Imaging Vulnerable Plaque by Ultrasound
Anthony N. DeMaria, MD, MACC*,a,*,
Jagat Narula, MD, PhD, FACC
,
Ehtisham Mahmud, MD, FACC* and
Sotirios Tsimikas, MD, FACC*
* Division of Cardiology, University of California San Diego, San Diego, California, USA
Division of Cardiology, University of California-Irvine School of Medicine, Irvine, California, USA
Manuscript received June 16, 2005;
revised manuscript received November 2, 2005,
accepted November 8, 2005.
* Reprint requests and correspondence: Dr. Anthony N. DeMaria, Cardiology Division, UCSD Medical Center, 200 West Arbor Drive, San Diego, California 92103-8411 (Email: ademaria{at}ucsd.edu).
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Abstract
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Diagnostic techniques to identify vulnerable plaques are rapidly evolving. Intravascular ultrasound (IVUS) has the ability to detect and localize plaque as well as quantitate plaque burden. Recent IVUS studies have suggested that patients presenting with acute coronary syndromes have an approximate 25% incidence of additional ruptured plaques in arteries other than the culprit lesion. The ability of IVUS to detect vulnerable plaques before rupture is currently being evaluated by novel techniques. Initially, IVUS was shown to be able to characterize plaque broadly as calcified or fibrofatty but was limited in its ability to more precisely detect lipid-rich plaques, necrotic cores, and thrombus. Recent advances in new applications of IVUS, such as integrated backscatter, wavelet analysis, and virtual histology, have focused on evaluating and mathematically transforming the radiofrequency signal from ultrasound waves into a color-coded representation of plaque characteristics such as lipid, fibrous tissue, calcification, and necrotic core. In addition, targeted contrast agents, applicable to both intravascular and transthoracic studies, are being evaluated in experimental models and aim to highlight specific plaque components, such as endothelial adhesion molecules and other plaque components that might be useful in targeting vulnerable plaques. These advances pave the way for future clinical trials in assessing the ability of such techniques to diagnose vulnerable plaques and to assess the effects of both pharmacologic and mechanical therapies on plaque characteristics.
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Abbreviations and Acronyms
| | 3D-IB-IVUS = three-dimensional intravascular ultrasound with integrated back scatter | | ACS = acute coronary syndromes | | ICAM = intracellular adhesion molecules | | IVUS = intravascular ultrasound | | PS = phosphatidylserine | | RF = radiofrequency |
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Attempts to identify vulnerable plaques have focused on imaging techniques, including cardiac ultrasound. These efforts have primarily employed intravascular ultrasound (IVUS), although recently contrast echocardiographic approaches have been pursued. Intravascular ultrasound was made possible by the miniaturization of ultrasound transducers so that they could be placed at the tip of very small diameter catheters. With an IVUS catheter positioned in a coronary artery, an ultrasound beam is directed perpendicular to the course of the vessel and steered either electronically or mechanically throughout its 360° circumference. Thereby, an image of cross-sectional arterial anatomy is obtained (1). Intravascular ultrasound’s cross-sectional images in normal arteries depict a sharp, bright endothelial/lumen border, a clear sonolucent media, and an echo dense adventitia (2).
Plaque formation results in a thickening of the intimal-medial segments and an overall thickening of the vessel wall. Plaque morphology by ultrasound is often characterized by the intensity of the signals as soft (gray) echoes, very high intensity (bright) reflectors that create distal shadowing, and echoes of intermediate intensity, features that correspond to tissue, calcification, and fibrosis (3). In addition, echolucent or signal free zones have been found to represent lipid accumulations (4–7). Plaques might be circumferential and occupy the entire perimeter of a vessel or be eccentric and occupy only a portion of the vessel wall. Atherosclerotic lesions often result in an expansion of the overall vessel to accommodate plaque without encroaching upon the lumen, a process termed positive remodeling (8). In addition, ruptures or ulcerations of lesions can be detected, typically in culprit vessels responsible for acute coronary syndromes (ACS) (9). Thus, an IVUS examination can detect and localize plaque, characterize it as hypoechoic, fibrous, or calcified, and determine whether it is ulcerated or manifests positive expansile remodeling. As compared with angiography, which evaluates atherosclerosis only by its indirect effect upon the lumen, IVUS has the obvious advantage of looking directly at plaque contained within the vessel wall.
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Prevalence of unstable plaques
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Angiographic and angioscopic studies.
