·BAIE
Sanal sect 1 f artery sta ned by Sheridans El stic
(left) and PTAI as seen by Compar tot m croscop
pparatu (See Fe 4)
Pro by jll Ha ell

·THE PATHOGENESIS OF
CORONARY OCCLUSION
AD MORGAN
MA MD
Head of Morbid Anatomy Department and
Readis 11 Pathology Il estwnster Aldical School London
Consultant Pathologist Il estninstur Hospital
With a Foreword by
JOHN B DUGUID
MD
Professor of Pathology Undersity of Durhamn
BLACKWELL
SCIENTIFIC PUBLICATIONS
OXFORD

·This book is copyright It may not be reprod all y a ly means 311 11 ole or in part uithout pcrmission Applicato uick reg rd to copyrights be attressed to the p bl siers Published si laneously in the Un ted States of Ai en aby Charles Thomas Publish : 301 327 Eest la rence Avene Spr is field Illinois Published si altaneously in Canada by The Ryerso Press Quicen Street Il est Toronto PRINTED 1956 PRINTED IY GREAT BRITAIN IN THE CITY OF OXFORD AT THC ALDEN PRESS 4WD ROLD BY THE KFVP HILL BINDERY OTFORD ·FOREWORD to the A QUESTION which used to puzzle me m artenal pathology was how diseased arteries became narroned Arteries are elastic tubes carrying a hugh internal pressure whuch is constantly pulsating and we would expect them to gue way and dilate when diseased but in atherosclerosis and certain other lesions we sometimes find them narrowed almost point of occlusion This was not a problem wluch seemed to exercise other pathologists to any great extent since most of them accepted the orthodox teaching that narrowing was due to encroachnicnt on the lumen of the artery either by degenerative swellisigs or by overgrow ths of the numal connective tissue as the histological picture seemed to show Nevertheless when arterial function was considered it was difficult to take the picture quite at its face value It did not seem likely thar a degeneration or growth of young connective tissue could overcome the force of the blood pressure and actually close the arteries against it and so there remamed the suspicion that some other process was involved A possible solution suggested itself some ycars ago in the course of a demonstration of the principles of organization and canalization of artenal thrombs In this one saw how a thrombus could reduce the lumen of an artery and of organized look for all the world like an atherosclerond thickenmg Thus was born che thrombosis hypothesis and from its birth to its histological confirmaron was an unexpectedly short seep The first few examples of severe coronary discase when exammed with the hypothesis su nund scerned entirely to confirm t Mortover from a study of these and other arterial lesions in which starrowing was a feature 2 new principle seesned to emerge to the effect that when solid matter is deposited in the lumen of an artery it becomes covered with endodicium so that it is incorporated in the intima and forins a thickening of the vessel wall This principle has now been confirmed in one way or another by a number of observers but it has been left to Dr Morgan to undertake a criacal and sndependent examination of it from the pound of view of coronary discase In the following monograph he has prosided a comprchensive and I think is many ways decisive study on the subject of thrombosis he has put into words many of the views I myself would like to have stared and he has brought out other features – for example the relationship of incimal haemorrhage to farry change - which are sometimes forgotten when etiology is considered Above all he has given a glimpse of what can still be done in the field of human morbid histology how old problems when examined from a fresh vicu point can yield information which is both new and revolutsonary Coronary atherosclerosis we may be sure is not the only such problem calling for histological scassessment and it is to be hoped that others will follow Dr Morgan s example 1 personally am much indebted to hem Newcastk upon Tyk Auguse 1956 JOUN B DUGUID ·То нпү wife ·PREFACE Tuis book is bascd on naterial used for an MD thesis submitted to the University of Aberdeen in 1955 the main burden of which was to offer corroborative cvidence for Professor Dugud s thrombogenic theory of coronary occlusion It is theretorc neither a primer nor a manual and the sole reason for its presentation in book form is that condensation to a length appropriate to medical journals would reduce the argument to a series of dogmatic statements unsupported by cvidence Tlus evidence is contained in the second half of the book and is largely expressed in ternis of morbid histology as detailed and as fully illustrated as modern taste permits since it is this aspect of the pathogenesis of coroniry disease that has been (and still is) most keenly debated The earlier chapters are devoted to the relevant literature and are intended to provide not merely a histoncal background to the present status but an abbrevlated review of the literature of recent advances in other aspects of the pathogenesis of the discase It is a plcasure to express my indebtedness to the following the Governors of Westmonster Hospital for defraying cxpenditure on materials and technical assistance Professor R J V Pulverraft for his exhortations Mr H N Stafford lately HM Coroner for the Western District of London for kindly affording nic access to Police records of the circumstances in which several cases of sudden death were taken ill to the Public Relations Department of British Railways and London Transport for statistical information to Dr Peter Hansell and the staff of the Department of Medical Photography Westminster Hospital for assistance with the illustrations to Mr M Cuthbert for painstaking work with the histology and to Miss D Beasleigh for secretarial help ADM

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·CONTENTS PAGE بع S IO 13 19 0 PART ONE A HISTORICAL REVIEW I TIIE RISING INCIDENCE OF CORONARY DISEASE II EARLY OBSERVATIONS ON CORONARY SCLEROSIS III THE GERMAN SCHOOL OF THE NINETEENTH CENTURY IV EXPERIMENTAL ATHEROSCLEROSIS FATTY STREAKING AND ATHEROSCLEROSIS VI ATHEROSCLEROSIS AND CORONARY THROMBOSIS VII THE MORPHOLOGY OF CORONARY OCCLUSION VITI THE COLLATERAL CIRCULATION OF THE HEART IX THE INFLUENCE OF AGE AND STRESS х CARDIAC HYPERTROPHY ELECTROCARDIOGRAPHY XI DUGUIDS THROMBOGENIC IIYPOTHESIS XII TIIE BIOCHEMICAL APPROACHI XIII THE DIET AND ATIIEROSCLEROSIS XIV INIIIBITORY FACTORS XV CONTRIBUTORY FACTORS XVI THE STATISTICAL APPROACHI XVII LOCAL PREDISPOSING FACTORS 22 6 8 30 31 33 38 41 44 46 49 PART TWO A STUDY OF THE MORPHOLOGY OF CORONARY OCCLUSION XVIII METHODS AND MATERIALS SS XIX PATHOLOGICAL CHANGES IN THE ADVENTITIA AND MEDIA 60 XX TIJE EPISODIC NATURE OF INTLMAL DEPOSITS 67 XXI TIIE ROLE OF INTIMAL VASCULARIZATION AND HAEMORRHAGE 77 XXII THE NATURE OF ARTERIAL TIIROMBOSIS 91 XXIII FIBRIN IN ATHEROSCLEROTIC PLAQUES 10S XXIV DEGENERATION IN THE PLAQUE 109 XXV TIIC RELATION OF CORONARY OCCLUSION TO MYOCARDIAL INFARCTION 123 XXVI TIIE CORONARY ARTERIES AND THE REST OF THE CARDIOVASCULAR SYSTEM XXVII CORRELATIONS 141 XXVIII TIIE KIDNEYS IN CORONARY SCLEROSIS 143 XXIX CARDIAC WEIGHT IN CORONARY SCLEROSIS XXX REVALUATIONS 149 XXXI CONCLUSIONS IST APPENDIX 156 BIBLIOGRAPHY IS7 AUTHOR INDEX 165 SUBJECT INDEX 168 128 147

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·menant The Rising Incidence of Coronary Disease The annual number of deaths due to coronary onclusion shows no sign of decreasing Between the years 1949-52 the Registrar-General s figures for fatal cases of coronary occlu son reveal that the total is rising sharply as compared say with all forms of malignant disease at all agcs TABLE A Co orary Ds se ! ID 14 Female Wale Fale 1942 196 29 30 38 907 17 2332 42100 45 49 4nos 4 13 in the course of four years deaths from coronary occlusion have increased by 30 procent as compared with 5-0 per cent in cases of malignanc disease Even allowing for the increase of population or the greater expectation of life during tho e years they do not adequately account for the increased frequency in diagnosis of a condition that has been recognized by the medical profession for over 2 century and has been widely and energetically scudid during the last 25 years Confirmaron by autopsy was doubtless lacking in a substantial proportion, and the Coroner s pathologist may consider that a number of the sudden deaths diagnosed by the practitioner on clinical grounds alone may have been examples of rupture of the aorta high dissecting aneurysm aorac incompetence spontancous pulmonary embolism of heast block but when allowance has been made for these relatively uncommon conditions It is still clear that the figures given above reflect fairly accurately the depressing frequency of coronary disease Tht pathologist is lable to see more of coronary disease than his clinical colleagues especially in individuals who die suddenly during their first serious attack Thus at Westmunster Hospital during a 20-year period (1934-53) 377 autopsies were pertormed on ca es dyng of coronary occlusion of these st were sudden deaths -- 1e in persons gong about their daily duties or walking in the strect who were suddenly taken all and died at once or in the course of a few minutes The great majority of these died before they reached hospital the remander in the Casualcy Department One hundred and twenty- ix y crc patients admitted to hospital with a previous history of coronary insufficiency o a known myocardial infarction or who had survived their first atrach long cnough to be diagnosed, Clinically or by electrocardiogram Three hundred and thurscen + TIC Reg a Geral Santos Reiw (Dgland and lite feat 1933 Table 7 fnternat onali nos 140-as do It wonery Off Londo 1954 3 ·THE PATHOGENESIS OF CORONARY OCCLUSION were males 64 females 71 per cent of the males were brought in dead as against 44 per cent of the females At the beginning of this 20-year period deaths from coronary discase constituted 1 3 per cent of the total number of autopsies performed this figure steadily increased to 77 per cent in 1953 The greater frequency of sudden death in malos may in part be due to the geographical situation of Westminster Hospital in the heart of a metropolis where stress and strain are the rule and within a short distance of Victoria Station through which more than 150 000 people of all ages pass daily As will be shown later however there are indications that there is little relationship between heart attacks and the act of running to catch a bus or train In fact the frequency and the sex incidence may derive from an itinerant and predonnantly masculine mulatude equivalent to the population of a large town being concentrated in and around Victoria twice daily In view of the figures quoted it is remarkable that although the nature of atherosclerosts to which 95 per cent of the cases of coronary occlusion are still attributed (Il'artman and Hellerstem 1948) has been debated for upwards of a hundred years opinion is still sharply divided as to the origin of this highly lethal disease The role of cholesterol metabolism was long regarded as fundamental in the cvolution of atherosclerosis but in 1946 Dugid revived the teaching of Rolitansky by suggesting that the apparently atherosclerotic obstruction of coronary vessels could be more satisfactorily explained by interpreting the appearances as the late result of mural thrombosis The point is t is of considerable importance since adoption of the thrombogenic theory must inevitably modify the present approach to actiology and treatment To set the argument in its context however it is necessary to dip into the literature of the Before doing so a word on the terminology adopted will be appropriate The concept of atheronia as a purely intimal lesion in the form of raised discrete plaques is valid when applıcd to a large vessel like the aorta In the coronary arteries the degree of thickening of the vessel wall is often severe enough to convert whole lengths of it into a rigid tube with calcified walls and an atrophic or partially absent media It is still arguable whether such a change is the result of lipid deposits or organized thrombosis and the term atherosclerosis 15 employed here to designate a hardening or thickening of the vessel wall in which the fibrous and lipid elements of atheronia are recognizable This is the sense in which Afarchand introduced the term in 1904 To avoid circumlocution the unsuitabic but convenient expression atherontatous abscess has been retained to designate a focus of fatty softening in an atherosclerotic plaque It is at least sanctioned by usage whereas more rational terms - eg atherocheuma (Leary 1936a) – have not been widely adopted past ·Eurly Observations on Coronyry Sclerosis CONSIDERING the un crsal and lethal nature of coronary occlusion its recognition by the medical world and the clucidation of its actiology have been surprisingly tardy Thus Harley (1649) despite the brilliance of his observations on the circulation of the blood failed to comprehend the nature of Sir Robert Darcy s chest pains and atenbuted the rupture of hus left ventricle (alınost certainly the result of myomalacia cordes) to ʻan impeds. ment to the pa sage of blood from the left ventrick into the arterics In a valuable and scholarly revies of the early literature of angina pectoris Huchard (1889) quotes illustrious sufferers such as Seneca and Louis XIV in whom however the evidence is wholly symptomatic This same author credits Drelincourt (1700) with the first observations on che pathology of coronary sclerosis Thrce years later che Italıın anatomist Bull and the German Thebesmis independently recordad observations on calcification of the coronary artenes Thus, Bellin Vidinas nos lapidem aduarunt ramis coronarus majoribus qua de virum a sumisiro ventriculo dirammut (We observed a stone next to the main coronary branches which separate the right from the lefc venta.cle) and Thebesius Ita Lipak videre contigu ramos majors arteriaruit corde humano per com cram superficiem ad 1 pidum decrescentes Inc illic et parte osseus redduos et ex parte tantum membranaceos suisse (Thus at Leipzig one happened to see the main arterial branches to the human heart running over its surtalc towards the apex rendered bony in pare here and there and in part menbranous) Early con ments on the relation of coronary sclerosis to cardiac symptoms were made by Sinac (1749) and Aforgagui (1761) The former who was the consultant physician to Louis XV performed an autopsy on a certain triar who was subject to palpitations Les arteris coronaires etoient ossifices elles formosenst des samcam semblables a des branches de corail More detailed and certainly more celebrated is the extract from the De Sedibras of Morgagni in which he records che clinical history of a Venetian woman who had a history typical of angina pectoris and died in 1707 at the age of 42 A concitatis corporis motibus ingruedat mole eres quedar ang or intra superiorum thoracis sinistram partur cum sperandı difficultate ct sinistra brothm stupore quae omisia esix motus ille cessarent facile reminebant (A certain unpleasant pain in the left upper part of the chest accompanied by difficulty in breathing and numbness in the left arm became worse on violent bodily movements all of which readily subsided when these moviments ceased) An autops, was performed Universim 171107111 nisjort sigest ramos apercitus illoque ab ipsa ongine pone samaderares i alt ulas qilde durae hic illis erant ct an fitun Ossis titus ad iliacas risquit affitias descripre i stia auntadı ertimus (We opened the whole 1r ·THE PATHOGENESIS OF CORONARY OCCLUSION (aortic) trunk and its main branches and in that branch at its very ongin behind the semilunar valses which were hardened here and there with early bone formation we observed the lesions described right up to the illac arterics) The term Angina pectoris was suggested by Helerden who described the symptoms in 1768 in a paper read to the College of Physicians He was uncertain whether the inalady was scated in the sternum or more deeply and lamented the fact that the sudden death of hus patients prevented hus attending an autopsy on any of them In 1778 however Jenner wrote a letter to Heberden on the subject of their common friend John Hunter who had been having anginal attacks for several months Jenner offered his views on the pathology of the condition based on two recent autopsies In the first of these I found no material discase of the heart cxcept that the coronary artery appeared thickened As no notice had been taken of such a circumstance by anybody who had written on the subject I concluded that we must still seek for other causes as productive of the disease but about three weeks ago we found the same appearance of the coronary arteries as in the former case But what I had taken to be an ossification of the vessel itself Mr P* discovered to be a kind of firm fleshy tube formed within the vessel with a considerablc quantity of ossific matter deposited irregularly through it Jenner considered it possible that all the symptonis might anse from this one circumstance and concluded by asking Heberden s advice as to whether he should communicate che idea to Hunter in view of the latter s condition This historic letter was never posted and was found later among Jenner s papers He did however record his views in a second letter to Parry who reproduced it verbatim years later (1799) In this Jenner rccalled that he saw lus first fatal case of angina pectoris when he was 23 Thc autopsy was performed by Hunter in 1772 and subsequently published by Heberden but on that occasion wrote Jenner the coronary arteries were not examined The letter goes on to describe the two autopsies referred to above the writer adding that on the second occasion he had taken a wager with his collcagues that he would find the coronary artenes discascd Jenner is thus the first British pathologist to have understood the relation between coronary sclerosis and angina pectoris He deferred publishing his conclusions out of consideration for his mentor John Hunter and those colleagues to whom he privately comniunicated hus beliefs rejected them After Hunter s death in 1793 however Jenner had the satisfaction of receiving a letter from Home who had assisted at Hunter s autopsy freely admitting that the coronary arteries were considerably ossified and concluding with the remark this case is very much in favour of your theory Some years after Heberden s account of Angina Pectons Fotlurgill (1776) published full details of two fatal cases with autopsy reports In the first of these thc heart revcaled a small cicatrı near the apex but there is no mention of the coronary arteries The second autops was performed on March 14th 1778 by John Hunter who wrote 'The two coronary arteries from their ongin to many of their ramifications upon the heart were become one piece of bone Howeser he made no comment on this finding in relation to the simptomis nor did Fothergill in the discussion that followed and there is no written V Parthorus

·EARLY OBSERVATIONS ON CORONARY SCLEROSIS
EDWARD JANNER (1749-1823)
Mezzot :t by John Raphael Smith (1752 1812) From an impres on the Wellcome
He to cal Medical Muse m
7

·THE PATHOGENESIS OF CORONARY OCCLUSION
1
ht
GEPLA
CARL VON ROKITANSKY (1804 78)
From the Lthograph in the Wellcome Historical Med cal Museum

·EARLY OBSERVATIONS ON CORONARY SCLEROSIS evidence that Hunter over surmised the nature of the pathology of the disease that was to kill him although he did describe in some detail his symptoms to his son-in-law Everard Home (Home 1794) After his death however some misunderstanding arose on this score and in 1815 Hodgson wrote that Mt Hunter and subsequently* Di Jenner and Parry ascribed the symptoms of angina pectors to the deposition of calcarcous matter in the coronary arteries of the heart whereby the stream of blood destined for that organ is so much diminished that its substance degenerates and wastes its muscular power is lessened and ultimately is insufficient for the purposes of the circulation But if Hunter ever did suggest such a theory by word of mouth it is odd that Alatthew Baille his nephew and pupil should make no mention of it in the second edition of his Aforbud Anatomy published four years after his uncle s death yet in the third edition of 1807 he added a scction on the relation of coronary ossification to angina pectoris referring the reader in a footnote to Jenner s letter to Parry published 8 years earlier Hodgson goes on to observe that coronary sclerosis is not present in cvery case of angina which may also occur with cardiac or aortic aneurysm He has this to say on the actiology of atherosclerosis in general Thc frcquency of the deposition of calcarcous matter in the arteries of subjects advanced in life has been a cause of much speculation and some have conceived that in such instances it ought not to be regarded as a disease but as the natural effect of protracted existence Were this however the case we should expect that its extent would be proportionate to the age of the subject which is by no means the fact for in the few recorded instances of longevity which have been accurately examined this condition of the blood-vessels was not very remarkable In a footnote he adds On the other hand calcareous matter is sometimes deposited in the artçnics of very young subjects * My Italics 9 ·III The German School of the Nineteenth Century by the In the hundred years that followed the pathogenesis of coronary sclerosis was only one facet of the wider problem of atherosclerosis as the medical horizon came to be dominated great Curman school of morbid histology In view of recent publications the opinions of its founder Rolitansky arc of particular interest today in his Hamal of Pathological Anatomy (1841-46) he says of atherosclerosis It consists in an excessive formation and deposition of the lining membrine of the artery derived from the mass of the blood and at the same time constitutes hypertrophy of thus membranc A fairly accurate account of the gross pathology follows including obscrvations on its frequency at bifurcations or around the mouths of branch arteries There is a comment on the increased vascularity of the adventitia but as the scries may have included syphilıcıc arteries this observation is of dubious value In considering the actiology he notes the imporcance of age dismisses inflammation and regids the adventitial reactions as secondary phenomena The deposit he states flatly is an endogenous product derived from the blood and for the most part from the fibrin of the arterial blood The underlying cause of the fibrinous deposit hc regards as a particular type of blood-crasis The deposition continuously increases in thickness by addition of new scrata he continues Vascularization of the plaquc from the lumen was known to him for he describes a system of fine canals in aortic plaques which conscy blood from the lumen to the interior of the plaque but do not appear to link up with the adventitial vessels These canals are undoubtedly the result of partial resorption in the deposit the same process which we have noticed in a fibrinous coagulum in the heart where it rendered the coagula porous and caused them to acquire a cavernous structure The plaque then undergoes (1) an atheromatous process and (2) ossification in the former he describes pulcaccous softening with fatty globules cholesterin crystals and calcium salts liable to rupture by the force of the blood a process apt to be followed by fibrinous vegetations on the surface The presence of blood or haemic pigments in a softened plaque is regarded as the result of penetration from the lunen By ossification he means simple calcification which he adds nay coexist with atheromatous softening a view not widely shared at that time Rokitansky had also observed that arteries are affected to an unequal degree the aorta being more frequently involved than thc femoral artery the coronarics than the brachial artery while some vessels are barely affected at all Rokicansky s main thesis of fibrinous deposition was criticized by Virchon (1850) and thcreafter fell into disfavour Virchow distinguished carefully between fatty infiltration very likely 10 ·THE GERMAN SCHOOL OF THE NINETEENTH CENTURY (fatty usure) which he described as a degeneration of the connective nssuc cells below the lining endothelium of unknown origin and atheroma which he regarded as a tatty change occurring in the deepest part of the intima and separated from the lumen by a layer of connective tissuc As thus fibrous layer was directly continuous with that of the healthy anııma at the margins of the plaque he rejected Rokitansky s theory of a surface deposit presumably being unaware of the rate of regeneration of endothelium and elastic tissus He added an interesting note on cholesterol (1858) We sce in every case where fatty products remain stagnant for a considerable rime within a closed cavery in which but little interchange of matter can go on that the fat scts free cholestearine He held that cholesterol-formation was a late manifestation of atheroma and profes cd ignorance as to whether it previously existed in combination with the fat or whether a new formanon had occurred in the depo it Atheroma in Virchows vies was a chronic inflammatory disease of the intima (Endarteritis chronica deformans) At a later date he came to postulate a blood dyscrasia as the underlying cause Hus final views were elaborated by huss pupil Rundfleisch (1867) who believed that mechanical factors play a part in determining the localization of the plaque on those parts of the vessel wall exposed to the full impact of the blood Other factors are age alcohol and loose living Rundfcrsch explained the sequence of events thus first there is an overgrowth of fibrous tissue of unflammatory ongin Then since the intima is avascular thickening Icads to malnutrition of the deeper layers followed by fatty degeneration atheromatous softening abscess-formation and ulceration For the next 40 years Virchon s conception of atherosclerosis prevailed a conspicuous herctic being, Thoma (1883) who believed that the intimal changes were secondary to discase of the media Weakening of the vessel wall by pressure of the blood he argued causes the media to bulge outwards with the formation of shallou pouches In the course of a few months these are tilled up by connective tissue thickening of the mtima in order to restore the lumen to its normal size and shape The disease is progressive however and further stretching causes necrosis in the plaque with swelling probably due to the absorption of fluid and the plaque comes to project into the lumen Atheromatous softening of the hyalme portions follous This unorthodox theory has been pinodically revived (eg Bord 19.6 Cranford ard Lerene 1953) Meanwlule the effect of coronary occlusion on the myocardium had been studied by Cmwellner (1852) who observed gangrene following calcareous infiltration of the mouths of the discased vessels It is surprising in view of the injection experiments of Thebesius and Morçagni more than a century before that he should have considered the coronary arteries as incapable of affording a collateral anulation in 1880 !!'ergert ada Lanced the view that sudden coronary occlusion causes myocardial infarction wlule gradual narrowing icads to replacement fibrosis Alaric (1896) showed that cardiac rupturc cardiac ancurysm and certain forms of myo cardial fibrosis are all the result of obliteration of the coronary lumen He insisted that atheroma alone even if severe or calcfied is not enough to cause infarction and that ·THE PATHOGENESIS OF CORONARY OCCLUSION carcful dissection will always revcal total occlusion of one of the main coronary branches He differed from Weigert on the evolution of myocardial fibrosis believing that if the collateral circulation is good the resultant fibrosis is patchy and massive if it is not but in either casc thc fibrosis is the result of necrosis following sudden occlusion of a large branch The cra of static microscopy ended with Jores (1898 1903) who cmphasized the significance of hyperplasia of the elastic lamına in arterial discase Since the days of Lobstein (1833) wlio introduced the word arteriosclerosis had been regarded as a thickening of the arterial walls sometimes but not necessarily associated with atheroma or calcification Jores however proposed that its usage should be limited to intimal hyperplasia accompanied by proliferation of the musculo-clastic layer as distinct from atheroma which he regarded as a purcly degenerative phenomenon charıcterized by fatty change Klotz (1906) pointed out that after all arteriosclerosis was a clmical term too and there was a danger that clinician and pathologist might use the same word in a different sense What was worse people came to think of atheroma and arteriosclerosis as two quite different discases (eg Pilt 1908) and thus resulted in a muddled nomenclature for many years to come Alarchand (1904) had suggested the hybrid atherosclerosis not so much to avoid this confusion as to emphasize the frequency with which lıyperplastic and degenerative changes are found in the same vessel the term however has not met with universal acceptance 12 ·Experimental Atherosclerosis It was about thus time that experimental atherosclerosis became a reality Early attempts to induce lesions by traumatızıng the vessel in various ways lad done little but cause intimal fibrosis probably post-thrombotic This work is briefly reviewed and dismissed by Klotz (1900) In 1903 Josuu by giving rabbits repeared injections of adrerzalın obtamed changes in the abdomural aocta resembling calcified atherosclerosis But a closer mucroscopic study convinced Fischer (1905) that they were essentsally medial in ongin first fatey then calcareous and that any esratsanal cluckenmg was in the nature of a secondary and compensatory plenomenon Today these changes would be considered analogous to the sclerosis of Monckeberg Klotz (1906) injected vanous strans of bacteria intravenously into rabbits and produced intimal lessons which Saltykow (1908) who repeated the experiments claimed to be very like those of human atherosclerosis --- raised yellow plaques single or contluent throughout the aorta and particularly involving the mouths of the intercostal arteries Microscopically the intima and the inner layer of the media contained fine fat droplets later taken up by phagocytes The fatty accumulation was often covered over by a fibroblastic proliferatron just below the endothelum lnng the vessel Other changes were mucoid degeneratron proliferation of fine elastic fibrls and on one occasion calcification Saltykow regarded the fibrosis as infiammatory in ongin and believed lus experiments supported the theory of an infective origin in human atherosclerosis Honever in the following year Ignatou shi (1909) produced comparable intimal lessons by feeding rabbits on a diet of milk meat-extract and egg-yolk The orx plaques took some time to evolve and were accompanied if noc preceded by arrhotic changes in the liver a type of nephritis and hypertrophy of the adrenal glands Microscopically the characteristic intimal lesson was an accumulation of large cells with a foamy cytoplasm As the protein intake of a rabbit is normally low igratowskı attıbuted his results to protein toucation They were confirmed by Staroladomsky and Ssobolin (1909) who failed at the same time to reproduce Saltykow s findings also by Stakley (1910) and Falir (191.) Stukkey by feeding rabbits on combinations of milh egg-white egg-yolk and meat extract was able to show that the aortic lesions were most severe in animals fed on an egs-yolk combulation He later (1912) was able to produce similar lesions by feeding or-brain to rabbits Falır suggested that Saltykow s results were due not to the bactrial agency but to the milk on which they were fed and for many years hirzle more yvas heard of the mfective theory of atherosclerosis Chalatou (1912) fed egg yolk to sabbits and observed Ispid ·THE PATHOGENESIS OF CORONARY OCCLUSION deposits in the liver and aortic inama which he suggested were largely cholesterol an observation which Il esselkın (1913) was able to confirm The obvious inference now was that the rabbit lesions were due not to protein but to cholesterol which is in considerably greater concentration in egg-yolk than in the other proteinous foods administered Accordingly imitschlon and Chalatou (1913) fed rabbits with cholesterol dissolved in sunflower seed oil over a long period and were able to reproduce consistently severe atheromatosis of the aorta and lipid infiltration of the liver spleen and adrenal glands each of which contained cholesterol Microscopically the intima showcd first of all fat droplets mostly anisotropic and with the thermal rcactions of cholesterol These lay in the subendothelial ground substance and did not involve the lining endothelium Later on leucocytes and large foam-cells appeared the latter containing anisotropic lipid The variety of intermediate cell forms led the authors to conclude that the foam cells were storage cells derived from the lymphocytes and monocy tes of the blood elaborated to deal with the excess of cholesterol infiltrating the intima from the blood-stream Subscquent breakdown of these cells led to an extracellular accumulation of lipid Maturc lesions showed degeneration of the subjacent elastic lamella and the formation of a finc elastic network in the plaque Sometines the underlying media also showed degenerative changes Finally fibrous thickening of the intima took place and as a result of damage to the elastic lamella dilatation of the whole vessel This work is quoted in some detail because it was a distinct milestond in the study of atherosclerosis The normal rabbit diet is cholesterol-free and spontaneous atheroma is very rare in rabbits (Stemboss 1913 Nuzum et al 1930) Still since all animal cells contain cholesterol the rabbit must be provided with some metabolic device for synthesizing it (Schonhutmer 1931) The rabbits metabolism appears to be incapable of dealing with large amounts in the diet and the entire reticulo-endothelial system becomes saturated (Schonheuer 1924) including the aortic intima through which the excess lipid infiltrates from the bloodstream causing atherosclerosis The animals all havc hypercholesterolacmia though the degree of atheroma is not proportional to the dosage of cholesterol (Wacker and Huech 1913) It has since been shown however that it is approximately parallel to the degree of hypercholesterolaemia (Pollil 1945) Finally while some other experimental animals - eg guinea-pigs – are susceptible to feeding experiments (Amtschkou 19-2) others – eg white rats -- are not presumably owing to a different type of cholesterol metabolism (Amtschlou 1913) The significance of all this lies in the fact that by feeding cholesterol to animals unused to it lesions closely resembling human atherosclerosis can be produced the first stage of which appears to be a fatty infiltration and not a primary degeneration as had hitherto been supposed in the case of human lesions this being so the metabolic factor in human atherosclerosis acquired a new significance from that date The seeds of this theory had already been sown It had been claimed by Ribbert (190.4) that plasma containing lipid infiltrates the vessel wall and inutiates atheromatous changes a view that must have influenced Aschoff who was present at the lecture as he later (1907) 14 ·EXPERIMENTAL ATHEROSCLEROSIS wrote that the cholesterol in atheromatous plaques was derived from lipid infiltration from the circulating blood Lemone (191.) had expounded the theory that the lipid deposits in human arturies are due to an excess of cholesterol in the blood and now Antschkou s experiments gave a practical foundation to these concepts The implications of this spatc of cxperimental activity profoundly influenced the approach to the problem for the next 20 years Anıtschlows observations were repeatedly confirmedeg by Buly (1916) who gave the first account of cholesterol atherosclerosis in English Modifications of the fuding method narrowed the 897 between experimental and human atherosclerosis Scorf (19-7) showed that by feeding cholesterol to rabbits for 7 months followed by 6 months of cholesterol-free diet the patches formerly nich in lipid became fibrous He also showed that diutarv atherosclerosis in the rabbit s aorta could involve the mouths of coronary arteries Anitschlou (19-8) described in detail the regressive changes in the lesions of experimental ammals fed over a period of 2-3 years But although the simularity between human and cxpcruncntal lesions scemed clearly established doubts remained about the pathogenesis 4schoff (1914) while admitting the Valıdıty of Amtschlow s results was unable to accept the idea that the process in man was simply an overloading with lipid and formulated a thcory which involved an additional mechanical factor He held that functional wear and tear and overstretching of the elastic causc a loosening of the ground substance of the intima tollowed by reactive proliferation of clastic tissus but at the same time permitting lipid to permeate the intima The latter is taken up by phagocytes causing a cellular reaction Continued swelling of the ground substance and accumulation of lipid lead to a secondary degeneration with breakdown of foam cells and the formation of cholesterol esters Fatty acids are released which combine with calcium to form indurated plaques Thus atherosclerosis (wroze Aschoff} as the result of diverse causes and the process may be accelerated by secondary factors such as diabetes or hypertension in the Lane Lecture (Aschoff 19-4) he went further and distinguished between the atheromatosts of youth an infiltrative change which he regarded as largely reversible and a herosclerosis in the second half of life with irreversible tissue changes produ the second generative breakdown mentioned above Dugind (1926) suggested that the localization of lesions around the mouths of branch arteries was du to a sheaning stress occasioned by overstretching the main vessel At least one fairly obvious contabutory factor was hypertension and Anirschkon lumself (1914) now showed that fuctuations in the blood pressure evoked by compression of the rabbit s abdominal aorta or by suspension by the legs or by injections of adrenalın when followed by cholesterol feeding would produce atherosclerosis earlier or with smaller amounts of hpid in the diet The feeding experiments of tu ck (1915) also suggested the presence of some toxic or mechanical factor Ssolou sew (1932) by first traumatızın, the carond artaries of rabbits and then feeding cholesterol demonstrated that the injured intima was more prone to lipid infiltration than the adjacent healthy vascular lining The importance of local factors in determining the ·THL PATIOGENESIS OF CORONARY OCCLUSIO tanic forun to its dit Other anınds ful to respond only because their cholesterol mictabolist i is adequate In any case few will de ay that the cholesterol feeding experiments have quien a tremen dous impetus to rescarchio uhcrock ro 15 nd thic method is still widely used in the assessmunt of contributory factor O draubzel has been the time taken in the solution of the lesions but in ILCLUE Beats Beins at (1949) lase shown that intra cnous injections of colloidal chok sterol will produc qucảce results with less lipid indeed Pellul (1953) tuus chc resulem lesions are more lin human plaques than those induced by the feed ng tuchnique ·EXPERIMENTAL ATHEROSCLEROSIS wrote that the cholesterol in atheromatous plaques was derived from lipid infiltration from the circulating blood Lemone (191.) had expounded the theory that the lipid diposits in human arccries are due to an excess of cholesterol in the blood and now Anıtschkow s experiments gave a practical foundation to these concepts The implications of thus spate of experimental activity profoundly influenced the approach to the problem for the next 20 years Anitschkows observations were repeatedly confirmed - eg by Barley (1916) who gave the first account of cholesterol atherosclerosis in English Modifications of the feeding method narrowed the gap between experimental and human atherosclerosis Scarff (19-7) showed that by feeding cholesterol to rabbits for 7 months followed by 6 months of cholesterol-free diet the patches formerly rich in lipid became fibrous He also showed that dietary atherosclerosis in the rabbic s aorta could involve the mouths of coronary arteries Anıtschkou (19-8) described in detail the regressive changes in the lesions of experimental animals fed over a period of 2-3 years But although the similarity between human and experimental lesions seemed clearly established doubes remained about the pathogenesis Aschoff (1914) while admitting the validity of Anıtschkou s results was unable to accept the idea that the process in man was simply an overloading with lipid and formulated a theory which involved an additional mechanical factor He held that functional wear and tear and overstretching of the elastic cause a loosening of the ground substance of the intima followed by reactive proliferation of elastic tissue but at the same time permitting lipid to permeate the intima The latter is taken up by phagocytes causing a cellular reaction Continued swelling of the ground substance and accumulation of lipid lead to a secondary degeneration with breakdown of foam cells and the formation of cholesterol esters Fatty acids are released which combine with calcium to form indurated plaques Thus atherosclerosis (wrote Aschoff) is the result of diverse causes and the process may be accelerated by secondary factors such as diabetes or hypertension in the Lane Lecture (Aschoff 1924) he went further and distinguished between the atheromatosis of youth an infiltrative change which he regarded as largely reversible and atherosclerosis in the second half of life with irreversible tissue changes produced by the secondary degencrative breakdown mentioned above Dugund (1920) suggested that the localization of lesions around the mouths of branch arteries was due to a shearing stress occasioned by overstretching the main vessel At least one fairly obvious contributory factor was hypertension and Amtschkou himsell (1914) now showed that Auctuations in the blood-pressure evoked by compression of the rabbit s abdominal aorta or by suspension by the legs or by injections of adrenalin when followed by cholesterol feeding would produce atherosclerosis earlier or with smaller amounts of lipid in the diet The feeding experiments of Knack (1915) also suggested the presence of some toxic or mechanical factor Ssolon jeu (1932) by first traumatızıng the carotid arteries of rabbits and then feeding cholesterol demonstrated that the injured intima was more prone to lipid infiltration than the adjacent healthy vascular lining The importance of local factors in derermining the 15 ·THE PATHOGENESIS OF CORONARY OCCLUSION site of the lesions was also demonstrated by Harrison (1933) who administered irradiated ergosterol to rabbits in order to produce a patchy calcification of the inedia and then fed cholesterol to evoke atherosclerotic plaques The two lesions occurred independently and were situated alternately in the vessel s circumference without overlapping By reversing the order of the experiment die produced the same result As both types of icsion reduced the mobility of the vessel wall he concluded that disordurly morcment was a factor in their localization In a later experiment involving lumbar sympathectomy to cause persistent arterial dilatation in one hind limb Harrison (1939) found that cholesterol fccding caused more extensive lesions on the affected side He considered that this result lent some support to Thoma s theory that atherosclerosis is secondary to a scakness of the underlying media A minority rejected the role of cholesterol even m experimental atherosclerosis es Neuburgh and Clarkson (19-3 1926*) who argued that Saltykou s rabbits had been fed on milk which has a low cholesterol content but is rich in protein nevertheless the lessons that followed contained as much cholesterol as those of Anitschkow s experiments In their own cxperiments Newburgh and Clarkson produced lypercholesterolaemia and aortic lesions in rabbits by fecding lean meat with a chiolesterol equivalent of only onctenth of that required to produce atheroma by feeding cholesterol alonc The hypercholesterolacmia they attributed to a metabolic disturbance evoked by the toxic influence of a hugh protein dict The infectie theory too was revived by Burson et al (1931) Noting that septicaemia in the young may be accompanied by fatty infiltration of the aorta and that streptococcus viridans had been recently recovered from the clots in certain fatal cases of coronary thrombosis they injected streptococci into rabbits and fed them with cholesterol This produced small intimal thickenings mostly fibrous whưrcas the control animals fed on cholesterol without bacterial injection showed nothing They therefore concluded that infection plays an important part in precipitating cholesterol on the inflamed walls of arteries Jones and Rogers (1934) also found streptococci in the walls of sclerotic coronary vessels and maintained that chronic sinusitis was a factor in the disease These views find httle favour today A champion of the cholesterol infiltration theory of hunian atherosclerosis was Leary (1934) who found the aortic plaques of young people identical with the experimental lesions in rabbits He formulated the theory that in youth the cholesterol is largely reabsorbed and replaced by fibrous tissue but that the cholesterol metabolism of the aged is defective and the lipid accumulates to form atheromatous abscesses and ulcers -- lesions by the way not observed in expenmental atherosclerosis Later (193 sa) he elaborated this theory stating that milk and eggs are foods intended for the embryonic or infant stage of animal life and that prolonged ingestion of such substances leads to atheroma Man he declared is the only animal that ingests eggs and milk during a lifetime Man is also the only anunal that dies in early life from coronary sclerosis The inference intended to be drawn from thus fallacious syllogism is obvious * Sec Clarkson and Newburgh (19 6) 16 ·EXPERIMENTAL ATHEROSCLEROSIS Leary s painstaking studies of youthful human lesions (1936a) lcd him to conclude that the first change is the appearance of fine neutral fat droplets in the ground-substance of the intima These are taken up by globular lipoplages situated near the surface in which cholesterol droplets are seen in ester form These cells migrate by amoeboid action to the deeper layers where they disintegrate and deposit their contents The cholesterol is then taken up again this tine in crystalline form by phagocytic fibroblasts – branching amocboid cells wiuch Lcary terms fibrolipophages -- after which the lipid loses its anisotropism and disappears altogether The fibrolipophages which show no tendency to disintegrate like their globular cquivalents now revert to fibroblasts and form a loosc rcticular tissuc In old age globular lipophages only arc scen and the lipid tends to accumulate to form atheromatous abscesses with a minimal reticulin response In a later series of experiments on rabbits Leary (1941) modified these views He was able to photograph foam cells apparently cntering the aortic intima from the lumen Since simular cells can be demonstrated in the animals liver adrenals and pulmonary capillaries he suggested that the cholesterol after being absorbed by the gut is esterified in the liver and the excess stored in the Kupffer cells These then migrate into the bloodstrcam and are conveyed to other organs including the aortic intima Thesc foam cells besides being amoeboid are tissue irritants and cause fibrosis in the liver as well as in the aortic plaques The theory that the foam cells arc con cycd to thc plaquc by the bloodstream has suffered a reverse following the observation of MicMillans and Duff (1948) that mutatic figures are not uncommon in purc foam-cell lesions strongly suggesting that most if not all of these cells arise in situ However their irritant effect is supported by the work of Christianson (1939) who showed that of various fatty substances are injected into the femoral arterics of dogs most of the injected material is rapidly absorbed but the cholesterol tends to remain and to provoke a fibrous reaction Leary (1944) believes that after the foam cells have dısıntegrated the fibroblasts come to contain an excess of fatty acids in which the cholesterol is dissolved The lipid then disappears from these cells which return to normal leaving only a fibrous thickening in this way regression of the atheromatous lesions may In a notable survey Duff (1935) critically examined the relation of experimental atheroma to human lesions Among other things he stressed that (1) the experimental lesions are produced by feeding a substance not ordinarily in the rabbit s dict and in an alumal 10€ normally susceptible to atherosclerosis (w) age is not a factor in the rabbit lesions (3) only certam experimental animals will develop the discase (4) hypercholesterolacmia and cholesterosis of certain viscera are constant and necessary conditions for the development of vascular lesions He therefore concluded that while cholesterol might be a factor in human atherosclerosis there must be some additional clement probably traumatic, which determines the localization of the lesions I cary (1936b) replicd that the absence of spontaneous atherosclerosis in the rabbit made it an ideal experimental animal and that the saturation of its blood and reticulo-endothelial system following cholesterol feeding were simply due to defective metabolism of a sub occur C ·THE PATHOGENESIS OF CORONARY OCCLUSION stance forcign to its dict Other animals fail to respond only because their cholesterol metabolism is adequate In any case few will deny thar the cholesterol feeding experiments have given a tremendous impetus to rescarch on atherosclerosis and the method is still widely used in the assessnient of contributory factors Onc draw back has been the time taken in the evolution of the lesions but m recent years Buians et al (1948) have shown that intravenous injections of colloidal cholesterol will produce quicker results with less lipid indeed Pollah (1953) thinks the resulting lesions are more like human plaques than those induced by the fieding technique 18 ·V Fitty Streiking and Atherosclerosis This is a convenient occasion to discuss the relation of the fatty streaks that are commonly found in the aortic intima of quite young subjects lying immediately below the litung endothelium Virchou (1856) had regarded them as a degenerative process of unknown origin differing from the more deeply placed tatty accumulations of atheroma which he believed to be post inflammatory jores (1903) observed an accompanying connective tissue proliferation and was the first to believe the process to be merely an early stage of atherosclerosis Aslanazy (1907) agreed but thought the carly streaking was a reversible process capable of complete regression in muld cascs Klotz and Manung (1911) observed that fatty streaking is common in voung subjects suffering from acute infections The process starts with oedema of the subendothelial connective tissue and musculo-elastic layer followed by the appearance of spindle-shaped cells containing far droplets some of which are anisotropic Fibrous thuckening of the subendothelial laver follows and although the fat may be cventually absorbed a certain amount of fibrosis always remains Klotz (191 sa and b) later modified this view and came to believe that in toxaemia a reversible fatty degeneration can occur within the cells of the intima without involving the elastica He therefore restricted the detinition of atheroma to the stage when the cells break down and the fat comes to lie free in the ti sue spaces Aschoff (1924) took much the same view but Disgund (1926) denying that the fatty change was primarily degenerative and intracellular as Klotz believed asserted that the process was one of lipid infiltration from the plasma into a damaged intima followed by phagocytosis and fibrosis so injuring the intima further and initiating a vicious cycle that resulted in atherosclerosis The majority of observers thereafter come to regard fatty streaking as an early form of atherosclerosis (Zinscrling 1925 Wolloff 19.9) Ssolowjeu (1931) found lipid droplets in the intima and inner media of the aortas of suckling rabbits a phenomenon not observed in older animals he therefore concluded that the maternal milk nch in cholesterol could initiate fatty streaking in voung animals without invoking the agency of infection or toxaemja Leary (1935a) neatly adapted the phenomenon to fit his own theory stating that the process was not completely reversible producing a muld residual fibrosis in younger subjects and gross atheromatosis in the aged Recently Golberg and Norantz (1955) have been able to produce an infiltration of chicken aortas in titro remarkably like their human counterpart by injecting solutions containing cholesterol under pressure into the lumen of the vessel This was een successful in evoking a phagocytic response 19 ·VI Atherosclerosis and Coronary Thrombosis It is difficult for the pathologist of today to realize that the interest and enthusiasm aroused by the work of Anitschkow and his colleagues was not because of any light it might shed on the problem of coronary thrombosis the simple truth being that in 1913 this ailment was not a subject of widespread concem Though the relation of coronary thronibosis to underlying atherosclerosis had been observed by Weigert Marie and others many years cather the prevalence of the condition and its occurrence in the absence of visiblc myocardial infarction were facts not universally appreciated Thus the observation by Brooks (1906) that coronary atherosclerosis was present in 270 out of 400 consccutive autopsics and inore than twice as frcquent as any other form of visceral atherosclerosis was largely of academic interest Osler (1910) had noticed an increase in fatal cases of angina pectors which had risen to 28 per million in England (the present death rate from coronary discase is something like 1200 per nullion) but he made no distinction between the symptoms of angina pectoris and coronary thrombosis Indeed not long before Osler s Lumleian Lectures Sir William Broadbent had said (1906) that there are no characteristic signs or symptonis by which thrombosis of the coronary arteries can be diagnosed Herrick (1912) was among the first to realize that coronary thrombosis could give rise to symptoms differing from the angina of effort and Allbutt (1915) concurred cven going so far as to assert that angina was not related to coronary occlusion Some manifestations of coronary diseasc remained unrecognized particularly in the form of sudden death and acute coronary occlusion without previous synıptoms was considered quite unusual (Hillons 1925) According to Rolleston (1933) the prevalence of coronary thrombosis was not widely accepted in England until about 1926 and I\'am (1923) had written Coronary thrombosis with infarction of the heart as a clinical entity is a condition which is generally classed among the rarities of medicine Indeed it is considered so rare and of so little importance that most of the textbooks of medicine fail to give it mention or perhaps dismiss it with a brief paragraph while several of the larger systems of medicine ignore it altogether At best it is looked on as a terminal event impossible to diagnose and therefore of little clinical import The literature on the subject morcover consists for the most part of a very small number of case reports no attempt has been made to study a large series of cases confirmed by necropsy so that a clinical picture might be constructed wluch would enable one to recognize the condition It is little wonder then that the diagnosis is generally left for the pathologist to make As a matter of fact the condition is not a very rare one it merely goes unrecognized 20 ·ATHEROSCLEROSIS AND CORONARY THROMBOSIS during life To account for this failure of recognition in part at least one needs only to consider the mode of death of the individuals who die from this cause As a rule death is sudden or follows a brief acute illness so that inany of the patients are never seen by a plıysician at all or are only examined after death by a coroner If I have laboured this point it is to emphasize the background against which the alarming statistical increase in ischacmuc heart discase began to be noticed In the late twentics the familiar clinico-pathological syndrome rapidly took form Leime and Broui (19-9) reviewing 145 cases found the disease commoner in males than females (72) with an average age of 578 and particularly affecting the antenor descending branch of the left coronary artery Hypertension was the commonest single associated feature In 44 instances of myocardial infarction 23 vessels were occluded by a definite thrombus wlulc 12 showed severe narrowing without thrombosis for the latter group D. Coursey (1934) suggested that the term coronary occlusion was preterable This was particularly applicable to cascs Brought in Dead a considerable percentage of whomi showed this condition (Bedford 1933) Most were agreed that the lett coronary artery is affected much more frequently than the night (Wear 19-3 I aulkner et al 1924 IVolff and Whit 1926 Parkinson and Bedford 1928 Wollof 19-9 Levine and Brown 1929 Di Coursey 1934 Saphir et al 1935 etc) Others have dissented (Bomes and Ball 1932 Master et al 1937a Horn and Finkelstein 1940) It was further noted that the most severely affected segments of the vessel lic outside the myocardium especially the first few centimetres of the main branches (Let une and Broun 1929 Leary 1934 Saplır et al 1935) There was practically universal agreement about the correlation of coronary thrombosis and underlying vascular disease ( 11 cam 1923 Wellins 19-5 Levine and Broun 1929 Wolloff 1929 Saphir et al 1935 etc ) and statements to the contrary (eg Libman 19-5) werc unsupported by evidence Hamman (19-6) allowed that occlusion was on occasion duc to embolism but summarized the common pathological experience thus The chief cause of occlusion is arteriosclerosis of the coronary arteries and the final closure is duc to thrombosis Thrombosis never happens in a healthy vessel By the most recent estimate 95 per cent of cases of coronary occlusion are attributable to atherosclerosis (Wartman and Hellerstein 1948) I ·VII Thc Morphology of Coronary Occlusion ATTENTION was therefore directed with renewed vigour to the morphology of the occluded segments No more than a brief chronological outline is given here most of the more detailed discussion being contained in the sccond part of this work in order to avoid irksome cross-reference А pioneer in this field was Leary (1934) who thought that occlusion in the aged followed rupture of an atheromatous abscess and in the younger age groups infarction of a fibrous plaque occurred initiating thrombosis Below the line of attachment of the thrombı he observed a substance ncar the surface of the devitalized plaquc with the tinctorial scactions of fibrin ingled with argyrophil fibrils from which he concluded that fibrinoid necrosis of the collagen had occurred due to infarction of the plaquc The same phenomenon had been previously observed by Mfallory (1914) who regarded the substance as fibrın from the blood in view of its association with disintegrating red cells Following Leary s article Clark et al (1936) cut serial sections through a number of blocked arteries and noting the association of a fibrin-like substance with degenerate or ulcerated areas they concluded that it was fibrın deposited by blood infiltrating the diseased surface of the plaquc from the lumen Hom and Finkelstein (1940) sought to explain the occasional absence of red cells in the fibrinoid material by suggesting that the latter was due to seepage of plasma into the weakened intina Learys theory of fibrinoid necrosis was revived by Schlossinan (1942) who treated sections with trypsin before staining and showed that only a part of the material is dissolved Asfibrin is digested by trypsın he concluded that the residuum must be degenerate collagen This however does not necessarily follow and the subsequent work of Duguid and others has done much to support the view that the substance in question is in fact fibrin Considerable interest was aroused by the observations of Paterson (1936 1938) on the frequent association of intramural haemorrhage with coronary thrombosis Serial sections revealed that the overlying intima was often intact indicating that the bleeding had come from the capillaries of the thickened intima A significant clinical corollary (Paterson 1939a) was the plausible explanation it offered in cases of sudden death when the individual was at rest or asleep since a small intimal haemorrhage could well have initiated thrombosis some hours or even days previously Paterson excluded hypertension as a contnbutory factor in capıllary rupture, since he observed the latter in the plaques of pulmonary arteries (1939) The arterial intima which in health denves its nutriment from the circulating blood in the lumen undergoes vascularization when thickened by atherosclerosis a fact that had

