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Coronary Plaque DisruptionErling Falk, Prediman K. Shah, Valentin Fuster

https://doi.org/10.1161/01.CIR.92.3.657Circulation. 1995;92:657­671Originally published August 1, 1995Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease, and plaque disruptionwith superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina,myocardial infarction, and sudden death. Therefore, for event­free survival, the vital question is notwhy atherosclerosis develops but rather why, after years of indolent growth, it suddenly becomes complicatedby life­threatening thrombosis. The composition and vulnerability of plaque rather than its volume or theconsequent severity of stenosis produced have emerged as being the most important determinants for thedevelopment of the thrombus­mediated acute coronary syndromes; lipid­rich and soft plaques are moredangerous than collagen­rich and hard plaques because they are more unstable and rupture­prone and highlythrombogenic after disruption. This review will explore potential mechanisms responsible for the suddenconversion of a stable atherosclerotic plaque to an unstable and life­threatening atherothrombotic lesion—anevent known as plaque fissuring, rupture, or disruption.

Atherogenesis

Atherosclerosis is the result of a complex interaction between blood elements, disturbed flow, and vessel wallabnormality, involving several pathological processes: inflammation, with increased endothelial permeability,endothelial activation, and monocyte recruitment ; growth, with smooth muscle cell (SMC)proliferation, migration, and matrix synthesis ; degeneration, with lipid accumulation ; necrosis,possibly related to the cytotoxic effect of oxidized lipid ; calcification/ossification, which may represent anactive rather than a dystrophic process ; and thrombosis, with platelet recruitment and fibrin formation. Thrombotic factors may play a role early during atherogenesis, but a flow­limiting thrombus does not

develop until mature plaques are present, which is why thrombosis often is classified as a complication ratherthan a genuine component of atherosclerosis.

Mature Plaques: Atherosis and Sclerosis

As the name atherosclerosis implies, mature plaques typically consist of two main components: soft, lipid­richatheromatous “gruel” and hard, collagen­rich sclerotic tissue (Fig 1A⇓). The sclerotic component (fibroustissue) usually is by far the more voluminous component of the plaque, constituting >70% of an averagestenotic coronary plaque. Sclerosis, however, is relatively innocuous because fibrous tissue appears tostabilize plaques, protecting them against disruption. In contrast, the usually less voluminous atheromatous

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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 life­threatening event.

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Figure 1.

Photomicrographs illustrating composition and vulnerability of coronary plaques. A, A matureatherosclerotic plaque that consists of two main components: soft, lipid­rich atheromatous “gruel” (*) andhard, collagen­rich 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 samesystemic risk factors, the plaque to the left is collagenous and stable, but the plaque to the right isatheromatous and vulnerable, with disrupted surface and superimposed nonocclusive thrombosis (red). Cthrough E, A vulnerable plaque, containing a core of soft atheromatous gruel (devoid of blue­stainedcollagen) that is separated from the vascular lumen by a thin cap of fibrous tissue. The fibrous cap isinfiltrated by foam cells that can be clearly seen at high magnification (E), indicating ongoing diseaseactivity. Such a thin and macrophage­infiltrated cap is probably very weak and vulnerable, and it wasindeed disrupted nearby, explaining why erythrocytes (red) can be seen in the gruel just beneath themacrophage­infiltrated cap. F, Atherectomy specimen from culprit lesion in non–Q­wave myocardialinfarction. At high magnification it can be clearly seen that this plaque specimen is heavily infiltrated byred­stained macrophages. A through E, trichrome stain; F, immunostaining for macrophages usingmonoclonal antibody PG­M1 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 theperiphery of the core), rich in extracellular lipids, and soft like gruel. The pathogenesis of this, the clinicallymore important plaque component, however, remains controversial. Insudated blood­derived lipid,preferentially LDL, may be trapped and accumulate directly within the extracellular space, or it may beendocytosed by macrophages, probably via their scavenger receptors after oxidative modification, andaccumulate indirectly after necrosis of the lipid­filled macrophages (foam cells). The relativecontribution of direct lipid trapping versus foam cell necrosis in the formation of the atheromatous core and itsgrowth is unknown, although foam cell necrosis is widely believed to be more important. Therefore, the softlipid­rich core within a plaque is also called a “necrotic core” and “atheronecrosis.” Recentobservations, however, suggest that the core does not originate primarily from dead foam cells in the

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superficial intima (fatty streaks) but rather arises from lipids accumulating gradually in the extracellular matrix ofthe deep intima as a result of complex binding between insudating LDL and glycosaminoglycans, collagen,and/or fibrinogen.

