CLINICAL RESEARCH: EDITORIAL COMMENT
Picking Plaques That Pop ...*
Jagat Narula, MD, PhD, FACC ,*,
Aloke V. Finn, MD and
Anthony N. DeMaria, MD, MACC
University of California Irvine School of Medicine, Irvine, California, US
Massachusetts General Hospital, Boston, Massachusetts, US
University of California San Diego School of Medicine, San Diego, California, US
* Reprint requests and correspondence: Dr. Jagat Narula, UCI Medical Center, 101 The City Drive, Building 53, Rt. 81, Orange, California 92868-4080 (Email: narula{at}uci.edu).
In the U.S. alone, over 13 million individuals suffer from coronary artery disease. Of these, 1.1 million patients present with acute myocardial infarction (AMI) every year and 400,000 succumb to the episode (1). In addition, about 150,000 new cases of unstable angina are diagnosed annually and 450,000 individuals experience sudden death as the first manifestation of the atherosclerotic process. Rupture of an atherosclerotic plaque is responsible for up to 75% of acute coronary episodes (2). Clinically, we have been unable to identify the culprit plaques before rupture, and intervention has always focused on management only after rupture has produced an acute coronary event. This reactive strategy does little to prevent future events. Although multiple circulating markers may help identify patients at higher risk of acute coronary syndromes (3), it may be equally important to identify coronary lesions susceptible to rupture with the expectation that appropriate time-sensitive preventive strategies will eventually be developed.
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Characteristics of vulnerable plaque
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Histopathologic characteristics of ruptured plaques are well defined (4) (Table 1) and, except for a fibrous cap which is intact, it is reasonable to assume that vulnerable plaques exhibit similar features. Knowledge of such histopathologic characteristics should allow development of appropriate imaging techniques (5) to detect these lesions. The disrupted plaques have significantly attenuated fibrous caps, which almost always demonstrate intense macrophage infiltration. The thickness of the cap near the plaque rupture site has been reported to be 23 ±19 µm and plaques with caps 2 standard deviations above the mean (64 µ) are presumed to be vulnerable to rupture (6). Accordingly, vulnerable plaques are termed "thin cap fibroatheroma" (TCFA). The attenuation of the fibrous cap is directly related to the extent of macrophage infiltration (4). The site of minimum thickness along the longitudinal or circumferential course of the plaque is believed to be prone to rupture, and this site may not necessarily correspond to the shoulders or summit of the plaque.
Although it is a common knowledge that the plaques undergoing rupture might not be critically occlusive, the pathologic characterization of vulnerable plaques and ruptured plaques (disrupted and healed ruptures) reveals that they need to mature to sizable extent before disruption (4,7). Two-thirds of TCFA are >50% and one-quarter are >75% cross-sectionally stenotic, whereas three-quarter ruptures are >50% and one-half are >75% stenotic; <50% cross sectional narrowing is observed in only 40% TCFA and 20% in ruptures (7). It is therefore reasonable to presume that detection of sufficiently large and thin-capped plaques would be possible by morphology-based imaging techniques, such as intravascular ultrasound (IVUS).
The necrotic core in a given plaque is independent of luminal narrowing and needs to exceed a critical threshold to convey vulnerability. It occupies more than 25% of the plaque area in at least two-thirds of disrupted lesions (2,6). The necrotic core in ruptured plaques and TCFA varies from 2 to 22 mm in length and demonstrates >60° circumferential involvement of the vessel. Such dimensions may offer an adequate target to the imaging strategies. Macrophage infiltration is intimately linked to the evolution of necrotic core. During the process of subintimal migration, uninhibited ingestion of lipids converts macrophages into foam cells. Cholesterol esters and free cholesterol pack the foam cells and eventually lead to their annihilation; dying foam cells contribute to the enlargement of necrotic core. Progression from non-disrupted to disrupted lesion is associated with an increase in ratio of free-to-esterified cholesterol (8) which may result from intraplaque hemorrhage and red blood cell (RBC) deposition in the core area. The cholesterol content of the erythrocyte membrane constitutes 40% of its weight; it is elevated in hypercholesterolemia and decreases with statin treatment (9). The extent of iron deposits in the plaque and the reactivity to glycophorin (a protein specific to the RBC membrane) correspond to the size of the necrotic core. Changes in these variables parallel an increase in macrophage density, suggesting that hemorrhage may serve as an inflammatory stimulus (8). Intraplaque hemorrhage is believed to occur from the disruption of thin-walled microvessels that are lined by a discontinuous endothelium without supporting smooth muscle cell (SMC) (10). These microvessels represent a part of neoangiogenesis within the plaque confines and are associated with extensive vascular proliferation around the adventitial vascular layer.
