SOHAIB AHMAD;NADIA SHIRAZI; M.U. RABBANI 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 increased risk of causing thrombosis and lesion progression [1]. 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 would be termed non-vulnerable [1]. 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 type VI as complicated lesions [3,4]. CHARACTERISTICS OF A VULNERABLE PLAQUE Although evidence suggests that certain features can identify vulnerable plaques but no conclusive data exists. The following features in a plaque have been implicated as being predictive of an adverse outcome: [5,6] A] Large lipid core (40% of the entire plaque) B] Thin cap C] Increased macrophage content D] Increased proteoglycan content E] Presence of a calcified nodule There 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 plaques comes from postmortem studies [1]. Three major factors determine the vulnerability of the fibrous cap: [7] A] Circumferential wall stress or cap fatigue B] Lesion characteristics- location, size and consistency C] Blood flow characteristics Platelet disruption involves inflammation as an important adjunct to mechanical factors [8] 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 muscle cells across the basement membrane [9]. 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 with cell apoptosis [11]. 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
Keywords: vulnerable plaque, Intravascular ultrasound, Thin-cap Fibroatheroma JK- Practitioner Vol.13, No. 1, January - March 2006

Authors’ affiliations: Sohaib Ahmad Prof. M.U.Rabbani Centre of Cordiology NADIA SHIRAZI Department of Pathology JN Medical College Aligarh Muslim University, ALIGARH

ADDRESS FOR CORRESPONDENCE DR. SOHAIB AHMAD 2-Basera,Dodhpur, Opposite Bombay Merchantile Bank, Aligarh (UP)-202002, INDIA E-mail: Phone No. 0091-571-2702284/ 00919412460098/ 0091-9837172466

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

Plaque rupture is defined as a necrotic core with a thin fibrous cap that is disrupted or ruptured, allowing the flowing blood to come in contact with the necrotic core. Rupture of the fibrous cap usually occurs in the shoulder regions, the weakest portion where the stress is highest and matrix metalloproteinase production is increased [12]. The frequency of plaque rupture reported in various series of sudden coronary deaths varies from 30% [13] to over 85% [14, 15]. Calcification is present in 80% of plaques that rupture but is usually either speckled or fragmented and infrequently diffuse. The coronary plaques in plaque rupture are equally concentric or eccentric and are more frequent in men and postmenopausal women [16]. 2] Plaque Erosion It is defined as a lesion with luminal thrombus with a base rich in smooth muscle cells and proteoglycan matrix [17]. At the site of thrombosis, there is absence of an endothelial layer. These lesions are usually not calcified, or have speckled calcification if calcified [18]. Majority of plaque erosions are eccentric and occur most frequently in young men and women less than 50 years of age and are associated with smoking especially in premenopausal women [19]. 3] Calcified Nodule An infrequent cause of thrombosis in patients dying a sudden cardiac death, it refers to a lesion with a fibrous cap disruption, absence of endothelium and thrombus associated, dense calcified nodule with bone formation. The origin of calcified nodule is thought to be associated with healed plaque ruptures. Mid-right coronary artery accounts for over 50% of the cases because of maximum torsion stress and is the lesion is usually seen in elderly males with heavily calcified and tortuous arteries [20]. 4] Thin-cap Fibroatheroma The thin-cap fibroatheroma (TCFA) has been defined as a lesion with a fibrous cap < 65µm thick and infiltrated by macrophages (>25 cells per 0.3 mm diameter field) [21]. The cap may or may not be eccentric and the necrotic core is well developed. Over 50% of the plaque ruptures, healed plaque ruptures and TCFAs occur in the proximal portions of the major coronary arteries with < 50% diameter stenosis and another third in the midportion of these arteries while the rest are distributed in the distal segments [22]. Fifty percent of TCFAs have absent or speckled calcification, and the remainder has a diffuse or a fragmented calcification pattern [18]. DIAGNOSIS OF THE VULNERABLE PLAQUE Since the consequences of rupture of vulnerable plaque may be catastrophic, their identification is of paramount significance to enable the development of treatment modalities to stabilize such plaques. a)Coronary Angiography: It is the gold standard for assessment of obstructive lesions but it fails to assess the plaque burden. Also, since 70% of acute coronary occlusions are in areas that were angiographically

