Atherogenicity Of Lp Research Articles

Lipoprotein(a) and risk-weighted apolipoprotein B: a novel metric for atherogenic risk

BackgroundRetention of apolipoprotein B (apoB)-containing lipoproteins within the arterial wall plays a major causal role in atherosclerotic cardiovascular disease (ASCVD). There is a single apoB molecule in all apoB-containing lipoproteins. Therefore, quantitation of apoB directly estimates the number of atherogenic particles in plasma. ApoB is the preferred measurement to refine the estimate of ASCVD risk. Low-density lipoprotein (LDL) particles are by far the most abundant apoB-containing particles. In patients with elevated lipoprotein(a) (Lp(a)), apoB may considerably underestimate risk because Mendelian randomization studies have shown that the atherogenicity of Lp(a) is approximately 7-fold greater than that of LDL on a per apoB particle basis. In subjects with increased Lp(a), the association between LDL-cholesterol and incident CHD (coronary heart disease) is increased, but the association between apoB and incident CHD is diminished or even lost. Thus, there is a need to understand the mechanisms of Lp(a), LDL-cholesterol and apoB-related CHD risk and to provide clinicians with a simple practical tool to address these complex and variable relationships. How can we understand a patient’s overall lipid-driven atherogenic risk? What proportion of this risk does apoB capture? What proportion of this risk do Lp(a) particles carry? To answer these questions, we created a novel metric of atherogenic risk: risk-weighted apolipoprotein B.MethodsIn nmol/L: Risk-weighted apoB = apoB - Lp(a) + Lp(a) x 7 = apoB + Lp(a) x 6. Proportion of risk captured by apoB = apoB divided by risk-weighted apoB. Proportion of risk carried by Lp(a) = Lp(a) × 7 divided by risk-weighted apoB.ResultsRisk-weighted apoB agrees with risk estimation from large epidemiological studies and from several Mendelian randomization studies.ConclusionsApoB considerably underestimates risk in individuals with high Lp(a) levels. The association between apoB and incident CHD is diminished or even lost. These phenomena can be overcome and explained by risk-weighted apoB.

Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis

BackgroundLipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate. ObjectivesThe authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle. MethodsGenome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed. ResultsThe Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis. ConclusionsWe conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.

Contemporary perspectives on the genetics and clinical use of lipoprotein(a) in preventive cardiology.

The pathogenicity of lipoprotein(a) [Lp(a)] as a risk factor for atherosclerotic cardiovascular disease (ASCVD) is well evidenced and recognized by international consensus-based guidelines. However, the measurement of Lp(a) is not routine clinical practice. Therapeutic agents targeting Lp(a) are now progressing through randomised clinical trials, and it is timely for clinicians to familiarize themselves with this complex and enigmatic lipoprotein particle. Recent developments in the understanding of genetic influences on the structure, plasma concentration and atherogenicity of Lp(a) have contextualized its clinical relevance. Mendelian randomization studies have enabled estimation of the contribution of Lp(a) to ASCVD risk. Genotyping individual patients with respect to Lp(a)-raising single nucleotide polymorphisms predicts ASCVD, but has not yet been shown to add value beyond the measurement of Lp(a) plasma concentrations, which should be done by Lp(a) isoform-independent assays capable of reporting in molar concentrations. Contemporary gene-silencing technology underpins small interfering RNA and antisense oligonucleotides, which are emerging as the leading Lp(a)-lowering therapeutic agents. The degree of Lp(a)-lowering required to achieve meaningful reductions in ASCVD risk has been estimated by Mendelian randomization, providing conceptual support. Measurement of Lp(a) in the clinical setting contributes to the assessment of ASCVD risk, and will become more important with the advent of specific Lp(a)-lowering therapies. Knowledge of an individual patient's genetic predisposition to increased Lp(a) appears to impart little or not additional clinical value beyond Lp(a) particle concentration.

