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Open Access 01-12-2021 | Hypercholesterolemia | Research

Monitoring of up to 15 years effects of lipoprotein apheresis on lipids, biomarkers of inflammation, and soluble endoglin in familial hypercholesterolemia patients

Authors: J. Víšek, M. Bláha, V. Bláha, M. Lášticová, M. Lánska, C. Andrýs, J. Duintjer Tebbens, Ivone Cristina Igreja e Sá, K. Tripská, M. Vicen, I. Najmanová, P. Nachtigal

Published in: Orphanet Journal of Rare Diseases | Issue 1/2021

Abstract

Background

Lipoprotein apheresis (LA) is considered as an add-on therapy for patients with familial hypercholesterolemia (FH). We aimed to analyze the data collected in the last 15 years from FH patients treated with LA, to elucidate the benefit of this procedure with respect to plasma lipids, biomarkers of inflammation, and endothelial dysfunction and soluble endoglin.

Results

14 patients (10 heterozygous FH patients (HeFH), 4 homozygous FH patients (HoFH)) were treated by long-term lipoprotein apheresis. Lipid levels were examined, and ELISA detected biomarkers of inflammation and soluble endoglin. Paired tests were used for intergroup comparisons, and a linear regression model served to estimate the influence of the number of days patients were treated with LA on the studied parameters. LA treatment was associated with a significant decrease of total cholesterol (TC), LDL-C, HDL-C, and apoB, in both HeFH and HoFH patients, after single apheresis and in a long-term period during the monitored interval of 15 years. Biomarkers of inflammation and endothelial dysfunction were reduced for soluble endoglin, hsCRP, and MCP-1, and sP-selectin after each procedure in some HeFH and HoFH patients.

Conclusions

LA treatment up to 15 years, reduced cholesterol levels, levels of biomarkers related to endothelial dysfunction, and inflammation not only after each procedure but also in the long-term evaluation in FH patients. We propose that long-term LA treatment improves lipid profile and endothelial dysfunction in familial hypercholesterolemia patients, suggesting a promising improvement in cardiovascular prognosis in most FH patients.

Kastelein JJP, Reeskamp LF, Hovingh GK. Familial hypercholesterolemia: the most common monogenic disorder in humans. J Am Coll Cardiol. 2020;75:2567–9. https://doi.org/10.1016/j.jacc.2020.03.058.CrossRefPubMed

Abifadel M, Elbitar S, El Khoury P, et al. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs. Curr Atheroscler Rep. 2014;16:439. https://doi.org/10.1007/s11883-014-0439-8.CrossRefPubMed

Alnouri F, Athar M, Al-Allaf FA, et al. Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia. Atherosclerosis. 2018;277:425–33. https://doi.org/10.1016/j.atherosclerosis.2018.06.878.CrossRefPubMed

Kim YR, Han KH. Familial hypercholesterolemia and the atherosclerotic disease. Korean Circ J. 2013;43:363–7.CrossRef

Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478–3490a. https://doi.org/10.1093/eurheartj/eht273.CrossRefPubMedPubMedCentral

Cenarro A, Etxebarria A, de Castro-Orós I, et al. The p. Leu167del mutation in APOE gene causes autosomal dominant hypercholesterolemia by down-regulation of LDL receptor expression in hepatocytes. J Clin Endocrinol Metab. 2016;101:2113–21.CrossRef

Civeira F, Plana N. Treatment of heterozygous familial hypercholesterolemia in children and adolescents: an unsolved problem. Revista Española de Cardiología (Engl Ed). 2017;70:423–4. https://doi.org/10.1016/j.rec.2017.02.008.CrossRef

Creider J, Hegele R. Clinical evaluation for genetic and secondary causes of dyslipidemia. In: Elsevier (ed) Clinical lipidology, 2nd ed. Philadelphia (USA), 2015, p. 128–34.

Bambauer R, Bambauer C, Lehmann B, et al. LDL-apheresis: technical and clinical aspects. Sci World J; 2012.

10.