normal previously, the technique is severely limited in identifying vulnerable plaque. [23] b)Angioscopy: More sensitive than angiography, it offers direct visualization of the plaque surface and intraluminal structures like tears and color of the thrombi. . However, angioscopy is difficult to perform, is invasive, is associated with a risk of peri-procedural ischaemia and only a limited part of the vessel tree can be investigated. [24] c) IntravascularUltrasound (IVUS): Provides real time high-resolution images of the vessel wall and lumen. Only structures over 160 µ m can be visualized 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 characterized by a bright echo signal with distal shadows that hide plaque components and deeper vessel structures. The sensitivity of detection of micro-calcification is around 60% [25]. Lipid deposition is described as echoluscent zones and can be detected on IVUS with a sensitivity of between 78 and 95% and specificity of 30% [26]. The sensitivity to differentiate between fatty and fibrous tissue is between 39 and 52% [27]. IVUS assessment of vascular remodeling may help to classify plaques with the highest [28] probability of spontaneous rupture . d)Intravascular Elastography: Based on the concept that upon uniform loading, the local relative amount of deformation of a tissue is related to the local mechanical properties of that tissue, this technique differentiates between hard and soft tissue that may be important for detection of a deformable plaque prone to rupture. e) Other Techniques: l Optical Coherence Tomography l Thermography l Raman Spectroscopy l Near-Infrared Spectroscopy l Magnetic Resonance Imaging l Shear Stress Imaging All the techniques are still under development and at present none of them can identify a vulnerable plaque alone or predict its further development. Thus a combination of various modalities will be important in the future to ensure high sensitivity and specificity in detecting vulnerable plaque. CAN PERIPHERAL BLOOD BE USED TO IDENTIFY VULNERABLE PLAQUES? Several candidate markers in peripheral blood either singly, or in combination identify patients at high cardiovascular risk – LDL and oxidized LDL, C-reactive proteins and other acute phase reactants, p-selectins, monocyte chemoattractant protein-1 and macrophage colony
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stimulating factor, CD-40 ligand, interleukins (1b and 6), matrix metalloproteinases- to name a few. Pregnancyassociated plasma protein is a new marker for vulnerable plaque and is currently under extensive study [29]. THERAPY FOR VULNERABLE PLAQUE Drugs (Plaque Stabilizers) 8 HMG CoA reductase inhibitors (Statins) 8 Angiotensin converting enzyme inhibitors (ACEI) 8 Antihypertensive agents 8 b-blockers 8 w-3 fatty acids Antiplatelet agents (Aspirin/ Clopidogrel) Others - Peroxisome proliferator activated receptor agonists - Anti-inflammatory agents - Antibiotics - Antioxidants Therapies that may possess plaquestabilizing effects Gene therapy 8 Metalloproteinase inhibitors 8 CD-40 pathway inhibitors Photodynamic therapy

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directional coronary atherectomy. Am Heart J 1995; 129: 631-7. 27. Hiro T, Leung CY, Russo RJ et al. Variability of a three layered appearance in intravascular ultrasound coronary images: a comparison of morphometric measurements with four intravascular ultrasound systems. Am J Cardiol Imaging 1996; 10: 219-27. 28. von Birgelen C, Klinkhart W, Mintz GS et al. Plaque distribution and vascular remodeling of ruptured and unruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol 2001; 37: 1864-70. 29. Touchard AG, Bayes-Genis A, Lesser JR et al. Vulnerable plaque: detection paradigms from molecules in peripheral blood. Handbook of the vulnerable plaque. Eds. Waksman, Serruys 2005: 125-51.


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