Plaque Size and Composition

Pathoanatomic studies indicate that the atheromatous component enlarges with plaque growth, but thevariability 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, buta repeat study months to years later may identify the kinds of plaques that most frequently progress toocclusion and/or become culprits; ie, the likelihood of a plaque’s becoming complicated with disruption and/orthrombosis may be assessed. Serial angiographic studies indicate that the more obstructive a plaque is, themore frequently it progresses to coronary occlusion and/or gives rise to myocardial infarction. TheCoronary Artery Surgery Study (CASS) prospectively evaluated 2938 nonbypassed coronary segments in 298patients. Of 2161, 430, 258, and 89 segments narrowed <5%, 5% to 49%, 50% to 80%, and 81% to 95% atbaseline, respectively, 0.7%, 2.3%, 10.1%, and 23.6%, respectively, became occluded during the 5­year follow­up period (Fig 2⇓, top). Although an individual severe stenosis became occluded more frequently than did anindividual less severe stenosis, the less obstructive plaques (<80% stenosis at baseline) gave rise to moreocclusions 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 (Fig2⇓, top and middle), as initially reported by Ambrose et al and Little et al and later confirmed by others (Fig 2⇓, bottom). This has given rise to the notion that less obstructive plaques are more lipid­rich and

vulnerable to rupture than larger plaques. The smaller plaques, however, could be most dangerous justbecause of their greater number—they by far outnumber the severely obstructive plaques. Furthermore,the smaller rather than the larger plaques are more likely to lead to acute clinical events in case of abruptocclusion because they are less frequently associated with protective collateral circulation. The fact thatsome severe coronary stenoses do regress with lipid­lowering therapy clearly indicates that the advanced andobstructive plaques also may contain a significant lipid­rich component. By angiography, severely stenoticplaques at the carotid bifurcation frequently appear ulcerated and disrupted, and such lesions are indeeddangerous, being associated with a high risk of ipsilateral stroke.

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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 segmentis at baseline, the more frequently it progresses to occlusion (top ) and/or gives rise to infarction(middle ). Because less­obstructive plaques by far outnumber severely obstructive plaques, mostocclusions 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 obstructivemonths to years before infarction (bottom). The bar graphs are constructed from data published by (top)Alderman et al ; (middle) Nobuyoshi et al ; and (bottom) Ambrose et al, Little et al, Nobuyoshi etal, and Giroud et al.

Risk Factors and Plaque Composition

Endothelial dysfunction, demonstrable in atherosclerotic arteries as well as in arteries resistant toatherosclerosis (forearm blood vessels and microcirculation), appears to be an early and reliable marker forthe presence of atherogenic risk factors. There is, however, a remarkable and poorly understoodvariability in the way plaques evolve (Fig 1B⇑), and it is unclear how the various risk factors for clinical diseaseinfluence the development, composition, and vulnerability of coronary plaques. Age, male sex,hypercholesterolemia, hypertension, smoking, and diabetes correlate with the coronary plaque burden (extentof “plaquing”) found at autopsy, but apart from an increase in calcification with age and possiblymale sex, a relation of specific risk factors to composition of plaque remains to be identified. Fibrous tissue

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seems to constitute the most voluminous component of mature coronary plaques, irrespective of individual riskfactors. Preliminary data, however, do suggest that smokers have more extracellular lipids,particularly oxidized LDL, in their plaques than nonsmokers.

Plaque Disruption: Vulnerability and Triggers

Plaques containing a soft atheromatous core are unstable and may rupture; ie, the fibrous cap separating thecore from the lumen may disintegrate, tear, or break, whereby the highly thrombogenic gruel is suddenlyexposed to the flowing blood. Such disrupted plaques are found beneath about 75% of the thrombi responsiblefor acute coronary syndromes. Beneath the remaining thrombi, superficial macrophage­relatedintimal erosions without frank disruption (no deep injury) are usually found, often in combination with a severeatherosclerotic stenosis.

