical properties of Lp(a), the genetic aspects of Lp(a), the need for accurate determination of Lp(a), the synthesis, and recent findings on metabolism of Lp(a). Lastly, the patho-physiological mechanisms by which Lp(a) may increase athero-thrombosis and an overview on the therapeutic modalities to interfere with Lp(a) are summarized., (© 2017 Wiley Periodicals, Inc.)

Background: Genetic studies have shown lipoprotein(a) (Lp[a]) to be an important causal risk factor for coronary disease. Apolipoprotein(a) isoform size is the chief determinant of Lp(a) levels, but its impact on the benefits of therapies that lower Lp(a) remains unclear., Methods: HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) is a randomized trial of niacin-laropiprant versus placebo on a background of simvastatin therapy. Plasma Lp(a) levels at baseline and 1 year post-randomization were measured in 3978 participants from the United Kingdom and China. Apolipoprotein(a) isoform size, estimated by the number of kringle IV domains, was measured by agarose gel electrophoresis and the predominantly expressed isoform identified., Results: Allocation to niacin-laropiprant reduced mean Lp(a) by 12 (SE, 1) nmol/L overall and 34 (6) nmol/L in the top quintile by baseline Lp(a) level (Lp[a] ≥128 nmol/L). The mean proportional reduction in Lp(a) with niacin-laropiprant was 31% but varied strongly with predominant apolipoprotein(a) isoform size ( P Trend =4×10 -29 ) and was only 18% in the quintile with the highest baseline Lp(a) level and low isoform size. Estimates from genetic studies suggest that these Lp(a) reductions during the short term of the trial might yield proportional reductions in coronary risk of ≈2% overall and 6% in the top quintile by Lp(a) levels., Conclusions: Proportional reductions in Lp(a) were dependent on apolipoprotein(a) isoform size. Taking this into account, the likely benefits of niacin-laropiprant on coronary risk through Lp(a) lowering are small. Novel therapies that reduce high Lp(a) levels by at least 80 nmol/L (≈40%) may be needed to produce worthwhile benefits in people at the highest risk because of Lp(a)., Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00461630., (© 2018 The Authors.)

Background: Low plasma lipoprotein(a) concentrations are associated with type 2 diabetes. Whether this is due to low lipoprotein(a) concentrations per se or to a large number of kringle IV type 2 (KIV-2) repeats remains unclear. We therefore aimed to identify genetic variants associated selectively with lipoprotein(a) concentrations or with the number of KIV-2 repeats, to investigate which of these traits confer risk of diabetes., Methods: We genotyped 8411 individuals from the Copenhagen City Heart Study for 778 single-nucleotide polymorphisms (SNPs) in the proximity of the LPA gene, and examined the association of these SNPs with plasma concentrations of lipoprotein(a) and with KIV-2 number of repeats. SNPs that were selectively associated with lipoprotein(a) concentrations but not with KIV-2 number of repeats, or vice versa, were included in a Mendelian randomization study., Results: We identified 3 SNPs (rs12209517, rs12194138, and rs641990) that were associated selectively with lipoprotein(a) concentrations and 3 SNPs (rs1084651, rs9458009, and rs9365166) that were associated selectively with KIV-2 number of repeats. For SNPs selectively associated with lipoprotein(a) concentrations, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.03 (95% CI, 0.86-1.23). In contrast, for SNPs selectively associated with KIV-2 number of repeats, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.42 (95% CI, 1.17-1.69)., Conclusions: Using a novel genetic approach, our results indicate that it is a high number of KIV-2 repeats that are associated causally with increased risk of type 2 diabetes, and not low lipoprotein(a) concentrations per se. This is a reassuring finding for lipoprotein(a)-lowering therapies that do not increase the KIV-2 number of repeats., (© 2017 American Association for Clinical Chemistry.)

Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine. "Progress lies not in enhancing what is, but in advancing toward what will be." (Khalil Gibran)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Essentials Elevated lipoproteinp(a) is an independent and causal risk factor for atherothrombotic diseases. rs3798220 (Ile/Met substitution in apo(a) protease-like domain) is associated with disease risk. Recombinant I4399M apo(a) altered clot structure to accelerate coagulation/delay fibrinolysis. Evidence was found for increased solvent exposure and oxidation of Met residue., Summary: Background Lipoprotein(a) (Lp[a]) is a causal risk factor for a variety of cardiovascular diseases. Apolipoprotein(a) (apo[a]), the distinguishing component of Lp(a), is homologous with plasminogen, suggesting that Lp(a) can interfere with the normal fibrinolytic functions of plasminogen. This has implications for the persistence of fibrin clots in the vasculature and hence for atherothrombotic diseases. A single-nucleotide polymorphism (SNP) (rs3798220) in the gene encoding apo(a) has been reported that results in an Ile→Met substitution in the protease-like domain (I4399M variant). In population studies, the I4399M variant has been correlated with elevated plasma Lp(a) levels and higher coronary heart disease risk, and carriers of the SNP had increased cardiovascular benefit from aspirin therapy. In vitro studies suggested an antifibrinolytic role for Lp(a) containing this variant. Objectives We performed a series of experiments to assess the effect of the Ile→Met substitution on fibrin clot formation and lysis, and on the architecture of the clots. Results We found that the Met variant decreased coagulation time and increased fibrin clot lysis time as compared with wild-type apo(a). Furthermore, we observed that the presence of the Met variant significantly increased fibrin fiber width in plasma clots formed ex vivo, while having no effect on fiber density. Mass spectrometry analysis of a recombinant apo(a) species containing the Met variant revealed sulfoxide modification of the Met residue. Conclusions Our data suggest that the I4399M variant differs structurally from wild-type apo(a), which may underlie key differences related to its effects on fibrin clot architecture and fibrinolysis., (© 2017 International Society on Thrombosis and Haemostasis.)

Lipoprotein (a) (Lp(a)) is a modified low-density lipoprotein (LDL) particle with an additional specific apolipoprotein (a), covalently attached to apolipoprotein B‑100 of LDL by a single thioester bond. Increased plasma Lp(a) level is a genetically determined, independent, causal risk factor for cardiovascular disease.The precise quantification of Lp(a) in plasma is still hampered by mass-sensitive assays, large particle variation, poor standardization and lack of assay comparability.The physiological functions of Lp(a) include wound healing, promoting tissue repair and vascular remodeling. Similarly to other lipoproteins, Lp(a) is also susceptible for oxidative modifications, leading to extensive formation of pro-inflammatory and pro-atherogenic oxidized phospholipids, oxysterols, oxidized lipid-protein adducts in Lp(a) particles, that perpetuate atherosclerotic lesion progression and intima-media thickening through induction of M1-macrophages, inflammation, autoimmunity and apoptosis. The oxidation-specific epitopes of modified lipoproteins are major targets of pre-immune, natural IgM antibodies, that may attenuate the pro-inflammatory and pro-atherogenic effects of Lp(a).Although the data are still insufficient, recent studies suggest a potential anti-neoplastic role of Lp(a).

