Phenotypic changes in low-density lipoprotein particles as markers of adverse clinical outcomes in COVID-19

Helison Rafael P Carmo; Marcos Y Yoshinaga; Alejandro Rosell Castillo; Adriano Britto Chaves-Filho; Isabella Bonilha; Joaquim Barreto; Stéfanie Primon Muraro; Gabriela Fabiano de Souza; Gustavo Gastão Davanzo; Maurício W Perroud Jr; Kishal Lukhna; Mpiko Ntsekhe; Sean Davidson; Licio A Velloso; Wilson Nadruz; Luiz Sérgio F Carvalho; Miguel Sáinz-Jaspeado; Alessandro S Farias; José Luiz Proença-Módena; Pedro M Moraes-Vieira; Sotirios K Karathanasis; Derek Yellon; Sayuri Miyamoto; Alan T Remaley; Andrei C Sposito

doi:10.1016/j.ymgme.2023.107552

Phenotypic changes in low-density lipoprotein particles as markers of adverse clinical outcomes in COVID-19

Mol Genet Metab. 2023 Apr;138(4):107552. doi: 10.1016/j.ymgme.2023.107552. Epub 2023 Feb 27.

Authors

Helison Rafael P Carmo¹, Marcos Y Yoshinaga², Alejandro Rosell Castillo¹, Adriano Britto Chaves-Filho³, Isabella Bonilha¹, Joaquim Barreto¹, Stéfanie Primon Muraro⁴, Gabriela Fabiano de Souza⁴, Gustavo Gastão Davanzo⁵, Maurício W Perroud Jr⁶, Kishal Lukhna⁷, Mpiko Ntsekhe⁷, Sean Davidson⁸, Licio A Velloso⁹, Wilson Nadruz¹, Luiz Sérgio F Carvalho¹, Miguel Sáinz-Jaspeado¹⁰, Alessandro S Farias¹¹, José Luiz Proença-Módena¹², Pedro M Moraes-Vieira¹³, Sotirios K Karathanasis¹⁴, Derek Yellon⁸, Sayuri Miyamoto³, Alan T Remaley¹⁴, Andrei C Sposito¹⁵

Affiliations

¹ Cardiology Division, Unicamp Medical School, SP, Brazil.
² Department of Biochemistry, Institute of Chemistry, University of São Paulo, SP, Brazil. Electronic address: marcosyukio@gmail.com.
³ Department of Biochemistry, Institute of Chemistry, University of São Paulo, SP, Brazil.
⁴ Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil.
⁵ Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil.
⁶ Pneumology Division, Unicamp, SP, Brazil.
⁷ Division of Cardiology, University of Cape Town, Cape Town, South Africa.
⁸ Hatter Cardiovascular Institute, University College London, London, UK.
⁹ Internal Medicine Department, Unicamp Medical School, SP, Brazil.
¹⁰ Mercodia AB, Uppsala, Sweden.
¹¹ Laboratory of Neuroimmunomodulation, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil; Hub of Global Health (HGH), University of Campinas, Campinas, SP, Brazil.
¹² Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil; Hub of Global Health (HGH), University of Campinas, Campinas, SP, Brazil.
¹³ Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, SP, Brazil; Hub of Global Health (HGH), University of Campinas, Campinas, SP, Brazil.
¹⁴ Lipoprotein Metabolism Laboratory Translational Vascular Medicine Branch National Heart, Lung and Blood Institute National Institutes of Health, Bethesda, MD, USA.
¹⁵ Cardiology Division, Unicamp Medical School, SP, Brazil. Electronic address: sposito@unicamp.com.

Abstract

Background and aims: Low-density lipoprotein (LDL) plasma concentration decline is a biomarker for acute inflammatory diseases, including coronavirus disease-2019 (COVID-19). Phenotypic changes in LDL during COVID-19 may be equally related to adverse clinical outcomes.

Methods: Individuals hospitalized due to COVID-19 (n = 40) were enrolled. Blood samples were collected on days 0, 2, 4, 6, and 30 (D0, D2, D4, D6, and D30). Oxidized LDL (ox-LDL), and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were measured. In a consecutive series of cases (n = 13), LDL was isolated by gradient ultracentrifugation from D0 and D6 and was quantified by lipidomic analysis. Association between clinical outcomes and LDL phenotypic changes was investigated.

Results: In the first 30 days, 42.5% of participants died due to Covid-19. The serum ox-LDL increased from D0 to D6 (p < 0.005) and decreased at D30. Moreover, individuals who had an ox-LDL increase from D0 to D6 to over the 90th percentile died. The plasma Lp-PLA2 activity also increased progressively from D0 to D30 (p < 0.005), and the change from D0 to D6 in Lp-PLA2 and ox-LDL were positively correlated (r = 0.65, p < 0.0001). An exploratory untargeted lipidomic analysis uncovered 308 individual lipids in isolated LDL particles. Paired-test analysis from D0 and D6 revealed higher concentrations of 32 lipid species during disease progression, mainly represented by lysophosphatidyl choline and phosphatidylinositol. In addition, 69 lipid species were exclusively modulated in the LDL particles from non-survivors as compared to survivors.

Conclusions: Phenotypic changes in LDL particles are associated with disease progression and adverse clinical outcomes in COVID-19 patients and could serve as a potential prognostic biomarker.

Keywords: COVID-19; Lipoprotein-associated phospholipase A2; Oxidized low-density lipoprotein; Quantitative lipidomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Alkyl-2-acetylglycerophosphocholine Esterase*
Biomarkers
COVID-19*
Humans
Lipoproteins, LDL
Lysophosphatidylcholines

Substances

1-Alkyl-2-acetylglycerophosphocholine Esterase
Lipoproteins, LDL
Biomarkers
Lysophosphatidylcholines