The risk of plaque disruption is related to intrinsic properties of individual plaques (their vulnerability) andextrinsic forces acting on plaques (rupture triggers). The former predispose plaques to rupture, whereas thelatter 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 foamcells, and therefore weakest. For eccentric plaques, that is often the junction between the plaque and theadjacent less­diseased vessel wall, called the shoulder region of the plaque. Pathoanatomic examination ofintact and disrupted plaques and in vitro mechanical testing of isolated fibrous caps from aorta indicate thatvulnerability to rupture depends on (1) size and consistency of the atheromatous core, (2) thickness andcollagen content of the fibrous cap covering the core, (3) inflammation within the cap, and (4) cap “fatigue.”Long­term repetitive cyclic stresses may weaken a material and increase its vulnerability to fracture, ultimatelyleading to sudden and unprovoked (ie, untriggered) mechanical failure due to fatigue. Therefore, fatigue isdiscussed here as one of the determinants of plaque vulnerability rather than being included in the subsequentsection on rupture triggers.

Atheromatous Core

The size and consistency of the atheromatous core vary greatly from plaque to plaque and are critical for thestability of individual lesions (Fig 1C⇑ and 1D⇑). Although the average stenotic coronary plaque contains muchmore hard fibrous tissue than soft atheromatous gruel, a significant atheromatous component is usuallypresent in culprit lesions responsible for acute coronary syndromes. Gertz and Roberts reported thecomposition of plaques in 5­mm segments from 17 infarct­related arteries examined postmortem and foundmuch larger atheromatous cores in the 39 segments with plaque disruption than in the 229 segments withintact surface (32% and 5% to 12% of plaque area, respectively). In aortic plaques, Davies et al found asimilar 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 vulnerableand at high risk of rupture and thrombosis.

The atheromatous core is rich in extracellular lipids, especially cholesterol and its esters. The consistencyof the gruel depends on lipid composition and temperature; it usually is soft, like toothpaste, at roomtemperature postmortem, and it is even softer at body temperature in vivo. Lipid in the form of cholesterylesters softens plaque, whereas crystalline cholesterol has the opposite effect. On the basis of animalexperiments, lipid­lowering therapy in humans is expected to deplete plaque lipid, with an overall reduction incholesteryl esters (liquid and mobile) and a relative increase in crystalline cholesterol (solid and inert),theoretically resulting in a stiffer and more stable atheromatous lesion.

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Cap Thickness

The thickness and collagen content of the fibrous cap are important for the stability of a plaque. Fibrous capsvary widely in thickness, cellularity, matrix, strength, and stiffness, but they are often thinnest (and macrophageinfiltrated) at their shoulder regions, where disruption most frequently occurs. Collagen is important for thetensile strength of tissues, and disrupted aortic caps contain fewer SMCs (the collagen­synthesizing cell inplaques) and less collagen than intact caps. The cause of this potentially dangerous relative lack of SMCsin disrupted caps is unknown, but SMCs could vanish as the result of apoptotic cell death. Loss of cells andcalcification in fibrous caps are associated with increased stiffness, but the significance of cap stiffness forrupture propensity is unknown.

Cap Inflammation

Disrupted fibrous caps usually are heavily infiltrated by macrophage foam cells (Figs 1E⇑, 1F⇑, and3C⇓ through 3F). These rupture­related macrophages are activated, indicating ongoing inflammation at the siteof plaque disruption. For eccentric plaques, the shoulder regions are sites of predilection for both activeinflammation (endothelial activation and macrophage infiltration ) and disruption, and in vitromechanical testing of aortic fibrous caps indicates that foam cell infiltration indeed weakens caps locally,reducing their tensile strength.

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Figure 3.

Photomicrographs illustrating disruption and rapid progression of coronary plaques. A and B, Disruptedplaque with hemorrhage into the soft gruel through a defect in the cap. In addition, a small mural thrombuscan be seen at the edges of the defect where thrombogenic plaque components have been exposed. Cand D, Disrupted plaque with occlusive thrombosis superimposed. The disrupted cap beneath thethrombus is thin and heavily infiltrated by foam cells, probably macrophages. E and F, Disrupted plaquewith occlusive thrombosis superimposed. The thin fibrous cap is heavily foam cell infiltrated, andatheromatous gruel (*) has been extruded through the disrupted cap into the lumen, where it can be seensurrounded by thrombus, clearly indicating the sequence of events: plaque disruption exposingthrombogenic plaque components and resulting in luminal thrombosis. Trichrome stain, rendering collagenblue and erythrocytes (plaque hemorrhage) and thrombus red. c indicates contrast medium injectedpostmortem.

