04RC2. The biology of vulnerable plaques. Jozef L. Van Herck 1, Christiaan J. Vrints 1, Arnold G. Herman 2

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1 04RC2 The biology of vulnerable plaques Jozef L. Van Herck 1, Christiaan J. Vrints 1, Arnold G. Herman 2 1 Department of Cardiology, Antwerp University Hospital, Edegem, Belgium 2 Department of Pharmacology, University of Antwerp, Wilrijk, Belgium Saturday, June 12, :00-16:45 Room: 101d Ischaemic heart disease remains the leading cause of death in the Western world. Acute coronary syndromes, including acute myocardial infarction, unstable angina and sudden death, are often the first clinical presentation of underlying coronary artery disease. It was previously thought that progressive luminal narrowing from continued growth of smooth muscle cells in atherosclerotic plaques was the main cause of myocardial infarction. However, it has become clear that the majority of acute coronary syndromes result from rupture of atherosclerotic plaques that did not cause flow limitation before the acute event. Coronary atherosclerotic plaques can remain silent for decades, but suddenly become unstable, triggering thrombus formation and acute coronary syndromes. The term vulnerable plaque is used to define plaques that are thrombosis-prone and have a high probability of undergoing rapid progression [1]. A synonym for vulnerable plaque is a high risk or thrombosis-prone plaque [1]. Luminal thrombi can arise from three different plaque morphologies: plaque rupture, plaque erosion and calcified nodules. Plaque rupture is the major cause of coronary thrombi (55-60%), while plaque erosion and calcified nodule account for 30-35% and 3-7%, respectively [2]. Plaque rupture Plaque rupture is defined as an area of fibrous cap disruption, with an overlying thrombus in direct continuity with the underlying necrotic core. Post-mortem pathologic studies suggest that thin cap fibroatheroma (TCFA) are the precursor lesions for plaque rupture [2]. TCFA are characterized by a thin inflamed fibrous cap covering a large necrotic core, as opposed to stable plaques that contain large numbers of smooth muscle cells (SMC) and a large amount of extracellular matrix (ECM) (Figure 1). Other characteristics of TCFA include micro-calcifications and localised expansive enlargement of the vessel wall, known as positive remodeling. Rupture of the fibrous cap leads to exposure of the thrombogenic lipid core to the circulating blood, with activation of the coagulation cascade, aggregation of blood platelets and thrombus formation (Figure 1). Plaque rupture is the result of the interaction between intrinsic plaque features ( vulnerability ) and extrinsic stresses ( rupture triggers ). Plaque vulnerability predisposes a plaque to rupture, whereas rupture triggers may precipitate it [3]. In the next section, we first present the intrinsic features of a vulnerable plaque, followed by an overview of the extrinsic stresses. Intrinsic features of vulnerable plaques Critical fibrous cap thickness The stability of an atherosclerotic plaque is determined by the thickness of the fibrous cap, which prevents contact between the highly thrombogenic necrotic core and the circulating blood. In a post-mortem study of 41 ruptured coronary plaques, 95% of the fibrous caps were less than 65 µm thick (mean 23 µm) [4]. Based on this study, a thin fibrous cap in coronary plaques is usually defined as a cap with a thickness < 65 µm

2 Figure 1 Schematic presentation of a stable, unstable and ruptured atherosclerotic plaque Stable atherosclerotic plaque Unstable atherosclerotic plaque Plaque rupture and thrombus formation Smooth muscle cell Collagen fibers Endothelial cell Macrophage Necrotic core Neovessel - 2 -

3 Necrotic core The necrotic core is composed of free cholesterol, cholesterol crystals and cholesterol esters. The consistency of the necrotic core is determined by the relative composition: lipids in the form of cholesterol esters soften the necrotic core, whereas crystalline cholesterol has the opposite effect [3]. A soft core is considered more vulnerable because it is not able to bear the imposed circumferential stress, which is then redistributed to the fibrous cap [3]. In addition to the consistency, the size of the necrotic core is important for plaque stability. In approximately two thirds of ruptured plaques, the necrotic core occupies more than 25% of the plaque area [2]. Especially atherosclerotic plaques with a necrotic core occupying more than 40% of