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).

scholarly journals Galactose-specific asialoglycoprotein receptor is involved in lipoprotein (a) catabolism

2003 ◽  
Vol 376 (3) ◽  
pp. 765-771 ◽  
Author(s):  
Andelko HRZENJAK ◽  
Sasa FRANK ◽  
Xingde WO ◽  
Yonggang ZHOU ◽  
Theo van BERKEL ◽  
...  
Keyword(s):  
Physiological Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Asialoglycoprotein Receptor ◽  
Fractional Catabolic Rate ◽  
Wild Type ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Catabolic Rate ◽  
First Time

Lp(a) [lipoprotein (a)] is a highly atherogenic plasma lipoprotein assembled from low-density lipoprotein and the glycoprotein apolipoprotein (a). The rate of Lp(a) biosynthesis correlates significantly with plasma Lp(a) concentrations, whereas the fractional catabolic rate does not have much influence. So far, little is known about Lp(a) catabolism. To study the site and mode of Lp(a) catabolism, native or sialidase-treated Lp(a) was injected into hedgehogs or ASGPR (asialoglycoprotein receptor)-knockout (ASGPR−) mice or wild-type (ASGPR+) mice, and the decay of the plasma Lp(a) concentration was followed. COS-7 cells were transfected with high- (HL-1) and low-molecular-mass ASGPR subunits (HL-2), and binding and degradation of intact or desialylated Lp(a) were measured. In hedgehogs, one of the few species that synthesize Lp(a), most of the Lp(a) was taken up by the liver, followed by kidney and spleen. Lp(a) and asialo-Lp(a) were catabolized with apparent half-lives of 13.8 and 0.55 h respectively. Asialo-orosomucoide increased both half-lives significantly. In mice, the apparent half-life of Lp(a) was 4–6 h. Catabolism of native Lp(a) by wild-type mice was significantly faster compared with ASGPR− mice and there was a significantly greater accumulation of Lp(a) in the liver of ASGPR+ mice compared with ASGPR− mice. The catabolism of asialo-Lp(a) in ASGPR− mice was 8-fold faster when compared with native Lp(a) in wild-type mice. Transfected COS-7 cells expressing functional ASGPR showed approx. 5-fold greater binding and 2-fold faster degradation of native Lp(a) compared with control cells. Our results for the first time demonstrate a physiological function of ASGPR in the catabolism of Lp(a).

Quantification of lipoprotein(a) in plasma by assaying cholesterol in lectin-bound plasma fraction

1994 ◽  
Vol 40 (3) ◽  
pp. 400-403 ◽  
Author(s):  
L J Seman ◽  
J L Jenner ◽  
J R McNamara ◽  
E J Schaefer
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cholesterol Content ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Plasma Fraction ◽  
Chd Risk ◽  
Increased Risk ◽  
The Mean ◽  
High Concentrations

Abstract Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle in which apolipoprotein(a) [apo(a)] is disulfide-linked to apolipoprotein B (apoB). High concentrations of Lp(a) in plasma are associated with an increased risk of coronary heart disease (CHD). Lp(a) has traditionally been measured by immunoassay and expressed as total mass of Lp(a). Measuring Lp(a) by its cholesterol content will provide a way to directly compare Lp(a) with other lipoproteins that are measured by cholesterol. We have developed an assay to quantify Lp(a) by its cholesterol content [Lp(a)-C], using lectin affinity to isolate Lp(a) from other lipoproteins, and then measuring the cholesterol within the isolated fraction. We compared the Lp(a)-C assay with an ELISA for Lp(a) mass in 47 plasma samples from normotriglyceridemic, fasting individuals with high Lp(a) contents (mean +/- SD, 446 +/- 350 mg/L). The mean Lp(a)-C concentration was 110 +/- 89 mg/L and correlated very highly with Lp(a) mass (r = 0.9975). Lp(a)-C measurement is an alternative method to screen for this CHD risk factor.

