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(Circulation. 1995;92:657-671.)
© 1995 American Heart Association, Inc.

Articles

Coronary Plaque Disruption

Erling Falk, MD, PhD; Prediman K. Shah, MD; Valentin Fuster, MD, PhD

From the Department of Interventional Cardiology, Skejby University Hospital, Aarhus, Denmark (E.F.); the Division of Cardiology, Cedars-Sinai Medical Center, and the University of California, Los Angeles (P.K.S.); and the Cardiovascular Institute, Mount Sinai Medical Center, New York, NY (V.F.).

	Introduction

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease, and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden death.^{1 2 3 4 5} Therefore, for event-free survival, the vital question is not why atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicated by life-threatening thrombosis. The composition and vulnerability of plaque rather than its volume or the consequent severity of stenosis produced have emerged as being the most important determinants for the development of the thrombus-mediated acute coronary syndromes; lipid-rich and soft plaques are more dangerous than collagen-rich and hard plaques because they are more unstable and rupture-prone and highly thrombogenic after disruption.⁶ This review will explore potential mechanisms responsible for the sudden conversion of a stable atherosclerotic plaque to an unstable and life-threatening atherothrombotic lesion—an event known as plaque fissuring, rupture, or disruption.^{7 8}

	Atherogenesis

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
Atherosclerosis is the result of a complex interaction between blood elements, disturbed flow, and vessel wall abnormality, involving several pathological processes: inflammation, with increased endothelial permeability, endothelial activation, and monocyte recruitment^{9 10 11 12 13 14} ; growth, with smooth muscle cell (SMC) proliferation, migration, and matrix synthesis^{15 16} ; degeneration, with lipid accumulation^{17 18} ; necrosis, possibly related to the cytotoxic effect of oxidized lipid¹⁹ ; calcification/ossification, which may represent an active rather than a dystrophic process^{20 21} ; and thrombosis, with platelet recruitment and fibrin formation.^{1 22 23} Thrombotic factors may play a role early during atherogenesis, but a flow-limiting thrombus does not develop until mature plaques are present, which is why thrombosis often is classified as a complication rather than a genuine component of atherosclerosis.

Mature Plaques: Atherosis and Sclerosis
As the name atherosclerosis implies, mature plaques typically consist of two main components: soft, lipid-rich atheromatous "gruel" and hard, collagen-rich sclerotic tissue (Fig 1A). The sclerotic component (fibrous tissue) usually is by far the more voluminous component of the plaque, constituting >70% of an average stenotic coronary plaque.^{24 25 26} Sclerosis, however, is relatively innocuous because fibrous tissue appears to stabilize plaques, protecting them against disruption. In contrast, the usually less voluminous atheromatous component is the more dangerous component, because the soft atheromatous gruel destabilizes plaques, making them vulnerable to rupture, whereby the highly thrombogenic gruel is exposed to the flowing blood, leading to thrombosis—a potentially life-threatening event.

View larger version (0K): [in this window] [in a new window]   Figure 1. Photomicrographs illustrating composition and vulnerability of coronary plaques. A, A mature atherosclerotic plaque that consists of two main components: soft, lipid-rich atheromatous "gruel" (*) and hard, collagen-rich sclerotic tissue (blue). B, Two adjacent plaques, one located in the circumflex branch (left) and another proximal in a side branch (right). Although both plaques have been exposed to the same systemic risk factors, the plaque to the left is collagenous and stable, but the plaque to the right is atheromatous and vulnerable, with disrupted surface and superimposed nonocclusive thrombosis (red). C through E, A vulnerable plaque, containing a core of soft atheromatous gruel (devoid of blue-stained collagen) that is separated from the vascular lumen by a thin cap of fibrous tissue. The fibrous cap is infiltrated by foam cells that can be clearly seen at high magnification (E), indicating ongoing disease activity. Such a thin and macrophage-infiltrated cap is probably very weak and vulnerable, and it was indeed disrupted nearby, explaining why erythrocytes (red) can be seen in the gruel just beneath the macrophage-infiltrated cap. F, Atherectomy specimen from culprit lesion in non–Q-wave myocardial infarction. At high magnification it can be clearly seen that this plaque specimen is heavily infiltrated by red-stained macrophages. A through E, trichrome stain; F, immunostaining for macrophages using monoclonal antibody PG-M1 from Dako. c indicates contrast medium injected postmortem.

Atherosis: Lipid Trapping and/or Cell Death?
The atheromatous core within a plaque is devoid of supporting collagen, avascular, hypocellular (except at the periphery of the core), rich in extracellular lipids, and soft like gruel.^{27 28} The pathogenesis of this, the clinically more important plaque component, however, remains controversial. Insudated blood-derived lipid, preferentially LDL, may be trapped and accumulate directly within the extracellular space, or it may be endocytosed by macrophages, probably via their scavenger receptors after oxidative modification, and accumulate indirectly after necrosis of the lipid-filled macrophages (foam cells).^{17 18 19} The relative contribution of direct lipid trapping versus foam cell necrosis in the formation of the atheromatous core and its growth is unknown, although foam cell necrosis is widely believed to be more important.¹⁹ Therefore, the soft lipid-rich core within a plaque is also called a "necrotic core" and "atheronecrosis."^{28 29 30} Recent observations, however, suggest that the core does not originate primarily from dead foam cells in the superficial intima (fatty streaks) but rather arises from lipids accumulating gradually in the extracellular matrix of the deep intima as a result of complex binding between insudating LDL and glycosaminoglycans, collagen, and/or fibrinogen.^{31 32 33 34}

