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  IN THIS Article
 ::  Abstract
 ::  Does Plaque Size...
 ::  What Causes the ...
 ::  Role of Inflamma...
 ::  Characteristics ...
 ::  Identification o...
 ::  Non-Invasive Tec...
 ::  Drugs That May E...
 ::  Conclusion
 ::  References

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REVIEW ARTICLE
Year : 2003  |  Volume : 49  |  Issue : 4  |  Page : 361-368

Vulnerable Plaques, Inflammation and Newer Imaging Modalities


1 Department of Internal Medicine, SUNY, Buffalo, NY, USA
2 Department of Molecular Biology, University of Houston, Texas, USA

Correspondence Address:
V Bhatia
Mercy Hospital of Buffalo, 565, Abbott Road, Buffalo, NY, 14220,
USA
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Source of Support: None, Conflict of Interest: None


PMID: 14699240

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 :: Abstract 

Currently, inflammation is considered to be the central player in the pathogenesis of atherosclerosis. It leads to the formation of multiple plaques in the arterial beds including coronary vasculature. Recent studies using the latest imaging techniques have shown that in patients with acute coronary syndromes (ACS) multiple plaques are ruptured and have thrombus formation on them. Various factors make these plaques unstable, these include structural components of plaque like thin fibrous cap, high lipid content of the plaque core and inflammation, both localized and generalized. It has been shown that most of the ACS are caused by plaques causing non-critical stenosis as seen on traditional X-ray angiography. Also, the phenomenon of remodelling makes angiography a poor technique for plaque visualization. Hence newer modalities are required to identify these “vulnerable plaques”. Intravascular ultrasound (IVUS), thermography and Magnetic Resonance Imaging (MRI) are a few such promising techniques. Here we review the invasive and non-invasive modalities that can be helpful in the identification of these plaques before they become unstable and cause ACS, and also the available therapies to stabilize these plaques.


Keywords: Vulnerable plaque, Coronary artery disease, Intravascular ultrasound.


How to cite this article:
Bhatia V, Bhatia R, Dhindsa S, Virk A. Vulnerable Plaques, Inflammation and Newer Imaging Modalities. J Postgrad Med 2003;49:361-8

How to cite this URL:
Bhatia V, Bhatia R, Dhindsa S, Virk A. Vulnerable Plaques, Inflammation and Newer Imaging Modalities. J Postgrad Med [serial online] 2003 [cited 2019 Nov 18];49:361-8. Available from: http://www.jpgmonline.com/text.asp?2003/49/4/361/4984


Coronary artery stenosis is generally asymptomatic until stenosis exceeds 70 or 80%. These large lesions can produce a critical reduction in blood flow to the myocardium, resulting in typical symptoms of angina pectoris. However, acute coronary and cerebrovascular syndromes are often due to the rupture of plaques with less than 50% stenosis.[1],[2],[3],[4] The ischaemic syndrome results from subsequent thrombus formation. This leads to the concept of “vulnerable plaque” and is supported by findings in post-mortem studies in patients with ACS.[5] The reason behind the rupture of these plaques was originally thought to be the result of localized mechanical shearing and stressing forces.[6] However, on the basis of emerging evidence of a prevalent inflammatory component in ACS, inflammatory mechanisms of plaque instability began to receive considerable attention.[7] Recently, a lot of research and effort has gone into the identification of those coronary atherosclerotic plaques that might become unstable and thus trigger ACS. This concept of vulnerable plaques is already stimulating the development of imaging and other techniques for their detection before they become unstable.



  ::   Does Plaque Size Matter in Acute Coronary Syndrome? Top


A major finding in the last 2 decades was the recognition that plaque composition, rather than the severity of stenosis may determine the risk of thrombotic complications associated with ACS.[2],[8] It is now well established that disruption of the atherosclerosis lesion 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 3000 non-bypassed coronary segments in approximately 300 patients observed over a period of 42 to 66 months.[11] It was shown that less obstructive plaques (< 80% stenotic at baseline) gave rise to more occlusion than severely obstructive plaques because of their greater number.[11] Ambrose et al[3] and Little et al[4] 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 today it is accepted that in approximately 70% of cases, the clot responsible for an acute coronary event occurs in a plaque that is < 50% stenotic.[8],[12],[13] 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. It is likely that there are other factors that make a non-critically stenotic plaque unstable and prone to rupture.