Prognostic utility of lipoprotein(a) combined with fibrinogen in patients with stable coronary artery disease: a prospective, large cohort study

BackgroundElevated lipoprotein(a) [Lp(a)] and fibrinogen (Fib) are both associated with coronary artery disease (CAD). The atherogenicity of Lp(a) can be partly due to the potentially antifibrinolytic categories. We hypothesize that patients with higher Lp(a) and Fib may have worse outcomes.MethodsIn this prospective study, we consecutively enrolled 8,417 Chinese patients with stable CAD from March 2011 to March 2017. All subjects were divided into 9 groups according to Lp(a) (Lp(a)-Low, Lp(a)-Medium, Lp(a)-High) and Fib levels (Fib-Low, Fib-Medium, Fib-High) and followed up for CVEs, including nonfatal acute myocardial infarction, stroke, and cardiovascular mortality. Kaplan–Meier, Cox regression and C-statistic analyses were performed.ResultsDuring a median of 37.1 months’ follow-up, 395 (4.7%) CVEs occurred. The occurrence of CVEs increased by Lp(a) (3.5 vs. 5.3 vs. 5.6%, p = 0.001) and Fib (4.0 vs. 4.4 vs. 6.1%, p < 0.001) categories. When further classified into 9 groups by Lp(a) and Fib levels, the CVEs were highest in the 9th (Lp(a)-High and Fib-High) compared with the 1st (Lp(a)-Low and Fib-Low) group (7.2 vs. 3.3%, p < 0.001). The highest risk of subsequent CVEs was found in the 9th group (HRadjusted 2.656, 95% CI 1.628–4.333, p < 0.001), which was more significant than Lp(a)-High (HRadjusted 1.786, 95% CI 1.315–2.426, p < 0.001) or Fib-High (HRadjusted 1.558, 95% CI 1.162–2.089, p = 0.003) group. Moreover, adding the combined Lp(a) and Fib increased the C-statistic by 0.013.ConclusionCombining Fib and Lp(a) enhance the prognostic value for incident CVEs beyond Lp(a) or Fib alone.

ASSOCIATION OF LIPOPROTEIN(A) AND FIBRINOGEN AS PROGNOSTIC PREDICTORS FOR CARDIOVASCULAR OUTCOME IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE: A PROSPECTIVE, LARGE COHORT STUDY

Elevated plasma lipoprotein(a) [Lp(a)] and fibrinogen (Fib) levels are both associated with cardiovascular disease (CVD) and the atherogenicity of Lp(a) can be partly due to the potentially antifibrinolytic categories. We hypothesize that patients with higher Lp(a) and Fib may have worse outcomes.

Abstract 262: Lipoprotein(a) Stimulates Pro-Inflammatory Phenotypes in Vascular Cells: Demonstration of a Role for the Lysine-Binding Properties of Apolipoprotein(a)

Elevated plasma Lp(a) concentrations are a causal risk factor for a variety of atherosclerotic disorders. Although the role of Lp(a) in vascular disease remains poorly understood, the atherogenicity of Lp(a) may stem from the direct atherosclerotic effects of its LDL-like component, or from the presence of the unique protein component apolipoprotein(a) (apo(a)). It has been hypothesized that Lp(a) contributes to early atherogenesis by initiating a program of endothelial cell (EC) dysfunction which results in increased EC permeability and the adoption of a pro-coagulant and pro-inflammatory phenotype. In support of the latter, studies have shown that Lp(a) stimulates expression of cell adhesion molecules (CAMs) on ECs, and induces monocyte recruitment to these cells. In the present study we demonstrate that a recombinant 17 kringle form of apo(a) (17K) stimulates expression of CAMs on primary human umbilical vein endothelial cells (HUVECs) in both a time- and dose-dependent manner, as determined by qRT-PCR analysis. We found that 17K was able to induce the expression of ICAM1, E-Selectin, VCAM1, but not PE-CAM at pathophysiologically-relevant concentrations of apo(a). However, 17KD57A, lacking the strong lysine-binding site (sLBS) in KIV10, lacked these effects. 17K was also able to induce a dose dependant increase in ICAM1 expression in the THP-1 monocyte cell line, an effect that was completely abolished by the NF-B inhibitor BAY-11-7082. In a fluorescent monocyte adhesion assay, both Lp(a) and 17K apo(a) were able to stimulate increased monocyte adhesion to ECs. Using 17KD57A, we were able to show that this effect is dependent on the sLBS in KIV10. The presence of the sLBS in KIV10 has also been found to be required for the covalent oxidized phospholipid modification on apo(a). We report that multiple KIV10 sLBS mutants lack the oxPL modification, further supporting a pro-inflammatory role for an intact KIV10 domain. Taken together, these studies contribute to a more complete understanding of the pathophysiological role that the apo(a) component of Lp(a) plays in the initiation and progression of atherosclerosis, and has the potential to aid in the development new therapeutics aimed at reducing the harmful effects of Lp(a) in the vasculature.