Plaque burden usually does not compromise lumen size unless 40% or greater cross-sectional luminal narrowing has occurred, causing compensatory enlargement or remodeling of the entire vessel (11,12). In particular, lesions with hemorrhage, large necrotic cores, and macrophage inflammation are more likely to demonstrate vascular remodeling. Conversely, with nonrupture-related acute coronary events, such as those resulting from plaque erosion, plaques demonstrate arterial shrinkage. The extent of arterial remodeling is closely associated with the expression of activated metalloproteinases (13). The expansile growth of vessel ensures that vulnerable plaques are sizable and enhances their ability to be imaged.
More than one-half of TCFA show either an absence or only speckled calcification, and the other half demonstrate a large variation in the degree of calcification (5), which is dependent on patient age. From the pathologic standpoint, coronary calcification correlates with the magnitude of plaque burden, but does not offer further association with plaque vulnerability. Based on the available information, it is unlikely that a measure of calcification alone would allow assessment of plaque vulnerability.
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Incidence and distribution of TCFA
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In patients dying of an AMI, the mean number of TCFA could be as high as 2.5 in men and 1.5 in women (3,7). In contrast, the incidence of TCFA in patients dying suddenly is a little over one per heart and similar in both genders. The majority of TCFA occur predominantly in the proximal portion of the three major coronary arteries, and about one-half arise in the mid-portion of these arteries; they are only infrequently seen in the distal coronary circulation. Because the vulnerable plaques are not abundant and are often located proximally in major arteries, an effort to detect vulnerable plaques is justified.
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IVUS for the detection of vulnerable plaques
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Cross sectional IVUS images of normal coronary arteries demonstrate a sharp endothelial border, thin, clear echolucent media, and dense adventitial layer (14). When intimal thickening occurs during development of atherosclerotic plaques (11), signal free zones represent lipid accumulations, soft echoes correspond to SMCs, fibrosis or collagen deposition, and bright intensity indicates calcification (15,16). Further, rupture or ulceration of lesions can often be detected in culprit vessels (17). An IVUS interrogation of all three epicardial vessels in more than 200 patients (18) closely concurred with the pathologic literature that plaque rupture of the infarct-related vessel occurred in two-thirds of patients presenting with AMI; of these, one-fifth of the patients had evidence of multiple ruptures. The plaques underlying culprit lesions were hypoechoic, eccentric, and positively remodeled. It is therefore expected that vulnerable plaques would demonstrate similar findings. Such presumption has been vindicated by serial observations in a two-year follow-up of 100-plus patients (19). The lesions that developed into an acute coronary event were characteristically large and contained relatively shallow but prominent echolucent zones. These features support the concept that vulnerable plaques are generally not trivial, have a large necrotic core and thin fibrous covers, and demonstrate outward remodeling at the site of culprit lesions.
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Supplementing ultrasonic strategies for the detection of vulnerable plaques
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Several modifications of ultrasonic techniques have allowed improved characterization of vulnerable plaques. For instance, palpography (or elastography) assesses local deformation of the fibrous cap tissue caused by the application of intraluminal pressure on the plaque surface (20,21). This technique can demonstrate significant differences between fibrous and fatty tissue in autopsied coronary and femoral arteries. Clinical studies have revealed high strain (1% to 2%) in non-calcified and low strain (0% to 0.2%) values in calcified areas of plaque. It is expected that high strain or vulnerable regions will be better characterized with the development of three-dimensional elastography for the full length interrogation of a coronary artery.
Similarly, contrast echocardiography has been used to evaluate plaque vulnerability by IVUS (22). Since vulnerable plaques have extensive adventitial network of vasa vasorum and intraplaque neoangiogenesis, it has been presumed that increased contrast intensity should indicate plaque vulnerability. Further, negatively-charged microbubbles may transiently attach to positively charged endothelium (of the neovessels) to enhance their residence time and detectability (23). The increased porousness of the neoangiogenic vessels, which allows constant RBC leakage, may (although untested) allow similar exit for microbubbles, which might then be phagocytosed by core macrophages to render them echogenic (24). Such detection can be further enhanced by imparting targeting specificity to microbubbles directed at the novel receptors expressed on macrophages. In one such exploitation of shell properties in an experimental model of atherosclerosis, phosphatidylserine was incorporated in the liposome contrast agent to target the ubiquitously expressed phosphatidylserine receptors of macrophages (25).