  ::   What Causes the Plaque to be Unstable? Top


The concept that instability is the consequence of the disruption of a lipid-rich plaque, resulting from either mechanical stress and/or from inflammatory weakening of its fibrous cap, is now widely accepted. This model, which implies a single type of culprit coronary plaque as a cause for instability, does not appear to adequately fit the findings of comprehensive reviews of post-mortem studies.[10],[14] In some patients with ACS, fissure of the culprit lesion is the most dramatic finding of angioscopy and IVUS, as well as of post-mortem studies. However, in other patients with ACS, post-mortem studies reveal endothelial erosions underneath a variety of plaques with inflammatory cell infiltrates, some with a lipid core, others entirely fibrous.[15] In addition, particularly in younger patients and in women, endothelial erosions are found over stenotic plaques poor in lipids and rich in smooth-muscle cells and proteoglycans but without inflammatory cell infiltrates.[10] Therefore, plaque erosion without the vulnerable plaque features of fissuring or lipid-rich core may lead to ACS. Post-mortem studies in patients with ACS show that most culprit thrombi are composed of platelets or platelets and fibrin. Often, thrombi are composed of multiple layers of different age, suggestive of recent recurrences of weak thrombogenic stimuli.[14]



  ::   Role of Inflammation in Plaque Instability Top


There are a number of studies that have shown that inflammation, both localized and generalized, causes the plaques to be unstable. Inflammatory cell infiltrates were found in culprit plaques with and without fissures.[15] Inflammatory activation of metalloproteases can weaken the fibrous cap of lipid-rich plaques, increasing the likelihood of their rupture. In this event, thrombus growth would be related to the size and thrombogenicity of the fissured plaque, as well as to the number and activation of exposed inflammatory cells.[14] Alternatively, enhanced inflammation of the circulating blood may lead to activation of the clotting system, whereas inflammatory activation of the endothelium can modify its physiological vasodilatory and antithrombotic properties (production of endothelial-derived relaxing factor [EDRF], prostacyclin [PGI2], tissue plasminogen activator or [tPA], or eparansulphates) into pathological vasoconstrictor and prothrombotic properties.[16] A transient acute widespread coronary endothelial inflammatory process is suggested by transcoronary activation of neutrophils in patients with unstable angina.[17],[18] Neutrophil activation appears confined to the acute phase of instability, as it is no longer detectable at the time of discharge from the hospital.[19] Such acute endothelial inflammatory activation appears unrelated to coronary atherosclerosis or recurrent ischaemia, as it was not observed in patients with chronic stable angina and multivessel coronary disease or in patients with active variant angina.[18] The causes of such acute coronary endothelial inflammation are unknown, but both neutrophil activation and the number of inflamed coronary plaques correlated with the systemic level of C-reactive protein (CRP).[17],[20] An acute activation of the clotting system and the endothelium by inflammatory cytokines might not necessarily be related to the presence of chronic inflammatory cell infiltrates within plaques, as such infiltrates were not found in some unstable plaques.[10] Conversely, plaque inflammation can often be found in patients with stable coronary disease, as suggested at autopsy, and in vivo studies using a thermistor catheter.[21],[22],[23] This can be explained as atherosclerosis is a chronic inflammatory process but what causes these “chronically inflamed” plaques to become unstable suddenly is still not clear. Hence the precursors of unstable plaques that trigger ACS are multiple and complex, structurally and functionally.



  ::   Characteristics of Vulnerable Plaques Top


Structurally unstable plaques

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.[24] There is high circumferential stress at the luminal border of the plaque, hence rupture is more likely to occur.[25],[26] It has been shown that circumferential stress increases critically when cap thickness is less than approximately 150 microns.[25],[26]

Lipid core: A large lipid core (more than 40%) rich in cholesterol carries high risk of rupture. Lipid in the form of cholesteryl ester softens the plaque, whereas crystalline cholesterol may have the opposite effect. A few studies have shown that a negative relation exists between temperature and core stiffness.[27],[28] If temperature increases, as in inflammation, the core becomes softer. A soft core may be more vulnerable to rupture since 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.[26]



Functionally unstable plaques

Thrombosed plaques without detectable fissures represent a substantial percentage of culprit lesions found post-mortem, yet they must have been thrombogenic enough to lead to an ACS. Their vulnerability is most likely caused by thrombogenic or high-risk blood and/or local proinflammatory cytokines that promote thrombosis, sometimes also in the absence of intraplaque inflammatory cell infiltrates and in the absence of a lipid core.[10] In patients with multiple fissured plaques and/or thrombi with layers of different ages, the possibility of a widespread coronary inflammation and/or of systemic blood thrombogenicity should be considered, which may or may not be superimposed on a baseline structural vulnerability. The presence of multiple inflamed plaques or of widespread endothelial activation and elevated systemic inflammatory markers in some patients with ACS suggests that there may be not only isolated or multiple inflamed vulnerable plaques or a vulnerable endothelium, but also some vulnerable patients who remain vulnerable for a period of weeks and months and who could be identified by persistent elevation of systemic inflammatory markers.[29],[30] In such inflamed patients, it may be difficult to identify which coronary plaque may suddenly flare up and become unstable, particularly if such an event may also occur in the absence of inflammatory cell infiltrates and of a central lipid pool.



