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Article ; Online: Supporting evidence for lipoprotein(a) measurements in clinical practice.

Matveyenko, Anastasiya / Pavlyha, Marianna / Reyes-Soffer, Gissette

Best practice & research. Clinical endocrinology & metabolism

2023 Volume 37, Issue 3, Page(s) 101746

Abstract: High levels of lipoprotein(a) [Lp(a)] are causal for development of atherosclerotic cardiovascular disease and highly regulated by genetics. Levels are higher in Blacks compared to Whites, and in women compared to men. Lp(a)'s main protein components are ...

Abstract	High levels of lipoprotein(a) [Lp(a)] are causal for development of atherosclerotic cardiovascular disease and highly regulated by genetics. Levels are higher in Blacks compared to Whites, and in women compared to men. Lp(a)'s main protein components are apolipoprotein (apo) (a) and apoB100, the latter being the main component of Low-Density Lipoprotein (LDL) particles. Studies have identified Lp(a) to be associated with inflammatory, coagulation and wound healing pathways. Lack of validated and accepted assays to measure Lp(a), risk cutoff values, guidelines for diagnosis, and targeted therapies have added challenges to the field. Scientific efforts are ongoing to address these, including studies evaluating the cardiovascular benefits of decreasing Lp(a) levels with targeted apo(a) lowering treatments. This review will provide a synopsis of evidence-based effects of high Lp(a) on disease presentation, highlight available guidelines and discuss promising therapies in development. We will conclude with current clinical information and future research needs in the field.
MeSH term(s)	Male ; Female ; Humans ; Risk Factors ; Atherosclerosis/diagnosis ; Atherosclerosis/drug therapy ; Lipoprotein(a)/metabolism ; Lipoprotein(a)/therapeutic use ; Cardiovascular Diseases/etiology
Chemical Substances	Lipoprotein(a)
Language	English
Publishing date	2023-02-11
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2052339-7
ISSN	1878-1594 ; 1532-1908 ; 1521-690X
ISSN (online)	1878-1594 ; 1532-1908
ISSN	1521-690X
DOI	10.1016/j.beem.2023.101746
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Article ; Online: Apolipoprotein(a) production and clearance are associated with plasma IL-6 and IL-18 levels, dependent on ethnicity.

Groenen, Anouk G / Matveyenko, Anastasiya / Matienzo, Nelsa / Halmos, Benedek / Zhang, Hanrui / Westerterp, Marit / Reyes-Soffer, Gissette

Atherosclerosis

2024 Volume 391, Page(s) 117474

Abstract: Background and aims: High plasma lipoprotein (a) [Lp(a)] levels are associated with increased atherosclerotic cardiovascular disease (ASCVD), in part attributed to elevated inflammation. High plasma Lp(a) levels inversely correlate with apolipoprotein ( ... ...

Abstract	Background and aims: High plasma lipoprotein (a) [Lp(a)] levels are associated with increased atherosclerotic cardiovascular disease (ASCVD), in part attributed to elevated inflammation. High plasma Lp(a) levels inversely correlate with apolipoprotein (a) [(APO(a)] isoform size. APO(a) isoform size is negatively associated with APO(a) production rate (PR) and positively associated with APO(a) fractional catabolic rate (FCR). We asked whether APO(a) PR and FCR (kinetics) are associated with plasma levels of interleukin (IL)-6 and IL-18, pro-inflammatory interleukins that promote ASCVD. Methods: We used samples from existing data of APO(a) kinetic studies from an ethnically diverse cohort (n = 25: 10 Black, 9 Hispanic, and 6 White subjects) and assessed IL-6 and IL-18 plasma levels. We performed multivariate linear regression analyses to examine the relationships between predictors APO(a) PR or APO(a) FCR, and outcome variables IL-6 or IL-18. In these analyses, we adjusted for parameters known to affect Lp(a) levels and APO(a) PR and FCR, including race/ethnicity and APO(a) isoform size. Results: APO(a) PR and FCR were positively associated with plasma IL-6, independent of isoform size, and dependent on race/ethnicity. APO(a) PR was positively associated with plasma IL-18, independent of isoform size and race/ethnicity. APO(a) FCR was not associated with plasma IL-18. Conclusions: Our studies demonstrate a relationship between APO(a) PR and FCR and plasma IL-6 or IL-18, interleukins that promote ASCVD. These studies provide new insights into Lp(a) pro-inflammatory properties and are especially relevant in view of therapies targeting APO(a) to decrease cardiovascular risk.
MeSH term(s)	Humans ; Apoprotein(a) ; Interleukin-6 ; Ethnicity ; Interleukin-18 ; Kinetics ; Apolipoproteins A ; Lipoprotein(a) ; Atherosclerosis ; Protein Isoforms/metabolism
Chemical Substances	Apoprotein(a) (EC 3.4.21.-) ; Interleukin-6 ; Interleukin-18 ; Apolipoproteins A ; Lipoprotein(a) ; Protein Isoforms
Language	English
Publishing date	2024-02-13
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2024.117474
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Article ; Online: Association of free-living diet composition with plasma lipoprotein(a) levels in healthy adults.