Plaque Size and Composition
Pathoanatomic studies indicate that the atheromatous component enlarges with plaque growth,^{8 35 36} but the variability is great, and data on a possible relation between size and composition of plaques are incomplete. The actual composition and vulnerability of plaques are not revealed by a single angiographic examination, but a repeat study months to years later may identify the kinds of plaques that most frequently progress to occlusion and/or become culprits; ie, the likelihood of a plaque's becoming complicated with disruption and/or thrombosis may be assessed. Serial angiographic studies indicate that the more obstructive a plaque is, the more frequently it progresses to coronary occlusion³⁷ and/or gives rise to myocardial infarction.^{38 39} The Coronary Artery Surgery Study (CASS) prospectively evaluated 2938 nonbypassed coronary segments in 298 patients.³⁷ Of 2161, 430, 258, and 89 segments narrowed <5%, 5% to 49%, 50% to 80%, and 81% to 95% at baseline, respectively, 0.7%, 2.3%, 10.1%, and 23.6%, respectively, became occluded during the 5-year follow-up period (Fig 2, top). Although an individual severe stenosis became occluded more frequently than did an individual less severe stenosis, the less obstructive plaques (<80% stenosis at baseline) gave rise to more occlusions than did the severely obstructive plaques (52 versus 21) because of their much greater number. Thus, coronary occlusion and myocardial infarction most frequently evolve from mild to moderate stenoses (Fig 2, top and middle), as initially reported by Ambrose et al⁴⁰ and Little et al⁴¹ and later confirmed by others^{38 39} (Fig 2, bottom). This has given rise to the notion that less obstructive plaques are more lipid-rich and vulnerable to rupture than larger plaques.^{1 38 41} The smaller plaques, however, could be most dangerous just because of their greater number—they by far outnumber the severely obstructive plaques.^{37 39} Furthermore, the smaller rather than the larger plaques are more likely to lead to acute clinical events in case of abrupt occlusion because they are less frequently associated with protective collateral circulation.⁴² The fact that some severe coronary stenoses do regress with lipid-lowering therapy clearly indicates that the advanced and obstructive plaques also may contain a significant lipid-rich component.⁴³ By angiography, severely stenotic plaques at the carotid bifurcation frequently appear ulcerated and disrupted, and such lesions are indeed dangerous, being associated with a high risk of ipsilateral stroke.⁴⁴

View larger version (31K): [in this window] [in a new window]   Figure 2. Bar graphs showing stenosis severity and associated risk of coronary occlusion and myocardial infarction (MI) as evaluated by serial angiographic examination. The more stenotic an individual coronary segment is at baseline, the more frequently it progresses to occlusion (top37 ) and/or gives rise to infarction (middle38 ). Because less-obstructive plaques by far outnumber severely obstructive plaques, most occlusions and infarctions result from progression of the former plaques (52 vs 21 and 29 vs 10, respectively), ie, MI evolves most frequently from plaques that are only mildly to moderately obstructive months to years before infarction (bottom). The bar graphs are constructed from data published by (top) Alderman et al37 ; (middle) Nobuyoshi et al38 ; and (bottom) Ambrose et al,40 Little et al,41 Nobuyoshi et al,38 and Giroud et al.39

Risk Factors and Plaque Composition
Endothelial dysfunction, demonstrable in atherosclerotic arteries as well as in arteries resistant to atherosclerosis (forearm blood vessels and microcirculation), appears to be an early and reliable marker for the presence of atherogenic risk factors.^{45 46 47} There is, however, a remarkable and poorly understood variability in the way plaques evolve (Fig 1B), and it is unclear how the various risk factors for clinical disease influence the development, composition, and vulnerability of coronary plaques. Age, male sex, hypercholesterolemia, hypertension, smoking, and diabetes correlate with the coronary plaque burden (extent of "plaquing") found at autopsy,^{48 49 50 51 52} but apart from an increase in calcification with age and possibly male sex,⁵³ a relation of specific risk factors to composition of plaque remains to be identified. Fibrous tissue seems to constitute the most voluminous component of mature coronary plaques, irrespective of individual risk factors.^{24 25 26 54 55 56 57} Preliminary data, however, do suggest that smokers have more extracellular lipids, particularly oxidized LDL, in their plaques than nonsmokers.³³

	Plaque Disruption: Vulnerability and Triggers

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
Plaques containing a soft atheromatous core are unstable and may rupture; ie, the fibrous cap separating the core from the lumen may disintegrate, tear, or break, whereby the highly thrombogenic gruel is suddenly exposed to the flowing blood. Such disrupted plaques are found beneath about 75% of the thrombi responsible for acute coronary syndromes.^{58 59 60 61} Beneath the remaining thrombi, superficial macrophage-related intimal erosions without frank disruption (no deep injury) are usually found, often in combination with a severe atherosclerotic stenosis.^{58 59 60}

The risk of plaque disruption is related to intrinsic properties of individual plaques (their vulnerability) and extrinsic forces acting on plaques (rupture triggers). The former predispose plaques to rupture, whereas the latter may precipitate disruption if vulnerable plaques are present.