Blaha V, Blaha M, Lanska M, et al. Lipoprotein apheresis in the treatment of dyslipidemia–the Czech Republic Experience. Physiol Res. 2017;66:S91.CrossRef

11.

Stefanutti C, Zenti MG. Lipoprotein apheresis and PCSK9-inhibitors. Impact on atherogenic lipoproteins and anti-inflammatory mediators in familial hypercholesterolaemia. Curr Pharm Des. 2018;24:3634–7.CrossRef

12.

Blaha V, Blaha M, Solichova D, et al. Antioxidant defense system in familial hypercholesterolemia and the effects of lipoprotein apheresis. Atheroscler Suppl. 2017;30:159–65.CrossRef

13.

Chepelenko GV. Pathogenesis of atherosclerosis in patients with lipid metabolism disturbances: hypothesis on cholesterol utilization and atheromatous plaque formation. Angiol Sosud Khir. 2003;9:20–5.PubMed

14.

Ridker PM, Silvertown JD. Inflammation, C-reactive protein, and atherothrombosis. J Periodontol. 2008;79:1544–51. https://doi.org/10.1902/jop.2008.080249.CrossRefPubMed

15.

Hajilooi M, Sanati A, Ahmadieh A, et al. Circulating ICAM-1, VCAM-1, E-selectin, P-selectin, and TNFRII in patients with coronary artery disease. Immunol Invest. 2004;33:263–75.CrossRef

16.

Szabolcs MJ, Cannon PJ, Thienel U, et al. Analysis of CD154 and CD40 expression in native coronary atherosclerosis and transplant associated coronary artery disease. Virchows Arch. 2000;437:149–59.CrossRef

17.

Blaha M, Krejsek J, Blaha V, et al. Selectins and monocyte chemotactic peptide as the markers of atherosclerosis activity. Physiol Res. 2004;53:273–8.PubMed

18.

Schoonderwoerd MJA, Goumans MTH, Hawinkels L. Endoglin: beyond the endothelium. Biomolecules. 2020. https://doi.org/10.3390/biom10020289.CrossRefPubMedPubMedCentral

19.

Blann AD, Wang JM, Wilson PB, et al. Serum levels of the TGF-beta receptor are increased in atherosclerosis. Atherosclerosis. 1996;120:221–6.CrossRef

20.

Blaha M, Cermanova M, Blaha V, et al. Elevated serum soluble endoglin (sCD105) decreased during extracorporeal elimination therapy for familial hypercholesterolemia. Atherosclerosis. 2008;197:264–70. https://doi.org/10.1016/j.atherosclerosis.2007.04.022.CrossRefPubMed

21.

Vicen M, Vitverova B, Havelek R, et al. Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro. FASEB J. 2019. https://doi.org/10.1096/fj.201802245R.CrossRefPubMed

22.

Strasky Z, Vecerova L, Rathouska J, et al. Cholesterol effects on endoglin and its downstream pathways in ApoE/LDLR double knockout mice. Circ J. 2011;75:1747–55.CrossRef

23.

Rathouska J, Vecerova L, Strasky Z, et al. Endoglin as a possible marker of atorvastatin treatment benefit in atherosclerosis. Pharmacol Res. 2011;64:53–9. https://doi.org/10.1016/j.phrs.2011.03.008.CrossRefPubMed

24.

Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis. 2019;290:140–205.CrossRef

25.

Adults EPoDEaToHBCi. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA: J Am Med Assoc. 2001;285: 2486–97. https://doi.org/10.1001/jama.285.19.2486.

26.

Parham JS, Goldberg AC. Mipomersen and its use in familial hypercholesterolemia. Expert Opin Pharmacother. 2019;20:127–31. https://doi.org/10.1080/14656566.2018.1550071.CrossRefPubMed

27.

Bruckert E, Gallo A. Is lomitapide a life-saving drug in homozygous familial hypercholesterolemia. Eur J Prev Cardiol. 2017;24:1841–2. https://doi.org/10.1177/2047487317734387.CrossRefPubMed

28.

