Imaging of the vulnerable plaque: new modalities.

Abstract: Atherosclerosis is currently considered to be an inflammatory and thus a systemic disease affecting multiple arterial beds. Recent advances in intravascular imaging have shown multiple sites of atherosclerotic changes in coronary arterial wall. Traditionally, angiography has been used to detect and characterize atherosclerotic plaque in coronary arteries, but recently it has been found that plaques that are not significantly stenotic on angiography cause acute myocardial infarction. As a result, newer imaging and diagnostic modalities are required to predict which of the atherosclerotic plaque are prone to rupture and hence distinguish "stable" and "vulnerable" plaques. Intravascular ultrasound can identify multiple plaques that are not seen on coronary angiography. Thermography has shown much promise and is based on the concept that the inflammatory plaques are associated with increased temperature and can also identify "vulnerable patients." Of all these newer modalities, magnetic resonance imaging has shown the most promise in identification and characterization of vulnerable plaques. In this article, we review the newer coronary artery imaging modalities and discuss the limitations of traditional coronary angiography.

Key Words: electron beam computed tomography, intravascular ultrasound, magnetic resonance imaging, thermography, vulnerable plaque

Vulnerable Plaque

Thickness of the Fibrous Cap

The cap overlying the atheromatous core is increasingly being recognized as a dynamic structure in which collagen synthesis is modulated by positive and negative growth factors produced by inflammatory cells and in which collagen is degraded by metalloproteinases derived from activated macrophages. Most of the fissures and fractures occur in eccentric lesions at the shoulder region of the cap. This is usually the thinnest area with reduced collagen content. (1) When there is also high circumferential stress at the luminal border of the plaque, plaque rupture is more likely to occur. (2), (3) It has been shown that circumferential stress increases critically when cap thickness is less than approximately 150 [micro]m. (2), (3)

Size, Composition, and Effect of Temperature on the Atheromatous Lipid Core

A large lipid core (>40%) rich in cholesterol is at a high risk for rupture. Also, lipid in the form of cholesteryl ester softens the plaque, whereas crystalline cholesterol may have the opposite effect. A negative relation exists between temperature and core stiffness. (4), (5) If temperature increases, as in inflammation, the core becomes softer. A soft core may be more vulnerable to rupture because it may not be able to bear the imposed circumferential stress, which is then redistributed to the fibrous cap, where it may be critically concentrated. (3)

Inflammation Within or Adjacent to the Fibrous Cap

An inflammatory-cell infiltrate is a marker of plaque vulnerability. Oxidized lipoproteins may provoke a chronic inflammatory reaction in the atherosclerotic plaque. Endothelial cells, monocytes, and T cells play a role in the promotion of inflammation. As a result, heavy local infiltration by macrophages and often by T lymphocytes is observed in atherosclerotic plaques that are at risk of rupture. Furthermore, elaboration of cytokines and matrix-degrading proteins leads to weakening of the connective tissue framework of the plaque. (6) It is clear that a hemodynamically nonsignificant coronary atherosclerotic plaque can rupture and produce a cardiac event long before it produces significant lumen narrowing and angina pectoris, if the above-mentioned plaque characteristics are met. It is therefore important that newer imaging techniques, based on recent insights into the vulnerable plaque, become available in clinical practice.