Vulnerability of Plaques
Plaque disruption occurs most frequently where the fibrous cap is thinnest, most heavily infiltrated by foam cells, and therefore weakest. For eccentric plaques, that is often the junction between the plaque and the adjacent less-diseased vessel wall, called the shoulder region of the plaque.⁵⁹ Pathoanatomic examination of intact and disrupted plaques and in vitro mechanical testing of isolated fibrous caps from aorta indicate that vulnerability to rupture depends on (1) size and consistency of the atheromatous core, (2) thickness and collagen content of the fibrous cap covering the core, (3) inflammation within the cap, and (4) cap "fatigue." Long-term repetitive cyclic stresses may weaken a material and increase its vulnerability to fracture, ultimately leading to sudden and unprovoked (ie, untriggered) mechanical failure due to fatigue. Therefore, fatigue is discussed here as one of the determinants of plaque vulnerability rather than being included in the subsequent section on rupture triggers.

Atheromatous Core
The size and consistency of the atheromatous core vary greatly from plaque to plaque and are critical for the stability of individual lesions (Fig 1C and 1D). Although the average stenotic coronary plaque contains much more hard fibrous tissue than soft atheromatous gruel, a significant atheromatous component is usually present in culprit lesions responsible for acute coronary syndromes.⁵ Gertz and Roberts⁶² reported the composition of plaques in 5-mm segments from 17 infarct-related arteries examined postmortem and found much larger atheromatous cores in the 39 segments with plaque disruption than in the 229 segments with intact surface (32% and 5% to 12% of plaque area, respectively). In aortic plaques, Davies et al⁶³ found a similar relation between atheromatous core size and plaque disruption, and they identified a critical threshold; intact aortic plaques containing a core occupying >40% of the plaque were considered particularly vulnerable and at high risk of rupture and thrombosis.

The atheromatous core is rich in extracellular lipids, especially cholesterol and its esters.^{27 28} The consistency of the gruel depends on lipid composition and temperature; it usually is soft, like toothpaste, at room temperature postmortem, and it is even softer at body temperature in vivo. Lipid in the form of cholesteryl esters softens plaque, whereas crystalline cholesterol has the opposite effect.^{27 28} On the basis of animal experiments, lipid-lowering therapy in humans is expected to deplete plaque lipid, with an overall reduction in cholesteryl esters (liquid and mobile) and a relative increase in crystalline cholesterol (solid and inert), theoretically resulting in a stiffer and more stable atheromatous lesion.^{28 64 65}

Cap Thickness
The thickness and collagen content of the fibrous cap are important for the stability of a plaque.⁶⁶ Fibrous caps vary widely in thickness, cellularity, matrix, strength, and stiffness, but they are often thinnest (and macrophage infiltrated) at their shoulder regions, where disruption most frequently occurs.⁵⁹ Collagen is important for the tensile strength of tissues, and disrupted aortic caps contain fewer SMCs (the collagen-synthesizing cell in plaques) and less collagen than intact caps.^{63 67} The cause of this potentially dangerous relative lack of SMCs in disrupted caps is unknown, but SMCs could vanish as the result of apoptotic cell death.⁶⁸ Loss of cells and calcification in fibrous caps are associated with increased stiffness,⁶⁹ but the significance of cap stiffness for rupture propensity is unknown.

Cap Inflammation
Disrupted fibrous caps usually are heavily infiltrated by macrophage foam cells^{58 70 71} (Figs 1E, 1F, and 3C through 3F). These rupture-related macrophages are activated, indicating ongoing inflammation at the site of plaque disruption.⁶⁰ For eccentric plaques, the shoulder regions are sites of predilection for both active inflammation (endothelial activation^{10 72} and macrophage infiltration⁵⁹ ) and disruption,⁵⁹ and in vitro mechanical testing of aortic fibrous caps indicates that foam cell infiltration indeed weakens caps locally, reducing their tensile strength.⁷³

View larger version (0K): [in this window] [in a new window]   Figure 3. Photomicrographs illustrating disruption and rapid progression of coronary plaques. A and B, Disrupted plaque with hemorrhage into the soft gruel through a defect in the cap. In addition, a small mural thrombus can be seen at the edges of the defect where thrombogenic plaque components have been exposed. C and D, Disrupted plaque with occlusive thrombosis superimposed. The disrupted cap beneath the thrombus is thin and heavily infiltrated by foam cells, probably macrophages. E and F, Disrupted plaque with occlusive thrombosis superimposed. The thin fibrous cap is heavily foam cell infiltrated, and atheromatous gruel (*) has been extruded through the disrupted cap into the lumen, where it can be seen surrounded by thrombus, clearly indicating the sequence of events: plaque disruption exposing thrombogenic plaque components and resulting in luminal thrombosis. Trichrome stain, rendering collagen blue and erythrocytes (plaque hemorrhage) and thrombus red. c indicates contrast medium injected postmortem.

Richardson et al⁵⁹ studied 85 coronary thrombi postmortem and found a disrupted atheromatous plaque beneath 71 (84%) of the thrombi. The fibrous cap had ruptured at shoulder regions of eccentric plaques in 42 cases (67% of rupture sites were foam cell infiltrated) and at other locations in the other 29 cases (86% of rupture sites were foam cell infiltrated). van der Wal et al⁶⁰ identified superficial macrophage infiltration in plaques beneath all the 20 coronary thrombi examined, whether the underlying plaque was disrupted or just eroded. The macrophages and adjacent T lymphocytes (SMCs were usually lacking at rupture sites) were activated as assessed by immunohistochemical techniques, indicating ongoing disease activity. These postmortem studies of patients who died of coronary thrombosis have been confirmed by an in vivo study of atherectomy specimens from culprit lesions responsible for stable angina, unstable rest angina, or non–Q-wave myocardial infarction.⁷⁴ Culprit lesions responsible for the acute coronary syndromes contained significantly more macrophages than did lesions responsible for stable angina pectoris (14% versus 3% of plaque tissue occupied by macrophages) (Figs 1F and 4).

