J Br 1993;69(Supplement):S 3-S 11 S 3 : what is it and why does it occur? Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from

M J Davies, N Woolf

The limits of what is encompassed by the luminal balloon injury or external compres- term atherosclerosis are fundamental to sion. A localised intimal pro- understanding the pathogenesis of the disease liferation occurs which simulates one and the ways in which clinical symptoms are component of the human atherosclerotic produced. plaque. Post in humans is an example of such a response to injury by an atherosclerotic vessel but the created is Basic definitions ofatherosclerosis different from a human plaque. Atherosclerosis is an intimal disease of within a range of size from the down to approximately 3 mm external diameter. The Clinical symptoms and atherosclerosis distribution of the disease is far from uniform; Plaque formation begins in early life, by the some arteries such as the internal mammary third decade advanced plaques are almost are largely spared while others such as the ubiquitous in Western populations. Therefore are at high risk. Similarly, in there is a long presymptomatic phase before the same individual the degree of coronary, the disease appears above the clinical horizon. cerebral, and carotid atherosclerosis is often The conversion from a person with athero- disparate. sclerosis, but no clinical symptoms, to a Atherosclerosis is a focal not a diffuse inti- patient with symptoms is an important break- mal disease. The focal nature can be appreci- point and may be largely determined by com- ated by examining the intimal surface of an plications most of which involve opened , when discrete or developing in association with plaques. Any plaques are visible. analysis of therapy should consider separately and the connective tissue matrix the prevention of plaque formation and the proteins are the two major components of reduction of plaque complications.

plaques. The lipid may be extracellular or Clinical symptoms depend on four mecha- http://heart.bmj.com/ intracellular and both forms are usually found nisms. The primary process of atherogenesis in advanced plaques. Most lipid-containing (that is, lipid accumulation and connective foam cells are derived originally tissue matrix production by smooth muscle from circulating that have entered cells) may increase the volume of one or more the intima. Connective tissue matrix proteins key plaques so that they encroach on the are synthesised by smooth muscle cells. The lumen and become flow limiting. Second, a matrix protein is . This is present plaque may enter an unstable phase and be in large amounts, conferring mechanical complicated by the formation of a . on September 25, 2021 by guest. Protected copyright. strength to the tissues and thereby holding the This thrombus may itself encroach on, or plaque together as a stable structure. occlude, the arterial lumen, or break away Some of the processes involved in athero- embolise and impact in smaller more distal sclerosis do occur in other vascular diseases, vessels. Third, though atherosclerosis is a and it is important that the definition of focal disease it is associated with a generalised atherosclerosis is not blurred or confused. abnormality of vascular tone in affected arter- The medial smooth muscle hypertrophy and ies that favours vasoconstriction often at in- British Heart subsequent fibrosis that occur in appropriate times such as on exercise. Finally, Foundation and affect smaller arteries are not athero- medial atrophy and destruction secondary to Cardiovascular Pathology Unit, St sclerosis. The medial calcification that occurs intimal atherosclerosis may lead to George's Hospital with age in the lower limb arteries is not formation. Many patients suffer combinations Medical School, atherosclerosis. The use of the generic term of all these mechanisms. London often converted into the M J Davies "", lay term "hardening of the arteries", leads to University College and Middlesex Medical tremendous confusion by lumping all of these School ofMedicine, entities into one age-related arterial disease. Pathogenesis of atherosclerosis Histopathology Isolated intimal smooth muscle prolifera- Any consideration of what comprises human Department, London N Woolf tion is not atherosclerosis. Smooth muscle atherosclerosis raises the following salient is a to issues: Correspondence to proliferation general response injury by Professor M J Davies, the arterial wall and does occur in athero- (a) What is the origin of the intimal lipid? British Heart Foundation Cardiovascular Pathology sclerosis. But it is neither unique to nor (b) Why is there an intimal inflammatory Unit, St George's Hospital specific for atherosclerosis. Many animal response in which monocytes migrate into Medical School, Cranmer Terrace, London models of arterial disease have been created in and become permanently resident in the SW17 ORE. which vascular damage is induced by intra- intima? S 4 Davies, Woolf