Invasive Techniques for Evaluation of the Atherosclerotic Vulnerable plaques

Angiographic Recognition of the Vulnerable Plaque

It has been known for a while that nonobstructive plaques are responsible for the majority of acute coronary syndromes (ACS). A major finding in the last two decades was the recognition that plaque composition, rather than the severity of stenosis, may determine the risk of thrombotic complications associated with ACS. (7), (8) It is well established now that atherosclerosis lesion disruption and the superimposed thrombus formation play a key role in the pathogenesis of ACS. (9), (10) The Coronary Artery Surgery Study used angiography to prospectively evaluate nearly 3,000 nonbypassed coronary segments in approximately 300 patients observed over a period of 42 to 66 months. (11) It was shown that, although an individual severe stenosis becomes occluded more frequently than a severe stenosis, less obstructive plaques (<80% stenotic at baseline) give rise to more occlusion than do severely obstructive plaques because of their greater number. (11) Ambrose et al (12) and Little et al (13) first demonstrated that in approximately 50% of the cases of myocardial infarction, the lesions leading to occlusion were <50% stenotic. Other groups have shown similar results, and it is well accepted that in approximately 70% of cases, the clot responsible for an acute coronary event occurs in a plaque that is <50% stenotic. (7), (14), (15) Therefore, the assumption that only highly stenotic sites seen on angiography are at risk for thrombotic occlusion and subsequent myocardial infarction, whereas those coronary arteries that do not contain obstructive stenosis (<50%) are nearly free of risk for thrombotic occlusion, is not valid. Other limitations of coronary angiography in recognition of the vulnerable atherosclerotic plaque are that coronary angiography is only luminography and gives variable information about arterial wall disease (luminal irregularity can often be appreciated on angiography).

Remodeling and Angiography

In the early phases of atherosclerosis development, when coronary artery disease (CAD) is minimal, luminal size is not affected by plaque growth because of the expansion of external elastic membrane and the enlargement of vessel size; this represents the "positive remodeling." (16-19) As CAD becomes moderate, there is no increase in the vessel size, but rather the plaque approaches the lumen, which shrinks; this is "negative remodeling." Positive remodeling, larger plaque areas, and echolucent plaques may be associated with unstable angina, whereas negative remodeling and smaller plaque areas may be associated with stable angina. (18) Positive remodeling is also seen in an acute myocardial infarction at the site of plaque rupture. (19) These findings are consistent with other observations that inflammation, calcification, and medial thinning are primary determinants of positive remodeling, which appears to be a feature of plaque instability. (20) This phenomenon of remodeling makes angiography a poor technique with which to assess the true atherosclerotic burden and nature because the shadows of the coronary lumen seen on angiography provide only indirect and incomplete information concerning the extent of the atherosclerosis process in the arterial wall.

Intravascular Ultrasound and Vulnerable Plaque

Intravascular ultrasound (IVUS) is a new technology that allows in vivo visualization of variations in arterial geometry and atherosclerotic plaque by using a miniature transducer at the end of a flexible catheter. (16), (17) It provides a two-dimensional cross-sectional image of the arterial wall and can accurately assess the plaque burden. (21) However, the resolution of the ultrasound system is related to its frequency. Axial resolution is approximately 100 [micro]m and 200 [micro]m for 40-MHz and 20-Mhz systems, respectively. Lateral resolution varies widely. For high-frequency (40-50 MHz) systems, imaging may be hampered by an increased back-scatter of blood. (22) Histopathologic studies mostly report low sensitivity for IVUS in detecting lipid-rich lesions, although IVUS radiofrequency signal analysis may improve tissue characterization. (23), (24) Although axial resolution remains too low for measuring cap thickness of the fibrous cap with its rupture, a recent study reports that the thickness of the fibrous cap with its rupture were visualized. (25) IVUS permits the investigation of plaque morphology and the direction and extent of arterial remodeling with much accuracy.

Angioscopy

The color of plaques as detected with angioscopy may vary among patients with different acute syndromes. Xanthomatous plaques (yellowish), which cannot be recognized with arteriography, are more common in patients with acute myocardial infarction and unstable angina (26), (27), such plaques are found in all three major coronary arteries, suggesting that the development of these vulnerable plaques is a pancoronary process. (28) These plaques often have an irregular intimal surface because of plaque rupture, ulceration, and intimal flap. Smooth white plaques are observed in patients with old myocardial infarction and stable angina. The differences in plaque composition are associated with varying degrees of stability. Xanthomatous plaque is likely to have a high concentration of cholesterol at its base, and the fibrous cap overlying the lipid core may be thin. Plaque with a high concentration of lipid and a thin fibrous cap may be easily cracked by increased shear force at the level of the stenosis and by acute changes in coronary tone or exercise. (29) By comparison, white plaques are less likely to rupture because the increased fibrous content over the lipid core provides stability. Although angioscopy allows visualization of the plaque and thrombus with high sensitivity, it remains a research tool because of the inability to examine the different layers within the arterial wall and to provide estimation of cap thickness or lipid content. (30)

