P5322Oxidized phospholipids on apolipoprotein B-100 among black US adults with and without PCSK9 loss-of-function variants

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Mefford ◽  
S Marcovina ◽  
V Bittner ◽  
M Cushman ◽  
T Brown ◽  
...  
Keyword(s):  
Racial Differences ◽  
Apolipoprotein B ◽  
Population Distribution ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
P Value ◽  
Loss Of Function ◽  
Black Adults ◽  
Lipoprotein A ◽  
Increased Risk

Abstract Background High oxidized phospholipid-apolipoprotein B-100 (OxPL-apoB) levels are associated with an increased risk for coronary heart disease (CHD). Genetic PCSK9 loss-of-function (LOF) variants result in life-long lower levels of LDL-C and lipoprotein(a) and reduced CHD risk, but the association with OxPL-apoB is unknown. Purpose To estimate the association between PCSK9 LOF variants and OxPL-apoB levels among black adults. Methods Genotyping for LOF variants (Y142X and C679X) was conducted for 10,196 black Reasons for Geographic And Racial Differences in Stroke study participants. OxPL-apoB was measured using antibody E06 for all participants with LOF variants (n=241) and randomly selected participants, matched at a 1:3 ratio, without LOF variants (n=723). Low OxPL-apoB was defined as the bottom quartile of the population distribution (<1.6 nM). Prevalence ratios (PR) and 95% confidence intervals (CI) were calculated for the association between PCSK9 LOF variants and low OxPL-apoB levels adjusting for age, sex, and estimated glomerular filtration rate. Results Adults with versus without PCSK9 LOF variants had lower LDL-C and lipoprotein(a) and were less likely to be taking a statin. (Table) A higher proportion of adults with versus without PCSK9 LOF variants had low OxPL-apoB levels (30.3 vs 23.4, p=0.03). After adjustment for covariates, the PR of low OxPL-apoB was increased for participants with compared to without LOF variants (PR 1.31, 95% CI 1.00, 1.72). Characteristics of REGARDS participants PCSK9 loss-of-function variant p-value Yes (n=241) No (n=723) Age, years, mean (SD) 63.7 (9.2) 63.8 (8.6) 0.81 Female, % 61.4 60.6 0.82 Diabetes, % 34.4 27.4 0.04 LDL-C, mg/dL, mean (SD) 85 (32) 118 (37) <0.001 Lp(a), nmol/L, median (25th, 75th percentile) 63.2 (30.4, 119.6) 80.4 (39.7, 138.4) 0.02 Statin use, % 13.3 30.4 <0.001 OxPL-apoB <1.6 nM, % 30.3 23.4 0.03 Abbreviations: LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); LOF, loss-of-function; nM, nanomolar; OxPL-apoB, oxidized phospholipids on apolipoprotein B-100; PCSK9, proprotein convertase subtilisin/kexin type-9; REGARDS, REasons for Geographic And Racial Differences in Stroke; SD, standard deviation. Conclusion Among black adults, PCSK9 LOF variants were associated with lower OxPL-apoB levels. Acknowledgement/Funding Industry/academic collaboration between Amgen Inc., University of Alabama at Birmingham and the Icahn School of Medicine at Mt. Sinai; and U01NS041588

scholarly journals Extremely elevated lipoprotein (a) as an independent risk factor for peripheral arterial disease in large patient cohort

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.R Poudel ◽  
S Kirana ◽  
D Stoyanova ◽  
K.P Mellwig ◽  
D Hinse ◽  
...  
Keyword(s):  
Peripheral Arterial Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Arterial Disease ◽  
P Value ◽  
Lipoprotein A ◽  
Large Patient ◽  
Increased Risk ◽  
Revascularization Therapy ◽  
Peripheral Arterial