When should we measure lipoprotein (a)?

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, Lp(a) Lipoprotein, and Coronary Artery Disease

Lp(a) lipoprotein binds proinflammatory oxidized phospholipids. We investigated whether levels of oxidized low-density lipoprotein (LDL) measured with use of monoclonal antibody E06 reflect the presence and extent of obstructive coronary artery disease, defined as a stenosis of more than 50 percent of the luminal diameter. Levels of oxidized LDL and Lp(a) lipoprotein were measured in a total of 504 patients immediately before coronary angiography. Levels of oxidized LDL are reported as the oxidized phospholipid content per particle of apolipoprotein B-100 (oxidized phospholipid:apo B-100 ratio). Measurements of the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein levels were skewed toward lower values, and the values for the oxidized phospholipid:apo B-100 ratio correlated strongly with those for Lp(a) lipoprotein (r=0.83, P<0.001). In the entire cohort, the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein levels showed a strong and graded association with the presence and extent of coronary artery disease (i.e., the number of vessels with a stenosis of more than 50 percent of the luminal diameter) (P<0.001). Among patients 60 years of age or younger, those in the highest quartiles for the oxidized phospholipid:apo B-100 ratio and Lp(a) lipoprotein levels had odds ratios for coronary artery disease of 3.12 (P<0.001) and 3.64 (P<0.001), respectively, as compared with patients in the lowest quartile. The combined effect of hypercholesterolemia and being in the highest quartiles of the oxidized phospholipid:apo B-100 ratio (odds ratio, 16.8; P<0.001) and Lp(a) lipoprotein levels (odds ratio, 14.2; P<0.001) significantly increased the probability of coronary artery disease among patients 60 years of age or younger. In the entire study group, the association of the oxidized phospholipid:apo B-100 ratio with obstructive coronary artery disease was independent of all clinical and lipid measures except one, Lp(a) lipoprotein. However, among patients 60 years of age or younger, the oxidized phospholipid:apo B-100 ratio remained an independent predictor of coronary artery disease. Circulating levels of oxidized LDL are strongly associated with angiographically documented coronary artery disease, particularly in patients 60 years of age or younger. These data suggest that the atherogenicity of Lp(a) lipoprotein may be mediated in part by associated proinflammatory oxidized phospholipids.

Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.

This study was performed to assess whether oxidized low-density lipoprotein (OxLDL) levels are elevated after percutaneous coronary intervention (PCI). Patients (n=141) with stable angina pectoris undergoing PCI had serial venous blood samples drawn before PCI, after PCI, and at 6 and 24 hours, 3 days, 1 week, and 1, 3, and 6 months. Plasma levels of OxLDL-E06, a measure of oxidized phospholipid (OxPL) content on apolipoprotein B-100 detected by antibody E06, lipoprotein(a) [Lp(a)], autoantibodies to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL), and apolipoprotein B-100-immune complexes (apoB-IC) were measured. OxLDL-E06 and Lp(a) levels significantly increased immediately after PCI by 36% (P<0.0001) and 64% (P<0.0001), respectively, and returned to baseline by 6 hours. In vitro immunoprecipitation of Lp(a) from selected plasma samples showed that almost all of the OxPL detected by E06 was bound to Lp(a) at all time points, except in the post-PCI sample, suggesting independent release and subsequent reassociation of OxPL with Lp(a) by 6 hours. Strong correlations were noted between OxLDL-E06 and Lp(a) (r=0.68, P<0.0001). MDA-LDL and Cu-OxLDL autoantibodies decreased, whereas apoB-IC levels increased after PCI, but both returned to baseline by 6 hours. Subsequently, IgM autoantibodies increased and peaked at 1 month and then returned to baseline, whereas IgG autoantibodies increased steadily over 6 months. PCI results in acute plasma increases of Lp(a) and OxPL and results in short-term and long-term immunologic responses to OxLDL. OxPL that are released or generated during PCI are transferred to Lp(a), suggesting that Lp(a) may contribute acutely to a protective innate immune response. In settings of enhanced oxidative stress and chronically elevated Lp(a) levels, the atherogenicity of Lp(a) may stem from its capacity as a carrier of proinflammatory oxidation byproducts.