Two studies published in this issue of the Journal (26,27), offered refined analysis of IVUS data s for quantitative tissue characterization of plaque composition. Whereas Kawasaki et al. (26) applied three-dimensional IVUS with integrated color-coded backscatter maps, Murashighe et al. (27) used a mathematical model for wavelet analysis of radiofrequency IVUS signals. These studies suggest that identification of lipid-rich plaques from fibrous lesions may become clinically feasible. The former study evaluated the interval change in atherosclerotic lesion composition in response to treatment with statins or placebo, and demonstrated the feasibility of detection of reduction in lipid volume and concomitant increase in fibrous (and mixed) lesion volume in response to statins even before regression in geometric parameters became apparent (26). The latter study (27) accurately differentiated lipid-rich from fibrotic plaques that were histologically verified in tissue specimens from necropsy or directional atherectomy.
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Quo vadis vulnerable plaque imaging
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Although detection of various morphologic features of vulnerable plaque should become possible with IVUS techniques, it will be reasonable to propose that simultaneous efforts are invested in development of strategies that define macrophage infiltration of fibrous caps. For IVUS to become capable of such identification, it will be necessary to refine targeted imaging with microbubbles (28). It may also be possible to superimpose functional imaging strategies onto morphology-based techniques. The functional imaging can be performed by radionuclide agents, such as F-18 FDG (29) or Tc-99m-labeled Annexin-A5 which target macrophage infiltration (30,31). Intravascular beta detectors are now being investigated to provide estimates of macrophage infiltration within the atherosclerotic lesions (32).
Another novel attempt employing intravascular magnetic resonance imaging (MRI) is presented in this issue of the Journal (33). Schniderman et al. (33) used a self-contained MRI probe integrated within the tip of a coronary catheter that provided cross-sectional images with a field of view of 250 µm in depth and lateral resolution of 60°. Intravascular MRI was able to correctly identify shallow lipid cores, predominantly fibrous lesions and interestingly foam cell rich fibrous caps. Although the need to identify vulnerable plaque (beyond detecting the vulnerable patient) has not yet found universal acceptance, we believe that it will constitute one of the most important developments in our fight against acute coronary events.
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Footnotes
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Supported by NIH/NHLBI RO1 HL 68657-01.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. American Heart Association 2001 Heart and Stroke Statistical UpdateDallas, TX: American Heart Association; 2001.
2. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly N Engl J Med 1997;336:1276-1282.[Abstract/Free Full Text]
3. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events N Engl J Med 2002;347:1557-1565.[Abstract/Free Full Text]
4. Kolodgie FD, Burke AP, Farb A, et al. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes Curr Opin Cardiol 2001;16:285-292.[CrossRef][Web of Science][Medline]
5. Narula J, Virmani R, Iskandrian AE. Strategic targeting of atherosclerotic lesions J Nucl Cardiol 1999;6:81-90.[CrossRef][Medline]
6. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary deatha comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262-1275.[Free Full Text]
7. Virmani R, Burke AP, Kolodgie FD, Farb A. Vulnerable plaquethe pathology of unstable coronary lesions. J Interv Cardiol 2002;15:439-446.[Medline]
8. Kolodgie FD, Gold HK, Burke AP, et al. Erythrocyte membranes contribute to free cholesterol in necrotic cores in human N Engl J Med 2003;349:2316-2325.[Abstract/Free Full Text]
9. Koter M, Broncel M, Chojnowska-Jezierska J, Klikczynska K, Franiak I. The effect of atorvastatin on erythrocyte membranes and serum lipids in patients with type-2 hypercholesterolemia Eur J Clin Pharmacol 2002;58:501-506.[CrossRef][Web of Science][Medline]
10. Virmani R, Narula J, Farb A. When neoangiogenesis ricochets Am Heart J 1998;136:937-939.[CrossRef][Web of Science][Medline]