Multiplicity of high-risk plaques

ACS appears to be caused by the rupture of an unstable coronary plaque that appears as a single lesion on angiography. However, there is increasing evidence that systemic effects, such as inflammation, are more widespread within the coronary circulation and this may be leading to the instability of multiple plaques.[18],[31],[32],[33],[34],[35]



Complex angiographic appearance

Coronary angiography in patients with ACS often reveals a complex plaque, which is an eccentric-appearing lesion with overhanging edges and irregular borders, ulceration, impaired flow, and often thrombosis. Complex plaques are an indicator of plaque rupture and/or thrombus in patients with unstable symptoms and have been considered to be the “culprit lesion”.[3],[31],[32],[36] Another report showed the presence of multiple complex plaques in the majority of patients with ACS, they required bypass surgery during admission more often and, during the subsequent year, had a significantly higher incidence of ACS.[31] However, some complex plaques that undergo remodelling may become smooth, whereas others may remain complex but eventually become functionally stable, as angiographically complex lesions can also be found in a substantial percentage of patients with stable coronary artery disease (CAD). Thus, outside of clinically unstable phases, neither complex stenoses nor severe flow-limiting stenoses, which are typical of chronic stable angina, represent plausible, isolated, morphological markers of instability.



Remodelling of plaques

In the early phases of atherosclerosis development, when CAD is minimal, luminal size is not affected by plaque growth because of the expansion of the external elastic membrane (EEM) and enlargement of the vessel size; this represents “positive remodelling”.[37],[38] Further, as CAD becomes moderate there is no increase in the vessel size, but rather the plaque approaches the lumen which shrinks; this is “negative remodelling”. Positive remodelling, larger plaque areas, and echolucent plaques are associated with unstable angina, while negative remodelling and smaller plaque areas are associated with stable angina.[39] Positive remodelling is also seen in acute myocardial infarction at the site of plaque rupture.[40] These findings are consistent with other observations that inflammation, calcification, and medial thinning are primary determinants of positive remodelling, which appears to be a feature of plaque instability.[41]



  ::   Identification of Vulnerable Plaques Top
Invasive Techniques

Angiography: The X-ray coronary angiogram reflects luminal diameter and provides a measure of stenosis with excellent resolution or irregular luminal surface implying the presence of atherosclerotic disease. But this imaging method does not image the vessel wall or provide information about the composition of the atherosclerotic plaque. The phenomenon of remodelling makes angiography a poor technique for assessing the true atherosclerotic burden. The shadows of the coronary lumen seen on angiography provide only indirect and incomplete information concerning the extent of the atherosclerotic process in the arterial wall.



Intravascular ultrasound (IVUS): It is a new technology that allows in-vivo visualization of variations in arterial geometry and atherosclerotic plaque by utilizing a miniature transducer at the end of a flexible catheter.[37],[38] IVUS provides a two-dimensional cross-sectional image of the arterial wall and can accurately assess the plaque burden.[43] This issue of multiple complex lesions was addressed in an IVUS study of 72 arteries in 24 patients referred for percutaneous coronary intervention after a first non-ST elevation MI; all had a clearly identified culprit lesion on angiography.[35] IVUS revealed a mean of 2.1 plaque ruptures per patient; at least one was found somewhere other than in the culprit lesion in 19 (79%), 17 of which were in a different artery from the culprit artery. The ruptures in the non-culprit plaques were less severe, less calcified, and non-stenosing. These observations are consistent with another IVUS study of 32 patients who underwent follow-up catheterisation one month after an acute myocardial infarction (MI).[42] However, the resolution of the ultrasound system is related to its frequency. For high- frequency (40 to 50 Mhz) systems, imaging may be hampered by an increased back scatter of blood.[44] Histopathological studies mostly report low sensitivity for IVUS in detecting lipid-rich lesions although the analysis of IVUS radio-frequency signals may improve tissue characterization.[45],[46] 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.[47]



IVUS elastography: IVUS elastography is based on the principle that tissue components that differ in hardness as a result of their different histopathological composition are expected to be compressed differently if a defined pressure is applied.[38] The technique is able to discriminate between soft and hard material and assess the mechanical properties of the vessel wall.[59] Hard and soft regions can be identified using this technique, while in the original image, it is not possible to discriminate the different tissue types.[60] This technique has the potential to identify plaque vulnerability since the detected areas of increased radial strain represent regions of high circumferential stress, a feature of plaque vulnerability. However, a major problem in advancing IVUS elastography to cardiac in vivo applications is the acquisition of data in a pulsating artery located in a contracting heart.



