Trends in Cardiovascular Medicine
Volume 15, Issue 1 , Pages 17-24, January 2005

Imaging of Atherosclerosis — Can We Predict Plaque Rupture?

  • James H.F. Rudd
    • ,
  • John R. Davies
    • ,
  • Peter L. Weissberg

      Affiliations

    • Corresponding Author InformationAddress correspondence to: Peter Weissberg, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Box 110, Level 6, ACCI Building, Hills Road, Cambridge CB2 2QQ, United Kingdom. Tel.: (+00 44) 1223-331504; fax: (+00 44) 1223-331505.

James H.F. Rudd, John R. Davies, and Peter L. Weissberg are at the Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom

Article Outline

Rupture of so-called vulnerable or unstable atherosclerotic lesions is responsible for a significant proportion of myocardial infarcts and strokes. However, timely identification of such plaques, in order to allow for aggressive local and systemic therapy, remains problematic. In order to address this problem, there is a need to develop techniques that can image the cellular, biochemical, and molecular components that typify the vulnerable plaque. In this article, both techniques that are in current clinical use and those being evaluated in clinical trials are reviewed with regard to their ability to identify unstable lesions at risk of rupture. Trends Cardiovasc Med 2004;15: - )

 

Atherosclerosis affects medium- and large-sized arteries and is characterized by thickening of the arterial intima due to gradual lipid accumulation. The typical lesion, often referred to as the plaque, is composed of a lipid core with an overlying fibrous cap (Figure 1).

The majority of atherosclerotic plaques remain asymptomatic. Others cause clinical syndromes in one of two ways. A plaque may gradually narrow the vessel lumen, resulting in a reduction in blood flow reserve that precipitates symptoms of ischemia during periods of high oxygen demand. An example of this is the coronary plaque that causes angina during physical exertion that is rapidly relieved by rest. Alternatively, the fibrous cap of a plaque may suddenly erode or rupture, resulting in the formation of a thrombus that may partially or totally occlude flow. Although such events can be clinically silent, they are often life threatening, as in myocardial infarction or stroke.

Whether and how a plaque becomes symptomatic is determined by its macroscopic structure and its microscopic composition. Plaques that cause chronic symptoms of reversible ischemia are characterized by a thick fibrous cap with an abundance of vascular smooth muscle cells and a lipid core that typically represents less than half the plaque volume. Inflammatory cells such as the macrophage and the T lymphocyte are present only in low numbers. These plaques are typically described as stable (Davies 1996). In contrast, plaques that precipitate acute thrombotic events are characterized by a thin fibrous cap with few smooth muscle cells and a heavy infiltrate of inflammatory cells (principally macrophages), with a lipid core that accounts for more than half the volume of the plaque. Such lesions—usually referred to as unstable, vulnerable, or high-risk plaques—can be very small and therefore asymptomatic up to the point of the thrombotic event (Davies 1996). Figure 2 illustrates the contrasting features of stable and unstable plaque.

It has recently been recognized that vulnerable plaques do not occur in isolation, so that patients presenting with plaque rupture have a high risk of a subsequent fatal or nonfatal episode when compared with those who present with symptoms of stable, reversible ischemia (Golledge et al., 2000, Walter et al., 2002). Thus, it has become an important clinical goal to rapidly identify those with potentially unstable plaques who are at high risk of clinical syndromes. The development of imaging techniques that can differentiate between unstable and stable lesions in vivo would enable the clinician to target both local and systemic therapies appropriately.

Because of the vessel's ability to adapt to the presence of an atherosclerotic plaque by positive remodeling—a process in which the vessel dilates to accommodate the plaque without narrowing the lumen (Glagov et al. 1987)—there is no clear relationship between degree of luminal stenosis and risk of fibrous cap disruption.

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Imaging of atherosclerosis: The essential objectives 

The perfect imaging technique would be noninvasive, cheap, and safe. It would identify all plaques, regardless of their impact on vessel lumen, and would characterize plaque structure as well as inflammatory cell content. Needless to say, no such technique exists. This article reviews existing and emerging techniques for imaging atherosclerosis in the context of these exacting criteria.

