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  • Review Article
  • Published:

Molecular, cellular and functional imaging of atherothrombosis

Nature Reviews Drug Discovery volume 3, pages 913–925 (2004)Cite this article

Key Points

  • Atherosclerosis is a systemic disease that is characterized by the build-up of lipid-rich plaques within the walls of large arteries, and underlies the clinical conditions of myocardial infarction, chronic stable angina, stroke and peripheral vascular disease.

  • However, until recently, there has been no effective way to detect the presence of atherosclerosis in patients until it has reached a relatively advanced stage, and so a large window of opportunity for primary prevention through lifestyle modification and drug therapy targeted at individuals with sub-clinical disease is missed.

  • The appreciation that a considerable atherosclerotic burden, including plaques vulnerable to rupture or susceptible to erosion, can be accommodated in the vessel wall without impingement on the lumen has led to a new imperative for direct plaque imaging. In addition, an increasing appreciation of the molecular and cellular events involved in atherothrombosis opens up new vistas for targeted imaging.

  • This article reviews approaches for imaging atherosclerosis, including magnetic resonance imaging and intravascular ultrasound. For both clinical and research applications, imaging techniques allow non-invasive appraisal of disease processes and provide the potential for serial monitoring in the same individual.

  • The careful selection of validated imaging endpoints will allow clinical trials to be conducted more quickly and often with many fewer patients than are required for conventional 'clinical outcome' studies.

Abstract

Recent years have seen a dramatic expansion in our knowledge of the events of atherogenesis and in the availability of drugs that can retard the progression — and even induce the regression — of this disease process. Our understanding has been advanced considerably by developments in genetics and molecular biology and by the use of genetically modified mouse models that have provided key mechanistic insights. Increasingly sophisticated imaging techniques will capitalize on these advances by bringing forward diagnosis, enhancing disease characterization and providing more precise evaluation of the effects of treatment. In this review, techniques for imaging atherosclerosis and thrombosis will be discussed. Particular attention will be given to magnetic resonance imaging techniques that enable lesion characterization and allow the targeted imaging of cells, molecules and biological processes. Emphasis is given to the potential contribution of magnetic resonance imaging methods to therapeutic monitoring, drug delivery and drug discovery.

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Figure 1: Imaging targets in atherothrombosis.
Figure 2: Magnetic resonance imaging of atherosclerosis.
Figure 3: Coronary artery intravascular ultrasound.
Figure 4: Mouse models of atherosclerosis.
Figure 5: Generic model for contrast-targeted imaging.
Figure 6: Examples of targeted imaging using magnetic resonance.
Figure 7: Fluorescence imaging and positron emission tomography.

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Acknowledgements

This work was supported in part by NIH/NHLBI R01 HL071021 (ZAF).

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, University of Oxford, Level 5, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Robin P. Choudhury

  2. The Zena and Michael A. Wiener Cardiovascular Institute. The Marie-Josée and Henry R. Kravis Cardiovascular Health Center. Mount Sinai School of Medicine, One Gustave L. Levy Place, Imaging Science Laboratories, Box 1234, New York, 10029, New York, USA

    Valentin Fuster & Zahi A. Fayad

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Correspondence to Zahi A. Fayad.

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Related links

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DATABASES

Entrez Gene

αvβ3

αIIbβ3

E-selectin

ICAM1

MMP2

myeloperoxidase

thrombin

VCAM1

FURTHER INFORMATION

American Heart Association

Glossary

PLAQUES

Lesions within the wall of a large artery that contain high levels of lipids, lipoproteins, macrophage- derived foam cells, lymphocytes and smooth muscle cells. Advanced lesions can be covered by a fibrous cap that can rupture or erode, leading to thrombosis formation and vessel occlusion.

MYOCARDIAL INFARCTION

Commonly known as a heart attack, this is the death of part of the heart muscle due to sudden loss of blood supply. Typically, the loss of this supply is caused by a complete blockage of a coronary artery by a blood clot.

ECHOGENICITY

The degree to which sound waves are reflected by a tissue (and, by implication, the corresponding brightness on the visual representation).

STENOSIS

The narrowing of a blood vessel, often due to the build-up of plaque.

INTIMA

The innermost layer of arteries.

MEDIA

The middle layer of arteries that lies between the intima and the adventitia and which normally comprises well-ordered layers of smooth muscle cells.

CONTRAST AGENTS

Compounds that enhance the differences between or within tissues in imaging studies and which are often used to highlight abnormalities.

RELAXATION TIMES

In magnetic resonance, after radiofrequency excitation, the return of nuclei to an equilibrium state within the static magnetic field is associated with loss of transverse magnetization (with time constant T2) and return of longitudinal magnetization (with time constant T1).

EXTERNAL ELASTIC LAMINA

Concentric layers of elastic membranes that separate the media from the adventitia in arteries.

STATIN

Drugs in the statin class inhibit a key enzyme in cholesterol biosynthesis — 3-hydroxy-3-methyl-glutaryl-CoA reductase — and reduce plasma levels of low-density lipoprotein cholesterol.

VOXEL

A three-dimensional analogue of a pixel.

Z-STACKS

Three-dimensional constructs made by sequential aggregation of images from spatially adjacent [x,y] planes.

APOLIPOPROTEIN E KNOCKOUT MOUSE

This genetically modified mouse lacks apolipoprotein E, a ligand for low-density-lipoprotein receptors. As a consequence, these mice become hypercholesterolaemic and develop spontaneous atherosclerosis, which has some features in common with the human disease. This mouse had become the pre-eminent animal model for the study of atherosclerosis.

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Choudhury, R., Fuster, V. & Fayad, Z. Molecular, cellular and functional imaging of atherothrombosis. Nat Rev Drug Discov 3, 913–925 (2004). https://doi.org/10.1038/nrd1548

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