thepathology of myocardial ischaemiaof the left ventricular muscle from epicardium to endocardium....

J. clin. Path., 30, Suppl. (Roy. Coll. Path.), 11, 45-52

The pathology of myocardial ischaemiaM. J. DAVIES

From the Department of Histopathology, St George's Hospital Medical School, Tooting, London

To understand the pathology of myocardialischaemia detailed knowledge of the anatomy andphysiology of the coronary arterial tree is required.The anatomy of the major coronary arteries runningon the epicardial surface of the heart has been com-mon knowledge for years. The equally importantmicro-anatomy of vessels within the myocardiumhas been neglected along with the physiology ofintramyocardial blood flow.

Coronary artery anatomy

The anatomy of the major coronary arteries is sowell known that it does not need lengthy considera-tion apart from emphasizing a few salient points.Each major arterial branch supplies its own segmentof the left ventricular muscle from epicardium toendocardium. There is little functional anastomoticor collateral blood flow between major branches inthe normal heart and thus the coronary vessels areoften referred to as 'end arteries'.The left anterior descending coronary artery

constantly supplies 50-60 per cent of the total leftventricular muscle mass, including the anterior walland the anterior two-thirds of the interventricular(I-V) septum. As a general rule the left circumflexartery supplies the lateral wall and the right coronaryartery the posterior wall of the left ventricle includingthe posterior third of the I-V septum. These twoarteries are, however, inverse in size with a spectrumof which the two extremes are a left circumflexsupplying the lateral and posterior walls of bothventricles and a right coronary artery supplying thewhole posterior wall and the lateral aspect of the leftventricle in addition to the whole right ventricle. Inthe former case (extreme left dominance) the rightcoronary is represented only by the tiny conus arteryto the right ventricular outflow tract and in the latter(extreme right dominance) the left circumflex arteryis absent. Every intermediate variation occurs.Generally the terms right (70 per cent of individuals)or left (30 per cent of individuals) dominance areused to indicate whether the right or left circumflexartery gives rise to the posterior descending coronaryartery. Within each group so defined there is, how-

ever, a wide range ofthe actual mass ofleft ventricularmuscle supplied by a particular artery.While there is no functional communication

between the major epicardial arteries in normalhearts, collateral flow rapidly develops in patho-logical conditions. The usual stimulus for theappearance of collateral vessels is probably a press-ure differential between areas supplied by differentmajor arterial branches (Gensini and Da Costa,1969; Sheldon, 1969). The cause in virtually allinstances is atheroma in one of the arteries inquestion, but some evidence suggests collateral flowalso develops in severe hypertrophy of the leftventricle without arterial disease. Collateral vesselsare recognized with ease in coronary arteriogramstaken in life, or at necropsy, by their characteristiccorkscrew course. This appearance probably resultsfrom an incomplete medial muscle layer in suchvessels. The speed with which collateral vesselsappear makes it certain that they exist as anatomicalstructures in all human hearts, but remain 'unused'unless required. Clinical experience indicates thatthere is considerable individual variation in thedegree to which collateral blood flow develops.The micro-anatomy of the intramyocardial

arteries received little attention until the detailedwork of Farrer-Brown (1968). He has shown that theepicardial arteries send arborizing branches into themyocardium as far as the endocardium with a secondsystem of unbranching straight vessels passingdirectly to the trabeculae carneae and centre of thepapillary muscles (fig 1). A subendocardial plexus ofvessels probably receives flow from both systems, butonly in the ischaemic scarred myocardium serves animportant function in collateral flow.

Physiology of coronary arterial blood flow

The major epicardial arteries fill in ventricularsystole and have a pressure trace similar to that ofthe aortic root; in contrast intramyocardial flowother than the immediate subepicardial zone isentirely diastolic. Flow into the depths of themyocardium is dependent on the pressure gradientbetween the epicardium (X) and the endocardium

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\\\\ Y

Fig. 1 Diagrammatic representation of intramyocardialarterial supply. X represents the epicardial surface, Y theendocardial. The papillary muscle receives its own supplywithout branches to the remainder of the myocardium.