·THE MORPHOLOGY OF CORONARY OCCLUSION
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·THE PATHOGENESIS OF CORONARY OCCLUSION
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·genesis of THE MORPHOI OGY OF CORONARY OCCLUSION hitherto attracted little attention alth rush it had been uit d by Rokitansboy and stressed by Raynaud (1863) - by the latter as evidence of the intiunmuur nature of atherosclero- SES i oster (1876) had emphasized the role of hyperto phu a vasa vasorum in arterial disease but erroneously assumed that they existed in the healthy intima as well Wolloff (1929) had described a vasculur network denved (a) from th hypertrophied vasa vasorum and (6) directly from the lumen de clopiny after tlu de poi 1100 < f cholesterol and conamned exclusis cly with its resorption Leary (19351 1936a) whosc principal observations had been on aortic plaques where vascularization is luss conspu uous considered the Vessels a late manifestation and insignificant in thu cvolution of the disease Paterson however had not claimed that the capillaries played a purt in the atherosclerosis he had merely emphasized their role in the subsequent coronary thrombosis a view endorsed by IVartman (1938) Horn and Finkelste 19 (1940) Nelson (1941) and others in the words of Horn and Finkelstein Once established the capillary network comes to form part of a vicious cycle through which the atherosclerotic process is advanced and may act as a decisive underlying factor mi the subsequent occlusion of the main lumen Wintermits et al (1938) had perceived the truth of this but had gone on to ascribe the whole of the atherosclerotic process to infimal haemorrhage a thesis which necessitated the existence of capillaries in the healthy intima in order to initiate the bleeding but an extensive review of the investigations into the blood supply of artery walls by Ramsey (1936-37) clearly reveals this view as untenable It was by this time becoming apparent that the mechanism of coronary occlusion and the pathogenesis of atherosclerosis were problems which if not independent were at least separate a truth appreciated by Levine and Bronn (19-9) and glimp ed by Alanie 40 years earlier cach of whom had observed that severe coronary occlusion may be found along with a fairly healthy arterial tree elsewhere (Fig 1) For one thing the Coronary arteries seemed to be more prone to occlusion than other vessels for another the occlusions were varied in type and often multiple koch and Kong (1932) believed that coronary occlusion (excluding syplulitic aortitis) took onc of three forms (1) atheromatous softening raising the surface (-) fibrou proliferation (3) thrombosis Saphir et al (1935) saw no rcason to distinguish (2) from organizing thrombosis Leary (1035b) in addition to the forms of occlusion quoted above thought that spasm might be a contnbutory factor Paterson (1936) thought thrombosis followed intimal haemorrhage and II artman (1938) showed how an intimal haematoma may cause fatal compression of the lumen without necessarily rupturing into it Von Allerts » (1938) observed organizing thrombi in certain coronary segments related to zones of nicdial necrosis and perivascular lymphocytic infiltration of the adventitia He termed this condition chronic stenosing attentis believing it to be a complication of focal sepsis and differing from true atherosch rosis 25 ·VIII The Collateral Circulation of the Heart BEFORE going on to more recent advances mention should be made of the researches into the coronary circulation as a whole During the nmeteenth century opinion had differed on the cxistence of a collateral circulation some holding that the coronary arteries were end-arteries (Crumulher 1852 Hyrıl 1855 Coluheun 1881) others the contrary (IVest 1882 Alarie 1896) The evidence for the latter viewpoint is summarized below (a) Clinico-pathological evidence-eg cases of complete and chronic closure of the mouth of a whole coronary artery without myocardial infarction (IVest 1882 Galli 1903 Merkel 1906) (6) Injection of onc coronary artery with a dyc followed by its reappearance in the other vessel micro-cxamination ret caling the dye in the smallest branches (West 1882) (C) Experimental ligation of one or other division of the left coronary artery in dogs may be followed by complete recovery of the myocardium (Afiller and Matthens 1909 Smith 1920) or by an infarct much smaller than the arca supplied by the ligated vessel (Smth 1918) Le Count (1918) claimed that injection techniques on post-mortem specimens were not a measure of the degree to which the vessels arc functionally terminal -- ic wherc occlusion of a branch may cause infarction without the collaterals being able to prevent it Further light was thrown on this subject by Gross (1921) in a major contribution which was based on injecting the coronary arteries of hearts of all age groups with a radio-opaque flud and subjccting them to stereoscopic radiography He was able to show that the collateral circulation improves with advancing years suggesting that the aged are better able to withstand sudden coronary occlusion than middle-aged subjects By injecting onc coronary artery with mercury erhielman and Le Count (19-4) demonstrated variations in the extent of the capillary bed of hcalthy hearts and argued that in some individuals the collateral circulation is adequate in the event of sudden coronary occlusion but in others it is adequate only if the occlusion occurs gradually Application of the Spaltcholz technique (IVoodruff 19-6 Robertson 1930) revealed unsuspected anastomoses between the small arteries in the epicardial fat and the vasa vasorum of the aorta and still more were discovered by Smetana (1929) and Hudson et al (1932) All this helped to explain the survival of the myocardium in the presence of multiple occlusions (Willius 1925 Afaster et al 1937a) Icarn (1928) recorded two remarkable cases in which the mouths of both coronary arteries were completely occluded by syphulıtıc aortitis although both vessels were of normal diameter os cm from their origin and there was no gross infarction Wearns perfusion experiments on post-mortem hearts showed that 60-90 per cent of the coronary ·THE COLLATERAL CIRCULATION OF CHE HEART flow escapes not into the coronary sinus buc directly into the cardiac chambers through the Thebesian veins and he suggested these as a likely source of collateral circulation in the event of gradual coronary occlusion It was eventually realized that coronary thrombosis is not only a recoverable incident but may be a recurrent phenomenon in the life of one individual Parkinson and Bedford (1928) and Barnes and Bill (1930) commented on the frequency of two or more infarcts in the same heart and Saplır et al (1935) by careful dissection of 34 hearts showing infarction were able to demonstrate 2 3 or 4 vascular occlusions in every case and concluded that at least a branches must be blocked before infarction occurs A corollary of this work was the realization that the angina of effort coronary throm bosis and sudden death from coronary narrowing without thrombo is (generally attributed to ventricular fibrillation) might all have a common underlying pathology Saphir and his co-workers also confirmed the ob ervation of Parkinson and Bedford (1927- 29) that despite the fact of the right coronary artery being occluded in a substantial proportion of cases myocardial infarcts occurred in the overwhelming majority of instances in the distribution of the left artery - a curious phenomenon that has never been satis factorily explained White et al (1950) found that the average man after the age of 49 has a moderately severe degree of occlusion (grade 3 according to the classification detaik d in Chapter XX) ut some point in both right and Icft coronary arteries And Schlesinger (1940) stated that in 145 consecutive autopsies on males dvins from a variety of causes 40 per cent of the hearts of men over ss showed occlusions As most of these are less than 5 mm long more than half of them arc hable to be overlooked in routine autopsy dissections (Schlesinger and Zoll 1941) Coronary disease is most severe where the bulk of the blood supply to the heart comes from the left coronary artery intermediate where the right coronary artery predominates and least of all where the blood supply is cvcnly balanced between the two vessels (Schlesinger 1940) -7 ·I! The Influence of Age und Stress AGE Tize age factor in atherosclerosis - even of coronary atherosclerosis – had been a subject of speculation for over a concury The remarks of Hodgson (1815) on this subject were noted carlier (p 9) Atherosclerotic arteries of different age groups were studied by Aschoff (19-4) Il olkoff (1929) and Leary (1934) All were agreed that fatty streaking is more characteristic of youth and largely rci crsible while athcromatous abscesses are a feature of the older age groups Ziering (19-5) demonstrated fatty infiltration in the aortas of 6-month-old infants with the same localization as adult atherosclerosis Out of 302 aortas in children under 16 fatty streaking was present in 95 4 per cent Gross et al (1934) scudied the coronary arteries of normal subjects from birth to old age and observed hypertrophic changes in the intima shortly after birth with increased elastic and connective tissue In the second half of life they found all gradations to atherosclerosis and they therefore came to regard the whole process as the result of ageing However the accumulated traumata infections dietary indiscretions and metabolic upsets that constitute the so-called wear and tear of a lifetime are not to be regarded as strictly physiological since they may be avoidable or preventable thus while the observations of Gross and his colleagues on the vessels of different age groups arc of considerable value their overall conclusion is not generally accepted Some had noted an abnormal thickness in the coronary intima as compared with other arteries cven at birth (Elrich et al 1931 Spalteholz and Hochrein 1931 Sappington et al 1930 1941) and in 1946 Doch observed that this was more marked in male infants which he suggested might account for the apparent predilection of atherosclerosis for coronary arteries and the higher incidence in males He described connective tissuc cushions on the uch he regarded as an inherited peculiarity concerned wi blood-flow loweser Fangman and Helling (1947) found lipid droplets and elastic fragmentation in these structures and preferred to consider them as an carly manifestation of atherosclerosis White et al (1950) recognized four degrees of coronary narrowing and were able to show that there is a rapid increase in the severity of coronary occlusion in males between the ages of 30 and 49 reaching a maximum between so and 59 and thereafter faling off slightly In women the degree of severity is less and the curve rises steadily nearmg the malc curve at about 70 (Acherman et al 1950) There is thus a wide scx difference in the sixth decade (Firstbrook 1991) STRESS It may have been the mental association with the angina of effort that led to the belief intima 28 ·THE INFLUENCE OF AGF AND STRESS that stress was a precipitating factor in coronary thrombosis Doubtless another reason was the quite frequent occurrence of sudden death during periods of overactivity However in an early series by offf and tl'hite (1926) it was shown that some attacks occurred during sleep or at rest and Lilin (1931) found no rclation of coronary thrombosis to effort at all Fitzlugli and Hamilton (1933) investigated the activities preceding attacks in 100 cases and found they usually followed some departure from the subject s normal habit of life - unduc effort or fatiguc travel emotional strain overcating alcohol or a surgical operation Leary (1935b) suggested that death during sleep might be due to coronary spasm occasioned by nightmares Lesy and Brienn (1936) pointed out that as the fatal thrombus is nearly alwavs hours or days old it is rarely the monedtate cause of death The fullest correlation of coronary thrombosis with antecedent events was that of Alaster et al (1937a 1939a) Thev investigated many hundreds of cascs and found that the discasc occurred in all walks of life and all types of occupation Forty per cent occurred during sleep and there appeared to be no significant correlation with exertion emotion meals time of day or scason of ycar Intramural haemorrhages were as common in bedridden patients as in physically active ones and was therсtore probably fortuitous Paterson (1939a) rcasonably enough pointed out that if his thcory of hacmorrhage in the plaque initiating thrombosis hours or days before death was true then the patients activity at the time of death was irrelevant Recent work by Morris suggests that the man of active physical habit is less prone to coronary discasc than the more sedentary type As the approach is statistical it is treated in Chapter XVI ·1 Cırdınc Hypertrophy Electrocardiography Two other points deserve mencion The first is the myocardial hypertrophy which had been observed in association with coronary occlusion Somc authors merely recorded the fact (Faulkner et al 1924 !!'illius 1935 Levy and Bruenn 1936) Others ascribed it to hypertension (Birues and Ball 1932 Bedford 1933) and others to cardiac failure caused by multiple infarctions (Afaster et al 1937a) But it is a demonstrablc fact that in many cases of coronary occlusion the hypertrophy is not confined to the left ventricle and may occur in the absence of healed infarcts or gross interstitial fibrosis Thus Davis and Blumgart (1937) excluded cases of hypertension and cardiac tailure but still found the average weight of the remaining hearts well above the normal controls (440 as against 275 grammes) Employing an established physiological principle they argued that chronic coronary insufficiency icads to overstretching of the undernourished inyocardial fibres thereby stimulating the latter to hypertrophy From a recent large series Vater et al (1948) have reached the same conclusion A second point only to be touched on since it lies outside the scope of the present work is the dev clopment of clectrocardiography in ischaemic heart disease The experiments of Smith (1918 19-0) who ltgated branches of the coronary arteries in dogs have already been mentioned (Chapter VIII) They were accompanied by electrocardiographic studies and in duc course similar aberrations were recorded in the graphs of human subjects notably inversion of the T-wave (Smith 1923) Thus afforded thereafter a valuable diagnostic and especially in cases where the symptoms were equivocal or atypical 30 ·Dugud's Thrombogenic Hypothesis In chic course of an excellent article on the morphology of coronary occlusion Horn and Finkelstein (1940) remarked The occurrence of parietal thrombı such as we have seen in thus series and as others have observed also leads to confusion for when such a lesion is finally replaced by fibrous tissue and incorporated into the intima the affected segment of the wall appears exactly like an area which has been progressively chickened by fibrosis of a zone of intimal lipoidosis The implications of this observation however were not pursued The thrombogenic theory of Drugod (1946) on the aetiology of coronary atherosclerosis was something of a bombshell On cutting deeper into the block of a recanalized thrombus he had been struck by the fact that it merged into what looked like a typical atherosclerotic plaque Senal sectioning of a number of narrowed coronary arteries (alf admittedly of severe degree) strengthened his conviction that what is called coronarv atherosclerosis as frequently the end-result of arterial thrombosis Although he gave credit to Rokitarsky for the onginal hypothesis it is necessary to realize that Duguid considerably claborated the views of his prototype For example the concept of a clor at first completely or partially blocking the lumen and later shrinking to one side of the vessel to be overgrown by endothelium from the opposite side while the dceper part of the thrombus underwent fatty degeneration -- such a sequence of events could never have been entertained a century ago It was in faut because he knew nothing of the rate of endothelial overgrowth of mural thrombs that Rolitansky s theory found red under the attacks of Virchow A host of discovenes were made in the next hundred y cars that served to make Dugud s hypothesis plausible - to name only one the collateral circulation of the heart Besides mural thrombi Duguid noted that wisps of fibrın arc often to be found adherent to the inuma of the vessel or in varying stages of incorporation into the vessel wall by overgrowth of endothelium In this way it became possible to account for the buried streaks of fibrin that had puzzled others Indeed Duguid attached great importance to these believing them to be the essential link between thrombosis and atheroscleroses These observations were later extended to atherosclero is of the aorta (Dugud 1948) whicre he found similar minu e mcrustanons on the intuma of 19 out of so consecutive aorcas of individuals whose ages ranged from 3 to 73 who had died from a variety of Causes These fine wisps often too small to be een with the naked cye could in the course of a hfetime account for substantial thickening in young children they were commonly found at the mouths of branch arteries associated with fatty strcaling Other observations elaborated the basic concept and offered new explanations of old 31 ·THE PATHOGENESIS OF CORONARY OCCLUSION problems that had vexed carlıcı workers - eg disintegrating red cells were cited as a potential source of cholesterol superimposed layers of collagen separated by elastic imembranes were scen to be the result of recurrent thrombosis the vessels in the plaquc were the end-product of organized thrombosis (Duguid 1949) Gurmger (1951a) re-cxanmed occluded coronary segments in the light of tlus last suggestion and concluded that the superficial ple xus described by Il olloff (1929) was indeed the residuc of organized thrombosis but he maintained like Wolkoff that the vasa vasoruin also played a part in nutrition of the plaque If the superficial plexus is inadequate or absent the plaque is entirely dependent on the transmedial supply This however is capable of a strictly limited extension and of the plaquc is morc than o 35 mm thick (or o s mm in the aorta) the blood-supply is outstripped and the central layer of the plaque undergocs farty degeneration It is fundamental to realize asserts Geiringer thar intimal vascularization is a function of intimal thickness and not of atherosclerosis Cranford and Latin (195-) modified this concept still further and advanced the view that endothelial cells derived from the endothelium lining the vessel (or rather overgrowing the clot) are capable of assuming the function of fibroblasts and organizing the superficial part of the thrombus without cxtensive capillary activity Meanwhile Harrison (1948) had obtained confirinatory cxperimental cuidence by injecting fragments of fibrin into the vcins of rabbits and producing intimal thickenings in the pulmonary arteries by endothelial overgrowth of the cmboli followed by fibroblastic proliteration at their base Anisotropic lipid droplets werc found in one animal only probably because the fibrin did not contain red cells Heard (1952) improved on these results by injecting larger autogenous fibrın clots into rabbits veins and showed that endothelial overgrowth was complete after 4 days reticulın began to appear after 5 days and collagen in 6 Granulation tissue had replaced the fibrın in a weck and after a month only a fibrous thickening remained Afcletche (1952) by injecting rabbits with Russell viper venom produced two types of losion (a) a chun layer of fibrın spread diffuscly on the vessel wall which underwent organization accompanied by a proliferation of elastic tissue and (b) red mural thrombı which became organized superficially while the deeper parts underwent fatty degeneration resulang in a picture much like human atherosclerosis He noted that such plaques soon became pale as the hacmoglobin was washed out of them, so confirmung one of Duguid s earlier observations on human material Harrison s expenments were repeated by Thomas et al (1956) in rabbits also fed on different types of fat In so per cent of animals the pulmonary arterial lesions contained fat droplets The purpose of the experiment was to demonstrate the theory of lipid infiltration of the intima but a totally uncxpected finding was the presence of fat in the lesions of so per cent of the control animals on a fat-trec diet a result more consistent with the thrombogenic theory of atherosclerosis since the lipid must have been endogenous in ongin ·The Biochemicıl Approach UNTIL recent years the application of chemical methods to the problem of atherosclerosis had yielded results that were conflicting and unpromising and mainly concerned with quantitative estimates of the cholesterol in the blood and the lipid and muncral content of the aorta CHEMISTRY OF THE AORTA Aschoff (1997) is often credited with the identification of cholesterol in atherosclerotic plaques but its presence in crystalline form was well known to Rokitansky and Virchow Employing whole aortas from atherosclerotic subsccts Baldauf (1906) estimated the relative proportions of calcium neutral fat fatty acids and lecithin and IVmduus (1910) showed that the cholesterol cster content was sucnty times that of a healthy vessel Schonkenner (1926 1928) confirmed this observation using preparations of aortic inoma and inner layer of media and maintained that his results favoured the theory of lipid snfiltration since it was unlikely that such large amousses could be synthesszed locally (Ic has been recently demonstrated by Siperstein et al (1951) in experi mental animals that the aorta is capable of synthesizing cholesterol but only in small amounts ) Alecker and Jobling (1934) analysed 45 oruc plaques from different age groups and found thae the total fat and total cholesterol increased with the severity of the atheron sclerosis the most advanced lesions showed a nse in the proportion of free to esterified cholesterol The phospholipids remained constant throughout Attempts have been made to establish the theory of lipid Infiltration by companng the cholesterol content of the plaques with the secum level In 147 aortas from previously healthy persons dying from trauma and other causes of sudden death Land and Sperry (1936) were unable to show any correlation but IVenhouse and Hirsch (1940) found that the lipid proportions in the plaques themselves -- as distinct from whole vessels - corro spond closely to those of the scrum This was also the experience of McArthur (1942) Others have correlated changes in the chenustry of the media with advanang years Using micro-incineration methods ku (1933) found a steady increase in calcium ash apparently derived from degenerate elastic fibres up to the end of the third decade after wluch the increase was irregular lVenhouse and Hirsch (1940) observed that the lipid content of the media also increased with age although neither the lipid nor the calcium in the media were proportional to the degree of sclerosis of the overlying inamna They also made the observation that in the intima che cholesterol though enormously increased in farty plaques is actually reduced in calcareous plaques (Hirsch and I Veenhouse 1943) Laristig et al (1948) applied the micro-incineration technique to the coronary arteries 33 ·THE PATHOGENESIS OF CORONARY OCCLUSION and found that the increase in nicdial calcium started a decade carlier than in the aorta They believe that this process of clasto-calcınosis (not to be confused with Monckebergs sclerosis) is the localızıng factor in atherosclerosis a degenerative change due to age which not only prcccdcs but is essential to the deposition of cholesterol in the overlying intima (Lansing et al 1950a and b) Their views are considered further under Arteriosclerosis and Atherosclerosis in Chapter XVII Buick (1951) has shown that there is a logarithmic rate of increase in calcium magnesium and non-lipid phosphorus in the agemg aortic media Thcadded mineral increase in atherosclerosis is relatively slight compared to the carlıer agc mcrcase The degree of calcification may be missed in routine sections as calcium only stains with hacmotoxylın in the presence of iron Thus micro-incineration is a morc rchable guide Buick and Rossitur (1951) have observed that the total phospholipid content of tlic normal aorta riscs with age largely duc to an incrcase in sphingomyclu In atherosclerosis there is a further risc accompanied by an increase in lecithm Cephalın seems to play no part in lipid infiltration THE SERUM CHOLESTEROL Numerous assays of the serum cholesterol have been made with the aim of bringing human atherosclerosis into lie with Anitschkou s experimental work but opmion differs sharply on the results According to Mfjassulou (1925) a pupil of Anıtschlow lypercholesterolacmia is observed regularly in advanced atherosclerosis and in about half of the nulder cases Hc therefore emphasized the importance of the cholestcrol content of the diet in treatment Rabmou stch (19-7 19-9) also found a ratscd scrum cholesterol in severe atherosclerosis but Hunt (1929) was unable to correlate the two On the strength of the age factor in atherosclerosis (and disregarding the frequcucy of fatty streaking in voung subjects) others have correlated scrum cholesterol and age Page et al (1935) found no significant relationship but heys and others of the Minnesota School (1949 19502) found fault with their method of age grouping on the basis of 5000 measurements in both sexes of all ages Keys and his colleagues found a steady increase in serum cholesterol up to the age of 60 after which the curve tended to flatten and declinc Exception might be taken to the selection of subjects for the 45-55 age group (who for reasons which are not inade clear were chosen exclusively from local business and professional men in responsible positions) since others have suggested that there is an unduly high mcidence of ischaemic heart disease in this social age (Ryle and Russell 1949) A more direct link between hypercholesterolaenua and coronary discase was revcaled by Davis et al (1937) who found the average serum cholesterol in anginal cascs lugher than the control series in some cases far above the highest of the controls This was confirmed by Aſorrison et al (1948) who intestigated Loo consecutic unselected cases of proved coronary occlusion (employing electrocardiography) Hypercholesterolacmia was present in 68 per cent of cases under 60 and s- per cent of cases over 60 Essentially similar results were obtained by Geier (1949) group at this ·THE BIOCHEMICAL APPROACH THE SERUM LIPIDS However there is much to suggust - including experimental endence to be quoted later - that while cholesterol infiltration of the intima may be a factor in atherosclerosis it is not achieved simply by overflow of excess lipids in the plasma and that there are other factors which may operate even in the absence of hypercholesterolaemia Anong such factors those which have attracted most attention are (s) Chylomicrons (1) Altered cholesterol/ phospholipid ratio (112) Altered lipoprotein ratio (iv) Grant molecules (1) CHYLOMICROGRAPIIY Gage and Fish (19-4) described lipid particles which appear sa normal plasına 1-_ hours after the ingestion of food containing fat These are 3-14 in diameter and are known as chylomicrons By giving a standard fatty meal and examining hourly samples of blood under dark ground illumination a curve can be plored which indicates the frequency of these particles (Frozes and Sten ars 1937) Moreton (1947) showed that in conditions accompanied by hypercholesterolaemia diabetes nephrosis myxocdema etc -- the chylomicrons are unduly plentful High speed centrifugation shows them to contain cholesterol triglycerides and fatty acids He therefore formulated a new theory of atherogenesis arguing that the accumulatı c effect of many farty meals over a long period causes showers of lipid particles to appear in the plasma which are intermittently deposited in the tissue spaces of the intina The neutral fat and fatty acids are readily absorbed but the low solubility of the cholesterol causes it to remain even though the serum cholesterol has stayed withi normal limits Becker et al (1949) introduced the age factor noting that in the younger age groups the number of chylomicrons reaches its peak at-3 hours after a fatty meal and returns to the fasting level in s hours in older subjects the peak which is much highes is reached in 8-12 hours and does not return to the fasting level for hours (11) ALTERED CHOLESTEROL/PROSPHOLIPID RATIO It is a remarkable fact that the scrum lipids do not form an emulsion and that the serum remains clear even sn cases of hyperlipaema Ahrens and hanhel (1949) showed that this phenomenon was dependent on a corresponding rosess the secum phospholipid level and vuggested that the phospholipids may help to stabilize the colloidal dispersion of plasma cholesterol They further noted a correlation betiveen a raised cholesterol/phospholipid ratio and premature atherosclerosis These observations were confirmed by Gertler er al (19soa) and Olner and Bozd (1953) in cases of myocardial infarcton below the age of 40 (111) ALTERED LIPOPROTEIN RATIO The crasisparency of serum with a high lipid content had perplexed carly observers and had led Sorenson (1931) to maintain that the phenomenon was explicable only by assuming linkage between lecithin and sterols on the one hassd and the protein on the other These lipoproteins being water soluble may be concerned in the filtration and deposition of cholesterol in the intima 35 ·THE PATHOGENESIS OF CORONARY OCCLUSION Two fractions have been identified in human serum by mcans of clectrophoresis unch causes them to nugrate with the a- and B-globulins respectively (Oncley et al 1950) In healthy subjects the average rauges and ratios of the a- and B-lipoproteins as they have been styled have been determined (Russ er al 1951) Persons who have survived myocardial infarction or who have other definite cvidence of atherosclerosis show a tendency to reduction of a-lipoprotein and an increase in B-lipoprotein (Barr et al 1951) These differences may be present even though there is no significant rise in the serum cholesterol and in patients with diabetes or nephrosis they are present before vascular complications are chnically recognizable (14) GIANT MOLECULES Even more interest has been aroused by the work of Gofman and his colleagues in the University of California (Gofman et al 19501 and b) who in 1950 described a holesterolbearing giant lipoprotein molecules in the scrum of atherosclerotic patients with these characters (1) They are not related to mcals -- 1e they are not chylonucrons (2) Their presence cannot be predicted from the serum-cholesterol level (3) They are present with hugher frequency in those who have survived myocardial infarcts also in sufferers from diabetes nephrosis hypothyroidism hypertension and cardiac ischaemia - 1e all those conditions known to be associated with atherosclerosis These molecules are not normally present in rabbit serum but they appear after cholesterol feeding A high concentration causes turbidity of the scrum Their presence is revcalcd by ultracentrifugal Rotation analysis and their rate of inigration is expressed in Svedberg units which are determined by measurement of the refractive index gradient patterns Normal lipoprotein molecules are of the order of Sf 5-10 in atherosclerosis the larger Sf 10-.0 class begin to appear Gofman s vicw is that these grant molecules are responsible for the deposition of cholesterol in the 11tima and atherosclerosis is associated with or caused by an error in the metabolism of fat and other lipids as distinct from hypercholesterolaenua alone It is too carly to assess the value of thesc observations but already Keys (19911 and b) has objected that Gofman s normal ranges were from the 20-40 age group while the group cardial infarction ranged from 40-70 He therefore considers that the G substances (as he arbitrarily designates Gofman s giant molecules) are of no greater value than the serum cholesterol in the assessment of atherosclerosis since this too rises with age Indecd he denues that there is any evidence that the G substances indicate probability of present or impending coronary disease Gofman et al (1982) and Lyoncal (1952) have replied citing abundant statistical evidence that the Sf 10-.0 lipoprotein levels show at least a tuofold and perhaps a tenfold higher relationshup to atherosclerosis than the serum cholesterol does and that the slight relationship of the latter to atherosclerosis is by virtue of its partial correlation with the Sf 10-20 36 with myo- ·THE BIOCHEMICAL APPROACH lipoproteins The using of coronary disease as their criterion of atherosclerosis may be of debatable validity Further doubts have been throw on Gofmans theories by Paterson (1954) who determined the serum cholesterol the cholesterol/phospholiprd ratio and the Sf 10-20 lipoprotein molecules of patients before death and at subscquent autopsy found no abvious correlation between any of these and the degree of sclerosis or hpıd content of their coronary arturies A simlar discrepancy bets een lipoprotein molecular ranges and the degree of general atherosclerosis at auropsy was recorded by Clapman et al (1956) This is the barest outline of these recent advances The whole subject of the relation of atherosclerosis to a disorder of lipid metabolism has been lucidly reviewed by Gould (1951) Gutman (1953) considers that the increase in Sf 10-20 lipoproteins S-lipoproteins and the cholesterollphospholipid ratio are probably all facets of the same basic lipid discurbance 37 + ·XIII Thic Dict and Atherosclerosis ALLIED to the biochenucal approach is the dietetic one and animal feeding cxpennients have made it inevitable that human atherosclerosis should be attributed to the eating of foods rich in cholesterol (eg IVacker and Hueck 1913) These arc chiefly eggs mull butter and other animal fats all cherished by cıvılızations with a high basic standard of living and reduced or absent in undernourished communities Aschoff (1924) claimed that atherosclerosis decreased dunng the first World War when food rationing was universal in Germany Houcvcr Il ciss and Mfm0t (1933) in a study of the racial incidence of atherosclerosis found no proof that overnutrition or malnutrition was a factor It was scarcely fcasıble to demonstrate experimentally induced atherosclerosis in human subjects but Mijassıhon (1925) and Hunt (1929) failed to raise the serum cholesterol by feeding cholesterol-rich foods to healthy individuals The nearest approach to experimental atherosclerosis in man was cited by Leary (1936b) Reference has already been made to his theory that atherosclerosis is a discasc of overcıvılized communities where adults continue to cat in excess foodstuffs primarily intended for embryosand enfants (1 c milk and eggs) He claimed that from 1920 to 1930 when it was the practice to treat diabetics with a diet rich in cholesterol spectacular degrees of atherosclerosis became much commoner even in young subjects When this mode of treatment was abandoned the severity of the atherosclerosis became less In a series of autopsies on Okinawans whose diet is largely vegetarian Stemer (1946) found that atherosclerosis develops late is of moderate degree and may be absent altogether Opinion varies on the relation of atherosclerosis to obesity which although not wholly a matter of dietetics may be briefly considered here Dublin (1930) quoted insurance company statistics to show that death from angina pectoris and other forms of arterial disease is two or threc times as ommon in obese subjects as in those of normal or subnormal weight In 80 fatal cases of coronary discasc in servicenien between 0 and 36 French and Dock (1944) found overweight the most striking single predisposing factor Wilns (1947a) found advanced atherosclerosis to be trvice as common in obese subjects as in the poorly nourished groups His autopsy studies on the victims of wasting discases suggested that loss of weight was accompanied by regression of atherosclerotic lesions (Wilens 1947b) However Yater et al (1948) found no correlation between obesity and coronary occlusion in the under-40 age group while Faber and Lund (1949) in a chemical assay of 400 aortas concluded that if hypertensive cases were excluded obesity bore no relation to the degree of atherosclerosis Further statistical cvidence was supplied by Malmros (1950) who found that during World War II the mortality from atherosclerosis and coronary disease decreased in Finlund 38 ·THE DIET AND ATHEROSCLEROSIS Norway and Sweder where the consumption of eggs butter and other cholesterolrich foods was reduced in Denmark where the total fat consumption declined but that of eggs and butter increased the death rate rose slightly in the United States where the consumption of eggs and milk increased (though butter s as reduced) deaths from atherosclerosis steadily increased Best of dietary cholesterol is a factor in human atherosclerosis it is not just by causing hypercholesterolacmia keys et al (1950b) and keys (1992a) found that the consumption of a single large amount of cholesterol barely affects the scrum leve! They also showed in a cascful survey of 482 healthy adults over a period of 3 years that the serum cholesterol 15 sot significantly related to the cholesterol intake in the diet Gertler et al (1990b) found this was also true of convalescent cases of myocardial infarction (presumably atherosclerouc subjects) 1Vilkinson et al (1950) similarly failed to find a ck ar relationshup bersveen the serum cholesterol and the total intake of carbohydrate fat protein or cholesterol in patients wsth familial hypercholesterolacmia Theoretically of course there seems to be no reason to postularc a direct relationsłup berween ingested cholesterol and the serum level since it has been shown experimentally that the mammalian liver rcadily synthesizes cholesterol from acetate (Bloch and Rittenberg 1942) It is also known that any nechatısın shich raises the blood fat (including ingestion of fat) will automatically elevate the serum cholesterol which functions as a vehicle for facty acids (Gulmer and Ungerlerder 1949) The same lack of relationship between dietary intake scrum cholesterol levels and the severity of atherosclerosis has been observed in cholesterol-fed rabbits (Firstbrook 1951) keys (195.b) dismissed Steiner s work on Okinawan autopsies as lacking in data on the diet and degree of atherosclerosis Hc harshly crticized Malmross Scandinavian statistics as attempting to discover causation from a parallelism between crude esamates of national averages for two variables While agreeing that the serum cholesterol seems to be independent of the normal daily mtaks Keys showed in a series of human feeding experie ments that a high fat diet raises the serum cholesterol and chat on a fat-free diet the serum cholesterol is faicly rapidly reduced He therefore proposed that in the treatment of atherosclerosis tlsc fats generally should be restricted and not cholesterol specifically Controlled feeding experiments were carried out by Alorriso (1992) on cases of ischae. imic heart disease over a penod of 3 years He found that in the group subsisting on a low-fat low-cholesterol diet the serum cholesterol was lowered by 30 per cent and that mortality was 14 per cent as compared with 30 per cent in the group on an unrestricted dict In a recent speculative article Sinclair (1950) disputed Keys s vicw that the importante factor is atherosclerosis is the total fat in the diet He claimed that what matters is the amount and structure of the dietary fatty acids which are altered by modern food. processing Oxidation of animal fars and hydrogenation of vegetable oils in the diet lead in the human consumer to the formation of abnornial cholesterol esters whucı are difficult to dispose of and so cause atheroma and abnormal phospholipids further contribute to coronary thrombosis by increasing the coagulability of the blood 39 ·THE PATHOGENESIS OF CORONARY OCCLUSION Corroborative evidence has come from Bronte-Steu art et al (1956) who showed that animal fats and hydrogenated vegetable fat raise the scrum-cholestrol whereas natural vegetable oils and the oil of marine animals do not Fullerton et al (1953) prompted by Duguid s theory of atherogenesis studied the effect of fats on the coagulabılıty of the blood It had long been known that the latter increases after meals (Alills 1923 Afills and Micheles 1928) and there was reason to believe that a lipid factor may be concerned in the process (Afacfarlanı et al 1941, Waldron et al 1951) Fullerton showed that post-prandial lipaemua is accompanied by an accelerated coagulation time and suggested that this was a factor in atherogenesis Discussing the apparent increase in coronary occlusions he adds It is important not to let this particular aspect overshadow the general problem the cause of its carly and frequent localization in the coronary arteries may well be a problem separate from that of atherosclerosis in general ·Inhibitory Factors Tize simple concept of atherosclerosis following hypercholesterolaemia due to an excess of cholestrol in the diet does not stand up to animal or human feeding experiments since it has been shown that there is no clear relation between dietary intake and serum levels nor according to some authorities (heys is a conspicuous exception} berween serum cholesterol levels and the degree of atheroscleross Experiments mvolving the use of various trilubsting agents indicate that hypercholesterolaemsa may be a factor u cholesterol atherosclerosis but not necessarily the determing factor That experimental atherosclerosis can be inhibited in cholesterol-fed rabbits was first shown by Afurata (1918) who succeeded in retarding or preventing the lesions by adding chyroid to the diet Liebig (1929) produced a sinular ctfect by the administration of sodine compounds Both results were confirmed by Turner (1933) who also showed that the prorective effect of potassium iodide as destroyed by thyroidectomy (Tresses and Khayal 1933) Since then a number of agents have been employed wluch are alleged to inhibit atheron sclerosis (1) by prevenang hypercholesterolaema (2) by preventing deposition of cholen sterol or (3) by lowering the frequency of the grant lipoprotein molecules (1) INUUTTION OF ATTLEROSCLEROSIS BY PREVENTING FLYPERCHOLESTEROLAEMIA. Kesten and Silbowitz (194-) found that soya lecithin fed along with cholesterol to rabbits prevents the usual hypercholesterolaemia and diminishes the incidence of atherosclerosis Adlersberg and Sobotka (1943) added leathin to the diet of human cases of hypercholesteron faemua over a period of several months and greatly reduced the serum level włuch rose again wicza che lecithin was withdrawn A summilar effect was stored in cases of coronary disease by Steiner and Domausts (1944) Experimental depression of the scrum cholesterol in cholesterol-fed chucks has been recorded by Peterson (1951) using saya bean sterols Hermann (1946) claimed to have effected decholesterization of tissues (a) gradually by a low fat dict accompanied by thyroid extract and potassium iodide over a period of months or years (4) more rapidly by thic administration of cholinc methionine inositol alcaucıl or berenjesız Bilc is apparently necessary for the absorption of cholesterol from the bouel (Stpersteun et al 1952) and as ferric chlonde 15 known to precipitate bile salts 113 vitro this substance was fed along with cholesterol to birds resulang in a relatise depression of the serum cholesterol and a reduced degree of atherosclerosis (Siperdem et al 1953) Hopeful interest has been aroused by the discovery of Pollak (1953b and c) that sitom sterol the scerco-isomer of cholesterol is not resorbed in the alimentary track of rabbits of ·THE PATHOGENESIS OF CORONARY OCCLUSION Corroborativc evidence has come from Bronte-Sten art u al (1956) who sho: animal fats and hydrogenated vegetable fat raise the scrum-cholesterol u! vegetable oils and the oil of marine animals do not Fullerton et al (1953) prompted by Dugund s theory of atherogenesis s of fats on the coagulability of the blood It had long been known that thu 1 after meals (Mills 1923 Afilis and Necheles 1928) and there was reason to I lipid factor may be concerned in the process (Afacfarlane et al 1941 IValdrese Fullerton showed that post-prandial lipaemua is accompanied by an accelerated a time and suggested that this was a factor in atherogenesis Discussing the appareil in coronary occlusions he adds It is important not to let this parucular aspec shadow the general problem the cause of its early and frequent localization coronary arteries may well be a problem separate from that of atherosclerosis in gen 40 ·INHIBITORY FACTORS All those experiments in which the evidence for an inhibitory factor rests on a lesser degree of atherosclerosis in a treated group of rabbits as compared with a control senes may have to be reassessed in the light of work by Firstbrook (1950) By feeding cholesterol to animals on graded diets he found a close relationship between the severity of the atherosclerosis and the relative gain in body weight He has objected therefore that the results of the allovan-diabetes experiments of McGill and Holman and Duff and McMillan may be attnbutable not to an inhubitory effect but merely to loss of weight by the diabetic group of rabbits 43 ·Contributory Factors These are dealt with sumınanly because while interesting in themselves none of them has been scriously suggested as playing more than a secondary role in the genesis of athero sclerosis Age race physique and occupation being not so much single factors as a blending of multiple imponderable influences are not considercd here and are best included with the statistical surveys HYPERTENSION In soo consecutive cases of myocardial infarction Afaster et al (1939b) found this feature present in over so per cent of the malc cases and 80 per cent of females The contnbutory influence of fluctuations in the blood-pressure in experimental atherosclerosis was noted by Antschlow (1914) It is common experience that cases of prolonged hypertension rarely present in the autopsy room without severe atherosclerosis. It is equally true however that both myocardial infarction and advanced atherosclerosis are very frequently encountered in subjects with a normal blood-pressure DISORDERS OF METABOLISM Conditions in wluch the plasma cholesterol is raised are usually characterized by severe atherosclerosis eg diabetes mellitus (Rabınouitch 1935) myxoedema (Blick and Campinerer 1934) or familial xanthomatosis (Muller 1938) Cook et al (1947) recorded fatal coronary occlusion in a child of 13 suffering from xanthoma tuberosum ENDOCRINE FACTORS These are (a) thyroid (b) gonadal (a) THYROID The influence of the thyroid gland on experimental atherosclerosis has been mentioned (Afurata 1918 Turner and Khayat 1933) and Black and Campseier (1934) have revicwed the literature associating hypothyroidism with atherosclerosis and coronary occlusion Lerman and Il’hute (1946) observed a low basal metabolic rate and a raised serum cholesterol in persons under the age of 40 suffering from cardiac ischaemia In the expenmental field Shapiro (19-7) found that thyroidectomy accelerated cholesterol atherosclerosis in rabbits Steiner and Kendall (1946 1949) were able to induce ·CONTRIBUTORY FACTORS cholesterol atherosclerosis (and coronary occlusion) in dogs – normally resistant to feeding experiments – by administering throuracil Friedman et al (1952) found that in rats this drug reduced the rate of cholesterol excretion thus allowing more to be resorbed in the blood-stream while the giving of thyroid extract had the reverse effect The possible relation of dımınıshed thyroid activity to hypercholesterolaemia in the older age groups has not escaped notice (6) GONADAL The influcnce of gonadal disturbances as a contributory factor in atherosclerosis has aroused further speculation The inchoate evidence derived from experimental and human matenal may be summarized under the effects of (1) Castration (u) Oestrogen administration (1) Androgen administration (1) Castration Afurat 1 and Kataoka (1918) found that castration accelerates the development of atherosclerosis in cholesterol-fed rabbits an observation confirmed by Chuma (1923) and Shapiro (1927) Ruin and Dimitroff (1954) observed a raised incidence of atherosclerosis in autopsies of females who had undergone bilateral oophorectomy (11) Oestrogen adınınıstration The last-mentioned authors also noted a diminution in atherosclerosis in autopsies on males treated with oestrogens for prostatic cancer Barr et al (1952) noting that women of the child-bearing age are relatively immune to cardiac infarction treated a series of patients convalescing from this condition with oestrogens and observed a reduction in the serum cholesterol and in the B-lipoproteins Furman et al (1954) noted a corresponding rise in the a-lipoproteins in post-menopausal females treated by oestrogens the B-lipoproteins were barely altered Curious but interesting results have been obtained experimentally with cockerel chicks Katz (195-) found that implanted oestrogens cause hyperlipaemia and increased atherosclerosis In cholesterol-fed cockerels however while failing to check aortic athero sclerosis oestrogens apparently inhibit coronary atherosclerosis or cause regression of this condition if already established even in the presence of hyperlipaemia (Pick et al 198-a and b) These authors draw the significant conclusion that atherogenesis does not proceed according to the same biological laws in different vascular beds (111) Androgen administration Furman et al (1954) have observed that thescrum ofeunuchoid males treated by androgens shows a lowering of the a-lipoproteins From the foregoing there seems to be some justification for adding oustrogens to the list of Inhibitory Factors in human atherosclerosis ·The Statistical Approach DISEASES of high frequency but obscurc pathogenesis (eg cancer peptic ulcer etc) are inevitably subjected sooner or later to statistical surveys and in reane years coronary discase has also been attacked on this front Thic investigations have been chicfly concerned wich (a) the increased frequency of coronary disease and (b) the type of individual who suffers from it (a) INCREASED TREQUENCY OF CORONARY DISEASE Whatever inay be the truth about coronary sclerosis there seems to be little doubt that atherosclerosis is as old as luman history 15 was shown by the work of Shattoch (1908) and Ruffer (1911) on Egyptian mummies Ruffer examined a sufficient number to enable him to conclude that atherosclerosis in the aorta and limbs (the coronary arteries unfortunately had been removed with the rest of the viscera) had the same distribution gross characters and microscopic appearance in 1500 B C as it has today and that the disease was probably as common in ancient Egypt as it is in modern Western civilization Most of che mummies were menibers of the priesthood who according to Ruffer probably nto richly and shunned heavy manual work Anatomists have been familiar with atherosclerosis since the seventeenth century and probably carler but as we have seen they werc slow to recognize coronary occlusion For this reason Oskrs concern over the increased incidence of angina pectoris may have been no more than increased awareness of a cominon but undiagnosed condition and it can be furly presumed that a great many deaths certified in his day as myocardial degenerachronic niyocarditis and old age were in fact directly attributable to coronary Occlusion More recently however it has been felt that even allowing for improved diagnosis and increased expectation of hfe mortality from coronary disease is definitely increasing Ryl and Russell (1949) in a full statistical review showed that the mortality in people the age of 35 was 15 times greater in 1945 than in 1921 especially in the age group and particularly among the higher income groups Beru cen 1938 and 1948 the mortality doubled (Alorris 1951) Now while it might be argued that in 1921 the disease was not sufficiently widely recognized it is difficult to believe that this was so in 1938 Morris found that autopsy records at the London Hospital revealcd no increase in atherosclerosis of the coronary arteries since 1908 although clmcał coronary thrombosis had greatly increased a parador which suggested that more attention should be given to the occurrence of thrombosis than to atherosclerosis alone tion Over 40-55 mal 46 ·THE STATISTICAL APPROACH (b) THE TYPE OF INDIVIDUAL AFFECTED A sery carly reference to the predilection of coronary disease for a social group is contand in an article by Curtma (1897) who noted the frequency of angiisa pectoris xxz doctors Osler (1910) thought it affected the better classes generally and recalling that it had claimed such distinguished iceches as Hunter Charcot and Pepper said that agua pectoris faught be called the morbus medicorum Though this was subsequently distussed as che illusion of a successful physician with a chenteic preponderantly affluent confirmation has since conic from the Registrar Generals Reports which show that medical men have an incidence fac lugher than any other profession and immeasurably higher than that of heavy manual workers (Conyheore 195-) It is a commonplace to associate coronary disease with what is vaguely described as stress of (as if it were more precise) stresses and strains without further definition of these terms Certainly violent physical effort has been known to precipitare sudden death in individuals with coronary occlusion but statistically manual workers who for economic rcasons must go on working after an atrack of coronary thrombosis have a better expectation of survival than white.collar workers (Plupps 1936) Master et al (1937b 1939a and b) found that coronary thrombosis occurs in all walls of life and all types of occupation They failed to find a significant correlation berweer coronary discase and physical crection exciterent infection tobacco meals the time of day or the season of year in fact the only significant aecological factor was the sex of the individual since the incidence in males compared with feinales was 3 4 The difference in the 1scidence of coronary disease berween men and women of the sixth decide is particularly striking (Acherman et al 1950 Whart et al 1950 Fixstbrook 1951) The possibility that oestrogens exercise an inhibitory influence in women has already been commented on Ryle and Russell (1949) found that the increase in middle-aged nion is significantly greater than in women of like age and suggested an occupational or sociological influence In the social class which incorporates professional workers and business men with administrative responsibilities the mortality of the 40-53 age group is ten times that of their wives Stocks (1991) confirmed Phippss views by showing that only 148 per cent of cardiac deaths among heavy manual workers are due to coronary occlusion as compared with 38 6 per cent in the witc-collar class Recently Aforsrs et al (1953) Inave produced evidence suggesting that individuals 211 sedentary occupations are more prone to coronary discase than their more active fellows Arnou (1954) thinks that stress is a fallacy the fact being that patients prefer to be told that they are the victims of strain rather than of gluttony or physical indolence The statistical approach has ses caled significant data relating to males who develop coronary disease at a relatively early age Jator et al (1948) analysed a large series (866) of American service sen below the age of 40 suffering from coronary discasc The incidence in negrocs was only two-thirds of that in Cascasians Obesity was not a sig nificant factor Yater and his colleagues were umpressed with the hereditary factor which emerged from a study of the family hostonics Idlersiers et ol (1949) also found a famıkal 7 ·THE PATHOGENESIS OF CORONARY OCCLUSION relationship in coronary discase suggesting a liereditary hypercholesterolaemia especially in patients under so A genetic analysis of 35 families suffering from xanthomatosis indicated that the disturbance of cholesterol metabolism is inherited as an incomplete dominant trait Duff and McAfillan (1951) are inclined to regard hypercholesterolacmic patients with premature coronary discasc as a distinct group not representative of the generality of atherosclerotic subjects An even more elaborate statistical survey of coronary discasc in young adults has recently been compiled by Gertler and I lite (1954) who introduce biometric methods in their calculations Young coronary discasc patients are usually cndomorphic mcsomorphs and the physically oestrogenic type of male is less prone to cardiac anfarction than his more robust brother Reviewing recent rescarches on serum lipid chemistry these authors conclude that it should now be possible to pre-sclect coronary-prone individuals from the population Pending fuller clarification of these matters however the thoughtful physician might well question thc advisability of acting on this suggestion The subject of racial incidence involving as it docs questions of hercdıcy dict cconomic and social habits is debatable Since Osler s day Jews have been said to bu singularly prone to coronary discaso Asiatic peoples to be the reverse Recently Bronte-Steu art et al (1955) observed that the Europeans of Cape Peninsula had a higher incidence of coronary disease than the native Bantus while the Cape Coloured occupied an intermediatc position The incidence ran parallel to the serum cholesterol and P-lipoprotein levels in the three groups and the team (of which Keys was a member) detected a similar relationship to the fat intake of their respective diets thereby suggesting that the differentiating factors are not so much racial as social and cconomic However until the problem has been tackled on a world-wide scale it would be wiser to reserve judgment 18 ·1VII Local Predisposing Factors Tue biochemists and statisticians have carned their ins estigations sufficiently far from the atheroscleronc plaque for a morbid anatomust to appreciate the sardonic comment of Duff and Alcanlan (1951) that the casual reader of recent literature might wonder whether some authors concese of an atherosclerosis so independent of the vessel ss all that st may occur in the absence of the blood-vessels themselves It is true that while note is being learned yurly about the type of individual who dies prematurely of coronary occlusion, and the alterations in the blood-chemistry that predispose to this event little progress is being made in finding an answer to tu o crucial questions What determines the localizacion of atheroscleronc plaques generally And why in particular are the coronary artenes so frequently involved Arguments on these subjects have been and still are largely theoretical or based on flimsy evidence Reference has been made to the hypotheses of Rundfleisch (haemic currents) Thoma (medial bulging) Aschoff (overstretching) Durgued (shearing stress) Ssolonjen (local trauma) and Hornson (abnormal movement of the underlving media) Nanc of these affards a comprehensive explanation of all the established data ATIJEROSCLEROSIS AND ARTERIOSCLEROSIS The fact that atherosclerosts can be readily produced experimentally in previously healthy artenes by fccding cholesterol to animals has tended to obscure the question of underlying pre-exisning arterial changes in the human subject The added fact that fibro clastic proliferation carely occurs in the human intima in the absence of atheromatous plaqıses has led to sts being seglected in the consideration of atherogenesis In recent years however interest has been resived in the existence of arteriosclerosis as a separate if not independent entity from atherosclerosis It will be recalled that both Jorts and Aschoff had emphasized the changes in the classic layer and insmal ground substance which in their view preceded the depositon of lipids the former regarding the process as pathological (Jores 1934) the latter as the physological process of ageing ( Aschof 19-4) Thoma s theory that the plaques were secondary to a loss of medial clasgory has lately been reinstated Blumenthal et al (1944) using the micro-incineriaon technique found that medul clafication preceded the formation of intimal plaques and observed a relationship between calafication loss of classicity and increasing age They believe that clastic fragmentation and medial calcification are age changes which result in dılaration of the vesseand that the intimal plaques are secondary (Blumenthal et al 1950) A somewhat similar view is shared by Crawford and Lerene (1953) E ·180 THE PATHOGENESIS OF CORONARY OCCLUSION Lansing and his associates followed up tlus work by showing that while the calcium content of the media increases with age the elastin content is barely altered-ic the loss of clasucity in an ageing vessel is not accompanied by loss of clastic tissuc (Lansing it al 19500) But alone is not the cause of atherosclerosis since medial calcinosis and acherosclerosis arc not found in the pulmonary arteries of elderly subjccts unicss there is some unnatural stress such as pulmonarı hypertension (Lancing at al 19500) This school defines atherosclerosis as a process invoking fatty and fibrotic degeneration of the intima of vessels arteriosclerosis as an age-dependent process of farty and fibrotic degencration of the intima accompanied by and generally preceded by calcification of the medial elastic tissue (Lansmg et al 1950.) They insist hou cver that these vicus in no way involve a rejection of the theory of disordered lipid metabolism as a factor in atherosclerosis Lansing (1982) deliberately uses the term ageing to cover not only the passage of time but crogenous insults to the vessels Afoschcouit: (1950) wisely believes that in this respect it as impossible to say where normal ageing ends and disease begins He regards the lıyperplastic changes as an adaptation to rising intra-arterial pressure from birth to old age and concludes that atherosclerosis cannot be considered as synonymous with arteriosclerosis since it is not pronary and lacks the consistent morphologic and/or pathogenetic background of hyperplastic arteriosclerosis At best it is only a part or 1 facultative lesion of arteriosclerosis MUCINOUS DEGENERATION AS A LOCALIZING FACTOR Virchou (1856) observed a gelatinous swelling of the intinza preceding atherosclerosis and Saltylou (1908) found mucoid degeneration of the collagen in relation to the lipid deposits of cholesterol atherosclerosis Bjorling (1911) descnbed a metachromatic mucinous material in the ground substance of the intima and nicdia of normal arteries which was grcatly increased in arteriosclerosis It borc a special relation to the elastic fibres Schultz (1922) made similar observations on this substance and noted its affinity for lipids and calcium These discoveries received little attention until 1949 when Fiber traced a connection between cholesterol deposits and ageing or diseased tissues containing a substance that stains metachromatically with methylene blue and which he believed to be a sulphate-containing polyuronde In the human aorta he was able to trace a progressive increase in this material with the age of the subject and he advanced a theory that it acted as a localızing factor in the subsequent deposition of cholesterol In hypertensic or luctıc aortas thus material is present in cven greater amounts corresponding to the increased cholesterol Rmeliart and Greenberg (1949) observed an increase in a basophilic mucoid inatorial with the staining reactions of a mucopolysaccharide in the intimal ground substance of monkeys suffering from experimentally induced pyridoxine deficiency in prolonged experiments (ivhich incidentally do not invoke the feeding of cholesterol) lipids accunzulate in these mucoid arcas resulting in typical atherosclerotic plaques (Rinehart and Grenurg 1951) While these auchors do not claim that pyridoxine deficiency is the cause of human atheroso ·LOCAL PREDISPOSING FACTORS sclerosis they consider that the morphology and distribution of the monkey lesions bear 2 much closer resemblance to their human counterparts than does cholesterol atherosclerosis (Roehart 1954) Moon and Rinehart (1952) observed an increase in mucoid ground substance in the ultima and media of early lesions in human coronary arteries accompanied by a fragmentation and degeneration of elastic tissue This is followed by proliferation of collagen and elastic fibres and the deposition of cholesterol in the deeper lazers presumably carried there by the 125a vasorum and not through the intima Calafication intramural haemorrhage and thrombosis arc all late complications Small amounts of the mucoid substance are present in the normal aorta both in the intima and surrounding the clastic fibres of the media acting both as a cerent and as a marnx in which these fibras glide (Reseliart and Abul-Haj 1951) It is suggested chas it may be a mother-substance from which collagen and elastın are derived At all esents it appears to have an affinity for the scrum lipids OTILER LOCALIZING FACTORS Most of the cvidence from the isolated observations quoted below is derved from experiments whuch involve only one type of animal or from the use of traumata with no parallel in human atherosclerosis For example Paterson et al (1948) have shown that spontancous hydropic degeneration of the media occurs in the coronary arteries of certain breeds of chicken accompanied by secondary atherosclerosis Feeding of cholesterol causes more lipid to be deposited at the site of these spontaneous lesions Again Taylor et al (1950) and Kelly et al (1951) have confirmed Ssolowjew s experiments by first freezing segments of the rabbit s aorta with a cold necdle and then feeding cholesterol The lipid 15 deposited over the traumatized segments However medial disease as a precursor of human atherosclesosis (eg in syphiliac aortuis) has long been recogruzed The objection to the experiments quoted is that (assumng karty sercakung is an early form of atherosclerosas) they fail to explain the early istimal lesion occurring in the absence of demostrable medral disease in shost they do Iittle more than establish the fact that the deposition of cholesterol may be determined by local factors without revealing what those factors are As regards coronary atherosclerosis at least one localizing factor may have been explained by Gerringer (1951b) who showed that one in five coronary arteries runs for all or part of its course within the substasice of the myocardium Such sesscls have a thinner intima than their epicardial counterparts and atherosclerosis is much less common in them This Jends support to Leary s view (1936a) that contraction of the veritncles compresses dhe distal (or intramural) portions of the coronary vessels so imposing an urinatural strain on the proumal epicardial segments during systolc Mention has been made of the theory of Dock (1916) who considers that the unusual thickness of the coronary intima even at birth predisposes to atherosclerosis in latcr life Il sens (5991) has observed diffuse innmal thickening in other artenes prone to atherom st ·THE PATHOGENESIS OF CORONARY OCCLUSION sclerosis which he thinks is not a natural development but is related to the same mechanism that causes the plaques His earlier work also deserves comment He found thar loss of clasticity in the human aorta is directly related to the age of the subject and that the earliest and largest lipid deposits occur in areas most subject to loss of recoil He therefore suggested that lipid infiltration of the intima is related to immobility of the vessel wall (iVilens 1937) In Chapter IV I referred to the work of Hirrison (1939) who induced arterial dilatation (and presumably dımınıshed movement) by lumbar sympathectomy and found more severe atherosclerosis in the leg arteries on the affected side IVilens (1942) fitted silver cuffs round the caroud and femoral arteries of rabbits to render the enclosed segments less mobile and observed that cholesterol feeding causes more extensive lipid deposits in the immobilized vessel than clsewhere in the arterial tree Enough has been written of the historical background the scientific liccrature and the conflicting chconies concerning the pathogenesis of coronary sclerosis cnough at any rate to indicate the importance of the thrombogenic hypothesis with whuch Part Two of this work is largely concerned مهر

