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  • Review Article
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Form to function: current and future roles for atherosclerosis imaging in drug development

Nature Reviews Drug Discovery volume 7, pages 517–529 (2008)Cite this article

Key Points

  • The recent failure of novel anti-atherosclerotic therapies in Phase III clinical trials has emphasized the pressing need for robust imaging markers that can reliably assist in the development of drugs for the treatment of atherosclerosis.

  • Conventional methods of imaging atherosclerosis are able to provide quantitative and morphological data, and to date, have principally been used to assess the efficacy of cholesterol-lowering agents.

  • In this article we compare the main imaging modalities used to image atherosclerosis in the clinical trial setting so far, namely quantitative coronary angiography (QCA), carotid intima-media thickness (CIMT), magnetic resonance imaging (MRI), computed tomography (CT) and intravascular ultrasound (IVUS). The ability of these imaging modalities to predict clinical outcomes for a given sample size, and the regulatory considerations pertaining to their use, are also discussed.

  • However, these methods are likely to be inadequate to assess an emerging generation of therapies that modify plaque biology directly. For example, squalene synthase inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitors, and chemokine (C-C motif) receptor 2 (CCR2) antagonists.

  • We outline how emerging molecular and cellular imaging techniques offer the possibility to quantify changes in biological function at the level of the plaque, even without gross structural change. In this regard, two imaging modalities are discussed in detail: MRI and positron-emission tomography (PET).

  • Currently, no single ideal imaging modality exists. In the future, the careful application of imaging biomarkers will be necessary to ensure that new anti-atherosclerosis therapies are evaluated in the most efficient manner possible.

Abstract

There is a pressing need for robust imaging markers to assist in the development of drugs for the treatment of atherosclerosis. Conventional imaging methods provide quantitative and morphological data but may be inadequate for assessing a new generation of therapies that modify plaque biology directly. Here, we compare the main imaging modalities used to image atherosclerosis in the clinical-trial setting, and assess their ability to predict clinical outcomes for a given sample size. We consider how emerging molecular and cellular imaging techniques could offer the possibility to quantify changes in biological function at the level of the plaque, even without gross structural change.

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Figure 1: Techniques currently in use to image atherosclerosis in carotid and coronary arteries.
Figure 2: Schematic representation of information obtained from individual imaging modalities highlighting the different plaque components that can be visualized by each.
Figure 3: Emerging imaging techniques.
Figure 4: Illustration of processes of atherogenesis ranging from prelesional endothelial dysfunction (left) through monocyte recruitment to the development of complicated plaques complicated by thrombosis (right).
Figure 5: Targets for novel anti-atherosclerotic therapies.

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Acknowledgements

Work in this laboratory is funded by the Wellcome Trust and the British Heart Foundation.

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Authors and Affiliations

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

    Alistair C. Lindsay & Robin P. Choudhury

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  1. Alistair C. Lindsay
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  2. Robin P. Choudhury
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Correspondence to Robin P. Choudhury.

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Competing interests

R.P.C. has received research funding from GlaxoSmithKline and Merck (Darmstadt) for work involving atherosclerosis imaging with MRI. He has received travel awards/honoraria/speaker fees from or served as a consultant or on advisory boards to Merck, Sanofi Aventis, AstraZeneca, GlaxoSmithKline, Schering–Plough, Solvay Healthcare and Pfizer. R.P.C.'s work is supported by the Oxford Biomedical Research Centre, NIHR funding scheme.

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FURTHER INFORMATION

Atherosclerosis Risk in Communities (ARIC) MRI Study

European Medicines Agency Committee for Medicinal Products for Human Use

US FDA Medical Imaging and Drug Development

Glossary

B-mode (2-dimensional) ultrasound

A linear array of ultrasound transducers used to scan planes of the body to obtain a two-dimensional image.

Acoustic shadow

An area through which ultrasound waves fail to propagate, most often due to obstruction by calcification, leading to loss of signal.

Echogenicity

The ability to create a signal detectable by ultrasound.

Integrated backscatter

A measure of the mean reflected ultrasonic energy from a particular region of tissue.

Balloon angioplasty

A percutaneous procedure whereby a small balloon is inflated inside a tightly narrowed artery in order to relieve the obstruction.

Stent

A rigid wire mesh inserted into a narrowed artery and expanded by balloon angioplasty to hold the artery open.

Elastography

A method of assessing the integrity of a tissue by measuring its biomechanical properties, such as its stiffness or its response to strain.

OCT Doppler

The use of optical coherence tomography (OCT) to estimate blood flow using the Doppler effect.

Polarization-sensitive OCT

The use of optical coherence tomography (OCT) to measure tissue birefringence and estimate plaque collagen content.

Carotid endarterectomy

A surgical procedure involving the removal of the core of plaques in the severely diseased or symptomatic artery in the neck.

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Lindsay, A., Choudhury, R. Form to function: current and future roles for atherosclerosis imaging in drug development. Nat Rev Drug Discov 7, 517–529 (2008). https://doi.org/10.1038/nrd2588

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