View larger version (21K): [in this window] [in a new window]   Figure 4. Bar graph showing significantly more macrophage infiltration in culprit plaques responsible for unstable coronary syndromes (n=18) than in those responsible for chronic stable angina (n=8). Macrophages were identified by immunohistochemical technique, using a specific monoclonal antibody against macrophages (PG-M1 from Dako) (from Moreno et al74 ). MI indicates myocardial infarction.

Macrophages are capable of degrading extracellular matrix by phagocytosis or by secreting proteolytic enzymes such as plasminogen activators and a family of matrix metalloproteinases (MMPs: collagenases, gelatinases, and stromelysins) that may weaken the fibrous cap, predisposing it to rupture.⁷⁵ A wide variety of cells besides macrophages may produce MMPs.⁷⁵ They are secreted in a latent zymogen form requiring extracellular activation, after which MMPs are capable of degrading virtually all components of the extracellular matrix. The MMPs and their cosecreted tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 are critical for cell migration, tumor invasion and metastasis, inflammation, wound healing, and vascular remodeling.⁷⁵ Collagen is the main component of fibrous caps responsible for their tensile strength, and human monocyte-derived macrophages grown in culture are indeed capable of degrading cap collagen, and they do, simultaneously, express MMP-1 (interstitial collagenase) and induce MMP-2 (gelatinolytic) activity in the culture medium^{76 77} (Fig 5). Several studies have now identified MMPs in human coronary plaques,^{78 79 80} and lipid-filled macrophages (foam cells) may be particularly active in destabilizing plaques,⁸¹ predisposing them to rupture. Monocytes/macrophages could also play a detrimental role after plaque disruption, promoting thrombin generation and luminal thrombosis through the tissue factor pathway.^{30 82 83 84 85}

View larger version (14K): [in this window] [in a new window]   Figure 5. Data supporting the role of monocyte-derived macrophages and matrix-degrading metalloproteinases (MMPs) in inducing collagen breakdown in fibrous caps of human atherosclerotic plaques. A, Bar graph showing that incubation of fibrous caps with macrophages results in hydroxyproline release into the supernatant (indicative of collagen breakdown), a process inhibited by an MMP inhibitor. This is associated with macrophage expression of MMP-1 (reddish-brown immunostain using a specific antibody) (B) and MMP-2 (red fluorescence using an FITC-labeled specific antibody) (C). For details, see Shah et al.77

Activated mast cells may secrete powerful proteolytic enzymes, such as tryptase and chymase, that can activate pro-MMPs secreted by other cells (eg, macrophages), and mast cells are indeed present in shoulder regions of mature coronary plaques but at a relatively low density (ratio of mast cells to macrophages, 1:20).^{86 87} Neutrophils are also capable of destroying tissue by secreting proteolytic enzymes,⁸⁸ but neutrophils are rare in intact plaques.^{60 89} They may occasionally be found in disrupted plaques beneath coronary thrombi, probably entering these plaques shortly after disruption,⁶⁰ and neutrophils may also migrate into the arterial wall shortly after reperfusion of occluded arteries in response to ischemia/reperfusion.⁹⁰

Cap Fatigue
A steady load that does not fracture a material may weaken it if the load is applied repeatedly. This repetitive stress may ultimately lead to sudden fracture of the tissue due to fatigue, analogous to repetitive bending of a paper clip that weakens it until it suddenly breaks.⁹¹ Cyclic stretching, compression, bending, flexion, shear, and pressure fluctuations may fatigue and weaken a fibrous cap that ultimately may rupture spontaneously, ie, unprovoked or untriggered. Lowering the frequency (heart rate) and magnitude (flow- and pressure-related) of loading should reduce the risk of plaque disruption if fatigue plays a role.⁹²

Triggers of Plaque Disruption
Coronary plaques are constantly stressed by a variety of mechanical and hemodynamic forces that may precipitate or "trigger" disruption of vulnerable plaques.^{91 93} Stresses imposed on plaques are usually concentrated at the weak points discussed above, namely, at points at which the fibrous cap is thinnest and tearing most frequently occurs.⁹⁴

Cap Tension
The circumferential wall tension (tensile stress) caused by the blood pressure is given by Laplace's law, which 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.⁹³ If components within the wall (soft gruel, for example) are unable to bear the imposed load, the stress is redistributed to adjacent structures (fibrous cap over gruel, for example), where it may be concentrated at critical points.⁵⁹ The consistency of the gruel may be important for this stress redistribution because the stiffer the gruel, the more stress it can bear, and correspondingly less is redistributed to the adjacent fibrous cap.⁶⁵ Richardson et al⁵⁹ computed the distribution of circumferential tensile stress within simulated plaques and found that eccentric pools of soft material concentrated stress on the adjacent fibrous cap, especially near its shoulders, and these computed high-stress points correlated well with sites of rupture found in a necropsy series. Cheng et al⁹⁴ computed the stress distribution in plaques that actually had ruptured and confirmed that most fibrous caps (58%) indeed had ruptured where the computed circumferential stress was highest. Importantly, the thickness of the fibrous cap is most critical for the peak circumferential stress: the thinner the fibrous cap, the higher the stress that develops in it.⁶⁶ However, weak points caused not by cap thinning but rather by focal macrophage activities could explain why rupture does not always occur where the computed (thickness-dependent) circumferential stress is maximal.^{59 94} Furthermore, mechanical shear stresses may develop in plaques at the interface between tissues of different stiffnesses, resulting in shear failure. Calcified plates and adjacent noncalcified tissue, for example, may slide against each other, "shearing" plaques apart,^{21 93} as confirmed by necropsy findings of some tears at such sites.⁵⁹

According to Laplace's law, the tension created in fibrous caps of mildly or moderately stenotic plaques is greater than that created in caps of severely stenotic plaques (smaller lumen) with the same cap thickness and exposed to the same blood pressure. Consequently, mildly or moderately stenotic plaques are generally stressed more than severely stenotic plaques and could therefore be more prone to rupture.