Matveyenko, Anastasiya / Seid, Heather / Kim, Kyungyeon / Ramakrishnan, Rajasekhar / Thomas, Tiffany / Matienzo, Nelsa / Reyes-Soffer, Gissette

Lipids in health and disease

2023 Volume 22, Issue 1, Page(s) 144

Abstract: Background: Lipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels being positively associated with atherosclerotic cardiovascular disease. Lp(a) levels are genetically determined. However, previous studies report a negative ... ...

Abstract	Background: Lipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels being positively associated with atherosclerotic cardiovascular disease. Lp(a) levels are genetically determined. However, previous studies report a negative association between Lp(a) and saturated fatty acid intake. Currently, apoB100 lowering therapies are used to lower Lp(a) levels, and apheresis therapy is FDA approved for patients with extreme elevations of Lp(a). The current study analyzed the association of free-living diet components with plasma Lp(a) levels. Methods: Dietary composition data was collected during screening visits for enrollment in previously completed lipid and lipoprotein metabolism studies at Columbia University Irving Medical Center via a standardized protocol by registered dietitians using 24 hour recalls. Data were analyzed with the Nutrition Data System for Research (Version 2018). Diet quality was calculated using the Healthy Eating Index (HEI) score. Fasting plasma Lp(a) levels were measured via an isoform-independent ELISA and apo(a) isoforms were measured using gel electrophoresis. Results: We enrolled 28 subjects [Black (n = 18); Hispanic (n = 7); White (n = 3)]. The mean age was 48.3 ± 12.5 years with 17 males. Median level of Lp(a) was 79.9 nmol/L (34.4-146.0) and it was negatively associated with absolute (grams/day) and relative (percent of total calories) intake of dietary saturated fatty acids (SFA) (R = -0.43, P = 0.02, SFA …(% CAL): R = -0.38, P = 0.04), palmitic acid intake (R = -0.38, P = 0.05), and stearic acid intake (R = -0.40, P = 0.03). Analyses of associations with HEI score when stratified based on Lp(a) levels > or ≤ 100 nmol/L revealed no significant associations with any of the constituent factors. Conclusions: Using 24 hour recall, we confirm previous findings that Lp(a) levels are negatively associated with dietary saturated fatty acid intake. Additionally, Lp(a) levels are not related to diet quality, as assessed by the HEI score. The mechanisms underlying the relationship of SFA with Lp(a) require further investigation.
MeSH term(s)	Male ; Humans ; Adult ; Middle Aged ; Diet ; Lipoprotein(a) ; Apolipoproteins A ; Fasting ; Energy Intake
Chemical Substances	Lipoprotein(a) ; Apolipoproteins A
Language	English
Publishing date	2023-09-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2091381-3
ISSN	1476-511X ; 1476-511X
ISSN (online)	1476-511X
ISSN	1476-511X
DOI	10.1186/s12944-023-01884-2
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Article ; Online: Relationship of apolipoprotein(a) isoform size with clearance and production of lipoprotein(a) in a diverse cohort.

Matveyenko, Anastasiya / Matienzo, Nelsa / Ginsberg, Henry / Nandakumar, Renu / Seid, Heather / Ramakrishnan, Rajasekhar / Holleran, Steve / Thomas, Tiffany / Reyes-Soffer, Gissette

Journal of lipid research

2023 Volume 64, Issue 3, Page(s) 100336

Abstract: Lipoprotein(a) [Lp(a)] has two main proteins, apoB100 and apo(a). High levels of Lp(a) confer an increased risk for atherosclerotic cardiovascular disease. Most people have two circulating isoforms of apo(a) differing in their molecular mass, determined ... ...