Data regarding the prevalence of unstable plaques in patients undergoing cardiac catheterization have been provided by angiography, angioscopy, and IVUS. These studies have corroborated earlier pathologic studies (10). In a landmark angiographic study, Goldstein et al. (11) showed that approximately 60% of patients presenting with acute myocardial infarction (AMI) have single complex plaques, whereas approximately 40% of patients have multiple complex coronary plaques that portend a worse 1-year prognosis. The finding of multiple plaques with vulnerable characteristics is consistent with angioscopic data showing that approximately 90% of culprit, but not disrupted, lesions are yellow and are associated histologically with vulnerable characteristics (12). In addition, the prevalence of yellow plaques in non-culprit lesions per coronary artery was 3.2, suggesting a pan-coronary process. Interestingly, follow-up angioscopic studies do suggest that complete plaque healing, manifested by neointimal coverage of the disrupted plaque and resolution of thrombus, occurs only in a minority of lesions at 13-month follow-up (13). It has recently been shown that lipid-lowering therapy with atorvastatin reduced the yellow score of such lesions, compared with a control group, which had increased yellow score (14).
IVUS studies.
Recently, several IVUS studies have advanced these concepts by interrogating all three major epicardial vessels and quantitating the frequency of plaque rupture in patients presenting with ACS. In a small study of 24 patients (72 arteries) with troponin-positive ACS, Rioufol et al. (15) showed a mean prevalence of two ruptured plaques (range 0 to 6) per patient; 37.5% of patients had plaque rupture at the presumed culprit lesion, and 79% of patients also had ruptured plaques in non-culprit arteries. In addition, 12.5% of patients had plaque rupture in all three coronary arteries, and 69% of arteries had at least one plaque rupture. Hong et al. (16) showed in 235 patients that plaque rupture of the infarct-related vessel occurred in 66% of AMI patients and in 27% of stable angina patients. In addition, multiple plaque ruptures occurred in 20% of AMI and 6% of stable angina patients. Tanaka et al. (17) performed a similar study in patients with ACS and showed that 47% of culprit lesions had plaque rupture and that 24% of patients had plaque ruptures in more than one coronary artery. These data are consistent with other IVUS studies showing that culprit plaques have more vulnerable characteristics, such as more plaque burden, positive remodeling, and thrombus, than non-culprit plaques in patients with ACS (18,19). The overall prevalence of multiple ruptured coronary plaques in these studies as a whole is approximately 25% (20); however, it is possible that this is an underestimate, because IVUS is limited in adequately imaging plaque erosion and overlying thrombus, which might obscure ruptured plaques and the fact that some plaque ruptures might have occurred at bifurcations and branch vessels that were not imaged in these studies. Differences in the prevalence of plaque rupture in these studies also likely reflect differences in the patient population, selection bias in IVUS imaging, and the retrospective nature of some studies. Subsequently, Rioufol et al. (21) also showed that approximately 50% of these plaques heal in response to medical therapy without significant change in plaque dimensions, as also previously documented in pathological studies showing multiple layers of plaque rupture and healing within the same area (22).
Recent studies have also shown that the pattern of calcification is different in patients with ACS versus those with stable angina (23–25). Patients with ACS and ruptured plaques manifest a larger number of small, discrete calcium deposits, often present as spotty superficial and/or deep calcium deposits. Patients with ACS tended to have less overall calcification than patients with stable angina pectoris but also more positive remodeling.
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IVUS plaque characterization
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The initial attempts to identify vulnerable plaque by IVUS involved defining the image characteristics of culprit lesions that had lead to ACS (9). A number of lesion characteristics were described in the majority of patients in this setting (Table 1). Although these characteristics were observed with variable frequency, it was generally found that these plaques were hypoechoic, eccentric, positively remodeled, and relatively free of calcification. Volumetric analysis of IVUS images accurately quantitate atheroma volume and are useful in assessing changes in plaque regression and progression in trials of lipid lowering agents (26). Three-dimensional (3D) reconstruction allows morphological assessment of lesions but is not as useful in detecting clinically relevant plaque characteristics such as lipid content.
Obviously, plaque vulnerability can only be assessed with certainty by serial observations that demonstrate the transition of a lesion from stability to instability. To date, only one study has made such serial observations. Yamagishi et al. (27) examined 114 coronary sites in 106 patients by IVUS during a follow-up period of nearly 22 months. The coronary sites at which an event occurred that had been previously examined were characterized by large, eccentric lesions. The vast majority of these plaques contained echolucent zones that were usually shallow but occasionally deep in the vessel wall. Subsequent studies have also verified that positive (outward) remodeling is typically found in culprit lesions. Thus, the IVUS characteristics of a vulnerable plaque that have emerged include eccentric lesions with echolucent zones in areas of positive expansile remodeling.
