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

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

Helison Rafael P Carmo  1 , Marcos Y Yoshinaga  2 , Alejandro Rosell Castillo  1 , Adriano Britto Chaves-Filho  3 , Isabella Bonilha  1 , Joaquim Barreto  1 , Stéfanie Primon Muraro  4 , Gabriela Fabiano de Souza  4 , Gustavo Gastão Davanzo  5 , Maurício W Perroud Jr  6 , Kishal Lukhna  7 , Mpiko Ntsekhe  7 , Sean Davidson  8 , Licio A Velloso  9 , Wilson Nadruz  1 , Luiz Sérgio F Carvalho  1 , Miguel Sáinz-Jaspeado  10 , Alessandro S Farias  11 , José Luiz Proença-Módena  12 , Pedro M Moraes-Vieira  13 , Sotirios K Karathanasis  14 , Derek Yellon  8 , Sayuri Miyamoto  3 , Alan T Remaley  14 , Andrei C Sposito  15
Affiliations

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

Helison Rafael P Carmo et al. Mol Genet Metab. 2023 Apr.

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.

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Conflict of interest statement

Declaration of Competing Interest Dr. Miguel Sáinz-Jaspeado works at Mercodia company (Mercodia AB, Uppsala, Sweden) as product Manager & Medical Science Liaison and, kindly provided the enzyme-linked immunoassay (ELISA) kits for oxidized low-density lipoprotein measures.

Figures

Fig. 1
Fig. 1
Oxidized Low-density Lipoprotein (ox-LDL) measurements (U/L). The measurements were performed in plasma samples from 40 hospitalized patients on days 0, 2, 4, 6, and 30 (D0, D2, D4, D6, and D30, respectively). Ox-LDL was assessed by enzyme-linked immunosorbent assay kits according to the manufacturer's instructions. Data were analyzed through the Wilcoxon-Mann-Whitney U test.
Fig. 2
Fig. 2
Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity measurements in plasma samples (mmol/min/ml). The measurements were performed in plasma samples from 40 hospitalized patients on days 0, 6, and 30 (D0, D6, and D30, respectively). Lp-PLA2 was assessed by enzyme-linked immunosorbent assay kits according to the manufacturer's instructions. Data were analyzed through paired t-tests.
Fig. 3
Fig. 3
Linear regression of the change in oxidized low-density lipoprotein (ox-LDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2). Data expressed the change in ox-LDL and Lp-PLA2 from D0 to D6 were positively correlated (r = 0.65, p < 0.0001) verified through Spearman Rank correlation.
Fig. 4
Fig. 4
Heatmap of main LDL lipidome alterations between days 0 and 6. Heatmap representing the 32 lipid species from LDL displaying significant differences in concentration (as percentage of total lipids) between days 0 and 6 for 13 patients (A). The sum of LPC and LPE concentration as a percentage (%) of total lipids in the log scale and significant differences between days 0 and 6 (B). Data analyses were log-transformed and compared using the student's t-test. X: Y where X = carbon and Y = double bonds.
Fig. 5
Fig. 5
Volcano plots and Venn diagram. Volcano plots of paired data in survivors (A) and non-survivors (B) on day 6 versus day 0. Venn diagram displaying modulated lipids in survivors and non-survivors on day 6 versus day 0 (C). See Supplemental Table 3 for detailed information. Volcano plots and Venn diagram. Volcano plots of paired data in survivors (A) and non-survivors (B) on day 6 versus day 0. Venn diagram displaying modulated lipids in survivors and non-survivors on day 6 versus day 0 (C). See Supplemental Table 3 for detailed information.
Supplemental Fig. 1
Supplemental Fig. 1
Ox-LDL levels at each timepoint among survivors and non-survivors. One-way ANOVA with multiple comparison with Sidak adjustment reported no significant change from baseline among survivors, but ox-LDL levels varied significantly from baseline to D6 in non-survivors.
Supplemental Fig. 2
Supplemental Fig. 2
LP-LPA activity at each timepoint according to survival status. One-way ANOVA with multiple comparison with Sidak adjustment reported no significant change from baseline in both groups.
Supplemental Fig. 3
Supplemental Fig. 3
Linear regression of change in ox-LDL as a function of change in LP-PLA2 activity from D0 to D6. The curves represent the linear regression of survivors (light gray) and non-survivors (darker gray). The equations were y = 2979*x-3.33 for survivors (R2 linear = 0.640) and y = 4148*x + 20.4 for non-survivors (R2 linear = 0.637).
Supplemental Fig. 4
Supplemental Fig. 4
Flowchart of the samples used in the lipidomic analysis.
See this image and copyright information in PMC

References

    1. Mahat R.K., Rathore V., Singh N., Singh N., Singh S.K., Shah R.K., et al. Lipid profile as an indicator of COVID-19 severity: a systematic review and meta-analysis. Clin Nutr ESPEN. 2021;45:91–101. - PMC - PubMed
    1. Rott D., Klempfner R., Goldenberg I., Leibowitz D. Cholesterol levels decrease soon after acute myocardial infarction. The Israel Med. Associat. J. IMAJ. 2015;17(6):370–373. - PubMed
    1. Cheng K.H., Chu C.S., Lin T.H., Lee K.T., Sheu S.H., Lai W.T. Lipid paradox in acute myocardial infarction-the association with 30-day in-hospital mortality. Crit. Care Med. 2015;43(6):1255–1264. - PubMed
    1. Reddy V.S., Bui Q.T., Jacobs J.R., Begelman S.M., Miller D.P., French W.J., et al. Relationship between serum low-density lipoprotein cholesterol and in-hospital mortality following acute myocardial infarction (the lipid paradox) Am. J. Cardiol. 2015;115(5):557–562. - PubMed
    1. Acikgoz E., Acikgoz S.K., Yaman B., Kurtul A. Lower LDL-cholesterol levels associated with increased inflammatory burden in patients with acute ST-segment elevation myocardial infarction. Rev Assoc Med Bras(1992) 2021;67(2):224–229. - PubMed

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