Invasive techniques 

Angiography 

For the past 60 years, x-ray contrast angiography has been the universally accepted, gold-standard modality for imaging the vascular tree. Importantly, however, it does not provide any information about the vessel wall. The presence or absence of atherosclerosis is judged according to whether or not there is luminal narrowing. Thus, it fails to identify plaques in remodeled vessels. This is an important limitation because flow-limiting stenoses are present only in 30% to 40% of cases of myocardial infarction (Ambrose et al., 1988, Little et al., 1988).

Although angiography is an excellent technique for the high-resolution definition of the site and severity of symptomatic arterial stenoses, it cannot distinguish stable from unstable lesions. Furthermore, because x-ray angiography is invasive and uses ionizing radiation, it is therefore unsuitable for serial monitoring of asymptomatic patients. Some of these safety issues can be overcome by using noninvasive angiographic techniques such as computed tomography (CT) and, particularly, magnetic resonance imaging. However, all angiographic techniques suffer from the same fundamental limitation: they do not image the vessel wall.

Angiography therefore falls far short of fulfilling the criteria for the perfect imaging method to diagnose and monitor atherosclerosis. Nevertheless, it will continue to be used to guide intervention (angioplasty or bypass surgery) for symptomatic lesions for the foreseeable future.

Intravascular ultrasound 

An intravascular ultrasound (IVUS) study requires a miniature ultrasound probe to be introduced into the vessel of interest by means of an intravascular catheter. The technique provides a 360-degree, cross-sectional image of the vessel lumen and the vessel wall at the site of the probe. Therefore, unlike angiography, it can identify nonstenotic atherosclerotic lesions (Figure 3). Furthermore, it can differentiate different components of the vessel wall—such as the lipid core, fibrous cap, surface thrombus, intraplaque hemorrhage, and calcification—because of their differences in acoustic impedance (Nissen and Yock 2001). However, the acoustic impedance of calcium is so high that full characterization of calcified plaques is frequently impossible.

By imaging during gradual withdrawal of the probe along a length of vessel, a complete image of one or several atherosclerotic lesions can be obtained. Studies using IVUS to compare lesions in patients who have stable angina with those who have acute coronary syndromes have found a higher percentage of ruptured caps, larger lipid cores, and thinner fibrous caps in the latter group of patients (Ge et al. 1999). IVUS therefore has clear advantages over angiography for the detection of unstable lesions. Recently, spectral analysis of radiofrequency signals generated during an IVUS study have allowed for better characterization of different plaque components in real time (Nair et al. 2002).

Although IVUS does provide some of the information required to characterize individual plaques, it provides no information on plaque inflammatory cell content. There have been no large-scale, prospective studies on the effectiveness of IVUS to predict plaque rupture events. Because IVUS is costly and invasive, its use is currently confined to symptomatic patients undergoing angiography or an intervention in which it can aid in the selection of the most appropriate transcatheter therapy (Fayad and Fuster 2001). IVUS has also been used to monitor the effects of plaque stabilizing drugs, such as statins, on atheroma progression (Nissen et al. 2004). Although IVUS does not satisfy the criteria for the perfect imaging method, it provides valuable information on the natural history of atherosclerotic lesions, and how vessels adapt to the presence of atherosclerotic lesions that is not available from angiography.

Thermography 

Thermography involves the introduction of a temperature-sensitive thermistor mounted on an intravascular catheter into the lumen of an artery in order to detect small changes in artery wall temperature associated with atherosclerotic plaques (Stefanadis et al. 1999).

Ex vivo studies of carotid atherosclerotic plaques showed that the heat emitted from a plaque was proportional to macrophage density, a finding that has been confirmed in vivo (Casscells et al., 1996, Verheye et al., 2002). Therefore, measurable local increases in temperature are thought to reflect discrete areas of inflammation.

