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Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease

Nature Reviews Cardiology volume 16, pages 305–318 (2019)Cite this article

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Abstract

Epidemiological and clinical studies over the past decade have firmly established that elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important, independent and probably causal risk factor for the development of cardiovascular diseases. Whereas a link between Lp(a) levels and atherosclerotic cardiovascular disease (ASCVD) has been appreciated for decades, the role of Lp(a) in calcific aortic valve disease (CAVD) and aortic stenosis has come into focus only in the past 5 years. ASCVD and CAVD are aetiologically distinct but have several risk factors in common and similar pathological processes at the cellular and molecular levels. Oxidized phospholipids, which modify Lp(a) primarily by covalent binding to its unique apolipoprotein(a) (apo(a)) component, might hold the key to Lp(a) pathogenicity and provide a mechanistic link between ASCVD and CAVD. Oxidized phospholipids colocalize with apo(a)–Lp(a) in arterial and aortic valve lesions and directly participate in the pathogenesis of these disorders by promoting endothelial dysfunction, lipid deposition, inflammation and osteogenic differentiation, leading to calcification. The advent of potent Lp(a)-lowering therapies provides the opportunity to address directly the causality of Lp(a) in ASCVD and CAVD and, more importantly, to provide both a novel approach to reduce the residual risk of ASCVD and a long-sought medical treatment for CAVD.

Key points

  • Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an independent — and possibly causal — risk factor for atherothrombotic cardiovascular disease and calcific aortic valve disease.

  • The mechanisms by which Lp(a) accelerates these disorders are not fully understood, but the oxidized phospholipids present on apolipoprotein(a) might have an important role.

  • Lp(a) is the major carrier of oxidized phospholipids in human plasma, and interventions that lower plasma Lp(a) levels also reduce the oxidized phospholipid concentration in plasma.

  • The oxidized phospholipids on apolipoprotein(a) have been shown to mediate numerous, and partially overlapping, molecular and cellular events underlying atherothrombotic cardiovascular disease and calcific aortic valve disease.

  • Direct evidence demonstrating that lowering plasma Lp(a) levels reduces the risk of cardiovascular disease is lacking, as are conclusive data on the specific role of Lp(a)-associated oxidized phospholipids.

  • Cardiovascular outcome studies and further basic science investigations will be required to address these important questions.

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Fig. 1: Structure of lipoprotein(a).
Fig. 2: Regulation of lipoprotein(a) biosynthesis and catabolism.
Fig. 3: Cellular effects of lipoprotein(a) and lipoprotein(a)-associated oxidized phospholipids.
Fig. 4: Molecular events elicited by oxidized phospholipids on apolipoprotein(a) and lipoprotein(a).

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Acknowledgements

M.L.K. acknowledges grant support for her lipoprotein(a) research programme from the Heart and Stroke Foundation of Canada, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and ASPIRE Cardiovascular Research Awards.

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Nature Reviews Cardiology thanks G. Kostner, J. Witztum and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Biochemistry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada

    Michael B. Boffa

  2. Robarts Research Institute, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada

    Marlys L. Koschinsky

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Both authors researched data for the article and discussed its content. M.B.B. wrote the manuscript, and M.L.K. reviewed and edited it before submission.

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M.B.B. has a research contract from IONIS. M.L.K. has research contracts from CardioVax, Eli Lilly and IONIS and is on the advisory board and/or speakers’ bureau of Amgen, Eli Lilly, IONIS and Sanofi.

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Boffa, M.B., Koschinsky, M.L. Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease. Nat Rev Cardiol 16, 305–318 (2019). https://doi.org/10.1038/s41569-018-0153-2

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