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  • Review Article
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Oxidized phospholipids in cardiovascular disease

Nature Reviews Cardiology volume 21, pages 170–191 (2024)Cite this article

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Abstract

Prolonged or excessive exposure to oxidized phospholipids (OxPLs) generates chronic inflammation. OxPLs are present in atherosclerotic lesions and can be detected in plasma on apolipoprotein B (apoB)-containing lipoproteins. When initially conceptualized, OxPL–apoB measurement in plasma was expected to reflect the concentration of minimally oxidized LDL, but, surprisingly, it correlated more strongly with plasma lipoprotein(a) (Lp(a)) levels. Indeed, experimental and clinical studies show that Lp(a) particles carry the largest fraction of OxPLs among apoB-containing lipoproteins. Plasma OxPL–apoB levels provide diagnostic information on the presence and extent of atherosclerosis and improve the prognostication of peripheral artery disease and first and recurrent myocardial infarction and stroke. The addition of OxPL–apoB measurements to traditional cardiovascular risk factors improves risk reclassification, particularly in patients in intermediate risk categories, for whom improving decision-making is most impactful. Moreover, plasma OxPL–apoB levels predict cardiovascular events with similar or greater accuracy than plasma Lp(a) levels, probably because this measurement reflects both the genetics of elevated Lp(a) levels and the generalized or localized oxidation that modifies apoB-containing lipoproteins and leads to inflammation. Plasma OxPL–apoB levels are reduced by Lp(a)-lowering therapy with antisense oligonucleotides and by lipoprotein apheresis, niacin therapy and bariatric surgery. In this Review, we discuss the role of role OxPLs in the pathophysiology of atherosclerosis and Lp(a) atherogenicity, and the use of OxPL–apoB measurement for improving prognosis, risk reclassification and therapeutic interventions.

Key points

  • Phosphocholine-containing oxidized phospholipids (OxPLs) induce chronic inflammation, including in atherosclerotic lesions, and can be detected in plasma on apolipoprotein B-100 (apoB-100)-containing lipoproteins.

  • A method has been developed to quantify OxPLs on a normalized amount of apoB-100 (OxPL–apoB), so that the measurement is independent of plasma apoB-100 and LDL cholesterol levels.

  • Lipoprotein(a) (Lp(a)) particles carry the largest fraction of OxPLs among apoB-containing lipoproteins; the OxPLs are bound covalently to apolipoprotein(a) and are free in the lipid phase of the associated LDL-like particle.

  • Plasma OxPL–apoB levels predict the presence and extent of anatomical atherosclerotic cardiovascular disease, and elevated levels are associated with disease in multiple arterial beds; measurement of OxPL–apoB improves prognostication of peripheral artery disease, as well as incident and recurrent myocardial infarction and stroke, and improves risk reclassification, particularly in patients in intermediate risk categories, for whom improving decision-making is most impactful.

  • Plasma OxPL–apoB levels are reduced by treatment with antisense oligonucleotides aimed at reducing Lp(a) production and by lipoprotein apheresis, niacin therapy and bariatric surgery.

  • Plasma OxPL–apoB levels predict cardiovascular events with a potency similar to or greater than that of plasma Lp(a) levels, probably because OxPL–apoB levels reflect the levels of the most atherogenic and pro-inflammatory Lp(a) and apoB-100-containing particles.

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Fig. 1: Oxidized phospholipid-binding specificity of the E06 mouse monoclonal antibody.
Fig. 2: Differential patterns of macrophages, oxidized phospholipids, apoB-100 and apo(a) in atherosclerotic lesions.
Fig. 3: ApoB-100, oxidized phospholipid and apo(a) content in atherosclerotic lesions.
Fig. 4: Relationship between oxidized phospholipids and lipoprotein(a).
Fig. 5: Relationship of OxPL–apoB and Lp(a) levels according to size of the major apo(a) isoform.
Fig. 6: Association of OxPL–apoB with anatomical pan-arterial disease and cardiovascular events.
Fig. 7: Effect of therapeutic interventions on plasma levels of OxPL–apoB and lipoprotein(a).
Fig. 8: Effect of dietary interventions or statin therapy on OxPL–apoB levels.

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Acknowledgements

The authors thank X. Yang (UCSD, USA) and E. Miller (UCSD, USA) for expert technical assistance in the SCOR UCSD biomarker laboratory. The many members of the SCOR/PPG laboratory for the past 30 years and the hundreds of worldwide collaborators are greatly acknowledged for their contributions to the work discussed in this Review. The authors are supported by NIH R01 HL159156 and HL170224 (S.T.) and PO HL147835 (J.L.W.).

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  1. Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA, USA

    Sotirios Tsimikas

  2. Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA

    Joseph L. Witztum

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S.T. wrote the manuscript. Both authors researched data for the article, provided substantial contributions to discussion of the content, and reviewed and edited the manuscript before submission.

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Correspondence to Sotirios Tsimikas.

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Competing interests

S.T. and J.L.W. are co-inventors and receive royalties from patents owned by UCSD on oxidation-specific antibodies and on biomarkers related to oxidized lipoproteins, and are co-founders and have an equity interest in Kleanthi Diagnostics and Oxitope. The terms of this arrangement have been reviewed and approved by the UCSD in accordance with its conflict-of-interest policies. S.T. has a dual appointment at UCSD and Ionis Pharmaceuticals. J.L.W. is a consultant to Ionis Pharmaceuticals.

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Tsimikas, S., Witztum, J.L. Oxidized phospholipids in cardiovascular disease. Nat Rev Cardiol 21, 170–191 (2024). https://doi.org/10.1038/s41569-023-00937-4

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