Abstract	Lipoprotein(a) [Lp(a)] has two main proteins, apoB100 and apo(a). High levels of Lp(a) confer an increased risk for atherosclerotic cardiovascular disease. Most people have two circulating isoforms of apo(a) differing in their molecular mass, determined by the number of Kringle IV Type 2 repeats. Previous studies report a strong inverse relationship between Lp(a) levels and apo(a) isoform sizes. The roles of Lp(a) production and fractional clearance and how ancestry affects this relationship remain incompletely defined. We therefore examined the relationships of apo(a) size with Lp(a) levels and both apo(a) fractional clearance rates (FCR) and production rates (PR) in 32 individuals not on lipid-lowering treatment. We determined plasma Lp(a) levels and apo(a) isoform sizes, and used the relative expression of the two isoforms to calculate a "weighted isoform size" (wIS). Stable isotope studies were performed, using D3-leucine, to determine the apo(a) FCR and PR. As expected, plasma Lp(a) concentrations were inversely correlated with wIS (R
MeSH term(s)	Humans ; Lipoprotein(a) ; Apoprotein(a)/metabolism ; Apolipoproteins A ; Atherosclerosis ; Protein Isoforms
Chemical Substances	Lipoprotein(a) ; Apoprotein(a) (EC 3.4.21.-) ; Apolipoproteins A ; Protein Isoforms
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2023.100336
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Article ; Online: Effects of Recombinant Human Lecithin Cholesterol Acyltransferase on Lipoprotein Metabolism in Humans.

Reyes-Soffer, Gissette / Matveyenko, Anastasiya / Lignos, James / Matienzo, Nelsa / Santos Baez, Leinys S / Hernandez-One, Antonio / Yung, Lau / Nandakumar, Renu / Singh, Sasha A / Aikawa, Masanori / George, Richard / Ginsberg, Henry N

Arteriosclerosis, thrombosis, and vascular biology

2024

Abstract: Background: LCAT (lecithin cholesterol acyl transferase) catalyzes the conversion of unesterified, or free cholesterol, to cholesteryl ester, which moves from the surface of HDL (high-density lipoprotein) into the neutral lipid core. As this iterative ... ...

Abstract	Background: LCAT (lecithin cholesterol acyl transferase) catalyzes the conversion of unesterified, or free cholesterol, to cholesteryl ester, which moves from the surface of HDL (high-density lipoprotein) into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesteryl ester-enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport. Methods: We conducted a randomized, placebocontrolled, crossover study in 5 volunteers with atherosclerotic cardiovascular disease, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration (300-mg loading dose followed by 150 mg at 48 hours) on the in vivo metabolism of HDL APO (apolipoprotein)A1 and APOA2, and the APOB100-lipoproteins, very low density, intermediate density, and low-density lipoproteins. Results: As expected, recombinant human LCAT treatment significantly increased HDL-cholesterol (34.9 mg/dL; Conclusions: Our results suggest that an acute increase in LCAT activity drives greater flux of cholesteryl ester through the reverse cholesterol transport pathway without significantly altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis.
Language	English
Publishing date	2024-05-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.123.320387
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Article: TM6SF2 Determines Both the Degree of Lipidation and the Number of VLDL Particles Secreted by the Liver.

Reyes-Soffer, Gissette / Liu, Jing / Thomas, Tiffany / Matveyenko, Anastasiya / Seid, Heather / Ramakrishnan, Rajasekhar / Holleran, Steve / Zaghloul, Norann / Sztalryd-Woodle, Carole / Pollin, Toni / Ginsberg, Henry N

medRxiv : the preprint server for health sciences

2023

Abstract: In 2014, exome-wide studies identified a glutamine176lysine (p.E167K) substitution in a protein of unknown function named transmembrane 6 superfamily member 2 (TM6SF2). The p.E167K variant was associated with increased hepatic fat content and reduced ... ...

Abstract	In 2014, exome-wide studies identified a glutamine176lysine (p.E167K) substitution in a protein of unknown function named transmembrane 6 superfamily member 2 (TM6SF2). The p.E167K variant was associated with increased hepatic fat content and reduced levels of plasma TG and LDL cholesterol. Over the next several years, additional studies defined the role of TM6SF2, which resides in the ER and the ER-Golgi interface, in the lipidation of nascent VLDL to generate mature, more TG-rich VLDL. Consistent results from cells and rodents indicated that the secretion of TG was reduced in the p.E167K variant or when hepatic TM6SF2 was deleted. However, data for secretion of APOB was inconsistent, either reduced or increased secretion was observed. A recent study of people homozygous for the variant demonstrated reduced in vivo secretion of large, TG-rich VLDL1 into plasma; both TG and APOB secretion were reduced. Here we present new results demonstrating increased secretion of VLDL APOB with no change in TG secretion in p.E167K homozygous individuals from the Lancaster Amish community compared to their wild-type siblings. Our in vivo kinetic tracer results are supported by in vitro experiments in HepG2 and McA cells with knock-down or Crispr-deletions of TM6SF2, respectively. We offer a model to potentially explain all of the prior data and our new results.
Language	English
Publishing date	2023-06-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.23.23291823
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Article ; Online: DNA-Directed Polymerase Subunits Play a Vital Role in Human Telomeric Overhang Processing.

Diotti, Raffaella / Kalan, Sampada / Matveyenko, Anastasiya / Loayza, Diego

Molecular cancer research : MCR

2015 Volume 13, Issue 3, Page(s) 402–410

Abstract: Unlabelled: Telomeres consist of TTAGGG repeats bound by the shelterin complex and end with a 3' overhang. In humans, telomeres shorten at each cell division, unless telomerase (TERT) is expressed and able to add telomeric repeats. For effective ... ...

Abstract	Unlabelled: Telomeres consist of TTAGGG repeats bound by the shelterin complex and end with a 3' overhang. In humans, telomeres shorten at each cell division, unless telomerase (TERT) is expressed and able to add telomeric repeats. For effective telomere maintenance, the DNA strand complementary to that made by telomerase must be synthesized. Recent studies have discovered a link between different activities necessary to process telomeres in the S phase of the cell cycle to reform a proper overhang. Notably, the human CST complex (CTC1/STN1/TEN1), known to interact functionally with the polymerase complex (POLA/primase), was shown to be important for telomere processing. Here, focus was paid to the catalytic (POLA1/p180) and accessory (POLA2/p68) subunits of the polymerase, and their mechanistic roles at telomeres. We were able to detect p68 and p180 at telomeres in S-phase using chromatin immunoprecipitation. We could also show that the CST, shelterin, and polymerase complexes interact, revealing contacts occurring at telomeres. We found that the polymerase complex could associate with telomerase activity. Finally, depletion of p180 by siRNA led to increased overhang amounts at telomeres. These data support a model in which the polymerase complex is important for proper telomeric overhang processing through fill-in synthesis, during S phase. These results shed light on important events necessary for efficient telomere maintenance and protection. Implications: This study describes the interplay between DNA replication components with proteins that associate with chromosome ends, and telomerase. These interactions are proposed to be important for the processing and protection of chromosome ends.
MeSH term(s)	DNA-Directed DNA Polymerase/genetics ; DNA-Directed DNA Polymerase/metabolism ; HeLa Cells ; Humans ; S Phase ; Telomerase/metabolism ; Telomere/metabolism ; Telomere Homeostasis ; Telomere-Binding Proteins/metabolism
Chemical Substances	Ctc1 protein, human ; Stn1 protein, human ; Telomere-Binding Proteins ; Ten1 protein, human ; shelterin, human ; Telomerase (EC 2.7.7.49) ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2015-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-14-0381
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Article: LIM Protein Ajuba Participates in the Repression of the ATR-Mediated DNA Damage Response.

Kalan, Sampada / Matveyenko, Anastasiya / Loayza, Diego

Frontiers in genetics

2013 Volume 4, Page(s) 95

Abstract: LIM proteins constitute a superfamily characterized by the presence of a LIM domain, known to be involved in protein-protein interactions. Our previous work has implicated members of the Zyxin family of LIM proteins, namely TRIP6 and LPP, in the ... ...

Abstract	LIM proteins constitute a superfamily characterized by the presence of a LIM domain, known to be involved in protein-protein interactions. Our previous work has implicated members of the Zyxin family of LIM proteins, namely TRIP6 and LPP, in the repression of the DNA damage response (DDR) at telomeres. Here, we describe a role for Ajuba, a closely related LIM molecule, in repressing the ATR-mediated DDR. We found that depletion of Ajuba led to apparent delays in the cell cycle, accompanied with increased Rb phosphorylation, Chk1 phosphorylation, induction of p53, and cell death. Ajuba could be found in a complex with replication protein A (RPA), and its depletion led to RPA phosphorylation, known to be an early event in ATR activation. We propose that Ajuba protects against unscheduled ATR signaling by preventing inappropriate RPA phosphorylation.
Language	English
Publishing date	2013-05-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2013.00095
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Article ; Online: Effects of APOC3 Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolism.

Reyes-Soffer, Gissette / Sztalryd, Carol / Horenstein, Richard B / Holleran, Stephen / Matveyenko, Anastasiya / Thomas, Tiffany / Nandakumar, Renu / Ngai, Colleen / Karmally, Wahida / Ginsberg, Henry N / Ramakrishnan, Rajasekhar / Pollin, Toni I

Arteriosclerosis, thrombosis, and vascular biology

2018 Volume 39, Issue 1, Page(s) 63–72

Abstract: Objective- Apo (apolipoprotein) CIII inhibits lipoprotein lipase (LpL)-mediated lipolysis of VLDL (very-low-density lipoprotein) triglyceride (TG) and decreases hepatic uptake of VLDL remnants. The discovery that 5% of Lancaster Old Order Amish are ... ...

Abstract	Objective- Apo (apolipoprotein) CIII inhibits lipoprotein lipase (LpL)-mediated lipolysis of VLDL (very-low-density lipoprotein) triglyceride (TG) and decreases hepatic uptake of VLDL remnants. The discovery that 5% of Lancaster Old Order Amish are heterozygous for the APOC3 R19X null mutation provided the opportunity to determine the effects of a naturally occurring reduction in apo CIII levels on the metabolism of atherogenic containing lipoproteins. Approach and Results- We conducted stable isotope studies of VLDL-TG and apoB100 in 5 individuals heterozygous for the null mutation APOC3 R19X (CT) and their unaffected (CC) siblings. Fractional clearance rates and production rates of VLDL-TG and apoB100 in VLDL, IDL (intermediate-density lipoprotein), LDL, apo CIII, and apo CII were determined. Affected (CT) individuals had 49% reduction in plasma apo CIII levels compared with CCs ( P<0.01) and reduced plasma levels of TG (35%, P<0.02), VLDL-TG (45%, P<0.02), and VLDL-apoB100 (36%, P<0.05). These changes were because of higher fractional clearance rates of VLDL-TG and VLDL-apoB100 with no differences in production rates. CTs had higher rates of the conversion of VLDL remnants to LDL compared with CCs. In contrast, rates of direct removal of VLDL remnants did not differ between the groups. As a result, the flux of apoB100 from VLDL to LDL was not reduced, and the plasma levels of LDL-cholesterol and LDL-apoB100 were not lower in the CT group. Apo CIII production rate was lower in CTs compared with CCs, whereas apo CII production rate was not different between the 2 groups. The fractional clearance rates of both apo CIII and apo CII were higher in CTs than CCs. Conclusions- These studies demonstrate that 50% reductions in plasma apo CIII, in otherwise healthy subjects, results in a significantly higher rate of conversion of VLDL to LDL, with little effect on direct hepatic uptake of VLDL. When put in the context of studies demonstrating significant protection from cardiovascular events in individuals with loss of function variants in the APOC3 gene, our results provide strong evidence that therapies which increase the efficiency of conversion of VLDL to LDL, thereby reducing remnant concentrations, should reduce the risk of cardiovascular disease.
MeSH term(s)	Adult ; Aged ; Apolipoprotein B-100/metabolism ; Apolipoprotein C-III/deficiency ; Apolipoprotein C-III/genetics ; Apolipoprotein C-III/physiology ; Female ; Humans ; Lipids/blood ; Lipolysis ; Lipoproteins/metabolism ; Lipoproteins, IDL/metabolism ; Lipoproteins, VLDL/metabolism ; Male ; Middle Aged ; Mutation
Chemical Substances	Apolipoprotein B-100 ; Apolipoprotein C-III ; Lipids ; Lipoproteins ; Lipoproteins, IDL ; Lipoproteins, VLDL
Language	English
Publishing date	2018-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.118.311476
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Article ; Online: Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects.

Nandakumar, Renu / Matveyenko, Anastasiya / Thomas, Tiffany / Pavlyha, Marianna / Ngai, Colleen / Holleran, Stephen / Ramakrishnan, Rajasekhar / Ginsberg, Henry N / Karmally, Wahida / Marcovina, Santica M / Reyes-Soffer, Gissette

Journal of lipid research

2018 Volume 59, Issue 12, Page(s) 2397–2402

Abstract: Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is ... ...

Abstract	Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects.
MeSH term(s)	Adult ; Apolipoprotein B-100/blood ; Cholesterol, LDL/blood ; Chromatography, Liquid ; Female ; Humans ; Lipid Metabolism/drug effects ; Lipoprotein(a)/blood ; Male ; Mass Spectrometry ; Middle Aged ; Oligodeoxyribonucleotides, Antisense/pharmacology ; Oligonucleotides/pharmacology
Chemical Substances	APOB protein, human ; Apolipoprotein B-100 ; Cholesterol, LDL ; Lipoprotein(a) ; Oligodeoxyribonucleotides, Antisense ; Oligonucleotides ; mipomersen (9GJ8S4GU0M)
Language	English
Publishing date	2018-10-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.P082834
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