Lipoprotein (a) [Lp(a)] has attracted the interest of researchers and physicians due to its intriguing properties, including an intragenic multiallelic copy number variation in the LPA gene and the strong association with coronary heart disease (CHD). This review summarizes present knowledge of the structure, function, and genetics of Lp(a) with emphasis on the molecular and population genetics of the Lp(a)/LPA trait, as well as aspects of genetic epidemiology. It highlights the role of genetics in establishing Lp(a) as a risk factor for CHD, but also discusses uncertainties, controversies, and lack of knowledge on several aspects of the genetic Lp(a) trait, not least its function., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Elevated plasma concentrations of lipoprotein (a) [Lp(a)] have been determined to be a causal risk factor for coronary heart disease, and may similarly play a role in other atherothrombotic disorders. Lp(a) consists of a lipoprotein moiety indistinguishable from LDL, as well as the plasminogen-related glycoprotein, apo(a). Therefore, the pathogenic role for Lp(a) has traditionally been considered to reflect a dual function of its similarity to LDL, causing atherosclerosis, and its similarity to plasminogen, causing thrombosis through inhibition of fibrinolysis. This postulate remains highly speculative, however, because it has been difficult to separate the prothrombotic/antifibrinolytic functions of Lp(a) from its proatherosclerotic functions. This review surveys the current landscape surrounding these issues: the biochemical basis for procoagulant and antifibrinolytic effects of Lp(a) is summarized and the evidence addressing the role of Lp(a) in both arterial and venous thrombosis is discussed. While elevated Lp(a) appears to be primarily predisposing to thrombotic events in the arterial tree, the fact that most of these are precipitated by underlying atherosclerosis continues to confound our understanding of the true pathogenic roles of Lp(a) and, therefore, the most appropriate therapeutic target through which to mitigate the harmful effects of this lipoprotein., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples. Apo(a) is extremely variable in size not only between but also within individuals because of the presence of two different, genetically determined apo(a) isoform sizes. Therefore, the antigenic determinants per particle available to interact with the antibodies will vary in the samples and the calibrators, thus contributing to apo(a) size-dependent inaccuracy of different methods. The lack of rigorous validation of the immunoassays and common means of expressing Lp(a) concentrations hinder the harmonization of results obtained by different studies and contribute to the lack of common cut points for identification of individuals at risk for coronary artery disease or for interventions aimed at reducing Lp(a) levels. The aim of our review is to present and critically evaluate the issues surrounding the measurements of Lp(a), their impact on the clinical interpretation of the data, and the obstacles we need to overcome to achieve the standardization of Lp(a) measurements., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Atherosclerosis is one of the major cause of mortality in developed countries. The characteristic lesion of atherosclerosis is the atheroma or plaque that forms through thickening of the inner layer of the vessel wall (called the intima). The development of stent in 1980s revolutionised treatment of cardiovascular diseases, including atherosclerosis. However the advent of stenting was hindered by the new problem of in-stent restenosis. It was demonstrated that in-stent restenosis was the result of a new pathology in the form of neointimal hyperplasia, which was a maladaptive healing response to bare-metal stent implantation. Recent evidence suggests that although drug-eluting stent (DES) have reduced restenosis rates, important concerns have been raised regarding increased late stent thrombosis, myocardial infarction and death. With advances in nanotechnology and smart materials, covered stents has been proposed to overcome this problem. This is due to in-stent late restenosis and thromboses are mainly caused by smooth muscle cells (SMC) proliferation. Studies showed that there is a relation between high low-density lipoprotein (LDL) and lipoprotein (a) [Lp(a)] level in blood stream and chance of in-stent restenosis, moreover studies show that Lp(a) could stimulate SMC proliferation. We hypothesis development of covered stent with novel design and use of smart materials which could