Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Biomarkers

Application of intravascular ultrasound in anti-atherosclerotic drug development

Nature Reviews Drug Discovery volume 5, pages 485–492 (2006)Cite this article

Key Points

  • Despite major advances in diagnosis and treatment, such as the introduction of the statins, cardiovascular disease remains the leading cause of death in most Western countries and is rapidly emerging in the developing world.

  • Statins were initially approved on the basis of their ability to reduce levels of low-density lipoprotein (LDL) cholesterol, a biomarker of cardiovascular disease, and it was not until several years later that their ability to reduce morbidity and mortality was demonstrated.

  • The two extremes in anti-atherosclerotic drug development — use of a simple biomarker, such as LDL cholesterol, or conducting large and expensive morbidity/mortality trials — leave considerable room for intermediate endpoints.

  • Drug development teams need methods that enable the robust demonstration of anti-atherosclerotic drug efficacy via trials of a few hundred patients with relatively short follow-up before launching large morbidity/mortality trials. Atherosclerosis imaging fulfills many of these requirements, and is rapidly emerging as the most reasonable and appealing approach.

  • As discussed in this article, intravascular ultrasound (IVUS) is an imaging technology that can provide an accurate assessment of atheroma accumulation within the arterial wall. It can be used in the serial assessment of atheroma burden in response to a range of therapeutic strategies, and consequently is now a key technology in the evaluation and approval of novel drugs.

Abstract

The background use of a number of established therapies presents a key challenge for the development of novel anti-atherosclerotic agents: how to predict potential efficacy before the completion of long-term trials with endpoints such as mortality. This challenge has stimulated the search to develop intermediate measures of efficacy. Recent advances now allow intravascular ultrasound (IVUS) to provide an accurate assessment of atheroma accumulation within the arterial wall. Here we describe how IVUS can be applied to the serial assessment of atheroma burden in response to treatment with a range of anti-atherosclerotic strategies, which has resulted in its emergence as a key technology in the evaluation and approval of novel drugs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation of images by intravascular ultrasound.
Figure 2: Images from intravascular ultrasound.
Figure 3: Plaque progression and regression assessed by intravascular ultrasound.
Figure 4: Artefacts that can limit the quality of images from intravascular ultrasound.

Similar content being viewed by others

References

  1. Brown, M. S. & Goldstein, J. L. Heart attacks: gone with the century? Science 272, 629 (1996).

    Article  CAS  Google Scholar 

  2. Libby, P. The forgotten majority: unfinished business in cardiovascular risk reduction. J. Am. Coll. Cardiol. 46, 1225–1228 (2005).

    Article  Google Scholar 

  3. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).

  4. Pitt, B. et al. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation. J. Am. Coll. Cardiol. 26, 1133–1139 (1995).

    Article  CAS  Google Scholar 

  5. Jukema, J. W. et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 91, 2528–2540 (1995).

    Article  CAS  Google Scholar 

  6. Blankenhorn, D. H. et al. Coronary angiographic changes with lovastatin therapy. The Monitored Athero-sclerosis Regression Study (MARS). The MARS Research Group. Ann. Intern. Med. 119, 969–976 (1993).

    Article  CAS  Google Scholar 

  7. Arntz, H. R. et al. Beneficial effects of pravastatin (+/−colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study). Am. J. Cardiol. 86, 1293–1298 (2000).

    Article  CAS  Google Scholar 

  8. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 344, 633–638 (1994).

  9. Topol, E. J. & Nissen, S. E. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 92, 2333–2342 (1995).

    Article  CAS  Google Scholar 

  10. Glagov, S., Weisenberg, E., Zarins, C. K., Stankunavicius, R. & Kolettis, G. J. Compensatory enlargement of human atherosclerotic coronary arteries. N. Engl. J. Med. 316, 1371–1375 (1987).

    Article  CAS  Google Scholar 

  11. Mintz, G. S. et al. Atherosclerosis in angiographically 'normal' coronary artery reference segments: an intravascular ultrasound study with clinical correlations. J. Am. Coll. Cardiol. 25, 1479–1485 (1995).

    Article  CAS  Google Scholar 

  12. Schoenhagen, P., Ziada, K. M., Vince, D. G., Nissen, S. E. & Tuzcu, E. M. Arterial remodeling and coronary artery disease: the concept of 'dilated' versus 'obstructive' coronary atherosclerosis. J. Am. Coll. Cardiol. 38, 297–306 (2001).

