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

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 .

Keywords: Apheresis; Hypertension in pregnancy; Lipoprotein removal; Preeclampsia; Remnant lipoproteins.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the local ethics committee at the Medical Center - University of Freiburg, (local ethics committee number: 475/12; ClinicalTrails.gov: NCT01967355), and all patients gave informed written consent.

Consent for publication

Not applicable.

Competing interests

KW was supported by a grant for another trial regarding apheresis by B. Braun. The authors have no other conflicts of interest to declare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Serum lipid levels before and after apheresis. Samples were taken immediately before and after apheresis treatments (in total n = 23 treatments). Values before and after apheresis are given as median and interquartile range and tested with Wilcoxon matched pairs test

Fig. 2

Rebound of lipid levels after apheresis treatments in the six PE patients. Lipid levels before the first apheresis were set as 100%, all other lipid values are given in % relative to this value. A: apheresis treatment, D: delivery. Closed circles: LDL-cholesterol; open rectangles: total cholesterol; open triangles: ApoB

Fig. 3

Rebound of LDL-cholesterol. a: LDL-cholesterol measurements after H.E.L.P.-apheresis for all apheresis treatments in this study until day 5 (red open circles). Values before apheresis were set to 100% and all other values are given in % relative to this value, starting with the first value immediately after apheresis. The red line depicts a monoexponential fit of all data (r = 0.55), the black dotted line gives the 95% CI of the computed graph. b: Rebound of LDL-cholesterol after H.E.L.P.-apheresis, literature data (mean and s.d.). Blue open squares: 6 otherwise healthy subjects presenting isolated high Lp(a) levels [31]; magenta circles 4 healthy subjects, 75% of plasma volume treated; magenta triangles, 4 healthy subjects, 125% plasma volume treated [49]

Fig. 4

Lipoprotein profile before and after apheresis. Lipoproteins pre and post apheresis were separated into their density classes and LDL were divided into 6 subclasses by further ultracentrifugation. Density increases from left to right (see methods for details). a: Measured ApoB values (mean ± SD of 6 patients) are given as closed symbols (measured pre-apheresis values: closed triangles; measured post-apheresis levels: closed squares). Expected post apheresis values calculated by apheresis efficiency are given in open red circles. b: Comparison of measured and calculated post-apheresis levels by Wilcoxon matched pairs test, a value of p < 0.05 was considered statistically significant

Fig. 5

Cholesterol distribution in LDL-subfractions after H.E.L.P. apheresis in PE patients (a) compared with data derived from literature [33] (b). Cholesterol in the different subclasses is given in % as mean ± SD of total LDL-Cholesterol (set as 100%). *p < 0.05 with Holm-Sidak-Test. (Note, that the density ranges of individual subclasses are not identical in Fig. 5a and b)