Angioscopy: The colour 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.[48],[49] Such plaques are found in all three major coronary arteries, suggesting that the development of these vulnerable plaques is a pan-coronary process.[42] Smooth white plaques are observed in patients with old myocardial infarction and stable angina. A 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. Plaques 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.[50] By comparison, white plaques are less likely to rupture since 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 its inability to examine the different layers within the arterial wall and to provide an estimation of cap thickness or lipid content.[51]



Thermography- “Imaging the inflammation”: A persistent finding in the histopathological specimens of ruptured atherosclerotic plaques has been the presence of activated macrophages within the plaque.[2] Accumulation of these cells reflects the inflammatory process that has been implicated in the pathogenesis of ACS. Since the cardinal sign of inflammation is an increase in temperature, local differences in plaque temperature may be expected 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.[52] Recently, in vivo studies demonstrated temperature heterogeneity to be determined by plaque composition and more specifically by macrophage mass.[53] The exact mechanism for the increased local temperature in a 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 is involved in thermogenesis in that tissue) have been implicated in the generation of heat in the inflamed plaque.[54]

The direct measurement of the temperature of the coronary atherosclerotic plaque has become feasible with the use of specially designed thermography catheters.[23] 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 more in unstable angina and acute myocardial infarction patients, implying that it may be related to the pathogenesis of ACS.[23] Another clinical study showed that plaque temperature was higher in patients with ACS and predicted long-term clinical events in patients undergoing Percutaneous Transluminal Coronary Angioplasty (PTCA) and stent implantation.[55] Recently, a study showed a lesser temperature difference between the atherosclerotic plaques and the normal coronary artery in patients on statins. This finding supports a favourable effect of statins on heat release from the atherosclerotic plaques.[56]

There is increasing evidence that patients at high risk of ACS have multiple high-risk plaques.[18],[31],[32],[33],[34],[35] Based on the above principle, the 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.[57] Patients with significant lesions in the left coronary artery bed had the highest temperature difference between the blood from the coronary sinus and the right atrium.[58] Thus thermography can develop into a technique to identify “inflamed” patients.



Optical Coherence Tomography (OCT): A laser beam is directed at the plaques and the reflected light is analysed. It is capable of visualizing the atherosclerotic lesion with an axial resolution of 2 to 30 microns. The current penetration depth is limited to 1 to 2 mm. Studies revealed that OCT is capable of differentiating lipid tissue from water-based tissues.[61] Furthermore, the thickness of the fibrous cap overlying an atheroma can be demarcated by OCT.[61] The limitations of OCT for in vivo intravascular imaging include the reduction of image quality when imaging through blood or large volumes of tissue, the relatively slow data acquisition rate, and multiple scattering.



Raman Spectroscopy: Raman spectroscopy is ideal for identifying gross chemical changes in tissue, such as in atherosclerosis.[62] It is an imaging modality in an early stage of development that has great potential to discriminate in vivo between lipid-rich, calcified and fibrotic plaques. The 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. The current limitations of Raman spectroscopy are strong background fluorescence and laser light absorption by the blood.



Near-Infrared (NIR) Spectroscopy: Diffused reflectance near-infrared spectroscopy (NIR) has been used extensively to identify the chemical content of biological specimens. NIR spectroscopy (750-2500 nm) is based on the absorption of light by organic molecules. The reflectance spectra from wave lengths between 400 and 2400 nm allows detailed analysis of chemical composition.[63] The advantage of this technique is its deeper penetration into the atherosclerotic plaque and that it can be combined with other catheter-based techniques, but its use has been limited until now to in vitro studies.



  ::   Non-Invasive Techniques  Top


Electron beam computed tomography (EBCT): EBCT is a technique of imaging coronary artery calcium that uses a faster rate of image acquisition than conventional CT. With fast imaging the elimination of cardiac respiratory motion artifacts is accomplished. It has been suggested that in asymptomatic men and women aged 50 to 70, EBCT derived coronary calcium score accurately predicts coronary disease events independently of standard risk factors and can be used to refine the Framingham risk index.[64] Coronary calcification detected by EBCT is found in individuals who have significant angiographic CAD, 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 5.[65],[66],[67] Since 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 prior to invasive angiography and may be particularly helpful in patients with an equivocal exercise test.[68]

Limitations: Calcium severity on EBCT can identify asymptomatic patients at high risk of CHD, but it is not certain if this translates into the identification of asymptomatic patients who have silent ischaemia, which is of importance since the presence of silent ischaemia 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. It is expected that the greatest potential for coronary calcium scores appears to be in the detection of advanced coronary atherosclerosis in patients who are apparently at an intermediate risk. The site and extent of calcification do not equate with site-specific stenosis and a calcific plaque does not mean a stable plaque necessarily.