Figure 1 Diagram to L ----SI show plasma low density MA LDL (LDL) entering the subendothelial space Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from and being oxidised, and the consequentformation of a . iL _ _

Chemoattractant cz migration rzn C LOXIDISED LDL n o°°-,C:O J ----- 4) C C°~0? LIu 19 LI Activation N

Division

Phagocytosis

0 Foam cell formation 0 r-- EXTRACELLULAR 4 Cell LIPID

(c) How is smooth muscle proliferation and induces migration, initiates inflammatory collagen synthesis within the intima initi- responses, is toxic to monocytes, and is avidly ated and maintained? ingested by them via scavenger receptors.2 (d) What processes invoke thrombosis over Lipid uptake via this receptor is not down unstable plaques? regulated by intracellular lipid and the mono- Only when the answers to these questions, cyte becomes stuffed with lipid to become a all of which are discussed in this supplement, "foam cell". are known can truly rational therapy to con- Smooth muscle proliferation is controlled trol the progression of atherosclerosis be initi- by growth factors released from a wide range http://heart.bmj.com/ ated. of cells (fig 2) including , endothelial In the broadest terms atherosclerosis is cells, macrophages, and other smooth muscle now recognised to be an immune/inflamma- cells. Inflammatory reactions readily induce tory response of the intima to injury.' It is growth factor production. All of these also being increasingly realised that the injury processes are considered in individual chap- is initiated by lipid. There is, however, a para- ters of this supplement.

dox in that native plasma , in particular Any consideration of human atherosclero- on September 25, 2021 by guest. Protected copyright. low density , though they freely sis cannot deny the role of lipid in intimal enter the intima, do not initiate an inflamma- injury. This lipid is largely plasma derived tory response, are not ingested by monocytes, and results from plasma concentrations that and do not damage tissue. Oxidation or alter- are greater than ideal for that individual. It is ation of low density lipoprotein will however important to remember that the plasma lipid radically alter this passive state (fig 1): oxi- profile of an individual is the result of interac- dised lipid is chemotactic for monocytes, tions between genetic and environmental fac-

Figure 2 Influence of Platelets Endothelial cell growth factorproduction on smooth muscle proliferation.

T Lymphocyte a 0 \>: oMacrophage

Smooth muscle cells Atherosclerosis: what is it and why does it occur? S 5

tors the most important of the latter being containing: diet. Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from Foam cells 0 Intracellular lipid Progression ofplaques in humans An inherent drawback of any human necropsy study is that the state of the artery is seen at one moment only. Nevertheless, there are numerous morphological and histological descriptions of the different types of human plaque with speculation about how each is TRANSITIONAL PLAQUE related temporally. In reality the only safe containing: /~~~~~~~~~~ conclusion is that large plaques must evolve Foam cells 0 Intracellular lipid from smaller plaques but over what period of 1/I~~~~~~~/ Extracellular lipid time is unknown. The studies by Stary have provided many answers about plaque evolu- tion.' Detailed studies were made of the arteries in young subjects, from infancy to over 30 years of age, dying suddenly from non-cardiac disease. The cases were divided &z into cohorts by age. It was therefore possible ADVANCED FIBROLIPID PLAQUE to see the age at which lesions of any particu- containing: lar type first appeared, and the sequence of U~~ Extracellular lipid core plaque progression could be inferred. Smooth muscle cells The first observation was that in all human Foam cells 0 infants focal thickening of the intima develops due to smooth muscle proliferation. Stary has argued cogently that this is a ubiquitous adaptive response, and not early atherosclero- sis. Nevertheless, it does mean that the human coronary intima already contains smooth muscle cells, and is presensitised to COMPLICATED PLAQUE the later development of atherosclerosis if WITHTHROMBUS FORMATION certain conditions prevail. The first atherosclerotic lesions which appear are fatty dots or streaks barely raised

