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Carotid Plaque Morphology: Plaque Instability and Correlation with Development of Ischaemic Neurological Events

Written By

Reza Mofidi and Barnabas Rigden Green

Submitted: September 12th, 2013 Published: January 22nd, 2014

DOI: 10.5772/57254

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1. Introduction

Stroke is one of the major health care problems in the world today. It is the third leading cause of mortality in the western countries and the most common cause of mortality of any neurological disorder. Incidence of stroke is 160 per 100,000 population per year; 40 percent of victims require some type of special services and 10 percent require total care. [1, 2] Consequently, stroke rehabilitation places a large drain on national health care resources.

A significant proportion of strokes are ischemic in nature, one of leading causes for which is internal carotid artery (ICA) atherosclerosis. It is estimated that 20-25 percent of all strokes can be attributed directly to carotid bifurcation atherosclerosis. [1, 2]

Both internal carotid artery endarterectomy and carotid stenting in patients with preoperative ocular or cerebral embolic events are well established as procedures that reduce the risk of future ischaemic events. [3-7] In addition to the management of hypertension and commencement of antiplatelet and statin therapy, these interventions form the corner stone of stroke prevention policy in patients with significant ICA stenosis. As it is recognised that a significant proportion of patients have a disabling embolic stroke attributable to severe ICA stenosis without any prior symptoms, [8, 9] it would be advantageous if patients who are at highest risk of stroke from ICA stenosis could be identified and treated in advance of any ischaemic neurological events.

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2. Atherosclerotic plaque morphology

Atherosclerotic plaques are not static lesions; they undergo dynamic changes in their size and morphological characteristics. These changes manifest themselves as changes in plaque volume and consistency, otherwise known as plaque progression and regression. These, together with adaptive responses of the arterial wall, determine the degree of stenosis in the diseased artery. [10-12] This degree of stenosis is the measurable clinical finding which, together with timing and nature of symptoms and co-morbidities, correlates with the risk of developing further neurological events. [13]

Over the last 20 years a lot has been learned about the morphological characteristics of an atherosclerotic plaque responsible for plaque progression and instability. [10-12] Morphological characteristics of atherosclerotic plaques can be discussed in the context of plaque surface characteristics and the composition of the atherosclerotic lesion.

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3. Plaque surface characteristics

Julian et al in 1963 were the first to discuss the issue of carotid plaque ulceration. They reported 17 cases of macroscopic plaque ulceration with thrombosis in the ulcer crater and suggested this as a source for embolisation. [12] Ulceration has been described as an observable disruption of intima exposing the adjacent atheromatous plaque or media [13] (figure 1).

Figure 1.

A carotid endarterectomy specimen containing a large ulcer which is associated with intra-plaque haemorrhage.

There has been conflicting evidence regarding the significance of plaque ulceration in the evolution of symptomatic disease. In a large study, Imparato et al did not find any significant difference in the incidence of ulceration between symptomatic and asymptomatic groups. [14-16]

Other researchers have found a definite increase in the incidence of plaque ulceration in patients with symptomatic carotid artery disease. Most notably, following review of 593 angiograms in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), 34 percent of medically treated patients were found to have ulcerated plaques with reasonable certainty; this figure was 36 percent for those assigned to surgery. At 2 years, 30 percent of the medically treated group with ulceration had suffered a non-fatal stroke or vascular death compared to only 17 percent of those without plaque ulceration [17].

One reason for this difference may be the time interval between the duration of symptoms and surgery in some of the studies. Lusby et al reported re-endothelialisation of several plaques, and suggested that this is particularly likely when the time span between the onset of symptoms and endarterectomy exceeds 3 weeks. [18]

The strength of the evidence from the NASCET trial has meant that most clinicians recognise plaque cap ulceration as a risk factor for development of further carotid territory embolic neurological events. Preoperative evidence of plaque cap ulceration has been included in stroke risk calculators such as the Oxford Stroke Risk calculator. [19]

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4. Composition of an atherosclerotic plaque

The raised lesion or fibro-lipid plaque is the archetypal lesion of atherosclerosis and complications of this lesion (fissure and ulceration) form the basis of the vast majority of cases of occlusive arterial disease. All atherosclerotic plaques share two basic morphological components:

Fibrous cap: a thick layer of fibrous connective tissue, which is significantly thicker and much less cellular than the normal intima and contains lipid-filled macrophages, collagen and smooth muscle cells;

Atheroma: A necrotic mass of lipid that forms the core of the lesion. Loss of continuity of the endothelium is the main step in the progression of a plaque and increases the permeability of the intima to lipoproteins, permits platelet-vessel wall interaction and release of growth factors leading to formation of thrombus on the vessel wall.

Leahy demonstrated that various elements of the plaque are available as potential emboli. [20] This includes the fibrous cap overlying complex plaques, the contents that include cholesterol crystals, the breakdown products of intra-plaque haemorrhage, and fibrous or cartilaginous material as well as calcified tissue. Hollenhorst showed the presence of cholesterol emboli in the retinal artery of patients suffering from amaurosis fugax, in the form of bright plaques that were seen in the extra-cranial carotid vessels. [21] Bock et al reported that soft plaques (lipid laden and haemorrhagic plaque) behave in an unstable way and tend to ulcerate, whilst fibrous or calcified plaques behave differently. [22]

Based on the natural history and pathological changes within the plaque the American Heart Association (AHA) has classified atherosclerotic lesions [23] (table 1). This classification that has been modified by Virmani and Naghavi et al divides the atheromatous lesions into non-atherosclerotic intimal lesions and progressive atherosclerotic plaques. [24, 25] The classification, although not particularly directed at the carotid atherosclerotic lesions, is however applicable when classifying carotid plaques. Progressive atherosclerotic plaques (AHA plaque types V and VI) are relevant in the setting of clinically significant carotid disease (figure-2).

Type I Adaptive Lesion: Intimal Smooth Muscle Cells (SMC)
Type II Fatty Streak, Foamy Macrophages and underlying SMCs
Type III Pre Atheroma, Intimal Macrophages, deeper pools of extracellular lipid
Type IV Atheroma (Fibrous Plaque), dense large extra cellular lipid core deep to intima, and close to media.
Type V Fibroatheroma, multiple layers of lipid core encased in a fibrous cap
Type VI Complicated plaque:
VI a Disruption of the intimal surface
VI b Intra Plaque Haemorrhage
VI c Thrombosis related to the atherosclerotic plaque

Table 1.

American Heart Association has classification of atherosclerotic lesions [23] (Circulation 1995;92: 1355-74)

Figure 2.

American Heart Association Type VI (Complicated atherosclerotic lesion) obtained from a carotid endarterectomy specimen. (Br J Surg. 2001;88:945–950.)

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5. The concept of unstable atherosclerotic plaque

The concept that a sub-group of atherosclerotic plaques are prone to embolisation or thrombosis is not new. As early as 1926, Benson postulated that coronary thrombosis results from disruption of intima that exposes lipids to flowing blood. [26] Constantinides was the first to establish conclusively that plaque rupture was the immediate cause of coronary thrombosis. [27] In a series of subsequent studies Davies et al established the importance of plaque fissuring, ulceration and subsequent thrombosis in the development of acute coronary syndromes. [28-30] Further clinical and angiographic work has led to progression of this concept and introduction of thrombolytic therapy in the treatment of coronary artery atherosclerosis. [31-34]

Atherosclerotic plaques that are prone to rupture are known to have certain cellular, molecular and structural features. Notably these include an intense inflammatory process within the plaque, angiogenesis, and intra-plaque haemorrhage with gradual thinning of the fibrous cap, subsequent loss of plaque cap integrity and ulceration. [35] Burke et al defined a vulnerable plaque in the coronary arteries as a lesion with a cap thickness of less than 65 µM [36]. Gertz et al noted that the lipid cores were much larger in areas of atherosclerotic plaque disruption than in lesions with intact surfaces. [37-38] Inflammatory activity within the plaque is associated with plaque ulceration and has a role in pathogenesis of intimal damage. [39]

The evolution of atheroma is modulated by innate and adaptive immune responses which are recognized histologically as presence of an inflammatory infiltrate within the lesion [40]. These processes are responsible for replication and phenotypic change within the smooth muscle cell from contractile to secretory which results in formation of plaque cap and lesion growth. Intimal endothelial cell activation results in recruitment of macrophages and lymphocytes (predominantly CD4 positive T-cells) into evolving lesion. [40] Activation of Th-1 T-cells is known to initiate a potent inflammatory cascade which in turn leads to plaque instability [41]. Inflammatory cell infiltrate is a marker for plaque vulnerability. [42-47] Several factors such as oxidized lipoproteins, infectious agents or auto-antigens (heat shock protein) have been considered as the putative cause of the chronic inflammatory reaction in an atherosclerotic plaque. [40] This in turn results in weakening of the connective tissue framework of the plaque. [48, 49] Smooth muscles may help to counteract some of these effects by producing matrix protein, collagen and inhibitors of matrix degrading enzymes known as metalloproteinases. [50, 51] The net result of these two processes is thought to define whether or not the plaque ruptures or remains contained by the fibrous cap.

Structural:
Large Lipid rich core
Thin Fibrous Cap
Reduces Collagen content
Cellular:
Local Chronic inflammation
Increased macrophage density and activity
T Lymphocyte accumulation near site of rupture
Increased Neovascularity
Reduced Smooth muscle cell density
Increased number and activity of mast cells
Expression of markers of inflammatory activation
Molecular
Matrix Metalloproteinase Secretion
Increased Tissue Factor Expression

Table 2.

Features of Rupture prone (Unstable) Plaques [40]

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6. Angiogenesis in carotid atherosclerotic lesions

Normal human intima is devoid of blood vessels, [52] however newly formed blood vessels are often seen within atherosclerotic plaques [53-56] (figure-3). The presence and density of these new blood vessels in carotid atherosclerotic lesions has been associated with the histological features of plaque instability and intra-plaque haemorrhage as well as the development and timing of ipsilateral ischaemic or ocular events and presence of ipsilateral cerebral infarction on computer tomography (CT) scanning. [57-62] Microarray gene chip analysis revealed that the presence of newly formed vessels is associated with increased angiogenic gene expression. [63, 64] These new blood vessels are weak and could be responsible for intraplaque haemorrhage. Moreover, the endothelial lining of these microvessels express high levels of E-Selectin, ICAM-1, and VCAM-1, which indicates that these endothelial cells are in an activated state. Activated endothelial cells act as local site of inflammatory cell recruitment into the atherosclerotic plaque, perpetuating the inflammatory process within the lesion and contribute to plaque destabilization. [65-69]

Figure 3.

New blood vessels in a carotid atherosclerotic plaque. (Ann Vasc Surg 2008; 22(2): 266–272.)

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7. Plaque haemorrhage

Haemorrhage is a common feature of unstable carotid atherosclerotic lesions. [68-72] Intra-plaque haemorrhage has been associated with the development and growth of the necrotic plaque core, rapid changes in plaque volume, development of plaque instability, and ischaemic neurological events. [73-76]

The origin of plaque haemorrhage is uncertain. It has been suggested that it may occur from fissures within the plaque cap. [76] Alternatively the new blood vessels within the atherosclerotic plaque may represent the first site of morphologic change that leads to intra-plaque haemorrhage; features such as microvessel density and perivascular inflammatory infiltrate have been associated with the presence and quantity of intra-plaque haemorrhage. [55, 77, 78]

There is ample clinical and histological evidence that carotid atherosclerotic plaques with large necrotic lipid core, thin plaque cap or ulceration, dense inflammatory infiltrate, intra-plaque haemorrhage and angiogenesis are vulnerable to rupture and development of ischaemic neurological and ocular events. In vivo identification of these changes within carotid atherosclerotic plaques gives these findings clinical significance in the context of patients with significant carotid atherosclerosis. For over two decades, non-invasive imaging modalities such as duplex ultrasound and magnetic resonance imaging have been in clinical use. They have been used for the measurement of internal carotid artery stenosis. [79-81] These imaging modalities can also be used to study morphological changes associated with plaque instability and development of ischaemic neurological events. [82-85]

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8. Duplex ultrasound assessment of carotid plaque morphology

Duplex ultrasound is arguably the most important imaging modality for preoperative assessment of patients with carotid atherosclerotic disease. It is non-invasive, relatively inexpensive and very accurate at identification of significant ICA stenosis. [87-92] In measuring the degree of stenosis, the flow and velocity characteristics assessed by colour flow Doppler are utilized. Duplex devices also generate high resolution B-mode ultrasound images of the atherosclerotic lesion. These images do not contribute significantly to the assessment of carotid artery stenosis. However the B-mode ultrasound image can be used to assess morphologic characteristics of an atherosclerotic lesion. It has been known for some time that plaques that have low echogenicity (appear dark on Duplex ultrasound) or a high degree of heterogeneity are associated with histologic characteristics of plaque instability, ipsilateral neurological or ocular events, [93] CT evidence of carotid territory cerebral infarction or evidence of embolisation on trans-cranial ultrasound. [94] These ultrasound characteristics can be assessed subjectively and classified by a trained observer.

B-mode ultrasound assessment of atherosclerotic plaque morphology started some 30 years ago. Reilly et al recognised two distinct types of carotid atherosclerotic lesion. The first was termed homogenous and was defined as lesion with uniformly high or medium level echoes. Histologically, homogenous plaques are fibrous lesions. [95] The second type was termed heterogeneous and was defined as plaque with high, medium and low level echoes. [95]

Histologically heterogeneous plaques contain variable amounts of intra-plaque haemorrhage, lipids, cholesterol crystal and a loose stroma. A further refinement of subjective assessment of plaque morphology was the Gray-Wheal classification method (table-3). [96] In the Cardiovascular Health Study, which enrolled 5,201 individuals aged 65 years and over without prior cerebrovascular symptoms, and followed them for an average of 3.3 years demonstrated a significantly increased incidence of stroke in individuals who had echo-lucent plaques. [97]

Plaque Type Ultrasound characteristics
Type-1 Predominantly echolucent with a thin echogenic cap
Type-2 Intermediate echolucent lesions with small areas of echogenicity
Type-3 Intermediate echogenic lesions with small areas of echolucency (<25%)
Type-4 Uniformly echogenic lesions (equivalent to homogenous).

Table 3.

Gray-Wheal Classification of atherosclerotic plaques

Subjective observer dependent assessment of plaque morphology, whilst useful, is limited by high inter- and intra-observer variability, significantly limiting its clinical application. [98-99] Echogenicity and heterogeneity of an atherosclerotic plaque can be objectively assessed using image analysis techniques through the measurement of median grey scale (GS) value of the ultrasound image, percentage of echo-lucent pixels and entropy in GS characteristics of the lesion(figure-4). [99-103] In order to remove variability associated with acquisition of the ultrasound image, the US images are normalised using linear scaling so that the adventitia would have a grey scale median value of 185-195 and blood 0-5. Plaques with a low GS median were associated with a significantly higher annual risk of stroke. [99-104]

Interestingly, although characterisation of the internal structure of the plaque assessed by image analysis correlates closely with clinical symptoms, the correlation between computerised assessment of plaque morphology and histological features of the lesion is less strong. [94] This indicates that values such as GS median represent a median value of the whole atherosclerotic area and do not necessarily reflect the presence of particular regional components. The use of stratified GS median measurements which create a profile of the regional GS median as a function of distance from plaque surface combined with colour mapping correlates better with the presence of various histopathological components and identify determinants of plaque instability with a high degree of accuracy. [94]

Figure 4.

Calculation of Grey Scale Median of a hypo-echoic plaque. (Swiss Med 2005; 135:635–643.)

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9. Magnetic resonance imaging assessment of plaque morphology

Magnetic resonance imaging (MRI) is a promising modality for characterisation of carotid plaque morphology and assessment of composition of atherosclerotic plaques. It can accurately identify the presence of ulcerated or thin plaque cap, [105-107] quantify intra-plaque haemorrhage [105-107], or the presence of a large necrotic plaque core [105-107]. Serial MRI examinations in asymptomatic patients with moderate (50-70-percent) ICA stenosis have revealed correlation between these plaque findings and development of subsequent ipsilateral ocular and ischaemic neurological events [108] (Figure-5).

Figure 5.

Identification of intra-plaque haemorrhage using high spatial resolution, multi-contrast MRI image. (JACC Cardiovasc Imaging. 2009; 2:883-96.)

One of the strengths of MRI is the availability of multi-contrast weighted protocols. The most common application of carotid MRI remains the acquisition of an angiogram which uses a bright blood sequence using a 3-dimensional time of flight sequence. This attenuates the signal from stationary (plaque) tissues. Black blood sequences eliminate the luminal signal and help to characterise plaque morphology. [105-109] Combining the information, multiple-contrast weightings can be used to identify all plaque components. [105-110] Plaque compositional characteristics can be assessed using automatic classifiers such as morphology enhanced probabilistic plaque segmentation (MEPPS) algorithms with a high degree of accuracy (Figure-6). [111, 112] Administration of gadolinium-DTPA together with T1-weighted sequences in addition to bright blood time of flight sequence can be used to create maximal intensity projection (MIP) images for measurement of the degree of ICA stenosis [105-107] and accurately measure the thickness of plaque cap in relation to the necrotic core volume. [105-107]

Figure 6.

Automated segmentation of bright–and black-blood, high-spatial resolution, Multi-contrast in vivo MR images compared with histological characteristics of plaque. (JACC Cardiovasc Imaging. 2009; 2:883-96.)

High resolution MRI can identify and age intra-plaque haemorrhage. [113-115] Prospective serial MRI studies have demonstrated that haemorrhage in atherosclerotic plaques is associated with sudden increases in plaque volume, necrotic core, and progression of degree of stenosis. [115]

In addition to Duplex and MRI, other modalities such as fludeoxyglucose (FDG) positron emission tomography (PET) CT scanning has been used to assess the level of metabolic activity in carotid atherosclerotic plaque. This is used in turn as a surrogate marker of plaque instability.

PET CT scanning has shown some promise as a tool for assessment of plaque instability. [116] However it is unlikely to gain mainstream applicability due to its limited availability, expense, and the significant exposure to ionising radiation (meaning serial assessments are not possible) and availability of non-invasive accurate imaging modalities to assess plaque morphology.

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10. Conclusion

Over the last 20 years the advances in technology have led to the evolution of non-invasive imaging modalities with high spatial resolution. The application of this technology in the assessment of carotid plaque morphology has advanced our understanding of the natural history of atherosclerotic lesions more than the assessment of histological characteristics of atherosclerotic plaques. Consequently for the first time, plaque morphology could be assessed against the two functions that ultimately matter the most: time and occurrence of future embolic ischaemic events.

New and continuing advances in MRI technology such as higher field strength, phased-array coils, and the application of 3-dimensional and contrast enhanced ultrasound will provide even more tools for assessment of carotid plaque morphology. Gradual application of these modalities in clinical practice will help clinicians select patients with significant ICA stenosis who are likely to benefit from carotid intervention prior to occurrence of ischaemic neurological events.

References

  1. 1. Dennis M, Bamford J, Sandercock P, Warlow C. Prognosis of transient ischaemic attacks in the oxfordshire community stroke project. Stroke 1990; 21: 848-853
  2. 2. Shah KH, Kleckner K, Edlow JA. Short term prognosis of patients diagnosed in the emergency department with a transient ischemic attack. Ann Emerg Med 2008; 51: 316-323.
  3. 3. Barnet HJM, Taylor DW, M Eliasziw, Fox AJ. Benefit of Carotid endarterectomy in patients with Symptomatic moderate or severe stenosis. N Engl J Med 1998, 339: 1415-25
  4. 4. North American Symptomatic Carotid Endarterctomy Trial collaborators. Beneficial effects of carotid endarterectomy for symptomatic patients with high grade stenosis. N Engl J Med 1991, 325: 445-83
  5. 5. Medical Research Council European Carotid Surgery Trial. Interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis.Lancet 1991; 337: 1235-43
  6. 6. European Carotid Surgery Trialists Collaborative Group.MRC. Risk of stroke in the distribution of asymptomatic carotid artery. Lancet 1995 ;345: 209-12
  7. 7. European Carotid Surgery Trialists Collaborative Group.MRC. European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet; 337: 1235-43
  8. 8. Executive Committee for Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis JAMA 1995 273: 1421-8.
  9. 9. Halliday A, Harrison M, Hayter E. Kong X, et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic carotid stenosis (ACST-1): A randominsed trial. Lancet 2010; 376(9746):1074-1084.
  10. 10. Virmani R, Farb A, Burke AP. Understanding the atherosclerotic plaque.Progress in vascular surgery. Yao JST, Pearce WH. Appleton & Lange, USA. 1997; 3-19
  11. 11. Golledge J, Cuming R, Ellis M, Davies AH,Greenhalgh. Carotid Plaque characteristics and presenting symptoms. British J Surg. 1996, 84: 1697-1701.
  12. 12. Lovett J, Walton J, Hands L, Gallagher P J, Rothwell PM. Histological correlates of angiographic carotid plaque ulceration. Circulation 2004; 110: 2190-97
  13. 13. Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor W, Mayberg MR, Warlow CP, Barnet HJM for the Carotid Endarterectomy Trialists’ Collaboration. Pooled analysis of individual patient data from randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361: 107-16.
  14. 14. Mofidi R, Powell TI, Brabazon A, Mehigan D, Sheehan SJ, MacErlaine DP, Keaveny TV. Prediction of the exact degree of internal carotid artery stenosis using an artificial neural network based on duplex velocity measurements. Ann Vasc Surg2005; 19(6):829-37.
  15. 15. Jahromi AS, Cina AS, LiuY, Clase CM. Sensitivity and specificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and meta-analysis. J Vasc Surg 2005; 41(6):962-72.
  16. 16. Nederkoorn PJ, van der Graaf Y, Hunink MG. Duplex ultrasound and magnetic resonance angiography compared with digital subtraction angiography in carotid artery stenosis: a systematic review. Stroke 2003;34(5):1324-32.
  17. 17. Makris GC, Lavida A, Griffin M, Geroulakos G, Nicolaides AN. Three-dimensional ultrasound imaging for the evaluation of carotid atherosclerosis.Atherosclerosis 2011; 219(2):377-83.
  18. 18. Biasi GM, Froio A, Diethrich EB, Deleo G, Galimberti S, Mingazzini P, Nicolaides AN, Griffin M, Raithel D, Reid DB, Valsecchi MG. Carotid plaque echolucency increases the risk of stroke in carotid stenting: the Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) study. Circulation 2004 ; 110(6):756-62.
  19. 19. Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, et al. for the Carotid Endarterectomy Trialists’ Collaboration. Pooled analysis of individual patient data from randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361: 107-16.
  20. 20. Kawahara I, Morikawa M, Honda M, Kitagawa N.High-resolution magnetic resonance imaging using gadolinium-based contrast agent for atherosclerotic carotid plaque. Surgical Neurology 2007; 68(1):60-65.
  21. 21. Watanabe Y, Nagayama M. MR plaque imaging of carotid artery.Neuroradiology 2010; 52: 253-274.
  22. 22. Bock R Gray- Weale A C.Mock P. Natural history of asymptomatic carotid artery disease. J Vasc Surg 1993;17:160-71
  23. 23. Stary HC, Chandler AS, Dinsmore RE, et Al. A definition of advanced type of Atherosclerosis, A report from the committee on vascular lesions of the council on atherosclerosis AHA. Circulation 1995;92: 1355-74
  24. 24. 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(5):1262-75.
  25. 25. Naghavi M, Libby P, Falk E, Ward-Casscells S et al. From Vulnerable Plaque to Vulnerable Patient. Circulation 2003; 108: 1664-1672.
  26. 26. Benson RL. Present Status of Coronary Artery Disease. Arch Pathol Lab Med 1926;2:876-916
  27. 27. Constantinides P. Plaque fissures in human Coronary thrombosis. J Atherosclr Res 1966;6:1-17
  28. 28. Davies MJ Fulton WF, Robertson WB. Pathology of acute myocardial infarction with particular reference to occlusive coronary thrombi. Br Heart J 197638:659-64
  29. 29. Davies MJ Thomas A. thrombosis and acute coronary artery lesions in sudden cardiac ischemic death.. N Engl J Med 1984;310:1137-40
  30. 30. Davies MJ Thomas AC. Plaque fissuring-The cause of acute myocardial infarction, sudden ischemic death and cresendo angina..Br Heart J 1985;53:363-73
  31. 31. DeWood MA, Spores J, Notske R, and Mouser LT et al. Prevalence of total coronary occlusion during the early hours of transmutable infarction. N Engl J Med 1980; 303:895-902
  32. 32. Brown BG, Gallery CA, Badger RS, Kennedy JW et al. Incomplete lyses of thrombus in the moderate underlying atherosclerotic lesion during the intracoronary infusion of streptokinase for acute myocardial infarction: quantitative angiographic observations. Circulation 1986;73:653-61
  33. 33. Little WC, Constantinescu M, Applegate RJ, Kutcher MA et al. Can coronary angiography predict the site of subsequent myocardial infraction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78:1157-66
  34. 34. Kullo I, Edwards WD, Schwartz RS. Vulnerable Plaque: Pathobiology and Clinical Implications. Ann. Intern. Med. 1998; 129:150-60
  35. 35. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006; 47: (8 Suppl):C13-8.
  36. 36. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. New Engl J Med 1997; 336 (18): 1276-82.
  37. 37. Gertz SD, Roberts WC Heamodynamic Shear force in rupture of coronary arterial atherosclerotic plaque. Am J Cardiology 1990;66:1368-72
  38. 38. Loree HM, Tobias BJ, Gibson LJ, Kamm RD et al. Mechanical properties of model atherosclerotic lesion lipid pools. Arterioscler Thrmb 1994;14:230-4
  39. 39. Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A. Role of inflammation in atherosclerosis. J Nucl Med 2007; 48:1800-1815.
  40. 40. Hansson GK, Jonasson L, Lojsthed B, Stemme S, et al. Localisation of T Lymphocytes and macrophages in fibrous and complicated human atherosclerotic plaques Arteriosclerosis 1988;72: 135-41.
  41. 41. Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. Proc Natl Acad Sci 2003;100: 6658–6663.
  42. 42. Annovazzi A, Bonanno E, Arca M, et al. 99mTc-Interleukin-2 scintigraphy for the in vivo imaging of vulnerable atherosclerotic plaques. Eur J Nucl Med Mol Imaging. 2006;33:117–126.
  43. 43. Benagiano M, D'Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques. J Immunol. 2005;174:6509–6517.
  44. 44. Mauriello A, Sangiorgi G, Fratoni S, et al. Diffuse and active inflammation occurs in both vulnerable and stable plaques of the entire coronary tree a histopathologic study of patients dying of acute myocardial infarction. J Am Coll Cardiol. 2005;45:1585–1593.
  45. 45. Libby P. Molecular basis of the acute coronary syndrome. Circulation 1995; 91:, 2844-50.
  46. 46. Fustor V, Badimon J, Chesebro JH, Mechanisms of disease I: the pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992; 326:242-50
  47. 47. Falk E. Why do plaques rupture? Circulation 1992; 86(Suppl III): 36-42
  48. 48. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arteriosclerosis Throm. 1991; 11: 1223-30.
  49. 49. Moreno PR, Purushothaman KR, Fuster V, O'Connor WN. Intimomedial interface damage and adventitial inflammation is increased beneath disrupted atherosclerosis in the aorta: implications for plaque vulnerability. Circulation.2002; 105:2504–2511.
  50. 50. Uemura S, Matsushita H, Li W, et al. Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. Circ Res.2001;88:1291–1298.
  51. 51. Garcia-Touchard A, Henry TD, Sangiorgi G, et al. Extracellular proteases in atherosclerosis and restenosis. Arterioscler Thromb Vasc Biol.2005;25:1119–1127.
  52. 52. Geiringer E. Intimal vascularisation and atherosclerosis. Histologic characteristics of carotid atherosclerotic plaque. J Path. Bacteriol. 1951 63: 201-11
  53. 53. Barger AC, Beewikes R, Lainey LL, Silverman KJ. Hypothesis: Vasa vasarum and neo-vascularization of the human coronary arteries. N Engl J Med 1984, 310: 175-77
  54. 54. O'Brien ER, Garvin RD, Stewart DK, Hinohara T et al. Angiogenesis in human coronary atherosclerotic plaques. Am. J. Pathology 1994,145 (4): 833-94.
  55. 55. Jeziorska M, Woolley DE. Local Neovascularisation and cellular composition within vulnerable regions of atherosclerotic plaques of human carotid arteries. J. Pathology 1999; 188,189-96.
  56. 56. Jeziorska M, Woolley DE. Neovascularization in early atherosclerotic lesions of human carotid arteries: its potential contribution to plaque development. Hum. Pathol. 1999; 30(8): 919-25.
  57. 57. McCarthy MJ, Loftus IM, Thompson MM, Jones L, et al. Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology. J Vasc Surg. 1999; 30(2): 261-8.
  58. 58. Mofidi R, Crotty TB, McCarthy P, Sheehan SJ, Mehigan D, Keaveny TV. Association between plaque instability, angiogenesis and symptomatic carotid occlusive disease. Br J Surg. 2001;88:945–950.
  59. 59. Mofidi R, Powell TI, Crotty TB, McCarthy P, et al. Angiogenesis in Carotid Atherosclerotic Lesions Is Associated with Timing of Ischemic Neurological Events and Presence of Computed Tomographic Cerebral Infarction in the Ipsilateral Cerebral Hemisphere. Ann Vasc Surg 2008; 22(2): 266–272.
  60. 60. Dunmore BJ, McCarthy MJ, Naylor AR, Brindle NP. Carotid plaque instability and ischemic symptoms are linked to immaturity of microvessels within plaques J Vasc Surg. 2007; 45(1): 155-159.
  61. 61. Post S, Peeters W, Busser E, Lamers D, et al. Balance between Angiopoietin-1 and Angiopoietin-2 Is in Favor of Angiopoietin-2 in Atherosclerotic Plaques with High Microvessel Density. J Vasc Res 2008; 45: 244–250.
  62. 62. Virmani R, Ladich ER, Burke AP, Kolodgie FD et al. Histopathology of carotid atherosclerotic disease. Neurosurgery 2006; 59(S3): 219-227.
  63. 63. Virmani R, Kolodgie F, Burke AP, Finn AV et al. Atherosclerotic Plaque Progression and Vulnerability to Rupture Angiogenesis as a Source of Intraplaque Hemorrhage. Arterioscler Thromb Vasc Biol.2005;25: 2054-61.
  64. 64. Davies MJ, Gordon JL, Gearing AJ, Pigott R, et al. The expression of Adhesion Molecules ICAM-1, VCAM-1, PECAM, and E Selectin in Human Atherosclerosis. J Pathol 1993; 171(3): 223-9.
  65. 65. Mofidi R, Crotty T, McCarthy P, Mehigan D et al. Neovascular endothelial-cell activation: the link between angiogenesis, intimal leukocyte content, and development of symptomatic carotid occlusive disease. Int J Angiology 2004; 13(1):15-21.
  66. 66. O'Brien KD, McDonald TO, Chait A, Allen MD, Alpers CE. Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 1996; 93(4): 672-82.
  67. 67. Galkina E, Ley K. Vascular Adhesion Molecules in Atherosclerosis. Arterioscler Thromb Vasc Biol.2007; 27: 2292–2301.
  68. 68. Paterson JC. Capillary rupture of with intimal haemorrhage as the causative factor in coronary thrombosis. Arch Pathol. 1938; 25: 474-87.
  69. 69. Imparato AM, Riles TS, Mintzer R, Baumann FG The importance of hemorrhage in the relationship between gross morphologic characteristics and cerebral symptoms in 376 carotid artery plaques. Ann. Surg. 1983; 197(2):195-203
  70. 70. Lusby RJ, Ferrell LD, Ehrenfeld WK, Stoney RJ, Wylie EJ. Carotid plaque hemorrhage. Its role in production of cerebral ischemia. Arch Surg 1982; 117(11): 1479-88.
  71. 71. Milei J, Parodi JC, Alonso GF, Barone A, et al. Carotid rupture and intraplaque hemorrhage: immunophenotype and role of cells involved. Am. Heart J. 1998; 136(6): 1096-105.
  72. 72. Fryer JA, Myers PC, Appleberg M. Carotid intraplaque haemorrhage: The significance of neovascularity. J. Vasc. Surg. 1987; 6 (4): 341-9
  73. 73. von Maravic C, Kesler C, von Maravic M, Hohlbach G, Kompf D. Clinical relevance of intraplaque hemorrhage in the internal carotid artery. Eur J Surg 1991; 157(3): 185-8.
  74. 74. Feely TM, Leen EJ, Colgan MP, Moore JD, et al. Histologic Characteristics of carotid artery plaque. J Vasc Surg 1991, 13:719-24.
  75. 75. Mofidi R, Powell TI, Crotty TB, Sheehan SJ, et al. Increased Internal Carotid Artery Peak Systolic Velocity Is Associated with Presence of Significant Atherosclerotic Plaque Instability Independent of Degree of ICA Stenosis. Int J Angiology 2005; 14(2):74-80.
  76. 76. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J.1985; 53:363–373.
  77. 77. Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation 2006; 113: 2245–2252.
  78. 78. Türeyen K, Vemuganti R, Salamat MS, Shahriar M, Dempsey RJ. Increased Angiogenesis and Angiogenic Gene Expression in Carotid Artery Plaques from Symptomatic Stroke Patients. Neurosurgery 2006; 59: 971-977.
  79. 79. Mofidi R, Powell TI, Brabazon A, Mehigan D, Sheehan SJ, MacErlaine DP, Keaveny TV. Prediction of the exact degree of internal carotid artery stenosis using an artificial neural network based on duplex velocity measurements. Ann Vasc Surg 2005; 19(6):829-37.
  80. 80. Jahromi AS, Cina AS, LiuY, Clase CM. Sensitivity and specificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and meta-analysis. J Vasc Surg 2005; 41(6):962-72.
  81. 81. Nederkoorn PJ, van der Graaf Y, Hunink MG. Duplex ultrasound and magnetic resonance angiography compared with digital subtraction angiography in carotid artery stenosis: a systematic review. Stroke 2003;34(5):1324-32.
  82. 82. Makris GC, Lavida A, Griffin M, Geroulakos G, Nicolaides AN. Three-dimensional ultrasound imaging for the evaluation of carotid atherosclerosis. Atherosclerosis 2011; 219(2):377-83.
  83. 83. Biasi GM, Froio A, Diethrich EB, Deleo G, et al. Carotid plaque echolucency increases the risk of stroke in carotid stenting: the Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) study. Circulation 2004 ; 110(6):756-62.
  84. 84. Kawahara I, Morikawa M, Honda M, Kitagawa N.High-resolution magnetic resonance imaging using gadolinium-based contrast agent for atherosclerotic carotid plaque. Surgical Neurology 2007; 68(1):60-65.
  85. 85. Watanabe Y, Nagayama M. MR plaque imaging of carotid artery. Neuroradiology 2010; 52: 253-274.
  86. 86. Perkins JM, Galland RB, Simmons MJ, Magee TR. Carotid duplex imaging: variation and validation. Br J Surg 2000; 87: 320-322.
  87. 87. Padayachee TS, Cox TC, Modaresi KB, Colchester AC, Taylor PR. The measurement of internal carotid artery stenosis: comparison of duplex with digital subtraction angiography. Eur J Vasc Endovasc Surg 1997; 13: 180-185.
  88. 88. Chen JC, Salvian AJ, Taylor DC, Teal PA, Marotta TR, Hsiang YN. Predictive ability of duplex ultrasonography for internal carotid artery stenosis of 70%-99%: a comparative study. Ann Vasc Surg 1998; 12: 244-247.
  89. 89. Hood DB, Mattos MA, Mansour A, et al. Prospective evaluation of new duplex criteria to identify 70% internal carotid artery stenosis. J Vasc Surg 1996;23:254-261.
  90. 90. Moneta GL, Edwards JM, Papanicolaou G, et al. Correlation of North American Symptomatic Carotid Endarterectomy Trial (NASCET) angiographic definition of 70-99% internal carotid artery stenosis with duplex scanning. J Vasc Surg 1993; 17: 152-159.
  91. 91. Geroulakos G, Hobson W, Nicolaides A. Ultrasonographic carotid plaque morphology in predicting stroke risk. Br J Surg. 1996; 83:582-87.
  92. 92. TJ Tegos, MM Sabetai, AN Nicolaides, Robless P. et al. Correlates of embolic events detected by means of transcranial Doppler in patients with carotidatheroma J Vasc Surg 2001; 33(2): 131-138.
  93. 93. Golledge J, Cuming R, Ellis M, Davies AH, Greenelgh. Carotid Plaque Characteristics and presenting symptoms. Br J Surg. 1996; 84:1697-1701.
  94. 94. Sztajzel S. Ultrasonographic assessment of the morphological characteristics of the carotid plaque. Swiss Med 2005; 135:635–643.
  95. 95. Reilly LM, LusbyRJ, Hughes L, Ferrell LD, StoneyRJ, Ehrenfeld WK.. Carotid plaque histology using real-time ultrasonography. Am J Surg 1983, 146:188-193.
  96. 96. Gray-Weale AC, Graham JC, Burnett JR, Byrne K, Lusby RJ. Carotid artery atheroma: Comparison of preoperative B Mode ultrasound appearance with carotid endarterectomy specimen pathology. J Cardiovascular Surg. 1988; 29:676-81
  97. 97. Polak JI, Shemanskil, O’Leary D, Lefkowitz D, Price TR, Savage P et al. Hypoechoic plaque at US of the carotid artery: An independent risk factor for individual stroke in adults aged 65 years or older. Radiology 1998, 208:649-654.
  98. 98. Sabetai MM, Tegos TJ, Nicolaides AN, Dhanjil S, et al. Reproducibility of Computer-Quantified Carotid Plaque Echogenicity Can We Overcome the Subjectivity? Stroke 2000;31: 2189-2196.
  99. 99. Arnold JAC, Modaresi KB, Thomas N, Taylor PR, Padayachee TS. Carotid plaque characterization Vascular by duplex scanning: observer error may undermine current clinical trials. Stroke. 1999; 30:61–65.
  100. 100. Sabetai MM, Tegos TJ, Nicolaides AN, El-Atrozy T, et al. Hemispheric symptoms and carotid plaque echomorphology. J Vasc Surg 2000; 31(1): 39–49.
  101. 101. El Atrozy T, Nicolaides A, Tegos T, Griffin M. Objective Characterization of Carotid Plaque Features. Eur J Vasv Endovasc Surg. 1998; 16:223-30.
  102. 102. Tegos TJ, Sabetai MM, Nicolaides AN, El-Atrozy T, et al. Patterns of brain computed tomography infarction and carotid plaque echogenicity. J Vasc Surg 2001; 33(2): 334-339.
  103. 103. Nicolaides AN, Kakkos SK, Griffin M, Sabetai M et al. Effect of Image Normalization on Carotid Plaque Classification and the Risk of Ipsilateral Hemispheric Ischemic Events: Results from the Asymptomatic Carotid Stenosis and Risk of Stroke Study. Vascular 2005;13: 211-221.
  104. 104. Kakkos SK, Stevens JM, Nicolaides AN, et al. Texture analysis of ultrasonic images of symptomatic carotid plaques can identify those plaques associated with ipsilateral embolic brain infarction. Eur J Vasc Endovasc Surg 2007;33; 422-429.
  105. 105. Kerwin WS, Hatsukami T, Yuan C, Zhao XQ. MRI of Carotid Atherosclerosis. Am J Roentgenology 2013; 200(3): 304-313.
  106. 106. Wasserman BA. Advanced Contrast-Enhanced MRI for Looking Beyond the Lumen to Predict Stroke Building a Risk Profile for Carotid Plaque. Stroke 2010;41: 512-516.
  107. 107. Chu B, Ferguson MS, Chen H, Hippe DS, et al. Magnetic resonance imaging features of the disruption-prone and the disrupted carotid plaque. JACC Cardiovasc Imaging. 2009; 2(7):883-96.
  108. 108. Sievers M. Detection of unstable carotid artery stenosis using MRI. J Neurol 2007; 254: 1714-1722.
  109. 109. Altaf N, Akwei S, Auer DP, MacSweeney ST, et al. MR detected carotid plaque hemorrhage is associated with inflammatory features in symptomatic carotid plaques. Ann Vasc Surg 2013;27(5): 655–661.
  110. 110. Kawahara I, Morikawa M, Honda M, Kitagawa N, et al. High-resolution magnetic resonance imaging using gadolinium-based contrast agent for atheroscleroticcarotid plaque. Surgical Neurology 2007;68(1):60-65.
  111. 111. Kerwin W, Xu D, Liu F, Saam T, Underhill H, et al. Magnetic resonance imaging of carotid atherosclerosis: plaque analysis. Top Magn Reson Imaging. 2007;18: 371–378.
  112. 112. Liu F, Xu D, Ferguson MS, Chu B, et al. Automated in vivo segmentation of carotid plaque MRI with Morphology-Enhanced probability maps. Magn Reson Med. 2006; 55:659–668.
  113. 113. Chu B, Kampschulte A, Ferguson MS, Kerwin WS et al. Hemorrhage in the Atherosclerotic Carotid Plaque: A High-Resolution MRI Study Stroke 2004;34: 1079-1084.
  114. 114. Honda M, Kitagawa N, Tsutsumi K, Nagata I, et al. High-Resolution Magnetic Resonance Imaging for Detection of Carotid Plaques. Neurosurgery 2006; 58: 338-346.
  115. 115. Takaya N, Yuan C, Chu BC, Saam T, Polissar NL, et al. Presence of Intraplaque Hemorrhage Stimulates Progression of Carotid Atherosclerotic Plaques: A High-Resolution MRI study. Circulation 2005; 111: 2768–2775.
  116. 116. Sakalihasan N, Michel JB. Functional Imaging of Atherosclerosis to Advance Vascular Biology. Eur J Vasc Endovasc Surg 2009; 728-734.

Written By

Reza Mofidi and Barnabas Rigden Green

Submitted: September 12th, 2013 Published: January 22nd, 2014