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Association of D-dimer with Plaque Characteristics and Plasma Biomarkers of Oxidation-Specific Epitopes in Stable Subjects with Coronary Artery Disease

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Abstract

D-dimer has emerged as a biomarker of cardiovascular event risk, yet pathophysiological factors associated with plasma D-dimer levels in stable coronary artery disease (CAD) subjects are poorly understood. In 106 stable CAD subjects undergoing intravascular ultrasound with virtual histology (IVUS-VH), we measured D-dimer, lipoprotein(a) (Lp(a)), plasminogen, biomarkers reflecting oxidation-specific epitopes (OSE) such as oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), OxPL on plasminogen (OxPL-PLG), and autoantibodies to phosphorylcholine-BSA [PC-BSA] and a malondialdehyde [MDA] mimotope. In univariate analysis, D-dimer was positively associated with Lp(a), OxPL-apoB, OxPL-PLG, and coronary artery calcium, and inversely associated with autoantibodies to OSE and plaque fibrosis. D-dimer levels > 500 ng/ml also showed positive association with plaque necrosis. After multivariate analysis, D-dimer remained significantly associated with Lp(a) and plaque calcium. While further studies are needed, results provide evidence that plasma D-dimer levels are associated with levels of OxPLs and IVUS-VH indices linked to plaque erosion and rupture.

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Abbreviations

MDA-LDL:

Malondialdehyde-LDL

PC:

Phosphorylcholine

Lp(a):

Lipoprotein(a)

OxPL-apoB:

Oxidized phospholipids on apoB-100-containing lipoproteins

OxPL-PLG:

Oxidized phospholipids on plasminogen

OSE:

Oxidation-specific epitopes

IVUS-VH:

Intravascular ultrasound-virtual histology

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Acknowledgements

We would like to thank Chantel McSkimming, James Garmey, Melissa Marshall for technical assistance, and Frances Gilbert for coordinating human studies and sample acquisition.

Sources of Funding

This work was supported by National Institutes of Health R01-HL-136098 (CAM) and American Heart Association National Scientist Development Grant 13SDG16970030 (HK).

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Author notes

  1. Angela Taylor and Coleen A. McNamara contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Research Center, University of Virginia, 415 Lane Road, Bldg MR-5, Rm-G231, Charlottesville, VA, 22908, USA

    Hema Kothari, Anh T. Nguyen, Angela Taylor & Coleen A. McNamara

  2. Department of Medicine, Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, University of California San Diego, San Diego, CA, USA

    Xiaohong Yang & Sotirios Tsimikas

  3. Department of Medicine, Division of Hematology and Oncology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Yohei Hisada & Nigel Mackman

  4. K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway

    Yohei Hisada

  5. Department of Medicine, Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA, USA

    Angela Taylor & Coleen A. McNamara

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  1. Hema Kothari
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Correspondence to Hema Kothari.

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Conflict of Interest

ST is co-inventor of and receives royalties from patents or patent applications owned by the University of California San Diego on oxidation-specific antibodies.

Ethical Approval

All protocols and procedures were approved by the Institutional Review Board for human subjects at UVA and performed in accordance with the Declaration of Helsinki.

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Informed written consent was obtained for all patients prior to enrollment in the study.

Additional information

Associate Editor Craig Stolen oversaw the review of this article

Clinical Relevance

The present study demonstrating positive association of elevated D-dimer with plaque necrosis and calcification and plasma levels of Lp(a) provides potential pathophysiological insights into the association of D-dimer with cardiovascular events. Demonstration of an inverse association of D-dimer with IgM to oxidation-specific epitopes suggests potential pathways of protection from atherothrombosis.

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Kothari, H., Nguyen, A.T., Yang, X. et al. Association of D-dimer with Plaque Characteristics and Plasma Biomarkers of Oxidation-Specific Epitopes in Stable Subjects with Coronary Artery Disease. J. of Cardiovasc. Trans. Res. 11, 221–229 (2018). https://doi.org/10.1007/s12265-018-9790-4

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