above the intimal surface. Each lesion is http://heart.bmj.com/ made up by a focal collection of lipid-filled foam cells within the intima. On one hand there is evidence that such simple fatty Figure 3 Human plaque progression. Thefatty streak contains onlyfoam cells. streaks or dots are the precursor of larger Extracellular lipid, smooth muscle cells, and collagen appear successively and lead to an tran- thrombosis can arise. plaques. Pathological studies show that advanced plaque on which the of sitional forms exist between fatty streaks and advanced plaques, and that advanced plaques

develop in the sites where fatty streaks are on September 25, 2021 by guest. Protected copyright. most frequent. On the other hand it is clear that not all fatty streaks progress. Necropsy surveys of infants from geographical popula- tions in which the advanced atherosclerosis does not develop and there is a negligible incidence of ischaemic heart disease show large numbers of fatty streaks.4 The cohort studies by Stary show that pro- gression beyond the fatty streak stage is asso- ciated with a sequence of changes starting with the appearance of extracellular lipid which begins to form a core to a lesion that is becoming more elevated (fig 3). Smooth muscle cells migrate into and proliferate with- in the plaque, forming a layer over the lumi- nal side of the lipid core. More and more collagen is produced and plaque size increas- es. The process culminates in what is known as a raised fibrolipid or advanced plaque. In the aorta such plaques may be a centimetre or ....8 more in length. a M mi I The aorta and coronary arteries of adults Figure 4 Micrograph showing cross section of human coronary plaque showing a large show all stages of plaque development, imply- pool oflipid (coded yellow) encapsulated in the plaque. ing that new lesions are generated throughout S 6 Davies, Woolf

adult life. The work by Stary indicates that a can shift outward. In extreme cases the fully developed plaque can take up to 10-15 plaque is almost extruded from the original