    Article  CAS  Google Scholar 

  13. Schoenhagen, P. et al. Association of arterial expansion (expansive remodeling) of bifurcation lesions determined by intravascular ultrasonography with unstable clinical presentation. Am. J. Cardiol. 88, 785–787 (2001).

    Article  CAS  Google Scholar 

  14. Tuzcu, E. M. et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation 103, 2705–2710 (2001).

    Article  CAS  Google Scholar 

  15. Nissen, S. E. et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 291, 1071–1080 (2004).

    Article  CAS  Google Scholar 

  16. Nissen, S. E. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290, 2292–2300 (2003).

    Article  CAS  Google Scholar 

  17. Nissen, S. E. et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 292, 2217–2225 (2004).

    Article  CAS  Google Scholar 

  18. Mintz, G. S. et al. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J. Am. Coll. Cardiol. 37, 1478–1492 (2001).

    Article  CAS  Google Scholar 

  19. Guedes, A. et al. Long-term safety of intravascular ultrasound in nontransplant, nonintervened, atherosclerotic coronary arteries. J. Am. Coll. Cardiol. 45, 559–564 (2005).

    Article  Google Scholar 

  20. Ramasubbu, K. et al. Repeated intravascular ultrasound imaging in cardiac transplant recipients does not accelerate transplant coronary artery disease. J. Am. Coll. Cardiol. 41, 1739–1743 (2003).

    Article  Google Scholar 

  21. Jensen, L. O., Thayssen, P., Pedersen, K. E., Stender, S. & Haghfelt, T. Regression of coronary atherosclerosis by simvastatin: a serial intravascular ultrasound study. Circulation 110, 265–270 (2004).

    Article  CAS  Google Scholar 

  22. Okazaki, S. et al. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation 110, 1061–1068 (2004).

    Article  CAS  Google Scholar 

  23. Nissen, S. E. et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N. Engl. J. Med. 352, 29–38 (2005).

    Article  CAS  Google Scholar 

  24. Cannon, C. P. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 1495–1504 (2004).

    Article  CAS  Google Scholar 

  25. Ridker, P. M. et al. C-reactive protein levels and outcomes after statin therapy. N. Engl. J. Med. 352, 20–28 (2005).

    Article  CAS  Google Scholar 

  26. Nissen, S. E. et al. Very high-intensity statin therapy and coronary atherosclerosis: the ASTEROID Trial JAMA 2006 Mar 13 [epub ahead of print].

  27. Badimon, J. J., Badimon, L. & Fuster, V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J. Clin. Invest. 85, 1234–1241 (1990).

    Article  CAS  Google Scholar 

  28. Chiesa, G. et al. Recombinant apolipoprotein A-IMilano infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ. Res. 90, 974–980 (2002).

    Article  CAS  Google Scholar 

  29. Nicholls, S. J. et al. Reconstituted high density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation 111, 1543–1550 (2005).

    Article  CAS  Google Scholar 

  30. Shah, P. K. et al. High-dose recombinant apolipoprotein A-IMilano mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein E-deficient mice. Circulation 103, 3047–3050 (2001).

    Article  CAS  Google Scholar 

  31. Brown, B. G. et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N. Engl. J. Med. 345, 1583–1592 (2001).

    Article  CAS  Google Scholar 

  32. Taylor, A. J., Sullenberger, L. E., Lee, H. J., Lee, J. K. & Grace, K. A. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 110, 3512–3517 (2004).

    Article  CAS  Google Scholar 

  33. Nissen, S. E. et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N. Engl. J. Med. 354, 1253–1263 (2006).

    Article  CAS  Google Scholar 

  34. Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366, 1279–1289 (2005).

    Article  CAS  Google Scholar 

  35. Tuzcu, E. M. et al. Intravascular ultrasound evidence of angiographically silent progression in coronary atherosclerosis predicts long-term morbidity and mortality after cardiac transplantation. J. Am. Coll. Cardiol. 45, 1538–1542 (2005).

    Article  Google Scholar 

  36. Eisen, H. J. et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N. Engl. J. Med. 349, 847–858 (2003).

    Article  CAS  Google Scholar 

  37. Chambless, L. E. et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am. J. Epidemiol. 146, 483–494 (1997).

    Article  CAS  Google Scholar 

  38. Hodis, H. N. et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann. Intern. Med. 128, 262–269 (1998).

    Article  CAS  Google Scholar 

  39. Taylor, A. J. et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 106, 2055–2060 (2002).

    Article  CAS  Google Scholar 

  40. Greenland, P., LaBree, L., Azen, S. P., Doherty, T. M. & Detrano, R. C. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA 291, 210–215 (2004).