Magnetic resonance imaging (MRI): High resolution MRI holds the promise of non-invasively imaging high-risk plaques. High-resolution fast spin echo and optimized computer processing have enhanced the spatial resolution (0.4 mm) during the visualization of atherosclerotic plaques in vivo. In experimental studies in small hypercholesterolemic animal models, in atherosclerotic lesions, an excellent agreement was observed between high-resolution MRI (9T system, in plane spatial resolution 97 microns) and histopathology. MRI studies are currently being performed to study the progression and regression of atherosclerotic plaques over time.[69],[70] Using ultra small super paramagnetic particles of iron oxide, macrophage accumulation in the aorta could be seen in hypercholesterolemic rabbits before atherosclerotic lesions were detected.[71] MRI is also used to visualize and characterize arterial thrombi in vivo.[49], [72]

High-resolution MRI is an excellent tool to visualize fibrous cap thickness and rupture in plaques.[73],[74]

Limitations: Although MRI is a promising non-invasive tool for detecting vulnerable plaques, at present it lacks sufficient resolution (currently 400 microns) 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 the analysis of intimal thickness and accurately determines plaque size.[75] 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 non-invasive MRI to detect high-risk vulnerable atherosclerotic plaques and enhance patients' risk stratification.[76],[77] At present, MRI not only provides a non-invasive method of visualizing plaque and discriminating its components, but also provides 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. But certain technical improvements are still desired.



Positron Emission Tomography (PET Scan): The cellular components of the atherosclerotic plaque, such as macrophages, exhibit high glucose metabolic activity. Fluorodeoxyglucose (FDG) positron emission tomographic (PET) scans showed an increased vascular FDG uptake in older patients that was explained by smooth muscle metabolism in the media, subendothelial smooth muscle proliferation from senescence, and the presence of macrophages within the atherosclerotic plaque.[78] Further studies are required to substantiate this observation. Hence the PET scan can evolve into an important tool for imaging vulnerable atherosclerotic plaques.



  ::   Drugs That May Enhance Plaque Stability  Top


At present there is no proven drug or modality to stabilize the vulnerable plaques. A number of drugs that are beneficial for patients with coronary disease may act in part by improving the stability of plaques that are vulnerable for future rupture.[79], [80]

l Beta blockers lower circumferential wall stress via reductions in blood pressure, heart rate, left ventricular mass, and catecholamine surges that occur with stress and exertion.[80]

l Angiotensin converting enzyme (ACE) inhibitors lower the blood pressure and may have plaque-stabilizing effects by reducing the synthesis of angiotensin II.

l Lipid-lowering therapy, particularly with statins, can stabilize vulnerable plaques or those that have already ruptured by improving endothelial function and reducing thrombogenicity, platelet aggregation, and possibly inflammation.[81]

l Antithrombotic therapy, including antiplatelet agents and warfarin do not stabilize the vulnerable plaque, but they do limit thrombosis, which is an important consequence of plaque rupture.



  ::   Conclusion Top


At present the ideal of these newer modalities for optimum use remains undefined. The ideal approach would provide both anatomic and functional data about vulnerable plaques. It seems that these modalities can provide useful information for risk stratification. In patients found to be at high risk based on family history and the presence of co-morbid conditions like diabetes or high serum CRP level, this information may add to the “awareness of vulnerability” for the patient and the physician. This can improve the patient's compliance with diet and medications, and can possibly define new treatment goals for optimum weight, blood pressure, lipids and glucose control. The presence of vulnerability may merit multiple systemic therapies, such as aspirin, clopidogrel, ACE inhibitors, [beta]-adrenergic blockers and statins once their role in plaque stabilization has been proved further. Another potential use of these modalities can be the identification of subsets of patients with atherosclerosis who can benefit the most from the anti-oxidant therapies.