years to develop. outline of the vessel. Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from Raised fibrolipid plaques have a very char- The result of both these medial changes is acteristic microanatomy (fig 4) with a core of that it is impossible ever to be sure that an extracellular lipid separated from the media angiographically normal segment of artery by smooth muscle cells and covered and sep- does not contain a hidden plaque. A corollary arated from the lumen by a thick cap of colla- is that the degree of lumen stenosis bears no gen-rich fibrous tissue containing smooth constant relation to plaque size. Yet another muscle cells. Surrounding the lipid core are corollary is that the term "new" as applied to lipid-filled foam cells. Much of the core lipid a stenosis appearing between two angiograms is thought to be derived from the death of is a misnomer: the plaque may have been lipid-containing foam cells and there for years and have recently undergone a the release of their intracytoplasmic content change making it angiographically visible. (fig 1). This process of plaque is an important facet of human disease and has Animal models of atherosclerosis considerable influence on the later develop- There is one incontrovertible feature of ment of thrombosis. Even in the same indi- animal models. This is that only when plasma vidual there are major plaque to plaque lipid concentrations are increased is a disease variations in the relative proportions of extra- produced which has morphological similari- cellular lipid and collagen that are present. ties to atherosclerosis in humans. The raised fibrolipid or advanced athero- Plasma lipid concentrations can be raised sclerotic plaque is the substrate on which either by high diets or by the use of plaque complications develop, and therefore animals that have an inherent defect in lipid clinical symptoms appear. The evidence for leading to hyperlipidaemia. this view comes from large geographical All animal models have merits and demer- studies of the number of raised plaques at its. Rabbit models based on the use of high necropsy in the and coronary arteries fat diets are cheap and relatively quick. An in subjects who did not die from ischaemic increase in the percentage of the aortic intima heart disease. In any specific geographical occupied by stainable lipid can be seen 12 population the mean number of plaques pre- weeks after the start of a high fat diet. This sent mirrors the frequency of death from provides ideal circumstances for testing anti- ischaemic heart disease in the same pop- atherogenic drugs. But are aortic lesions pro- ulation.5 A further fact to emerge is that indi- duced by very unphysiological diets over a viduals with hypertension have more aortic short period of time analogous to human and coronary plaques than normotensive atherosclerosis? The great bulk of the lipid in individuals.67 Whereas the number of the aorta is within foam cells: in effect what advanced plaques is an important determi- has been produced are numerous giant fatty nant of the risk of developing clinical symp- streaks not advanced plaques. Hereditary http://heart.bmj.com/ toms there will always be unlucky individuals defects in such as that found who have very few plaques but develop acute in the Watanabe or St Thomas' rabbit do or die suddenly because of throm- allow the effect of more chronic, less extreme bosis on a single strategically placed plaque, hyperlipidaemia and do reproduce plaques for example at the origin of the left anterior with lipid cores. Long-term dietary athero- descending coronary artery. sclerosis in both primate and porcine models term will also reproduce a more typically human Though the "advanced", adopted by on September 25, 2021 by guest. Protected copyright. Stary, is accurate in indicating the lesion has type of plaque but these models are expen- developed over years it may be misleading in sive. a clinical setting. Most advanced plaques are The value of animal models is that they not angiographically visible. This unfortunate have allowed sequential studies of plaque fact means that accurate angiographic assess- development in terms of cellular events. The ment of the amount of wall disease, as animal models are consistent in showing that distinct from the degree of stenosis, is impos- the initial event is adhesion of monocytes to sible. The angiogram can indicate focal nar- an intact endothelial surface followed by their rowing of the lumen, nothing more. migration into the intima. Endothelial The reasons for the angiographic insensi- denudation (that is, exposure of subend- tivity in the detection of plaques lie in the othelial matrix) which causes adhe- medial changes that develop in atheroscler- sion or activation is not present and therefore otic vessels. When intimal plaques develop does not play any part in plaque initiation.9 the arterial media undergoes a remodelling Once plaques are established endothelial process which increases the external diameter denudation with subsequent platelet/vessel of the vessel. The plaques are therefore wall interactions do occur.'0 accommodated without any reduction in the Lipid ingestion by monocytes within the cross sectional area of the lumen.8 Only when intima leads to the appearance of foam cells this capacity for remodelling is overcome do in increasing numbers. As lipid-filled foam plaques compromise the lumen and become cells accumulate within the intima defects do angiographically visible. A second mechanism appear in the endothelial surface over which is that behind plaques the media atrophies platelets do adhere. Further cellular events and can virtually vanish, the internal elastic very much follow the sequence described by lamina may rupture, and the whole plaque Stary in human disease. Atherosclerosis: what is it and why does it occur? S 7

Clinical symptoms and atherosclerosis lesions in which the lumen at the point of STABLE EXERTIONAL maximum stenosis has several channels.'2

Clinical angiographic studies show that most These appearances result from the organisa- Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from patients with stable angina have one or more tion of an occluding thrombus. areas of high grade stenosis. Stenoses that The pathological basis of most cases of sta- reduce the luminal diameter by more than ble angina is therefore the stable plaque caus- 50%, when compared with adjacent segments ing high grade stenosis. "Stable", as applied judged to be normal, are considered to be to a plaque, means that no acute thrombosis flow limiting when myocardial is occurring. demand rises. The angiographic assessment of the degree of stenosis is at best semi-quantitative, and Endothelial status over stable plaques liable to unpredictable errors." The major Use of the term stable with regard to a plaque source of error lies in the comparison with a does not imply that no inflammatory activity reference "normal" segment. This segment or endothelial damage is occurring. Animal may in fact be diffusely narrowed or even models show that once advanced plaques are dilated. Computerised reconstruction of the established endothelial denudation injury and normal distal tapering of the vessel will only localised adhesion of platelets are common. partly overcome this difficulty. A case can be Human studies in which coronary arteries made for the use of absolute measurements of were perfused with gluteraldehyde and the lumen size in sequential angiograms. Even so endothelial surface examined by scanning the capacity of the coronary artery to remodel electron microscopy confirm that similar itself makes sequential change difficult to changes occur.'4 15 interpret. The endothelial surface over plaques shows The morphological characteristics of high loss of individual cells, or several contiguous grade stenoses have several variables. Plaques cells, exposing the subendothelial matrix- may be eccentric (that is, occupy only an arc over which a monolayer of platelets forms (fig of the vessel circumference) or be concentric 5). Adjacent to these areas of endothelial loss and surround the entire circumference. In macrophage foam cells are present. The pres- eccentric plaques there is a residual arc of ence of these foci of denudation over human vessel in which the medial structure is intact coronary plaques is the rule rather than the and may be capable of vasomotor tonal varia- exception. These findings imply that the tion. In concentric plaques both the splinting endothelium over atherosclerotic lesions is effect of the plaque and the associated general undergoing constant regeneration and that loss of media mean that there is no capacity many individual endothelial cells are imma- for tonal variation in lumen size. ture. These microthrombi consisting of a The reported frequency of stenoses which monolayer of platelets do not mechanically