Abstract Background Elevated lipoprotein (a) [LP (a)] levels are an independent, genetic, and causal factor for cardiovascular disease and associated with myocardial infarction (MI). Although the association between circulating levels of lipoprotein(a) [Lp(a)] and risk of coronary artery disease (CAD) is well established, its role in risk of peripheral arterial disease (PAD) remains unclear. PAD affects over 236 million individuals and follows ischaemic heart disease (IHD) and cerebrovascular disease (CVD) as the third leading cause of atherosclerotic cardiovascular morbidity worldwide. LP (a) is genetically determined, stable throughout life and yet refractory to drug therapy. While 30 mg/dl is considered the upper normal value for LP (a) in central Europe, extremely high LP (a) levels (&gt;150mg/dl) are rare in the general population. The aim of our study was to analyse the correlation between lipoprotein (a) [LP (a)] levels and an incidence of PAD in high-risk patients. Patients and methods We reviewed the LP (a) concentrations of 52.898 consecutive patients admitted to our cardiovascular center between January 2004 and December 2014. Of these, 579 patients had LP (a) levels above 150 mg/dl (mean 181.45±33.1mg/dl). In the control collective LP (a) was &lt;30mg/dl (n=350). Other atherogenic risk factors in this group were HbA1c 6.58±1.65%, low density lipoprotein (LDL) 141.99±43.76 mg/dl, and body mass index 27.81±5.61. 54.40% were male, 26.07% were smokers, 93.2% had hypertension, and 24% had a family history of cardiovascular diseases. More than 82.6% were under statins. The mean glomerular filtration rate (GFR) was 69.13±24.8 ml/min [MDRD (Modification of Diet in Renal Disease)]. Results 45.00% (n=261) of the patients with LP (a) &gt;150mg/dl had PAD. The prevalence of PAD in patients with LP (a) &lt;30mg/dl in our control collective was 15.8%. (P- Value 0.001). Patients with LP (a) &gt;150mg/dl had a significantly increased risk for PAD (Odds ratio 4.36, 95% CI 2.94–6.72, p: 0.001). 19.1% of patients were re-vascularized by percutaneous angioplasty (PTA) and 7.09% of patients had to undergo peripheral vascular bypass (PVB). Mean LP (a) level in patients with PAD was 182.6±31.61. Conclusion Elevated LP (a) levels above 150 mg/dl are associated with a significantly increased risk of PAD in our collective and it confirms our hypothesis. Over one fourth of these patients had severe PAD and requiring revascularization therapy. We need more prospective studies to confirm our findings. Funding Acknowledgement Type of funding source: None

Should we Consider Lipoprotein (a) in Cardiovascular Disease Risk Assessment in Patients with Familial Hypercholesterolaemia?

2019 ◽  
Vol 24 (31) ◽  
pp. 3665-3671 ◽  
Author(s):  
Panagiotis Anagnostis ◽  
Pavlos Siolos ◽  
Dimitrios Krikidis ◽  
Dimitrios G. Goulis ◽  
John C. Stevenson
Keyword(s):  
Cardiovascular Disease ◽  
Familial Hypercholesterolaemia ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pcsk9 Inhibitors ◽  
Cvd Risk ◽  
Lipoprotein A ◽  
Increased Risk

Background: Familial hypercholesterolaemia (FH) is a genetically determined lipid disorder, affecting 1 per 200-500 individuals in the general population. It is significantly and independently associated with an increased risk of Cardiovascular Disease (CVD), although it remains still an underrecognized and undertreated disease. Lipoprotein (a) [Lp(a)] is a low-density-lipoprotein (LDL)-like molecule, containing an additional protein, apolipoprotein (a). Objective: This review aims to present and discuss available data on the role of Lp(a) in patients with FH, in terms of its potential augmentation of CVD risk. Methods: A comprehensive search of the literature was performed to identify studies evaluating the CV effects of Lp(a) in patients with FH. Results: Lp(a) has been recognised as an independent risk factor for CVD, mainly coronary artery disease (CAD). Most, but not all, studies show increased Lp(a) concentrations in adults and children with FH. There is also evidence of an independent association between Lp(a) and CVD (mainly CAD) risk in these patients. Conclusion: Some therapeutic modalities, such as niacin, oestrogens, tibolone and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors may effectively reduce Lp(a) concentrations by 25-30%, although their clinical benefit of this effect remains to be established.

Quantification of lipoprotein(a) particles containing various apolipoprotein(a) isoforms by a monoclonal anti-apo(a) capture antibody and a polyclonal anti-apolipoprotein B detection antibody sandwich enzyme immunoassay

1993 ◽  
Vol 39 (7) ◽  
pp. 1382-1389 ◽  
Author(s):  
W C Taddei-Peters ◽  
B T Butman ◽  
G R Jones ◽  
T M Venetta ◽  
P F Macomber ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Sandwich Elisa ◽  
Density Lipoprotein ◽  
Low Density ◽  
Linear Calibration ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Assay Format ◽  
Capture Antibody

Abstract A quantitative sandwich ELISA for lipoprotein(a) [Lp(a)], utilizing a monoclonal capture antibody that recognizes human and rhesus monkey apolipoprotein(a) [apo(a)] isoforms in combination with a polyclonal anti-apolipoprotein B-peroxidase conjugate was developed. This assay generates a linear calibration curve from 31.2 to 1000 mg/L, is highly reproducible (intra- and interassay CV of &lt; 5% and &lt; or = 12%, respectively), and shows no interference from plasminogen (1 g/L), low-density lipoprotein (6.00 g/L), triglycerides (27.00 g/L from chylomicrons and 10.00 g/L from very-low-density lipoprotein), hemoglobin (5 g/L), or bilirubin (30 mg/L). This assay format quantifies the concentration of Lp(a) on an equal molar basis regardless of apo(a) isoform. In contrast, a commercially available ELISA [Macra Lp(a)] method with a monoclonal anti-apo(a) capture antibody and a polyclonal anti-apo(a) conjugate was found to underestimate the Lp(a) concentrations of individuals with lower-M(r) apo(a) isoforms--whether quantifying the Lp(a) in plasma or the purified lipoprotein. This demonstrates the importance of assay format selection in quantifying Lp(a).