Although, the IVUS descriptors of vulnerable plaque that have been proposed seem reasonable, a number of considerations prevent them from being accepted as definitive. Nearly all of the studies upon which the descriptors are based have been retrospective. Knowing plaque morphology after an acute event cannot provide certain information regarding morphology before that episode. Secondly, the characteristics reported for vulnerable plaque by IVUS have differed from study to study. Thirdly, non-culprit plaques in stable patients have often been found to show the same characteristics associated with vulnerable plaque. For example, a study by Schoenhagen et al. (28) found that culprit lesions from patients with ACS were identical in "vulnerable IVUS characteristics" to lesions observed in patients with stable angina, thereby casting uncertainty on the ability of IVUS to identify plaques susceptible to rupture, fissure, or erosion. Fourthly, the resolution of IVUS (150 to 300 µm) is too low to detect thin fibrous caps (50 to 75 µm), which have been identified as one of the features of vulnerable plaques.
These limitations notwithstanding, several novel approaches have recently been developed to more precisely define plaque characteristics.
3D IVUS with integrated back scatter.
Three-dimensional IVUS with integrated back scatter (3D-IB-IVUS) allows color coding and integration of sequential 1-mm segments obtained by motorized pullback to provide more optimal plaque characterization. Radiofrequency (RF) signals digitized at 2 GHz can be obtained with a conventional 40 MHz IVUS catheter. Subsequent IB signals of the RF signal can be calculated and color coded, providing a quantitative visual readout. This system uses a conventional IVUS instrument, a digital analog converter, and computer software to identify, and quantitate, various plaque characteristics. For example, Kawasaki et al. (29) recently described the usefulness of 3D-IB-IVUS in detecting lipid-rich plaques and monitoring their response to lipid lowering therapy. They evaluated the tissue characteristics of a coronary arterial segment 18-mm-long and then randomized patients to atorvastatin, pravastatin, or placebo for 6 months. The 6-month 3-IB-IVUS images showed a significant reduction in lipid volume and a similar increase in fibrous and mixed lesion volume in response to both statins but not to placebo (Figs. 1 and 2).
These changes were detected despite no significant changes in lumen area, vessel area, plaque area, and diameter stenosis, further defining the ability of this technique to identify early changes in plaque characteristics before geometric plaque regression and suggesting a role for defining plaque stabilization.
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Figure 1 (A) Three-dimensional (3D) color-coded maps of the coronary arterial plaques constructed by 3D intravascular ultrasound with integrated back scatter. (B) 3D color-coded maps of each characteristic. The number of voxels of each tissue characteristic was automatically calculated. Reprinted with permission from Kawasaki et al. (29).
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Figure 2 Color-coded maps of the coronary arterial plaques constructed by three-dimensional (3D) intravascular ultrasound with integrated back scatter imaging at baseline and after statin therapy. (A) At baseline. The plaque consists of a large lipid core (blue) that is covered with a fibrous cap (green). (B) After statin therapies. The lipid core (blue) decreased and the fibrous area (green) increased. (C) Cut out image of 3D color-coded map at baseline. There was a small lipid core (blue) in the center of the plaque. (D) Cut-out image of 3D color-coded map after statin therapy. Note the reduction in the lipid core. Red = high signal lesion; yellow = mixed lesion. Reprinted with permission from Kawasaki et al. (29).
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Wavelet analysis.
Wavelet analysis of RF IVUS signals is a novel mathematical model for assessing focal differences within arterial walls. Color coding of the wavelet correlation coefficient derived from the RF signal allows detection of changes in the geometrical profile of time-series signals to derive an image of plaque components (Figs. 3 and 4). With wavelet analysis, Murashige et al. (30) showed that lipid-rich plaques, derived from necropsy specimens and subsequently confirmed as such by histology, could be detected with a sensitivity of 83% and specificity of 83% in an in vitro system. Furthermore, IVUS imaging of the coronary arteries performed in 13 patients showed similar results with confirmation of the presence of lipid-rich components by histology after obtaining tissue by directional atherectomy.