retain a segment of normal media varies obstruct flow and fall far short of being angio- http://heart.bmj.com/ widely in pathological studies.'2 13 This varia- graphically visible. These platelets, however, tion reflects several factors. Plaques that are have the potential to stimulate smooth muscle not yet angiographically visible are far more proliferation within the plaque. The lesions likely to be eccentric than plaques that are also show that plaque stability is a relative already causing stenosis. The frequency of term and that some element of microthrom- eccentric lesions falls as the degree of stenosis bosis is an integral part of the progression of rises. The situation can, however, be summed advanced lesions. Endothelial denudation up in the fact that most patients with stable injury is associated with foam cell infiltration on September 25, 2021 by guest. Protected copyright. angina will have at least one stenosis of more in the superficial layers of the plaque and is a than 50% by diameter which has the potential marker of the inflammatory activity in the to vary the degree of obstruction as vaso- plaque. motor tone changes. A further variable in plaques causing steno- sis is the relative proportion of collagen and and acute myocardial lipid. At one extreme the plaque may be vir- infarction tually all collagen: at the other extreme 70% Unstable angina and acute myocardial infarc- of the plaque volume may be lipid. The pro- tion, though often regarded as clinically dis- portion of lipid tends to fall with increasing tinct, form the two ends of a spectrum which stenosis but there are many exceptions to this results from thrombosis occurring over unsta- rule. Overall, however, there is a marked ble plaques. The difference between the two trend for high grade lesions to be predomi- conditions lies in the effect these thrombi nantly collagenous, suggesting that smooth have on the myocardium.'6 muscle proliferation, however initiated, is the Thrombosis of sufficient magnitude to factor leading to the later stages of obstruc- obstruct flow and be visible angiographically tion. High grade lesions (> 70% by diameter) is due either to superficial or deep injury to ,are often histologically complex with several the plaque.'7 layers of collagen of different structure: distal Superficial injury is the continuation of the and proximal to the main plaque concentric process of focal endothelial denudation that intimal smooth muscle proliferation occurs. A occurs over many plaques. When large con- high proportion of patients (> 75%) with fluent areas of denudation occur, thrombi stable angina, irrespective of whether they build up in size and may even become occlu- have had previous , have sive. Plaques with this degree of endothelial S 8 Davies, Woolf Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from

Figure 5 Electron micrograph of a human coronary plaque showing loss of endothelial cells and a monolayer ofplatelets adhering to exposed subendothelial tissue.

denudation are those in which there is a result in thrombus formation in the arterial heavy inflammatory component and many lumen. Such fissures would lead to sudden lipid-filled foam cells lying between fragmen- increases in the degree of stenosis but not ted collagen at the plaque surface. The necessarily either clinical symptoms or angio- thrombus which forms is stuck onto the lumi- graphic alterations in the outline of the nal surface of the plaque which itself appears plaque. Subclinical episodes of plaque insta-

intact. bility, intraplaque thrombosis, and fissuring http://heart.bmj.com/ Deep plaque injury differs from the super- are a major factor in disease progression once ficial injury in many ways. The basic process advanced plaques are present. is one in which the plaque tears or splits open Larger plaque fissures and tears may be exposing its lipid core to in the lumen. associated with a combination of intraplaque The tear or split goes deep into the plaque thrombosis and thrombosis within the lumen and is of far greater magnitude than the loss over the site of plaque disruption (fig 6). The of endothelium or superficial injury. The thrombus over the site of disruption is made result of what is known as plaque tearing, up of both and platelets whereas within on September 25, 2021 by guest. Protected copyright. fissuring, splitting or rupture is that blood the plaque itself platelets often predominate. enters the plaque from the lumen. Contact of For this number of platelets to be recruited, blood with collagen and (TF) blood must enter and leave the interior of the leads to thrombus formation within the plaque via the tear site for an appreciable plaque, which is expanded and distorted- time. The thrombus over the tear projects initially from within. into the lumen but does not prevent antero- The type of plaque which undergoes this grade flow. This type of mural thrombus over fissuring process is predominantly one that a fissured plaque produces the typical angio- contains a large core of extracellular lipid, graphic appearances highlighted as being pre- and it is into this core that the tear extends.'8 sent in the "culprit" vessel in unstable angina Plaques in which the extracellular lipid core and designated as type II.'9 The ragged out- makes up more than 40% of the overall line (which contrasts with the smooth stenosis plaque volume are particularly susceptible. A (type I) typical of stable angina) and over- few plaque tears occur in the plane between a hanging edges are produced by contrast plate of and the adjacent intima and medium entering the tear and by thrombus bear no relation to lipid pools. This type of projecting into the lumen. Angioscopy can tearing may be due to shear stresses within demonstrate both the mural thrombus and the plaque and may be more common in the torn plaques.20 Thrombi projecting into older subjects. the lumen but not preventing anterograde Plaque fissuring comes in various shapes flow are associated with embolisation of and sizes. The tear may be small, measuring platelet clumps into the distal vascular bed. 100-200 ,um across. Such tears allow blood Such platelet emboli are associated with focal to enter and expand the plaque but may not microscopic myocardial necrosis.2122 Atherosclerosis: what is it and why does it occur? S 9 Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from

Figure 6 Thrombus projecting into the lumen of a human coronary artery from the centre of a ruptured plaque.

Lesions which progress to become occlu- fissuring have a dynamic course. The appear- sive enter a final phase of intraluminal throm- ance found at necropsy is a reflection of the bosis in which the thrombus is poor in interaction of processes such as thrombus platelets and rich in a loose network of fibrin propagation, thrombolysis, organisation, and that enmeshes red cells. This final occluding smooth muscle proliferation. The final result phase thrombus is very susceptible to fibrino- can range from restoration of a virtually nor- lysis whether natural or iatrogenic. The struc- mal lumen size to chronic total obstruction the final occluding thrombus, ture of phase (fig 7). http://heart.bmj.com/ which is rich in fibrin and red cells, suggests The healing process after an episode of fis- that it forms within a very slow flowing or sta- suring is mediated by what is the ubiquitous tic column of blood. vascular repair response-smooth muscle It is likely that many variables determine proliferation and collagen production. The whether an unstable plaque proceeds rapidly fissure site is thus resealed, incarcerating to an occlusive thrombus with the potential within the plaque a mass of thrombus which for acute infarction or persists at an inter- will itself stimulate further collagen produc-

mediate stage as a mural non-occlusive tion. In a sense the plaque is restabilised but on September 25, 2021 by guest. Protected copyright. thrombus.23 The factors which favour rapid it has also been stimulated into a growth progression to occlusion are probably phase. enhanced thrombotic activity or diminished If thrombus has formed within the lumen fibrinolytic activity, larger fissures with a this is either removed by lysis or becomes greater thrombogenic potential, and severe invaded by and replaced by fine reduction in flow mediated by local spasm or connective tissue in the process of organisa- distal vascular shutdown. tion. The lumen may be chronically occluded Large fissures associated with occlusion or replaced by several vascular channels. and infarction are often very complex. The Very large plaque tears lead to the loss of plaque may develop a spiral tear over several the whole cap of the plaque with washout of millimetres and an intimal flap may be raised. the lipid contents, leaving a crater which Some plaques develop a proximal entry point partially fills with thrombus. In the carotid tear and the contents are extruded as a plug arteries and aorta such craters commonly of -rich debris via a distal break. become chronic and provide a source of distal The lumen in these cases may be occluded by platelet emboli. Such chronic craters are rare a mixture of thrombus and debris distal to in the coronary arteries but may be outlined rather than at the plaque site itself. The major on in some patients who have plaque tears probably cause thrombosis in had fibrinolytic therapy for acute infarction. which the vessel lumen cannot be reopened Angiography based on the criteria of a rag- by lysis and reoccludes very rapidly. ged outline and overhanging edges does not detect all plaque fissures even when it is car- ried out at necropsy with high resolution film Course ofunstable plaques with fissuring and lack of movement. Recanalised vessels The events which follow an episode of plaque with several lumens will reproduce exactly the S 10 Davies, Woolf

Plaque fissure Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from

Occluding Mural thrombus thrombus

Chronic /Recanalised" Residual higher No increase occlusion occlusion grade stenosis in stenosis

Figure 7 Potential outcomes ofan episode ofplaquefissuring.

irregular outlines of active fissures. Thus clin- episodic plaque growth and acute ischaemic http://heart.bmj.com/ ical angiography cannot be very sensitive or syndromes, understanding its pathogenesis specific for plaque fissures. The best evidence might lead to suggestions how it could be that subclinical episodes of plaque fissuring avoided. occur comes from postmortem studies of Tearing could result either from reduced control populations in which coronary athero- mechanical strength or from enhanced stress sclerosis was present but was not the cause of on the tissues. One solid fact to emerge from death.24 At least one episode of recent fissur- several pathological studies is that the plaque ing but without intraluminal thrombus for- at risk has a large lipid core and that it is the on September 25, 2021 by guest. Protected copyright. mation was found in 8% of individuals plaque cap tissue that tears. whereas in those with hypertension or dia- In one approach the alterations in the dis- betes the figure was 16%. These facts show tribution of circumferential wall stress in sys- that fissuring is a common event in subjects tole across this type of lipid-rich pool have with atherosclerosis and that it is an integral been simulated."8 Stress on the cap is much part of plaque progression whether or not increased because the soft lipid core cannot clinical symptoms occur at the time. carry a load, which has to be redistributed. Numerous factors must determine whether Stiff cap tissue and an eccentric position of the stimulus of a fissure produces significant the plaque enhance this tendency for stress to intraluminal thrombus. Predominant among be concentrated on the cap at its junction these factors are the size of the fissure and the with the more normal vessel wall. balance of thrombotic/lytic systemic factors at In other approaches the cap tissue of aortic the time. Some intraplaque thrombus is, plaques was mechanically tested, analysed however, inevitable. Drugs with an anti- biochemically, and the proportions of cell thrombotic action might not only prevent the types measured.25 The caps of plaques which development of acute clinical episodes but had ulcerated had a reduced mechanical also delay the progression of atherosclerosis strength, reduced collagen content, a reduced by reducing plaque growth. smooth muscle content, and an increased proportion of lipid-filled macrophages. Plaque instability is thus seen to be a func- Cause ofplaque instability tion of increasing extracellular lipid content, Given that plaque instability is the cause of increasing macrophage content, and dimin- the thrombosis which precipitates both silent ishing smooth muscle content. The decline in Atherosclerosis: what is it and why does it occur? s 1 1

smooth muscle numbers may indicate that pathological determinant of atherosclerosis in youth study. JAMA 1990;264:3018-24. the normal reparative process which main- 8 Glagov S, Weisenberd E, Zarins C, Stankunavicius R, has been overcome. Kolettis G. Compensatory enlargement of human Br Heart J: first published as 10.1136/hrt.69.1_Suppl.S3 on 1 January 1993. Downloaded from tains plaque stability atherosclerotic coronary arteries. N Engl J Med 1987; 316:1371-5. 9 Faggiotto A, Ross R, Harker L. Studies of hypercholes- Regression of atherosclerosis terolaemia in the non-human primate. I Changes that lead to fatty streak formation. Arteriosclerosis 1984; Animal models suggest that regression of 4:323-40. lesions can occur after plasma lipid concen- 10 Faggiotto A, Ross R. Studies of hypercholesteolaemia in non-human primates. II Fatty streak conversion to trations are reduced. What does regression fibrous plaque. Arteriosclerosis 1984;4:341-56. mean in the context of animal models? Many 11 de Feyter P, Serruys P, Davies M, Richardson P, Lubsen of J, Oliver M. Quantitative coronary angiography to mea- use the simple estimation of the proportion sure progression and regression of coronary atheroscle- the intimal surface occupied by plaques or by rosis. Value, limitations, and implications for clinical stainable lipid. What is required in humans trials. Circulation 1991 ;84:412-23. 12 Hangartner J, Charleston A, Davies M, Thomas A. is a reduction in plaque mass leading to Morphological characteristics of clinically significant angiographic improvement. Given that many coronary artery stenosis in stable angina. Br Heart 7 1986;56:501-8. high grade stenoses in humans consist largely 13 Saner H, Gobel F, Salomonowitz E, Erlien D, Edwards J. of collagen this may not be readily achieved. The disease free wall in coronary atherosclerosis: its relation to degree of obstruction. J Am Coll Cardiol Many patients with symptomatic atheroscle- 1985;6:1096-9. rosis would happily settle for a guarantee of 14 Davies M, Woolf N, Rowles P, Pepper J. Morphology of the endothelium over atherosclerotic plaques in human no further acute episodes or progression of coronary arteries. Br Heart f 1988;60:459-64. their stenoses. Animal models in which the 15 Burrig K. The endothelium of advanced arteriosclerotic plaques in humans. Arterioscl Thromb 1991 11:1678-89. qualitative changes in the constituents of 16 Bitker H, Ravkilde J, Sigaard P, Jirgensen P, Hirder M, plaques were examined after lipid lowering Thygesen K. Gradation of unstable angina based on a sensitive immunoassay for serum creatine kinase MB. showed a reduction in lipid with a concomi- BrHeartJ 1991;65:72-6. tant increase in smooth muscle cells and col- 17 Davies M. A macroscopic and microscopic view of coro- nary thrombi. 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The pathogenesis of atherosclerosis-an update. leading to infarction and/or sudden N EnglJ Med 1986;314:488-500. death. Circulation 1985:71:699-708. 2 Steinberg D, Parthasarathy S, Carew T, Khoo J, Witztum 22 Davies M, Thomas A, Knapman P, Hangartner R. J. Beyond cholesterol. Modifications of low-density Intramyocardial platelet aggregation in patients with lipoprotein that increases its atherogenicity. N Engl J unstable angina suffering sudden ischaemic cardiac Med 1989;320:915-24. death. Circulation 1986;73:418-27. 3 Stary H. Evolution and progression of atherosclerotic 23 Fuster V, Badimon L, Badimon J, Chesebro J. The patho- lesions in coronary arteries of children and young genesis of and the acute co; adults. Arteriosclerosis 1989;9:1-19. nary syndrome II. NEnglJMed 1992;326:310-8. http://heart.bmj.com/ 4 Restrepo C, Tracy R. Variations in human aortic fatty 24 Davies M, Bland J, Hangartner J, Angelini A, Thomas A. streaks among geographic locations. 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