adsorb cholesterol and prevent contact between Lp(a) and vessel wall to overcome problem indicated in DES. In addition cost of stents will significantly reduce by elimination of drugs as well as complex manufacturing of the drug incorporation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Lipoprotein(a) (Lp(a)) is a highly atherogenic and heterogeneous lipoprotein that is inherited in an autosomal codominant trait. A unique aspect of this lipoprotein is that it is fully expressed by the first or second year of life in children, a pattern that is distinctly different from other lipoproteins, which typically only reach adult levels after adolescence. Despite decades of research, Lp(a) metabolism is still poorly understood but what is abundantly clear is that it is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents does not recommend measuring Lp(a) levels as part of routine screening except in youth with an ischemic or hemorrhagic stroke or youth with a parental history of ASCVD not explained by classical risk factors. One of the reasons that both the pediatric and adult guidelines fail to include this lipoprotein as part of routine lipid screening is the absence of data to show that lowering Lp(a) will reduce current or future ASCVD risk independently of low-density lipoprotein cholesterol (LDL-C) lowering. The cholesterol carried by Lp(a) is included in the low-density lipoprotein cholesterol measurement, but a separate test is used to measure the lipoprotein mass and/or cholesterol carried only by Lp(a). Because levels seem to be largely under genetic control, studies of lifestyle modification have been inconclusive although one study in obese children showed a decrease in the Lp(a) level comparable with the favorable effect on other lipids. The most compelling data regarding the importance of Lp(a) in the pediatric population are the increased risk associated with arterial ischemic stroke, a risk that is comparable with that associated with antiphospholipid antibodies or protein C deficiency. Although no specific pharmaceutical treatments are recommended to lower Lp(a) levels in youth, it is vitally important to educate youth and their parents about the excessive risk associated with this lipoprotein and the need to avoid the acquisition of other lifestyle-related risk factors such as smoking, excess weight, and physical inactivity to preserve more ideal cardiovascular health in adulthood., (Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Lipoprotein(a) [Lp(a)] is acknowledged to be an independent atherothrombotic risk factor. Although genetic studies have highlighted the causal relationship between coronary disease and Lp(a), it is uncertain which strategies maximize the therapeutic benefit of patients with high Lp(a) levels. We report the challenging case of a young coronary heart disease (CHD) patient who underwent 10 percutaneous coronary interventions due to repeated acute coronary syndromes (2006-2009) despite an optimally controlled, traditional risk-factor profile. For the first time, we performed specific Lp(a) immunoadsorption in the presence of very low levels of low-density lipoprotein cholesterol (LDL-C) while the patient was on a high-dose statin regimen. There have been no previous reports of patients with high Lp(a) levels who achieved LDL-C goals when treated with an isolated Lp(a)-lowering method. Despite the very high risk of cardiovascular death, targeting Lp(a) resulted in dramatic improvement of the patient's clinical condition. Thus, we suggest that specific Lp(a) apheresis should be considered an effective new treatment strategy for patients with progressive CHD who have reached LDL-C goals but harbor elevated Lp(a) levels., (© 2014 Wiley Periodicals, Inc.)

Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A novel technique for preparation affinity sorbent based on tyramine and tryptamine was proposed. It was shown that tryptamine-Sepharose and tyramine-Sepharose effectively bind IgG, IgA, lipoprotein (a) (Lp(a)) and low density lipoproteins (LDL) from blood plasma. The sorption capacity is 4-9 mg of IgG, 2-4 mg IgA, 3-5:mg of Lp(a) and 5-7 mg of LDL per mL of gel. It was found that new sorbents can bind Lp(a) and IgG as themselves or in a complex of Lp(a) with IgG. The existence of this complex may indicate the presence of anti-Lp(a) autoantibodies in the blood of some patients. The advantages of new sorbents are easiness of its synthesis and stability during use and storage. In practice they can be applied for medical and biotechnological purposes where it is necessary to bind Lp(a), LDL, IgG, IgA.