Thermography

Background

A persistent finding in the histopathologic specimens of ruptured atherosclerotic plaques has been the presence of activated macrophages within the plaque. (8) The accumulation of these cells reflects the inflammatory process that has been implicated in the pathogenesis of ACS. Because the cardinal sign of inflammation is an increase in temperature, it is logical to assume that local differences in plaque temperature may be present, depending on the degree of inflammation. Ex vivo studies in human carotid atherosclerotic plaques showed that temperature differences within the plaque were related to the cell density of macrophages. (31) Recently, in vivo studies demonstrated temperature heterogeneity to be determined by plaque composition and, more specifically, by macrophage mass. (32) The exact mechanism for the increased local temperature in the coronary atherosclerotic plaque is not clearly understood. Neovascularization within the vulnerable plaque as well as expression by activated macrophages of mitochondrial uncoupling proteins (proteins homologous to uncoupling protein-1 that is found in brown fat and involved in thermogenesis in that tissue) have been implicated in the generation of heat in the inflamed plaque. (33) Regardless of the exact mechanism, heat produced in the plaque may contribute to the vulnerability of the plaque by softening the lipid core and redistributing and critically concentrating circumferential stress on the fibrous cap, in addition to reflecting the degree of inflammatory process.

The direct measurement of the temperature of the coronary atherosclerotic plaque has become feasible with the use of specially designed thermography catheters of 3-French size. (34) A hydrofoil configuration was constructed opposite to the thermistor to facilitate contact of the thermistor against the vessel wall. In the first clinical study with the thermography catheter, thermal heterogeneity within atherosclerotic coronary arteries and constant temperature in normal coronary arteries was documented. This heterogeneity was found to be larger in unstable angina and acute myocardial infarction patients, implying that it may be related to the pathogenesis of ACS. (34) In another clinical study, using the thermography catheter, the impact of increased local temperature of the atherosclerotic plaque on clinical events, after percutaneous transluminal coronary angioplasty and stent implantation, was evaluated. (35) The temperature difference ([DELTA] T) between the atherosclerotic plaque and the healthy vessel wall was greater in patients with adverse cardiac events than in patients without events. Moreover, [DELTA] T was greater in the patients exertional angina and unstable angina with adverse cardiac events as compared with those without events. The [DELTA] T was a strong predictor of adverse cardiac events during the follow-up period (odds ratio, 2.14; 95% confidence interval, 1.31-6.85; P = 0.043). Sensitivity and specificity analysis showed that the threshold of the [DELTA] T value cutoff point above which the risk for an adverse outcome after the intervention was significantly increased was 0.5[degrees]C (receiver operating characteristic curve area, 77%). The sensitivity for this cutoff point was 86% (18 of 21 patients) and the specificity was 60%. The incidence of adverse cardiac events in patients with [DELTA] T >0.5[degrees]C was 41%, as compared with 7% in patients with [DELTA] T <0.5[degrees]C (P <0.001). A Cox survival plot adjusted for [DELTA] T and stratified for the cutoff point showed a clear relationship between [DELTA] T and event-free survival (Fig. 1). This study showed that plaque temperature was higher in patients with ACS and predicted long-term clinical events in patients undergoing percutaneous transluminal coronary angioplasty and stent implantation. Recently, a study showed a smaller temperature difference between atherosclerotic plaques and normal coronary artery in patients on statins, thus documenting a favorable effect on heat release from the atherosclerotic plaques by statins. (36) This could not be attributed to the lipid-lowering effect of statins because there was no correlation between temperature measurements and cholesterol levels.

[FIGURE 1 OMITTED]

Thermography for Detection of the Vulnerable Patient

Postmortem studies have documented a multifocal inflammatory cell infiltration in several coronary branches in

Key Points

* Atherosclerosis is an inflammatory disease affecting multiple arterial beds and causes multiple coronary artery lesions and plaques.

* Plaque composition rather than the degree of stenosis determines the risk of acute coronary syndrome.

* Coronary angiography has limited utility in identifying the vulnerable plaque.

* Thermography can detect the vulnerable plaques on the basis of temperature difference caused by ongoing inflammation in the plaques.

