Depletion of Homeostatic Antibodies against Malondialdehyde-Modified Low-Density Lipoprotein Correlates with Adverse Events in Major Vascular Surgery.

Hasan Ali Shah,Joseph Shalhoub,Wolfgang Koenig,Anna Chow,Dorian O Haskard,Adam Hartley,Michael Fisher,Ameer Hamid Ahmed Khan,Magapu Pradeep,Ramzi Y Khamis,Victor Van Den Berg,Mikhail Caga-Anan,Mohammed Allaf

doi:10.3390/antiox11020271

Abstract

We aimed to investigate if major vascular surgery induces LDL oxidation, and whether circulating antibodies against malondialdehyde-modified LDL (MDA-LDL) alter dynamically in this setting. We also questioned relationships between these biomarkers and post-operative cardiovascular events. Major surgery can induce an oxidative stress response. However, the role of the humoral immune system in clearance of oxidized LDL following such an insult is unknown. Plasma samples were obtained from a prospective cohort of 131 patients undergoing major non-cardiac vascular surgery, with samples obtained preoperatively and at 24- and 72 h postoperatively. Enzyme-linked immunoassays were developed to assess MDA-LDL-related antibodies and complexes. Adverse events were myocardial infarction (primary outcome), and a composite of unstable angina, stroke and all-cause mortality (secondary outcome). MDA-LDL significantly increased at 24 h post-operatively (p < 0.0001). Conversely, levels of IgG and IgM anti-MDA-LDL, as well as IgG/IgM-MDA-LDL complexes and total IgG/IgM, were significantly lower at 24 h (each p < 0.0001). A smaller decrease in IgG anti-MDA-LDL related to combined clinical adverse events in a post hoc analysis, withstanding adjustment for age, sex, and total IgG (OR 0.13, 95% CI [0.03–0.5], p < 0.001; p value for trend <0.001). Major vascular surgery resulted in an increase in plasma MDA-LDL, in parallel with a decrease in antibody/complex levels, likely due to antibody binding and subsequent removal from the circulation. Our study provides novel insight into the role of the immune system during the oxidative stress of major surgery, and suggests a homeostatic clearance role for IgG antibodies, with greater reduction relating to downstream adverse events.

Highlights

Low-density lipoprotein (LDL) readily undergoes chemical modification leading to the formation of malondialdehyde (MDA)-LDL and other peroxidation products that have a variety of toxic effects on endothelial and other cells [1]
We have developed a set of enzyme-linked immunosorbent assays (ELISAs) for measuring MDA-LDL, anti-MDA-LDL antibodies, and MDA-LDL immune complexes, and in this study we have applied them to assess how the humoral immune system is involved in MDA-LDL clearance following the challenge of vascular surgery
There is consumptive depletion of IgG and IgM antibodies involved in antigen clearance as MDA-LDL complexes

Summary

Introduction

Low-density lipoprotein (LDL) readily undergoes chemical modification leading to the formation of malondialdehyde (MDA)-LDL and other peroxidation products that have a variety of toxic effects on endothelial and other cells [1]. The humoral immune system is involved in the protective clearance of these and other oxidatively modified proteins. IgM and IgG antibodies targeting MDA-LDL are a significant component of the antibody repertoire that reacts with modified LDL [2]. Higher circulating levels of IgM anti-MDA-LDL have been generally found to confer protection from cardiovascular events [3], but the prognostic relevance of. IgG anti-MDA-LDL levels with disease states is less clear [4,5,6]. Circulating antibodies can form complexes with modified LDL, and levels of IgM-LDL complexes are postulated to be protective [7,8,9,10]. IgG-LDL complexes, on the other hand, may be detrimental [5,11]

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