11. McPherson DD, Sirna SJ, Hiratzka LF, et al. Coronary arterial remodeling studied by high-frequency epicardial echocardiographyan early compensatory mechanism in patients with obstructive coronary atherosclerosis. J Am Coll Cardiol 1991;17:79-86.[Abstract]
12. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis Circulation 2002;105:297-303.[Abstract/Free Full Text]
13. Kai H, Ikeda H, Yasukawa H, et al. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes J Am Coll Cardiol 1998;32:368-372.[Abstract/Free Full Text]
14. Nishimura RA, Edwards WD, Warnes CA, et al. Intravascular ultrasound imagingin vitro validation and pathologic correlation. J Am Coll Cardiol 1990;16:145-154.[Abstract]
15. Wickline SA. Plaque characterizationsurrogate markers or the real thing?. J Am Coll Cardiol 2004;43:1185-1187.[Free Full Text]
16. Honda O, Sugiyama S, Kugiyama K, et al. Echolucent carotid plaques predict future coronary events in patients with coronary artery disease J Am Coll Cardiol 2004;43:1177-1184.[Abstract/Free Full Text]
17. Maehara A, Mintz GS, Bui AB, et al. Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound J Am Coll Cardiol 2002;40:904-910.[Abstract/Free Full Text]
18. Hong MK, Mintz GS, Lee CW, et al. Comparison of coronary plaque rupture between stable angina and acute myocardial infarctiona three-vessel intravascular ultrasound study in 235 patients. Circulation 2004;110:928-933.[Abstract/Free Full Text]
19. Yamagishi M, Terashima M, Awano K, et al. Morphology of vulnerable coronary plaqueinsights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol 2000;35:106-111.[Abstract/Free Full Text]
20. de Korte CL, Sierevogel MJ, Mastik F, et al. Identification of atherosclerotic plaque components with intravascular ultrasound elastography in vivoa Yucatan pig study. Circulation 2002;105:1627-1630.[Abstract/Free Full Text]
21. Schaar JA, De Korte CL, Mastik F, et al. Characterizing vulnerable plaque features with intravascular elastography Circulation 2003;108:2636-2641.[Abstract/Free Full Text]
22. Hamilton AJ, Huang SL, Warnick D, et al. Intravascular ultrasound molecular imaging of atheroma components in vivo J Am Coll Cardiol 2004;43:453-460.[Abstract/Free Full Text]
23. Yasu T, Schmid-Schonbein GW, Cotter B, et al. Flow dynamics of QW7437, a new dodecafluoropentane ultrasound contrast agent, in the microcirculationMicrovascular mechanisms for persistent tissue echo enhancement. J Am Coll Cardiol 1999;34:578-586.[Abstract/Free Full Text]
24. Christiansen JP, Leong-Poi H, Klibanov AL, et al. Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography Circulation 2002;105:1764-1767.[Abstract/Free Full Text]
25. Vannan MA, Ahsan C, Verjans J, Petrov AD, Narula J. Ultrasonic detection of vulnerable coronary plaques. In: Virmani R, Narula J, Casscells SW, Willerson JT, editors. Vulnerable Plaque. Washington, DC: American Registry of Pathology. In press..
26. Kawasaki M, Sano K, Okubo M, et al. Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using three dimensional integrated backscatter intravascular ultrasound J Am Coll Cardiol 2005;45:1946-1953.[Abstract/Free Full Text]
27. Murashige A, Hiro T, Fujii T, et al. Detection of lipid-laden atherosclerotic plaque by wavelet analysis of radiofrequency intravascular ultrasound signalsin vitro validation and preliminary in vivo application. J Am Coll Cardiol 2005;45:1954-1960.[Abstract/Free Full Text]
28. Villanueva FS, Jankowski RJ, Klibanov S, et al. Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells Circulation 1998;98:1-5.[Abstract/Free Full Text]
29. Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography Circulation 2002;105:2708-2711.[Abstract/Free Full Text]
30. Kietselaer BL, Reutelingsperger CP, Heidendal GA, et al. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis N Engl J Med 2004;350:1472-1473.[Free Full Text]
31. Kolodgie FD, Petrov A, Virmani R, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin Va technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003;108:3134-3139.[Abstract/Free Full Text]
32. Mari C, Strauss HW. Radiotracer characterization of coronary artery lesions Nucl Med Commun 2002;23:703-706.[CrossRef][Medline]
33. Schneiderman J, Wilensky RL, Weiss A, et al. Diagnosis of thin fibrous cap atheromas by a self-contained intravascular magnetic resonance imaging probe in ex-vivo human aortas and in-situ coronary arteries J Am Coll Cardiol 2005;45:1961-1969.[Abstract/Free Full Text]
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Characteristics of vulnerable...
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