* Magnetic resonance imaging has excellent utility in visualizing plaque and discriminating its components and can soon become the gold standard. patients dying as a result of an acute myocardial infarction. (37) Recently, in patients with unstable angina, an extensive spread of the inflammatory process was also detected. (38) These findings challenge the concept of a single vulnerable plaque in patients with ACS and underscore the need for techniques that will detect the "vulnerable patient" rather than the "vulnerable plaque." One way to approach this is the application of the thermographic concept to the blood of the coronary sinus. According to this concept, temperature of the blood that passes through the inflammatory coronary territories and empties into the coronary sinus is expected to be higher in patients with CAD and unstable coronary plaques than in those without coronary lesions. Stefanadis et al (39) showed that the patients with significant lesions in the left coronary artery bed had the highest temperature difference between the blood from coronary sinus and right atrium. Thus, thermography can develop into a technique to recognize "coronary vulnerable patients."

IVUS Elastography

IVUS elastography is based on the principle that tissue components that differ in hardness as a result of their different histopathologic composition are expected to be compressed differently if a defined pressure is applied. (17) The technique can discriminate (40) between soft and hard material and can assess the mechanical properties of the vessel wall. Hard tissues (calcifications and collagen) will be compressed less than soft tissue types (lipids). Using the radiofrequency data of ultrasound images that have been obtained mainly in the diastolic phase of the heart cycle, strain images are constructed using the relative local displacements, which are estimated from the time shifts between gated echo signals acquired. Hard and soft regions can be identified using this technique, whereas in the original image, it is not possible to discriminate the different tissue types. (41) This technique has the potential to identify plaque vulnerability because the detected areas of increased radial strain represent regions of high circumferential stress, a feature of plaque vulnerability. However, a major problem in advancing intravascular elastography to cardiac in vivo applications is the acquisition of data in a pulsating artery located in a contracting heart.

Optical Coherence Tomography 

Using a laser as the light source, a beam of low coherent infrared spectrum is directed and reflected within the tissue, and the intensity of the reflected infrared light rather than acoustic waves is measured. The intravascular device is capable of visualizing the atherosclerotic lesion with an axial resolution of 2 to 30 [mu]m, depending on the spectral width of the source and a lateral resolution of 5 to 30 [mu]m determined by the beam waist. The current penetration depth is limited to 1 to 2 mm. Studies revealed that optical coherence tomography (OCT) is capable of differentiating lipid tissue from water-based tissues. (42) Furthermore, the thickness of the fibrous cap overlying an atheroma can be demarcated by OCT. (42) There are some limitations of OCT for in vivo intravascular imaging including the reduction of image quality when imaging through blood or large volumes of tissue, the relative slow data acquisition rate, and the multiple scattering.

Raman Spectroscopy

Raman spectroscopy is ideal for identifying gross chemical changes in tissue, such as in atherosclerosis. (43) It is an imaging modality in an early stage of development that has great potential to discriminate in vivo among lipid-rich, calcified, and fibrotic plaques. Raman spectroscopy uses light of a single wavelength from a laser that is directed onto the tissue sample via glass fibers. Light scattered from the sample is collected in fibers and launched into a spectrometer. It may be considered the acquisition of a molecular fingerprint. Penetration depth of Raman spectroscopy in arterial tissue is reported to be 1.0 to 1.5 mm. This would allow the Raman technique to examine tissue types beneath fibrous caps and within the atheromatous core. Current limitations of Raman spectroscopy are the strong background fluorescence and the laser light absorption by the blood.

Near-infrared Spectroscopy

Diffused reflectance near-infrared spectroscopy (NIR) has been used extensively to identify the chemical content of biologic specimens. NIR spectroscopy (750-2,500 nm) is based on the absorption of light by organic molecules. The reflectance spectra from wavelengths between 400 and 2,400 nm allow detailed analysis of chemical composition. (44) The advantage of this technique is its deeper penetration into the atherosclerotic plaque and that it can be combined with other catheter-based techniques; however, its use has been limited until now to in vitro studies.