Kroon AA, Van’Hof MA, Demacker PN, et al. The rebound of lipoproteins after LDL-apheresis Kinetics and estimation of mean lipoprotein levels. Atherosclerosis. 2000;152:519–26. https://doi.org/10.1016/s0021-9150(00)00371-3.CrossRefPubMed

29.

Beliard S, Gallo A, Duchene E, et al. Lipoprotein-apheresis in familial hypercholesterolemia: Long-term patient compliance in a French cohort. Atherosclerosis. 2018;277:66–71. https://doi.org/10.1016/j.atherosclerosis.2018.08.007.CrossRefPubMed

30.

Kolovou G, Hatzigeorgiou G, Mihas C, et al. Changes in lipids and lipoproteins after selective LDL apheresis (7-year experience). Cholesterol. 2012;2012:976578. https://doi.org/10.1155/2012/976578.CrossRefPubMedPubMedCentral

31.

Makino H, Harada-Shiba M. Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia. Therapeutic Apher Dial. 2003;7:397–401. https://doi.org/10.1046/j.1526-0968.2003.00073.x.CrossRef

32.

Masaki N, Tatami R, Kumamoto T, et al. Ten-year follow-up of familial hypercholesterolemia patients after intensive cholesterol-lowering therapy. Int Heart J. 2005;46:833–43. https://doi.org/10.1536/ihj.46.833.CrossRefPubMed

33.

Orsoni A, Saheb S, Levels JH, et al. LDL-apheresis depletes apoE-HDL and pre-beta1-HDL in familial hypercholesterolemia: relevance to atheroprotection. J Lipid Res. 2011;52:2304–13. https://doi.org/10.1194/jlr.P016816.CrossRefPubMedPubMedCentral

34.

Neumann CL, Schulz EG, Hagenah GC, et al. Lipoprotein apheresis – More than just cholesterol reduction? Atheroscler Suppl. 2013;14:29–32. https://doi.org/10.1016/j.atherosclerosissup.2012.10.017.CrossRefPubMed

35.

Higashi Y, Noma K, Yoshizumi M, et al. Endothelial function and oxidative stress in cardiovascular diseases. Circ J. 2009;73:411–8.CrossRef

36.

van Wijk DF, Sjouke B, Figueroa A, et al. Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia. J Am Coll Cardiol. 2014;64:1418–26. https://doi.org/10.1016/j.jacc.2014.01.088.CrossRefPubMed

37.

Utsumi K, Kawabe M, Hirama A, et al. Effects of selective LDL apheresis on plasma concentrations of ICAM-1, VCAM-1 and P-selectin in diabetic patients with arteriosclerosis obliterans and receiving maintenance hemodialysis. Clin Chim Acta. 2007;377:198–200. https://doi.org/10.1016/j.cca.2006.09.026.CrossRefPubMed

38.

Kobayashi S, Oka M, Moriya H, et al. LDL-apheresis reduces P-Selectin, CRP and fibrinogen – possible important implications for improving atherosclerosis. Ther Apher Dial. 2006;10:219–23. https://doi.org/10.1111/j.1744-9987.2006.00332.x.CrossRefPubMed

39.

Sampietro T, Tuoni M, Ferdeghini M, et al. Plasma cholesterol regulates soluble cell adhesion molecule expression in familial hypercholesterolemia. Circulation. 1997;96:1381–5.CrossRef

40.

Empen K, Otto C, Brödl UC, et al. The effects of three different LDL-apheresis methods on the plasma concentrations of E-selectin, VCAM-1, and ICAM-1. J Clin Apher. 2002;17:38–43.CrossRef

41.

Pulawski E, Mellwig KP, Brinkmann T, et al. Influence of single low-density lipoprotein apheresis on the adhesion molecules soluble vascular cellular adhesion molecule-1, soluble intercellular adhesion molecule-1, and P-selectin. Ther Apher. 2002;6:229–33.CrossRef

42.