120 -

y

,'j.1t' AORTICp

LVpo

I

Fig. 2 Comparison of aortic root pressure (p) which isvirtually identical to pressure in the epicardial arteriesand LV cavity pressure (L Vp). Intramyocardial flow onlyoccurs in diastole and is proportional to the shaded areabetween X and Y.

Fig. 3 Venn diagram of the clinical features of ischaemicheart disease (after Rose, 1972).

(Y) in figure 1. Consideration of the aortic rootpressure trace represented by X and the left ventri-cular cavity pressure trace represented by Y showsthat only in diastole can such a gradient exist (fig 2).Coronary flow is proportional to the shaded areabetween the two pressure traces in diastole asillustrated in figure 2. This area can be easilyreduced by many factors (Hoffman and Buckberg,1975), the most important of which are rapid heartrate shortening diastole, lowered aortic systolicpressure, or elevated diastolic pressure in the leftventricle. The micro-anatomy and physiology ofintramyocardial blood flow are such that all factorsreducing overall coronary perfusion will, particularlyif the small intramyocardial vessels are at maximumvasodilatation, have a maximal effect on the sub-endocardial zone, including the centre of the papil-lary muscles. The vulnerability of the subendocardialzone is exemplified by the occurrence of transientsubendocardial ischaemia, demonstrable on ECG,with maximum exercise even in young, fit athletes(Barnard et al, 1973).

Clinical expression of myocardial ischaemia

Three major symptom complexes occur in myo-cardial ischaemia: angina, myocardial infarction andsudden death. The three overlap to a considerabledegree (fig 3) (Rose, 1972), but the pathology can beconsidered separately with profit.

ANGINAIn general the patient with stable angina has a wellpreserved and even morphologically normal leftventricular muscle but with significant coronaryartery disease in the form of one or more areas ofsevere stenosis (Roberts, 1976). Angina resultsfrom a temporary failure of an adequate bloodsupply being provided to one area of the myocardiumfor a work load increased by exercise. Occasionallyangina may be precipitated by rate or rhythm changeor emotion. When the work load is reduced below acritical level, blood supply is again adequate and painvanishes within a few minutes. The work load atwhich any individual with stable angina developspain is remarkably constant after correction forvariation in heart rates (Robinson, 1967). While itcan be demonstrated that the great majority ofpatients with stable angina have significant coronaryatherosclerosis, the exact pathophysiology within thearterial tree is obscure. The critical degree ofstenosis at one point necessary to produce angina isuncertain. Experiments in vitro of flow in isolatedarteries suggest that only severe stenosis withreduction of the lumen of 80 per cent or moresignificantly reduces flow (May et al, 1963). Clinical

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experience suggests that multiple areas of stenosis inseries may be as significant as a single area of greaterstenosis. Abnormal flow patterns are thought to beimportant in the pathogenesis of the pain. Where aseries of branches open between areas of stenosiswhich fix flow at a low level, exercise may so increaseblood flow in the proximal branches that pressurefalls to a level at which no flow occurs in the distalbranches (Soloff, 1972). Clinical study of patientswith angina by coronary arteriography, as well aspostmortem studies, allow grading of cases of anginainto those with single, double or triple major vesselstenosis. The majority of patients with angina havesevere stenosis in more than one major vessel (Zollet al, 1951; Roberts, 1976) and histological exami-nation frequently indicates that such areas were oncetotal occlusions in which recanalization has occurred.While the great majority of patients with angina

can be subsequently proven to have coronary arterydisease, a small minority do not. Such patients usuallyhave abnormal left ventricular function with, mostcommonly, severe myocardial hypertrophy (Vlodaveret al, 1972). In aortic stenosis perfusion pressure inthe major epicardial arteries is reduced at the sametime as left ventricular wall thickness is increased andend diastolic cavity pressure raised. Angina is a

A

TRANSMURAL *NREGIONAL INFARCT ZONAL INFARCTISEGMENTAL SUEDCR A

common presenting symptom indicating subendo-cardial ischaemia. Hypertension may be associatedwith angina, provoked by the same mechanism.Aortic regurgitation, mitral regurgitation andcongestive cardiomyopathy all reduce overallcoronary perfusion and occasionally may beassociated with angina. Angina is a common pre-senting symptom of hypertrophic obstructivecardiomyopathy (Frank and Braunwald, 1968). Afterelimination of those cases ofangina due to coronaryartery disease and abnormal ventricular haemo-dynamics, a tiny but identifiable group remainswhere no cause is ever shown. Current hypothesesfor this fascinating tiny group of patients includesome abnormality of oxygen transport at cell leveland the usual risk factors for coronary artery diseaseare strikingly absent (Herman, 1971).

MYOCARDIAL INFARCTIONThe occurrence of myocardial necrosis is usuallytaken to indicate total deprivation of blood supplyto an area ofcardiac muscle for an appreciable periodof time. The period need be as little as seven to 10minutes as judged by experimental work in animals.While at first sight the pathology in man is straight-forward, considerable controversy exists over some

B

)IFFUSE SUBENDOCARD IALECROS IS

AMNAR INFARCTIRCUNFERENTIAL INAC

I

Fig. 4 Diagrammatic representation of the variousforms of myocardial necrosis. Type A are segmental orregional infarcts and type B diffuse subendocardialnecrosis or circumferential infarcts.

"MIXED" INFARCTION

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Fig. 5 Fresh myocardial slices stainedby Nitro BT method with addedsucecinate substrate. Myocardial necrosisremains unstained. Normalmyocardium is dark blue.

a Small antero-lateral regional orsegmental infarct (arrows) involving fullthickness (transmural) of left ventricle.Occlusion due to recent thrombus ofleft circumflex artery.b Large postero-septal regional

transmural infarct involving wholeinterventricular septum. Recent occlusionof main right coronary artery and oldocclusion left anterior descendingartery.

Fig 5b

aspects. Much of the difficulty arises from failure toappreciate that several patterns of myocardialnecrosis occur in man whose causes at a patho-physiological level are very different and the ter-minology used is very confused. The demonstrationof the shape and topography of areas of necrosis isbest made by the various modifications of the NitroBT staining method, using fresh slices of myo-

cardium (Nachlas and Shnitka, 1963). By thistechnique normal muscle stains dark blue; the areasof necrosis remain pale. The method reflects loss ofsubstrate and enzyme activity in the dead muscle.Two basic macroscopic patterns of myocardial

necrosis can be recognized. A single segment orquadrant or region of the ventricular circumferencemay be involved, that is anterior, lateral, posterior or

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Fig. 6 Diffuse subendocardialnecrosis (laminar infarction)involving the whole circumferenceof the left ventricle and also areasof the right ventricle. Death 48hours after left ventricular bypassand aortic valve replacement(Nitro BT with substrate).

septal (fig 4A). Such necrosis may be full thickness,ie, transmural (fig 5), or involve only the sub-endocardial zone. A quite distinct second basic formof necrosis (fig 4B) involves the whole circum-ference of the subendocardial zone, scattered foci upto 1 2 cm in diameter and the centres of the papillarymuscles (figs 4, 6). This type is probably best knownas diffuse subendocardial necrosis but is also re-ferred to as laminar or circumferential infarction.Combinations of transmural regional infarction withdiffuse subendocardial necrosis are, however, nowbecoming more common (fig 4), confusing the dis-tinction even further.The terminology is confusing and has created

confusion. Current practice at St George's Hospitalis to draw the infarct on sketches of the heart, ratherthan to indulge in confusing semantics in the necropsyreport.The pathophysiology of the two basic types, ie,

transmural regional and diffuse subendocardialnecrosis, is quite different. The former results fromsevere reduction and most often total cessation ofblood flow in one major epicardial artery, the latterfrom an overall fall in coronary perfusion withabnormality in distribution of blood within themyocardium.

Regional or segmental infarction

This is the type most frequently seen in the necropsyroom and is the classic myocardial infarct for whichECG criteria are well defined and accurate localiza-tion to the segment of ventricle involved is possibleby the clinician even before necropsy. While there isgeneral agreement that the epicardial artery supply-ing that area of myocardium is severely affected by

atheroma, the details are highly controversial. Someauthorities, particularly in the United States andItaly, consider severe stenosis alone may precipitateinfarction (Roberts and Buja, 1972; Baroldi, 1965);others consider total occlusion by a mixture ofthrombus and atheromatous debris is the precipita-ting event, a view most widely held in Britain (Davieset al, 1976), but also by some workers in the UnitedStates (Chapman, 1974). A further extension of thefirst view is to regard coronary thrombi, whenpresent, as secondary and merely a consequence ofstasis following infarction (Roberts, 1974).

Opinion over the presence or absence of occlusivethrombi in acute regional infarction has undergone aseries of extreme swings during this century. Thevariation is so great that it cannot be explained byother than differences in definition, selection orinterpretation and not in actual pathology. The twoextremes (Burchell, 1974) are represented by anincidence of occlusive thrombi in the regional arteryof less than 50 per cent to virtually 100 per cent(Chandler, 1974).

Personally, I have always found occlusive thrombito be present in genuine regional infarcts (Davies etal, 1976). Reasons for lower figures for occlusivethrombi may lie in poor dissecting technique,inclusion of all forms of myocardial necrosis, bothregional and laminar, inclusion of sudden deathswithout acute infarction being present and simply adifferent philosophy on the part of the prosector. Thecontroversy, however, is futile; no one would dis-agree that acute regional infarction results from afailure of regional blood flow in one main coronaryartery branch whatever the mechanism. Even thosewho deny the role of occlusive thrombi admit thatincorporation of mural thrombus is largely respon-

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sible for areas of stenosis increasing to a point atwhich flow almost ceases (Roberts, 1973).The regional or segmental subendocardial infarc-

tion may be considered as a variant in which the sub-endocardial zone, always most vulnerable, has under-gone necrosis with collaterals just enabling sub-epicardial flow to be maintained. This type of infarctis uncommonly seen in the necropsy room andadequate pathological study is difficult. The lesion iscertainly more commonly diagnosed in life by ECGcriteria than it is seen in cases in the necropsy room.The infinite variation in sizc and site of a trans-

mural infarct is explicable by different sites ofarterial occlusion, anatomical variations of the majorarteries and by different degrees of collateral develop-ment. The preponderance of infarcts involving theanterior-septal segment is associated with the highincidence of disease in the left anterior descendingartery and its relative importance in supplying up to60 per cent of the ventricle. Posterior and lateralinfarcts follow anterior lesions in the approximateratio of 8.5.1 (Davies et al, 1976).

Diffuse subendocardial necrosis

This type of myocardial necrosis in the pure form isless commonly seen. Clear recognition that thepathophysiology was a failure of overall coronaryflow to a level at which the subendocardial zone wasnot perfused came from open heart surgery. Inpatients placed on left heart bypass, a characteristicsequence of a stormy postoperative period culmina-ting in death from left ventricular failure with diffusesubendocardial necrosis seen at necropsy wasrecognized. The major coronary arteries wereanatomically normal and relatively disease free, butcommon clinical features were impaired ventricularperformance before operation, lengthy periods onbypass, severe ventricular hypertrophy and pro-longed ventricular fibrillation during the operation(Najafi et al, 1969; Buckberg et al, 1972). Subsequentimprovement of technique to maintain coronary

1 AnatomicalDiffuse coronary atherosclerosis Triple vessel disease

Peripheral extension atheromato small vessels

2 PathophysiologicalFall diastolic aortic root pressure Aortic valve disease, shockRise LV end diastolic pressure LV failure, mitral

regurgitationShort diastole Rapid rate

3 Altered left ventricular shapeThick LV wallDilated LV cavity

Table Factors associated with an overall fall inmyocardial perfusion maximal in subendocardial zone

Fig. 7 Aortic stenosis with sudden death. No significantcoronary artery disease. Muscle necrosis involves theinner layer of the left ventricle and particularly thecentres ofpapillary muscles and trabeculae (Nitro BTwith substrate).

perfusion during arrest at operation has greatlyreduced the complication, but Hoffman andBuckberg (1975) were stimulated to define clearly thefactors which influence subendocardial perfusion.Some factors which reduce subendocardial perfusioneven with anatomically normal epicardial vessels arelisted in table. Severe triple vessel stenosis reducingoverall perfusion in the epicardial arteries is often animportant potentiating factor or may be a primarycause of diffuse subendocardial necrosis in its ownright (Davies et al, 1976). Patients with longstandingangina toward the end of the clinical course maydevelop steadily increasing pain which is associatedwith diffuse subendocardial necrosis at necropsy.Mitral regurgitation often develops in this terminalphase from papillary muscle damage and a viciouscircle of a dilating left ventricle with more musclenecrosis occurs. The actual event starting this cycle,however, is difficult to pinpoint.The most frequent valve lesion associated with

diffuse subendocardial necrosis is severe aorticstenosis where left ventricular failure has occurred.In this situation, aortic root pressure falls to very lowlevels associated with very high end-diastolic pres-sure within the left ventricle. At the same time themyocardial wall thickness is increased and developedtension in the endocardial zone much increased.These factors all make it seem certain that at timessubendocardial flow can cease in severe aortic stenosis

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The pathology of myocardial ischaemia 51

I~~~~~~~~~~~~~~~~~~~~~~~~~~~~.....

Fig. 8 Male with many years ofangina and hypertension. Terminal14 days severe left ventricularfailure. Triple vessel coronaryatherosclerosis. Two episodesof different age segmentalinfarction on posterior-lateralwall (A and B). Widespreadsubendocardial andfocal I cmareas ofnecrosis in remainderof left ventricle.

(fig 7). The clinical effects include a high incidence ofsudden death, progressive left ventricular failure andmitral incompetence developing as a consequence ofpapillary muscle necrosis. End-stage aortic stenosisis often associated with considerable degrees of sub-endocardial fibrosis (Moller et al, 1966).

Mixed infarction patterns

Increasing numbers of patients managed in intensivecare units have meant longer survival of patients withregional infarcts large enough to diminish seriouslyleft ventricular performance and produce the clinicalsyndrome of shock. In such cases a combination oftransmural regional infarction with superimposeddiffuse subendocardial necrosis may occur (fig 8).This pattern is in fact the most common form ofdiffuse subendocardial necrosis encountered by thehospital pathologist in routine practice. Factorstending to promote the superimposition of diffusesubendocardial necrosis or regional infarctioninclude severe left ventricular failure, shock, severestenosis in all three vessels, coexistent mitralregurgitation, peripheral extension of atheroma intosmall arteries as in diabetes or myxoedema, previousold infarcts and left ventricular hypertrophy.

Sudden death

It is indisputable that patients suffering from anginawith or without a history of previous infarction andpatients without previous overt clinical symptomscan die suddenly of ischaemic heart disease (Myersand Dewar, 1975); the number who do so is verylarge (Paul, 1974). It is therefore surprising (Camps,1969) that neither the exact pathology nor the patho-physiology of the terminal event is known.

A proportion of cases are patients in whom anacute transmural regional infarct would havedeveloped had they survived longer; death hasoccurred in the first 12 hours before it is easy todemonstrate the area of infarction. The coronaryartery pathology is identical with that in acuteregional infarction in that occlusive thrombi arefound in a major epicardial artery. Opinions of theincidence of such thrombi in sudden death rangefrom 20 per cent to 90 per cent but agreement on 50-60 per cent would be accepted by many people work-ing in the field; few would deny that a significantproportion of cases do not have histological evidenceof any recent acute event in the coronary arteries(Friedman et al, 1973; Liberthson et al, 1974).Death must be presumed to be due to an electro-

physiological aberration and some evidence existsfor ventricular electrical instability in patients withcoronary artery stenosis (Chiang et al, 1969; Lownand Wolf, 1971; British Medical Journal, 1973). Ifthis view of the event is accepted, the question arisesas to how much coronary artery stenosis must bepresent for sudden death to occur. No answer to thisquestion is available, but most cases do have double-or triple-vessel disease in a degree equivalent topatients with angina. A minority have only single-vessel disease and inevitably the suspicion mustarise in such cases that death was due to a causeother than coronary artery disease. It is an astonish-ing fact that we do not as yet know the minimaldegree of coronary artery stenosis which can beassociated with sudden death.ReferencesBarnard, R. J., MacAlpin, R., Kattus, A. A., and Buckberg,

G. D. (1973). Ischemic response to sudden strenuousexercise in healthy men. Circulation, 48, 936-942.



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