Elevated plasma concentrations of lipoprotein(a) (Lp[a]) are an emerging risk factor for the development of coronary heart disease (CHD). Recent genetic and epidemiologic data have provided strong evidence for a causal role of Lp(a) in CHD. Despite these developments, which have attracted increasing interest from clinicians and basic scientists, many unanswered questions persist. The true pathogenic mechanism of Lp(a) remains a mystery. Significant uncertainty exists concerning the appropriate use of Lp(a) in the clinical setting. No therapeutic intervention remains that can specifically lower plasma Lp(a) concentrations, although the list of compounds that lower Lp(a) and LDL continues to expand., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The importance of lipoprotein (a)-Lp(a)-as a cardiovascular (CV) risk marker has been underscored by recent findings that CV risk is directly related to baseline Lp(a) levels, even in well-treated patients. Although there is currently little that can be done pharmacologically to lower Lp(a) levels, knowledge of its serum concentration is important in overall risk assessment. This review focuses on 1 aspect of Lp(a) that is rarely discussed directly: how to express its levels in serum. There is considerable confusion on this point, and a fuller understanding of what the concentration units mean will help improve study-to-study comparisons and thereby advance our understanding of the pathobiology of this lipoprotein particle. As discussed here, the term Lp(a) mass refers to the entire mass of the particle: lipids, proteins, and carbohydrates combined. At present, there are no commercially available assays that are completely insensitive to the variability in particle mass, which arises not only from differences in apo(a) isoform mass but also from variations in lipid mass. Because lipoprotein "particle number" (molar concentration) has been found to be superior to component-based metrics (ie, low-density lipoprotein particle vs cholesterol concentrations) for CV disease risk prediction, the development of a mass-insensitive Lp(a) assay should be a high priority., (Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Recent studies showed that lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease (CVD). However, whether Lp(a) modifies clinical risk assessment was not established., Objectives: This study was conducted to determine whether Lp(a) improves CVD risk prediction., Methods: In 1995, Lp(a) was measured in 826 men and women (age range, 45 to 84 years) from the general community. Incidence of CVD was recorded over 15 years of follow-up., Results: In models adjusted for Framingham Risk Score (FRS) and Reynolds Risk Score (RRS) variables, the hazard ratio (HR) for incident CVD was 1.37 per 1-SD higher Lp(a) level (SD = 32 mg/dl) and 2.37 when comparing the top fifth quintile with other quintiles. The addition of Lp(a) to the RRS increased the C-index by 0.016. Of the 502 subjects who remained free of CVD, 82 were correctly reclassified to a lower risk category and 49 were reclassified to a higher risk category (predicted 15-year categories: <7.5%, 7.5% to <15%, 15% to <30%, ≥30%) (p < 0.001). Of the 148 subjects who developed CVD, 18 were correctly reclassified to a higher risk category and 17 were reclassified to a lower risk category. In subjects at intermediate risk (15% to <30%), the net reclassification improvement afforded by Lp(a) was 22.5% for noncases, 17.1% for cases, and 39.6% overall. Allele-specific Lp(a) levels did not add to the predictive ability of the FRS or RRS or to Lp(a)., Conclusions: Elevated Lp(a) predicts 15-year CVD outcomes and improves CVD risk prediction. These findings suggest that Lp(a) levels may be used in risk assessment of subjects in the general community, particularly in intermediate-risk groups., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Observational and genetic studies have shown that lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] isoform size are both associated with coronary heart disease (CHD) risk, but the relative independence of these risk factors remains unclear. Clarification of this uncertainty is relevant to the potential of future Lp(a)-lowering therapies for the prevention of CHD., Methods: Plasma Lp(a) levels and apo(a) isoform size, estimated by the number of kringle IV (KIV) repeats, were measured in 995 patients with CHD and 998 control subjects. The associations between CHD risk and fifths of Lp(a) levels were assessed before and after adjustment for KIV repeats and, conversely, the associations between CHD risk and fifths of KIV repeats were assessed before and after adjustment for Lp(a) levels., Results: Individuals in the top fifth of Lp(a) levels had more than a twofold higher risk of CHD compared with those in the bottom fifth, and this association was materially unaltered after adjustment for KIV repeats [odds ratio (OR) 2.05, 95% confidence interval (CI) 1.38-3.04, P < 0.001]. Furthermore, almost all of the excess risk was restricted to the two-fifths of the population with the highest Lp(a) levels. Individuals in the bottom fifth of KIV repeats had about a twofold higher risk of CHD compared with those in the top fifth, but this association was no longer significant after adjustment for Lp(a) levels (OR 1.13, 95% CI 0.77-1.66, P = 0.94)., Conclusions: The effect of KIV repeats on CHD risk is mediated through their impact on Lp(a) levels, suggesting that absolute levels of Lp(a), rather than apo(a) isoform size, are the main determinant of CHD risk., (© 2013 The Association for the Publication of the Journal of Internal Medicine.)