Dlouha D, Blaha M, Blaha V, et al. analysis of circulating miRNAs in patients with familial hypercholesterolaemia treated by LDL/Lp(a) apheresis. Atheroscler Suppl. 2017;30:128–34. https://doi.org/10.1016/j.atherosclerosissup.2017.05.037.CrossRefPubMed

43.

Rathouska J, Jezkova K, Nemeckova I, et al. Soluble endoglin, hypercholesterolemia and endothelial dysfunction. Atherosclerosis. 2015;243:383–8. https://doi.org/10.1016/j.atherosclerosis.2015.10.003.CrossRefPubMed

44.

Blazquez-Medela AM, Garcia-Ortiz L, Gomez-Marcos MA, et al. Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients. BMC Med. 2010;8:86. https://doi.org/10.1186/1741-7015-8-86.CrossRefPubMedPubMedCentral

45.

Gallardo-Vara E, Gamella-Pozuelo L, Perez-Roque L, et al. Potential role of circulating endoglin in hypertension via the upregulated expression of BMP4. Cells. 2020. https://doi.org/10.3390/cells9040988.CrossRefPubMedPubMedCentral

46.

Vitverova B, Blazickova K, Najmanova I, et al. Soluble endoglin and hypercholesterolemia aggravate endothelial and vessel wall dysfunction in mouse aorta. Atherosclerosis. 2018;271:15–25. https://doi.org/10.1016/j.atherosclerosis.2018.02.008.CrossRefPubMed

47.

Dlouha D, Blaha M, Blaha V, et al. analysis of circulating miRNAs in patients with familial hypercholesterolaemia treated by LDL/Lp (a) apheresis. Atherosclerosis Supplements. 2017;30:128–34.CrossRef

48.

Vaverkova H, Tichy L, Karasek D, et al. A case of autosomal recessive hypercholesterolemia caused by a new variant in the LDL receptor adaptor protein 1 gene. J Clin Lipidol. 2019;13:405–10.CrossRef

49.

Blaha M, Cermanova M, Blaha V, et al. Safety and tolerability of long lasting LDL-apheresis in familial hyperlipoproteinemia. Ther Apher Dial. 2007;11:9–15. https://doi.org/10.1111/j.1744-9987.2007.00450.x.CrossRefPubMed

50.

Solichova D, Melichar B, Blaha V, et al. Biochemical profile and survival in nonagenarians. Clin Biochem. 2001;34:563–9.CrossRef

51.

Blaha M, Kostal M, Lanska M, et al. The decrease of mean platelet volume after extracorporeal LDL-cholesterol elimination. Atheroscler Suppl. 2013;14:77–81. https://doi.org/10.1016/j.atherosclerosissup.2012.10.019.CrossRefPubMed

52.

Blaha M, Zadak Z, Blaha V, et al. Extracorporeal LDL cholesterol elimination (25 years of experience in CZ). Atheroscler Suppl. 2009;10:17–20. https://doi.org/10.1016/S1567-5688(09)71804-5.CrossRefPubMed

53.

Blaha M, Pecka M, Urbankova J, et al. Activity of thrombocytes as a marker of sufficient intensity of LDL-apheresis in familial hypercholesterolaemia. Transfus Apher Sci. 2004;30:83–7. https://doi.org/10.1016/j.transci.2003.11.002.CrossRefPubMed

Title: Monitoring of up to 15 years effects of lipoprotein apheresis on lipids, biomarkers of inflammation, and soluble endoglin in familial hypercholesterolemia patients
Authors: J. Víšek
M. Bláha
V. Bláha
M. Lášticová
M. Lánska
C. Andrýs
J. Duintjer Tebbens
Ivone Cristina Igreja e Sá
K. Tripská
M. Vicen
I. Najmanová
P. Nachtigal
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Hypercholesterolemia
Biomarkers
Published in: Orphanet Journal of Rare Diseases / Issue 1/2021
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-021-01749-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Monitoring of up to 15 years effects of lipoprotein apheresis on lipids, biomarkers of inflammation, and soluble endoglin in familial hypercholesterolemia patients

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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