the plaque area appear to be vulnerable to plaque rupture [5]. Positive remodelling Pathological studies from patients with fatal coronary events have consistently shown that at sites of plaque rupture with superimposed occlusive thrombosis, the underlying lesion is large [6]. However, the majority of the culprit lesions do not cause significant luminal narrowing before the acute event [6]. One of the mechanisms that may explain why culprit lesions do not cause a significant stenosis is the process of arterial remodelling. Positive remodelling is a compensatory mechanism that maintains coronary arterial lumen size until plaques occupy about 40% of the vessel cross-sectional area [7]. Consequently, positive remodelling may prevent luminal stenosis despite a large plaque size. Pathological studies suggest a relationship between plaque composition and the degree of positive or negative remodelling. Patients with acute coronary syndromes are more likely to display positive remodelling of the culprit lesion [8]. By contrast, constrictive remodelling is associated with fibrotic and presumably more stable plaques. These results imply that positive remodelling should be seen as a double-edged sword. Although positive remodelling compensates for plaque growth and avoids luminal stenosis, it harbours potential vulnerable plaques, preventing their early detection by coronary angiography. Oligofocal disease Initial studies have suggested that a high percentage of the patients with acute coronary syndromes have multiple ruptured plaques. For example, Goldstein et al [9] found multiple complex angiographic lesions in 40% of patients with acute myocardial infarction, suggestive of multifocal plaque rupture. Many of these lesions were located in vessels not related to the acute event. Subsequent studies have reported a lower incidence of multiple plaque ruptures [10]. Currently, it is estimated that approximately 20% of patients with acute coronary syndromes has more than one disrupted plaque [10]. Therefore, rupture-prone plaques are oligofocal, rather than diffuse or multifocal. Neovascularisation In normal arteries, vasa vasorum-derived microvessels are limited to the adventitia and outer media. Diffusion of oxygen and other nutrients from the lumen is sufficient to nourish the intimal layer and the inner media of normal arteries. A progressive increase in plaque volume is associated with the development of zones of hypoxia in the atherosclerotic plaque. Hypoxia stimulates neovascularisation of the atherosclerotic plaque. New vessels sprout from the adventitial vasa vasorum through the media into the intimal lesion. Accumulating evidence links plaque angiogenesis with progressive and unstable vascular disease. Vessel density is increased two-fold in vulnerable plaques and four-fold in disrupted plaques compared with obstructive stable disease [11]. New vessels may serve as a pathway for recruitment of leucocytes to high-risk areas of the plaque [12]. Moreover, thin-walled new vessels are often leaky and fragile, and disruption of microvessels can result in intraplaque haemorrhage, contributing to enlargement of the necrotic core. Inflammation and matrix degradation Ruptured fibrous caps are heavily inflamed. At the actual rupture site, large numbers of inflammatory cells are present [2]. A macrophage density of 26% has been reported in the fibrous cap of ruptured plaques [2]. The inflammatory cells consist mainly of macrophages, but also include mast cells and T-lymphocytes

4 Macrophages, but also all other cell types in the atherosclerotic plaque, can produce a variety of proteolytic enzymes, capable of degrading the ECM. Three major families of enzymes participate in ECM degradation: matrix metalloproteinases, cysteine proteases (including cathepsins), and serine proteases (urokinase and plasmin). These proteolytic enzymes act together to degrade the ECM. Degradation of collagen can impair the tensile strength of the fibrous cap [13]. Disrupted fibrous caps contain less collagen than intact caps [5]. These results suggest an important role for proteolytic enzymes in plaque rupture. Apoptosis of macrophages Multiple factors, such as high concentrations of oxldl, tumour necrosis factor-α (TNF-α) and Fas-ligand, can induce apoptosis of macrophages. The effect of macrophage apoptosis on the progression of advanced atherosclerotic plaques is complex. Advanced atherosclerotic plaques have an impaired clearance of apoptotic cells [14]. Defective phagocytosis of apoptotic cells