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

PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate

2018 ◽  
Vol 132 (10) ◽  
pp. 1075-1083 ◽  
Author(s):  
Mikaël Croyal ◽  
Thi-Thu-Trang Tran ◽  
Rose Hélène Blanchard ◽  
Jean-Christophe Le Bail ◽  
Elise F. Villard ◽  
...  
Keyword(s):  
Production Rate ◽  
Nonhuman Primates ◽  
Numerical Models ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Human Hepatocytes ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Pcsk9 Inhibition

Therapeutic antibodies targeting proprotein convertase subtilisin kexin type 9 (PCSK9) (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here, we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivo. Six nonhuman primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood samples were collected sequentially over 48 h. Enrichment of apolipoproteins in [2H3]-leucine was assessed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Kinetic parameters were calculated using numerical models with the SAAMII software. Compared with IgG1, alirocumab significantly reduced total cholesterol (TC) (−28%), LDL-C (−67%), Lp(a) (−56%), apolipoprotein B100 (apoB100) (−53%), and apo(a) (−53%). Alirocumab significantly increased the fractional catabolic rate of apoB100 (+29%) but not that of apo(a). Conversely, alirocumab sharply and significantly reduced the production rate (PR) of apo(a) (−42%), but not significantly that of apoB100, compared with IgG1, respectively. In line with the observations made in human hepatocytes, the present kinetic study establishes that PCSK9 neutralization with alirocumab efficiently reduces circulating apoB100 and apo(a) levels by distinct mechanisms: apoB primarily by enhancing its catabolism and apo(a) primarily by lowering its production.

scholarly journals Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a)

2020 ◽  
Vol 41 (24) ◽  
pp. 2262-2271 ◽  
Author(s):  
Lotte C A Stiekema ◽  
Koen H M Prange ◽  
Renate M Hoogeveen ◽  
Simone L Verweij ◽  
Jeffrey Kroon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Cvd Risk ◽  
Inflammatory Gene Expression ◽  
Lipoprotein A ◽  
Inflammatory Gene ◽  
Apolipoprotein A ◽  
Inflammatory Activation

Abstract Aims Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a). Methods and results Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (−17%, P &lt; 0.001). In contrast, PCSK9ab treatment lowered Lp(a) by 16% and did not alter transcriptome nor functional properties of monocytes, despite an additional reduction of 65% in low-density lipoprotein cholesterol (LDL-C). Conclusion Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).

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 Resistance of lipoprotein(a) to lipid peroxidation induced by oxygenated free radicals produced by γ radiolysis: a comparison with low-density lipoprotein

1996 ◽  
Vol 314 (1) ◽  
pp. 277-284 ◽  
Author(s):  
Jean-Louis BEAUDEUX ◽  
Monique GARDES-ALBERT ◽  
Jacques DELATTRE ◽  
Alain LEGRAND ◽  
François ROUSSELET ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Free Radicals ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Peroxyl Radicals ◽  
Low Density ◽  
Lipoprotein A ◽  
Acetylneuraminic Acid ◽  
Paired Samples ◽  
Apolipoprotein A

Lipid peroxidation of lipoprotein(a) [Lp(a)] by defined oxygen-centred free radicals (O2-· /OH·, O2-·, O2-· /HO2·) produced by γ radiolysis was compared with that of paired samples of low-density lipoprotein (LDL). Lp(a) appeared to be more resistant to oxidation than LDL, as indicated by the kinetic study of four markers of lipid peroxidation: decrease in vitamin E, formation of conjugated dienes and aldehydic products, and modification of electrophoretic mobility. In contrast, similar kinetics of lipid peroxidation were obtained for LDL and Lp(a-), which is the lipoparticle issued following the reductive cleavage of apolipoprotein(a) from Lp(a), thus suggesting that the greater resistance of Lp(a) to lipid peroxidation was due to the presence of apolipoprotein(a). Lipid peroxidation of Lp(a) and LDL induced by peroxyl radicals, which were produced by an azo compound [2,2′-azobis-(2-amidinopropane)dihydrochloride], confirmed both the resistance of Lp(a) to lipid peroxidation and the propensity of Lp(a-) to exhibit a greater susceptibility to oxidation than intact Lp(a). Our findings also indicated that the high content of apolipoprotein(a) in N-acetylneuraminic acid residues was only partly responsible for the resistance of Lp(a) to oxidation.

