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HOW TO DEFINE A VULNERABLE PLAQUE?The term, vulnerable plaque, has been used synonymously with the

terms high-risk plaque, thrombosis-prone plaque, thin-cap fibroatheromas (TCFAs), unstable plaque and disrupted plaque and refers to a plaque at

[1]increased risk of causing thrombosis and lesion progression . Plaque rupture was first recognized as the initiating event of most

cardiovascular diseases in 1966 and has been under extensive study ever since[2].

Prospectively, a vulnerable plaque can be defined as a plaque identified by the technology tested and documented to have a high likelihood of forming a thrombogenic focus. The thrombus could thus produce immediate disease onset, or rapid, asymptomatic, angiographic progression. On the other hand, a plaque with a low likelihood of causing such an outcome

[1]would be termed non-vulnerable .The American Heart Association (AHA) classifies plaques into six

types based on histologic features – Type I (initial changes); type II (fatty streak); type III (pre-atheroma); type IV (atheroma); type V (fibroatheroma); and type VI (complicated plaque) – all thrombosed lesions are included in

[3,4]type VI as complicated lesions .CHARACTERISTICS OF A VULNERABLE PLAQUEAlthough evidence suggests that certain features can identify

vulnerable plaques but no conclusive data exists. The following features in a [5,6]plaque have been implicated as being predictive of an adverse outcome:

A] Large lipid core (40% of the entire plaque)B] Thin capC] Increased macrophage content D] Increased proteoglycan contentE] Presence of a calcified noduleThere are no prospective studies clearly establishing any particular

histologic type as being vulnerable plaque; also it is not possible to identify the frequency of vulnerable plaque due to unavailability of a simple method of identifying such plaques. Autopsy based studies have a certain selection bias, but the best evidence about the frequency of various histologic types of

[1]plaques comes from postmortem studies . [7]Three major factors determine the vulnerability of the fibrous cap:

A] Circumferential wall stress or cap fatigue B] Lesion characteristics- location, size and consistencyC] Blood flow characteristicsPlatelet disruption involves inflammation as an important adjunct to

[8]mechanical factors and activated inflammatory cells have been detected in the disrupted areas of atherectomy specimens from patients with acute coronary syndromes. These inflammatory cells secrete proteolytic enzymes such as matrix metalloproteinases and are capable of degrading the extracellular matrix, affect vascular remodeling and migration of smooth

[9]muscle cells across the basement membrane . Lesion thrombogenicity has also been linked with tissue factor

content and local tissue factor inhibition reduces lesion thrombogenicity [10]. Evidence also suggests that increased tissue factor expression is associated

[11]with cell apoptosis . LESIONS THAT LEAD TO ACUTE CORONARY SYNDROMES

Atleast 65-70% of the atherothrombi are caused by plaque rupture, 25-30% of thrombi occur from plaque erosion and 2-5% of atherothrombi occur as a result of calcified nodules that protrude into the lumen.1] Plaque Rupture

VULNERABLE PLAQUES

SOHAIB AHMAD;NADIA SHIRAZI; M.U. RABBANI

Authors’ affiliations: Sohaib AhmadProf. M.U.RabbaniCentre of CordiologyNADIA SHIRAZIDepartment of Pathology JN Medical CollegeAligarh Muslim University, ALIGARH

ADDRESS FOR CORRESPONDENCEDR. SOHAIB AHMAD2-Basera,Dodhpur, Oppos i te Bombay Merchantile Bank,Aligarh (UP)-202002, INDIAE-mail: sohadia@hotmail.comPhone No. 0091-571-2702284/ 0091-9412460098/ 0091-9837172466

JK- Practitioner 2006; 13 (1):1-4

JK- Practitioner Vol.13, No. 1, January - March 2006

Keywords: vulnerable plaque, Intravascular ultrasound, Thin-cap Fibroatheroma

Plaque rupture is defined as a necrotic core with normal previously, the technique is a thin fibrous cap that is disrupted or ruptured, allowing severely limited in identifying

[23]the flowing blood to come in contact with the necrotic vulnerable plaque. core. Rupture of the fibrous cap usually occurs in the b)Angioscopy: More sensitive than angiography, it shoulder regions, the weakest portion where the stress is offers direct visualization of the plaque highest and matrix metalloproteinase production is surface and intraluminal structures like

[12]increased . tears and color of the thrombi. . The frequency of plaque rupture reported in However, angioscopy is difficult to

various series of sudden coronary deaths varies from 30% perform, is invasive, is associated with [13] [14, 15] a risk of peri-procedural ischaemia and to over 85% . Calcification is present in 80% of

only a limited part of the vessel tree can plaques that rupture but is usually either speckled or [24]fragmented and infrequently diffuse. The coronary be investigated.

plaques in plaque rupture are equally concentric or c) IntravascularUltrasound (IVUS): Provides real eccentric and are more frequent in men and time high-resolution images of the

[16] vessel wall and lumen. Only structures postmenopausal women .µ2] Plaque Erosion over 160 m can be visualized

It is defined as a lesion with luminal thrombus a c c u r a t e l y. C a l c i f i c a t i o n i s with a base rich in smooth muscle cells and proteoglycan characterized by a bright echo signal

[17].matrix At the site of thrombosis, there is absence of an with distal shadows that hide plaque endothelial layer. These lesions are usually not calcified, components and deeper vessel

[18] structures. The sensitivity of detection or have speckled calcification if calcified . Majority of [25]

plaque erosions are eccentric and occur most frequently in of micro-calcification is around 60% . young men and women less than 50 years of age and are Lipid deposition is described as associated with smoking especially in premenopausal echoluscent zones and can be detected women [19]. on IVUS with a sensitivity of between

[26]3] Calcified Nodule 78 and 95% and specificity of 30% . An infrequent cause of thrombosis in patients The sensitivity to differentiate between

dying a sudden cardiac death, it refers to a lesion with a fatty and fibrous tissue is between 39 [27]fibrous cap disruption, absence of endothelium and and 52% . IVUS assessment of

thrombus associated, dense calcified nodule with bone vascular remodeling may help to formation. The origin of calcified nodule is thought to be classify plaques with the highest

[28]associated with healed plaque ruptures. Mid-right probability of spontaneous rupture .coronary artery accounts for over 50% of the cases d)Intravascular Elastography: Based on the because of maximum torsion stress and is the lesion is concept that upon uniform loading, the usually seen in elderly males with heavily calcified and local relative amount of deformation of

[20]tortuous arteries . a tissue is related to the local 4] Thin-cap Fibroatheroma mechanical properties of that tissue,

The thin-cap fibroatheroma (TCFA) has been this technique differentiates between µ hard and soft tissue that may be defined as a lesion with a fibrous cap < 65 m thick and

infiltrated by macrophages (>25 cells per 0.3 mm important for detection of a deformable [21] plaque prone to rupture. diameter field) . The cap may or may not be eccentric

e)Other Techniques:and the necrotic core is well developed. Over 50% of the l Optical Coherence Tomographyplaque ruptures, healed plaque ruptures and TCFAs occur l Thermographyin the proximal portions of the major coronary arteries l Raman Spectroscopywith < 50% diameter stenosis and another third in the mid-l Near-Infrared Spectroscopyportion of these arteries while the rest are distributed in the

[22] l Magnetic Resonance Imagingdistal segments . Fifty percent of TCFAs have absent or l Shear Stress Imagingspeckled calcification, and the remainder has a diffuse or a

[18] All the techniques are still under development and at fragmented calcification pattern .present none of them can identify a vulnerable plaque alone or DIAGNOSIS OF THE VULNERABLE PLAQUEpredict its further development. Thus a combination of Since the consequences of rupture of vulnerable various modalities will be important in the future to ensure plaque may be catastrophic, their identification is of high sensitivity and specificity in detecting vulnerable paramount significance to enable the development of plaque.treatment modalities to stabilize such plaques.CAN PERIPHERAL BLOOD BE USED TO IDENTIFY a)Coronary Angiography: It is the gold standard VULNERABLE PLAQUES?for assessment of obstructive

Several candidate markers in peripheral blood either lesions but it fails to assess the singly, or in combination identify patients at high plaque burden. Also, since 70% of cardiovascular risk – LDL and oxidized LDL, C-reactive acute coronary occlusions are in proteins and other acute phase reactants, p-selectins, areas that were angiographically monocyte chemoattractant protein-1 and macrophage colony

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stimulating factor, CD-40 ligand, interleukins (1b and 6), Antiplatelet agents (Aspirin/ Clopidogrel)matrix metalloproteinases- to name a few. Pregnancy- Othersassociated plasma protein is a new marker for vulnerable - Peroxisome proliferator activated receptor agonists

[29]plaque and is currently under extensive study . - Anti-inflammatory agentsTHERAPY FOR VULNERABLE PLAQUE - Antibiotics

Drugs (Plaque Stabilizers) - AntioxidantsTherapies that may possess plaque-HMG CoA reductase inhibitors stabilizing effects (Statins)Gene therapyAngiotensin converting enzyme

Metalloproteinase inhibitorsinhibitors (ACEI)CD-40 pathway inhibitorsAntihypertensive agents

Photodynamic therapyb-blockersw-3 fatty acids

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coronary syndromes: Implications for sudden coronary death victims. Z 1. Muller JE, Moreno PR. Definition of plaque rupture. Circulation 1994; 90: Kardiol 2000; 89: 49-53.

the vulnerable plaque. Handbook of 775-8. 19. Burke AP, Farb A, Malcom GT et al. the vulnerable plaque. Eds. Waksman, 10. Badimon JJ, Lettino M, Toschi V et al. Effect of risk-factors on the Serruys 2005: 1-15 Local inhibition of tissue factor mechanism of acute thrombosis and

2. Constantinides P. Plaque fissures in reduces the thrombogenicity of sudden coronary death in women. human coronary thrombosis. J disrupted human atherosclerotic Circulation 1998; 97: 2110-6.Atheroscer Res 1966; 6: 1-17. plaque: effects of local tissue factor 20. Virmani R, Kolodgie FD, Burke AP et

3. Stary HC, Chandler AB, Dinsmore E pathway inhibitor on plaque al. Lessons from sudden coronary et al. A definition of advanced types of th rombogen ic i ty under f low d e a t h : a c o m p r e h e n s i v e atherosclerotic lesions and a conditions. Circulation 1999; 99: morphological classification scheme h i s t o l o g i c c l a s s i f i c a t i o n o f 1780-7. f o r a t h e r o sc l e r o t i c l e s i o n s . atherosclerosis. A report from the 11. Mallat Z, Tedgui A. Current Arterioscler Thromb Vasc Biol 2000; Committee on Vascular Lesions of the perspective on the role of apoptosis in 20: 1262-75.Counci l on Ar ter iosc leros is , atherothrombotic disease. Cir Res 21. Burke AP, Farb A, Malcom GT et al. American Heart Associat ion. 2001; 88: 998-1003. Coronary risk-factors and plaque Circulation 1995; 92: 1355-74. 12. Galis ZS, Sukhova GK, Lark MW, morphology in men with coronary

4. Stary HC, Chandler AB, Glagov S et Libby P. Increased expression of disease who died suddenly. N Engl J al. A definition of initial, fatty streak, matrix metalloproteinases and matrix Med 1997; 336: 1276-82.and in te rmedia te l es ions o f degrading activity in vulnerable 22. Kolodgie FD, Burke AP, Farb A et al. atherosclerosis. A report from the regions of human atherosclerotic The thin-cap fibroatheroma: a type of Committee on Vascular Lesions of the plaques. J Clin Invest 1994; 94: 2493- vulnerable plaque: the major Counci l on Ar ter iosc leros is , 503. precursor lesion to acute coronary American Heart Associat ion. 13. Virmani R, Burke A, Farb A et al. syndromes. Curr Opin Cardiol 2001; Arteioscler Thromb 1994; 14: 840-56. Pathology of the vulnerable plaque. 16: 285-92.

5. Kolodgie FD, Burke AP, Farb A et al. Handbook of the vulnerable plaque. 23. Little WC, Constantinescu M, The thin-cap fibroatheroma: a type of Eds. Waksman, Serruys 2005: 33-48. Applegate RJ et al. Can coronary vulnerable plaque: the major 14. Davies MJ. Pathological view of angiography predict the site of a precursor lesion to acute coronary sudden cardiac death. Br Heart J subsequent myocardial infarction in syndromes. Curr Opin Cardiol 2001; 1985; 45: 88-96. patients with mild-to-moderate 16: 285-92. 15. Davies MJ, Thomas A. Thrombosis coronary artery disease? Circulation

6. Virmani R, Burke AP, Kolodgie FD, and acute coronary artery lesions in 1988; 78: 1157-66.Farb A. Pathology of the thin-cap sudden ischaemic death, and 24. Mizuno K, Satomura K, Miyamoto A fibroatheroma: a type of vulnerable crescendo angina. Br Heart J 1985; et al. Angioscopic evaluation of plaque. J Interv Cardiol 2003; 16: 53: 363-73. coronary artery thrombi in acute 267-72. 16. Burke AP, Farb A, Malom G, Virmani coronary syndromes. N Engl J Med

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