·PART TVO
A STUDY OF THE MORPHOLOGY OF
CORONARY OCCLUSION
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·YVIII Methods and Mateuals The next eight chapters are devoted to a histopathological study of coronary occlusion The work was originally undertaken in an attempt to assess the role of capillary haemorrhages in atherosclerotic plaques as a factor in coronary occlusion (Paterson 1936) and to examine the thrombogenic hypothesis of Dugind (1946) – a viewpoint it must be admitted which at the outset the present author was reluctant to accept It was felt that a three-dimensional picture of the more seriously diseased segments of occluded coronary arteries might best be obtained by serial sections and differential statning Similar methods had been employed by previous investigators but on a smaller scale and with limited objectives It was also considered advantageous to try to assess the extent and degree of atherosclerosis in the whole coronary tree and to compare these with the condition of the rest of the cardiovascular system Thus Chapters XXV-XXIX contain a rough attempt at correlation between coronary atherosclerosis and the state of other visceral and skeletal arteries the condition of the kidneys cardiac weight and myocardial infarction For the purpose material was collected from 40 consecutive cases of advanced coronary disease Thirty-cıght died of coronary insufficiency 2 of unrelated causes (No 3 spontancous rupture of the aorta No 18 carcinomatosis and bronchopneumonia - see Table B) Twenty-six of the 38 werc cascs of sudden death -2 being ambulant individuals who died at home at work in the street in the ambulance or within an hour of admission to hospital these were examined on instructions from the Coroner The other 4 sudden dcaths were in hospital during convalescence from other illnesses (No 9 chronic nephritis No i gastrectomy for peptic ulcer No 14 pneumonectomy for carcinoma No 25 diabetes myxocdema and hypertension) The remaining 1. were examples of gradual death from coronary discase - 1 e dying in hospital some days or weeks after a hcart attack At first it was felt that the cardiovascular system of those dying suddenly would yield more accurate information on the pathology of acute coronary insufficiency than those dying with myocardial infarcts some days or weeks lacer where extensive chrombosis is the rule but the advantages of examining and comparing both types were rapidly appreciated in all 116 blocks of coronary artery were sectioned senally and some 5700 sections examined Their distribution as to the branch affected and the type of death is shown in Table C It is important to remember that although the whok coronary trce was examuned macroscopically the microscopic study was confined to segments wholly occluded or severely narrow cd and did not cover carly lestons It is therefore concerned with the 55 ·THE PATHOGENESIS OF CORONARY OCCLUSION serious late effects of coronary atherosclerosis and only indırcctly with the much wider problem of atherosclerosis TABLE B Cast no Age Type of Death L. Cor LA I M SO Gradual Block Sert oned Se tally L Cor Thisk DB amfier R Cor Other Ail psy r dngs Cerebral embolism Bron hopneumona 1 Spontaneous rupture of Aorta T 2 M M SI Sudden 67 Other cau es 3 4 5 M M 66 Sudden 14 Gradu ] II 1 Malignant hypert n ton and tiracmia Chron: pulmonary tuberculos: 6 M 55 Sudden 1 7 8 A 11 74 Sudd 4) Gradual Hyperte sion and pulmonary ocdens Ellis type Il nephr tus hyperten on syph 9 M 48 S dderi ort tus 2 10 II 12 M F M1 68 Sudden 68 Sudden 76 Sudden 13 14 IS 16 17 18 M M1 M F M F 59 Gadual SS Sudden 78 Sudd n 6 Crad al 54 Sudd no Othe cause דור ודורון 7 1 3 Post gastrectomy Myomalacia ordis nd hemoperi ard um Mult ple infacts Post ne monectomy Muit plc infarcts Mela om of sye with multiple mecast ses P cumont 2 Mulc plc infarces Diabetes mellitus 19 O 21 2 3 24 25 M1 M M1 M F м F 70 Sudden 37 Gt dual 64 Sudden 58 Sudd n 74 Cr dual 75 Sudden $) Sudden 1 Di betes Infarct of bain S Diabetes myrocdem hypertension 26 7 M M M 67 Sudden 59 Sudden 66 G dual 8 Post pro tatecton y Hyr rien 11 29 JO 31 32 33 34 35 36 37 78 39 40 M M M M M M M ME F M M1 M 6) S dden 71 Sudden SI Sudden 47 S dden $9 Gadual 53 S dden 80 Gradual 48 Cadust 04 Sudden 63 Sudden 67 Gadual Sudden Acute pastrc ulcc Myon alacia cordis Hypertension I Hyp rtension SO 49 56 ·METHODS AND MATERIALS TABIE Sudden Deutsk Grada Death from Oda Caves Tuis No of Cases 2-5 12 2 40 No of Blacks 30 B 138 2 LCs (Trunk} LADD I Curcumnex R Cor 22 26 1$ 3 20 SO IS 49 PROCEDURE During the autopsy the coronary arteries were subjected to as few clits as possible in establishing the cause of death These were made at nght angles to the long axis of the vessel and opening the artery by sitting along sts lumen with fine-pointed scissors was expressly avoided since this method as dfanie observed as long ago as 1896 as bable to disladge an unsuspected shrombus not to mention the further disadvantages of damagug the vessel lining and destroying the continuity of the vascular coats in the subscquent microscopic examination The heart was then weighed packed with cotron wool soaked in s per cent formolsaline and fixed along with che whole aorts and segments of visceral and peripheral arteries The choice of brachial poputeal and renal arteries for comparison was to some extent arbitrary but to give some sort of unformity the limbartesies were always removed at the same level-sc har of the adjacent joints - and the renal artery sampled in its middle third When complercly fixed the coronary arteries were examined throughout their cpicardial course by making a series of slices ar ngkat angles to the long axis of the vessel at intervals of approximately s mm Diseased segments were listed under one of the following headings Left Coronary Artesy (mai trunk) - Left Anterior Descending Branch 3 Left Circumflex Branch 4 Right Coronary Artery and its Mam Branches Those slices showing gross narrowing or occlusion by atherosclerosis intimal haemor chage or thrombosis were then transferred to Perenyi s Fluid* (to facilitate decalafication) a note besng hepe of these sequence and the distal aspect of each block of tissue being identified by a short loop of horschar threaded through the fat or muscle surrounding she artery This ensured that all segments were bloched with the provmal surface towarde the cutting end of the block After decalcification the vessels were processed in the usual say and blocked in paraffin. * Set appads $7 ·THE PATHOGENESIS OF CORONARY OCCLUSION In this manner it was possible to cut serially through several blocks comprising a diseased stretch of artery perhaps several centimetres in length, and with a minimum of tissue loss Most of the occluded segments could be included in the course of two or three blocks less commonly six to eight were necessary Serial sections were then cut at su and cvery sixth section mounted the remainder being preserved between shects of paper for future use if required Each slide could conveniently accommodate thrcc sections and as six different stains were employed the sections were mounted in batches of cighteen in the following manner (3) 37 73 7 43 79 13 4) 85 19 15 91 25 61 17 31 67 103 It was appreciated from the outset that hacmatoxylın-cosin is an inadequate stain for vessels gencrally and for atherosclerotic arteries in particular Muscle elastic fibres collagen reticulın fibrın conglutinated red cells – all stain an almost unuform rcd colour and the varied naturc of an intimal deposit may be overlooked as shown in Figs 5-6 As there is no onc stain which reveals all the clements involved normal and abnormal the following were employed in regularly rccurring series Haematovy lin-cosin Sheridan s clastic stain* Periodic Acid-Schuff Heidenhain s Azan Foot s Silver Impregnation Phosphotungstic Acid-Hacmatovylın In the first few blocks cxamined the Benzidune and Prussian Blue reactions were employed routinely but the practice was discontinued in view of the limited or redundant information they yielded It will be seen that the mounting of every sixth section cut at su means that it is possible to compare differently stained sections at intervals of 3ou throughout the block procceding along the vessel in a distal direction The average block yıelded about 100 sections by tłus reckoning The comparison was effected by means of a comparator eyepiece mounted on tuo microscopes (Fig 4) the two images occupying their respective halses of the visual field (sce Frontispiece) Equivalent areas of consecutive sections differentially stained could then be studied at varying magnifications without the observer having to depend on the memory of a visual image and without unduc ocular strain This method enables one to construct a three-dimensional image of the elements involved in repair recanalization anomalous vascularization intimal haemorrhages lipid accumulations calcified plaques fibrnous encrustations mural thrombosis ctc The * Sec Appendix 58 ·METHODS AND MATERIALS absence of fat staining is an undoubted flaw in the method but for the present purpose it would have been impossible to maintain and follow the continuity of the finer structures by any other method than that employed In each case the thoracic and abdominal aorta were sectioned and in the great majority the brachial popliteal and renal arteries Where necessary a similar technique of serial section was employed but in the aorta and other artenes where serious narrowing is not a feature the various accidents and adaptations in the diseased intima are less complex and can be conveniently studied by a single set of six serial sections stained differentially The appearances in the coronary arteries are described first To facılıtate descriptions which are apt to be tedious numerous photomicrographs arc appended and these form an integral part of the argument The wide variety of the nucroscopic lesions makes it impossible to asscss the frequency of each in terms of percentages and it is hoped that the volume of material examined will be considered a mutigating feature for the use of such vague terms as frequently sometimes rarely etc 59 ·THE PATHOGENESIS OF CORONARY OCCLUSION In this manner it was possible to cut serially through several blocks comprising a diseased stretch of artery perhaps several centímetres in length and with a minimum of tissue loss Most of the occluded scgments could be included in the course of two or three blocks less conimonly six to cight were necessary Serial sections were then cut at su and cvery sixth section mounted the remainder being preserved between sheets of paper for future use if required Each slide could conveniently accommodate three sections and as six different stains acre employed the sections were mounted in batches of eighteen in the following manner (3) (s) (6) 7 19 37 73 43 ng 13 4) 85 23 бі 97 31 6 TO 91 It was appreciated from the outset that hacmatoxylın-cosin is an inadequate stain for vessels generally and for atherosclerotic arteries in particular Muscle clastic fibres collagen reticulin fibrın conglutinated red cells – all stain an alniost uniform red colour and the vaned nature of an intimal deposit may be overlooked as shown in Figs 5-6 As there is no one stain which reveals all the clements involved normal and abnormal the following were employed in regularly recurring series Hacnuatoxylin-cosin Sheridan s elastic stain* Periodic Acid-Schiff Heidenhain s Azan Foot s Silver Impregnation Phosphotungstic Acid-Hacmatoxylın In the first few blocks evanuned the Benzıdıne and Prussian Blue rcactions were employed routinely but the practice was discontinucd in view of the lunited or redundant information they yielded It will be seen that the mounting of every sixth seccion cut at sh means that it is possible to compare differently stained sections at intervals of you throughout the block proceeding along the vesscl in a distal direction The average block yıcided about 100 sections by this reckoning The comparison was effected by micans of a comparator cyepiecc mounted on two microscopes (Fig 4) the two images occupying their respective halves of the visual field (sce Frontispiccc) Equivalent areas of consecutive sections differentially stained could then be studied at varying inagnifications without the observer having to depend on the memory of a visual image and without undue ocular strain This method enables one to construct a chrec-dimensional inage of the elements involved in repair recanalization anomalous vascularization intunad haemorrhages lipid accumulations calcificd plaques fibrinous encrustations mural thrombosis etc The * Sce Append 58

·PATHOLOGICAL CHANGES IN THE ADVENTITIA AND MEDIA
FIGS
Anterior descending branch L coronary artery Cro
sgt & ring deformity Case 31 HE 25
Fico
htlicom
Same essel, showing
Az 1923
irt che plugu
F1C1
occur.
Ad ent tual congestion sucre corora
LADB Case it PTAH X 18
FIG $
Penyasula lymphocytosis of ad mtaa R. Cor Case
HE

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 9
Atheromatous abscess in dscntit a surrou ded by foan
cells and altered blood peg nent R Co
Case 18 HE
x65
FIG ID
Atrophy of media at b se of plaq c R Cor Case 34
Sheridan x 30
2
FIC II
Gap in nedia at base of plaque L Corcunuflex Case 25
PAS X 30
FIC 12
Fee va cular comunication through gap 1 med
Curcumiex Case 35 A an X 30
L.

·PATHOLOGICAL CHANGES IN THE ADVENTITIA AND MEDIA similarly affected The significance of this is difficult to assess particularly in relation to syphilis The lesions were scanty compared to the extent and distribution of atherosclerosis and were not related to the main coronary orifices in the aorta In many cases there was no other evidence of syphilis clinically serologically or in the aorta or other arteries and such a diagnosis would have to rest on the appearances in the coronary vessels alone With such a chronic and pervasive infection as syphilis ngid cxclusion of the diagnosis is hardly possible but in the total absence of lesions elsewhere It seems more likely that the infiltration is a low-grade reaction to the atherosclerotic process possibly concerned in the scavenging of degenerate material Horn and Fmhelstern (1940) observed similar lymphocytic accumulations and unless these were accompanied by endarteritis of the vasa they were regarded as non-syphilitic These authors pointed out that in four of their cases of syphulitic aortitis the coronary vessels showed simple atherosclerosis only It has also been my experience that adventitial lymphocytosis can occur in definitely non-syphilitic conditions notably the arteriosclerotic aneurysms of larger arteries where it appears to be an inflammatory reaction to the subjacent thrombosis RARER LESIONS Hiemorrhage into the adventitia was observed only once in a hypertensive female aged 61 with a dissecting aneurysm of the media of the left coronary artery A somewhat similar case was recorded by Uehlinger (1947) On another occasion a form of atheroniatous softening in all respects resembling an atheromatous abscess was found in the adventitia (Fig 9) apparently nght outside the vessel but this was shown a few sections later to communicate with a similar lake of altered blood and lipid in a large intimal plaquc from which it had been extruded through a small gap in the degeneratıd media The only reference encountered in the literature relating to lesions of this type was a paper by Lerry (1936a) who recorded an atheromatous abscess of the aorta which ruptured through the adventitia and caused death vaşa vasorum CHANGES IN THE MEDIA These are (a) Atrophy (6) Penetration by hypertrophic (a) ATROPILY The late results and complications of atherosclerosis are to a great cxtent determined by the width of the vessel involved in the aorta atheroma is largely confined to the intima and does not encroach seriously on the lumen Some degree of fibrous replacement of the musculo-clastic tissue is sometimes noted in the superficial (1 e innermost) media just below the plaque but only in very advanced cases is this sufficient to cause serious weakening and it is generally agreed that neither dissecting aneurysins nor arteriosclerotic aneurysms are due to atheroma per se but to degenerative changes in the medial muscle In coronary atherosclerosis however the base of an intimal plaque is much larger in relation to the circumference of the vessel at once causing narrowing of the lumen and 63 or clastic ·THE PATHOGENESIS OF CORONARY OCCLUSION disuse atrophy of a large part of the media The degree of medial atrophy is considcrably less conspicuous in haematoxylın-cosin preparations than in sections selectively stained to show up muscle or elastic fibres These reveal that the atrophy is usually co-extensive with the intimal plaque. (Fig 10) or diffuse if the intima is thickened uniformly Over the thickest part of the plaque the media may be absent altogether (Fig 11) or represented by the approximated layers of the internal and external lamınae only when this occurs there may be a very free communication between the adventitial vasa and the vessels in the plaquc (Fig 12) It is inconceivable that the atrophied media splinted by a rigid plaque of intimal fibrosis perhaps six or cight times as thick as the media itself should be capable of contraction and it is thus probable that distese is a major factor in causing the atrophy In some instances however degenerative swelling of the plaque especially if decply placed and calcareous appears to be capable of exerting direct pressure on the adjacent media resulting in focal atrophy An extreme example of pressure atrophy due to focal calaficarion is shown in Fig 13 Crawford and Let ene (1953) have argued that if the atrophy is due to disuse the media should be thunned without being bulged outward by the plaque and that as the only pressure to which the media is subjected comes from the lumen the interposition of an atherosclerotic plaque cannot increase the pressure to which the media is exposed These arguments do not take sufficient account of the fact that any muscle will atrophy if it is denied the power to contract and chat once weakened in this way it as liable to stretch (6) PENETRATION BY HYPERTROPHIC VASA VASORUM Though seldom encountered in single routine sections a very constant feature of discased coronary arteries is the periodic interruption of the media by abnormally large vasa vasorum The prominence of the adventitral vasa has already received comment and their penetration of the media is merely a stage in their passage to or from the thickened intima Their significance will be more fully discussed in a later section In the healthy media the vasa are quite inconspicuous and require special injection techniques for their demonstration Ivoodruff (19-6) and Robertson (1929) although differing slightly on the depth of penetration were agreed that the vasa normally stop short of the internal clastic lamina and that the intima is nourished directly by the blood in the lumen The extensive literature on thus aspect of the subject has been ably condensed by Ramsey (1936) In acherosclerosis however the penetrating vasa may be wider than the media itself (Fig 14) a phenomenon frequently exaggerated by the corresponding atrophy of the latter in fact Geininger (1951a) holds that the gaps so created are capable of weakening the media and in the example illustrated in Fig 12 this may be true But a hiatus of such magnitude is rare and even with the smaller ones a false impression may be gained from a two-dimensional cross-section The media immediately proumal and distal to the average gap is intact and these infrequent becaches represent no more than a few minute and sudely separared perforations in a substantial layer of muscle and elastic 6.4

·PATHOLOGICAL CHANGES IN THE ADVENTITIA AND MEDIA
FIG 53
Fo I calaf cat on 17 peu
Cor Case 35 PTAH30
atrophy of meda R
FIG 14
Huxe plan b hank toph didat josta
Crescent of esel 6 of luc LADB C G
PAS * 45
7
1
Fic 15
Normal o out y tory fom a fensa! aged 31 who de
of m le pl anu'es HEX 135
FIG 16
5 g - gd fomny sonny i jening RC Cases
Shadon x 4

·THE PATHOGENESIS OF CORONARY OCCLUSION
V
FIC 17
Con chiri th kening of nitt 13 due to ove lapping of
deposits LADB Case 10 Sh di 30
FIG 18
Irregula lycri causan signet n g deformity R Cor
Case o Sh rid 1 0
FIG 19
Recent depos sta ruing 1 ke collagen superisiposed on
older denser d posc R Cor Case 34 Sherida a Y 30
KG 20
Elastosis extending beyond base if plaque Its posicitated
by a large vas LADB Case 23 Sherid 110

·The Episodic Nature of Intimal Deposits In the first few hundred sections examined the differential stains revealed bewildering contrasts of a variety unsuspected in the haematorylin-eosin preparations but later it became possible to disentangle the various clements and to recognize certain patterns that tended to recur throughout the series One of the earliest impressions gained was that coronary atherosclerosis is not merely a progressive disease but that it progresses in a series of episodes rather than gradually This is in accordance with Dugud s view that severe narrowing is the result of recurrent thrombosis The subsequent findings in the present investigation all tcnded to support this contention It should be re-emphasized however that this study has largely been confined to the more severe degrees of atherosclerosis A rough grading of the scvcrity of coronary narrowing has been made by It hite it al (1950) in which they recognize four degrees (a) Slight diffuse thickening of the intima (6) Concentric thickening of the intima up to a thickness of two or three times greater than that of the media (c) Signet-ring atheroma narrowing the lumen to about half its original width (d) Subtotal occlusion in which the intima is reduced to a tiny slic to one side of the vessel It will be seen from the subsequent photomicrographs that the majority of the series were on grades (c) and (dl) For comparison the wall of a normal coronary artery is shown in Fig 15 Before considering the evidence for the episodic nature of coronary atherosclerosis an argument to the contrary may bu quoted from a study of 536 hearts with coronary disuase Lober (1953) has demonstrated a steady parallelism from youth onwards between the subjects age and the degree of coronary sclerosis This merely confirms what was alrcady known namely that atherosclerosis increases with age and it is difficult to see why Lober and his supporters should claim that this work disproves the episodic naturc of the disease Whether atherosclerosis be episodic or gradual due to recurrent thrombosis or gradual lipid accumulation there will still be a correlation between the age of the subject and the degree of intimal thickening A LAYERING In haematoxylın-eosin sections the intimal thickening may be signet ning or concentric in type according to whether the lumen is eccentrically placed or not However selective staining of the elastic tissue reveals that there is no essential difference in the nature of the deposits both showing the phenomenon of recurrent layenng In signct-ring deformities the serial layers are sct one on top of the other (Fig 16) whereas in concentric 67 ·THE PATHOGENESIS OF CORONARY OCCLUSION narrowing a series of roughly crescentic deposits Overlap (Fig 17) SRING thic impression that the roundness of the lumen has been preserved by the force of the blood-stream Fig 18 shows how a sig net-ring deformity may also be produced by irregularly overlappmg deposits Each laver consists basically of a network of coarse fibres with the tinctoral rcactions of collagen with feu cells and a nuagte blood-supply The most recent de posit is usually less dense than its predecessor (Fig 19) Superadded features are foc of hacmorrhage old or recent and various forms of degeneration and inccrosis lipid accumulations or plaques of calcification B INCREASED ELASTIC An increise in the amount of intimal clastic is a prominent feature 117 coronary occlusion and takes three forms (1) Multiplication of the internal clastic lamina (2) A covorng of the scrial deposits by fine clastic membranes (3) Elastic cn clopment of the bloodspaces in a recanalizing thrombus (1) MULTIPLICATION OF THE INTERNAL ELASTIC LAMINA Jores (1898) observed a hypertrophy of the intimal clastic of arteries which increases with age He did not regard this as the result mcrcly of physiological ageing however but as a pathological process due to increased strain Thayer and Fahyan (1907) showed that reduplication of the internal clastic lamina can be scen in the radial arteries of healthy children and by the thurd decade is a constant feature Since it may occur in the absence of atherosclerosis or hypertension they believed the elastic changes sigrufied wear and fear of ageing arteries rather than a specific discase Others have claimed that clastic reduplication is not a primary change but is preceded by degenerative lesions in the intima both in the human subject (Klotz 1915a) and experimental anunals (Saltylor 1908) Whether the phenomenon be degenerative or regenerative in origin the term elastosis will be used in this text in the interest of brevity to signify the increased layers of intunal clastic that frequently lic at the base of atherosclerotic plaques (Fig 22) It has now been shown that the coronary arteries of healthy infants shosi reduplication of the internal elastic lamına soon after birch (Gross et al 1934) At an early age longitudinal muscle fibres proliferate to form the nursaulo-elastic layer and the inner classic membrane continues to split off finer layers to forni the elastic hyperplastic layer a process that increases with age Fibrosis calcification and lipid deposits are regarded by Gross as late secondary phenomena the whole process being the inevitable result of ageing Gross s obscrvations were made on individuals who had not died of cardiovascular disease The relation of age to atherosclerosis is discussed in Chapter IX at this stage one may observe that attempts to scparate the physiological from the pathological in thc ageprocess have not only been unsuccesstul but have led to confusion Many others have looked on this fibro-elastic thickening of the intima as an indication of that intimal damage which predisposes to lipid infiltration and atherosclerosis It is *The tern is uxdın the sense of an increased nun ber of fb es without implying acti e prol ferat of the way in since lett known hich clastic tissue is formed 68

·THE EPISODIC NATURE OF INTIMAL DEPOSITS
FIG 21
Elasto s showing d scontinu ty and poor taining quality
of new fibres LADD Case 32 Sheridan x 75
FIG 22
Thick Layer of clasto is between media and vascular
Crescent (c pre cding pl que formation) LADB
Case 16 Shend 11 x 35
cele mai
FIG 23
Sc al lic Layers continuous with chi ti at marg s of
und fading off towards centre of plaque R Co
FIC 24
Deposit to dmo hofb ch artery show & Lyering
nd co tinuty fel tcm mbranes with elastic of br ch.
LADB Cake 30 Sherida Y IS
Det er het hom

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG
Serual clastic latrinae ontinuous wath clast at margins of
plaque defectu e ner centre Considerable el stosis.
LADB C se 16 Sheridan x 35
FIG 26
Magn of pl que shown g serial clasti laminae on
tinuou with intemal lamin of vesel R Lo Casc 29
Sherid 1 X 40
FIC -7
Buned clistic probably distorted by rupture due to
bact otthage R. Cor Case Sheridan x 45
FIC 28
Recanalized thrombus showing clastic lo ng blood spaces
continuous with clastic of branch vessel R. Cor Case IS
Sheridan x 40

·THE EPISODIC NATURE OF INTIMAL DEPOSITS arturly a fairly regular feature of atherosclerotic vessels but the extent of the elastosis us nos confined to the arca of the plaque (Fig 20) The finer fibrls benveen the man layers lack the continuity and sharp affinity for orcein that characterize the healthy lamuna (hig wi) and it may be that these are cather an immature or a debised form of the threcker membranes in some plaques a brond layer of elastosis at their base is a prominent feature (Fig 22) (2) COVERING OF SENIAL DEPOSITS In the substance of the plaque itself are fine elastic membrates sharply demarcaring the serial deposits and continuous with the clastic at the margins of the plaque (Fig -3) or with the healthy intima of a branch artery (Fig 24) The central part of the membrane may be defective (Fig zs) as though a fresh deposit had occurred before the elastic coating of the old one was complete As the recurrent deposits become thicker a phenomenon already referred to as layering their elastec integuments are more widely spaced and advanced accunzularise lesions the senal layers of elastic may be clearly presened (Fig 20) Fragmentation or distortion of the layers such as appear in Fig 27 are unusual and probably due to secondary degeneration or hacmorrhage in the plaque The resistant nature of elastic assuç is notorious and it is the last formed element to disappear in necrotic lessons like infarcts or gummata The importance of this observation lies in the fact that an clastic membrane deeply situated in a sclerouc plaque could act as a barrier to the ingrowth of nutrstive vessels from the media The continuous clastic membrane also appears to prevent firm inon between the collagenous surfaces on eithes side of it so affording a natural plane of fission between deposits when the plaque is disrupted by haemorrhage This occurrence is dealt with in Chapeut XXIV under Dissection The purpose of the newly formed clasic can only be guessed at but i docs seem to form a protective covering for the discased and porous antima a basis for a new endothe- Ital luing and a burtress against the blood-flow at arcersal pressure (3) PLASTIC TISSUE IN CANALIZED THROMBI A simular phenomenon is observed in the course of recanalization of a thrombus where the clastic can be traced from the mima of a branch to the liming of blood-spaces formed by retraction of the clot (Fig 28) It would appear tizat whenever blood takes a ress cousse classic tissue forms a protective wall around it and that when a new blood channel is forned an effectue clastic membrane in its wall is a condition of its permanence Irregularly disposed elastic may also be seen in the heart of an organizing chrombus enshcathug the newly formed blood channels (Fig -2) and both clastic and blood channels can be traced in serial sections esther to the lumen at onc or other end of the thrombus or more frequently to the mouth of a branch artery It is of interest to note that young elastic tissue stams vividly in PAS preparations apparently before it has acquired an afwury for orcein (Figs 30 31) 71 ·THE PATHOGENESIS OF CORONARY OCCLUSION C SMOOTH MUSCLE PROLIFERATION The apparently reparatic qualities of clastic tissue arc cqualled in cxtunt if not in frequency by smooth musclc which proliferates freely in atherosclerotic plaques or segments occluded by organized thrombosis This is a phenomenon liable to be overlooked in hacmatoxylın-cosin preparations though it shows up readily cnough in sections stained by PTAH or Azan Musclc-fibres in plaques can usually be traced to one or other of the followmg (1) The media at the margin of a plaquc (Fig 3-) (2) The longitudinal fibres of the musculoelastic layer (Fig 33) (3) The media surrounding the mouth of a branch vessel (Fig 34) In one instance muscle fibres appear to have grown directly into the plaque from the media at its base (Fig 3») The new muscle usually lies just below the lining of the narron cd lumen sometimes completely cncircling it and apparently serving no useful function (Fig 36) Sumirly in organizing thrombı muscular ingrowth as with the elastic can be traced to the vessel wall at either end of the clot (Fig 37) or from the mouth of a branch vessel (Figs 38 39) encircling cither the blood-spaces formed by retraction of the clot or the small channels supplying it although only a minority of the latter may be so favourcd (Fig 40) As with the elastic growth may be rather irregular or excessive On one occasion a substantial cylinder of new muscle had formed round the vascular channels running through the heart of an organized thrombus completely surrounded by a thick layer of atherosclerosis (Fig 41) The similarity in distribution between new muscle and clastic tissue suggeses a simular rationale namely the provision of clements required to furnish a new artery wall irrespective of whether they can function effectively or not The significance and origin of smooth muscle fibres in early intimal threkening have been considered at length by Altschul (1950) Finally the tendency for elastic tissue and smooth muscle to occur both in atherosclerotic plaques and in organizing thrombi should not go unnoticed by protagonists of the thrombogenic theory

·THE EPISODIC NATURE OF INTIMAL DEPOSITS
)
FIG 30
FIG
El stic irreg 1 rly she thing blo d-sp n recanald
th ombus R Co Case 7 Sheridan 45
E rc like ti su tily PAS po ti
cogniz)
thrombus (fFg 31) R Co CscIO PAS 30
FIG 31
Th same show Ebsence of Futy of ela ac like tuss
fr re orci
Sheridan X 30
FIC 32
Muscle grow g into plaque fom med at its margih
where clastic lam na is defecte LADB Case II
PTAHY 60

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 34
FIC 33
Muscle app rently anang fom fbres internal to shner
clasti la uha (scen as a white vylune) LADD Case
8 PTAH
45
Aluscle at marun of plaqe directly ontinuous sth
med: of b anch essc R Cor Cas 3S PTAH Y 33
FIC 35
Proliferating muscle deep in plaque linked with medus by
growth round a nutrient capillary LADB Case 23
PTAH X 85
FIC 36
Complete encuçlement of a towed lumen by musele
fbres. L Circun Alex Case YTAH X

·THE EPISODIC NATURE OF INTIMAL DEPOSITS
FrG 37
Org nized thrombus w ch new blood-hrinel surrounded
ty non-funcuonung ss oth suscle L Cucu Aer Case
3
PTAH Y 30
FIC 38
Muse! grow ng mor en lized thrombos from ned a of
or rea II 1) ICE FIS 30) R Lor se IS PTAH X
40
FIG 40
FIG 39
Th same Higher thagtu cation of adj en segon
showing muscke za spruer berwcen blood graces PTAK
Org nzug thrombus showing muscle sound one Nood
part nly 1 Cor Cake to PTAH* 45
Y75

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG 41
Cylinder of muscle urrounding blood-chann Is in centre
of recanadız d thromb , R Cor Case 7 PTAH JS
FIG 42
Superfcial and deep fbrosis wth termedi te zone of
degeneration R Cor Case 28 Sherid n x 35
FIC 43
Vessel penetrating media to link up with peniphe al blood
sunuses thase of plaque R. Cor Case 25 PAS X 75
FIG 44
Large y s traers gm da to join blood suos tb se
of pl que LADB Case 16 Azan x 40

·VI The Role of Intimal Vascularization and Hiemorrhage INTIMAL VASCULARIZATION More important in the evolution of coronary atherosclerosis though perhaps less spectacular is the proliferation of capillaries throughout the plaque To comprehend what follows a brief consideration of the earlier literature is necessary The intima of healthy human arteries as stated previously is nourished by direct imbibition from the blood in the lumen and is not supplied by the vasa vasorum (II oodruff 1926 Robertson 19-9) In atherosclerosis however the bulk of the plaque renders some degree of vascularization necessary if nutrition is to be maintained Vascularization of the intima in arterial disease was known to Rokitansky long ago (1841-46) until recently however its role in the pathogenesis of coronary occlusion was overlooked Wolkoff (19-9) described a plexus of small vessels in atherosclerotic patches derived from the vasa vasorum and from capıllaries communicating directly with the main lumen but she regarded its function as connected solely with the resorption of lipid from degenerate plaques and not as an important factor in the evolution of the lesions Similarly Leary (1935a) stated The influence of the vasa vasorum in connection with the lesions of atherosclerosis is relatrely unimportant However Paterson (1936) found that haemorrhage from the capillaries in athero sclerotic plaques was a frequent source of coronary thrombosis He attributed a nutritve function to the vessels the plexus derived from the vasa supplying the deeper part of the plaque the superficial network arising from the lining endothelium to subserve the top layer These two plexuses communicated but as some of the vessels lay in degenerate areas they were liable to be ill-supported and certain of them communicating with the main lumen at arterial pressure were prone to rupture In a later paper (1938) he maintained that secondary thrombosis in the lumen could result from (1) Superficial haemor- Thage causing diffusion of a thromboplastic substance from the intima to the lumen (2) Rupture of nutrient capillaries leading to necrosis of the overlying intimal lining (3) Retrograde thrombosis from a ruptured capillary in the direction of the lumen I artman (1938) showed that a larger haematoma in the depths of the plaque could cause fatal occlusion merely by raising the overlying intima and compressing the lumen to a narrow slit H interniz and his associates (1938) by employing the Spalteholz technique on diseased arterial segments were able to confirm the eastence of the two communicating vascular networks but the value of their work was somewhat marred by their arguments (1) that the healthy intima has a capillary blood supply (a claim they were unable to substantiate) and (-) that atherosclerosis is no more than the end-result of repeated intimal haemorrhages a theory that brought a reminder from Leary (1938) ·THE PATHOGENESIS OF CORONARY OCCLUSION that atheroma begins in the most superficial layers of the intima in the part furthest removed from the vasa Following Digurds theory of the thrombotic origin of atherosclerosis carlier beliefs ucre somewhat modified Geirmger (1951a) dev cloping Paterson s concept mamtained that vascularization is a function of intimal thickness and that when the coronary intima excecds the critical thickness of o 35 mm nutrition by imbibaion from the lumen is no longer adequate and vessels grow into the plaque to nourish it The deeper lavers are supplied by transnicdral ingrowth from the adventinal plcxus the superficial zone by vessels derived from the organızıng thrombus which (by Duguid s postulate) is the basis of the plaque These two plcxuses may anastomose but should the superficial one be laching the plaquc is sustained by the vasa alone and necrosis of the central part mav follow Crau ford and Learn (1952) have advanced the theory that the superficial plexus 15 derived from the endothchum of the lumen which overgrows the clot from its margins They believe that endothelial cells are also capable of assuming the function of fibroblasts and help to organize the superficial part of the thrombus The superficial and deep organizing processes may fail to link and the residue of the clot deprived of blood may undergo fatty dcgencration and necrosis This would account for the appearance of Fig 42 in which the degenerate zone is sandwiched between inner and outer rings of fibrosis a not uncommon phenomenon The present investigation carries these arguments a stage further The concept of sup - ficial and deep vascularization is sustained with certain modifications set forth below asa vasorum The deep plus Reference has been made to the gaps in the media caused by the passage of hypertrophied On entering the base of the plaque these often link up with a series of peripheral blood sinuses (Fig 43) The latter though thin-walled are not capillaries in the ordinary sense being much larger and often irregularly shaped Crescents of these Saiu es are scen between the media and the base of the plaque (F1g 44) and this distribution is so striking that it is difficult to escape the conclusion that they are the late result of retraction of the thronibus from the vessel wall-ie marginal recanalization Their mode of origin in a recently thrombosed attery is suggested by Fig 45 Thus belief is strengthened by a study of plaques showing layering When a second thrombus is deposited on the first a crescent of vessels derived from the endothelium couching the first chrombus may be formed berw cen the deposits (Fig 46) If therc are several deposits the vascular crescents may be found to be closely related to the clastic membranes separating them (Figs 47 48) The stiperficial ple rus This too would seem to be primanly a by-product of thrombosis rather than a purposeful attempt to nourish the superficial layers of the plaque - which are in any case already nourished by imbibition from the lumen As organization proceeds the blood- 78

·THE ROLE OF INTIMAL VASCULARIZATION AND HAEMORRHAGE
F16 45
I tertupt d tatg10 non frecent thonbus show
1g how penph lbl od pesminy originate LADB
(sen in series) HEX 20
FIG 46
Re ent thob e fbr us pl je
c 1 ton ad gowth and th'
sinus S R Co C 33 HE 75
tharginal
round blod
F16 47
Sgnet
sel
& defo ty #th se 10 sets of
(cf Fg 48) LADÚ C16 PTAR X 25
FIC 48
The e shows how vessels run betweetse 1deposit
(dent cated by clastic membranes) She dun x 25

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 4)
Ort, az ng thr mbus ith large blood s ses liked to
lumen la pit on surfa e of depot RC Ces
Sh ridn X 75
FIGO
Sm Il vessel communicat ng wth Jumen Se al section
rev al urio i wth plerus scen deep tin plaquc LADI
Ca e 4 PAS X 100
FIG SI
Organizing depout showing angul vessels #th mar
ginal and decphatmorth ges R Cos Case 33 PTAH
X 25
FC $2
This-walled vessel ran ifying in murgin of degenena e
zone L Circumir Case 13 PAS X 40

·THE ROLE OF INTIMAL VASCULARIZATION AND HAEMORRHAGE FG 53 Dagrammatic represc atation of va ulanization of a ngle depost ficfe) and a depo in posrd of two l crs ( bst> FIOS FIC S4 Thu walled L-suppo ed a cular tuigs un degenerate Prof plaq c LAD} Case 23 PAS 8s anzug thrombus showing ingrowth of endothlum from lumen ra line a blood-sinus L Cor Case 9 HEX 125

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 6
Pitting of surface (top left) at po nr whe e vessel in plaque
communicate with lumen L Corumflex Case 21 Azan
X 40
FIG $7
Blood-spaces between ser al depo it comin
Jumon thro gh large rregul ropening ton mgm R
Cor C se 2
Azan x 35
I ing with
F: 39
FIC 18
Capsul res pa sing fom branch artery into plaque ur
tounding south of branch R Cor Case 33 PTAH X
10
Fibrood DCCTOSiS of an arterole in t brous pl q c of a
kyperten ned betic subject R Cor C se as PAS X
2ST

·THE ROLE OF INTIMAL VASCULARIZATION AND HAEMORRHAGE spaces are reduced in size and number (Fig 49) until a network is left which is adequate for the supply of the plaque Onice organization is complete however there is no reason to suppose that the superficial plexus continues to derive blood from the lumen as some have maintained indeed all the evidence indicates that while communications with the lumen undoubtedly occur (Fig so) they are sufficiently scarcı even in serial sections to be wholly inadequate for the maintenance of an effective blood-supply Free communication however can readily be demonstrated between the superficial and deep plcxuses and it is thus likely that when organization is completed the extent and distribution of the vascular network is thereafter determined by the requirements of the plaque only and that the united plexuses function as one supplied by the enlarged vasa vasorum Angular i essels Besides being nourished from its base the plaque very frequently receives a sa blood-supply from fairly prominent vessels which enter it from the margins These angular vessels are a highly characteristic feature of degenerate plaques and are a prime source of haemorrhage (Fig si) They can be traced by serial sections into the atheromatous focus (Fig sz) and in the other direction they communicate with the vasa vasorum Being primarily concerned with scavenging they ramify in the degenerate areas where they are thinwalled and poorly buttressed (Fig s4) and so are liable to rupture causing haemorrhage into the softened area Their presence in degenerate foci was taken by Leary (1936a) to negative any claim that the vessels supplied nutrition to the plaque but there is good reason to suppose that the degeneration occurred first and that the vascular twigs in such areas are a response to the need for absorption of necrotic tissue If this is true it is an observation of some importance and the subject is discussed later under Degeneration in the plaque In gross signct-ring deformities with several superimposed deposits a whole series of these vessels may form a prominent plexus at the margins of the plaque Branches are given off to cach layer and if atheromatous softening is a feature micro-haemorrhages are common (Fig 7) The vasculature of the plaque as described up to this point is shown diagrammatically an Fig 53 Communication with the lumen This is so infrequent that it may be regarded as both incidental and insignificant Ingrowth of capillary endothelium from the lumen may occur in recent thrombosis as shown in Fig s5 and as suggested by Crawford and Levene but this seems to be a feature of organization and not a provision for the nutrition of the plaque later on Occasionally a small pit can be observed in the surface of the plaque communicating with a superficial nctwork One of these has been shown in an organizing thrombus (Fig 49) and others were scen in fibrous plaques (Figs s6) Their mode of formation is suggested by Fig s7 which shows a partially organized thrombus on the deep aspect of 83 ·THE PATHOGENESIS OF CORONARY OCCLUSION which are several large blood sinuses communicating with the lumen through a large opening Paterson (1936) was first inclued to think that communication with the arterial blood in the lumen was a factor in causing rupture of the capillaries in the plaque but later (1938) he revised this view and stated that lack of support by the degcncrate lipid was the most important consideration Miscellaneous ohsertations A bizarrc appearance noted on several occasions was caused by scveral small vessels passing into the plaquc on either side of a narrowcd lunien close to the mouth of a branch artery (Fig s8) A similar picture is illustrated on pp -s-o in the monograph of Il mtum: ct al (1938) attributed by them to the passage of vasa vasorum from the branch vessel Comparison with Fig 24 however shows that they arc simply a part of the deep vascular network that forms between scrial deposits -- in this case round the mouth of a branch artery In fact one of the cwigs ternunates m a zone of necrosis Fibrinod necrosis of an arteriolu in the centre of a plaque was observed only once (Fig 59) in a diabetic patient with £1y pertension The conclusions rcached on the subject of intimal vascularization may be bricfly summarized (1) The deeper parts of the plaque are supplied by peripheral vascular clefts which form as a result of marginal retraction of the clot and later link up trinsmedially with the hypertrophied vasa vasorum (2) The superficial vessels arc the residuc of organization of a mural thrombus ultimately deriving their blood-supply from the deep plexus and not trom the main lunien (3) When organization is complete the subsequent extension of the vascular network is determined by the dual requirements of nutrition and degeneration (4) This network though readily demonstrated > inefficient and inadequate for these requirements and so degeneration and hacmorrhage occur in the plaque and thur waste-products accumulate therein HAEMORRHAGE IN THE PLAQUE Once an atherosclerotic plaque has undergonc degeneration small lisemorrhages into the softened arca from the ill-supported vessels at its margins are an almost constant feature Thcsc cxtravasations are no micro terminal event and the frequency wich whichi they occur is indicated by the presence of several small hacmorrhages in a single deposit clearly of different age though all recent cnough to be identifiable microscopically (rg SI) It is thereforc safe to assunie that the average atheromatous abscess has been subjccted to repeated micro-hacmorrhages over a long period and that its pultaccous contents are partly haemic in origin When blood is discharged into a degencrate focus it disrupts the contents and becomas intimatcly mixed with them (Figs 60 61) When the haemorrhages are multiple and of different ages it becomes difficult to distinguish atheromatous softening froin altered blood although staining by Azan and PTAH assists in differentiating sonic of the elements Fig 62 shows a typical atheromatous abscess in which macrophages with foarny cytoplasm 84

·THE ROLE OF INTIMAL VASCULARIZATION AND HAEMORRHAGE
F60
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61
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63
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·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 64
Angular haemorrhage in organizing depost m turn
surrounded by gross fibrous thickening LADB Case
28 Azan x 30
FIC 65
M ssive recent haemor hage i to athero: atous bscess
LADB Case 4 Azan x 20
FIC 66
Recent haemorrhage into plaque reducing lumen to a
Tartow she LADB Case 17 HEX O
FIG 67
Recent h emorrhage into plaq e leaking through int na
and nating a sin 11 polypord thrombus LADB
(Case not in series) HE X 20

·THE ROLE OF INTIMAL VASCULARIZATION AND HAEMORRHAGE cosinophilic granular proteinous debris recently extravasated red cells and a coarse fibrillar network of degenerating fibrin are all recognizable In fact every possible combination of degenerative and haemic clements was observed throughout this series with every possible transition between atheromatous softening and altered blood The wide range of appearances can be satisfactorily accounted for only on the assumption that they represent the degenerative products of haemorrhage as well as necrosis Therefore Dugud s hypothesis that atheroma is a process of fatty degeneration occurring in a thrombus should be extended to includc the residues of intimal hacmorrhage It may be objected that thus is not the manner in which hacmorrhage or thrombosis are dealt with in other tissues but consideration must be given to the fact that the atheromatous abscess owes its presence to inadequate vascularity of the phique and the resistance of cholesterol to absorption Thus the usual features of haemic organization - 1c granulation tissue phagocytosis of haemosiderin ctc - are not gencrally observed In seins the conditions preceding thrombosis are very different since the intima on whiclı the clot is deposited is usually a hсalthy vascularized membrane which allows rapid ingrowth of capillaries into the thrombus followed by the customary features of organzation But in atherosclerotic arteries the intima has been replaced by a thick relatively avascular plaquc and quite large thrombi may become scaled off from the rest of the circulation by a fibrous cylinder and ultimately degenerate into a yellow pultaccous flud with a high lipid content This process is not confined to coronary arteries and may be seen in long-occluded arteriosclerotic ancurysms (Fig 3) The factors producing intimal haemorrhage have been fully reviewed by Paterson (1936 1938) the main ones being the thinness of the vessel wall in relation to its diameter and the lack of support afforded by the surrounding degenerate material in the resorption of wluch the vessel is engaged (Fig 63) The ertent of the haemorrhage is determuned by the nature of the supporting tissue in the reticular network of granulation tissue it is generally quite small (Fig (4) whercas in soft pultaccous foci it may be massive (Fig 65) Larger haemorrhages are readily visible to the naked eye varying from red to brown according to their age The track of such haemorrhages is also determined by morphological considerations Dense collagen acts as a barrier and in a deeply placed focus of softening the blood may be confined and converted into a hacmatoma which swells the plaque and narrows the lumen further (Fig 6) In the more superficially placed focı however the blood tracks towards the lumen and causes occlusion or sudden death (1) By raising the overlying intima and compressing the lumen into a narrow shit at onc side of the vessel (Fig 66) In the autopsy room this is often mistaken for a clot occluding the lumen (2) By damaging the intima by leakage (Fig 67) so initiating secondary thrombosis in the lumen (3) By croding the roof of an atheromatous abscess causing rupture of its contents into the lumcn followed by sccondary thrombosis (Fig 68) A deep hai morrhage may track obliquely towards the lumen between two senal deposits and emerge at the margin giving rise to thrombosis or even rupture of the plaquc (Fig 140) This phenonienon is considered later under the hcading Dissection and scems to 87 ·THE PATHOGENESIS OF CORONARY OCCLUSION be due to the existence of a natural plane of fission between the deposits I believe that this is because they are separated by an elastic membrane w luch prevents firm union of the collagen on either side (Fig 138) Small subendothelial haemorrhages are common too raising the endothelium and its basement membrane from the underlying plaque They are frequently observed to occur at the margin of a superficial layer of lipid-containing macrophages (Fig 69) where as in the deeper foci marginal vascularization occurs The importance of the superficial haemorrhages lies in their capacity to initiate thrombosis Summarızıng one may say that the small haemorrhages are important because of the cumulative effect of their degenerative products wlule the larger ones are important because they may cause occlusion or initiate thrombosis Their ability to compress the lumen against arterial pressure has been questioned (English and IVillius 1943) and Drury (1984) his stated that all the larger haemorrhages are due to irruption of blood from the lumen through a tear in the plaque His experience is in direct opposition to the scrialsection studies of Paterson (1936) Wartman (1938) and myself Fig 67 for example shows a recent haemorrhage in a deeply placed atheromatous abscess Blood has leaked through the roof of the plaque and has caused a small thrombus to form on the devitalized lining of the vessel shortly before death It is difficult to see how thuis could have resulted from irruption of blood from the lumen 88

·THE ROLE OF INTIMAL VASCULARIZATION AND HAEMORRHAGE
FIG 68
Rupture of thero tous b sit 1 m
th omboss LADB C se 34 ITAH X 25
cusing
FIG 64
Smllhe hgfon binalssel b dothelial
pid depo it overly: 5 fb o pla LC cu fx
C13 HE45
FIC 70
Si ghtly atherosclerotic artery tally ocl d d by
06 ning the brich in vessel cl!
d hacmo
denn (exe pt 4 LADB Cax 40 HEX 30
FIG 71
ganizing thrombus an essel fre dy grosslyn trow d
by t brous atheroscleros RCA Case to HEY 30

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG 72
Narrow bald of granulation tissue in to corona y
oc lusion showing, vasculr base der ved from healthy
segmi nt ef vessel w 11 L Ci un Case 13 Sheridan
40
FC 73
Atypx 1gr nul tror is ue of a fou d long wth gros
intin al tibro is LADU Case 9 HEX 40
FIG 74
F10 75
Re ent thrombu retra ing to allow na ginal reca aliza
tion at oncs de LADB Case 34 Azan X JO
Suhro al occlusion by z success ve deposits a densely
fibrous and avascula LADD Case 32 Sheridan y
35

·XXII The Nature of Arterial Thrombosis Most of our concepts of the morphology of intravascular thrombosis and recanalization are based on a study of diseased ruins But the circumstances under which arterial thrombosis occurs are rather different especially if the artery is atherosclerotic For one thing there is the force of the blood-stream at arterial pressure tending to mould the surface of the clot and to dislodge the looser elements Secondly there is the avascular state of the intima exaggerated in atherosclerosis and forming a poor basis for organization as compared with the vascularity of its venous counterpart Thirdly there is the difference in oxygen tension in venous thrombosis the low oxygen tension is a stimulus to capillary growth whercas in arteries both the higher oxygen tension and the greater hydrostatic pressure impede the growth of young vessels (Crau ford and Lovene 1952) Again the venous system is a network and when one passage is obstructed the blood fairly easily finds an alternative route When an artery is blocked however infarction occurs unless the circulation is maintained by (a) recanalization or (b) collateral circulation Early in the present investigation the differences between arterial and venous thrombosis and their sequelae became apparent Complete occlusion of the lumen by granulation tissue alone similar to that seen an organization of a venous thrombus is on the whole exceptional in coronary atherosclerosis (Fig 70) although lesser degrees are common enough ¢g in the final closure of a vessel already severely narrowed (Fig 71) In such instances the granulation tissue contrasts sharply with the acellular plaque and its basis can always be traced to a segment in which the intima has escaped severe thickening An extreme example of this is illustrated in Fig 7- Even the granulatton tissue may be atypical with the usual capillaries and reticulın network but few fibroblasts or leucocytes and little sign of a vascular communication with the surrounding plaque (Fig 73) A reasonable inference is that healthy granulation tissue demands an ample vascular supply and this is lacking on the surface of an atherosclerotic plaque But if this is so how do the crescentic and relatively avascular serial deposits come to be organized onc on top of the other cven to the point of occluding the vessel (Fig 74) If we believe that they originate in thrombi there must be something different either in the manner of their formation or their organization - or both Two other anomalies demand explanation Firstly there is surprisingly little evidence of red cell destruction in the form of haemosiderin in young atherosclerotic plaques although it is a prominent fcature of organuzing venous thrombi Secondly despite the frequency of superimposed deposits there is little sign of intermediate stages between whole blood and collagen recent deposits apparently having a coarsely laminated structure at an early stage 91 ·I have come THE PATHOGENESIS OF CORONARY OCCLUSION After examining a considerable number of plaques and thrombı ot all types to the conclusion that such atherosclerotic plaqucs originate in this manner following thrombosis the majority of the red alls are washed out of the fibrin network by the force of the blood-strcam which nioulds thc fibrin into a pale laminated crescent to one side of the vessel and that thercafter organization is effected by fibroblastic ingrowth from the surface transformug the fibrinous laminat to collagen without the aid of extelisive capillary proliferation Thc germ of this hypothesis is not neu Rohomsky (1841-46) u rote Thc deposit is ancha dogenous product derived from the blood and for the most part from the fibrın of the arterial blood Dugud (1949) stated that most arterial thrombı do not cause total occlusion but merely forın fibrinous deposits on the intimal surface Niclutchue (1952) noted that mural thrombi induced in the pulmonary arteries of experimental animals by injections of Russell viper venom rapidly became pale and concluded that thc haemoglobin had been washed out of them Crau ford and Liten (1952) suggested that fibrinous lamınae could be converted to collagen by endothelial cells growing in from the surface and assunung the function of fibroblasts Fig 75 shows a recent thrombus retracting from the vessel wall to permit a certain amount of marginal recanalization A higher magnification (Fig 76) shows se to contam a number of irregularly shaped lakes ot red cells and leucocytes lined by fine membranos not unlike the lines on a contour map and tinctorilly cquivalent to fibrin* It will be noted that the proportion of fibrın to cells is unusually high As thic fibrin continues to retract the cells will be squeczed from the interstices assisted by a blood flow at arterial pressure RECANALIZATION As a rule the clot is attached to the vessel wall on one side only and becomes flattened towards its base by the pressure of the arterial blood the fibrin network being compressed into a series of lamunac parallel to the vessel wall rather like the layers in an ancurysmal sac (Figs 77 78) Most of the red cells arc saslıcd away but the remainder coagulate betwecn the fibrinous lamınac and come to form part of the deposit The whole thrombus soon loses the staining properties of fibrin and red cells (Fig 79) and in hacmatorylıncosin sections comes to resemble hyalınızed collagen a fact also noted by Dugud (1948 1955) Ar an carly stage the retracting surface becomes overgrown by the lunumal cndothelium at the margins a phenomenon that seems occur fairly rapidly (Fig 80) Elastic overgrowth also occurs and the superficial layers of the clot are organized from the surface (Fig 81) possibly in the manner suggested by Cranford and Li vcne (1952) The deuper part is orgamzed by means of the plezus which forms between vessel wall and deposits and if this is inadequate degeneration follows Retraction of the clot is a major factor in restoring blood fiow and preventing myocardial infarction It thus occurs carly before the constituents of the clot have lost their staining *?ly colcague DJ H Humble of the H e ngrology Department of Westm nster Hospital his suggest the these Iskes in the fbnn Biay be due to the action of fb znolys n elaborated by the leuco ytes in theri 92

·THE NATURE OF ARTERIAL THROMBOSIS
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·THE PATHOGENESIS OF CORONARY OCCLUSION
1
1
FIG 80
Recent mu al thrombus (fib saill etained affi aty for
PTAH) Iready ochrown by lining endothelium L
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FIC 81
Depost undergoing organa arion ſro >>51 fac
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FIC 8
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Case 30 PTAH x 20
FIC 83
Contracted ofya ized thrombus causing wrink's of
older depos t outside t f brin hus pozed into terven ng
cleft LADB Case 34 PTAHY 45

·THE NATURE OF ARTERIAL THROMBOSIS
F 84
Reca al zat on effect d by la ge blood paces in tre of
for Note da kly sta ning fb in sept b ewech sp
R Cor Cees PTAH 40
FIC 8
Ag ng ibn us n twork in 1 en nd hact ma in
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18 4 fog zcd t t bu out ug It ple
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FIG 87
Dst 1 nd of org niz g thrombu show & vs La
granult well as blood-sp ses formed by tc
tion RE Lase 33 PTAM X 25

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG 88
Mural thrombu shos no cal loss of spec fc st ang
reaction f br1 LADB CC 31 PTAH DO
FIG 8)
The ne tain d by h 11 ryb -osin Nor cscna
blance fag in, f brit hyalınızed llag HE 90
FIG 90
Lam nated th onbus quite acellul and scul r super
ficially resembl ng hyali: ed co!l gen (cf Fig 91) R
Cor Case 29 HEX 45
FIC 91
The same showing streaks of fbria in the depot
PTAH X 90

·THE NATURE OF ARTERIAL THROMBOSIS properties A thrombus previously filling the whole lumen may retract from most of the vessel wall so that the circulation is partially restored (Fig 75) Often however it remains tacked to the wall at several points giving rise to the crescentic spaces at the periphery that later form the marginal blood sinuses (Fig 45) Occasionally contraction may be enough to detach the superficial layer of an atherosclerotic plaquc from its deeper layers (Fig 8-) creating a cleft into which bleeding may occur similarly central cicatricial shrinkage later on may lead to wnnkling of the fibrous periphery of the plaque (Fig 83) Should the occluding thrombus remain anchored to the vessel wall all round its periphery recanalization may be affected by the persistence of large blood channels in the clot (Fig. 84) In Fig 85 a large haematoma in the plaque has initiated thrombotic occlusion of the lumen followed by recanalization of this type As the fibrın beconres organized spaces are left which confluesce towards the tail-end of the clot Such channels may be quite numerous (Fig 86) and their presence at the distal end of an organized thrombus may be due to the fact that the latter has not been subjected to the same moulding effects by the blood-stream as at the provimal end Formations of this type could hardly result from organization by granulation-tissuie although both types may coexist (Fiz 87) presumably depending on the vagaries of the vascular supply FIBRIN OR COLLAGEN In recent thrombı fibrın stains an intense purple with PTAH At an early date it losus its specificity at first staining patchily (Fig 88) and later on a light brown like collagen At this stage in haematoxylın-eosin sections it is barely distinguishable from the surrounding collagen (Fig 89) and so may escape notice in routine autopsy sections Fig 90 shows a laminated thrombus scained by haematory lin-cosin which superficially resembles collagen It is however palcr and closer inspection reveals that it is quite acellular and avascular PTAH (Fig 91) shows streaks of fibrin in the deposit and there is an cven more streaky appearance with Azan (Fig 9-) This equrvocal caction with Azan is very common in superficial plaques parts staining deep blue like mature collagen while others are pale blue or red There is however no break in the continuity of the individual fibres parts of which may be blue others red Clark et al (1936) noting a similar app arance in some of their cases reported that well presers cd fibres staining as collagen are secn side by side and even dove-tailing within fibrin-staining bands Since fibrin retains its affinity for carmine for a longer period than with PTAH there is reason to believe that such plaques consist of fibrın in the process of being transformed to collagen This is an important point since the paucity of recognizable intermediate stages between arterial thrombosis and collagenous plaques – for example cicatrizıng granulation tissue – is a formidable objection to Duguid s theories If however fibrinous lamınac are converted to collagen by fibroblastic activity alone this objection is removed The full understanding of this cu olution would require experimental work outside the scope this study but one may note that recently Lisine (1955) has examined apparently collagenous plaques by the electron microscope and found that they consist mainly of fibrin of H 97 ·THE PATHOGENESIS OF CORONARY OCCLUSION TOTAL OCCLUSION AND COLLATERAL CIRCULATION When occlusion of the lumen is complete and permanent then circulation can only be maintajied by collatcral reserves It is well known that in certain mdividuals complete obstruction can occur without infarction (llam 1928 Saphir et al 1935 Schle singer and Zoll 1941) a phenomenon attributed to an unusually rich collateral circulation (Oberhelman and Li Count 1924) Barnes and Ball (1932) estimated that coronary thrombosis was a slow process which might take one to three days to causc total occlusion an interval which should allow time for the collateral circulation to become sufficiently effective to avoid massive myocardial infarction Doubtless the higher arterial pressure is a factor in unsuring that the circulating blood is coaxed into every available collateral channel The collatcral circulation is affected through the branch vessels and their ramifications including the rich adventitial plexus and it is therefore obvious why foc of severe atherosclerosis (1с old thrombosis) are so frequently found occupying a segment of the main vessel between the mouths of consecutive branch arteries Clearly part of the blood in che proximal branch is deviated through anastomotic channels to a more distal branch and so back to the main lumen This has been well illustrated by Il trotz if ol (1938) That such a phenomenon occurs and occurs frequently cannot be doubted for if it did not the rest of the vessel distal to the obstruction would be blocked by orgamzed thrombus A fairly typical appearance at the proximal end of an occluded segment is seen in Fig 22 where several crescentic deposits are superimposed opposite the mouth of a branch artery It is not fancıful to infer that it is the current from main lumen to branch that is responsible for moulding the serial deposits in this manner In such a casc the occlusion of the main lumen is completed in a series of thrombotic episodes and so the load is not thrown all at once on the collateral circulation Eventually the residual lumen of the main vessel closes off altogether and Fig 93 shows how the dımınıshing current produces a series of crescentic laminae in the fibrın of a recent thrombus a pattern reproduced then it later becomes organized as can be scen in the older adjacent plaque Before occlusion is complete the lumen of the main vessel may extend into a grossly sclerotic segment for a short distance in the form of a tapering cone emerging as an expanding cone at the distal end Tlus is repeatedly scen in scrial sections of narrowed vessels Fig 74 shows how the rotundity of the lumen is retained even in extreme narrowing and despite the eccentric distribution of the serial deposits This phenomenon is not observed in venous thrombosis and is doubtless due to the moulding effect of arterial blood Even in larger thrombt one may observe the tendency to retain a rounded fluid channel at the centre (Fig 94) Eventually the tapering channel is scaled off altogether a process illustrated by differently stained scrial sections (Figs 95 96) They show that this terminal deposit consists of concentric layers of fibrin which later undergo transformation to collagen Such an appearancc could not result from the more orthodox fornis of organization through the medium of a capillary network 98

·THE NATURE OF ARTERIAL THROMBOSIS
FIGO
The san show 8 st e ky react on with Az n (da k
er v=red pale g y -- bl ) Azan 00
F6 93
Dnb ng cus ph, prod d series frescere
fbru ous la duri gths b sis S 1 rlam n ton
seen n old rdepo (be) R. Lo Case , HE
30
FIG 94
Receitth bo th p ph 1fibrin hetwo k Blood
cerul ounded anch ot co lated LAB
Cac 17 PAS X 26
FIC OS
Res du 11 n be g se led off by lamin
for the collagen R. CO C 510 Azn 120
of geng

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG 97
FIL 10
Th sa se 3cions deeper in block Tocal oction
by co 1 entric laminae wth nuclei ( 1 urocyı c) in th
tershes HE IO
Subendothelul ocdemia t mouth of b hreyli ed
by mur Ithronibus L Crun A x C s 13 HE 65
FIC 23
Snuall subendothelial haemorrhage (below centr ) raising
untimal linang (cf Fe 99) LADD Case 17 Shendan
x 40
FIG
The same showing chat on off brinnctwo kin overlynas
thrombus to a cs of hiemorrhage PAS < 40

·THE NATURE OF ARTERIAL THROMBOSIS Reference has been made earlier to the say in which an organizing thrombus causing total occlusion mav become permeated by substantial vessels of artenal type formed by the extension of elastic and smooth muscle from the mouths ot branch arteries or from cither end of the deposit (Figs 29 40) These remarkable structures are quite out of proportion to the requirements of granularıon tissue and constitute a form of recanalization Thc dilated state of the vasa vasorum in total occlusion suggests that they too play a small part in the collateral circulation LOCAL FACTORS IN THE CAUSATION OF THROMBOSIS So far i lasc buon concerned with thromb of substantial dimensions only and the term mural thrombi has not been applied to tho e small wisps of fibrin that adhere to the snaima and are later incorporated in it by endothelial overgrowth These are treated in the next chapter From time to time however one cncounters small recent thrombe which afford the opportunity for looking for abnormalities in the underlving intima It is unlikely that the precipitating factors in coronary thrombosis will be discovered through morbid histology alone but ob crvation of morphological abnormalities must constitute at least part of the answer One great difficulty that bescts the study of the inama underlying large or old thrombı is that any conclusion can be rendered invalid by the argument that the momal changes arc just as likely to be the result of thrombosis as the cause The following observanons were all on small or recent thrombi and their causation would appear to be varicd (a) Old 1922 Fig 97 shows early mural thrombosis at the mouth of a branch artery The underlying intimal stronia is teased our by ecdema (b) Hemorrlı ge In Fig 99 a small superficial haemorrhage has raised the endothelial lining of the vessel und the threads of fibrin in the resultant thrombus can be traced to this point (Fig 20) (c) Recut thrombosis I have sugçested carlier that overgrowth of a thrombus bv an classic niembrancis essential to the hcaith of the nay mtimal hning This is supported by the frequency with which a fresh thrombus is deposited on an older one s hich is incompletely coscred by clastic (Fig 100) (d) I branous encrustations A recent fibrinous encrustation completely assimilated by overgrowth of cndow thelium may forin a basis for fresh massive thrombosis (Fig soil This is really a variant of (c) TOI ·THE PATHOGENESIS OF CORONARY OCCLUSION (e) Subendothelial lipid Fig 10_ illustrates mural thrombosis at an angle in a lumen deformed by signet-rug atherosclerosis Below the lining endothclium is a broad layer of lipid-containing macrophages not co-cutensive with the clor and clearly present before thrombosis occurred (6) Ruptın of an atherosclerotic plaque The causes of rupture are discussed later Loss of the lining endotheliu n alone mas initiate thrombosis Its occurrence at the margin of an intimal tear is shown in Fig 103 (s) Degeneration or necrosis of the ma It a hacmorrhage or an atheromatous abscess should extend to just below the surface ot the plaqur the damage to the overlying endothelun inay Icad to thrombosis (Fig 104) Multiple occlusions and their relation to myocardial infarction arc dealt with later 102

·THE NATURE OF ARTERIAL THROMBOSIS
FIG 100
Receith on bu on old dp i of o ered by n lastic
? cur le LADB Case 20 Sherid nx 15
Rc ont th
FIC IOT
bos on plaq c how gth 1 yers off n
of CC LADB CSC 34 PTAHI 80
just blow
FIC 103
all oural throb 10 erlyt g 1 yer of fo melk
Cor CS3] HE * 150
FIG 103
Small th onb at site of inter LADU Cx23
HEY 40

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 107
Erly thrombu on ntina r ndered degenerare by under
lyung atheromatou ab oss R Cor Casc 13 TAHY
FG 105
Superf tal wisps of f brın being ass 1 ted by plgu
Cor Case 7 PTAH < 135
R
40
FC 106
Moral thrombus coveing plaq • with superf stal Layers
separated by f brinous lain iae LADB Case 28
FG 307
Ha jorth ge track ng uregul rly towards ! on to
initiate thron his. LADB Case 28 PTAH X 30

·XIII Fibrin in Atherosclerotic Plaques The presence in atherosclerotic plaques of fibrin or a fibrın-like substance with special stains has attrauced attention for many years Mallory (1914) was among the first to obscrve in the subendothekal layers thin Rates of this material which he took tor tibrin from the blood undergoing organization a process which he regarded as responsibk tor the fibrous component of atherosclerosis Leary (1934) found argyrophil fibres in this matcrial which he therefore interpreted as pobrmod necrosis of collagen due to partial infarction of thu plaque and considered a frequent source of coronary thrombosis in the younger age groups Clark et al (1936) obs ruda simular substance in the fatty degenerate arcas sometimes mingled with red cells and Jeucocytes and concluded like Mallory what it was fibnn Its pre once in the floor of atherosclerotic ulcers suggested secpage into the plaque from the blood-stream The layers below the surface endothchum (fig rol) they regarded as surface thrombs undercoing organization They turther pointed out that the argyrophil fibres observed by Leary mught have been laid down by fibroblasts in the course of organization or alternatively formed by the splitting of collagen into its component fibrils before or after penetranon of the plaque by hacmic clements Schlossman (1942) tried to revive the theory of fibrınad necrosis by showing that only a part of the material is digested by trypsin and the residve not being tbrin must therefore be necrotic collagen The argument however is unconvincing Digms (1948) showed that fine hibrinous encruscations on the surtace of the plaque too small to be seen by the naked eye ser much commoner than was supposed nuing present in 19 out of so aortas ot pursons hetween the ages of 3 and 73 who had dicd from saned causes Thes, he showed ucre rapidly assimilated into the plagur bv Oyurgronch of endothelium and organization from the surface Fibrin unlike the other elements of atherosclerosis as rendered difficult of interpretation by the transient nature of its specific staining reactions Bleeding into a plaque rapidly undergoes chrombosis and when this is qmtr fresh che thrcads of fibrin can be seest in the form of a fine network entangling red cells and leucocytes With PTAH as stated earlier the intense purple reaction soon becomes blotchy (Fig 88) and later disappears altogether in the same way the vivid red reaction with Azan giscs way to blur but the change occurs rather later It chus happens that a fairly recent laminated thrombus mas come to resemble dense collagen The appcarances Duguid destibed in the aorta are not unusual in coronary arteries (Fig 105) and it may be noted in pa ang that they occur in the ab«ence of cholesterol deposits Such small lesions could by a process of repeated accretion and organization 195 ·THE PATHOGENESIS OF CORONARY OCCLUSION cause intimal thickenmg but it is difficult to see how they could give rise to the serial plaques that constitute layering cach of which has the appcarance of being formed complete at one time Small fibrinous encrustations may however precipitate thrombosis as was shown in the preceding chapter Sometimes thun layers of fibrin are sccn embedded in the plaque at a depth which makes it unlikely that they have been assimilated by endothelial overgrowth while retaining their staining properties and the absence of a covering clastic membrane suggests that plasma has secped into the plaquc from the surface A similar phenomenon occurs in the floor of atherosclerotic ulcers (Clarl et al 1936) and the coarse mesh of parallel collagen fibres may Iend itself to such an event (Fig 100) Fibrinous accumulations in the decpest part of the plaque are almost certainly the sequel of local haemorrhage These too are liable to show evidence of interstitial scopage ar the margins cspecially in the presence of degenerative softening Haemorrhages of this type may track irregularly towards the lumen causing thrombosis (Fig 107) Simular oozings occur round the walls of unsupported vessels in degenerative ſoci or at the margins of fat spaces in the same way capillary haemorrhages in the vascular granulation tissue of an organızıng thrombus may Icave their residuc of fibrın Nou here in this series were the appearances suggestive of fibrinoid necrosis and it is my impression that the fibrın in the plaques is derived from surface cncrustations seepage of plasma or haemorrhage into a degenerate part of the plaque 106

·FIBRIN IN ATHEROSCLEROTIC PLAQUES
ES
FIG 108
Two p le staining fo of mucinous dege_rat on Note
ab_nce of cells vess 1 and lipid LÄDB Casc 17
HEX 65
FIC 109
tunto
Deg ncratc fcus show g collage fb es reas d
1 hoffn fb 1 R Cor CSS Aza y 35
FIC 111
FIG IIO
St ek of PAS po! ntnl in degener te
LADB C 517 PAS X 380
5
Degenerate focus 1 fib ous pla harply om sted
by layer of calm 2 LADB Lax 17 HE. X 120

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG II
Gossswell ng of fibrous pla que duc ton ucinousd gener
ation No calcification LADB Case 18 HEX 45
FIC 113
Extension of degenerato Older zo e below 1 ore cent
tow ds centre of pictu e c bounded by calaf d m
IN LADD Case 18 PTAH 45
FIG 114
Calcified area in plaque containing cholesterol cry tals.
LADB Casc 28 Azn X 65
FIC 135
Large degenerate zo un plaque wth clafed magn
and fatty Lake in centre L'ADD Case 11 HE X JO

·XXIV Degeneration in the Plaque DEGENERATION of the atherosclerotic plaque is a prominent featurc of the larger lesions and an imporcant factor in their subsequent cvolution As the proct $s involves mucious degeneration calcification lipid accumulation and phagocytosis these may be convcniently bracketed together MUCINOUS DEGENERATION A gelatinous swelling of the intima was observed by Virchon (1856) to procede lipid deposition in carly atherosclerotic lsions Its mucinous nature is suggested by the fact that it stais metachromatically with scveral dyes Thc literature on the subject is reviewed in Chapter XVII under Local Predisposing Factors Streaks with a similar tinctorial reaction may also appcar in the larger theroscle ofic plaques accompanied by swelling of the collagen fibres to form a pale-staining focus generally situated decply in the plaque at the point of its greatest thuchness - 16 where its blood supply is Itable to be poorest (Fig 108) Closer inspection reveals that the collagen fibres in this arca arc teased out into fine threads separated by broader ribbons of palestaining macerial granular at the margins hyalıne towards the centre The fine fibrils are argyrophilic (Fig 109) and PAS positiva (Fig 110) Thrse early toct of degeneration occur in parts which are acellular avascular and frec ot gross lipid they have therefore been interpreted as mucinous degeneration due to inadequate hutrition micro-infarcts in some instances As cach degenerare fibre is swollen to several times its normal thickness the bulk of the focus as a whole is considerably thickened These localized lesions are frequently surrounded by 3 fine shell of calcium sharply demarcating them from the surrounding collagen (Fig 1) The degenerate area may be qute small or it niay evolve the bulk of the plaquc sparing only its surface and margus in this way a plaquc may double its thickness by degenerative swelling alonc quite apart from further deposits on the surfacc (Fig 112) Calcification at the margins of the degenerate arca mnay cut sharply across the fibres at right angles and there is evidence that the process of degeneration and calcification may estend periodically (Fig 113) Considerablc wedges of a fibrous plaque may undergo this typu of degeneration without a conspicuous farty accompaniment - certamly without the accumulanon of lipid in macrophages In other calcified foci the fibrillar structure may be replaced at the centre by collections of cholesterol crystals (Fig 114) or farty material in the form of large globules or irregular lakes (Fig 115) The close relationship between these patches of mucinous and lipid degeneration and the calcareous wall that surrounds them leases little 109 ·THE PATHOGENESIS OF CORONARY OCCLUSION doubt that the latter is merely a seal round a necrotic focus similar to that of a gumma or tuberculoma The liquefaction of the degenerate contents may lead to the formation of large spaces in paraffin sections walled by a thin laver of calcium outside which the collagen fibres are abruptly interrupted at nght angles (Fig 116) When such a focus (atheromatous abscess) ruptures into the lumen the walls of the residual cavity thus have the same sharply gouged appearance (Fig 117) The avascular nature of these foci is a clue to their ongin Organization of arterial thrombi is not accompanied by a rich blood-supply and as has been shown only the margins and superficial layers recent adequate nutrition derived cither from the lumen or the deep plexus growing in from the vasa vasorum By the time this vascular ingrowth has occurred the central part of the plaque may have undergone infarction and subsequent extension of vessels into the degenerate area is more likely to be concerned with resorption than nutrition This interpretation accounts for the frequent presence of small vessels extending from the enlarged vasa to within a short distance of the necrotic focus (Fig 118) It is presumably from these that capillary extension into the degenerate zone takes place (Fig sz) buc by this time the damage is done How clse can one cxplain the presence of vessels in the most degenerate parts of the plaque It has been shown how repeated small haemorrhages from these vessels may further increase the bulk of the pultaceous material and afford a source of cholesterol Fig 119 shows extension beyond a calcareous focus to a wider zone of necrosis not walled off by calcium and containing numerous foam-cell macrophages and a small recent haemorrhage at one corner of the concretion The foam cells are in direct contact with the interrupted collagen-fibres a not unusual appearance in atheromatous abscessus CALCIFICATION Demonstrable strata of calcification were observed in the plaques of roughly half of the cases investigated and were sometimes a very prominent feature Though rather more constant in the older age groups calcification was also a very common finding in those below 50 (see Table D) TABLE D Age Sohy Under 50 Orer 70 lof Vo of Lipid Cases 5! & Dege exan ed at o 32 20 33 16 of T / 65 483 Calafi etion of Tor! IS 469 20 606 In severe signet-ring deformities several calcified focı may be superimposed onc in the depths of each deposit (Fig 115) Eventually these may fuse into one (Fig 1-4) It was stated earher that deep foc of calcification appeared to cause pressure atrophy of the related media but it is likely that in the first instance the pressure was duc to swelling of ITO

·DEGENERATION IN THE PLAQUE
FIG 117
FIC 116
I quefon n of d genert zone w d chun al th d wall
cutting across collig nfb es nicht anglet LADB
Case 18 HEX 45
Sh rply & uged walls of ather statous abscets whih has
discharged contents into lu R Cor Case 13
Foot 31
n
FIG 518
Vessel p sung from m gun of plaque touards n Crot
ne but not enitcnng LADU Case 12 HEX 60.
FIC 119
Collagen fibres interrupted at nghe a gheos by foamcell
accumulation. No swall mortlure ar or angke of
coordon LADD Case S PTAH

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG 10
Degenerative swelling and calf ation at base of plaque
Caus ng pressu trophy of adjacent media 1 Cor Case
0 PTAH,00
FX 121
Calafication of fib ous pl que vol 1
Co Case 35 HE40
surfacR
L
FIG 12
Organized put thrombus overlyng claf cat on which
turmerly on olved surtace of plaque but not comxtcase
with it I Cor Case 6 HEY 40
FIC 123
Haemorrhage into clef betwee lafied Layer and o
Jyang fibrous tasue of plaque LADB Case 3: II.
хбо

·DEGFNERATION IN THE PLAQUE the degenerate collagen fibres (Fig 1-0) Subscquent calcification by rundering the swelling permanent and immobile doubtless accentuates the atrophy especially in severe signet-ring deformties Calcium is not always deposited at the periphery of an infarct in the plaquc as described above it may be found at the centre of a small degenerate focus or scattered widely through the substance of a larger one in the form of small granules or around fat globulcs But its association with degeneration and necrosis is constant During the cighteenth and ninctcenth centuries calcification was regarded as the very essence of coronary sclerosis By 1935 opinion was sufficiently reversed for a careful observer like Leary to write from any standpoint calcification is of no importance in the actiology of the lesions and is only significant in that a coronary vessel converted into a rigid cube is no longer subject to the influence of spasm of the media though on the other hand it is no longer capable of dilatıng (Leary 1935) Paterson (1936) did not consider calcification a factor in initiating thrombosis but Horn and Finkelstein (1940) recorded bone-formation in a plaque eroding a capillary and causmg haemorrhage From the present study it is safe to say that a calcsficd plaque is inuch less prone to hacinorrhage thrombosis or rupture than a plaque which has undergone fatty softening Thus calcification may involve the surface of a plaquc without necessarily causing chrombosis (Fig 1.) Incidentally this shows that nutrition from the lumen is not invariably maintained to a depth of 035 mm as Gerringer (1951) suggests Calcified plaques may lie immediately below a thrombus or organized deposit (Fig 1-2) but unless the two are co-cxtensive tliere is no reason to postulate a causal connection In short calcification does not appear to be an essential or even an important feature in thc progress of the atherosclerotic lcsion Calcificd plaques are said to contain less cholesterol than the normal intima (Hirsch and It enhouse 1943) but so far no one has demon strated that calcium actually protects the intima from lipid degeneration Harrison (1933) showed that experimental atherosclerosis docs not occur over calcified patches in the media but the latter lesions were more like thosc of Monckeberg s sclerosis than human atherosclerosis In the present scries the only complications that might be considered attributable to calcification apart from mcdial atrophy were occasional narrow clefts at the margin of an affected focus At first these were deemed artefacts due to cutting across a calcareous artery with a heavy knife prior to processing and indeed this may account for some of them but in others the clefts were associated with local vital reactions and alternative cxplanations must be sought Thcsc rcactions include haemorrhagc (Fig 1-3) fibrın or albuminous fluid between the calcificd focus and the rest of the plaque and even endothelial or giant cells lining the clcft In theniselves these isolated phenomena muy be unimportant but they do suggest that a calcificd sliver is liable to partial dislocation from the more pliable fibrous tissuc of the plaquc and that this may on occasion gite rise to intimal hacmorrhaçe and its scquclac A simular observation was made by English and Illus (1943) There are two ways in 113 S ·THE PATHOGENESIS OF CORONARY OCCLUSION which such dislocation might occur by spasmodic contraction of the media or by retraction of the surrounding fibrous tissue The second is more likely I have postulated a degenerative focus in which thic collagen fibres first suell and then become surrounded by a shell of calcium This would prevent the affected wedge from contracting escnly with the rest of the plaque In time the plaque cones to grc the impression of being tightly contracted round a disproportionatcly large calcified block sometimes to the cytont of compressing the media or distorting the vessels outline (Fig 124) LIPID DEGENERATION Lipid deposits in the plaquc are a highly characteristic feature of the drecase indeed 3ccording to most authorities they constitute the essential lesion of atherosclerosis The lipid may be (a) intracellular in the form of macrophages with a foamy cytoplasm () cxtracellular in the form of rounded globules or crystalline deposits The foam cells ace almost certainly macrophages brought in from the margins of the plaquc by small blood vessels Even in small atherosclerotic plaques a collection of lymphocytes at either margin is a familiar feature and in the presence of abundant lipid larger mononuclear forms are observed (Fig 125) These cells are no longer believed to be infiammatory in origin as was suggested by Boyd (1928) and their function is regarded cven by adherents of the cholesterol-imbibition theory as phagocytic 4nut chlou (1933 p 288) in a study of experimental atherosclerosis was able to observe all transitional forms becw cen the small lymphocyte and monocytic cells on the onc hand and the large lipid cells on the other so that development of the lipid cells from the frec mononuclear cells probably derived from the blood would seem to be the most plausible hypothesis of their origin () DEEP LIPID ACCUMULATION The route by which the macrophages arc con cyed to a deeply situated focus of degeneration where thic lipid is separated from the lumen by a thick layer of dense and avasculas collagen (Fig 120) seems fairly clear It is qwic unlikely that the macrophages could penctrate the plaque from the lumen and onc inust conclude that they are carned to the dcgencrate zone by the ingrowing capillaries In such a case the accumulation of cells is not the primary lesion as is widely maintained but a secondary phagocytic phenomenon The acellular nature of the carly degenerative foci (Fig 111) supports this vicw The source of the ispid has always been a major problem According to Dugud (1946) It is the product of fatty degencration in a chrombus and on this hypothesis it would be consistent with what has already been described to regard it as a late stage in the degcncration of an organized clot The sanic author believes that fatty change can occur » fibrın thrombs but he gives no grounds for this bchef Wintermitz et al (1937) by mjccting the intimal vasculaturc of aortic plaques and claring by the Spaltehoiz technique were able to demonstrate vessels all round the softened foci and concluded thac capillary haemorshage was the source of the lipid The following extract from their paper is explicit There appears to be a gradual accumulation at the site of the hacmorrhage of facty 114

·T
DEGENERATION IN THE PLAQUE
1
FIG 124
1) genc tc 2 new th calah ! dippo fort ly
bulky ontp redt bo 4 pphe y of pl que
LADD Case 11 HE 30
MD
FI 125
Moin nula
huwa
van lion
Vtoplasm LADB C JOITE
gin of th
b
ng
$
840
Fig 16
Fyp ! fpea kofd pf try depot sep rated on
Un en bytys Ed na ilagen R Co Case 12 HE
JS
FA
Conglu nad ce copped arh
ut dlatt
12

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 128
Fat droplets extracellular and intracellular in laminated
wh te thrombus in aneuryson I sac Ao ta (Ca e not in
series) Sud II 960
FIC 12)
Same case Pe iv scular accum 1 r on of 1 pad u fibrou
w nl of neurys n 1 sac Sudan III 30
FIC 130
The sane using polaroid screenis to d monstrate anuco
FIG TJI
Organizing har orthage 1 nodular gosre shox ng
cholest ol dl fts 8 nt cells, I acrophages ( ont in
h emosider n) and proteinou mush HLEY 135
tropic patur of hp d

·DEGENERATION IN THE PLAQUE matenal which is stainable with Sudan III and which frequently contains the so-called cholesterin clefts giving the appearance of the classical atheroma It is reasonable to suppose therefore that this facty material is derived from and centually replaces the blood of the original haemorrhage a process analagous to the apparent changes observed ss haemorrhages in thryoid adenomas and in caserous haemangiomas Such a conclusion 25 bome out by the fact repeatedly confirmed that a typical yellow atheromatous plaque may on carchi 1 examination by the methods outlined above shox at its periphery z network of capillanes contaming red blood cells and anastomosing outside the zon ot fat and necrosis with obviously well-delineated and well-functionsng blood-channels argument docs not take into account the fact that focal necrosis occurs in the first place in parts of the plaque that are avascular and free of recognizable lipid Once these areas become vascularized however foam cells appear and thereafter the hupothesis is valid Indeed before reading the above passage I had concluded that capillary hacmorrhages into a necrotic focus repeared oser a long period constitute at least one source of cholesterol and set in mouon the vicious cycle that ultunately results in an atheromutous abscess The extra-cellular lipid accumulations at the centre arc of course no more than the debris of brokeri-down foan cells There is however another source of cholesterol It has not been proved that collagen or fibrın are subject to lipsd degeneration but it is certain that as a mural thrombus retracts a variable number of red cells ase trapped in the fibrinous network and squeezed between its lamınae and must ultimately in broken-down for constitute an element in the deposit capable of providing a source of cholesterol (Fig 1-7) in testing this idea frozen sections of a lammated thrombus m an arteriosclerotic aneurysm were stained by Sudan III and examined under polaroid screens If Duguds theory is correct ac that the lipid is due to fatty degeneration in a thrombus something of the same sort should occur in the serially deposited thrombu in an aneurysmal sac Fig 128 shows scattered throughout the granular hacnnc dcbns munute. droplets of extracellular fat similar in appearance to the subendothelial fat dust of catly athero sclerosis also clusters of largez granules apparently gamered by macrophages Borh are isotropic Deeper down where the periphery of the thrombus has undergone some degree of organization is a broad lipid layer costly extracellular and partly anusotropic Leadmg from this into the fibrous wall of the sac arc perusascular chains of foam cells swollen with anisotropre lipid in its greatest concentration (Figs 1.9 130) The inference is that a thrombus undergocs fatty degeneration isotropic globules being taken up by any macrophages sunt ning within the clot or capable of entering it in the oldest part the lipid 15 anisotropic cither as a result of chemical synthesis or accumulation of the more insoluble components over a long persod in short st is clear that many of the features of lipid accumulation in atherosclerosis are also present in degenerate arterial thrombi Now the relation of cholesterol to atherosclerosis has beca energetically du bared particularly (as was shown in Pzt 1) in connection with fatty streaking cxpcrinanca! atherosclerosis and sccent work on scrum lipids Wsthout prejudice to the biochemical 117 ·THE PATHOGENESIS OF CORONARY OCCLUSION findings the histopathologist may note that (1) Cholesterol is present in every animal cell is very stable and is relatively insoluble (Schonheimer 1931) It is certainly present in red blood cells (2) Cholesteatomata surrounded by altered blood pigment are not unusual sequelae of haemorrhage into a nodular goitre (Figs 131 132) They have also been observed to follow traumatic hacmorrhage in bone (Fig 133) (3) Cholesterol like calcium tends to accumulate in necrotic material eg caseous tubercles (Calduell 1919) and their cholesterol content may be increased by fceding cholesterol to tuberculous animals (Jaffe and Levinson 1925) a fact that may help to explain the excess in the plaques of diabetics and other hypercholesterolaemic subjects It is thus possible to account for the presence of cholesterol in an atheroniatous abscess without necessarily invoking a disorder of lipid metabolism Lary (1938) objected that normal blood contains less than 1 per cent of total fats whercas nost of the fat in atnerosclerosis is cholesterol but this 11 nores the cumulative effect of recurrent small haemorrhages over a long period and the resistance of cholesterol to absorption Moreover as Duft (1935) pointed out no one has postulated å disorder of calcium metabolism to cxplain calcification in atherosclerosis (6) SUPERFICIAL LIPID ACCUMULATION Less easily explained however are the broad layers of foam cells observed on the surface of an atherosclerotic plaque immediately below the lining endothelrum (Fig 134), Admittedly such appearances were observed in a few cascs only and a study of serial sections sencrally revealed that these layers were only an outcrop from a mort deeply placed atheromatous focus communicating with the surface of the plaque along an oblique cleft a phenomenon related to dissection which is discussed at the end of this chapter This is not always so however and it must be conceded that superficial foam cell accumulation independent of deep-seated softening is a phenomenon not readily ca plained by the thrombogenic hypothesis of atherosclerosis Dugard (1948) is prepared to admit that superficial lipid may be due to disordered mctabolism and therefore of a different nature from the deeper deposits and by feeding rabbits with cholesterol he has satisfied himself that experimental lesions are produced by repeated endothelial o crgrowth of foam cells which have migrated from the circulating blood to the lining of the vessel (Dugud 1954) He has therefore postulated a dual pathology in atherogenesis but this work requires fuller confirmation This is an opportune moment to introduce very briefly the theories of Luary (1934 1935a 1936a 1941) Basing his views on experimental atherosclerosis induced in rabbits by feeding cholesterol he concludes that the capacity of humans to metabolize cholesterol dımınishes with age The excess lipid is conveyed from the blood-stream to the intimi by globular lipophages and is later taken up by phagocytic cells with the properties of fibroblasts In younger subjects the cholesterol acts as an irritant and provokes a fibrous response and as their ability to metabolize cholesterol is greater a fibrous plaque results in old age the fibrous response is less and the lipid tends to accumulate hence the freqıkıncy of atheromatous abscesses in the aged II8

·DEGENERATION IN THE PLAQUE
Fb 732
Ogan dua north ge et adult « « -
ccator a und d by bol
HE
35
choles.
A 133
Og nzing ho na n boc follwetun wth
farty P
190 and m crop
contas ng
to
70 ides
HE
45
FIG 13+
Supe fies!!poderost 10 ecly but wha ng endo
thlu IAD Case jo PTAK X 160
FIG 135
Peni ascut rh 1705 H ximnse som fbro В к
of bero fou abscess to detaily photo fl Co
Cax 17 PAS X 100

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG 136
FIG 137
G cat d stortion of lumen au cd by former tears and
ruptures LADB Case 28 Azan x 20
Healing by g. nulacio afte rupt re of pl que 1 nn ted
f gments of which re stil son R Cor Case 10
An X 30
FIG 132
FIC 138
Overlappin deposits sh ply separted by elastc laser
predisposing to d ssect on LADB Cases Sherid n
Y 125
Oblique ! yer of degenerat e softer between a deguo
sit pred spos stod section LADb Cases Foix
15

·DEGENERATION IN THE PLAQUE Howet ir Horn and Finkelstein (1940) in a study of 100 tatal cases of coronary disease were unable to correlato old age with atheromatous absuesics and the present study supports their views (see Table D) It may therefore bu seen that Leary s theories readily explain the superficial lipid but not the decper focı He also made much of cholesterol laden cells which he observed half way through the lining endothelium and which he regarded as lipophages passing through the plaque fron the blood-stream He does not appear to have considered the possibility that these might simply be macrophages which had derived their cholesterol content from the red cell residuc in the plaque and which had been observed in the act of passing back into the lumen in the course of phagocytosis PHAGOCYTOSIS This has already been dealt with in relation to lipid but it is also concerned in the removal of altered blood-pigments Now some have objccred that if cholesterol is derived from broken-down rud cells there should be more evidence of haemosiderin in atherosclerotic plaques But in fact Prussian Blue preparations reveal a good dual more haemosiderin than superficial examination of haematorylın eosin sections leads one to suspect much of it dispersed in finc extra-cellular particles Indeed it is only when haemosiderin is concentrated within macrophages that it becomes conspicuous - eg Fig 13$ where siderophages may be traced from a haemorrhagic focus in the plaque to the adventual lymphatics In any case of the earlier observations on arterial thrombi arc correct one would not expect to find the saine concentration of haemosiderin as in a venous thrombus Firstly an arterial thrombus is mainly fibrinous next the red cells trapped within it may have their haemoglobin washed out of thcnt within a few days lastly the scantv vascular supply imposes a restriction on the number of available phagocytes and such bloodpigment as may be left in the plaque must remain unconcentrated and dispersed Incidentally Pater on (1954) has employed the Prussian Blue technique on gross specimens and detected large amounts of unsuspected haemosiderin in humın aortas which had not shown any macroscopic cvidence of haemorrhage RELATION OF AGE TO DEGENERATIVE CHANGES In this series the various types of degeneration did not appear to be closely related to the subjects age To test this the vessels of the s cases under 30 were conipared with the 7 over 70 involsing the cxamunation of 65 blocks of the main divisions of the coronary arteries (see Table D) No conclusion can be drawn from this small scries but it can at least be stated that it does not support the idea that lipid degeneration is significantly commoner in the older age groups Calcification while more frequent in the over- 70 group is also present in nearly half the under-so group RUPTURE AND DISSECTION OF THE PLAQUE Rupture of an atherosclerotic plaque is a fairly conimon finding The predisposing ILI ·in older THE PATHOGENESIS OF CORONARY OCCLUSION cause of course is degenerative softening in the depths of the plaque with gradual extension towards the surface When the roof of an atheromatous abscess glies way (Fig 104) the contents are discharged into the lumen leaving a cavity with sharply gouged walls (Fig 117) Rupture may be precipitated by haemorrhage into the abscess and complicated further by secondary thrombosis (Fig 68) Leary (1934) regarded thus as the usual mode of death age groups He believed that the blood from the lunch might also rupture to the abscess and so initiate thrombosis It 19 very probable that the force of the arterial blood is capable of disrupting the plaque still further and Fig 68 shows a tear extending right down to the media causing great deformity of the lunien This is further emphasized in Fig 136 where multiple foci of softening have resulted in a lumen with a bizarre outline and irregular healıng has formed ridges and clefts on its Iming Should thrombosis follow the resultant granulation tissue may fail to obscure completely the lincaments of the original rupture (Fig 137) There is another very distinctive type of accident which I have termed dissection in which the line of cleavage is along the former junction of two overlapping deposits There is a natural plane of fission at this level the serial deposits being separated by an elastic membrane (Fig 138) and not firinly knit together by a process of vascular organization 15 was stated in the section entitled Layering in Chapter XX This weakness is exag- Serated by the tendency to degenerative softening in the deeper part of the superficial deposit which is furthest removed from the main bloodstream and incapable of deriving adequate nutrition from the decper layer (Fig 139) This is accentuated as in the deeper abscesses by microhacmorrhages from the vessels growing in from the margins and the softening tends to extend along an oblique plane from the depths of the plaque towards the surface It has already been shown that superficial lipid accumulations arc generally no more than an outcrop from one of these strata In the same way larger haemorrhages are liablc to cause rupture into the lumen raising the margin of the overlying deposit in a very characteristic manner (Fig 140) As with the more conventional atheromatous abscess such an accident niay lead to thrombosis What happens to the particulate debris discharged into the lumen followmg rupture of an atheromatous abscess is a matter of speculation but it is reasonable to suppose that some of it may cause at least a temporary occlusion of the finer twigs in the distal reaches of the y cssc] Cholesterol embolisin is not unknown (Flory 1945 Meyer 1947) and Zah and Elas (1949) have shown that it can result from coronary atherosclerosis producing small foci of necrosis or fibrosis in the related myocardium L.2 ·The Relation of Coronary Occlusion to Myocardial Infarction In a rough attempt to gauge the total degree of coronary insufficiency and the relative frequency of the lesions in the main branches the following grades of obstruction weru recognized (1) Total occlusion (2) Subtotal occlusion (3) Severi narrowing Total occlusion was due to (n) Thrombosis recent (Fig 94) organizing (Fig 70) or fibrous (Fig 141) The last-mentioned although reyarded by Koch and Long (193--33) as a separate cntity is treated here as the end-stage of organized thrombosis (b) Hue morrhage into the plaque cither raising the intimal lining and compressing the lumen or damaging it and initiating thrombosis Examples of how this occurs are given in Figs 66 and 67 Subtotal occlusion is a term reserved for those instances where a minuti vascular channel quito inadequate as a functioning conduit was preserved in any of the following Extreme signet-ring defornuty (Fig 142) extreme concentric narrowing (Fig74) cxcess atheromatous softening with or without hacmorrhage (Fig 143) marginal retraction of a thrombus (Figs 45 144) recanalization of a thrombus (Fig 41) Serere narron ing is a somewhat arbitrary term applied when the lumcn was reduced to a circle 2 mm in diameter or a slit not more than i mm in its shorter diameter The degree of narrowing at some point in each of the main branches was then related to the presence of an infarct and the mode of death The analysis as set out in full in Table F but the relative frequency of disease of the three branches is summarized in Table E T LE E Dee of N OH LADB LG A RC Y 4 13 5 Total Old 7 Oc lus on R t6 S bt tt Old 41 Od oni Rectis Sc TS Natr w No Sgn t cat 6 Old Rcctis Old 1 R IO Old $ Rece 2 Old 616 Recento 2 s 14 NO It will be scen that out of a total of 39 cases 33 had severe to completc occlusion of the left anterior descending branch -s of the right coronary and 17 of the left circumflex branch from a functional standpoint blockage was complete in the left anterior descending branch in 18 in the night coronary in 14 and in the left circumflex branch in 7 These figures support those observers who have found the left coronary artery and its branches more frequently involved than the right (IIc im 19-3 Faulkner et al 19-4 Il olff and II liige 19.6 H11 19-6 Pirkinson and Bedford 19-8 Leine and Brown 1-3 ·THE PATHOGENESIS OF CORONARY OCCLUSION 1929 Wollof 1929 Di Coursey 1934 Saplır et al 1935) They disagree with those who find the right coronary artery as frequently or more frequently affected (Barnes and Ball 1932 Master et al 1937a Horn and Fmke Iste in 1940) TABLE F Cie L4DB No of L Curainflex R C ron ry ees el offered I fuction Typeſ 1 Ant (R) 1 3 2 1 3 Ant (R) 4 5 6 7 8 Ant (0) Gadual Sudden Gadual Sudden Gradu 1 Sudd n Sudd n Gadual Sudden Sudd n Sudden Sudden Gr dual Sudden I Po t(0) 3 Post(O) SN Ant (R) Anc (R) Ant (O) 3 IO It 22 13 14 I 16 17 78 19 0 Sudd n بحه با Post(0) Ant (O) 1 Ant (R) T (R) ST (0) SN SN SN SN ST (R) T (R) SN SN SN T (0) SN T (0) SN SN SN SN T (0) SN SN SN SN T(0) T (O) SN SN SN ST (0) TO SN ST(0) T(R) SN SN SN IN SN T(0) T (O) T(0) r (0) ST (O) SN SN SN ST (R) T(0) T (0) T(0) ST (O) T (R) T (R) SN T (R) T (O) ST (0) TO SN ST(0) ST(0) T (O) T (R) SN T (R) SN SN T (R) ST (0) ST (0) ST(0) T(0) SN SN MATERIAL INCOMPLETE Gadu 1 Sudden Gr dual* Sudden Gr dua! يعا 2 2 Post(O) P (0) A (R) Ant (0) 1 Sudd n 1 3 24 J Small TE Ant (O) 6 22 8 9 30 31 32 33 Ant (O) I ost(R) Sdden G du * Sudden Sudd Sudden S dd 1 Gadu 1 Sudden Sudden Sudden Sudde Cadual Sudden Gadu! Gadu 1 Sudd 1 Sudden Cadu 1 2 3 Ant (0) الما 1 Post(R) Post(R) 35 36 37 38 39 40 } Ant (0) Ant (R) R = Rc O Old t T - Total oc lu on ST = Subtotal oc s 11 SN - Severe nar o vig *Ded fro 12 och r causes All three mai vessels were severely diseased in 11 cases two vessels in 14 and only one in the remaining 14 Of the 2. cases exhibiting signs of old or recent infarction two or even all three vessels were seriously diseased in 17 (Figs 145-8) This gives some support to the view of Saphir et al (1935) that occlusion of more than one branch is required to produce infarction This is only approximately true however sincu in s cases of infarction only one vessel was seriously narrowed whereas 3 other cases (Nos 2 10 and 34) had 1-4

·THE RELATION OF CORONARY OCCLUSION TO ALL ARDIAL INFARCTION
FIG 140
Dssect on of plaque following hacho have to focu
of softe
& between depots RCor Ce 34
Sherid n x 35
FIG 141
Total o el un off brous type LADB Cac9 HEA
30
FIG 112
s brilor on by ce ne sont ring def
R Cor c 31 PTAH X 30
FC TA)
Sbtlo i onds to hacnorthage nto atherom tou
bscess. LADB Care 30 HEX 20.
ty

·THE PATHOGENESIS OF CORONARY OCCLUSION
2
Fir 144
FIG 14)
LADB showing se
ren
Subtotal oclusion due to narg nal retr ction of recest
th onlus LADB Case 20 Aza IS
owg
13 HE
>
FIG 146
L Ci cutnfics branch of
mec se showing subtotal
occlusion by recent h morrhage to athco ratou
Theress HE 45
Fır 147
Anothe pa t of L C rcu nfl br ach of samec se show
ing tot loc ion by org nized th on boa HEX 30

·THE RELATION OF CORONARY OCCLUSION TO MYOCARDIAL INFARCTION severe to total occlusion of all 3 major branches without visible infarction This clearly illustrates thu variability in the collateral circulation of different hearts a subject mort fully discussed in Chapter VIII As was to be anticipated all the cases of įradual death showed myocardial infarcts excepting those who died of unrelated causes On the other hand 14 of the cases of sudden death showed no visible infarct This is in accordance with the view that many cases of sudden death are due to acute myocardial ischaemia butore infarction has had time to cause esible lesions while those who survive the acute attack and die days or weeks later exhibit the familiar features of a cardiac intarct ·VIVI The Coronary Arteries and the Rest of the Cardiovascular System REPRESENTATIVE samples of visceral and skeletal arteries were removed ar cach autopsy for comparison with the coronary lesions These included cross-sections of the thoracic and abdominal aorta the renal artery the brachial artery at the level of the clbow-joint and the poplitcal artery at the level of the knce-joint Broadly spcaking it can be said that intimal lesions comparabic to those in the coronary arteries were present in the aorta and popliteal arteries but that in the brachual and renal arteries the intimal lesions werc inconspicuous and mcdial degencration predominated The microscopic lesions are described first the correlations are trcated later and so on) THE AORTA Every case investigated showed atheroma always more sevcrc in the abdominal portion cspccially in the 2-3 inches between the origin of the renal arteries and the bifurcation In a rough attempt to gauge the severity thrce grades were recognized based on the extent of surface involvement degrec of ulceration and the microscopic characters (chickness of plaques degree of degeneration thinning of the media destruction of clasuc + indicates anything from fatty strcaking to a few widely separated plaques with an intact surface ++ indicates numerous plaques some with ulceration +++ indicates large confluent areas of ulceration Microscopically the features of coronary atherosclerosis arc gencrally reproduced modificd of course by the width of the aortic lumen and the absence of occlusion or its complications As with the coronary vessels the appcarances indicate that advanced lesions owo inore to thrombosis than to lipid infiltration or incimal fibrosis Thus layering is a regular feature with the deposits either uniformly superimposed (Fig 149) or overlapping (Fig 1so) although in ncither casc is the width of the lunien significantly reduced The button-like thickenings round the mouths of branch vessels so characteristic of aortic atherosclerosis show the same type of laycruig as their coronary counterparts (Fig 151) Newly formed elastic tissite either as a finely fibrillar tangle at the base of the plaque or in thc form of serial marginal membranes (Fig 152) is again common as is the extinsion of smooth muscle from the vessel wall (Fig 153) Intımal i ascularızation follows the broad patterns outlined in coronary plaques se with superficial and decp plexuscs and hypertrophied vasa vasorum passing transmedially to 1.8

·THE CORONARY ARTERIES AND THE REST OF THE CARDIOVASCULAR SYSTEM
1
FIC 749
FIG 148
R Coo
y of s me sh w ng subtotal occlu on
by alvish emo hage in 1 sc theo rou bess
Layering with d posits unif nly uperimposed Aot
C Se 18 Shend nx 60
HEX 35
*
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FIG 150
t overl PS An
Lay ng wth dep
Sheridan X JS
Cases
FIG ISI
Lay niny, ro to th of B ch it ry (f Fg )
Aort Case 10 Shond na 15

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIG 15
FIG 753
Recurrent clastic membranes continuous with elastic
lamına at n gin of plaque Aorta Case 11 Sheridan x
40
Same esse! showing ingrowth of n uscle app rently
derived f on nusculo-el stic 1 yer PTAH X 40
FIG 154
FIG 155
Muralth ombus with lughfbrin content in forn of coarse
nernork enclosing red cells (cf F: 76) Aorta Cases
PTAH X 150
Wap of fbrin on su fce of atheroscl totic plaque
Aorta Case 5 PTAH 40

·THE CORONARY ARTERIES AND THE REST OF THE CARDIOVASCULAR SYSTEM
The propone
Fre 156
Cranular sud of fbros plague Aorti Cac 14.
Azan X 410
FIG 157
Myrto degeneral) ih p der shaped it
Aorta r se 9 PIANI 430
FIC 15€
PAS pos ri e streaks a descriera plaque Aorta (se
33 PAS 40
FIG 153
Dssection of the pugut wuh uporncu brid rutet f
Horta Case 4220 $

·THE PATHOGENESIS OF CORONARY OCCLUSION
Cos
Aort
FIG 160
1edral atrophy t base of athro 1 atous abscess
C se 2 She ida 1 x JO
FIG II
Superfici l depost of age ng lau need fibrin
Case 6 PTAH X 30
Ao ta
7
FIC 163
FIG 16
Samic case Superfc al foan-cell deposit Aorta Aza x
85
F dust below 1 timal endoth Tu in ftty te king
Aorta (Case not in sre) Froze sect on Sud n lll X
700

·THE CORONARY ARTERIES AND THE REST OF THE CARDIOVASCULAR SYSTEM link up with the deep plexus But the vascularity is directed to the requirements of the plaque and not at all to the tormation of a collateral circulation as in the case of severe coronary narrowing This may account for the impression gained (from an admittedly inadequate survey of aortic plaques) that superficial plexuses are more prominent in the aorta and transmedial ingrouths of vasa less than in their coronary equivalents The deep plexus again appears to follow marginal retraction but in this case there is little need for collateral channels Haemorrhages into degenerative plaques augment the athcromatous lesions as in the coronary vessels thrombosis is of the mural type with the same high proportion of fibrın (Fig 154) and the same tendency to be compressed into laminae parallel with the vessel wall and wisps of fibrin as shown by Dugud (1948) are found adhering to the surface (Fig 155) or undergoing assimilation into the body of the plaque Degenerate changes follow the familiar pattern The collagen fibres undergo a fincly granular swelling (Fig 156) or disintegrate to form a myxomatous matrix containing spider-shaped nucle (Fig 157) The abundance of PAS-positive material indicates a mucinous change (Fig 158) Lipid accumulates in the depths of the plaque into which microhaemorrhages occur Larger haemorrhages may be followed by rupture of the plaque and secondary thrombosis Oblique degencrative fissures in the plaque may lead to dissection or cause lipid outcrops to appear below the surface (Fig 159) Calcification of course is all too common and even foci of ossification Focal atrophy of the media is particularly common below large plaques and the degree and excent of musculo-clastic destruction are sufficient to account for the so-called arteriosclerotic aneurysms (Fig 160) Superficial foam-cell accumulations again raise the question of the dual nature of acherogenesis Figs fór and 16. show neighbouring and purely superficial excrescenccs on the intima of the same aorta the one largely fibrinous the other almost wholly fatty In an unsuccessful attempt to answer this problem frozen sections of superficial aortic Icsions were cxamined In the main the morphological observations of others on fatty infiltration were con firmed Below the endothelium at the margins of a fatty streak and therefore presuniably representing the earliest form of the accumulation a fine isotropic fat dust can be seen (Fig 163) Below this and lying between the clastic laminac are macrophages containing isotropic lipid droplets (Fig 104) These appcar to be spindle-shaped but sections parallel to the surface show they are discoid the shape possibly beins, determined by intra-arterial pressure In older plaques the lipid becomes anisotropic and connective tissue is formed as is shown by paraffin and frozen sections of the same lesion using polaroid screens (Figs 165-7) Leary theories of atherogenesis have been referred to under Superficial Lipid Accumulation (Chapter XXIV) and were claborated in l'art I under Experimental Atherosclerosis (Chapter IV) He believes that the cholesterol is taken up by fibrolipophages - cells which have both phagocytic and fibroblastic properties - and that thesc lay down the fibrous tissue in the plaque Fig 168 shows a cell in an aortic plaque which answers his description of a fibrolipophage He has however no sery satisfactory explanation 133 ·THE PATHOGENESIS OF CORONARY OCCLUSION for the manner in which the cholesterol reaclies the decper parts of the plaque where it appears to evoke a similar reticulin response (Fig 169) THE POPLITEAL ARTERIES Poplitcal atherosclerosis is common affecting 25 of the 27 arteries cxamined (scc Table G) A sigmficant narrowing of the lumen may occur and this may be c\treme (Fig 170) TABLE G Case No Age 4 ta Bruchsal Popliteal Renal Cor 3 2 3 4 MF Normal 1 2 240/150 2 1 SO 51 67 66 54 SS 744 4) 48 68 68 75 ++ 1 ++ ++ + A1F + -40/130 200/100 بیه 3 7 8 ) TO 11 12 13 14 160180 + + + 0 2 MF O MF بیمه 160/130 145/80 1 ++ MF 270/115 16 17 18 19 o SS 78 61 54 70 0 37 64 58 145/70 MF No ) + MF 0 0 It aan ++*+10+01+I++ +++++++ I 1 170/70 MF I 3 210/110 75 5) 67 5) 66 MF + 22 33 14 25 26 27 28 29 კი 31 32 33 MF +++++++++ ++++ N E c +00+-+*+++00 + + + MF + MF 240/140 Nors ] 3 34 35 36 I 145175 No mal 100/40 60150 71 31 47 $9 $3 so 48 64 63 67 +++ ++ MATERIAL INCOMPLETE MF 2 1 38 39 40 *EN) of Coro vary bran h s occlud d by atheroscleross (sce Table E) MF= Mcdial fbro is no atheroma O- No atheron or med 1 f bross - Unknown In general it can be said that the lesions correspond more closcly to coronary athcrosclerosis than in any of the other arteries in this series 13+

·THE CORONARY ARTERIES AND THE REST OF THE CARDIOVASCULAR SYSTEM
FIG 164
M croph
berig i ot op lip d granul below
end theu i and between elast cl min Ao ta (Case
not in ser es) Fozen sction Sud a Ill x 400
FIC 165
Paraff n secto of 11 therosclerotic plaq how s
ft sp ces and f brous tis Aot (Case not n sertes)
HEX 40
F. 167
FIC 166
The same plaque show lop din m croph ges. Fro en
act on Suuntil y jo
The same sect on showing up to be an sotrop through
rol rod XTECTS

·THE PATHOGENESIS OF CORONARY OCCLUSION La FIC 768 F brol pophage (howing lipid granules n cytopl m nd tapering branches at the pole Aorta Case 3 PTAH TO20 FIG 169 Atheromatous bscess with n asse of cryst Il ne choles terol in reticulen netwok Aorta Case 35 Foot x 100 NYM FIC 171 FIG 170 Extreme signet-ring deform ty showing layer o vascular clefts between deposis and degeneration of decper layers Popl teal artery Case 25 Sheridan xo Dissection of pl que with hacmor h ge Popt te larte y Case 23 Shnd nx 40 ·THE CORONARY ARTERIES AND THE REST OF THE CARDIOVASCULAR SYSTEM Extreme narrowing of the lumen of the degree shown in Fig 170 is unusual but this is to be interpreted in the light of the random selection of the specimens in cases that owed their presence in hospital not to peripheral gangrene but coronary occlusion The case in question was a severe diabetic and it is noteworthy that while the amount of lipid excceds that of any other case the serial deposits show that they have been fibrous before undergoing lipid degeneration in the deepest layers in that part of the plaque furthest from the blood stream Ulceration of the plaques is not a prominent feature in popliteal arteries but other features observed are degeneration leading to mural thrombosis dissechon of the plaque (Fig 171) and the superficial deposition of fibrın (Fig 172) The last figure also shows an acellular lamunated deposit part of which takes the stain for fibrin with PTAH which I have suggested elsew here is an indication that the unstained lamınae are not truc collagen but are composed of compressed and ageing fibrın Comparable changes were observed in the occasional samples of the other large branches of the aorta Fig 173 shows medial atrophy unmistakably related to a deep focus of degeneration in a carotid artery and Fig 174 shows atherosclerosis of the external iliac artery in which layering deep degeneration angular hacmorrhage and calcification are all present The more sup«rficial of the angular vessels were derived in this instance from the lumen THE BRACHIAL ARTERIES Significant degrees of intimal thickening were rarely observed lipid degeneration in these even more rarely and gross atheromatous softening never (see Table G) in marked contrast to the popliteal artery On the other hand replacement fibrosis of the medial muscle fibres was a prominent feature in over half of the remainder (Fig 175) Its relation to atherosclerosis is discussed later The minor degrees of intimal sclerosis consist of an increase in connective tissue and reduplication of the internal elastic lamina These are the criteria of arteriosclerosis as defined by Jorts (1903) as distinct from atheroma Nodular calcification of the internal elastic lamina was observed only once and gross medial calcification of the Monckeberg type not at all which supports the view that the latter is a phenomenon unrelated to atherosclerosis THE RENAL ARTERIES The changes approximated fairly closely to those in the brachial arteries namely slight intimal thickening of the fibro-elastic typc unaccompanied by degenerative changes in 40 per cent of those examined and medial fibrosis in 60 per cent of the remainder (suc Table G) Sheridan staining of these intimal thickenings revcals a fine network of clastic on the intimal side of the internal lamina which may be fragmented or reduplicated (Fig 176) PTAH preparations ici cal scaining anomalies in the internal clasac lamina suggesting degeneration (Fig 177) Other features are slight lymphocytic infiltration and prolifera- 137 ·THE PATHOGENESIS OF CORONARY OCCLUSION tion of connective tissue There are no foam cells but frozen sections rci cal the presence of a small amount of isotropic fat Older lesions show clastosis and it is noteworthy thar the bulk of what looks with other stains like fibrous thuckening is in fact clastic (Figs 178 179) Dilatation of the lumen is known to be a feature of arteriosclerosis either related to 111crcascd tunision in the vessel or degenerative changes in its wall Thic function of the internal clastic lamına according to Thayır and Fabyan (1907) is the prevention of overstretching rather than the promotion of contraction Breaks in the elastic must therefore judicate that the limit of extensibility has bcen passed It may occasion surprise that the renal arteries failed to show gross intimal thickening in this series since atherosclerotic stenosis of the mouth of these vessels is well known Probably the rcason is that the samples were taken from the middle third of the artery whereas atherosclerosis and mural thrombosis are usually confined to its proximal centimetre (Heard 1949) The frontispiece shows the margin of an atherosclerotic plaque in a basılar artery This also shows rupturc of the internal elastic lamına and the extensive lipid infiltration of the media may be due to this affording another instance of the protective nature of the elastic barrier 138

·THE CORONARY ARTERIES AND THE REST OF THE CARDIOVASCULAR SYSTEM
FIL 17
Fb began Lated in plaque Poplit 1
Case 18 PTAH X 135
try
FIG 173
Cotid artery showing t ophy of d belo v athero
slot pl qu Cs Shend n 30
1 -
mi
1
FIC 175
FIG 174
Erten al ! cartery how 1 yeri 5 deg
calaf ct on (bottom right) and 'ngul haemorth g
Case 8 HEX O
ಬಾt of a d 1
Back ! howing fhorep
ooth m 1 Mulda to
bt
ety sł ghi Case 8 HE Y 45
t
{ th kcn ng

·THE PATHOGENESIS OF CORONARY OCCLUSION
FIC 176
FIC 177
Fine clastic network in slightly thickened into na Internal
cla tic la nina f gmc red and reduplicared Renal artery
Case O She idan X 120
The same howing, stal ng anomalies of cernal clastic
Tarnına alo, scanty lyn:pho ytes and fbroblasts in
int ma PTAH X 6S
FIG $79
FIG 178
Intimal thickening apparently f brous but in fact la gely
clastic (c! hg 579) Rental artery Case 28 PTAH X
The same showing the deg ce of cu tosis. Sheridan x
135

·XVII Correlations On the basis of the findings in tlic previous sections an attempt was made to correlate the degree of ses crity of atherosclerosis in the various arteries with the patients age and bloodpressure The results are presented with some reserve in view of the arbitrary selection of the material and the small range of cases RELATION OF ATHEROSCLEROSIS TO AGE* (a) AORTA All 39 cases examined showed some degree of atherosclerosis with the following distribution TABLE H s Dg S er ty No of CSS Aege Age ++++ ++ 6 18 15 65 2408 62 9+2 31 39 74 82 V c f Tbl G tly on of th ses (No 25) d bet c aged 59 Two other d b ti (No 21 d 3) & 64 nd 74 w 1 fed + nd ++ pe tv ly (6) POPLITEAL 25 out of _7 cases cxamined showed mild to sccrc atherosclerosis TA EI N fc A Ag De or S +++ ++ 59 521395 63 ] £235 47 5 NI 16 z () BRACHIAL 8 out of 7 cases examined showed atherosclerosis invariably slight * Average age of wh le serie = 61 631 60 141 ·THE PATHOGENESIS OF CORONARY OCCLUSION TABLE] Degree of Severity No of Caes A efige Age N.1 8 19 60 2+4 6 62 35 21 (d) RENAL 10 out of 26 cases examined showed atherosclerosis invariably slight TABLE I Degree ! А S ver ty No of CS ge Age + NI IO 16 59 33 98 63 7+2 32 RELATION OF ATHEROSCLEROSIS TO HYPERTENSION TABLE L BLOOD PRESSURE te el of C ses SIO All er Deg ee of Athe osc! Red Nor al Unk Aorta 39 II I I Popliteal 25 +++(6) ++ (18) +(15) +++ (0) ++ (8) + (16) +(8) +(10) 2 D 0 3 3 0 5 9 2 4 4 B chi 1 Rnal 8 10 2 RFLATION OF MEDIAL FIBROSIS TO AGE AND BLOOD PRESSURE TABLE M BLOOD PRESSURE essel Mo SC ses Sh its fodi I bross A eag Age Rsed N#al likoj 1 Bra hral Ren 1 65 45431 63 6+2 86 Now 10 3 ·CORRELATIONS RELATION OF VESSELS SHOWING NEITHER INTIMAL THICK ENING NOR MEDIAL FIBROSIS TO AGE AND BLOOD-PRESSURE TABIE N - BLOC D-PRESSURE 1 Ĉs Ces Red 0 o 1 norta Poplitcal Brach 1 Rnal 475 61 +6+ 6383460 7 10 6 N 3 3 Comments (1) The order of severity of atherosclerotic involvement in this series is firstly the aorta then the popliteal arteries and a long way after these the renal and brachial arters (2) In fatal cases of coronary occlusion atherosclerosis is very constant in the aorta and popliteal arteries especially in the older age groups (3) There is some suggestion of a correlation between the severity of aortic atherosclerosis and the patients age and between popliteal atherosclerosis as a whole and age although the figures are not statistically significant This docs not hold for the brachial and renal arteries (4) Atherosclerosis is slight or absent in the brachial and renal arteries but medial fibrosis is (s) Medial fibrosis cannot be specifically related to age in this group (6) The data on hypertension are insufficient to relate it to exther atherosclerosis or medial fibrosis common RELATION OF SEVERITY OF CORONARY OCCLUSION TO AGE TABLE O FB h oldu Acte Cass Ag 11 14 60 8265 60 9+ 63 2 69 * T ble G RELATION OF SEVERITY OF CORONARY OCCLUSION TO BLOOD-PRESSURE TABLE P BIODD-YPES LRE (Bans! a ! Cause Rsed Nos! $ 11 14 14 1 143 ·THE PATHOGENESIS OF CORONARY OCCLUSION Comment In fatal cascs of coronary diseasc although many cases are hypertensive and show renal arteriolosclerosis hypertensive granular contraction (nephrosclerosis) is an infrcquent accompaniment TABLE R Degree of Case bo Age athcs mia It! of BP Aeys Gross Apperte of And eys Arter of sclerosis Nopirosclerosts 11 othe res els JL of CA dd 1 Sardt Heart 1 N سا 4 Old 6 5 Ells II o O o T 9 IO II 12 13 14 15 16 17 18 19 0 21 22 23 24 3 SO Infarcts SI IS OZ Congested 67 100/40 9 OZ Normal 66 11 OZ Congested 54 240/150 I2 OZ Flea butten + + 55 140 Congested 74 12) oz. Congested 49 240/130 2 OZ No mal 48 oo/100 IS! oz. Large pale kidneys ++ 69 10 OZ Congested 68 160/80 No mat 75 12 OZ Infarcts + 59 160/130 Infarts 53 145/80 II OZ Normal 78 8 OZ Contacted 6) 270/115 Ilo I farcts 53 14 OZ Normal MO 145/70 7 oz Contracted 70 101 oz Contracted 37 Normal 90 Infarcts 64 140 Normal 58 Ito Infa cts 74 170/70 70 Contracted 75 14 OZ Congested L 8 oz Compens Hypet $2 ++ R 2 OZ Chr Pyeloneph 67 141 OZ Congested 59 13 Oz Congested 66 40/140 13 Oz Normal 69 90 Normal 71 Normal 9 OZ Norm 1 31 oz Congest d 47 14 OZ Congested $) i sos IO OZ. Norm! $3 95/60 Norinal 80 Normal No mal o 48 60/150 12 OZ Normal + 64 10) oz N mal 63 Norm 1 67 noz Normal MATERIAL INCOMPLETE 12 OZ Rec 17 OZ o poz o 18 OZ Old 28 OZ 13 Oz 0 23 Oz Old 2 OZ Old 23 OZ Old 12 OZ O 131 oz Rec IS OZ Rec 22 oz Old 13 OZ o 13) Oz Old 23 Oz Old 18 OZ Rec 134 OZ 0 18 OZ Old 16 OZ Old 20 OZ Old 17 OZ 0 OZ 0 16) oz 0 17) OZ 0 1) OZ Old 1) 1 oz o 19 0 Old 18] Oz 0 16) Oz 18 o Rec 16) Oz o 16 0 Old o 1210 Rec 23 Oz Rec 16 OZ o 20 OZ Old 201 oz Rec 10/110 5 3 25 26 7 28 29 30 31 32 33 OOOOOOO+ 4 S 5 o 1212 و او 4 Z 35 36 37 38 32 40 13 Oz 0 o o 7 146 ·\YIY CARDIAC WEIGHT IN CORONARY SCLEROSIS The weight of 39 hearts is recorded in Table R The average weight was 17 - 07 II blood-pressure was recorded in 18 cases only RELATION OF CARDIAC WEIGHT TO BLOOD-PRESSURE 1 ABLES D grees Hypert s01 of A cage Il ght cas s of Har 8 Sere Slight BP No mi 22 2+I I OZ 13 DS +1 140 13 4 +Ir2 OZ 5 RELATION OF CARDIAC WIIGHT TO RENAL ARTERIOLOSCLEROSIS TABLE T Ren 1A ter lo scle $ + V of Av rage Il g!! of He ! 11 19 25 75 OZ 16 17+023 Oz Comment Essential hypertension as manifested by raised blood-pressurc and/or renal arteriolosclerosis is the cause of the severcst degrees of cardiac hypertrophy but is not the only cause since 16 of the total series (40 per cent) showed no clinical or pathological evidence of hypertension yet the average cardiac weight was 17 oz The cardiac weight of this group of 16 non-hypertensive subjects was then related to the presence of infarcts and to the extent of coronary insufficiency as measured by the number of branches severely occluded RELATION OF INFARCTION TO CARDIAC WEIGHT IN NON- HYPERTENSIVE SUBJECTS TABLE U Heart Curdur IS Old Recent No inf at S 19 SET 28 oz 17 5+275 oz 164 +0250 8 147 ·THE PATHOGENESIS OF CORONARY OCCLUSION Comment There is no reason why a very recent infarct should affect the weight of the heart although it may initiate cardiac failure and by the time the infarct is organized there may be a compensatory myocardial hypertrophy There remains however a substantial group with no clinical or pathological cvidence of hypertension and no sign of organized cardiac infarct and in this group the cardiac weight is still so per cent above the average RELATION OF CORONARY INSUFFICIENCY TO CARDIAC WEIGHT IN NON-HYPERTENSIVE SUBJECTS Coronary insufficiency was based on the number of branches occluded (see Table G) TABLE V No of Coronary No of Average Meght Branches Oal ded ca es Het 7 7 2 10 2+1 O OZ 17+T 32 OZ 19 S OZ هما Despite the small series the figures are at least compatible with the suggestion that coronary insufficiency is a cause of cardiac hypertrophy apart froin hypertension infarction or myocardial failure Daiis and Blomgart (1937) have suggested that cardiac ischaemia leads to overstretching of the weakened myocardial fibres which then undergo a hypertrophy The subject is discussed more fully in Chapter X 148 ·XXX Revaluations In a review of the literature since 1935 Duff and McMillan (1991) lamented the fact that in each case the dominance of one concept appcars to have led not mcrcly to relegation of the previous one to an inferior position but practically to its elimination from further consideration It is undeniable that recent physico-chemical advances in lipid chemistry have overshadowed some of the earlier theories It may be of interest to reassess the more notablc of these in the light of subscquent observations While the bulk of Leary s morphological observations on the evolution of atherosclerotic plaques remains unchallenged his claim that they result simply from cxcess cholesterol in the diet requires modification in view of recent work on lipid metabolism And his theory that cholesterol is conveyed to the intima by macrophages in the bloodstream which penetrate the intima by amoeboid action has becn specifically denied by a number of observers- og Mic Villan and Duff (1948) and Moon and Rinehart (195.-) After repeating the cholesterol-feeding experiments in rabbits Dugad (1984) finds some support for Leary s claim but he thinks the foam cells are incorporated into the intima not by amocboid action but by endothelial overgrowth Leary (1946) has suggested that the circulating lipophages fall out of the axial blood-stream because of the temporary stasis in the cpicardial portions of the coronary arteries during systole and so come to adhere to the intima Gordon (1947) attributes this phenomenon to the lightness of the foam cells which are forced into the intima by arterial hydrostatic pressure but hus hypothesis is unsupported by personal observation Pollak and II adler (1991) have tried to bridge the gap between Gofman s macromolecular theory and the formation of intimal plaques Following intravenous injection of cholesterol sols of varying dispersion they found chat the larger particles tended to be deposited in the intima within a matter of minutes whercas chc finely dispersed particles caused no damage The process appears to be non-sprcficas particles of colloidal graphite or sodium stearatc arc deposited in a similar manner Paterson s account of capillary hacmorrhages into the plaques has been repeatedly confirmed but doubt has been cast on their capacity to initiate thrombosis English and It allenas (1943) consider it unlikely that the hacmorrhages can produce occlusion by elevating the intima against artenal pressure in the lumen and concludu that they must be secondary to thrombotic occlusion Drury (1954) regards small capillary haemorrhages as insignificant and thinks the larger ones are duc to irruption of blood from the lumen through a tear in the weatened intima since by serial section of such areas he was able to demonstrate a gap in the intima overlying the haemorrhage It must be added however that both Paterson (1936) and II artman (1938) also carried out serial sections of substantial intimal haemorrhages and found the overlying intima intact at all levels 149 ·THE PATHOGENESIS OF CORONARY OCCLUSION The point is of some importance especially in relation to anticoagulant therapy if ultimal haemorrhage is a hazard is this not increased by the administration of such drugs to cases of recent coronary thrombosis Apparently it is not since Peters et al (1946) Tulloch and Gilchrist (1950) London et al (1953) and Inght et al (1954) have all recorded a considerable reduction in mortality and thrombo-embolic accidents in a large series of cases treated by heparin dicoumarol or tromexan as compared with an untrcated control scries Dirgad s observation that sexcrc degrees of coronary occlusion resembling advanced atherosclerosis may in fact be the end-result of thrombosis rather than of lipid infiltration has not received the attention it deserves especially in the United States for example the comprehensive review of Duff and McAfillan (1951) which deals in some detail with recent literature on the morphology of atherosclerosis does not even mention it Dugud himself has never claimed that all atherosclerosis is the result of thrombosis and has lately emphasized that it may arise in two ways (a) by Jiped infiltration and (b) by thrombosis (Dugmd 1954) Antecedent intimal lesions he states are indeed a contribucory factor but not a controlling one for there may bc very severe atherosclerosis without thrombosis He is not convinced that duct is the only or cven the most important factor in causing thrombosis He quotes experiments carned out in his department (Dugind 1955) which show that fibrin injected intravenously into rabbits becomes adherent to the lining of the pulmonary arterioles and is rapidly overgrown by endothelium Some of his observations lend support to impressions gained in the present study of human coronary lesions which constitutes the second part of this work namely the presence of lipid droplets in red and white thromb the carly loss of a specific staining scaction by fibrinous thrombı which then come to resemble hyalınızed collagen or the moulding of mural clots to a crescentic form by intra-arterial pressure of the blood If the electron-nucroscopic work of Lesene (1955) is confirmed it will go a long way towards proving the validity of the thrombogenic theory of atherosclerosis for no other theory can possibly cxplain why an apparently collagenous plaque should consist largely of fibrin The very importance of this observation however makes the fullest confirmation necessary before it is finally accepted SO ·XXXI Conclusions The search for the cause of atherosclerosis has often been reminiscent of the tale of the six blind men who went into the jungle to study the elephant The first encountering the animals trunk said The elephant is a snake The second feeling the leg was sure the elephant was a trec the third felt a tusk and thought it a spear and the others called the elephant a fan a rope or a wall according to whether they felt his ear his tail or his flanks In the end they quarrelled among each other as to the true nature of the beast Thus many a seeker after the cause of atherosclerosis has touched some facet of the truth and mistaken it for the whole It has been variously claimed at one time or another that Vatherosclerosis is due exclusively to cholesterol to haemorrhage to thrombosis to chylomicrons to physiological ageing to mucoid degeneration and to a whole series of anomalies of lipid metabolism Some observing one attribute have proffered a new dcfinition of atherosclerosis in terms of that attribute The truth is that atherosclerosis is each and all of these things and many more some of them no doubt still to be discovered It is that tendency to thunk of fatty infiltration atheroma and arteriosclerosis as aetiological entities rather than makeshift descriptive terms that leads to error and retards advances Indeed the evidence suggests that we may be wrong in regarding atherosclerosis as a specific disease rather than a non-specific reaction by the artery wall to a variety of noxious stimuli There is a limited number of ways in which an organ or a tissue may alter morphologically and it may be that atherosclerosis is one type of reaction to a variety of insults The fact that a similar reaction can be provoked experimentally by this or that particular agency in no way contradicts this The wonder is that the arterial system retains its integrity as long as it does Day and night it must withstand a hydrostatic pressure that no other tissues are subjected to year in year out aided or hindered by the force of gravity it must convey by devious routes a feud with great clotting propensities and a high particulate quota without extravasation into its own walls or the surrounding tissues There is every reason to expect the effects of over-stretching or thrombosis with no great facilities for repair and it would be remarkable indeed if the adult artery showed no evidence of wear and tcar quite apart from what is implied by the term stress On this view nice distinctions between what is physiological and what is pathological in the elements of ageing of the arterial tree become superfluous It follows that if ageing is the underlying factor in atherosclerosis in its milder forms at least there is little likelhood of any great reduction in its incidence in the future For that matter there is little real evidence that atherosclerosis (including coronary atherosclerosis) has mcrcased to surinise ISI ·THE PATHOGENESIS OF CORONARY OCCLUSION any appreciable extent in the last fifty years What has increased -- or so it would appear – is 'coronary disease and it is the view of an increasing number of observers that this is a very different matter from atherosclerosis It has been and still is taken for granted that coronary occlusion whether lipid fibrous haemorrhagic or thrombotic in type is the end result of slowly accumulative atherosclerosis The reason for this belief is clear enough since the lipid fibrous and haemorrhagic elements are all part of what is called atherosclerosis and atherosclerosis is known to predispose to thrombosis Yet there are glarıng anomalies Coronary atheroma (if the London Hospital records are a reliable criterion) has not increased in half a century but coronary occlusion certainly has Moreover vessels of comparable dimensions such as the basılar artery show the lesser grades of atherosclerosis with great frequency especially in elderly subjects yet gross stenosis or thrombosis are relatively uncommon in such arteries Lastly one coronary segment frequently reveals occlusion of a ser crity quite disproportionate to the atherosclerosis in the aorta or the rest of the coronary trec For this reason some have postulated that local influences are of prime importance in determining the site of occlusion in the arteries But what is it that these local influences determine: All the evidence gathered in the second part of this work goes to show that coronary occlusion as distinct from the lesser degrees of coronary atherosclerosis is the result of old or recent thrombosis and that in this respect the coronary arteries differ from vessels of similar dimensions It is not denied that local factors may also play a part in determining the site of atherosclerosis which in turn predisposes to thrombosis but tlus is truc of all atherosclerotic plaques Thus any consideration of coronary occlusion must take in to account the factors which initiate clotting Once it is agreed that coronary occlusion is the result of thrombosis albert on the site of a damaged inama and that the coronary arteries are singularly (and increasingly) prone to thrombosis then the anomalies referred to above at once become explicable Thus is the great ment of Duguds suggestion that occlusive atherosclerotic plaques are Jargely composed of resolving thrombi The limitations of the term atherosclerosis are thus cxposed and the question arises as to whether it should be replaced by a nomenclature designed to differentiate the carly lesions (mucinous degencration clastosis and farry infiltration) from their thrombotic sequelae But the processes are undoubtedly connected and until the nature of the earlier lesions is more fully understood it would be wiser to retain atherosclerosis as a comprehensive morphological term which includes the disease in all its phases There is however some justification for the more frequent use of the older expression coronary thrombosis It has been stated often enough in thc past that little can be learned about the causation of a disease from a study of advanced lesions Generally speaking this is quite true and the observations on such carly lesions as mucinous degencration clastic proliferation and lipid deposition are undoubtedly of the greatest value in the clucidation of atherogenesis But the present study has concentrated not on atherogenesis but on the problems of coronary occlusion and the mechanisms that disable the heart or abruptly termunate the life of its owner And if coronary thrombosis can be prevented or arrested or dispersed IS ·CONCLUSIONS altogether it is not inconceivable that the death rate may be greatly reduced before thaetiology of this lethal disease is completely understood It has also been alleged that the morbid anatomical approach is unlikely to solve the problem of coronary disease This again is very probably truc and the same objectior may be raiscd to any other single form of approach But it should not be forgotten thathe preoccupation of the physician is the re-establishment of a circulation that has beer arrested by tissue changes and it is the duty of the morbid anatomist to prevent the chemisfrom wandering too far away from that small but complex tangle of fibres cells and vessel: that is responsible for the patient s precarious condicion For this reason no apology need be offered for employing once again the well-tried approach of the microscope I have attempted to show that arterial thrombı differ profoundly from their venous counterparts and that these differences are dependent on two factors the force of the arterial blood-stream which moulds the clot to the vessel wall and washes away much of its cellular content leaving a laminated fibrinous layer which by ordinary staining methods may be mistaken for collagen and the absence of capillaries in the arterial intima which results in a slow and relatively avascular and acellular organization of the deposit with a low phagocytic activity The shrinking thrombus is rapidly covered by endothelium and a layer of elastic tissue continuous with similar structures at the margin of the plaque or from the mouths of branch vessels The vasa vasorum penctrate the intima and link up with vascular clefts at the base of the deposit and with residual blood-spaces in the clot but on occasion the latter communicate directly with the lumen In time the whole deposit comes to be supplied by a vascular network which however is inadequatc for nutritive or resorptive purposes and degenerative changes lead to further swelling of the plaque and a patchy necrosis and calcification Later the degenerate areas become vascularized by the ingrowth of thin-walled and poorly supported vessels and the subscquent recurrent haemorrhages from these result in further deposition of insoluble cholesterol and the accumulation of foam cells derned from phagocytic macrophages which have emigrated from the marginal capillaries At any stage of the process the devitalized surface of the plaquc may be coated by a secondary chrombus due to defective blood-supply superficial necrosis the rupture of an atheromatous abscess or dissection of the plaque and so the whole vicious cycle may be repeated The complete argument may be regarded as highly telcological but it is difficult to sce in what other way the various phenomena are to be explained in any case the apparent purposefulness of the process is offset by the frequency of its failure to effect a permanent cure How is all this to be related to disturbances of lipid metabolism: If atherosclerosis is accepted fundamentally as an inevitable ageing process 11 normal individuals and hypercholesterolaemia or giant lipo-protein molecules or other forms of metabolic or endocrine disturbance as merely aggravating factors which cause an increased deposition of cholesterol in the plaques (whether by infiltration of the intima or the lipid content of mural thrombı or intimal haemorrhagcs) there is less difficulty in accounting for the 193 ·THE PATHOGENESIS OF CORONARY OCCLUSION difference between infantile fatty streaking or serule atherosclerosis on the one hand, and thc grosser lesions of diabctics or the coronary occlusion of voung subjects on the other It has been too readily assumed that the rescarches of Gofman and others indicate a correlation betw.cen anomalies of the serum lipids and atherosclerosis per se But it will be recalled that they used as their criteria of atherosclerosis hypertension inyocardial infarction diabetes nephrosis etc whereas autopsy records clearly show that a great many individuals of all age groups have coronary atherosclerosis in its inilder non-occlusive form without evidence of any of these discases It would therefore scem rcasonable to suggest that the possibility of a relationship between lipid metabolism and the coagulability of the blood is worthy of tuller mvestigation The significance of cholesterol in athcrogenesis has perhaps been exaggerated during the last half century This has been due to (1) its prominence in advanced lesions (2) the cholesterol fceding experiments and (3) the severity and frequency of atherosclerosis in a comparatively small group of discases accompanied by a raised serum cholesterol In seeking to relate these facts to the foregoing hypothesis one finds that they are not irreconcılable The cholesterol in the plaques may be derived from lipid infiltration of the intima in the early stages or the breakdown of red blood cells following mural thrombosis or capillary haemorrhage into the plaque What is common to the lipid infiltrate and the dısıntegrating hacmic elements is the insoluble naturc of cholesterol The amount of lipid in any one plaque may thus depend less on the cholesterol content of the serum than the size of the hacmorrhage or the number of red cells trapped in the thronibus As regards the feeding expenments it is char that atherosclerosis in rabbits can be produced simply by saturating the reticulo-endothelial system with cholesterol although contabutory factors may accelerate or accentuate the process There is no evidence that this is the case in man and a great deal of evidence to the contrary fmally the role of hypercholesterolaemua is clearly contributory in the case of diabetes xanthomatosis etc while in the aged the gradual increase in scrum cholesterol necd be no more a determining factor in atherosclerosis than the age effects on the arterial wall merely tending to increase che cholesterol content of the plaques It is certainly beyond dispute that typical atherosclerosis may cxist in individuals with a normal serum cholesterol The arguments applırd to hypercholesterolacmia arc cqually valid for other forms of disturbance of lipid chemistry Vascularization of the plaque is an important factor in the vicious cycle It is certainly the cause of the smaller haemorrhages and whether or not thesc play a part in initiating thrombosis (and I believe they do) they are an undoubted source of cholesterol apart from contributing a good deal of the non-lipid mush that goes to make an atheromatous abscess the thrombogenic propertics of which are not denied In this say many apparently conflicting theones can be reconciled from Jores Klotz and Aschoff to Leary Paterson and Duguid Atherosclerosis is then seen to be the result of multiple factors and the resultant plaques the product of numerous and discrse pro- 13+ ·CONCLUSIONS cesses Underlying all of them is the modification of the vessel wall in response to physiological strain and the accumulated effects of age on the tissues In youth the lesions are slight and take the form of mucinous degeneration elastic reduplication and lipid infiltration The lipid is resorbed by the youthful intima but leaves a small fibrous scar In later life the cumulative effect of earlier traumata coupled with a slow rise in hydrostatic pressure and serum cholesterol leads to an extension of the process and secondary thrombosis may occur initiating a vicious cycle and the more advanced lesions The end result is senile atherosclerosis a change which has probably characterized age in western man for centuries The problem of coronary occlusion is different Deaths from thus malady have increased alarmingly and the severity of the arterial changes is out of all proportion to those in vessels of similar calibre The reason is not likely to be found among the causes of early generalized atherosclerosis alone and it would be well to extend the search to the localızıng factors that predispose to thrombosis in the coronary arteries themseles 155 ·Append 3 PERENYI S FLUID (Chromo-nitnc Acid) 4 parts to per cent Nitric Acid Alcohol 3 os per cent Chromic Acid (The 1ficrotonlist s Vade Afiam Bolles Lee London 1928 p 36) Gm SIIERIDAN S STAIN (Modified Weigert s Elastic Stain) I Bring sections to water 2 Transfer to o 25 per cent Pot Permanganate bath 3 minutes 3 Rinse in distilled water 4 Decolorize in s per cent Oxalıc Acid 3 minutes S Wash in running water is minutes ninse in distilled water 6 Stain in Sheridan s Stain overnight preferably at 37° C Crystal Violet i Gm Resorcin Aq dest 7 Rinse in tap water 8 Differentiate in Absolute Alcohol a few minutes 9 Wash in tap water 10 Counterstain Jensen s Neutral Red 1 munute Differentiate in Absolute Alcohol 12 Rinse and pour on os per cent Pienc Acid 10 seconds 13 Rinse rapidly dehydrate clear and mount * Neutral Red stain artenes poorly and we found it an ad antag to omit 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(1954) DLGLID J B (1926) Atheonia of the Aorta i po Influence of And ogen c and Est ogenic Steroid on Ultracentaf gal and Electropho et c Pattems on the Bart 29 371 8 158 ·in Abop 1929) 2 BIBLIOGRAPHY Scruny Alpha and Veta Lipoprote nis and Globuh HARRISON CV (1978) Experimental Pulmonary Arte Eunuchord Males and I ost Men p us 1 Fem les 4m sclero s JP# B : 60 89-93 J 11 16 594 HARVEY W (1649) De clar cSg Alicia ad Ro(English translation by R Wuls GAGE S H and FISH P A (19 ) FD st Te li orks Ilm II ley - Printed fr the Syd to a dA mito in MI 1 An ni as Determ n'd ham Society 1847 P 127) by the DKF 18 M croscor and a Fat Solubl Dye HEARD B E (1949) Mural Thromboss in the Ren 1 Intel J A 34. 1 86 Artery and t R i to to Ath o lo Parls B, 61 635 7 GALLT G (1903) Uber ana to not b z kulton des H rzensch med It se, 50 1146-8 HEARD BE (195) An Expern tal St dy of Th ck n GEIER FM (1949) Cholesterol and Coronary Artery ing of the P Im n y A te es of Rabbits Produced by Dase Pennt eure Fd, Het BN 7 49-54 tho gan zation of brinj PB 64 19 20 GF1 INGEN E (1951a) It al V culan tion a id Athero- HEBERDEN (1768) So ne à count of a Disorder (th le Oss Breast Red Eth Coll ge of Physc ns July 21st 1768 PHB 63 OI IL GERINGEN É (195ıb) The Mural Co on Ty A (P bi hed in the Vedcal T 1 de Colles 1 не J 4135-68 Phys ulls Lo den 1769 Republ, hed n 4:Patr 1 CERTLER MM CARN S M and LERMAN J (1950) to the St dy ſy cdited by L C mm New Y k The I te relat onships of Scru Cholol Ch 1 te ol HERMANN GR (1946) Cholt IL i in Var Esters and Phosphol pd n Health and in Coronary D se scs and the E8 ct fD chol ste A tery Ds se calu 2 205 14 SAg nt T GERTLER M M GARN S M WHITE P D (1950b) St J lled 42 260-3 D Seru Cholt ol a d Coronary Artery Discase HERRICK J B (1912) Clon Features of S dd Obstec 2 696-704 tion of the Co on ry Artere] Amer med 4s 59 GERTIER MM nd WHITE 1 D (1954) Crny!!! 2015 20 Hirscht E a d WEINHOUSE S (1943) Th R 1 D¢ Clip all! 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D Coursey 22 124 DX 28 $ Deliac art 1 Drus y 69 523 Dub! 3B Dut ty 118 Duif asd McM!? (14 4 13 Dur nd Al Min (1941! * +) 443 Dutt nd Paya 42 Huyu d (1926) 19 49 Dugu (246) 4 3 124 jo Duud (1943) 32 2016 Dugu d (1749) 12 ) gold (1954) 5451) 30 Dugud (1945) 550 0 ERRITU?! 28 Eng! h and fuas 133 42 BALEY 25 Bald f 33 V load siga (1949) *2 Palo and 4 (1950) 42 Dalo and D nga (U53) 42 Dam nd Ball 21 27 30 9 221 Bayt II (1982) 36 1 II (1052) 45 Ucker et al JS Pedd 31 30 Delt nt 16 FABER SO F bes nd Lund 38 Fih 13 F ngestan a d 13 Blesse 8 Faulkn F brok (250) F stb ook (195) 28 47 13 F izhugh a dt* $ 39 Fry 122 Foth bello Fr 2 d Scart 35 ench nd Dk 38 F 81914 Fulston il 40 Fu111 11145 Fsh mson er 1 is et 8 B) 3m, so 3) KK pee 4+ Bloch na serb g )) Blumench 1! (1944) 49 Bluninth it! (750) 41 Bork 12 Boyd 114 Bro aberto Bronte Stwart! (1955) 4% 1 ont Securt al (1356) 49 Vookt 20 Mu * 3+ Bu k and Ro 5 34 GAGE AND Fest 35 GW 26 Ges G stage (1951) 32 04 78 ! 3 Getting (tagtb) St Coral 11 (175oa) 35 for (osobi 39 Cestle and WE 13 Gorns! (1950) 36 G ! (19sob) 36 Cofni (52) 36 nd Mior 12 1> Gordon han 12 Goss 26 Cost } 68 Gubri SU get a 39 F Golbre Gtuid37 CALDWEIL 18 Chalat w 13 chap zuan 11 37 Chtit on 17 Chuma 45 22 og tog Clark on dNwgh to Cohnhe rand von 5 h l s hibe g 20 Conybea € 47 Cookef ! 11 Cranfond Less (1982) 3 78 91 9 Laufod nd lovet (1953)? +964 Cruelbrit 26 Gutman 17 Curtin 47 HAMWIX 21 13 man (1933) 16 19 33 Ha 1990 s }}} 36 51 H sin (194%) 52 la cys * o(141)3 Hard (195) 32 165 DAYS AND BEL MCART 30 49 ·INDEX Lolstein, 12 Loudon et al 150 Lutch 29 Lyon et al 36 Heberden 6 Hermann 41 Herrick o Hirsch and Weinhouse 33 113 Hodgson 9 28 Home 69 Hort and Finkelstein 21 22 25 11 63 113 121 124 Huchards Hudson et al 26 60 Hunt 34 38 Hyrel 26 IGNATOWSKI 13 JAFFE AND LEVINSON 118 Jchicer o j nes and Rogers 16 Jores (1898) 12 63 j tes (1903) 12 19 49 Jorcs (19 +) 49 Josu 13 MCARTHUR 33 Mact arlanc et al 40 McGill and Holan 42 43 McLetchue 32 92 McMillan and Duff 17 149 Mall ry 22 105 Malmros 38 39 Marchand 4 12 Marie 11 20 25 26 57 Master et al (1937) 21 6 29 30 124 Master et al (1937b) 47 Master et al (193) 947 Master (1939b) 44 47 Mecker and Jobl ng 33 Merkel 26 Meyer 122 Miller and Matthews 26 Mills 40 Mills and Nechel 40 Mjasspikow 34 38 Moon a d Ranch art SI 147 Morcron 35 Mo gignis Morris 46 Mori et al 47 Morrison, 39 Morrison et al 34 Moschcowitz 30 Mulle 44 Murata 41 4+ Murats and Kataoka 45 KATZ 45 Kellnet a (19512) 42 Kellner el I (1951b) 44 Kelly er I si kesten and Sulbo vitz 41 Keys (194)) 34 keys (1951) 36 keys (1951b) 36 keys (1953) 1) Keys (1952b) 3) Keys et al (19502) 34 Keys et al (1950b) 39 Klotz (1 906) 12 13 Klotz (1915) 19 08 Klotz (1915) 19 Klotz and Mans ng 19 Knack 15 Koch a da 25 123 Koster 25 hu 33 NELSON 25 Neu burgh and CI kson 16 Nuzum e! 14 OBERYELMAN AND LE COUNT 26 99 Olcra d Boyd 35 Oncley et al 36 Osler 20 46 47 48 LANDE AND SPEARY 33 Lansing (1952) 50 Lansing (1954) +2 Lans ng et al (1948) 33 Lansing a I (19502) 34 so Lansing (19506) 34 Lans (19500) Le ry (1934) 16 i 22 8 ios TIR 12 Leary (1935a) 16 19 25 77 178 Leary (1935b) 25 Leary (1935€) 113 Leary (19362) 4 17 25 51 63 83 118 133 Leary (1936) 17 38 Leary (1938) 77 118 Leary (1941) 17 18 Leary (1944) 17 Leary (1946) 149 Le Cou 26 Lemio nc 15 Leridan d White 4+ Levene )7 150 Levinc and Brown 21 23 123 Levy a J Bruenn 29 30 I binan 21 Lieb g 41 Lober 67 PAGE et al 34 Parkinson and Bedford (1927 29) 27 Parkinson and Bedford (19 8) 21 27 123 P try 6 Paterson (1936) 2 S SS 7 84 87 88 113 149 Patson (1938) 22 87 Patson (19192) 22 29 Paterson (193;b) 22 Paterson (1994) 37 121 Paterson et al sr Payne and Duf! 12 Peters et al 150 Peterson 41 Phipps 47 Pick et al (1952a) 45 Pickes (1952b} 45 Pite iz Pollak (1945) 14 Pollak (1953:) 18 Poll k (1953b) 41 Pollak (19135) 41 1 oLk and Wadler 149 166 ·INDEX Stence and hend 3 47 Steney 144 St ner PE 18 Sta ks 47 Scukkey (1910) 13 Stukkey (12) 13 TAYLOR !! Th yer nd Fabyan 68 238 Thebes as TH 123 11 49 Tomas 11 Tuto hard G3 5 1 150 Tumer 41 Tum and Khyat 4+ 4+ UEFLINGER 63 VIRCHOR 20 19 SO 109 on Albert x 25 RABINSWITCH (1927) 14 Rabmowitch (1930) 14 Rub powsch (1935) 4% Rimsey 25 66 Raynaud is Ribbere t4 Rindfle ch it 49 Rinchart st Prehart and Abul Haj Sl Rinchart and G ccnbcrg (1949) 50 R nchart and Creenberg (1957) go Revin and Da nitrof 45 Robuttson (1919) 64 77 Robertson (1910) 26 60 Rokstansky 4 10 25 31 77 9 Roli stan 30 Ruffer $6 Nu set al 36 Xyle and Russell 34 46 47 SALZYKOW 13 50 68 Sph ! 21 25 27 98 124 S Ppington and Cook 28 Sappington and Horn # 28 Sart IS Schl Rg Shl ng nd Zoll 27 60 98 Shossthan 22 205 S honbc ner (1924) 24 Schonheim (196) 33 S honh mer (1928) 33 Schones set (1931) 64 118 Schultz so Senac S Sh2p ro 44 45 Sh ttock 46 Snr 39 Ini! (131) 33 Spe m} {{951) 40 s poc Sat 12 26 60 Smth (1978) 26 30 Sm th (1920) 630 $th (1923) 30 Seson on 36 Spaltehola nd Hoch 11 23 Solowzew (1931) 19 Sol w w (1937) 1949 51 Szarokadomsky and Sobolew 13 Stabs 14 Se me A42 Sc met and Dom a ke 4 WALKER AND BECK V. id $140 Wartıran 35 77 85 14) Warm n and HUR 4 21 We m (1923) 20 21 123 wam (1928) 26 98 We gert 11 20 Weinhouse nd 1 rsch 33 Weis d M not 38 We selkn 14 West 26 White ! 27 28 47 67 War (1937) 5 Wilns (194-) 52 Wins (19477) 38 Wilens (9470) 38 Wsen (1951) 5 Wek ORI39 Wibus 202 26 30 W nd 33 W nters 12 ! (1937) 154 ferts : { } { 938) 25 50 77 84 18 Wolff and Wht 21 29 223 Kolkoff 19 2 23 38 2 77 124 Wood F 26 60 64 77 nght 150 STI cil53) 47 YATER 130 3 47 ZAK AND E113 122 Z*35c 3g 1) 34 167 ·SUBJECT INDEX ADVENTITIA 60 ct se] hac horrhage into 63 In reased vascularity 60 101 ferivascular lymphocytos s 60 Age & atheros lcross and 9 28 11 151 holesterol metabobsnt a ld 118 hylomicrets and 35 conios tion of plaques and 16 33 34 68 118 oronary disease and, 36 728 34 47 67 IO II 143 ffects on med a 33 4) lashcity of vessels and so serum cholesterol a id 34 45 Androgens and bpoproten balance 45 Aneurysm arteriosclerotı 63 87 117 133 cardiac 11 Ang a pectoris ant cagulants and 4 orona y occlus os and 20 27 arly a counts of 6 obety and 38 serum cholesterol and 34 Angul r Vessels 83 Anticoagulines 42 150 Aorta atherosclerosi of r28 4 terual movement and athc oscl rosis 16 sz Arteriosclerosis definition of I Atherogenesis theories of Aschoft is Duguld (dual patholowy) 118 133 150 Duguid (niechanic I) 15 1 gtid (th ombogen c) 4 31 92 Gofos 35 36 Leary 16 22 118 133 149 Mo eton 3 Rindfle sch 11 Rokic nsky 10 31 92 Thoma IT 4) Virchos 10 W nternatz 25 77 114 Atheros la! atheros leross Atheroina arteriosclerosis 12 Arheron tous ab cess grad 150 ani, ular vessels in 87 causing occlusio 123 defitur on of 4 cxtravascular 62 haemorrhage into 87 122 p thogenesis of 87 110 117 rupture of 22 87 110 causing cholesterol embou 1 122 nittating thromboss 87 to 12 Atheroscleto ts vartoti sclerosis 12 49 137 Atherosclerosis age and (see Agc) chylomistons and 33 derse origns of 15 IST 154 catly lesions of 19 28 SO SS 152 endocrine factors in 41 H 153 cspeririental 13 et seg hypertension and is 44 142 inf chlort and is ro inflammation and it nhibstory factors in 41 et seq 45 lo al factors in 15 16 34 49 met bolic foctors in 44 158 193 obesity and 38 relative fequency in arcers 10 128 143 144 syph lis and SI ch ombo is and 152 thyroid influenc in 4+ trauma and 13 IS 17 SI use of tern + 152 Atherosclerotic plaque calificat on in Tro et sci af and 110 aortic 133 brachial artery 137 chem cal assay of 37 d Generatio 1 and 109 di location of us carly accounts of 3 6 9 10 inportance of 113 Latc afrear ncc of 31 local eff cts of 113 recurrent rog 110 thro bo sund 113 chemi try of 33 chol sterol n 114 et cg aortic 133 clcif ation and 113 chemi alas y of 33 degeneran n and 109 117 diabetes and 118 catly accounts of 10 II TS Irritant cffect of 17 18 134 role in atherobeness 154 serun cholesterol and 3j 118 sł w absorption of 11 17 87 118 sour c of 32 110 117 154 calen in 7 ct scq 105 137 degeneration in tog et seg orta 113 calcifcation and no et ses d ssccr on ud 12 haemorrh ge and 84 in tating thromb is 102 pid 114 et see Tog et see clation to ya cular plexuses & to 110 137 resorpt on of 77 Ito dissection of 122 ornc 133 elastic or brands and 75 haemorrhage and 87 nitating thrombo i 122 source f superficul lipid 118 sla uic lan nua internal fu con of 133 reduplication of 68 137 ruptu e of 339 dl stic inembranes in 71 di set on and 122 1 yeri g and 71 4 I ucinou ca tration and 43 stades of 128 168 ·INDEX 1 aort CIS brın he 1s and 84 corlimt i to with lun d 84 d op pl rus 77 78 ) 133 1 of 81 ea ly ou ts of 10 25 imp rt of 154 per pheral bl od s and 78 97 pe fcial pl rus and 3 78 thi k ot pl: 1 and 32 78 113 transmedial 60 64 73 BRACITAL ARTEKY ATHER CLFROSI OF 13 nd 113 s of ad 34 protect ve functi n of 71 101 138 elasta tsue 1 69 et se} hyperplas 1 hyp rplast cl ye 68 zature 71 cased 68 st sc1 ao tic 128 ren 1 tery 137 elasta is 168 138 ed thelial ocowth 11 31 32 9 149 cvol tun of 9 153 fibrin in 97 ros et sa aort c 133 encrustat ons 31 IOI 105 nitiating thto bo IOI 106 exp ental injection of 32 hacmo b c d 106 poplitcal a tety 137 5 bl ng collag 2 97 105 137 ISO Rok t ky on 10 staining popt of 2 97 105 137 150 fbri od n cross 1 84 IOS f am c 11 crophag si IIO 114 118 granulat on tiss) hc o rhage into 84 et seg ang 1 83 ot 133 calc foto 77 causing o lu on ithout thrombosis 25 77 87 g ruptur of th: tou bcss 87 I 2 caus sth nb ss 22 25 55 77 87 97 101 dcron and 2 extent ndt k of 87 sequ 1 of corona yolu on 149 ou e f bol st rol 110 114 154 sub ndothelial 88 c of dc th ng 30 h od n 91 121 nt to IOS 109 110 ng 11 67 et scg ort C 128 fb inous c cruttind 106 nt nt of 71 va ula ton rel tedt 78 1 pidi 114 et seg brach alt ry 137 calcif cation and rog d ep 14 c per ne tlly pr duced 32 tcclllr 114 117 nt 111 114 Lyn 118 1 y 139 p fcial 10 118 133 149 lymph cyt 14 137 odd ger i nsn 13 30 109 musel fb n 72 od m O Ossif c ton TO TI3 phagocyto 11 cssion of is 17 38 pt re of 2 87 ITO 121 133 of pls 11 106 thk ess of in rel to: to 1 tr ton ) 79 513 ul er ton of 106 137 Inter of 77 ct seq gu! ve sels 83 Col teral CALCIFICATION (See Ath 1 t pl qu) Chole te 1(sel Athurut pl dD embolis 11 122 filtrat on th ory 15 16 33 118 11) in n cott 118 on thyroid ha mato vas 117 118 int CO j ctor of 8 $ un 34 + 9 abe a d 34 45 buna pe to is d 34 chol sterol in plagu and 33 hylon ons dus corona y de se a d 34 d bctes a d 44 det a d 34 39 3) 40 myrocd ma and 35 44 phos, das s verity of ath to 1 sv th ss of 14 33 39 117 Choi ste ol ph ph Ipdrto 35 37 Chylo nicron 3 cul tto 26 ts09 advent talc in d 60 e ly ccounts f II thron bog theo y a d 31 tle lui nad 8 variablty f 26 127 Comparator cycp e 58 Co on y a ter cs -cth d fopo 5 $7 Co ona y athe os i rosis (o et see 4 21 cquency of 20 co o ary thro 1b si 46 152 Co I y d sease S ang Pto asympto tc 20 the oscl rossi oth vessels d zo 25 40 45 SS 128 144 15 death 1 3 20 38 47 d tand 39 doctors and 47 ton a d 29 47 5 dual death SS 127 h de y f ctors Ion and 21 30 44 84 143 unaid hs 21 57 124 increased cd nice of 3 20 46 152 153 fto nd 16 25 47 Ilfct $1 28 47 t xq Tor 152 155 obes ry de phy qu iait to sin 48 re id s sein 145 sed nury hab d 29 47 169 ocel so ul t 133 de Age 0 27 n hype ic парь se page d 48 V ·INDEX Coronary Disease- c ut HAEMOSIDERIN (S e Atherosclerotic plaque) serun cholesterol and 34 Hunter John 6 sex incidence in 1 28 47 Hypercholesteroliema social status in 47 age and 34 45 statistics of 3 o 46 et seq 152 any na pectors and 34 tress and 28 47 TSI athc osclerosts and 34 sudden death in 3 21 2 27 127 chyloptictons and 35 syphulis and 03 coronary discase and 34 thyroid function and 44 diabetes and 35 14 118 tobacco and 47 dict and 39 Coronary occlusion experimental 14 42 xertion and 947 famulial 39 4+ experimental 26 45 Si myxocdema and 35 4+ grades of 27 28 67 123 nephrosis and 35 timal bacno hage causing 2 25 77 87 1 3 Xanthomatosis and 44 mcals and 47 Hypertension (S e Atherosclerosis nd Coronary disease) mult p! 25 26 27 102 123 143 rate of 98 INFECTION (S e Athero cleros s rupture of plaque causing -2 87 122 Coronary D casc and Fatty infiltrat on ) spasm as a la tor n 25 ) Inh bitory factors 41 ct scq 45 subtotal 123 Istramural coro ary arteries si total >8 123 I thrombosis 21 7 KIDVEYS IN CORONARY DISEASE 145 Coron thrombosis 91 extent of 27 LAYERING (Sce Ather cl rotic pl qu ) re urrent 27 3 67 et seq Lipoph ges 17 118 133 Lipoprotens ca do 35 DEATH RAIE (S e Coronary disease altered balance of 45 Deep pl xus (See Atherose le one plaque sularizat on ) Loc 1 factors (Sre Ather is 1 rost and Coro v dose) Dabetes melltus ath rosclerosis and 38 44 137 15+ chylomicrons and 35 MEDIA 63 ct seg fbrinoid n cris in 84 atrophy of 63 giant molecul s1> 36 a rtc 133 Dit athc osclero is and 38 ct seg duc 64 cholesterol in and exper mental atheroscl rosas 14 ct seg Purc 64 110 114 119 calcif ation of 13 16 111 137 nd human thero cross 38 ct seq 149 chem try of 3} 34 and serum cholesterol 38 3) degener ton of cu ng theros le oss 11 49 50 fib osis of 137 oron ry d case nd 38 fat in and oalul blty of blod 39 40 ge and 142 and serum chol rerol 3) brachi 1 artery 137 food proceny 11 ) hypertension and 17 potein and ath rosclc os s 13 18 IC I artery 137 Mictlods and natcrial 55 ct scq and s um cholesterol 16 Doctor and coronary d sei e 47 M Cro-incineration n thods 33 49 Mo ckcbc gs scleros 13 13 137 EGYPTIAN MUMMIES therosclerosis in, 46 Moulding of arterial throub 91 98 133 150 Elastase 4 Mult ple co onary occlu on 25 26 27 10 123 143 Mu cul reltic layer 68 Elast city of arteries so Myo ardium El stic tissuc el trosis (Sce Ath roscle orc plaque and i bosis of rt 122 Thrombus organizi) Electroca dog aphy 30 hypertrophy of in coton y d scasc 30 147 of coon of 123 ct seq collateral circul con and 26 ct scq 9 FAT DLST 117 133 tly accounts of 1 Fatey infiltration fatty stre king (See Cholesterol nf Irra 8 dual death a ds17 tion theory ) lipoprotein balanc d35 aort 133 atheroscleross and 19 153 myocardial hypertrophy and 147 uly 1 (t-sided 27 carly accounts (fatty usure) 10 Alyxocde na experimental 14 19 th rosclerosis and 44 human is 19 133 hylogu crons and 35 inf chion and 19 hypercholesterolaemia and 44 in infants 28 intu nal du se and IS 68 Fibrin a d Fibrino d ne zosis (See Atheroscl tot c plaque) NORMAL ARTERIES nutrition of int mi 22 64 77 G14NT MOLECULES 36 42 10 stra non si vascularizat 1 of 64 Gradul de ch (See Coon ry discase ) 170 1 ·INDEX OBESITY 38 Thrombu Occupation and coronary d scase 47 dehaçmoglobunization of 32 92 1 1 Oestrogers 45 fat droplers in 3 150 fatty deg neration in aneurysmal 87 117 PENENYISS FLUID 57 256 in coronary 31 87 114 Phagocytosis (Scc Atle osclerotic plaquc ) erperir ental 32 Pho pholipids 33 34 39, vascula supply and 78 Popliteal arte y athe Osc rost of 134 organizin Pyridoxine deficiency and atherosclerosis so atypical 91 blood saces u 97 RADIAL ARTERY atherosclerosis of 68 elastic in 69 71 10 Renal art ry atherosclerosis of, 137 umumnatu e Reticulo-endoth lil s tem v experimental atherosclerosis 14. 17 4 154 fbrin in 106 Rupture of the heart 11 muscle fibres in 72 10! source of superf cual plerus 78 SHERIDAN S STAIN $8 156 surfac 32 78 Spaltcholzt hnique 77 vasculanty of int ma and or to Staining different ! 58 recanalized 92 Sudd a death (S e Coro ary disease ) cent al canalization in 71 97 98 Superficial pl rus (S e Atherosclerotic plaq e vasculanza clatcin 71 101 tion) marginal retr ction in 78 9 97 Syphilis (Sce Atheroscl osis a d Co onary d sease) muscle fb es in 72 101 sh inkage of 9 123 TITROM OSIS 91 et sa subt tal occlusion in 123 rteri I venous 87 91 121 153 Thyro d gland (See Athe osclerosis and Co o ry disease Ipdnet bolism and 39 40 154 mu 1 106 105 133 VASCULATURE OF ATHEROSCLEROTIC PLAQUE 81 83 recurrent 71 78 91 109 Vasculat of norm l artery 64 perin e tal 32 171

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