A novel strategy for the construction of a disposable integrated amperometric immunosensor for the sensitive and rapid determination of lipoprotein(a) (Lp(a)), an important predictor of cardiovascular disease risk, in human serum is reported. The approach uses a sandwich format involving the covalent immobilization of selective capture antibodies (antiLp(a)) on the surface of N-[Nα,Nα-bis(carboxymethyl)-lysine]-12-mercaptododecanamide (HS-NTA)-modified screen-printed carbon electrodes (SPCEs). After a blocking step with skimmed milk, the modified antiLp(a)-SPCEs were incubated with a mixture solution containing the target analyte and a fixed concentration of a specific biotinylated antibody (biotin-antiLp(a)) and a streptavidin-horseradish peroxidase (HRP) (Strep-HRP) conjugate. The amperometric responses of the resulting immunosensor at -0.10 V (vs an Ag pseudo-reference electrode), upon addition of 3,3',5,5'-tetramethylbenzidine (TMB) as electron transfer mediator and H2O2 as the enzyme substrate, were used to monitor the extent of the immunoreactions. The developed methodology exhibited a wide range of linearity between 0.02 and 10 μg mL(-1), a low detection limit (LOD) of 8 ng mL(-1), and a great selectivity against other serum components. The usefulness of the Lp(a) immunosensor was demonstrated by analyzing spiked serum samples as well as a reference serum containing a certified Lp(a) content.

Lipoprotein (a) is a strong and independent risk factor for atherosclerosis severity and a predictor of the risk of ischaemic heart disease and stroke. Many questions are still unanswered in relation to the clinical relevance of the scientific observations on Lp(a) and its application in the realms of cardiovascular prevention. Lp(a), a lipoprotein subtype, is linked to the Apo(a) gene located on chromosome 6q26-27 independently associated with increased risk of coronary artery disease (CAD). For this review, data sources from Cochrane, Pubmed, MEDLINE from 1960 till 2012 were analysed systematically. At least one-off measurement of plasma Lp(a) was found to be indicated in those with premature coronary disease when no real causative factor was identified. Management seemed promising with PCSK9 I, apheresis, CETPI, dietary choices and ACEi. There was clear evidence that Lp(a) is a definite risk marker for atherosclerotic cardiovascular disease (CVD).

Human plasma lactose-binding immunoglobulin (LIg) isolated by affinity chromatography on lactose-Sepharose was largely IgG with significant IgA and IgM contents. LIg-mediated agglutination of desialylated human RBC was inhibited equally by the α- and β-anomers of methyl galactoside. Recognition of either the terminal α-galactose (TAG)-containing glycans of bovine thyroglobulin or the N-acetyl lactosamine (LacNAc)-terminating glycans of asialofetuin by LIg was inhibitable nearly as much by the α-galactoside melibiose as by the β-galactoside lactose. Melibiose covalently conjugated to protein and coated on polystyrene wells captured several times more LIg molecules than its lactose analogue. LIg binding to bovine thyroglobulin or rabbit RBC membrane proteins, both bearing TAG was substantially reduced by prior treatment of the proteins with α-galactosidase to remove TAG though enzyme-treated glycans contained newly exposed LacNAc moieties. Desialylated O-linked oligosaccharides, however, were no ligand for LIg. Unlike LDL, plasma lipoprotein(a) [Lp(a)] coated on polystyrene well and desialylated by neuraminidase was recognized by LIg through terminal LacNAc moieties exposed by the enzyme on its apo(a) subunit. Further, same amount of added fluorescence-labelled LIg formed significantly more immune complex with Lp(a) in high Lp(a) plasma than in low Lp(a) plasma. Results suggest (1) possibility of a role for LIg in combating non-primate molecules and cells bearing TAG moiety and (2) a mechanism for Lp(a)-mediated vascular injury as diabetes, infections and inflammations induce greater release of neuraminidase into circulation., (© 2014 John Wiley & Sons Ltd.)