Noninvasive Techniques for Evaluation of the Atherosclerotic Vulnerable Plaques

Electron Beam Computed Tomography

Electron beam computed tomography (EBCT) is a technique of imaging coronary artery calcium that uses a faster rate of image acquisition than conventional computed tomography. With fast imaging, elimination of cardiac respiratory motion artifacts is accomplished. It has been suggested that in asymptomatic men and women aged 50 to 70 years, the EBCT-derived coronary calcium score accurately predicts coronary disease events independent of standard risk factors and can be used to refine the Framingham risk index. (45) Because the finding of calcium on EBCT correlates with the presence of a significant stenosis (50%) on coronary angiography, it may serve as a screening technique before invasive angiography and may be particularly helpful in patients with an equivocal exercise test. (46)

Coronary calcification detected by EBCT is found in individuals who have significant angiographic congential heart disease, with a sensitivity ranging from 90 to 100%, a specificity of 45 to 76%, a positive predictive accuracy of 55 to 84%, and a negative predictive accuracy of 84 to 100%. (47-49) Therefore, the presence of a negative EBCT test in the intermediate-risk population carries the highest predictive value, and it is in this scenario that the test is most powerfully applied.

Limitations

Calcium severity on EBCT can identify asymptomatic patients at high risk for congential heart disease, but it is not certain whether this translates into identification of asymptomatic patients who have silent ischemia, which is of importance because the presence of silent ischemia is predictive of a cardiac event. High-risk plaques often lack calcium, and the predictive value of coronary calcification, at least in high-risk subjects, may not be superior to that of standard coronary risk factors. Site and extent of calcification do not equate with site-specific stenosis, and a calcific plaque does not necessarily mean a stable plaque.

Magnetic Resonance Imaging

High-resolution magnetic resonance imaging (MRI) holds the promise of noninvasively imaging high-risk plaque. High-resolution fast spin echo and optimized computer processing have enhanced the spatial resolution (0.4 mm) during visualization of atherosclerotic plaques in vivo. In experimental studies, in small hypercholesterolemic animal models, in atherosclerotic lesions, an excellent agreement was observed between highresolution MRI (9-T system, in plane spatial resolution of 97 [mu]m) and histopathology. MRI studies are currently being performed to study the progression and regression of atherosclerotic plaques over time. (50), (51) Using ultrasmall superparamagnetic particles of iron oxide, macrophage accumulation in the aorta could be seen in hypercholesterolemic rabbits before atherosclerotic lesions were detected. (52) MRI is also used to visualize and characterize arterial thrombi in vivo. (53) High-resolution MRI is an excellent tool for visualizing fibrous cap thickness and rupture in plaques. (54-56)

Limitations

Although MRI is a promising, noninvasive tool for detecting vulnerable plaques, it currently lacks sufficient resolution (currently, 400 [mu]m) for accurate measurements of cap thickness and characterization of the atherosclerotic lesion within the coronary circulation. A newer high-resolution MRI technique shows an 80% agreement with histopathology in analysis of intimal thickness and accurately determines plaque size. (57) Taking advantage of the molecular processes involved in atherothrombosis, it has recently been shown that it is possible to target molecules with antibodies coupled to a contrast molecule, which can be detected by MRI. These molecular enhancers can potentially boost the ability of the noninvasive MRI to detect high-risk vulnerable atherosclerotic plaque and enhance patients' risk stratification. (58) At present, MRI provides not only a method of noninvasively visualizing plaque and discriminating its components but also a means of accurately assessing the effects of treatments, such as lipid-lowering therapy, and of timing the activity of clots to determine when they become inactive; however, certain technical improvements are still desired.

From the Department of Internal Medicine, State University of New York at Buffalo, Buffalo, NY; the Department of Radiodiagnosis, Safdarjung Hospital, New Delhi, India; and the SMS Hospital, Jaipur, India.

Reprint requests to Vishal Bhatia, MD, 808 Potomac Avenue, Buffalo, NY 14209. Email: [e-mail]

Accepted July 9, 2003.

Copyright [c] 2003 by The Southern Medical Association

0038-4348/03/9611-1142

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Vishal Bhatia, MD, Ruchi Bhatia, MBBS, Sandeep Dhindsa, MD, and Mandeep Dhindsa, MBBS