Clinical studies have shown that thermography can distinguish between normal coronary arteries, in which no difference between background (blood) and vessel wall temperature was found, and atherosclerotic coronary arteries, in which considerable temperature heterogeneity was documented (Stefanadis et al. 1999). The same study found that temperature heterogeneity was more profound in patients with unstable angina and acute myocardial infarction than in those with stable angina. Further work by the same investigators highlighted the ability of thermography to predict clinical events in a group of patients undergoing percutaneous intervention (Stefanadis et al. 2001). The potential usefulness of thermography to detect changes in inflammation has also been demonstrated by a study showing a reduction in thermal heterogeneity in patients treated with statins (Stefanadis et al. 2002).

Thermography, therefore, seems to have the potential to identify plaque inflammation. However, it provides no information on plaque size, site, or ultrastructure, and has to be combined with another imaging modality, such as angiography or IVUS, to identify lesions and guide placement of the thermistor. Consequently, it is likely to remain a research tool rather than a routine method for the investigation of atherosclerosis.

Spectroscopy 

Intravascular, catheter-based spectroscopy relies on the evaluation of electromagnetic emissions from a plaque excited by near infrared spectroscopy (NIRS), or laser light (Raman spectroscopy). Theoretically, the various components of plaque emit unique spectra that can be used to characterize its chemical composition. Both techniques are highly specific for differentiating calcified from lipid-rich plaque (Brennan et al. 1997), but differ in their respective tissue penetration (2 mm vs 0.3 mm, NIRS vs Raman). As with thermography, spectroscopy is invasive and must be combined with another imaging technique (such as IVUS) to yield functional and structural information on the same plaque (Romer et al. 2000). It is therefore likely to remain a research technique, rather than find a place in routine clinical practice.

Optical coherence tomography 

This catheter-based technique subjects the vessel wall to an infrared source and analyzes the returning optical echoes. It has the highest resolution of any intravascular imaging modality (5 μm), and therefore reliably differentiates various plaque components (Yabushita et al. 2002) and can quantify fibrous cap thickness (Brezinski et al. 1996). However, data acquisition is limited by signal interference from flowing blood within the artery. Like spectroscopy, optical coherence tomography is likely to remain a research tool for the foreseeable future.

Noninvasive techniques 

Noninvasive techniques have lower complication rates than do their invasive counterparts and are more acceptable to both patients and doctors. Noninvasive imaging, therefore, has greater potential for both screening of high-risk patients and for long-term follow-up studies. Coronary arteries, however, because of their relatively small size, their position deep within the thorax, and the rapid and complex motion of the heart, remain a challenge for noninvasive techniques.

Surface (transvascular) ultrasound 

Surface ultrasound is capable of imaging the vessel wall and lumen, as well as estimating the degree of luminal stenosis by measuring blood flow velocity. Surface ultrasound is used mainly to image accessible large arteries, such as the carotid, aorta, and lower limb arteries where the ultrasound probe can be placed directly over the site of interest. Unfortunately, transthoracic coronary imaging is not feasible. Accurate measurement of the thickness of the artery wall, intima-media thickness (IMT), and limited characterization of plaque morphology can be carried out with high-resolution surface B-mode ultrasound. The echogenicity of the plaque reflects its underlying composition, with a hypoechoic appearance on ultrasound being associated with the presence of lipids and hemorrhage, whereas a hyperechoic image suggests an underlying fibrous or calcified plaque (Figure 4). However, when compared with its invasive counterpart, IVUS, B-mode ultrasound has a much lower signal-to-noise ratio, such that it is often impossible to delineate the features of a lesion.

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  • Figure 4. 

    Surface ultrasound images of carotid atheroma. (A) Lipid-rich, soft plaque (arrow). (B) Calcified plaque (arrow) resulting in an acoustic shadow below the lesion (arrowhead).