Recently published epidemiological and genetic studies strongly suggest a causal relationship of elevated concentrations of lipoprotein (a) [Lp(a)] with cardiovascular disease (CVD), independent of low-density lipoproteins (LDLs), reduced high density lipoproteins (HDL), and other traditional CVD risk factors. The atherogenicity of Lp(a) at a molecular and cellular level is caused by interference with the fibrinolytic system, the affinity to secretory phospholipase A2, the interaction with extracellular matrix glycoproteins, and the binding to scavenger receptors on macrophages. Lipoprotein (a) plasma concentrations correlate significantly with the synthetic rate of apo(a) and recent studies demonstrate that apo(a) expression is inhibited by ligands for farnesoid X receptor. Numerous gaps in our knowledge on Lp(a) function, biosynthesis, and the site of catabolism still exist. Nevertheless, new classes of therapeutic agents that have a significant Lp(a)-lowering effect such as apoB antisense oligonucleotides, microsomal triglyceride transfer protein inhibitors, cholesterol ester transfer protein inhibitors, and PCSK-9 inhibitors are currently in trials. Consensus reports of scientific societies are still prudent in recommending the measurement of Lp(a) routinely for assessing CVD risk. This is mainly caused by the lack of definite intervention studies demonstrating that lowering Lp(a) reduces hard CVD endpoints, a lack of effective medications for lowering Lp(a), the highly variable Lp(a) concentrations among different ethnic groups and the challenges associated with Lp(a) measurement. Here, we present our view on when to measure Lp(a) and how to deal with elevated Lp(a) levels in moderate and high-risk individuals.

Oxidized phospholipids (OxPLs) are present on apolipoprotein (a) [apo(a)] and lipoprotein (a) [Lp(a)] but the determinants influencing their binding are not known. The presence of OxPLs on apo(a)/Lp(a) was evaluated in plasma from healthy humans, apes, monkeys, apo(a)/Lp(a) transgenic mice, lysine binding site (LBS) mutant apo(a)/Lp(a) mice with Asp(55/57)→Ala(55/57) substitution of kringle (K)IV10)], and a variety of recombinant apo(a) [r-apo(a)] constructs. Using antibody E06, which binds the phosphocholine (PC) headgroup of OxPLs, Western and ELISA formats revealed that OxPLs were only present in apo(a) with an intact KIV10 LBS. Lipid extracts of purified human Lp(a) contained both E06- and nonE06-detectable OxPLs by tandem liquid chromatography-mass spectrometry (LC-MS/MS). Trypsin digestion of 17K r-apo(a) showed PC-containing OxPLs covalently bound to apo(a) fragments by LC-MS/MS that could be saponified by ammonium hydroxide. Interestingly, PC-containing OxPLs were also present in 17K r-apo(a) with Asp(57)→Ala(57) substitution in KIV10 that lacked E06 immunoreactivity. In conclusion, E06- and nonE06-detectable OxPLs are present in the lipid phase of Lp(a) and covalently bound to apo(a). E06 immunoreactivity, reflecting pro-inflammatory OxPLs accessible to the immune system, is strongly influenced by KIV10 LBS and is unique to human apo(a), which may explain Lp(a)'s pro-atherogenic potential.

Atherosclerotic cardiovascular diseases (CVD) are still the leading cause of morbidity and mortality worldwide, although optimal medical therapy has been prescribed for primary and secondary preventions. Residual cardiovascular risk for some population groups is still considerably high although target low density lipoprotein-cholesterol (LDL-C) level has been achieved. During the past few decades, compelling pieces of evidence from clinical trials and meta-analyses consistently illustrate that lipoprotein(a) (Lp(a)) is a significant risk factor for atherosclerosis and CVD due to its proatherogenic and prothrombotic features. However, the lack of effective medication for Lp(a) reduction significantly hampers randomized, prospective, and controlled trials conducting. Based on previous findings, for patients with LDL-C in normal range, Lp(a) may be a useful marker for identifying and evaluating the residual cardiovascular risk, and aggressively lowering LDL-C level than current guidelines' recommendation may be reasonable for patients with particularly high Lp(a) level.

Background: The complexes of β₂-glycoprotein I (β₂-GPI) with lipoprotein(a) [β₂-GPI-Lp(a)] exist in human circulation and are increased in serum from patients with some autoimmune diseases. This study aims to investigate the concentration of β₂-GPI-Lp(a) in serum of children with idiopathic nephrotic syndrome (NS) and its relationship with serum lipids, oxidized lipoprotein and renal function parameters to explore the potential of the complexes as an additional marker for evaluating pediatric NS., Methods: Serum concentrations of β₂-GPI-Lp(a) complexes and oxidized Lp(a) [ox-Lp(a)] were measured by "Sandwich" ELISAs in 80 NS children and 82 age/sex-matched healthy controls. The levels of serum lipids and kidney parameters were also determined. Multivariate logistic regression analysis was performed to identify correlate of β₂-GPI-Lp(a) and NS., Results: The serum concentrations of β₂-GPI-Lp(a) complexes in children with NS were significantly higher than those in controls (median 0.95 U/ml vs 0.28 U/ml, P<0.0001). Ox-Lp(a) levels were also markedly elevated (median 14.55 mg/l vs 2.60 mg/l, P<0.0001] in NS children. The concentrations of β₂-GPI-Lp(a) were positively correlated with ox-Lp(a) (r=0.246, P=0.028), but not with Lp(a) level, and the concentrations of ox-Lp(a) were positively related with Lp(a) (r=0.301, P=0.007) in NS children. Multivariate logistic regression analysis identified a positive association between NS and β₂-GPI-Lp(a) (OR=13.694, 95% CI 6.400-29.299, P<0.0001), after adjusting for kidney function parameters, serum lipids and ox-Lp(a)., Conclusions: Elevated β₂-GPI-Lp(a) level was an independent and significant risk factor for pediatric NS and, enhanced Lp(a) oxidation partly contributes to the formation of β₂-GPI-Lp(a) complexes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: It has been demonstrated that oxidative stress can induce red blood cell rigidity and haemolysis, which in turn can cause hyperviscosity and hyperbilirubinaemia, respectively. However, haemolysis may be associated with a low level of haemoglobin, which reduces whole blood viscosity (WBV). Bilirubin can behave as antioxidant or oxidant, and one uncharted course for diagnostic pathology is how or whether bilirubinaemia and viscosity are associated. Further, oxidative stress is now being assessed using lipoprotein-a (Lp(a)), among other things but whether it is associated with blood viscosity has not been established., Aim: This study investigates the association and correlation of haemoglobin level and WBV with serum Lp(a) and bilirubin levels in a general population of patients., Materials and Methods: Sixty-eight cases that were tested for Lp(a), concomitantly with full blood count and liver function, in our archived clinical pathology database were used in this study. WBV levels were determined using a validated formula. Multivariate and univariate analyses as well as correlation were performed., Results: WBV was found to be significantly associated with bilirubin (P<0.02), but not with Lp(a). Haemoglobin concentration was inversely correlated with Lp(a) (P<0.04), but not with bilirubinaemia., Conclusion: This pilot study suggests that hyperbilirubinaemia and hyperviscosity are associated and positively correlated. Consideration of whether serum bilirubin (as an indirect index of oxidative stress) can be used in combination with WBV (as index of macrovascular effect of oxidative stress) to assess oxidative damage is recommended.