Cap/Plaque Compression
Blood pressure induces both circumferential tension in and radial compression of the surrounding vessel wall. If blood pressure and plaque disruption are related, it is probably via tensile rather than compressive stresses.⁶⁹ Plaque disruption, however, may occur not only from the lumen into the plaque but also in the opposite direction, from the plaque into the lumen, because of an increase in intraplaque pressure caused by, for example, vasospasm, bleeding from vasa vasorum, plaque edema, and/or collapse of compliant stenoses.

Vasospasm reduces the circumferential tension in fibrous caps by narrowing the lumen (Laplace's law). Nevertheless, spasm could theoretically rupture plaques by compressing the atheromatous core, "blowing" the fibrous cap out into the lumen.^{71 95 96} Plaque disruption and vasospasm do indeed frequently coexist,^{97 98} but the former most likely gives rise to the latter rather than vice versa.^{98 99 100 101} Onset of myocardial infarction is uncommon during or shortly after drug-induced spasm of even severely diseased coronary arteries,^{102 103} indicating that spasm rarely, if ever, precipitates plaque disruption and/or luminal thrombosis. According to Kaski et al,¹⁰³ spasm-prone lesions do not seem to progress more rapidly than do corresponding fixed lesions. Furthermore, spasmolytic drugs (calcium antagonists, for example) have never proved effective in preventing myocardial infarction in patients with vasospastic angina. However, contrary to the results of Kaski et al,¹⁰³ Nobuyoshi et al³⁸ found a strong positive correlation between ergonovine-induced coronary spasm and subsequent plaque progression, with or without infarct development.

Bleeding and/or transudation (edema) into plaques from the thin-walled new vessels originating from vasa vasorum and frequently found at the plaque base^{104 105} could theoretically increase the intraplaque pressure, with resultant cap rupture from the inside.¹⁰⁶ Although tiny areas of bleeding are frequent at the base of advanced lesions,¹⁰⁷ it is difficult to imagine how a small capillary bleeding can disrupt a fibrous cap against the much higher luminal pressure.¹⁰⁸

The high-grade stenosis may be subjected to strong compressive forces due to the accelerated velocities in the throat. The local Bernoulli's static pressure in the throat of the stenosis may become less than the external surrounding pressure of the artery, causing a negative transmural pressure around the stenotic region.¹⁰⁹ Collapse of severe but compliant stenoses due to negative transmural pressures may produce highly concentrated compressive stresses from buckling of the wall with bending deformation, preferentially involving plaque edges, and theoretically, this could contribute to plaque disruption.¹⁰⁹

Circumferential Bending
The propagating pulse wave causes cyclic changes in lumen size and shape with deformation and bending of plaques, particularly the "soft" ones.¹¹⁰ For normal compliant arteries, the cyclic diastolic-systolic change in lumen diameter is about 10%,⁹³ but it becomes smaller with age and during atherogenesis because of the increase in stiffness.¹¹¹ Generally, concentric plaques do not change as much during the cardiac cycle as eccentric plaques do. The latter typically bend at their edges, ie, at the junction between the stiff plaque and the more compliant plaque-free vessel wall. Also, changes in vascular tone cause bending of eccentric plaques at their edges. Cyclic bending may, in the long term, weaken these points, leading to unprovoked "spontaneous" fatigue disruption, whereas a sudden accentuated bending may trigger rupture of a weakened cap.

Longitudinal Flexion
The coronary arteries, particularly the left anterior descending coronary artery, tethered to the surface of the beating heart undergo cyclic longitudinal deformations by axial bending (flexion) and stretching. Angiographically, the angle of flexion was recently found to correlate with subsequent lesion progression, but the coefficient of correlation was low.¹¹² Like circumferential bending, a sudden accentuated longitudinal flexion may trigger plaque disruption, whereas long-term cyclic flexion may fatigue and weaken the plaque.

Hemodynamic Factors
Low and/or oscillating shear stress may influence endothelial function and promote atherogenesis below intact endothelium.^{113 114 115} High blood velocity within stenotic lesions, however, may shear the endothelium away,¹¹⁶ but whether high hemodynamic shear alone would disrupt a stenotic plaque is questionable.⁶² Hemodynamic stresses are usually much smaller than mechanical stresses imposed by blood and pulse pressures.⁹¹ Theoretically, fluttering of severe but compliant stenoses between collapse and patency^{109 117 118} and turbulent pressure fluctuations distal to severe asymmetric stenoses could fatigue the plaque surface, promoting plaque disruption.¹¹⁹ Unfortunately, the exact longitudinal location of plaque disruption (upstream, within, or downstream of the stenosis) is unknown for coronary plaques. Carotid plaques reportedly often tear proximal to or within the most stenotic region.^{120 121}

	Disease Onset: Disruption, Thrombosis, and/or Spasm?