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Figure 3 Representative examples of in vitro Wavelet analysis of radiofrequency (RF) intravascular ultrasound (IVUS) signals from a lipid-laden plaque (A) and from a fibrous plaque without a lipid core (B). The upper panel shows RF signals, the middle panel, the results of Wavelet analysis, and the lower panel, histologic specimen of the corresponding arterial cross-section with Masson’s trichrome. In the time-scale domain color-coded mapping of Wavelet analysis, an apparently different pattern of pink area from an RF signal vector of a lipid-laden plaque is observed between scale 20 and scale 30, compared with the fibrous plaque. F = fibrous area; L = lipid core. Reprinted with permission from Murashige et al. (30).
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Figure 4 Representative examples of in vivo Wavelet analysis of radiofrequency (RF) intravascular ultrasound (IVUS) signals from a lipid-laden plaque (A) and from a fibrous plaque without a lipid core (B). The left panel shows conventional IVUS images, the middle panel, the results of Wavelet analysis, the right panel, histologic cross section of the corresponding directional coronary atherectomy specimen with Hematoxylin-Eosin and Azan stains. A similar pattern of color mapping was observed from the RF signal vector of a lipid-laden plaque as seen in the in vitro study. Reprinted with permission from Murashige et al. (30).
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Virtual histology.
"Virtual histology" applies spectral analysis of the IVUS backscatter RF signal to characterize plaque components on the basis of tissue characteristics such as density, compressibility, concentration of various components, and size. With quantitative spectral parameters and advanced mathematical techniques to classify plaque composition, this approach has been validated with histological techniques on ex vivo coronary specimens in classifying lesions as calcified, fibrofatty, calcified-necrotic core, and lipid-rich areas (31,32). This methodology allows real-time, 3D plaque cross-sectional and longitudinal views of the entire vessel and allows one to visualize the complete length of the artery and assess individual plaque components. Although this technique seems promising and is currently at the forefront of this approach, its clinical usefulness awaits ongoing clinical trials.
These refinements of IVUS suggest that identification of plaque characteristics, including lipid-rich components, might be clinically feasible in the near future and might allow identification of vulnerable plaques and new avenues of diagnosis and therapy.
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IVUS and transthoracic ultrasound with targeted contrast agents
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Recent years have seen the development of new microbubble ultrasound contrast agents and enhanced recording instrumentation that enable the opacification and visualization not only of the cardiac chambers but also blood vessels and myocardium (33). Thus, myocardial contrast echocardiography can provide visualization of myocardial perfusion after the intravenous injection of a variety of ultrasonic contrast agents; however, the microbubble agents have a finite lifespan before dissolving and might be destroyed by the ultrasound energy applied in the process of imaging. In addition, the generalized myocardial and vascular opacification produced by contrast echocardiography might mask uptake of microbubbles by plaque. Therefore, there are a number of challenges to identifying vulnerable plaque by contrast echocardiography.
Imaging methods to detect vulnerable plaque have often been based on targeted imaging with the use of a signal-generating compound that, when attached to the target of interest, is detectable by the imaging technique. For ultrasound, the "beacon" that can be detected is the signal from microbubble contrast agents. Assuming that the target is specific for plaque (vulnerable or otherwise), it is not necessary to image the vessel to establish the presence of the target. Thus far, contrast echo has been confined primarily to the identification of white blood cells and endothelial cell surface markers such as adhesion molecules; however, the principles will be the same for identifying specific markers of vulnerable plaque when they are defined.
In light of the aforementioned issues, the strategy that has emerged to achieve targeted diagnostic imaging by contrast echocardiography has been to have the microbubbles or acoustically reflective liposomes ingested by or attached to the specific target to be visualized (33,34). Attachment has been achieved either by virtue of the inherent properties of the microbubble shell or by attaching specific ligands such as monoclonal antibodies. In experimental models, these microbubbles are then injected, and after a suitable time is allowed for either ingestion or attachment, conventional echocardiographic recordings are obtained. In this fashion the bulk of the contrast injected has disappeared, and the only residua are the microbubbles ingested by or attached to the target.
Although most microbubble ultrasonic contrast agents rapidly transit the capillary bed, it was an early observation that some microbubble agents became transiently attached to vessels, particularly venules (35). Subsequent studies related this prolonged residence within the microcirculation to a negative surface charge of the bubble (usually due to a lipid shell) with subsequent phagocytosis by white blood cells gathered along the surface of the endothelium. To date the ingestion of microbubbles by leukocytes has been found to be sufficiently avid to enable identification of inflammation such as that encountered after ischemia/reperfusion or transplant rejection in the experimental setting (36,37).