The lysine-binding function of Lp(a).

The atherogenicity of Lp(a) is attributable to the binding of its apolipoprotein(a) component to fibrin and other plasminogen substrates. It can attenuate the activation of plasminogen, diminishing plasmin-dependent fibrinolysis and transforming growth factor-beta activation. Apolipoprotein(a) contains a major lysine-binding site in one of its kringle domains. Destroying this site by site-directed mutagenesis greatly reduces the binding of apolipoprotein(a) to lysine and fibrin. Transgenic mice expressing wild-type apolipoprotein(a) have a 5-fold increase in the development of lipid lesions, as well as a large increase in the focal deposition of apolipoprotein(a) in the aorta, compared to the lysine-binding site mutant strain and to non-transgenic litter mates. Although the adaptive function of apolipoprotein(a) remains obscure, a gene with similar structure has evolved by independent remodeling of the plasminogen twice during the course of mammalian evolution.

Lipoprotein (a) and the kidney

Summary: Cardiovascular disease is the main cause of death in chronic renal failure patients. Lipoprotein (a) [Lp(a)] is an independent risk factor for development of vascular disease in non‐renal and renal populations. the atherogenicity of Lp(a) is thought to relate to the structural homology between its apolipoprotein moiety [apo(a)] and plasminogen. Raised low‐density‐lipoprotein (LDL) cholesterol concentrations increase the atherogenic potential of Lp(a). Normally Lp(a) level is genetically determined but in renal disease positive correlations with urinary protein loss and peritoneal dialysate protein loss have been found. Levels are highest in nephrotic patients and chronic renal failure patients treated with peritoneal dialysis but are also increased in pre‐dialysis and haemodialysis patients. Lipoprotein (a) falls following renal transplantation but cyclosporine therapy may adversely affect post transplant cardiovascular risk profile. Treatment with antiproteinuric drugs (converting enzyme inhibitors or non‐steroidal anti‐inflammatory agents) has been shown to reduce Lp(a) (and total cholesterol) concentrations. Most lipid‐lowering drugs do not affect Lp(a) concentration but lowering LDL‐cholesterol alone may significantly reduce the atherogenic effect of Lp(a). Routine measurement of Lp(a) concentration is not recommended but antiproteinuric therapy should have favourable effects on cardiovascular risk profile.

Lipoprotein(a), Plasmin Modulation, and Atherogenesis

Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein however the mechanisms by which Lp(a) promote the atherosclerotic process are not clear. The apolipoprotein(a) portion of Lp(a) shares partial homology with plasminogen, a finding that has stimulated numerous studies. Lp(a) binds to fibrin and the affinity between fibrin surfaces and Lp(a) appears to be related to the state of oxidation of the lipoprotein particle. Lp(a) also effects fibrin-dependent plasminogen activation. Recent findings suggest that dependent plasminogen activation. Recent findings suggest that depending upon the in vitro conditions, Lp(a) either promotes or inhibits plasmin formation. Lp(a) also inhibits cell-surface dependent plasmin generation that is associated with an inhibition of transforming growth factor-beta (TGF-beta) production in cell coculture systems. Lp(a) stimulates smooth muscle cell migration and proliferation as a secondary response to this decrease in TGF-beta concentration. Studies in transgenic mice containing the human apolipoprotein(a) gene, document that both plasmin and TGF-beta formation in the media of the aorta is markedly decreased in the presence of apo(a). Thus the atherogenicity of Lp(a) may be mediated, in part, through its modulation of plasmin and TGF-beta production in the blood vessel wall.

The effect of reduction of lipoprotein (a) on cellular cholesterol synthesis in non-diabetic and Type 2 diabetic subjects