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
Onset of acute coronary syndromes does not occur at random; a large fraction appear to be triggered by external factors or conditions.^{122 123 124} Myocardial infarction occurs at increased frequency in the morning,^{122 125 126} particularly within the first hour after awakening¹²⁷ ; on Mondays^{126 128} ; during winter months^{129 130} and on colder days the year around¹³¹ ; and during emotional stress^{132 133 134 135} and vigorous exercise.^{136 137} Possible triggers of disease onset—also called acute risk factors¹²⁴ —have been reported by nearly 50% of patients with myocardial infarction.¹³⁸ The pathophysiological mechanisms responsible for the nonrandom and apparently often triggered onset of infarction are unknown but probably related to (1) plaque disruption, most likely caused by surges in sympathetic activity with a sudden increase in blood pressure, pulse rate, heart contraction, and coronary blood flow¹³⁹ ; (2) thrombosis, occurring on previously disrupted or intact plaques when the systemic thrombotic tendency is high because of platelet hyperaggregability,^{140 141 142 143} hypercoagulability,¹⁴⁴ and/or impaired fibrinolysis^{145 146 147} ; and (3) vasoconstriction, occurring locally around a coronary plaque or generalized.¹⁴⁸

The beneficial effect of ß-blockade in the secondary prevention of myocardial infarction provides strong evidence for the theory that mechanical and/or hemodynamic forces may trigger plaque disruption and sudden disease onset. ß-Blocker therapy reduces reinfarction by 25%¹⁴⁹ without having any proven antiatherogenic,¹⁵⁰ antithrombotic,¹⁵¹ profibrinolytic,¹⁵² or antispasmodic¹⁵³ effects in humans. On the contrary, ß-blockers may induce or potentiate atherogenic dyslipoproteinemia,¹⁵⁴ platelet aggregation,¹⁵¹ and vasoconstriction.¹⁵³ Nonetheless, administration of ß-blockers blunts the morning peak in onset of infarction, probably by blunting the sympathetic surge in the morning, indicating that mechanical and hemodynamic forces could be critical in triggering plaque disruption and disease onset.¹⁵⁵ Accordingly, the beneficial effect of ß-blockers on reinfarction has been related to the reduction in heart rate,¹⁵⁶ and a similar effect on reinfarction has been obtained by the heart rate–reducing calcium antagonists verapamil and diltiazem,^{157 158 159} in sharp contrast to the results obtained with the heart rate–increasing calcium antagonist nifedipine.¹⁵⁹ It should be stressed, however, that activation of the sympathetic nervous system and hypercatecholaminemia associated with arousal, exercise, emotional stress, and smoking could trigger onset of acute coronary syndromes not only via ß-adrenergic receptors but also via -receptors, promoting platelet aggregation and vasoconstriction.^{143 148 160 161 162 163 164} Sudden thrombus growth on previously disrupted or intact plaques due to changes in platelet function, coagulation, and/or fibrinolysis is probably an important mechanism responsible for onset of acute coronary syndromes.²

	Identification of Vulnerable and Progressing Plaques

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
Coronary angiography may reveal advanced lesions, plaque disruption, luminal thrombosis, and calcification, but other qualitative features of the underlying plaque cannot be assessed by this imaging technique. Visualization of the vessel wall and the plaque itself rather than the lumen is necessary for the identification of early lesions and vulnerable plaques at high risk of becoming culprits. Intravascular ultrasound^{165 166} and angioscopy^{97 167 168} may reveal important plaque and surface features not seen angiographically, and magnetic resonance imaging,^{169 170} spectroscopy,^{171 172} and scintigraphy^{173 174 175} may in the near future further improve the in vivo identification and characterization of coronary plaques. Actively progressing atherosclerosis and vulnerable high-risk plaques are characterized by increased endothelial permeability with insudation of plasma constituents; lipoprotein accumulation; endothelial activation with expression of adhesion molecules; monocyte recruitment; macrophage retention and cell activation within lesions; denudation and ulceration of plaque surfaces with platelet adhesion, aggregation, and degranulation; activation of coagulation; and ongoing fibrinolysis—features that might be visualized in living persons by appropriate imaging techniques. Even a simple blood sample may prove to be useful in the identification of ongoing disease activity, revealing signs of inflammation¹⁷⁶ and activation of endothelial cells,¹⁷⁷ leukocytes,^{83 84 178} platelets,¹⁷⁹ coagulation,^{180 181 182} and fibrinolysis.^{181 182 183 184 185 186}

	Plaque Disruption: Clinical Manifestations

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
Plaque disruption is common.^{8 61} It is followed by variable amounts of hemorrhage into the plaque through the disrupted surface and luminal thrombosis causing rapid plaque growth (Fig 3), probably the most important mechanism responsible for the unpredictable, sudden, and nonlinear progression of coronary lesions frequently observed angiographically.¹⁸⁷ Another mechanism underlying episodic plaque growth could be accelerated SMC proliferation and matrix synthesis driven by superficial inflammation, endothelial denudation, platelet adhesion/degranulation, thrombin generation, and other blood-derived growth factors.¹⁸⁸ SMC proliferation by itself does not constitute a strong thrombogenic stimulus¹⁸⁹ and is, as recently pointed out,¹⁹⁰ an unlikely cause of acute coronary syndromes.

Silent Plaque Disruption
Plaque disruption itself is asymptomatic, and the associated rapid plaque growth is usually clinically silent. Autopsy data indicate that 9% of "normal" healthy persons have asymptomatic disrupted plaques in their coronary arteries, increasing to 22% in persons with diabetes or hypertension.¹⁹¹ Many persons who die of ischemic heart disease harbor both thrombosed and nonthrombosed disrupted plaques in their coronary arteries.^{107 192 193} In two studies of 47 and 83 persons who died of coronary atherosclerosis, 103 and 211 disrupted plaques, respectively, were identified,^{58 61} more than 2 disrupted plaques per person, and less than half (40 and 102, respectively) were associated with significant luminal thrombosis that caused critical flow obstruction. The majority of the other plaque disruptions were probably asymptomatic.