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

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Figure 4.

Bar graph showing significantly more macrophage infiltration in culprit plaques responsible for unstablecoronary syndromes (n=18) than in those responsible for chronic stable angina (n=8). Macrophages wereidentified by immunohistochemical technique, using a specific monoclonal antibody against macrophages(PG­M1 from Dako) (from Moreno et al ). MI indicates myocardial infarction.

Macrophages are capable of degrading extracellular matrix by phagocytosis or by secreting proteolyticenzymes 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. A wide variety ofcells besides macrophages may produce MMPs. They are secreted in a latent zymogen form requiringextracellular activation, after which MMPs are capable of degrading virtually all components of the extracellularmatrix. The MMPs and their cosecreted tissue inhibitors of metalloproteinases TIMP­1 and TIMP­2 are criticalfor cell migration, tumor invasion and metastasis, inflammation, wound healing, and vascular remodeling.

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Collagen is the main component of fibrous caps responsible for their tensile strength, and human monocyte­derived macrophages grown in culture are indeed capable of degrading cap collagen, and they do,simultaneously, express MMP­1 (interstitial collagenase) and induce MMP­2 (gelatinolytic) activity in the culturemedium (Fig 5⇓). Several studies have now identified MMPs in human coronary plaques, andlipid­filled macrophages (foam cells) may be particularly active in destabilizing plaques, predisposing them torupture. Monocytes/macrophages could also play a detrimental role after plaque disruption, promotingthrombin generation and luminal thrombosis through the tissue factor pathway.

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Figure 5.

Data supporting the role of monocyte­derived macrophages and matrix­degrading metalloproteinases(MMPs) in inducing collagen breakdown in fibrous caps of human atherosclerotic plaques. A, Bar graphshowing that incubation of fibrous caps with macrophages results in hydroxyproline release into thesupernatant (indicative of collagen breakdown), a process inhibited by an MMP inhibitor. This isassociated with macrophage expression of MMP­1 (reddish­brown immunostain using a specific antibody)(B) and MMP­2 (red fluorescence using an FITC­labeled specific antibody) (C). For details, see Shah etal.

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Activated mast cells may secrete powerful proteolytic enzymes, such as tryptase and chymase, that canactivate pro­MMPs secreted by other cells (eg, macrophages), and mast cells are indeed present in shoulderregions of mature coronary plaques but at a relatively low density (ratio of mast cells to macrophages,≈1:20). Neutrophils are also capable of destroying tissue by secreting proteolytic enzymes, butneutrophils are rare in intact plaques. They may occasionally be found in disrupted plaques beneathcoronary thrombi, probably entering these plaques shortly after disruption, and neutrophils may also migrateinto the arterial wall shortly after reperfusion of occluded arteries in response to ischemia/reperfusion.

Cap Fatigue

A steady load that does not fracture a material may weaken it if the load is applied repeatedly. This repetitivestress may ultimately lead to sudden fracture of the tissue due to fatigue, analogous to repetitive bending of apaper clip that weakens it until it suddenly breaks. 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 pressure­related) ofloading should reduce the risk of plaque disruption if fatigue plays a role.

Triggers of Plaque Disruption

Coronary plaques are constantly stressed by a variety of mechanical and hemodynamic forces that mayprecipitate or “trigger” disruption of vulnerable plaques. Stresses imposed on plaques are usuallyconcentrated at the weak points discussed above, namely, at points at which the fibrous cap is thinnest andtearing most frequently occurs.

Cap Tension

The circumferential wall tension (tensile stress) caused by the blood pressure is given by Laplace’s law, whichrelates luminal pressure and radius to wall tension: the higher the blood pressure and the larger the luminaldiameter, the more tension develops in the wall. If components within the wall (soft gruel, for example) areunable to bear the imposed load, the stress is redistributed to adjacent structures (fibrous cap over gruel, forexample), where it may be concentrated at critical points. The consistency of the gruel may be important forthis stress redistribution because the stiffer the gruel, the more stress it can bear, and correspondingly less isredistributed to the adjacent fibrous cap. Richardson et al computed the distribution of circumferentialtensile stress within simulated plaques and found that eccentric pools of soft material concentrated stress onthe adjacent fibrous cap, especially near its shoulders, and these computed high­stress points correlated wellwith sites of rupture found in a necropsy series. Cheng et al computed the stress distribution in plaques thatactually had ruptured and confirmed that most fibrous caps (58%) indeed had ruptured where the computedcircumferential stress was highest. Importantly, the thickness of the fibrous cap is most critical for the peakcircumferential stress: the thinner the fibrous cap, the higher the stress that develops in it. However, weakpoints caused not by cap thinning but rather by focal macrophage activities could explain why rupture does notalways occur where the computed (thickness­dependent) circumferential stress is maximal. 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 eachother, “shearing” plaques apart, as confirmed by necropsy findings of some tears at such sites.

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

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Cap/Plaque Compression

Blood pressure induces both circumferential tension in and radial compression of the surrounding vessel wall. Ifblood pressure and plaque disruption are related, it is probably via tensile rather than compressive stresses.Plaque disruption, however, may occur not only from the lumen into the plaque but also in the oppositedirection, from the plaque into the lumen, because of an increase in intraplaque pressure caused by, forexample, 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” thefibrous cap out into the lumen. Plaque disruption and vasospasm do indeed frequently coexist, butthe former most likely gives rise to the latter rather than vice versa. Onset of myocardial infarctionis uncommon during or shortly after drug­induced spasm of even severely diseased coronary arteries, indicating that spasm rarely, if ever, precipitates plaque disruption and/or luminal thrombosis. According toKaski et al, spasm­prone 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 preventingmyocardial infarction in patients with vasospastic angina. However, contrary to the results of Kaski et al,Nobuyoshi et al found a strong positive correlation between ergonovine­induced coronary spasm andsubsequent plaque progression, with or without infarct development.

Bleeding and/or transudation (edema) into plaques from the thin­walled new vessels originating from vasavasorum and frequently found at the plaque base could theoretically increase the intraplaque pressure,with resultant cap rupture from the inside. Although tiny areas of bleeding are frequent at the base ofadvanced lesions, it is difficult to imagine how a small capillary bleeding can disrupt a fibrous cap againstthe much higher luminal pressure.

The high­grade stenosis may be subjected to strong compressive forces due to the accelerated velocities inthe throat. The local Bernoulli’s static pressure in the throat of the stenosis may become less than the externalsurrounding pressure of the artery, causing a negative transmural pressure around the stenotic region.Collapse of severe but compliant stenoses due to negative transmural pressures may produce highlyconcentrated compressive stresses from buckling of the wall with bending deformation, preferentially involvingplaque edges, and theoretically, this could contribute to plaque disruption.

Circumferential Bending

The propagating pulse wave causes cyclic changes in lumen size and shape with deformation and bending ofplaques, particularly the “soft” ones. For normal compliant arteries, the cyclic diastolic­systolic change inlumen diameter is about 10%, but it becomes smaller with age and during atherogenesis because of theincrease in stiffness. Generally, concentric plaques do not change as much during the cardiac cycle aseccentric plaques do. The latter typically bend at their edges, ie, at the junction between the stiff plaque andthe more compliant plaque­free vessel wall. Also, changes in vascular tone cause bending of eccentric plaquesat 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 weakenedcap.

Longitudinal Flexion

The coronary arteries, particularly the left anterior descending coronary artery, tethered to the surface of thebeating 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

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the coefficient of correlation was low. Like circumferential bending, a sudden accentuated longitudinalflexion may trigger plaque disruption, whereas long­term cyclic flexion may fatigue and weaken the plaque.

Hemodynamic Factors

Low and/or oscillating shear stress may influence endothelial function and promote atherogenesis below intactendothelium. High blood velocity within stenotic lesions, however, may shear the endotheliumaway, but whether high hemodynamic shear alone would disrupt a stenotic plaque is questionable.Hemodynamic stresses are usually much smaller than mechanical stresses imposed by blood and pulsepressures. Theoretically, fluttering of severe but compliant stenoses between collapse and patency

and turbulent pressure fluctuations distal to severe asymmetric stenoses could fatigue the plaque surface,promoting plaque disruption. Unfortunately, the exact longitudinal location of plaque disruption (upstream,within, or downstream of the stenosis) is unknown for coronary plaques. Carotid plaques reportedly often tearproximal to or within the most stenotic region.