In patients with carotid disease who have suffered a stroke, both the North American Symptomatic Carotid Endarterectomy Trial and Asymptomatic Carotid Atherosclerosis Study trials have shown that the degree of stenosis and its hemodynamic consequences, as measured by B-mode ultrasound, are predictive of subsequent events (Barnett et al., 1998, ECST Group, 1998). Also, measurements of carotid IMT can predict stroke risk (Hollander et al. 2003) and extent of coronary atherosclerosis (O'Leary et al. 1999). Consequently, B-mode ultrasound has become the first-line investigation for patients with suspected carotid artery disease.

The great advantage of B-mode ultrasound is its widespread availability, low cost, lack of side effects, and short examination time. However, data acquisition is operator dependent and experience varies between centres. Most importantly, however, it is questionable whether B-mode ultrasound can delineate plaque composition sufficiently to predict outcome in individual lesions, and the technique cannot be applied to the coronary circulation.

CT 

Two different CT techniques have been developed specifically to image the coronary arteries. Both use very fast data acquisition, which minimizes movement artefact.

Electron beam CT 

Electron beam CT (EBCT) uses a beam of electrons to produce an image with an acquisition time of only 100 msec per slice. With electrocardiogram triggering, the heart can therefore be imaged during diastole when it is relatively still. Another major strength of EBCT is that it can detect and quantify vessel wall calcification. Calcification is an almost universal component of all but the earliest atherosclerotic lesions. Consequently, high calcium scores are predictive of advanced atherosclerosis, with low scores virtually excluding the likelihood of obstructive coronary disease. Increasingly, EBCT is being used as a screening test for the presence of coronary atheroma and as a noninvasive alternative to x-ray angiography to confirm or refute the diagnosis of coronary disease in patients with atypical symptoms or equivocal evidence for reversible ischemia. Disappointingly, EBCT does not discriminate other components of the atherosclerotic plaque. Also, some high-risk plaques may lack measurable amounts of calcium. Consequently, the ability of EBCT to predict risk of coronary events is somewhat debatable (Schmermund and Erbel 2001), and its uptake has been limited by the small number of scanners worldwide.

Multislice CT 

Multislice CT (MSCT) has been developed from traditional single-slice helical CT. It relies on the use of a rotating x-ray source, a rotating gantry, up to 256 rows of detectors, and the injection of contrast to differentiate vessel lumen from wall. This arrangement produces images that have a significantly higher resolution than does EBCT, but at a cost of more ionizing radiation per scan (9 millisiverts vs 1.5 millisiverts for EBCT). MSCT can detect plaque calcium in the coronary arteries as efficiently as does EBCT (Becker et al. 2001), but can give additional information about plaque components on the basis of their differing intensity expressed in Hounsfield units (Schroeder et al. 2001). Thus, plaques can be classified as soft (lipid rich), intermediate, or calcified (Figure 5). MSCT therefore has the ability to identify stenotic and nonstenotic plaque, provides some plaque characterization, and assesses luminal stenosis at the expense of a high radiation dose. With modern MSCT machines, noninvasive coronary angiography is becoming a reality (Figure 6); however, imaging of distal coronary artery segments is problematic. With further advances in scanning technology, however, this is likely to be overcome, and MSCT is likely to become the coronary imaging modality of the future, because it offers the potential to combine noninvasive angiography with some degree of individual plaque characterization.

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  • Figure 5. 

    Combined multislice computed tomography (MSCT) (left) and intravascular ultrasound (IVUS) (right) study illustrating differing characteristics of (A) soft, lipid-rich plaque; (B) calcified plaque; and (C) intermediate plaque. In each image, the plaque is marked by the arrow. Note that the IVUS image in (A) is taken in a longitudinal orientation. AO, aorta; LAD, left anterior descending coronary artery; PT, pulmonary trunk. (Reprinted from Journal of the American College of Cardiology, 37, S Schroeder, AF Kopp, A Baumbach, et al., Noninvasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography, 1430–1435. Copyright 2001 with permission from the American College of Cardiology Foundation.)

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  • Figure 6. 