The NHLBI Twin Study: heritability of apolipoprotein A-I, B, and low density lipoprotein subclasses and concordance for lipoprotein(a)

1991 ◽  
Vol 91 (1-2) ◽  
pp. 97-106 ◽  
Author(s):  
Stefania Lamon-Fava ◽  
Dolores Jimenez ◽  
Joe C. Christian ◽  
Richard R. Fabsitz ◽  
Terry Reed ◽  
...  
Keyword(s):  
Twin Study ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Lipoprotein A ◽  
Lipoprotein Subclasses ◽  
Apolipoprotein A

Analysis of strneture–fonction relationships in human apolipoprotein(a)

1994 ◽  
Vol 72 (3) ◽  
pp. 304-310 ◽  
Author(s):  
Ytje Y. van der Hoek ◽  
John J. P. Kastelein ◽  
Marlys L. Koschinsky
Keyword(s):  
Recombinant Expression ◽  
Low Density Lipoprotein ◽  
Expression System ◽  
Density Lipoprotein ◽  
Site Directed Mutagenesis ◽  
Human Populations ◽  
Low Density ◽  
Covalent Linkage ◽  
Lipoprotein A ◽  
Apolipoprotein A

Elevated levels of lipoprotein(a) (Lp(a)) have been strongly correlated with the development of atherosclerosis in human populations. Lp(a) is distinguishable from low density lipoprotein by the presence of the unique protein component apolipoprotein(a) (apo(a)), which contains repeated domains that closely resemble that of plasminogen kringle IV. Using human embryonic kidney cells, we have expressed a recombinant form of apo(a) (r-apo(a)) containing 17 kringle IV-like domains. We have utilized this recombinant expression system to study the assembly of Lp(a) particles. We have demonstrated that Lp(a) particles containing r-apo(a) can be assembled extracellularly in plasma by covalent linkage to low density lipoprotein. Using site-directed mutagenesis, we have demonstrated that a cysteine residue present at position 4057 of the apo(a) protein (i.e., in the penultimate kringle IV repeat) mediates this covalent linkage. Using polymerase chain reaction amplification of liver apo(a) complementary DNA, we have demonstrated the presence of a polymorphism in apo(a) kringle IV type 10, which results in the substitution of a threonine for a methionine. Preliminary studies indicate that the presence of a threonine at this position may enhance the interaction of Lp(a) with lysine–Sepharose.Key words: apolipoprotein(a), lipoprotein(a), kringles, lipoprotein(a) assembly, polymorphism.

scholarly journals Safety of statins: an update

2012 ◽  
Vol 3 (3) ◽  
pp. 133-144 ◽  
Author(s):  
Miao Hu ◽  
Bernard M.Y. Cheung ◽  
Brian Tomlinson
Keyword(s):  
Liver Disease ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Haemorrhagic Stroke ◽  
Statin Treatment ◽  
Atherosclerotic Vascular Disease ◽  
Nonalcoholic Fatty Liver ◽  
Statin Monotherapy ◽  
Increased Risk ◽  
Liver Tests

Statins are widely used and have been proven to be effective in the prevention of atherosclerotic vascular disease events, primarily by reducing plasma low-density lipoprotein cholesterol concentrations. Although statins are generally well tolerated and present an excellent safety profile, adverse effects from muscle toxicity and liver enzyme abnormalities may occur in some patients. Myopathy and rhabdomyolysis are rare with statin monotherapy at the approved dose ranges, but the risk increases with use of higher doses, interacting drugs and genetic predisposition. Asymptomatic increases in liver transaminases with statin treatment do not seem to be associated with an increased risk of liver disease. Therefore, statin treatment can be safely used in patients with mild to moderately abnormal liver tests that are potentially attributable to nonalcoholic fatty liver disease and can improve liver tests and reduce cardiovascular morbidity in this group of patients. The risks of other unfavorable effects such as the slightly increased risk of new-onset diabetes and potentially increased risk of haemorrhagic stroke are much smaller than the cardiovascular benefits with the use of statins.

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