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

Onset of acute coronary syndromes does not occur at random; a large fraction appear to be triggered byexternal factors or conditions. Myocardial infarction occurs at increased frequency in themorning, particularly within the first hour after awakening ; on Mondays ; during wintermonths and on colder days the year around ; and during emotional stress andvigorous exercise. Possible triggers of disease onset—also called acute risk factors —have beenreported by nearly 50% of patients with myocardial infarction. The pathophysiological mechanismsresponsible for the nonrandom and apparently often triggered onset of infarction are unknown but probablyrelated to (1) plaque disruption, most likely caused by surges in sympathetic activity with a sudden increase inblood pressure, pulse rate, heart contraction, and coronary blood flow ; (2) thrombosis, occurring onpreviously disrupted or intact plaques when the systemic thrombotic tendency is high because of platelethyperaggregability, hypercoagulability, and/or impaired fibrinolysis ; and (3)vasoconstriction, occurring locally around a coronary plaque or generalized.

The beneficial effect of β­blockade in the secondary prevention of myocardial infarction provides strongevidence for the theory that mechanical and/or hemodynamic forces may trigger plaque disruption and suddendisease onset. β­Blocker therapy reduces reinfarction by 25% without having any provenantiatherogenic, antithrombotic, profibrinolytic, or antispasmodic effects in humans. On thecontrary, β­blockers may induce or potentiate atherogenic dyslipoproteinemia, platelet aggregation, andvasoconstriction. Nonetheless, administration of β­blockers blunts the morning peak in onset of infarction,probably by blunting the sympathetic surge in the morning, indicating that mechanical and hemodynamic forcescould be critical in triggering plaque disruption and disease onset. Accordingly, the beneficial effect of β­blockers on reinfarction has been related to the reduction in heart rate, and a similar effect on reinfarctionhas been obtained by the heart rate–reducing calcium antagonists verapamil and diltiazem, in sharpcontrast to the results obtained with the heart rate–increasing calcium antagonist nifedipine. It should bestressed, however, that activation of the sympathetic nervous system and hypercatecholaminemia associatedwith arousal, exercise, emotional stress, and smoking could trigger onset of acute coronary syndromes not onlyvia β­adrenergic receptors but also via α­receptors, promoting platelet aggregation and vasoconstriction.

Sudden thrombus growth on previously disrupted or intact plaques due to changes inplatelet function, coagulation, and/or fibrinolysis is probably an important mechanism responsible for onset ofacute coronary syndromes.

Identification of Vulnerable and Progressing Plaques

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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 ofearly lesions and vulnerable plaques at high risk of becoming culprits. Intravascular ultrasound andangioscopy may reveal important plaque and surface features not seen angiographically, andmagnetic resonance imaging, spectroscopy, and scintigraphy may in the near futurefurther improve the in vivo identification and characterization of coronary plaques. Actively progressingatherosclerosis and vulnerable high­risk plaques are characterized by increased endothelial permeability withinsudation of plasma constituents; lipoprotein accumulation; endothelial activation with expression of adhesionmolecules; monocyte recruitment; macrophage retention and cell activation within lesions; denudation andulceration 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, revealingsigns of inflammation and activation of endothelial cells, leukocytes, platelets,coagulation, and fibrinolysis.