The detection of white blood cells associated with plaque inflammation as a marker of vulnerable plaque would present a serious challenge; however, an alternate approach consists of using microbubble contrast to identify leukocyte adhesion molecules such as selectins or integrins, which might be upregulated in vulnerable plaque. Initial in vitro studies, employing either microbubble contrast agents or lipid emulsions to which antibodies to intracellular adhesion molecules (ICAM) had been incorporated, documented the ability of these agents to attach to and be visualized on endothelium in which these molecules had been upregulated (38). Subsequently, targeted identification of leukocytes adherent to the endothelium of venules was accomplished by microbubbles to which phosphatidylcholine was incorporated into the lipid shell. Microbubbles, to which ligands to ICAM1 have been incorporated, have also been used to visualize transplant rejection in the experimental setting (39). Thus, exploiting both shell characteristics and incorporated ligands to specific targets, microbubbles have been found to be capable of identifying white blood cells as well as adhesion molecules (34,40). Imaging of additional inflammatory targets, such as phosphatidylserine (PS) receptors, which are ubiquitously expressed by macrophages, are being explored with echogenic liposomes enriched in PS phospholipids (Fig. 5). The imaging was performed with the premise that these bubbles will be preferentially attracted by the lesions that harbor abundant macrophages (or vulnerable plaque). With this hypothesis, experimental atherosclerotic lesions were developed in rabbits by balloon de-endothelialization of the infradiaphragmatic aorta, followed by 1% cholesterol, 6% peanut oil diet for 4 months. Such animals develop American Heart Association type II (20%), III (30%), and IV (50%) lesions. Intravenous administration of PS-rich microbubbles filled with perfluorocarbon were injected, and images were recorded showing enhancement of the aortic plaque. The potential for additional endothelial cell surface markers to be used as targets for contrast echo detection of atherosclerosis is obvious.
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Figure 5 The top panel shows the dissected intact aorta (left) and the opened aorta (right) showing yellow plaques. In the middle panel, (A) shows baseline ultrasound image of the aortic plaque (arrow), (B) shows microbubbles in the aortic lumen soon after intravenous injection, and (C) shows microbubble enhancement of the aortic plaque about 25 min after injection. The lumen is free of circulating microbubbles, and high mechanical index ultrasound imaging was done after 25 min. Note the brighter appearance of the plaque. The lower panel shows another example in which the figure on the left is the baseline image of a plaque and the figure on the right is color-coded, baseline-subtracted, videointensity image of the microbubble-enhanced atheroma.
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A number of challenges exist to the detection of vulnerable plaque by targeted echocardiographic contrast imaging. To begin with, it must be possible to achieve a minimum concentration of microbubbles at the target site. Secondly, the number of microbubbles and the ultrasonic signal transmitted must be capable of generating a sufficiently strong signal from the tethered/ingested microbubbles. Finally, one must be able to distinguish the resident microbubbles from both circulating microbubbles and from ultrasonic signals generated by the blood-intimal border. Thus, targets must be chosen that are present in sufficient quantity and that can attract an adequate number of microbubbles per target to be detected by external ultrasonic imaging. Given these constraints, it is likely that targeted imaging by contrast echocardiography might find that detecting vulnerable plaque in the carotid arteries or in the coronary arteries in conjunction with IVUS imaging will be its initial clinical application. Contrast echocardiography offers the opportunity to detect vulnerable plaque by noninvasive imaging but presents significant challenges to the recording of microbubbles tethered to specific sites. Nevertheless, the safety, repeatability of recording, portability, and cost of ultrasound provide a substantial incentive to develop approaches using this modality for the identification of vulnerable plaque.
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Conclusions
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At the moment, intravascular and transthoracic ultrasonic techniques for the detection of vulnerable plaque must be considered as either not established or experimental. Recent advances, however, suggest that plaque characterization with a variety of techniques might be feasible. Ultimately, clinical trials will determine whether ultrasound approaches might identify vulnerable plaques or result in new algorithms in patient care.
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Footnotes
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Dr. William A. Zoghbi acted as guest editor.
a Over the years, Dr. DeMaria has been on the scientific advisory boards, a consultant/speaker, and/or received research grants from virtually all echocardiography companies and pharmaceutical companies that distribute contrast agents. 
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Top
Abstract
Prevalence of unstable plaques