    Conventional selective coronary angiographic image in right anterior oblique projection (A); transverse, nonenhanced, four-detector row computed tomography (CT) image (B); and contrast-enhanced, four-detector row CT coronary angiographic image in transverse maximum intensity projection (C) in a patient with hemodynamically significant stenosis of the left main coronary artery. With conventional angiography, evaluation is restricted to assessment of the presence and degree of coronary artery stenosis (arrow in A). The cross-sectional nature of high-spatial-resolution multidetector row CT enables noninvasive evaluation of a soft-tissue-attenuation wall lesion (arrow in C) in posterior circumference of the left main coronary artery and demonstrates absence of macrocalcifications by means of nonenhanced CT (B). (Reprinted with permission from Schoepf et al. 2004, p. 18–37. Copyright 2004, Radiological Society of North America.)

Magnetic resonance 

For a magnetic resonance (MR) study, the patient is subjected to a high-strength magnetic field, usually 1.5 Tesla but increasingly greater, which aligns the protons in the plaque in the direction of the field. A radiofrequency pulse then excites these protons, and receiver coils detect the radiofrequencies emitted as they relax back toward baseline. Detected signals are influenced by the relaxation times (called T1 and T2), proton density, motion and flow, molecular diffusion, and magnetization transfer. Three additional gradient magnetic fields applied during scanning allow for selection of the slice and spatial information within it. The timing of the excitation pulses and the successive magnetic field gradients determine the image contrast.

By imaging the vessel wall directly, high-resolution MR can differentiate components of both stenotic and nonstenotic plaques on the basis of differing biophysical and biochemical parameters, including physical state, chemical composition and concentration, and water content. MR has the huge advantage that it does not involve ionizing radiation, and studies can therefore be repeated to monitor the progression and regression of disease. Fayad and his group have performed much of the experimental work that has validated the technique for atherosclerotic plaque imaging, and have confirmed that the physical components of the atherosclerotic plaque can be distinguished from one another on the basis of their MR relaxation times (Fayad and Fuster 2000).

Advances in both hardware and software have allowed for rapid development of in vivo MR imaging of atherosclerosis in humans. High-resolution carotid artery imaging can determine plaque volume and assess plaque microstructure, including the state of the fibrous cap (Yuan et al., 2001, Yuan et al., 2002b). In addition, plaque progression can be monitored with serial imaging (Corti et al. 2001). Even new blood vessel formation within advanced plaque has been imaged successfully with the use of a combination of noncontrast and gadolinium-enhanced MR (Yuan et al. 2002a). Prospective studies are now required to determine whether these features enable MR to predict future carotid territory ischemic events.

Other vascular beds have been imaged with MR, including peripheral arteries, on which vessel remodeling after balloon angioplasty was accurately documented (Coulden et al. 2000). Imaging of the coronary arteries with MR presents a special challenge for investigators; their deep location, small caliber, and susceptibility to respiratory and cardiac motion artefacts mean that the most useful images have been obtained using an MR coil embedded in a transoesophageal probe, although investigators are having increasing success using surface coils (Fayad and Fuster, 2000, Fayad and Fuster, 2001). Currently, research is being directed toward the use of MR contrast agents, such as ultrasmall particles of iron oxide that are engulfed by macrophages within the plaque, thus allowing for macrophage imaging (Kooi et al. 2003). It is anticipated that this technique might allow for targeted imaging of high-risk plaques using MR.

As with CT, the ability of MR to image the microstructure of small plaques within the coronary vasculature is currently limited. To date, there have been no large-scale studies to validate the ability of MR to predict adverse plaque events and thus allow for targeted localized therapy.

Nuclear imaging 

Many radiotracers, targeted against molecules and cells involved in atherosclerosis, have been evaluated as potential candidates for imaging by using single photon emission CT (SPECT). These have included lipoproteins, macrophages, vascular smooth muscle cells, and endothelial cell adhesion molecules (Vallabhajosula and Fuster 1997). They have met with limited success, however, because although they all accumulated to some extent in atherosclerosis, the target to background ratios were poor as a result of slow blood tracer clearance.