Plaque Disruption: Clinical Manifestations

Plaque disruption is common. It is followed by variable amounts of hemorrhage into the plaque through thedisrupted surface and luminal thrombosis causing rapid plaque growth (Fig 3⇑), probably the most importantmechanism responsible for the unpredictable, sudden, and nonlinear progression of coronary lesionsfrequently observed angiographically. Another mechanism underlying episodic plaque growth could beaccelerated SMC proliferation and matrix synthesis driven by superficial inflammation, endothelial denudation,platelet adhesion/degranulation, thrombin generation, and other blood­derived growth factors. SMCproliferation by itself does not constitute a strong thrombogenic stimulus and is, as recently pointed out,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 theircoronary arteries, increasing to 22% in persons with diabetes or hypertension. Many persons who die ofischemic heart disease harbor both thrombosed and nonthrombosed disrupted plaques in their coronaryarteries. In two studies of 47 and 83 persons who died of coronary atherosclerosis, 103 and 211disrupted plaques, respectively, were identified, more than 2 disrupted plaques per person, and less thanhalf (40 and 102, respectively) were associated with significant luminal thrombosis that caused critical flowobstruction. 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 suddenflow obstruction, giving rise to new or changing symptoms. Three major factors appear to determine thethrombotic response to plaque disruption/erosion: (1) character and extent of exposed plaque components(local thrombogenic substrates) ; (2) degree of stenosis and surface irregularities that activateplatelets (local flow disturbances) ; and (3) thrombotic­thrombolytic equilibrium at thetime of plaque disruption (systemic thrombotic tendency). The clinical presentation andoutcome depend on the location, severity, and duration of myocardial ischemia. A nonocclusive or transientlyocclusive thrombus most frequently underlies primary unstable angina with pain at rest and non–Q­wavemyocardial infarction, whereas a more stable and occlusive thrombus is most frequently seen in Q­waveinfarction—overall, modified by vascular tone and available collateral flow. The lesion responsible for out­of­

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hospital cardiac arrest or sudden death is often similar to that of unstable angina: a disrupted plaque withsuperimposed nonocclusive thrombosis. It is noteworthy that many coronary arteries apparentlyocclude silently without causing myocardial infarction, probably because of a well­developed collateralcirculation at the time of occlusion.

Prevention of Plaque Disruption

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 reducingpotential trigger activities.

Plaque Stabilization

Experimental animal studies indicate that atherosclerosis is a dynamic process in which arterial function, lumensize, plaque size, and plaque composition may change independently. After diet­induced atherosclerosis inmonkeys, lipid lowering results in rapid normalization of endothelial function, disappearance of macrophagefoam cells from lesions, depletion of plaque lipid (preferentially cholesteryl esters, resulting in a smaller andstiffer lipid­rich core), and loss of vasa vasorum. Furthermore, mature collagen mayincrease, resulting overall in a larger vascular lumen and a modified but not necessarily a smallerplaque. Such “regressive” changes should stabilize plaques against disruption, but this hypothesis has notbeen tested because of lack of a suitable animal model of plaque disruption. Experimentally, atheroscleroticplaques have been modified and probably stabilized by a variety of non–lipid­lowering approaches, includingelevation of HDL, antioxidants, some dietary fatty acids, exercise conditioning, avoidance ofpsychosocial stress, angiotensin­converting enzyme (ACE) inhibition, blood pressure lowering, andestrogen replacement therapy.

Clinical observations indicate that human plaques may be stabilized against disruption and thrombosis byantiatherogenic therapy, including modifications of lifestyle and serum lipids. It is noteworthy thatsignificant clinical benefit may be obtained by stabilizing plaques even when regression does not occur.Three lipid­lowering trials with angiographic follow­up have independently shown that stability of coronaryplaques over the short term is associated with a good long­term prognosis; disease progression on trialpredicted posttrial myocardial infarction and cardiac death. Plaque stabilization, thus, may be anapproach to convey clinical stability.

ACE activity may contribute to the development of coronary artery disease and myocardial infarction, andACE inhibition seems to reduce the risk of major ischemic events (reinfarction, cardiac death, and possiblyunstable angina) by about 22% in patients with low ejection fractions, probably via multiplebeneficial mechanisms. ACE inhibitors may influence both atherogenesis (plaque vulnerability) andtriggering mechanisms responsible for disease onset (plaque disruption, thrombosis, and/or vasospasm). Thelatter are discussed below in the section on trigger reduction. The hypothesis that these drugs areantiatherogenic 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, butcontrasting results have recently been reported for femoral artery disease treated with the strong antioxidantprobucol. Estrogen replacement therapy seems to provide powerful protection against myocardial infarctionand cardiovascular death in postmenopausal women, probably mediated via multiple anti­ischemicmechanisms that include a direct effect of estrogen on the vessel wall, but the effect on coronary arterydisease progression is still unknown.