has a number of consequences that promotes the progression and complications of atherosclerotic plaques. Apoptotic cells that are not ingested become secondarily necrotic, which can cause tissue damage from released intracellular proteases and other noxious material of these cells. Non-cleared apoptotic cells are also an important source of tissue factor, which increases plaque thrombogenicity. In addition, inefficient removal of apoptotic cells contributes to enlargement of the necrotic core. In this regard, macrophage apoptosis could be detrimental for the stability of advanced atherosclerotic plaques as it will further decrease the scavenging capacity in the plaque. However, macrophages are an important source of inflammatory cytokines and proteolytic enzymes, thus a decrease in macrophages may also have plaque-stabilizing effects. Taken together, the final effect of macrophage apoptosis on plaque stability is still unclear and remains an area of active research [15]. Apoptosis of smooth muscle cells Various mediators secreted by macrophages and T lymphocytes, including IFN-γ, Fas-ligand, TNF-α, IL-1 and reactive oxygen species, can induce SMC apoptosis [16]. Apoptosis of SMCs is important for plaque stability. Plaque rupture sites typically show very few SMCs. Apoptosis of SMCs will lead to loss of cells that are responsible for the synthesis of interstitial collagen fibers. Because SMCs in atherosclerotic plaques show very low values of cell replication, a slight increase in SMC apoptosis will lead to a drastic decrease in SMC content, which in turn will have a major influence on collagen synthesis and plaque stability [16]. Calcification There is controversy about the role of calcification in the stability of atherosclerotic lesions, with possibly a different role for macro- and micro-calcifications. Large calcifications have been associated with a protective role against plaque rupture. However, micro-calcifications seem to play an active role in plaque rupture [17, 18]. Phagocytosis of micro-calcifications by macrophages triggers a pro-inflammatory response with increased secretion of inflammatory cytokines (such as TNF-α, IL-1 and IL-18) [17]. In addition, micro-calcifications in the fibrous cap can increase the local stress concentrations, raising the risk of plaque rupture [18]. Extrinsic factors Coronary plaques are constantly stressed by a variety of haemodynamic forces. It is likely that external forces can trigger plaque rupture at sites where the fibrous cap is thin and weak. For eccentric plaques, this is often the junction between the plaque and the adjacent normal intima, called the shoulder region of the plaque

5 Shear stress Whereas low shear stress is important for the distribution and growth of atherosclerotic lesions, it has been suggested that high shear stress is associated with plaque rupture [19]. When the atherosclerotic lesion begins to intrude the lumen, the fibrous cap becomes exposed to high shear stress. High shear stress may stimulate breakdown of the fibrous cap through a decrease in SMC production of collagen and an increase in macrophage secretion of matrix metalloproteinases (MMP) [19]. However, it remains uncertain whether high shear stress alone can disrupt an atherosclerotic plaque. The absolute stresses induced by wall shear are usually much smaller than the mechanical stresses imposed by blood and pulse pressure [3]. Blood and pulse pressure The blood pressure induces circumferential tension in the arterial wall. The circumferential wall tension (tensile stress) is given by Laplace s Law: σ = Pr/h where σ is the circumferential wall tension, P is the pressure in the vessel, r is the radius of the vessel and h is the thickness of the wall. Laplace s Law relates luminal pressure and radius to wall tension: the higher the blood pressure and the larger the luminal diameter, the more tension develops in the wall. Richardson et al [20] computed the distribution of circumferential stress within simulated plaques and observed that eccentric pools of soft material increase the stress on the adjacent fibrous cap, especially near the shoulders. Moreover, the calculated high-stress points correlate well with sites of cap disruption in ruptured plaques [20]. The pulse pressure (the pulsatile component of blood pressure) causes cyclic deformation and bending of the plaques. Eccentric plaques typically bend at their edges - the junction between the stiff plaque and the more compliant plaque-free vessel wall. The repetitive pulsatile