In an attempt to overcome this problem, nuclear agents with a faster clearance rate from blood have been tested. One example is SPECT imaging using a radiolabeled antibody to the platelet glycoprotein IIb/IIIa receptor in order to image platelet-rich thrombus on the surface of vulnerable plaque. This method has shown promise in identifying thrombus within canine coronary arteries (Vallabhajosula and Fuster 1997), but studies have thus far not been carried out in humans.

More recently, the capability of positron emission tomography (PET) to image and quantify macrophage activity within the atherosclerotic plaque has been evaluated, in an attempt to relate this to plaque instability. PET is a nuclear imaging technique that uses positron-emitting radionuclides, as opposed to the γ-emitting radionuclides used in SPECT. When compared with SPECT, PET is far superior in terms of image resolution (5 mm vs. 15 mm) and sensitivity, thus making PET the more attractive modality for imaging small objects such as the atheromatous plaque.

The only atheroma-imaging PET studies published to date have all used the fluorine-18-labelled glucose analogue fluorodeoxyglucose (FDG) to image and, in some cases, quantify metabolic activity within the plaque. When FDG-PET was used to study patients with symptomatic carotid artery disease, it was found that unstable plaques accumulated significantly more FDG than did their contralateral stable counterparts (Rudd et al. 2002). Ex vivo evaluation of carotid endarterectomy specimens revealed that deoxyglucose was taken up predominantly by macrophages within the plaque, making FDG-PET a suitable candidate for assessing plaque vulnerability. Others have since noted similar findings in patients with atheroma undergoing FDG-PET imaging for cancer staging (Tatsumi et al. 2003). These studies provide promising evidence that individual plaque inflammation can be quantified.

Although FDG-PET is the first noninvasive imaging technique to quantify macrophage activity within the plaque, further studies need to be carried out to define its sensitivity and specificity for detecting unstable lesions. Correlation of FDG uptake with future risk of plaque rupture and clinical events is also necessary before it can become a clinical tool.

Unfortunately, FDG is taken up into other metabolically active tissues, not the least the myocardium, a problem that currently excludes its use for imaging of coronary atherosclerosis. The other major disadvantages of FDG-PET are radiation dose, high cost, limited availability, and the lack of anatomic detail. The latter problem has been overcome by combining an anatomic imaging technique such as CT or MR with the functional imaging obtained by FDG-PET (Figure 7).

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  • Figure 7. 

    Combined magnetic resonance (MR)/fluorodeoxyglucose positron emission tomography (FDG-PET) study in a patient with unstable right internal carotid artery (ICA) plaque. (Left) Transaxial MR image at level of proximal right ICA shows concentric plaque (yellow arrow) causing stenosis of the arterial lumen. (Right) Magnified image of carotid plaque with superimposed FDG-PET signal confirming FDG uptake into stenotic carotid plaque.

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Conclusions and future strategies for the prediction of plaque rupture 

The ideal imaging modality for detecting atherosclerotic plaques and assessing their vulnerability does not yet exist, and is some years away. For the foreseeable future, x-ray contrast angiography will continue to guide coronary intervention, aided at times by IVUS, with MSCT providing the most promising prospect in the near future for noninvasive angiography and screening to exclude coronary disease. The ideal coronary imaging modality of the future will need to combine the anatomic imaging potential of MR with the functional imaging potential of PET. Technologic advances in MR may be able to provide detailed images of the vessel wall in small coronary arteries, and development of macrophage-specific paramagnetic agents may also one day allow for accurate quantification of plaque inflammation. Until then, the various techniques described above, individually or in combination, will continue to be used in research aimed at identifying features of atherosclerotic plaques that render them potentially unstable.

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Acknowledgment 

The British Heart Foundation funded research carried out by the authors of this review.

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PII: S1050-1738(04)00182-3

doi:10.1016/j.tcm.2004.12.001

Trends in Cardiovascular Medicine
Volume 15, Issue 1 , Pages 17-24, January 2005

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