 
 :: References Top

1.Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242-50.  Back to cited text no. 1  [PUBMED]  
2.Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995;92:657-71.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12:56-62.  Back to cited text no. 3  [PUBMED]  
4.Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78:1157-66.  Back to cited text no. 4  [PUBMED]  
5.Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989;79:733-43.  Back to cited text no. 5  [PUBMED]  
6.Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989;2:941-4.  Back to cited text no. 6  [PUBMED]  
7.Buja LM, Willerson JT. Role of inflammation in coronary plaque disruption. Circulation 1994;89:503-5.  Back to cited text no. 7  [PUBMED]  
8.Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: biology. Lancet. 1999;353:S115-9.  Back to cited text no. 8    
9.Zaman AG, Helft G, Worthley SG, Badimon JJ. The role of plaque rupture and thrombosis in coronary artery disease. Atherosclerosis 2000;149:251-66.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262-75.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Alderman EL, Corley SD, Fisher LD, Chaitman BR, Faxon DP, Foster ED, et al. Five-year angiographic follow-up of factors associated with progression of coronary artery disease in the Coronary Artery Surgery Study (CASS). CASS Participating Investigators and Staff. J Am Coll Cardiol 1993;22:1141-54.  Back to cited text no. 11  [PUBMED]  
12.Nobuyoshi M, Tanaka M, Nosaka H, Kimura T, Yokoi H, Hamasaki N, et al. Progression of coronary atherosclerosis: is coronary spasm related to progression? J Am Coll Cardiol 1991;18:904-10.  Back to cited text no. 12  [PUBMED]  
13.Giroud D, Li JM, Urban P, Meier B, Rutishauer W. Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography. Am J Cardiol 1992;69:729-32.  Back to cited text no. 13  [PUBMED]  
14.Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation. 1996;94:2013-20.  Back to cited text no. 14    
15.van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36-44.  Back to cited text no. 15    
16.Sambola A, Osende J, Hathcock J, Degen M, Nemerson Y, Fuster V, et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 2003;107:973-7.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Mazzone A, De Servi S, Ricevuti G, Mazzucchelli I, Fossati G, Pasotti D, et al. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease. Circulation 1993;88:358-63.  Back to cited text no. 17  [PUBMED]  
18.Buffon A, Biasucci LM, Liuzzo G, D'Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347:5-12.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Biasucci LM, D'Onofrio G, Liuzzo G, Zini G, Monaco C, Caligiuri G, et al. Intracellular neutrophil myeloperoxidase is reduced in unstable angina and acute myocardial infarction, but its reduction is not related to ischemia. J Am Coll Cardiol 1996;27:611-6.  Back to cited text no. 19    
20.Zairis MN, Papadaki OA, Manousakis SJ, Thoma MA, Beldekos DJ, Olympios CD, et al. C-reactive protein and multiple complex coronary artery plaques in patients with primary unstable angina. Atherosclerosis 2002;164:355-9.  Back to cited text no. 20    
21.van der Wal AC, Becker AE, Koch KT, Piek JJ, Teeling P, van der Loos CM, et al. Clinically stable angina pectoris is not necessarily associated with histologically stable atherosclerotic plaques. Heart1996;76:312-6.  Back to cited text no. 21    
22.Arbustini E, Grasso M, Diegoli M, Pucci A, Bramerio M, Ardissino D, et al. Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes: a morphologic, immunohistochemical, and biochemical study. Am J Cardiol 1991;68:36B-50B.  Back to cited text no. 22    
23.Stefanadis C, Diamantopoulos L, Vlachopoulos C, Tsiamis E, Dernellis J, Toutouzas K, et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965-71.  Back to cited text no. 23    
24.Fuster V. Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994;90:2126-46.  Back to cited text no. 24    
25.Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res 1992;71:850-8.  Back to cited text no. 25    
26.Loree HM, Tobias BJ, Gibson LJ, Kamm RD, Small DM, Lee RT. Mechanical properties of model atherosclerotic lesion lipid pools. Arterioscler Thromb 1994;14:230-4.  Back to cited text no. 26    
27.Small DM. George Lyman Duff memorial lecture. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry. Arteriosclerosis 1988;8:103-29.  Back to cited text no. 27    
28.Lundberg B. Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis 1985;56:93-110.  Back to cited text no. 28    
29.Biasucci LM, Liuzzo G, Grillo RL, Caligiuri G, Rebuzzi AG, Buffon A, et al. Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability. Circulation 1999;99:855-60.  Back to cited text no. 29    
30.Bogaty P, Poirier P, Simard S, Boyer L, Solymoss S, Dagenais GR. Biological profiles in subjects with recurrent acute coronary events compared with subjects with long-standing stable angina. Circulation 2001;103:3062-8.  Back to cited text no. 30    
31.Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O'Neill WW. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000;343:915-22.  Back to cited text no. 31    
32.Maehara A, Mintz GS, Bui AB, Walter OR, Castagna MT, Canos D, et al. Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound. J Am Coll Cardiol 2002;40:904-10.  Back to cited text no. 32    
33.Keaney JF Jr, Vita JA. The value of inflammation for predicting unstable angina. N Engl J Med 2002;347:55-7.  Back to cited text no. 33    
34.Kerensky RA, Wade M, Deedwania P, Boden WE, Pepine CJ. Revisiting the culprit lesion in non-Q-wave myocardial infarction. Results from the VANQWISH trial angiographic core laboratory. J Am Coll Cardiol 2002;39:1456-63.  Back to cited text no. 34    
35.Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation 2002;106:804-8.  Back to cited text no. 35    
36.Ojio S, Takatsu H, Tanaka T, Ueno K, Yokoya K, Matsubara T, et al. Considerable time from the onset of plaque rupture and/or thrombi until the onset of acute myocardial infarction in humans: coronary angiographic findings within 1 week before the onset of infarction. Circulation 2000;102:2063-9.  Back to cited text no. 36    
37.Losordo DW, Rosenfield K, Kaufman J, Pieczek A, Isner JM. Focal compensatory enlargement of human arteries in response to progressive atherosclerosis. In vivo documentation using intravascular ultrasound. Circulation 1994;89:2570-7.  Back to cited text no. 37    
38.Vavuranakis M, Stefanadis C, Toutouzas K, Pitsavos C, Spanos V, Toutouzas P. Impaired compensatory coronary artery enlargement in atherosclerosis contributes to the development of coronary artery stenosis in diabetic patients. An in vivo intravascular ultrasound study. Eur Heart J 1997;18:1090-4.  Back to cited text no. 38    
39.Ahmed JM, Mintz GS, Weissman NJ, Lansky AJ, Pichard AD, Satler LF, et al. Mechanism of lumen enlargement during intracoronary stent implantation: an intravascular ultrasound study. Circulation 2000;102:7-10.  Back to cited text no. 39    
40.Berglund H, Luo H, Nishioka T, Fishbein MC, Eigler NL, Tabak SW, et al. Highly localized arterial remodeling in patients with coronary atherosclerosis: an intravascular ultrasound study. Circulation 1997;96:1470-6.  Back to cited text no. 40    
41.Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002;105:297-303.  Back to cited text no. 41    
42.Asakura M, Ueda Y, Yamaguchi O, Adachi T, Hirayama A, Hori M, et al Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol 2001;37:1284-8.  Back to cited text no. 42    
43.Gussenhoven EJ, Essed CE, Lancee CT, Mastik F, Frietman P, van Egmond FC, et al. Arterial wall characteristics determined by intravascular ultrasound imaging: an in vitro study. J Am Coll Cardiol 1989;14:947-52.  Back to cited text no. 43    
44.Potkin BN, Bartorelli AL, Gessert JM, Neville RF, Almagor Y, Roberts WC, et al. Coronary artery imaging with intravascular high-frequency ultrasound. Circulation 1990;81:1575-85.  Back to cited text no. 44    
45.Peters RJ, Kok WE, Havenith MG, Rijsterborgh H, van der Wal AC, Visser CA. Histopathologic validation of intracoronary ultrasound imaging. J Am Soc Echocardiogr 1994;7:230-41.  Back to cited text no. 45    
46.Komiyama N, Berry GJ, Kolz ML, Oshima A, Metz JA, Preuss P, et al. Tissue characterization of atherosclerotic plaques by intravascular ultrasound radiofrequency signal analysis: an in vitro study of human coronary arteries. Am Heart J 2000;140:565-74.  Back to cited text no. 46    
47.Ge J, Baumgart D, Haude M, Gorge G, von Birgelen C, Sack S, et al. Role of intravascular ultrasound imaging in identifying vulnerable plaques. Herz 1999;24:32-41.  Back to cited text no. 47    
48.Mizuno K, Miyamoto A, Satomura K, Kurita A, Arai T, Sakurada M, et al. Angioscopic coronary macromorphology in patients with acute coronary disorders. Lancet 1991;337:809-12.  Back to cited text no. 48    
49.Thieme T, Wernecke KD, Meyer R, Brandenstein E, Habedank D, Hinz A, et al. Angioscopic evaluation of atherosclerotic plaques: validation by histomorphologic analysis and association with stable and unstable coronary syndromes. J Am Coll Cardiol 1996;28:1-6.  Back to cited text no. 49    
50.Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988;77:1213-20.  Back to cited text no. 50    
51.Uchida Y, Nakamura F, Tomaru T, Morita T, Oshima T, Sasaki T, et al. Prediction of acute coronary syndromes by percutaneous coronary angioscopy in patients with stable angina. Am Heart J 1995;130:195-203.  Back to cited text no. 51    
52.Casscells W, Hathorn B, David M, Krabach T, Vaughn WK, McAllister HA, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996;347:1447-51.  Back to cited text no. 52    
53.Verheye S, De Meyer GR, Van Langenhove G, Knaapen MW, Kockx MM. In vivo temperature heterogeneity of atherosclerotic plaques is determined by plaque composition. Circulation 2002;105:1596-601.  Back to cited text no. 53    
54.Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J 2000;345:161-79.  Back to cited text no. 54    
55.Stefanadis C, Toutouzas K, Tsiamis E, Stratos C, Vavuranakis M, Kallikazaros I, et al. Increased local temperature in human coronary atherosclerotic plaques: an independent predictor of clinical outcome in patients undergoing a percutaneous coronary intervention. J Am Coll Cardiol 2001;37:1277-83.  Back to cited text no. 55    
56.Stefanadis C, Toutouzas K, Vavuranakis M, Tsiamis E, Tousoulis D, Panagiotakos DB, et al . Statin treatment is associated with reduced thermal heterogeneity in human atherosclerotic plaques. Eur Heart J 2002;23:1664-9.  Back to cited text no. 56    