This study investigates the effect of Lipoprotein (a) (Lp(a)) on cellular cholesterol synthesis in non-diabetic ( n = 7) and Type 2 (non-insulin-dependent) diabetic subjects ( n = 7) with elevated levels of Lp(a) (> 20 mg/dl). N-Acetylcysteine was used to lower Lp(a) in the control subjects and their lipoproteins were re-examined after 7 days of treatment. Low-density lipoprotein (LDL) was isolated and separated from Lp(a) by sequential ultracentrifugation. Regulation of cellular cholesterol synthesis was assessed by measuring incorporation of [ 14C]acetate into mononuclear leucocytes in the presence of LDL and Lp(a). Cellular cholesterol content was determined by a fluorometric assay. Delivery of cholesterol to the cell was examined using [ 3H]cholesteryl oleate-labelled LDL or Lp(a). LDL (5 μg/ml) from non-diabetic subjects suppressed cellular cholesterol synthesis by 66.2%, while Lp(a) at a similar concentration only suppressed cholesterol synthesis by 5.8% ( P < 0.001). At a concentration of 20 μg/ml, Lp(a) suppressed cholesterol synthesis by 31.7%. The situation was similar in the diabetic subjects. Serum LDL cholesterol in non-diabetic subjects was 4.2 ± 0.5 mmol/1 and the LDL esterified/free cholesterol ratio was 2.6 ± 0.2. Following treatment with N-acetylcysteine, LDL cholesterol did not change, while Lp(a) decreased significantly by 24% ( P < 0.05). The LDL esterified/free cholesterol ratio decreased to 2.2 ± 0.2 ( P < 0.05) and there was a significant increase in the ability of the subjects LDL to inhibit cellular cholesterol synthesis ( P < 0.05). There was a significant negative correlation between plasma Lp(a) and the ability of the patients' LDL to inhibit cellular cholesterol synthesis ( r = − 0.68, P < 0.01). [ 3H]Cholesteryl-oleate-LDL (5 μg/ml) delivered 266 ± 13 ng cholesteryl oleate/mg cell protein, while it took 20 μg of [ 3H]cholesteryl oleate-labelled-Lp(a) to deliver a similar concentration (315 ± 21 ng cholesteryl oleate/mg cell protein). In conclusion it appears possible that the atherogenicity of Lp(a) may be associated with its effect on the LDL receptor which alters LDL receptor uptake, LDL composition and cellular cholesterol synthesis.

Molecular genetics of lipoprotein (a): new pieces to the puzzle

Important advances have been made in the past year in our understanding of the genetics of lipoprotein (a) [Lp(a)]. The apolipoprotein (a) [APO(a)] gene has been cloned and mice have been engineered to express apo(a) and Lp(a). These developments have provided the tools to answer many fundamental questions concerning the genetics, metabolism, and atherogenicity of Lp(a).

Fibrinogen/fibrin in atherogenesis.

Fibrin is a major component of many atherosclerotic plaques. Within the intima there is continuous formation of fibrin, and continuous fibrinolysis. In aortic lesions, a lipoprotein bound to fibrin can be released by incubation with plasmin. Most of this lipoprotein is accounted for by Lp(a). The atherogenicity of Lp(a) may be more associated with lipid deposition than with inhibition of fibrinolysis. Fibrin degradation products may be chemotactic to monocyte-macrophages and stimulate smooth muscle cell proliferation.

Relationship of plasma lipoprotein Lp(a) levels to race and to apolipoprotein B.

Lipoprotein Lp(a) is an atherogenic subfraction of plasma lipoproteins which has been studied predominantly in white populations. We quantified Lp(a) by electroimmunoassay in plasma from 105 black and 134 white healthy men and women. Results were correlated with clinical variables and plasma levels of lipids, other lipoproteins, and apolipoprotein (apo) B determined by radioimmunoassay. Black subjects had levels of Lp(a) that averaged twice those of whites (p less than 0.001). Among blacks, Lp(a) levels showed a bell-shaped frequency distribution, while among whites the distribution was strongly skewed, with the highest frequencies at low levels. Contrary to previously published results, the apo B levels in our study correlated significantly, though weakly, with Lp(a) (r = 0.21, p = 0.001 among whites, and r = 0.15, p = 0.02 among blacks, Kendall rank correlation). The regression slopes and variances suggested that apo B in the Lp(a) lipoprotein could account for the correlation. Lp(a) levels did not correlate significantly with any other plasma lipoprotein or lipid levels. The implications of this study are as follows: Despite the high levels of Lp(a) among blacks in the Houston area, these blacks do not experience greatly increased atherosclerotic progression and mortality. Thus, the atherogenicity of Lp(a) in blacks must be decreased or counterbalanced by other factors. The correlation between Lp(a) and apo B should be taken into account when analyzing atherogenic risk, but this correlation is not strong enough to dispute the independence of Lp(a) and apo B as risk factors.