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Trigger Reduction

Avoiding or reducing trigger activities may prevent plaque disruption. Exercise and the associated sympatheticneurohormonal 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, vigorousexertion, and only sedentary people seem to be at increased risk of exercise­related infarction (relativerisk from 7 to 107 ). Although physically unfit people usually are advised to avoid heavy physicalexertion, it is unknown whether refraining from such activities reduces myocardial infarction in sedentarypeople or just postpones it. Of more interest for prevention, regular exercise may retard plaqueprogression and seems to provide protection against myocardial infarction and coronary deaths,

at least in part by eliminating the triggering effect of sudden vigorous exertion.

Cigarette smoking is the most important preventable cause of morbidity and mortality from coronary arterydisease. Clinical data indicate that smoking accelerates the progression of coronary artery disease.

The increased risk associated with smoking appears to be rapidly reversible by cessation, implicating acute triggering mechanisms (plaque disruption, thrombosis, and/or vasoconstriction) rather thanchronic atherogenic mechanisms as being primarily responsible for smoking­related disease progression.

Regarding atherogenesis and plaque stability, smoking seems to impairendothelial function and promote lipid oxidation, and preliminary autopsy data indicate that smokers havemore extracellular lipids in their plaques, which should imply greater vulnerability to rupture.

β­Blockers and possibly heart rate–reducing calcium antagonists may delay or prevent plaquedisruption by reducing the mechanical and hemodynamic load on vulnerable plaques, explaining the beneficialeffect of these drugs in the secondary prevention of myocardial infarction. As mentioned, the protectiveeffect of β­blockers has been related to their heart rate–lowering efficacy: the lower the heart rate, the betterthe protection against reinfarction and sudden death. The maximum benefit achievable by trigger reductiontherapy is limited, however, unless the progression of the disease is also arrested. Coronary plaques arestressed constantly, and just reducing peak stresses will probably only postpone the time at which aprogressing vulnerable plaque inevitably will rupture. Even complete elimination of the morning excess of acutecoronary events associated with the morning surge in sympathetic activity will prevent only a small fraction ofall clinical events, 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 bepursued.

As previously described, ACE inhibition may modify not only atherogenesis and plaque vulnerability but alsotriggering mechanisms responsible for disease onset. For example, the renin­angiotensin system mayinteract with fibrinolytic function, and ACE inhibition may influence endogenous fibrinolysis, resulting in areduced thrombotic response to plaque disruption. Importantly, ACE inhibition also seems to reducemortality and reinfarction in the presence of β­blocker therapy, suggesting an independent therapeuticeffect.

Treatment of Plaque Disruption

The most feared consequence of coronary plaque disruption is thrombotic occlusion. The function of thehemostatic and fibrinolytic systems at the time of plaque disruption, ie, the systemic thrombotic­thrombolyticequilibrium, is important for the outcome, as documented by the beneficial effect of antithrombotic therapy inpatients at risk of plaque disruption. After disruption, antiplatelet agents and/or anticoagulants maylimit the thrombotic response and prevent mural thrombosis from progressing to occlusive thrombosis. If

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the latter occurs, thrombolysis and/or mechanical intervention may reopen the culprit artery. It is noteworthythat lipid lowering may not only stabilize plaques against disruption but also improve endothelial and vasomotorfunctions and reduce the thrombotic response if disruption occurs via beneficial effects onplatelets, coagulation, fibrinolysis, and blood viscosity.

Conclusions

Atherosclerosis without thrombosis is in general a benign disease. However, acute thrombosis frequentlycomplicates the course of coronary atherosclerosis, causing unstable angina, myocardial infarction, andsudden death. The mechanism responsible for the sudden conversion of a stable disease to a life­threateningcondition is usually plaque disruption with superimposed thrombosis. The risk of plaque disruption dependsmore on plaque composition and vulnerability (plaque type) than on degree of stenosis (plaque size). Majordeterminants 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 disruptiontends to occur at points at which the plaque surface is weakest and most vulnerable, which coincide with pointsat 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 rupturetriggers (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 myocardialinfarction and death; to find and treat only angina­producing stenotic lesions is no longer enough. Forprevention and treatment, a systemic approach that addresses all coronary plaques will prove to be mostrewarding.

Footnotes

Reprint requests to Erling Falk, MD, Department of Cardiology, Skejby University Hospital, DK­8200 Aarhus N,Denmark.

Circulation. 1995;92:657­671.

Received April 5, 1995.

Revision received May 17, 1995.

Accepted June 3, 1995.

Copyright © 1995 by American Heart Association

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