scholarly journals Residual Cardiovascular Risk at Low LDL: Remnants, Lipoprotein(a), and Inflammation

2020 ◽  
Author(s):  
Ron C Hoogeveen ◽  
Christie M Ballantyne
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Residual Risk ◽  
Atherosclerotic Cardiovascular Disease ◽  
C Reactive Protein ◽  
Residual Cardiovascular Risk ◽  
Lipoprotein A ◽  
Reactive Protein ◽  
Increased Risk ◽  
Ascvd Risk

Abstract Background Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering. Content Non–LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C &lt; 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events. Summary We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.

Abstract 18085: Heparan Sulfate Proteoglycans Only Modestly Affect Postprandial Hepatic Remnant Clearance in Humans

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Geesje M Dallinga-Thie ◽  
Han Levels ◽  
Alinda M Schimmel ◽  
Max Nieuwdorp
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hepatic Clearance ◽  
Tolerance Test ◽  
Retinyl Palmitate ◽  
Diabetic Patients ◽  
Loss Of Function ◽  
Gene Score ◽  
Relative Contribution ◽  
Increased Risk

Introduction and Methods: Elevated circulating levels of Triglyceride-rich Remnant Lipoproteins (TLR) are strongly associated with increased risk for CVD. The hepatic clearance of TRL involves lipoprotein receptors i.e. the low-density lipoprotein receptor (LDLr) and heparin sulfate proteoglycans (HSPG). The relevance of each pathway in humans remains to be established. To further dissect the relative contribution of each of these receptors, we studied postprandial TRL metabolism with an oral fat tolerance test using cream supplemented with retinyl palmitate (RP) in 1) patients with a heterozygous loss-of-function (LOF) variant in LDLR stratified for a low (n=10) or high (n=10) HSPG gene score; 2) patients with heterozygous LOF variants in EXT1 or EXT2 (n=13), characterised by decreased HSPG chains length but normal sulfation pattern, and compared to matched healthy controls (n=13) and 3) diabetic patients (n=29) stratified for a functional SNP in SULF2, that predisposes to lower SULF2 expression and increased 6-O-sulfation of HSPG chains. Results: Postprandial TRL clearance was significantly delayed in patients with FH compared to controls (AUC-RP FH: 1971±190 vs Con: 646±110 nmol/l/h;P<0.0001 and iAUC-TG FH 6.9±1.0 vs Con 3.8±10 mmol/l/h, P<0.05) supporting the important role of LDLr in TRL clearance. No additional effect was observed if the FH group was stratified for HSPG gene score. Also, in patients with LOF variants in EXT, resulting in shorter HSPG chains, no difference in TRL clearance versus controls could be observed. In contrast, improved 6-O-sulfation due to lower hepatic protein expression of SULF2 resulted in improved fasting and postprandial TG levels and significantly lower iAUC-RP (iAUC-TG AA 6.9±1.1 vs GG 4.1±1.2 mmol/l/h P<0.05; AUC-RP AA 97±15 vs GG 15±2 mg/l/h; P<0.001) Conclusion: Our findings clearly indicate an important role for the LDLr in postprandial TRL clearance in humans. In contrast to murine studies, HSPGs do only modestly contribute to hepatic TRL clearance in humans, and implicate that sulfation of HSPG’s is of more relevance for TRL clearance than HSPG chain length.

scholarly journals Assembly of Very Low Density Lipoprotein: A Two-Step Process of Apolipoprotein B Core Lipidation

1999 ◽  
Vol 129 (2) ◽  
pp. 463S-466S ◽  
Author(s):  
Sabina Rustaeus ◽  
Karin Lindberg ◽  
Pia Stillemark ◽  
Catharina Claesson ◽  
Lennart Asp ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Step Process ◽  
Lipoprotein A

scholarly journals Apolipoprotein B and oxLDL levels in plasma of patients with diabetes, cardiovascular disease, and COVID-19

2021 ◽  
pp. 126-130
Author(s):  
M.D. Tronko ◽  
S.A. Cherviakova ◽  
V.V. Pushkarev ◽  
Y.B. Belchina ◽  
O.I. Kovzun ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Apolipoprotein B ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Enzyme Linked Immunosorbent Assay ◽  
Blood Levels ◽  
Optical Wavelength ◽  
Increased Risk ◽  
Patients With Diabetes

Elevated levels of low-density lipoprotein (LDL-X) cholesterol, apolipoprotein B (ApoB), and especially oxidized LDL in plasma are associated with an increased risk of cardiovascular disease (CVD). The aim of the study was to determine the levels of ApoB and oxLDL in the blood of patients with diabetes mellitus (DM), CVD and COVID-19. ApoB and oxLDL were determined using enzyme-linked immunosorbent assay kits (Elabscience, USA). The measurements were performed at an optical wavelength of 450 nm. It was found that ApoB and oxLDL levels in the blood of patients with diabetes and, especially, with COVID-19 are substantially higher than in the blood of healthy people. Blood levels of ApoB and oxLDL are higher in patients with both COVID-19 and diabetes or CVD as com pared to patients with COVID-19 without comorbidities. Thus, the levels of ApoB and oxidized LDL may be the promising markers of severe COVID-19.

Lipoprotein (a) und das fibrinolytische System

1992 ◽  
Vol 12 (01) ◽  
pp. 017-022
Author(s):  
G. M. Kostner
Keyword(s):  
Apolipoprotein B ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein A

ZusammenfassungLipoprotein (a) (Lp[a]) ist ein Apolipoprotein-B-haltiges Lipoprotein, welches dem Low Density Lipoprotein (LDL) sehr ähnlich ist, zusätzlich jedoch noch ein charakteristisches Protein, das Apo-a, enthält. Letzteres weist eine große Homologie zu Plasminogen auf. Lp(a) verhält sich stoffwechselmäßig deutlich anders als LDL und gilt heute als das atherogenste Lipoprotein. Seine Funktion ist noch weitgehend unbekannt, und Personen ohne nachweisbare Mengen Lp(a) im Blut sind vollständig gesund.Apo-a hat ein sehr hohes Molekulargewicht und kommt in mehr als 10 Isoformen vor, welche sich durch die Anzahl der Kringel-4-Repeats unterscheiden. Diese Strukturen sind auch dafür verantwortlich, daß Lp(a) die Aktivierung von Plasminogen zu Plasmin auf verschiedenste Weise inhibiert. Trotzdem konnte bis heute in vivo noch keine Korrelation der Plasma-LP(a)-Konzentrationen mit der fibrinolytischen Aktivität im Plasma nachgewiesen werden.

Apolipoprotein(a) Kinetics in Statin-Treated Patients With Elevated Plasma Lipoprotein(a) Concentration

2019 ◽  
Vol 104 (12) ◽  
pp. 6247-6255 ◽  
Author(s):  
Louis Ma ◽  
Dick C Chan ◽  
Esther M M Ooi ◽  
Santica M Marcovina ◽  
P Hugh R Barrett ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Low Density Lipoprotein ◽  
Univariate Analysis ◽  
Density Lipoprotein ◽  
Statin Treatment ◽  
Elevated Plasma ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Catabolic Rate ◽  
Increased Risk

Abstract Background Lipoprotein(a) [Lp(a)] is a low-density lipoprotein‒like particle containing apolipoprotein(a) [apo(a)]. Patients with elevated Lp(a), even when treated with statins, are at increased risk of cardiovascular disease. We investigated the kinetic basis for elevated Lp(a) in these patients. Objectives Apo(a) production rate (PR) and fractional catabolic rate (FCR) were compared between statin-treated patients with and without elevated Lp(a). Methods The kinetics of apo(a) were investigated in 14 patients with elevated Lp(a) and 15 patients with normal Lp(a) levels matched for age, sex, and body mass index using stable isotope techniques and compartmental modeling. All 29 patients were on background statin treatment. Plasma apo(a) concentration was measured using liquid chromatography–mass spectrometry. Results The plasma concentration and PR of apo(a) were significantly higher in patients with elevated Lp(a) than in patients with normal Lp(a) concentration (all P < 0.01). The FCR of apo(a) was not significantly different between the groups. In univariate analysis, plasma concentration of apo(a) was significantly associated with apo(a) PR in both patient groups (r = 0.699 and r = 0.949, respectively; all P < 0.01). There was no significant association between plasma apo(a) concentration and FCR in either of the groups (r = 0.160 and r = −0.137, respectively). Conclusion Elevated plasma Lp(a) concentration is a consequence of increased hepatic production of Lp(a) particles in these patients. Our findings provide a kinetic rationale for the use of therapies that target the synthesis of apo(a) and production of Lp(a) particles in patients with elevated Lp(a).

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