57.Spagnoli LG, Bonanno E, Mauriello A, Palmieri G, Partenzi A, Sangiorgi G, et al. Multicentric inflammation in epicardial coronary arteries of patients dying of acute myocardial infarction. J Am Coll Cardiol 2002;40:1579-88.  Back to cited text no. 57    
58.Stefanadis C, Toutouzas K, Vaina S, Vavuranakis M, Toutouzas P. Thermography of the cardiovascular system. J Interv Cardiol 2002;15:461-6.  Back to cited text no. 58    
59.de Korte CL, Cespedes EI, van der Steen AF, Pasterkamp G, Bom N. Intravascular ultrasound elastography: assessment and imaging of elastic properties of diseased arteries and vulnerable plaque. Eur J Ultrasound 1998;7:219-24.  Back to cited text no. 59    
60.de Korte CL, Carlier SG, Mastik F, Doyley MM, van der Steen AF, Serruys PW, et al. Morphological and mechanical information of coronary arteries obtained with intravascular elastography; feasibility study in vivo. Eur Heart J 2002;23:405-13.  Back to cited text no. 60    
61.Brezinski ME, Tearney GJ, Bouma BE, Izatt JA, Hee MR, Swanson EA, et al. Optical coherence tomography for optical biopsy. Properties and demonstration of vascular pathology. Circulation 1996;93:1206-13.  Back to cited text no. 61    
62.Romer TJ, Brennan JF, Schut TC, Wolthuis R, van den Hoogen RC, Emeis JJ, et al. Raman spectroscopy for quantifying cholesterol in intact coronary artery wall. Atherosclerosis. 1998;141:117-24.  Back to cited text no. 62    
63.Moreno PR, Lodder RA, Purushothaman KR, Charash WE, O'Connor WN, Muller JE. Detection of lipid pool, thin fibrous cap, and inflammatory cells in human aortic atherosclerotic plaques by near-infrared spectroscopy. Circulation. 2002;105:923-7.  Back to cited text no. 63    
64.Arad Y, Roth M, Newstein D, Guerci AD. Coronary Calcification, Coronary Disease Risk Factors, And Atherosclerotic Cardiovascular Disease Events: The St. Francis Heart Study. Data presented at 52nd scientific session of ACC, 2003.  Back to cited text no. 64    
65.Breen JB, Sheedy PF, Schwartz RS. Coronary artery calcification detected with ultrafast CT as an indication of coronary artery disease. Radiology 1992;185:435.  Back to cited text no. 65    
66.Bielak LF, Kaufmann RB, Moll PP. Small lesions in the heart identified at electron beam CT: Calcification or noise? Radiology 1994;192:631.  Back to cited text no. 66    
67.Devries S, Wolfkiel C, Fusman B. Influence of age and gender on the presence of coronary calcium detected by ultrafast computed tomography. J Am Coll Cardiol 1995;25:76.  Back to cited text no. 67    
68.Schmermund A, Baumgart D, Sack S, Mohlenkamp S, Gronemeyer D, Seibel R, et al. Assessment of coronary calcification by electron-beam computed tomography in symptomatic patients with normal, abnormal or equivocal exercise stress test. Eur Heart J 2000;21:1674.  Back to cited text no. 68    
69.Worthley SG, Helft G, Fuster V, Zaman AG, Fayad ZA, Fallon JT, et al . Serial in vivo MRI documents arterial remodeling in experimental atherosclerosis. Circulation 2000;101:586-9.  Back to cited text no. 69    
70.Helft G, Worthley SG, Fuster V, Fayad ZA, Zaman AG, Corti R, et al. Progression and regression of atherosclerotic lesions: monitoring with serial noninvasive magnetic resonance imaging. Circulation 2002;105:993-8.  Back to cited text no. 70    
71.Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 2001;103:415-22.  Back to cited text no. 71    
72.Moody AR, Allder S, Lennox G, Gladman J, Fentem P. Direct magnetic resonance imaging of carotid artery thrombus in acute stroke. Lancet 1999;353:122-3.  Back to cited text no. 72    
73.Hatsukami TS, Ross R, Polissar NL, Yuan C. Visualization of fibrous cap thickness and rupture in human atherosclerotic carotid plaque in vivo with high-resolution magnetic resonance imaging. Circulation 2000;102:959-64.  Back to cited text no. 73    
74.Yuan C, Zhang SX, Polissar NL, Echelard D, Ortiz G, Davis JW, et al. Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke. Circulation 2002;105:181-5.  Back to cited text no. 74    
75.Correia LC, Atalar E, Kelemen MD, Ocali O, Hutchins GM, Fleg JL, et al. Intravascular magnetic resonance imaging of aortic atherosclerotic plaque composition. Arterioscler Thromb Vasc Biol 1997;17:3626-32.  Back to cited text no. 75    
76.Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocca EA, et al. In vivo magnetic resonance imaging of transgene expression Nat Med 2000;6:351-5.  Back to cited text no. 76    
77.Tempany CM, McNeil BJ. Advances in biomedical imaging. JAMA 2001;285:562-7.  Back to cited text no. 77    
78.Yun M, Yeh D, Araujo LI, Jang S, Newberg A, Alavi A. F-18 FDG uptake in the large arteries: a new observation. Clin Nucl Med 2001;26:314-9.  Back to cited text no. 78    
79.Kullo IJ, Edwards WD, Schwartz RS. Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med 1998;129:1050-60.  Back to cited text no. 79    
80.Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001;104:1477-82.  Back to cited text no. 80    
81.Ambrose JA, Martinez EE. A new paradigm for plaque stabilization. Circulation 2002;105:2000-4.  Back to cited text no. 81  [PUBMED]  [FULLTEXT]



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© 2004 - Journal of Postgraduate Medicine
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