stress may weaken the fibrous cap and ultimately lead to sudden cap rupture due to fatigue [3]. Vasospasm Plaque disruption and vasospasm frequently occur together [3]. Theoretically, vasospasm could induce plaque rupture by compressing the atheromatous core. However, onset of myocardial infarction is uncommon during or shortly after drug-induced spasm of even severely diseased coronary arteries, indicating that vasospasm rarely precipitates plaque disruption or luminal thrombosis. Plaque erosion About 30-35% of coronary thrombi are caused by plaque erosion [2]. Plaque erosion is defined as an acute thrombus in direct contact with the intima, in an area of absent endothelium. The thrombus appears to be superimposed on a de-endothelialized, but otherwise intact plaque. The underlying plaque is rich in SMCs and proteoglycan matrix. Most eroded lesions lack a necrotic core, but when present, there is no direct communication with the luminal thrombus. These plaques are often associated with constrictive remodeling [2]. Plaque erosion is associated with smoking, especially in women. On average, patients with plaque erosion are younger than those with plaque rupture. Plaque erosion accounts for more than 80% of coronary thrombi occurring in women < 50 years of age. In comparison with plaque rupture, thrombi of plaque erosions tend to embolize more frequently (74% vs 40%, respectively) [2]. Plaque with calcified nodule The least frequent lesion associated with coronary thrombosis is the calcified nodule [2]. Calcified nodules are plates of calcium in advanced plaques that have broken down into fragments and erupt into the lumen, resulting in thrombosis and intimal reaction. Calcified nodules tend to occur in older men

6 Key learning points The occurrence of acute coronary syndromes is more related to plaque composition than to plaque size. Most acute coronary syndromes are caused by rupture of atherosclerotic plaques. Plaque rupture is the result of the interaction between intrinsic plaque features ( vulnerability ) and extrinsic stresses ( rupture triggers ). Thin-cap fibroatheroma, the precursor lesions for plaque rupture, are characterized by a large necrotic core, covered by a thin inflamed fibrous cap. Other characteristics of TCFA include the presence of micro-calcifications and localised expansive enlargement of the vessel wall, known as positive remodelling. References 1. Schaar JA, Muller JE, Falk E, et al. Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece. Eur Heart J 2004; 25: 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: Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997; 336: Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993; 69: Fishbein MC, Siegel RJ. How big are coronary atherosclerotic plaques that rupture? Circulation 1996; 94: Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316: Schoenhagen P, Ziada KM, Kapadia SR, et al. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes : an intravascular ultrasound study. Circulation 2000; 101: Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000; 343: Libby P. Atherosclerosis: disease biology affecting the coronary vasculature. Am J Cardiol 2006; 98: 3Q-9Q. 11. Moreno PR, Purushothaman KR, Fuster V, et al. Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: implications for plaque vulnerability. Circulation 2004; 110: de Boer OJ, van der Wal AC, Teeling P, Becker AE. Leucocyte recruitment in rupture prone regions of lipid-rich plaques: a prominent role for neovascularization? Cardiovasc Res 1999; 41: Lendon CL, Davies MJ, Born GV, Richardson PD. Atherosclerotic plaque caps are locally weakened when macrophages density is increased. Atherosclerosis 1991; 87: Schrijvers DM, De Meyer GRY, Kockx MM, Herman AG, Martinet W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: Martinet W, De Meyer GRY. Selective depletion of macrophages in atherosclerotic plaques: myth, hype, or reality? Circ Res 2007; 100: Kockx MM, Herman AG. Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res 2000; 45: Nadra I, Mason JC, Philippidis P, et al. Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and arterial calcification? Circ Res 2005; 96: Vengrenyuk Y, Carlier S, Xanthos S, et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci USA 2006; 103: Slager CJ, Wentzel JJ, Gijsen FJ, et al. The role of shear stress in the destabilization of vulnerable plaques and related therapeutic implications. Nat Clin Pract Cardiovasc Med 2005; 2: Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989; 2: