Lipoprotein turnover and possible remnant accumulation in preeclampsia: insights from the Freiburg Preeclampsia H.E.L.P.-apheresis study

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Abstract

Background

Preeclampsia is a life-threatening disease in pregnancy, and its complex pathomechanisms are poorly understood. In preeclampsia, lipid metabolism is substantially altered. In late onset preeclampsia, remnant removal disease like lipoprotein profiles have been observed. Lipid apheresis is currently being explored as a possible therapeutic approach to prolong preeclamptic pregnancies. Here, apheresis-induced changes in serum lipid parameters are analyzed in detail and their implications for preeclamptic lipid metabolism are discussed.

Methods

In the Freiburg H.E.L.P.-Apheresis Study, 6 early onset preeclamptic patients underwent repeated apheresis treatments. Serum lipids pre- and post-apheresis and during lipid rebound were analyzed in depth via ultracentrifugation to yield lipoprotein subclasses.

Results

The net elimination of Apolipoprotein B and plasma lipids was lower than theoretically expected. Lipids returned to previous pre-apheresis levels before the next apheresis even though apheresis was repeated within 2.9 ± 1.2 days. Apparent fractional catabolic rates and synthetic rates were substantially elevated, with fractional catabolic rates for Apolipoprotein B / LDL-cholesterol being 0.7 ± 0.3 / 0.4 ± 0.2 [day ^− 1] and synthetic rates being 26 ± 8 / 17 ± 8 [mg*kg ^− 1*day ^− 1]. The distribution of LDL-subclasses after apheresis shifted to larger buoyant LDL, while intermediate-density lipoprotein-levels remained unaffected, supporting the notion of an underlying remnant removal disorder in preeclampsia.

Conclusion

Lipid metabolism seems to be highly accelerated in preeclampsia, likely outbalancing remnant removal mechanisms. Since cholesterol-rich lipoprotein remnants are able to accumulate in the vessel wall, remnant lipoproteins may contribute to the severe endothelial dysfunction observed in preeclampsia.

Trial registration

ClinicalTrails.gov, NCT01967355.

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Most cited references 43

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Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.

Claudia Kreyssig, Thomas Benzing, Tuelay Kisner … (2011)

Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia. We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting.

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Maternal hyperlipidemia and the risk of preeclampsia: a meta-analysis.

Cassandra N. Spracklen, Caitlin J Smith, Audrey Saftlas … (2014)

Published reports examining lipid levels during pregnancy and preeclampsia have been inconsistent. The objective of this meta-analysis was to test the association between preeclampsia and maternal total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and triglyceride levels measured during pregnancy. We conducted a systematic search for studies published between the index date until July 2013 reporting maternal lipid levels in women with preeclampsia and normotensive pregnant women. Seventy-four studies met all eligibility criteria and were included in the meta-analysis. Weighted mean differences in lipid levels were calculated using a random-effects model. Statistical heterogeneity was investigated using the I(2) statistic. Meta-regression was used to identify sources of heterogeneity. Preeclampsia was associated with elevated total cholesterol, non-HDL-C, and triglyceride levels, regardless of gestational age at the time of blood sampling, and with lower levels of HDL-C in the third trimester. A marginal association was found with LDL-C levels. Statistical heterogeneity was detected in all analyses. Meta-regression analyses suggested that differences in body mass index (weight (kg)/height (m)(2)) across studies may be partially responsible for the heterogeneity in the triglyceride and LDL-C analyses. This systematic review and meta-analysis demonstrates that women who develop preeclampsia have elevated levels of total cholesterol, non-HDL-C, and triglycerides during all trimesters of pregnancy, as well as lower levels of HDL-C during the third trimester.

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Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia.

Ravi I. Thadhani, Henning Hagmann, Wiebke Schaarschmidt … (2016)

Preeclampsia is a devastating complication of pregnancy. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein believed to mediate the signs and symptoms of preeclampsia. We conducted an open pilot study to evaluate the safety and potential efficacy of therapeutic apheresis with a plasma-specific dextran sulfate column to remove circulating sFlt-1 in 11 pregnant women (20-38 years of age) with very preterm preeclampsia (23-32 weeks of gestation, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, new onset protein/creatinine ratio >0.30 g/g, and sFlt-1/placental growth factor ratio >85). We evaluated the extent of sFlt-1 removal, proteinuria reduction, pregnancy continuation, and neonatal and fetal safety of apheresis after one (n=6), two (n=4), or three (n=1) apheresis treatments. Mean sFlt-1 levels were reduced by 18% (range 7%-28%) with concomitant reductions of 44% in protein/creatinine ratios. Pregnancy continued for 8 days (range 2-11) and 15 days (range 11-21) in women treated once and multiple times, respectively, compared with 3 days (range 0-14) in untreated contemporaneous preeclampsia controls (n=22). Transient maternal BP reduction during apheresis was managed by withholding pre-apheresis antihypertensive therapy, saline prehydration, and reducing blood flow through the apheresis column. Compared with infants born prematurely to untreated women with and without preeclampsia (n=22 per group), no adverse effects of apheresis were observed. In conclusion, therapeutic apheresis reduced circulating sFlt-1 and proteinuria in women with very preterm preeclampsia and appeared to prolong pregnancy without major adverse maternal or fetal consequences. A controlled trial is warranted to confirm these findings.

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Author and article information

Contributors

Gerhard Pütz:

ORCID: http://orcid.org/0000-0002-0816-2018

+49 761 270 32070 , gerhard.puetz@uniklinik-freiburg.de

Journal

Journal ID (nlm-ta): Lipids Health Dis

Journal ID (iso-abbrev): Lipids Health Dis

Title: Lipids in Health and Disease

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-511X

Publication date (Electronic): 14 March 2018

Publication date PMC-release: 14 March 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 49

Affiliations

[1 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Institute of Clinical Chemistry and Laboratory Medicine, Medical Center - University of Freiburg, ; Hugstetter Straße 55, 79106 Freiburg, Germany

[2 ]ISNI 0000 0000 9428 7911, GRID grid.7708.8, Department of Obstetrics and Gynecology, , Medical Center - University of Freiburg, ; Hugstetter Straße 55, 79106 Freiburg, Germany

[3 ]GRID grid.5963.9, Department of Medicine IV (Nephrology and Primary Care), Medical Center, , University of Freiburg, ; Hugstetter Straße 55, 79106 Freiburg, Germany

[4 ]Andreas Hettich GmbH & Co KG, Engesser Straße 4a, 79108 Freiburg, Germany

[5 ]GRID grid.5963.9, Department of Pharmaceutical Biology and Biotechnology, , Albert-Ludwigs-University of Freiburg, ; Stefan-Meier-Straße 19, 79104 Freiburg, Germany

[6 ]ISNI 0000 0004 0646 2097, GRID grid.412468.d, Department of Gynecology and Obstetrics, , University Hospital Schleswig-Holstein Campus, ; Kiel, Germany

Author information

Gerhard Pütz http://orcid.org/0000-0002-0816-2018

Article

Publisher ID: 698

DOI: 10.1186/s12944-018-0698-4

PMC ID: 5853053

PubMed ID: 29540222

SO-VID: 6f610bde-f1da-471f-8975-43d0eab4ed4a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 20 December 2017

Date accepted : 7 March 2018

Funding

Funded by: B.Braun

Funded by: FundRef http://dx.doi.org/10.13039/501100002714, Albert-Ludwigs-Universität Freiburg;

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ScienceOpen disciplines: Biochemistry

Keywords: preeclampsia,hypertension in pregnancy,apheresis,lipoprotein removal,remnant lipoproteins

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ScienceOpen disciplines: Biochemistry

Keywords: preeclampsia, hypertension in pregnancy, apheresis, lipoprotein removal, remnant lipoproteins

Lipoprotein turnover and possible remnant accumulation in preeclampsia: insights from the Freiburg Preeclampsia H.E.L.P.-apheresis study

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Journal of Circulating Biomarkers

Most cited references 43

Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.

Maternal hyperlipidemia and the risk of preeclampsia: a meta-analysis.

Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia.

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