    Article  CAS  Google Scholar 

  41. Achenbach, S. et al. Detection of coronary artery stenoses using multi-detector CT with 16x0.75 collimation and 375 ms rotation. Eur. Heart J. 26, 1978–1986 (2005).

    Article  Google Scholar 

  42. Salm, L. P. et al. Comprehensive assessment of patients after coronary artery bypass grafting by 16-detector-row computed tomography. Am. Heart J. 150, 775–781 (2005).

    Article  Google Scholar 

  43. Worthley, S. G. et al. Noninvasive in vivo magnetic resonance imaging of experimental coronary artery lesions in a porcine model. Circulation 101, 2956–2961 (2000).

    Article  CAS  Google Scholar 

  44. Fayad, Z. A. et al. In vivo magnetic resonance evaluation of atherosclerotic plaques in the human thoracic aorta: a comparison with transesophageal echocardiography. Circulation 101, 2503–2509 (2000).

    Article  CAS  Google Scholar 

  45. Corti, R. et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 106, 2884–2887 (2002).

    Article  CAS  Google Scholar 

  46. Lima, J. A. et al. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation 110, 2336–2341 (2004).

    Article  CAS  Google Scholar 

  47. Yonemura, A. et al. Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques detected by noninvasive magnetic resonance imaging. J. Am. Coll. Cardiol. 45, 733–742 (2005).

    Article  CAS  Google Scholar 

  48. Corti, R. et al. The selective peroxisomal proliferator-activated receptor-g agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging. J. Am. Coll. Cardiol. 43, 464–473 (2004).

    Article  CAS  Google Scholar 

  49. Worthley, S. G. et al. A novel nonobstructive intravascular MRI coil: in vivo imaging of experimental atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 23, 346–350 (2003).

    Article  CAS  Google Scholar 

  50. Nair, A. et al. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 106, 2200–2206 (2002).

    Article  Google Scholar 

  51. Baldewsing, R. A. et al. Intravascular ultrasound elastography: a clinician's tool for assessing vulnerability and material composition of plaques. Stud. Health Technol. Inform. 113, 75–96 (2005).

    PubMed  Google Scholar 

Download references

Acknowledgements

We thank the technical expertise of the members of the Intravascular Ultrasound Core Laboratory of the Cleveland Clinic. S.J.N. is supported by a Ralph Reader Overseas Research Fellowship of the National Heart Foundation of Australia.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, 44195, Ohio, USA

    Stephen J. Nicholls, Ilke Sipahi, Paul Schoenhagen, Tim Crowe, E. Murat Tuzcu & Steven E. Nissen

Authors
  1. Stephen J. Nicholls
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilke Sipahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Schoenhagen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tim Crowe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. Murat Tuzcu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Steven E. Nissen
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

S.J.N., E.M.T. and S.E.N. have received honoraria from Pfizer, Inc. E.M.T. and S.E.N. receive research support from Pfizer, Inc. I.S. receives other funding from Pfizer, Inc.

Related links

Related links

DATABASES

OMIM

Type 2 diabetes

FURTHER INFORMATION

American College of Cardiology

European Society of Cardiology

Glossary

Biomarker

A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.

Lumen

The space inside the blood vessel through which blood flows.

Glagov hypothesis

The proposal that in the early stages of plaque accumulation, the outer wall of the blood vessel expands or remodels, tending to preserve lumen dimensions.

Plaques

Lesions within the wall of a large artery that contain high levels of lipids, lipoproteins, foam cells, lymphocytes and smooth muscle cells. Advanced lesions are covered with a fibrous cap that can rupture and cause arterial blockage.

Simpson's rule

A mathematical formula that allows for integration of area measurements to derive an estimation of volume.

C-reactive protein

A peptide secreted in the setting of inflammatory states. High levels are predictive of the extent of coronary artery disease and clinical outcome.

Foam cell

Macrophages in the arterial wall that ingest oxidized LDL and assume a foamy appearance. These cells secrete various substances involved in further plaque growth.

Calcification

Presence of calcium within the arterial wall.

Side-branch ostia

Entrance of small side branches off an artery.

Non-uniform rotational deformity

(NURD). The result of rhythmical changes in rotational velocity due to frictional drag on transducer rotation. Even mild forms of NURD can result in elliptical images that decrease the accuracy of measurements.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nicholls, S., Sipahi, I., Schoenhagen, P. et al. Application of intravascular ultrasound in anti-atherosclerotic drug development. Nat Rev Drug Discov 5, 485–492 (2006). https://doi.org/10.1038/nrd2040

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2040

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing