plaque fissuring--the myocardial infarction, sudden...

Br HeartJ 1985; 53: 363-73

Review

Plaque fissuring--the cause of acute myocardialinfarction, sudden ischaemic death, and crescendoangina

MICHAEL J DAVIES, ANTHONY C THOMAS

From the British Heart Foundation Cardiovascular Pathology Unit, St George's Hospital Medical School, London

The clinical management of acute myocardial infarc-tion and crescendo angina as well as the prevention ofsudden ischaemic death require accurate knowledgeof the underlying arterial pathology. It is on just thisaspect that until recently there has been disagreementparticularly among pathologists. In brief, this con-troversy was concerned with whether coronary arterythrombi were or were not directly responsible for allthree clinical pictures of acute ischaemia.

Resolution of the controversy has been derivedfrom coronary angiography in life in patients withacute infarction and crescendo angina and fromdetailed pathological studies. These latter studies dif-fer from many carried out previously by the use ofpostmortem coronary angiography and histologicalreconstruction of the microanatomy of occlusivelesions.

Findings in life

Clinical angiography has shown that the incidence ofocclusion in the coronary artery supplying a myocar-dial infarct is very high during the early period afterthe onset of symptoms. Figures of around 900/o areconsistently reported within an hour of the appear-ance of electrocardiographic changes of infarction,but the incidence of acute occlusions thereafter falls toaround 50% at 12-24 hours. ' 2The implication is thatblood flow has been restored by natural processeswhich, judged by their rapidity, can only be by lysisof thrombus or relaxation of spasm or a combinationof the two. A number of clinical angiographicappearances-including persistent retention of con-

Requests for reprints to Professor M J Davies, St George's HospitalMedical School, Cranmer Terrace, London SW17 ORE.

Accepted for publication 11 December 1984

trast medium by intraluminal material, an irregular orlobulated margin to the occlusion, and filling defectswithin the lumen-have been taken to indicate athrombotic occlusion.3 In postmortem coronaryarteriograms areas of stenosis with ragged marginsand intraluminal transluscency have been shown to bea reliable indicator of the presence of thrombus.4 Thesuccess of either intracoronary streptokinase infusionor systemic streptokinase-plasminogen activator inrestoring arterial patency strongly suggests thatthrombus is a major element in the occlusion. Flowcan be restored in 72-96% of such cases3 5-8 usingintracoronary infusion and in 45-65% of cases usingintravenous infusion of fibrinolysins.9 Fibrinolyticagents that specifically bind to recent thrombus'I maywell improve the latter rate. As the arterial flow isrestored by fibrinolysis a sequence of angiographicappearances develops which includes all those taken toindicate the presence of thrombosis.3."'-13 Suchappearances, in particular intraluminal filling defects,would be most unlikely to occur if the occlusion hadbeen due purely to spasm of an atheromatous artery.

After fibrinolysis, in most cases but not all, a highgrade stenotic lesion is usually found in the arterysupplying the area of infarction.6 7 14 15 Afterfibrinolysis thrombosis recurs in up to 25% ofcases,6-8 11 12 particularly in those with the highergrades of residual stenosis.'6

In crescendo angina, the causative role of thrombusis less firmly based, but angiographic appearancessuggesting non-occlusive (mural) thrombus to bepresent have been found in 85% of cases'7- '9or evenin all cases.20 In cases where an acute infarct hasdeveloped complete arterial occlusion has beenfound." 19 The beneficial effect of aspirin treatmentin reducing the risk of sudden death and acute infarc-tion in cases of crescendo angina also points to an

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underlying thrombotic process.2'Thus there are compelling reasons to believe that

thrombus plays a major role in both acute myocardialinfarction and in crescendo angina. What has beenadded by these clinical studies is the evidence thatthrombosis is a rapidly changing dynamic processreflecting equally rapid changes in the arterial lesion.

Necropsy findings

Recent pathological studies, in which the coronarythrombi found in fatal cases of acute myocardialinfarction were reconstructed from serial histologicalsections, have shown that virtually all were related torupture or fissuring of atheromatous plaques.22 23Rupture of a plaque leads to free communication be-tween the lipid content of the plaque and the bloodflowing within the arterial lumen. Dissection by bloodfrom the lumen into the plaque, in many cases, resultsin a large intraintimal thrombus rich in platelets. Overthe site of rupture thrombus develops within thelumen and often propagates distally into segments ofthe artery without significant intimal disease. Such

Davies, Thomas

studies emphasise that the head of the thrombus inrelation to the plaque is different from the thrombuspropagating distally24; the former is rich in platelets,the latter contains a higher proportion of fibrin. Thesepostmortem studies have usually been carried out incases where a large regional infarct is found at nec-ropsy and the coronary artery is totally occluded, thepatient having lived for at least 24 hours after theonset of symptoms.

Study bf patients who die suddenly of ischaemicheart disease25 shows that 95% of such cases have anacute evolving coronary arterial lesion. These lesionsare also atheromatous plaques undergoing fissuring orrupture. All the clinical angiographic appearancesregarded as indicating thrombosis are present also inpostmortem angiograms in sudden ischaemic death(Figs. 1 and 2). Histological examination confirmedthat in 74% of cases there was recent thrombus pres-ent in the lumen, but this did not necessarily totallyocclude the vessel. In a further 21% there were plaquefissures with recent thrombi within the intima but notin the lumen. Compared with that in patients dying inhospital with established myocardial infarction the

Fig. 1 Postmortem angiogram ofa man aged 44, who had no previous history ofanginaand was extremelyfit. Duing a game ofsquash he suddenly felt unwell with chest pain anddied 30 minutes later. The left anterior descending artery divided into two major branchesimmediately after the origtn. One of these showed an intraluminalfiling defect (arrow)associated with an irregular intimal oudine. Histology confirmed afissure ofa plaque withoverlying thrombus. The remainder of the coronary artery tree was angiographically andhistologically normal.



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Fig. 2 Postmortem angiograms showingplaquefissures with associatedintraluminal thrombus. All three patientsdied within one hour of the onset ofsymptoms. In (a) there is a high gradestenosis ofa major branch of the leftanterior descending artery. The proximalmargin of the stenosis has a smooth edge,but on the distal margin (arrow) there isan irregular intraluminalfilling defect. In(b) there is a large intralumzinalfillingdefect in the right coronary artery. Theproximal margin (arrow) shows a straightedge with some injection medium outsidethe lumen. In (c) there is a translucent(arrow) line projecting into the lumen witha small linear intraluminalfilling defect.In all three cases good distalfilling of thevessel was present.

incidence of a totally occlusive thrombus with distalpropagation is low in sudden ischaemic death. Thusthe lesions in the coronary arteries in cases of suddenischaemic death are essentially the same as thosefound in cases of acute infarction but have a lesserdegree of intraluminal thrombus formation.

Events in a dynamic process

Taking these clinical and pathological findingstogether a probable sequence of events can now beproposed. Atheromatous plaques, as seen in arteriesdistended and fixed at physiological pressures, bulgeoutward toward the media26 27 (Fig. 3). In lipid richplaques there is a crescentic mass of cholesterol and itsesters, the lipid pool, separated from the lumen byfibrous tissue. This fibrous cap is often thinnest over

the points of the crescentic shaped plaque. Rupture ofthe fibrous cap (Figs. 4-6) allows dissection into theintima by blood from the lumen into the lipid pool ofthe plaque. A mass of thrombus rich in platelets, butalso containing some red cells and fibrin, forms withinthe intima and leads to considerable expansion of theplaque. Over the site of rupture, thrombus forms inthe lumen but this mass of luminal thrombus initiallydoes not occlude the lumen but waxes and wanes insize over hours or even days. The amount of throm-bus forming within the lumen is not always directlyproportional to the magnitude of the exposure of lipidin the plaque. Some patients (Fig. 7) may have a mas-sive thrombotic response within the lumen with mini-mal fissuring. Ultimately, the intraluminal thrombusmay grow to become totally occlusive or be com-pletely lysed and the plaque fissure reseal, stabilising

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Fig. 3 Transverse histological section ofa coronary artery periused andfixed at100 mm Hg. No significant stensosis is present. The lumen contains angiographic mediumand is round in oudine. The plaque (AP) is a crescentic mass offree lipid in the intima. Thelipid pool is separatedfrom the lumen by afibrous cap which is thinnest over one point ofthecrescent (arrow).

the atheromatous plaque, albeit now considerablylarger than before. By these processes patients withcrescendo angina or those who suffer suddenischaemic death have coronary artery lesions in theearlier stages of plaque fissuring. Patients whodevelop an established regional infarction are those inwhom the thrombus had occluded the lumen at leastfor long enough to induce myocardial necrosis (Figs. 8and 9). Experimental evidence suggests that this mayneed to be only 18 minutes of total occlusion.28The basic arterial pathology of sudden ischaemic

death and acute myocardial infarction is thus identi-cal, only differing in being at different stages of thesame process. The question is now posed as to whysome patients should suddenly die of ventricularfibrillation before the arterial lesion is fully occlusive.Here the pathologist can give no firm answer but onlyhypothesise. In a small proportion of cases dissectionfrom the lumen into the intima raises a tissue flapgiving a degree of mechanical obstruction. In a largerproportion of cases the plaque has been suddenlyincreased in volume by thrombosis within the intimaand in such circumstances the plaque encroaches onthe lumen to the extent of suddenly increasing thedegree of obstruction. When thrombus developswithin the lumen it is a potential source of plateletemboli into small vessels in the myocardium. Some

investigators have reported a high incidence ofplatelet emboli within the myocardium at necropsy incases of sudden ischaemic death.2930 Sudden deathmay thus be the myocardial equivalent of transientcerebral ischaemic attacks due to platelet emboli aris-ing from fissured and ulcerated atheromatous plaquesin the carotid arteries. Finally, tearing of the intimaand consequent deposition of thrombus could invokelocal arterial spasm. An element of spasm in the totalocclusions causing myocardial infarction has beenreported3' but is probably rare.'2 It seems certain thatmany patients do survive plaque fissuring withoutdeveloping any clinical symptoms, and myocardialsusceptibility to ventricular fibrillation must be animportant and additional factor in precipatating sud-den ischaemic death in certain individuals.By this concept of the vascular pathology the three

acute cardiac ischaemic presentations have a commonbasis (Fig. 9). Patients with a plaque fissure but whoescape the three acute clinical expressions will be leftwith atheromatous plaques far larger than previously,and such episodic plaque growth32 is an importantfactor in the developement of stable angina.Previous contradictions explainedIf the proposed mechanisms are true then much in thepast that has apparently been contradictory can be

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y )Fig. 4 Transverse histological section of afissured plaque (AP) (a) with accompanyingdiagram (b). Angiographic medium is present in the lumen (L); despite the vessel havingbeen perfuse-fixed the plaque bulges into the lumen. Afissure extendsfrom the lumen into theplaque, which contains a mixture of angiographic medium and thrombus (7). Nointraluminal thrombus is present at this point. I, intima; M, media.

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Fig. 5 An adjacent distal histological section shows the plaque (AP) is smaller at this pointbut still contains injection media and thrombus (7). Mural thrombus (arrows) is presentprojecting into the lumen and attached at the intima close to thefissure site.

explained. If thrombi evolve and regress over a rela-tively short period of time a pathologist carrying out anecropsy cannot have a precise picture of the state ofthe coronary arteries some days earlier when thepatient first developed chest pain. Those pathologicalseries reporting a high incidence of coronarythrombi33-36 are biased towards patients with largeregional infarcts dying in hospital. It is just such casesthat have major plaque fissures with persistent totalocclusion and inexorable distal propagation of throm-bus. Series that -report a lower incidence of throm-bosis37-40 probably contain a higher proportion ofcases with smaller infarcts or even sudden death, inwhich the associated plaque fissure was less major andintraluminal thrombus smaller. These smallerthrombi may have spontaneously lysed before deathor not been discovered at necropsy.The acute arterial lesions associated with sudden

ischaemic death are smaller than those of regionalinfarction and require more technical expertise fortheir demonstration. As there is usually no infarctrecognisable at this stage the pathologist is notfocused to examine a particular artery. Few of thereported studies of sudden ischaemic death have usedtechniques that would demonstrate the arterialpathology with certainty. Postmortem arteriographyis almost certainly necessary unless the pathologist isunusually meticulous. Larger, more easily detected,

thrombi are likely to be present in patients who havelived longest from the onset of symptoms, and this isthe explanation of the often quoted work of Spain andBradess,4' who found the incidence of coronarythrombi to rise with the time interval between theonset of pain and death. A study of sudden ischaemicdeath in which postmortem angiography was usedfound thrombi in a high proportion of cases with norelation to the time interval.25Once it is accepted that distal propagation of

thrombosis occurs from a proximal nidus the discor-dant reported results of radiolabelled fibrinogenstudies are easily explicable. Erhardt et al gaveradiolabelled fibrinogen to patients with acute infarc-tion as soon as possible after the onset of pain.4243 Inthose who died radiolabel was found at necropsy inthe thrombus. These results led to the hypothesis thatthrombus was secondary to and not the cause ofinfarction. This view was effectively quashed byDavies et al and Fulton and Sumner,2444 who bysimilar techniques showed the head of the thrombusover the plaque to be radionegative, the distal tailonly being positive. This work is entirely in accordwith the current pathological concept being pro-pounded.

Clinical studies of patients resuscitated from appar-ent sudden death show that only a proportiondeveloped acute myocardial infarction,4546 which has

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0Fig. 6 Histological cross section ofa majorplaque rupture (a) and accompanying diagram(b). The plaque (AP) has a large defect in thefibrous cap, through which a dumb bell massof thrombus has formed, part being within the plaque and part virtually occluding thelumen.

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Fig. 7 Minimal plaquefissuring associated with massive intraluminal thromnbus. Theplaque itself(AP) was very small, but injection media (arrow) passed easily into the lipidpool, which also contains thrombus. The lumen is occupied by a large mass ofdark stainingthrombus (7), which is mixed with injection media.

been interpreted as indicating that "sudden ischaemicdeath" is bimodal-a group with coronary thrombosisand a group without. This view is probably an over-simplification, and it is more likely that every indi-vidual had a plaque undergoing fissuring but only asubset developed an intraluminal thrombus whichwas totally occlusive for long enough in time to causeinfarction. In the remainder the intraluminal throm-bus was not of this magnitude and subsequently lysedallowing the plaque to restabilise.

If it is accepted that plaque fissuring is a randomevent in lipid rich plaques there are some clinicalcorollaries. A proportion of patients with infarction orpending sudden death have been unfortunate enoughto develop fissuring in one of the few plaques theypossess. Their prognosis, if they survive, may beexcellent without a further episode for many years. Incontrast a patient with numerous plaques has a higherrisk of repeated episodes.Those plaques which do undergo rupture usually

have a large lipid rich pool. It is often assumed thatthese will cause sufficient stenosis to be recognised atclinical angiography. Study of the relation of the pre-vious degree of stenosis to thrombosis suggests thatthrombosis tends to occur on plaques where thelumen has already been reduced by more than 500/o bydiameter.40 It is, however, very difficult to measureaccurately the previous stenosis caused by a plaque

that has extensively fissured. Data on the degree ofstenosis present in clinical angiograms after treatmentof coronary thrombosis by fibrinolysis do not contri-bute since the plaques in question will have beenenlarged by a sequestered acute intraintimal throm-bus. It is far from clear what effect lysis has, if any, onthis intraintimal component. The residual stenosisdoes, however, decrease over days or weeks suggest-ing that remodelling of the plaque must occur.7Pathological studies of cases of sudden death,25 how-ever, do suggest that fissuring can develop in plaqueswhich are causing less than 50%/o stenosis by diameter.If such individuals develop a minor fissure over whicha large thrombus develops which is subsequentlylysed an angiographic appearance results which maybe interpreted as normal. This process probablyexplains an unknown proportion of patients in whominfarction occurs with apparently normal arteries andis an alternative explanation to spasm as the causativefactor.47-49

Process of plaque fissuringPlaque fissuring is not a recent dicovery; its impor-tance, however, is only now being fully appreciated.Throughout the last 60 years there has been con-siderable interest in the acute changes in plaquesthat initiate thrombosis. In 1926, Benson foundthat thrombi in the coronary arteries arose on

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Healed fissure -buried thrombus,plaque larger

IL

Mural intraluminalthrombus andintraintimal thrombus

t___

Occlusive intraluminalthrombus

Fig. 8 Diagrammatic representation of the evolution ofaplaquefissure either to reseal and stabilise or to progress tothrombotic occlusion.

the intima overlying plaques which had physicallybroken allowing, in his words, "dissecting haemor-rhage from the lumen into the plaque."50 Since thattime many others have confirmed these lesions

Plaque fissure

describing them as tears, breaks, ulcers, or rupturesof atheromatous plaques.51 52 An early study of 32coronary thrombi associated with myocardial infarc-tion showed all to be related to "ulceration" of theplaque.53 There was thus established the view thatcoronary thrombosis followed major physical disrup-tion of the intima exposing lipid to the flowing blood.By disruption was meant gaps many micrometres oreven millimetres in size demonstrable by conventionalmicroscopy.The basic principle was subsequently, and regret-

tably, undermined. Paterson described free red cellsto be present within atheromatous plaques andascribed this "haemorrhage" to bleeding from smallvessels entering the intima from the media.54 55 Pater-son concluded that plaque haemorrhage was commonand usually unassociated with overlying thrombosis.Argument raged over whether bleeding from suchtransmedial vessels could cause plaque growthsufficient to occlude the lumen but, in general, it wasthought that intraluminal pressure would limit thebleeding. To many authorities in the field,56 the workof Constantinides had finally re-established the impor-tance of fissures from the lumen.S7 In 17 thrombicausing acute myocardial infarction reconstructedfrom serial sections cracks or fissures were found and"haemorrhage" in the plaque could be traced to anentry into the plaque from the lumen.57 A view per-sisted, however, in the minds of some that fissureswere "artefacts." This scepticism may be related tothe ascendancy of the postulates of Duguid, whostated that fibrin within a plaque represented earliersurface thrombus incorporated into the intima.58 Thisview of the growth of atheromatous plaques would beseriously weakened if it were to be accepted thatintraplaque thrombus formation occurs via a fissurefrom the surface into the core of the plaque.

- P Reseal -

Sudden deathCrescendo angina

Sudden deathAcute infarction

Intraintimalthrombus

Mural intraluminalthrombus

4tOcclusive luminalthrombus

- 4I Organise -

- 4p Organise -

Recanaliseorganise

Stableangina

Fig. 9 Relation between the clinical expressions of ischaemic heart disease and the stages ofplaquefissuring.

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Plaquegrowth

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Conclusions 8 Serruys PW, Wijns W, van den Brand M, et al. Is transluminalcoronary angioplasty mandatory after successful thrombolysis? BrHeartJ 1983; 50: 257-65.

It can now be appreciated that there are two quite 9 Spann JF, Sherry S, Carabello BA, etal. High-dose briefdifferent processes encompassed by the term "plaque intravenous streptokinase early in acute myocardial infarction.haemorrhage." The fact that the media behind pla- Am HeartJ 1982; 104: 939-45.

becomes intensely vascularised and that these 10 Kasper W, Erbel R, Meinertz T, et al. Intracoronary throm-ques bolysis with an acylated streptokinase-plasminogen activatorvessels enter the intima is beyond dispute.59 60 Bleed- (BRL 26921) in patients with acute myocardial infarction. J Aming from such vessels crossing the media causes a Coll Cardiol 1984; 4: 357-63.limited number of red cells to lie free within the lipid 11 Ganz W, Buchbinder N, Marcus H, et al. Intracoronary throm-pool of many plaques. No fibrin or platelets are pres- bolysis in evolving myocardial infarction. Am HeartJ 1981; 101:POOl ~~~~~~~~~~~~~~~~4-13.ent, and the process is almost ubiquitous in large lipid 12 Mathey DG, Kuck KH, Tilsner V, Krebber HJ, Bleifeld W.rich plaques. The second process is the presence of Nonsurgical coronary artery recanalization after acute transmurallarge numbers of red cells, masses of platelets, and myocardial infarction. Circulation 1981; 63: 489-97.consierablamoutsoffibrn witin th plaqe.1I Reduto A, Smalling RW, Freund GC, Gould KL. Intracoronaryconsiderable amounts of fibrin within the plaque. If infusion of streptokinase in patients with acute myocardial infarc-

serial histological sections are used these elements can tion: effects of reperfusion on left ventricular performance. AmJbe traced to an entry into the lumen via a fissure, Cardiol 1981; 48: 403-9.although this may be closed by a mass of thrombus. 14 Mathey DG, Rodewald G, Rentrop P, et al. Intracoronary strep-The two processes must be clearly separated and the tokinase thrombolytic recanalization and subsequent surgicalbypass of remaining atherosclerotic stenosis in acute myocardialterm intraplaque thrombosis is more applicable to infarction: complementary combined approach effecting reducedthat associated with fissures from the lumen. It is pla- infarct size, preventing reinfarction, and improving left ventricu-que fissuring with related intraintimal thrombosis lar function. Am Heart_ 1981; 102: 1194-201.progehge formation of an intraluminal 1 Meyer J, Merx W, Schmitz H, et al. Percutaneous transluminalcoronary angioplasty immediately after intracoronary streptolysis

thrombus that is the important dynamic process of transmural myocardial infarction. Circulation 1982; 66: 905-13.unifying crescendo angina, acute myocardial infarc- 16 Harrison DG, Ferguson DW, Collins SM, et al. Rethrombosistion, and sudden ischaemic death. after reperfusion with streptokinase: importance of geometry ofItiisnd * . . . residual lesions. Circulation 1984; 69: 991-9.It is difficult to escape the conclusion that the fall- 17 Neill WA, Wharton TP Jr, Fluri-Lundeen J, Cohen IS. Acuteure of pathologists to think in terms of dynamic pro- coronary insufficiency-coronary occlusion after intermittentcesses and to believe what was seen at necropsy was an ischemic attacks. N Engl J Med 1980; 302: 1157-62.immutable reflection of events in life that occurred 18 Vetrovec GW, Cowley MJ, Overton H, Richardson DW.

before has seriously hindered the understandig .Intracoronary thrombus in syndromes of unstable myocardialdays before has seriously ndered the understanding ischemia. Am HeartJ 1981; 102: 1202-8.by clinicians of how atheroma produces acute clinical 19 Vetrovec GW, Leinbach RC, Gold HK, Cowley MJ. Intracoro-symptoms. nary thrombolysis in syndromes of unstable ischemia: angiog-

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