Symptomatic Plaque Disruption and the Acute Coronary Syndromes
After plaque disruption, hemorrhage into the plaque, luminal thrombosis, and/or vasospasm may cause sudden flow obstruction, giving rise to new or changing symptoms. Three major factors appear to determine the thrombotic response to plaque disruption/erosion: (1) character and extent of exposed plaque components (local thrombogenic substrates)^{6 189 194} ; (2) degree of stenosis and surface irregularities that activate platelets (local flow disturbances)^{6 44 58 195 196 197 198 199} ; and (3) thrombotic-thrombolytic equilibrium at the time of plaque disruption (systemic thrombotic tendency).^{2 179 181 200 201} The clinical presentation and outcome depend on the location, severity, and duration of myocardial ischemia. A nonocclusive or transiently occlusive thrombus most frequently underlies primary unstable angina with pain at rest and non–Q-wave myocardial infarction, whereas a more stable and occlusive thrombus is most frequently seen in Q-wave infarction—overall, modified by vascular tone and available collateral flow.² The lesion responsible for out-of-hospital cardiac arrest or sudden death is often similar to that of unstable angina: a disrupted plaque with superimposed nonocclusive thrombosis.^{107 202 203} It is noteworthy that many coronary arteries apparently occlude silently without causing myocardial infarction, probably because of a well-developed collateral circulation at the time of occlusion.^{37 42 204}

	Prevention of Plaque Disruption

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
The risk of plaque disruption is a function of both plaque vulnerability (intrinsic disease) and rupture triggers (extrinsic forces); the former predisposes the plaque to rupture, and the latter may precipitate it. Therefore, plaque disruption may be prevented by stabilizing plaques against disruption and/or by avoiding or reducing potential trigger activities.

Plaque Stabilization
Experimental animal studies indicate that atherosclerosis is a dynamic process in which arterial function, lumen size, plaque size, and plaque composition may change independently. After diet-induced atherosclerosis in monkeys, lipid lowering results in rapid normalization of endothelial function, disappearance of macrophage foam cells from lesions, depletion of plaque lipid (preferentially cholesteryl esters, resulting in a smaller and stiffer lipid-rich core), and loss of vasa vasorum.^{205 206 207 208 209 210 211} Furthermore, mature collagen may increase,²⁰⁷ resulting overall in a larger vascular lumen and a modified but not necessarily a smaller plaque.²⁰⁹ Such "regressive" changes should stabilize plaques against disruption, but this hypothesis has not been tested because of lack of a suitable animal model of plaque disruption. Experimentally, atherosclerotic plaques have been modified and probably stabilized by a variety of non–lipid-lowering approaches, including elevation of HDL,²¹² antioxidants,²¹³ some dietary fatty acids,²¹⁴ exercise conditioning,²¹⁵ avoidance of psychosocial stress,²¹⁶ angiotensin-converting enzyme (ACE) inhibition,²¹⁷ blood pressure lowering,²¹⁸ and estrogen replacement therapy.²¹⁹

Clinical observations indicate that human plaques may be stabilized against disruption and thrombosis by antiatherogenic therapy, including modifications of lifestyle and serum lipids.^{43 220} It is noteworthy that significant clinical benefit may be obtained by stabilizing plaques even when regression does not occur.²²¹ Three lipid-lowering trials with angiographic follow-up have independently shown that stability of coronary plaques over the short term is associated with a good long-term prognosis; disease progression on trial predicted posttrial myocardial infarction and cardiac death.^{222 223 224} Plaque stabilization, thus, may be an approach to convey clinical stability.

ACE activity may contribute to the development of coronary artery disease and myocardial infarction,²²⁵ and ACE inhibition seems to reduce the risk of major ischemic events (reinfarction, cardiac death, and possibly unstable angina) by about 22% in patients with low ejection fractions,^{226 227 228} probably via multiple beneficial mechanisms.²²⁹ ACE inhibitors may influence both atherogenesis (plaque vulnerability) and triggering mechanisms responsible for disease onset (plaque disruption, thrombosis, and/or vasospasm). The latter are discussed below in the section on trigger reduction. The hypothesis that these drugs are antiatherogenic and prevent or slow progression of coronary artery disease is now being tested in clinical trials.

Preliminary data suggest that antioxidant vitamins may slow the progression of coronary artery disease,²³⁰ but contrasting results have recently been reported for femoral artery disease treated with the strong antioxidant probucol.²³¹ Estrogen replacement therapy seems to provide powerful protection against myocardial infarction and cardiovascular death in postmenopausal women, probably mediated via multiple anti-ischemic mechanisms that include a direct effect of estrogen on the vessel wall,² but the effect on coronary artery disease progression is still unknown.

