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The importance of the endothelium in atherothrombosis and coronary stenting

Nature Reviews Cardiology volume 9, pages 439–453 (2012)Cite this article

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A Correction to this article was published on 23 May 2013

This article has been updated

Abstract

Deployment of drug-eluting stents instead of bare-metal stents has dramatically reduced restenosis rates, but rates of very late stent thrombosis (>1 year postimplantation) have increased. Vascular endothelial cells normally provide an efficient barrier against thrombosis, lipid uptake, and inflammation. However, endothelium that has regenerated after percutaneous coronary intervention is incompetent in terms of its integrity and function, with poorly formed cell junctions, reduced expression of antithrombotic molecules, and decreased nitric oxide production. Delayed arterial healing, characterized by poor endothelialization, is the primary cause of late (1 month–1 year postimplantation) and very late stent thrombosis following implantation of drug-eluting stents. Impairment of vasorelaxation in nonstented proximal and distal segments of stented coronary arteries is more severe with drug-eluting stents than bare-metal stents, and stent-induced flow disturbances resulting in complex spatiotemporal shear stress can also contribute to increased thrombogenicity and inflammation. The incompetent endothelium leads to late stent thrombosis and the development of in-stent neoatherosclerosis. The process of neoatherosclerosis occurs more rapidly, and more frequently, following deployment of drug-eluting stents than bare-metal stents. Improved understanding of vascular biology is crucial for all cardiologists, and particularly interventional cardiologists, as maintenance of a competently functioning endothelium is critical for long-term vascular health.

Key Points

  • Normal vascular endothelium produces many molecules with antithrombotic properties, including nitric oxide, prostacyclin, tissue plasminogen activator, thrombomodulin, heparin-like molecules, and tissue factor pathway inhibitor

  • The integrity of the endothelial barrier is conferred by intercellular junction complexes that regulate signal transduction and endothelial permeability

  • Stent implantation causes intravascular injury and endothelial denudation; the regenerated endothelium is incompetent with poorly formed cell junctions, reduced expression of antithrombotic molecules, and decreased nitric oxide production

  • Stent implantation causes local blood flow disturbances associated with complex spatiotemporal changes in shear stress, which can change the endothelium phenotype from quiescent to inflammatory and increase its thrombogenicity

  • The regenerated incompetent endothelium lacks antithrombotic and antiatherogenic properties; this deficiency can lead to late and very late stent thrombosis, as well as the development of in-stent neoatherosclerosis

  • Use of drug-eluting stents is associated with accelerated progression and an increased prevalence of in-stent neoatherosclerosis versus bare-metal stents

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Figure 1: The structure and function of healthy endothelium.
Figure 2: Postulated G-protein-mediated signal transduction process in normal and regenerating endothelial cells.
Figure 3: Radiographs and electron micrographs from a 71-year-old woman who died of stroke.
Figure 4: Transmission electron micrographs of endothelial cell junctions in rabbit iliac arteries 14 days after stent implantation.
Figure 5: Dual immunofluorescence-labelled images showing PECAM-1 (green) and thrombomodulin (red) expression in stented and nonstented segments of rabbit iliac arteries.
Figure 6: Stent-induced flow disturbances affect thrombogenicity and re-endothelialization following stent implantation.
Figure 7: In vitro evaluation of blood flow and endothelialization after stenting.
Figure 8: Neoatherosclerosis following the deployment of bare-metal and drug-eluting stents in human coronary arteries.

Change history

  • 03 April 2013

    In the version of this article originally published online and in print, the following sentence should have been included in the Figure 3 legend: Parts c, e, and h were previously published in Guagliumi, G. et al. Images in cardiovascular medicine. Sirolimus-eluting stent implanted in human coronary artery for 16 months: pathological findings. Circulation 107, 1340–1341 (2003). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

CVPath Institute Inc., Gaithersburg, USA provided full support for this work. F. Otsuka is supported by a research fellowship from the Uehara Memorial Foundation, Tokyo, Japan.

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Authors and Affiliations

  1. CVPath Institute Inc., 19 Firstfield Road, Gaithersburg, 20878, MD, USA

    Fumiyuki Otsuka, Saami K. Yazdani, Masataka Nakano, Frank D. Kolodgie & Renu Virmani

  2. Emory University School of Medicine, 550 Peachtree Street NE, Atlanta, 30322, GA, USA

    Aloke V. Finn

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  1. Fumiyuki Otsuka
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Contributions

F. Otsuka, A. V. Finn, S. K. Yazdani and R. Virmani researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission. M. Nakano and F. D. Kolodgie researched data for the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Renu Virmani.

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Competing interests

A. V. Finn has received grant or research support from Boston Scientific and Medtronic. R. Virmani has been a consultant for Abbott Vascular, Arsenal Medical, Atrium Medical, Biosensors International, GlaxoSmithKline, Lutonix, Medtronic Arterial Vascular Engineering and W. L. Gore. The other authors declare no competing interests.

Supplementary information

Supplementary Figure 1

Histologic sections from a patient with an occluded sirolimus-eluting stent. (DOC 1211 kb)

Supplementary Figure 2

The proposed role of mTOR in vascular repair. (PDF 85 kb)

Supplementary Figure 3

Cumulative incidence of neoatherosclerosis with time after implantation of BMS, PES, and SES. (DOC 173 kb)

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Otsuka, F., Finn, A., Yazdani, S. et al. The importance of the endothelium in atherothrombosis and coronary stenting. Nat Rev Cardiol 9, 439–453 (2012). https://doi.org/10.1038/nrcardio.2012.64

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