Trigger Reduction
Avoiding or reducing trigger activities may prevent plaque disruption. Exercise and the associated sympathetic neurohormonal activation could precipitate onset of myocardial infarction via sudden plaque disruption, activation of platelets and coagulation promoting thrombosis, and/or coronary vasoconstriction. Nonetheless, only a small fraction of all myocardial infarctions (about 5%) are related to, or triggered by, vigorous exertion,^{139 232} and only sedentary people seem to be at increased risk of exercise-related infarction (relative risk from 7¹³⁷ to 107¹³⁶ ). Although physically unfit people usually are advised to avoid heavy physical exertion, it is unknown whether refraining from such activities reduces myocardial infarction in sedentary people or just postpones it.¹³⁶ Of more interest for prevention, regular exercise may retard plaque progression²³³ and seems to provide protection against myocardial infarction and coronary deaths,^{234 235 236 237 238} at least in part by eliminating the triggering effect of sudden vigorous exertion.^{136 137}

Cigarette smoking is the most important preventable cause of morbidity and mortality from coronary artery disease.^{239 240} Clinical data indicate that smoking accelerates the progression of coronary artery disease.^{241 242 243} The increased risk associated with smoking appears to be rapidly reversible by cessation,^{244 245} implicating acute triggering mechanisms (plaque disruption, thrombosis, and/or vasoconstriction) rather than chronic atherogenic mechanisms as being primarily responsible for smoking-related disease progression.^{162 163 164 246 247 248 249 250 251} Regarding atherogenesis and plaque stability, smoking seems to impair endothelial function⁴⁶ and promote lipid oxidation,²⁵² and preliminary autopsy data indicate that smokers have more extracellular lipids in their plaques, which should imply greater vulnerability to rupture.³³

ß-Blockers¹⁴⁹ and possibly heart rate–reducing calcium antagonists^{157 158 159} may delay or prevent plaque disruption by reducing the mechanical and hemodynamic load on vulnerable plaques, explaining the beneficial effect of these drugs in the secondary prevention of myocardial infarction.^{92 156} As mentioned, the protective effect of ß-blockers has been related to their heart rate–lowering efficacy: the lower the heart rate, the better the protection against reinfarction and sudden death.¹⁵⁶ The maximum benefit achievable by trigger reduction therapy is limited, however, unless the progression of the disease is also arrested. Coronary plaques are stressed constantly, and just reducing peak stresses will probably only postpone the time at which a progressing vulnerable plaque inevitably will rupture. Even complete elimination of the morning excess of acute coronary events associated with the morning surge in sympathetic activity will prevent only a small fraction of all clinical events,²⁵³ because the vast majority occur "untriggered" in the morning or at other times of the day. Successful plaque stabilization eliminates the prerequisite for plaque disruption: the vulnerable plaque. Therefore, to obtain maximum benefit, both approaches, plaque stabilization and trigger reduction, should be pursued.

As previously described, ACE inhibition may modify not only atherogenesis and plaque vulnerability but also triggering mechanisms responsible for disease onset.²²⁹ For example, the renin-angiotensin system may interact with fibrinolytic function,²⁵⁴ and ACE inhibition may influence endogenous fibrinolysis, resulting in a reduced thrombotic response to plaque disruption.²⁵⁵ Importantly, ACE inhibition also seems to reduce mortality and reinfarction in the presence of ß-blocker therapy, suggesting an independent therapeutic effect.²²⁸

	Treatment of Plaque Disruption

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
The most feared consequence of coronary plaque disruption is thrombotic occlusion. The function of the hemostatic and fibrinolytic systems at the time of plaque disruption, ie, the systemic thrombotic-thrombolytic equilibrium, is important for the outcome, as documented by the beneficial effect of antithrombotic therapy in patients at risk of plaque disruption.^{2 256 257} After disruption, antiplatelet agents and/or anticoagulants may limit the thrombotic response and prevent mural thrombosis from progressing to occlusive thrombosis.^{2 258} If the latter occurs, thrombolysis and/or mechanical intervention may reopen the culprit artery. It is noteworthy that lipid lowering may not only stabilize plaques against disruption but also improve endothelial and vasomotor functions^{259 260 261 262 263} and reduce the thrombotic response if disruption occurs via beneficial effects on platelets, coagulation, fibrinolysis, and blood viscosity.^{264 265 266}

	Conclusions

Top Introduction Atherogenesis Plaque Disruption: Vulnerability... Disease Onset: Disruption,... Identification of Vulnerable and... Plaque Disruption: Clinical... Prevention of Plaque Disruption... Treatment of Plaque Disruption... Conclusions References

 
Atherosclerosis without thrombosis is in general a benign disease. However, acute thrombosis frequently complicates the course of coronary atherosclerosis, causing unstable angina, myocardial infarction, and sudden death. The mechanism responsible for the sudden conversion of a stable disease to a life-threatening condition is usually plaque disruption with superimposed thrombosis. The risk of plaque disruption depends more on plaque composition and vulnerability (plaque type) than on degree of stenosis (plaque size). Major determinants of vulnerability of a plaque to rupture are size and consistency of the atheromatous core, thickness of the fibrous cap covering the core, and ongoing inflammation within the cap. Plaque disruption tends to occur at points at which the plaque surface is weakest and most vulnerable, which coincide with points at which stresses resulting from biomechanical and hemodynamic forces acting on plaques are concentrated. Therefore, the risk of plaque disruption is a function of both plaque vulnerability (intrinsic disease) and rupture triggers (extrinsic forces). The former predisposes the plaque to rupture, and the latter may precipitate it. Today's challenge is to identify and treat the dangerous vulnerable plaques responsible for myocardial infarction and death; to find and treat only angina-producing stenotic lesions is no longer enough. For prevention and treatment, a systemic approach that addresses all coronary plaques will prove to be most rewarding.

	Footnotes

 
Reprint requests to Erling Falk, MD, Department of Cardiology, Skejby University Hospital, DK-8200 Aarhus N, Denmark.

Circulation. 1995;92:657-671.

Received April 5, 1995; revision received May 17, 1995; accepted June 3, 1995.

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