OF IN CORONARY ARTERY

impossible de delimiter la periode exacte du d6but ou de la fin de la menopause, ni comment telle ou telle femme reagira dans cette periode de sa vie. On peut se permettre 'affirmer que les femmes qui ont de bonnes relations familiales et sociales eprouveront beaucoup moins de difficulte a traverser la menopause que les femmes qui vivent dans une atmosphere tendue. TRAITEMENT: II faut, grace a des examens periodiques, eliminer la possibilit6 de neoplasme. On doit surveiller le taux d'hemoglobine afin de prevenir l'anemie qui saperait la force et la vitalite de la femme et l'empecherait de remplir un r6le utile et efficace a cette epoque de son existence. I1 faut s'efforcer d'etablir entre le medecin et la patiente une relation telle qu'il n'y ait pas d'anxiete excessive de la part de l'une ni un manque de cooperation de la part de l'autre. La patiente a besoin de beaucoup d'encouragement et de persuasion; on doit lui expliquer son etat ainsi que les moyens a employer pour l'ameliorer, facilitant ainsi l'accomplissement de les circonstances; il faut lui faire comprendre que les manifestations de desordre caracteriel sont normales et transitoires, et qu'il est possible, sinon facile, d'atteindre a l'equilibre emotif avec une aide appropriee. Le medecin doit indiquer clairement comment remedier a la sensation accablante de fatigue ou de decouragement qui peut survenir inopinement, de temps a autres. Aux femmes entre deux Ages qui ont perdu confiance en elles-memes, on doit prescrire le travail a l'exterieur, a temps complet ou partiel, ou le volontariat. I1 ne faut pas hesiter, le cas echeant, 'a faire appel aux services d'un psychiatre. Les medicaments, sans etre souvent employes, peuvent jouer un role important dans le traitement de la m6nopause: (a) des sedatifs a doses filees peuvent rendre de reels services; (b) on peut employer un sedatif plus fort au coucher pour 3 ou 4 nuits consecutives, de temps en temps, pendant une crise; (c) les stimulants ne doivent etre administr6s que sous une surveillance etroite. L'opotherapie est necessaire pour quelques femmes, mais doit repondre a des besoins specifiques: (a) l'extrait thyroidien peut s'averer fort utile dans ces conditions: (b) les oestrogenes ont une valeur inestimable et peuvent decider du bonheur d'une patiente. Sauf indication contraire, elles peuvent servir de 3 manieres: (1) pour le soulagement imm6diat des bouff6es de chaleur; (2) comme epreuve therapeutique; (3) comme traitement des complications medicales de la menopause. Les oestrog'enes sont formellement contreindiques dans les cas de cancer. Enfin, on ne saurait trop insister sur l'importance de la comprehension, de l'affection et de la bonne humeur a cette epoque critique de la vie feminine. M.R.D.

impossible de delimiter la periode exacte du d6but ou de la fin de la menopause, ni comment telle ou telle femme reagira dans cette periode de sa vie. On peut se permettre 'affirmer que les femmes qui ont de bonnes relations familiales et sociales eprouveront beaucoup moins de difficulte a traverser la menopause que les femmes qui vivent dans une atmosphere tendue. TRAITEMENT: II faut, grace a des examens periodiques, eliminer la possibilit6 de neoplasme. On doit surveiller le taux d'hemoglobine afin de prevenir l'anemie qui saperait la force et la vitalite de la femme et l'empecherait de remplir un r6le utile et efficace a cette epoque de son existence. I1 faut s'efforcer d'etablir entre le medecin et la patiente une relation telle qu'il n'y ait pas d'anxiete excessive de la part de l'une ni un manque de cooperation de la part de l'autre. La patiente a besoin de beaucoup d'encouragement et de persuasion; on doit lui expliquer son etat ainsi que les moyens a employer pour l'ameliorer, facilitant ainsi l'accomplissement de les circonstances; il faut lui faire comprendre que les manifestations de desordre caracteriel sont normales et transitoires, et qu'il est possible, sinon facile, d'atteindre a l'equilibre emotif avec une aide appropriee.
Le medecin doit indiquer clairement comment remedier a la sensation accablante de fatigue ou de decouragement qui peut survenir inopinement, de temps a autres.
Enfin, on ne saurait trop insister sur l'importance de IN THE COURSE of a study of the coronary arteries from 100 consecutive autopsies employing a special perfusion and clearing technique, it was noted that in 22 cases the immediate cause of death was related to disease in the coronary arteries. Because this method of examination permits an unusual degree of thoroughness in assessing all lesions, both grossly and microscopically, it was considered worth while to examine the manner in which these lesions produced death.

MATERIAL AND METHODS1
The assessment of each case was based on a complete autopsy and all available clinical history provided by the hospital records.
At autopsy the heart was removed intact with sufficient aorta to allow perfusion at 100 mm. Hg pressure via the aorta and coronary ostia, the fluid returning by the coronary sinus. In brief, the coronary arteries were "flushed out" with saline at roughly mid-diastolic pressure to remove fluid blood; they were then similarly perfused for one hour with 10% formalin which fixed them in situ. After fixation of the heart was completed by 48 hours in formalin, the vessels were dissected from the heart, intact down to the smaller surface branches (about 1 mm. external diameter). The vessels were then' decalcified and cleared by a succession of immersions until the final product was a set of semi-translucent, moderately pliable tubes into which air could be introduced to outline the lumen. Plaques were more opaque and lesions containing blood stood out as reddish-black masses on the faintly yellow background. After the significant lesions were drawn and described, the vessels were cut transversely at intervals of 2 or 3 mm. until lesions were approached. The segments containing narrow and occluded points, as well as many of the haemorrhages, were mounted intact for multiple microscopic sections. The histology was not altered by the process, and the fixation-perfusion tended to leave the vessels and vasa vasorum in a filled, rather than a collapsed position. It will be noted that no abnormal pressures and no foreign materials were introduced in the preparation of the specimen.

REVIEW OF LITERATURE
When the cases had been collected, it was evident that these victims of coronary atherosclerosis had come to their deaths by a variety of mechanisms. From the standpoint of pathology the common denominator was reduction in coronary artery lumina, but this was not always sudden, and it did not necessarily coincide in time with the initiation of the mechanism leading to death. When a fresh coronary occlusion is found, the pathologist can be reasonably satisfied that he has demonstrated the pathological lesion responsible for death, while well aware that the mechanisms by which it effects the death of the individual are variable and frequently not clear.2 At the same time clinicians and pathologists have long recognized that in a number of the manifestly "cardiac" deaths autopsy fails to demonstrate a correspondingly recent lesion in the coronary arteries. Several studies,2-5 based on a variety of techniques of examination, have recently not only reaffirmed the existence of such a phenomenon but indicated that it is not an uncommon occurrence.
With the recognition that sudden cardiac death is not synonymous with coronary occlusion, it became customary to divide the so-called coronary deaths into two categories. A diagnosis of acute coronary occlusion would be made whenever a fresh block could be demonstrated, while the term acute coronary insufficiency was employed to account for that considerable residuum of cases in which there was clinical evidence of a myocardial ischemic death, autopsy revealed no extracardiac cause, and, although stenosed, the coronary arteries contained no fresh occlusive lesion. However, the various usage in the literature of the terms "acute coronary failure", "acute coronary insufficiency", "coronary failure" and other like terms has prompted a review as a background for our own use of the terms.
In 1941 Blumgart, Schlesinger and Zoll3 proposed the term "coronary failure" to designate a syndrome of cardiac pain which is intermediate between angina pectoris and myocardial infarction, yet unaccompanied by clinical or autopsy evidence of myocardial infarction. In 1948 the same group6 elaborated upon the clinical features, suggested therapy, and expressed their belief that the term should be incorporated into the terminology of cardio- Master's group4' 7 have questioned the advisability of setting the term apart to denote a clinical syndrome. These authors consider the more prolonged episodes of ischoemic-type pain merely as one in a spectrum of several possible manifestations of the temporary state in which myocardial requirement exceeds coronary blood supply. They maintain that it is this temporary state of affairs (and not its clinical manifestation) which deserves, by reason of priority and for clarity, the distinction of the name "acute coronary insufficiency". The same authors4 draw attention to a distinct pathological entity which they attribute specifically to acute coronary insufficiency, namely the widespread, patchy, disseminated myocardial necrosis which they found in 25 cases unassociated with recent coronary occlusion. This patchy and often microscopic necrosis of myocardial fibres was more prominent in the subendocardial region of the left ventricle but did not conform to the distribution of a coronary artery. This report also provides a discussion of precipitating and aggravating factors in acute coronary insufficiency.
There are other circumstances, however, in which a diagnosis of acute coronary insufficiency is commonly applied. An example is the "syndrome of acute coronary insufficiency" as alluded to by Paterson,8 in which the subject dies suddenly from a "heart attack" without premonitory symptoms. As he suggests, this very dramatic but ill-understood phenomenon is presumably related to exaggerated myocardial irritability producing ventricular fibrillation in a person with impaired coronary flow. The relationship between the hyperirritability and a state of acute coronary inadequacy is not clear and in fact far from proven. However, unless a better explanation is found, the practice of attributing this type of death to acute coronary insufficiency is likely to continue.
On this topic the recent report of McQuay2 should be mentioned. This investigator applied the term "acute coronary failure" to describe a type of death encountered in 23% of 133 deaths from massive myocardial infarction. These patients died unexpectedly during convalescence from a typical attack of infarction. At autopsy he was unable to find a fresh coronary lesion to account for the recurring chest pain and death in these cases. He attributed death to "acute coronary failure".
To summarize, terms indistinguishable in meaning have been applied by recent workers with emphasis on four related but different entities, namely: a clinical syndrome of prolonged ischaemic pain without infarction; a pathological entity of focal disseminated necrosis without fresh occlusion; a mode of death following myocardial infarction; and a clinicalpathological syndrome of sudden death without fresh coronary or myocardial lesions. It is not surprising, as these authors indeed recognized,2'4,'7that confusion in terms has resulted. The matter is clarified, however, by a realization that these investigations have all been concerned with various manifestations of a single phenomenon-the acute disturbance of physiology, transient and potentially reversible, in which myocardial demand, for one reason or another, exceeds the pre-existing capacity of the coronary arteries to meet nutritional requirements.
In the present study, aimed at examining the manner in which coronary disease leads to death, we have purposely avoided appropriating the term "acute coronary insufficiency" for any single entity in the belief that it should retain its inherent meaning and therefore denote a dynamic concept of the type just defined. In those cases where the sequelhe of acute coronary insufficiency were encountered in the form of focal myocardial necrosis or sudden death in the circumstances already noted, this diagnosis appears accompanied by more specific anatomical findings upon which it is dependent. PATHOLOGICAL LESIONS In the 100 autopsies studied there were 22 coronary deaths. Twelve additional hearts showed evidence of old myocardial damage attributable to ischaemia (focal or diffuse fibrosis or old healed infarcts), but the person had died from unrelated causes.  1. In the 10 recent infarct cases (by which we mean the localized, well delineated, massive type, unhealed) there was in each instance a correspondingly recent thrombus. In addition, several of these had suffered a fresh episode of thrombosis at adjacent or remote sites. The fresh thrombosis was distinct histologically from the earlier initial thrombosis and appeared to correspond to clinical events surrounding the rapid termination.
2. None of the cases of patchy myocardial necrosis was associated with recent thrombosis; recent intimal heemorrhages were present in three of the five cases but these did not narrow the lumen. 3. In two instances early death precluded the development of infarction after a fresh thrombosis. Here again there was both clinical and histological evidence of two distinct episodes of thrombosis in the last three weeks of life, with death in shock shortly after the second episode. 4. Of the two patients whose sudden deaths were attributed to atherosclerotic narrowing of coronary arteries without fresh occlusion or myocardial necrosis, one was further handicapped by marked congenital dominance of the right (most narrowed) artery, while the other patient had a well capillarized but recent (three weeks) thrombus in his right coronary artery immediately proximal to an old organized thrombus. Neither fresh thrombus nor myocardial necrosis was present, however. Both these hearts contained evidence of previous myocardial ischeemia-patchy fibrosis in the first instance and two old infarcts in the second.
5. Both patients who died after prolonged heart failure had long histories indicative of atherosclerotic heart disease and both had old myocardial infarcts. No recent lesions were discovered. 6. This patient had no significant coronary atherosclerosis.

PRECIPITATING CAUSES OF DEATH
Above is an outline of the anatomical findings held responsible for death in 22 consecutive "coronary deaths". They do not generally indicate the mechanism of death or the terminal events and therefore are difficult to relate to the therapeutic problems involved. The following table is constructed solely with a view to analysis of the precipitating mechanisms (as currently understood) from the prophylactictherapeutic standpoint.

THE THROMBOTIC PROCESS
The most important underlying process responsible for death was (not surprisingly) recent thrombosis, which figured in 13 out of the 22 deaths; embolism occurred in another. More striking, though, was the frequent occurrence of a new episode of thrombosis while the patient was not yet recovered from the effects of the first. The evidence for distinct differences in age in separate portions of a thrombosed segment or in separate segments of vessel was not accepted unless clear-cut on histological grounds. The clinical events surrounding the fatal attack were frequently of further assistance, for in most cases these events were in complete accord with the estimated age of the second thrombus. Particular attention was given to examining the whole thrombosed section by serial cuts. An appearance suggesting that individual thrombi were built up in successive stages was observed in most segments thus examined, but this was not accepted as suffi--1 1.. cient proof of time lapse for the purposes of this report. In the cases labelled "recurrent" in the table, portions of thrombus were found superimposed, adjacent or at remote sites which displayed such sharp contrast in age as to leave no doubt. The histological feature of greatest value was the degree of organization and capillarization, which is entirely lacking in fresh thrombi of hours' to two or three days' duration. In most cases the second (fresh) thrombus was small and could readily be missed with the usual methods of examination. When it is considered that a new encroachment is added at a time when blood supply is already rendered critical and before collateral circulation has become adequate, the serious effects of tiny thrombi are understandable.
The natulre of this tendency to recurrence is niot clear but its implications are obvious. If detailed examination of a larger group of cases yields similar results, then the patient who experiences the abrupt onset of ischoemic pain, particularly if accompanied by the syndrome of infarction, should be suspected not only of having incurred a coronary thrombosis but also of having acquired a thronmbotic tendency, at least as far as his coronary arteries are concerned. This consideration is not weakened by the fact that most patients with infarction recover without incident. We are concerned with the fatalities, and of those whose cardiac accident was in the form of thrombosis, over half showed repetition of the process. In weighing the use of anticoagulant therapy this aspect of coronary thrombosis deserves attention; this treatment may counteract such a tendency in addition to its effects in reducing embolic phenomena and aiding recanalization of thrombi."

ACUTE CORONARY INSUFFICIENCY AS INITIATING DISORDER
The state of acute inadequacy of coronary flow may be precipitated by a number of acute disturbances which lead to reduced cardiac output (e.g., shock, acute heart failure, tachycardia) and may be aggravated by pre-existing states such as aortic stenosis or anaemia. In all cases in the present series there was also marked impairment of coronary flow due to pre-existing coronary atherosclerosis. The combination of one or more of the "low output" states with coronary narrowing and disseminated foci of myocardial necrosis provides solid grounds for a diagnosis of acute coronary insufficiency as a principal event in the final illness. In Cases 14 to 18 (inclusive) in the table the term is employed on these grounds and describes the underlying cardiac disaster from which later developments stem. It is in this syndrome that the term appears most valuable.

AcuTE INSUFFICIENCY AND THE TERMINAL EPISODE
Terminal episodes in coronary disease deserve careful analysis because means may be at hand for prevention not only in the case of recurrence of thrombosis but in some instances where the onset of heart failure or arrhythmia precipitates a state of acute coronary insufficiency. It is in connection with the fatal episode, in particular the abrupt and dramatic termination, that the term "acute coronary insufficiency" is apt to be less accurately applied.
From the table it is seen that the final episode was relatively prolonged (2-36 hours) in 10 cases and sudden in nine. In the prolonged episode group, all of whom had shock, pain and varying degrees of failure, seven terminal episodes could be attributed directly to fresh occlusions. The remaining three cases are believed to be true instances of acute coronary insufficiency in which acute heart failure appeared to precipitate the attack in patients with preexisting but no fresh coronary lesions. Only one of the seven whose attack was caused by a fresh thrombus had a significant degree of heart failure before the development of shock, pain and collapse. It would appear that, in the absence of a precipitating cause for acute coronary insufficiency, the onset of pain and shock more likely than not signifies an acute thrombosis. These cases illustrate the danger which an attack of heart failure or tachyeardia may constitute for the patient with atherosclerotic heart disease.
In the cases of sudden death interpretation of the final episode (lasting only minutes) is more difficult. The most probable explanation, accepted by most cardiologists, is that persons dying suddenly of coronary disease suffer the sudden onset of an arrhythmia which increases myocardial work while simultaneously decreasing coronary flow-a circumstance promoting the most acute degree of coronary insufficiency Canad. M. A. J.
in persons with narrowed vessels, and incompatible with continuing function. Upon close examiniation of histories and autopsies in the nine cases (all of which were in hospital) we' found no acceptable precipitating cause for acute coronary insufficiency apart from marked tachycardia in two cases. "Last minute" observations are lacking on the remainder for obvious reasons. Our negative findings would appear to be in accord with the hypothesis that a paroxysm of disordered rapid rhythm was the precipitating factor. We wish to emphasize the purely secondary nature of the acute insufficiency in this type of case because unfortunately the application of the term "acute coronary insufficiency" as a diagnosis in sudden cardiac death tends to obscure the initiating mechanism, i.e., arrhythmia. If any measure of reduction in this type of death is achieved (e.g., in post-infarction cases), it will probably be through treatment designed to reduce hyperirritability, which is believed to be responsible, In the examples of sudden death in this series, there was no evidence that exertion led to sudden death.

PRODROMAL PAIN
It has been frequently observed clinically that, in some cases, chest pain suggestive of angina pectoris (although often not typical) heralds by days to weeks the development of the typical syndrome of myocardial infarction. It is of interest that in the group under discussion there were four patients who had complained of chest pain of recent onset; in three it was not typical and went undiagnosed. When each of the four subsequently developed a fresh thrombus and died, it was found that the three "atypical" cases had been going about with unhealed myocardial infarcts of duration compatible with their symptoms. In two of these, electrocardiograms, taken because of the symptoms, had failed to reveal the diagnosis. In the fourth case the pain might be called genuinely prodromal in that the onset of angina was caused by an incompletely obstructing thrombus without infarction; three weeks later, fresh occluding thrombus caused death in a few hours. Although the series is too small to warrant conclusions, it is of interest that of four cases giving the impression of "prodromal pain syndrome", three already had their infarcts when first complaining and all four patients were victims of recurrent thrombosis.
SUMMARY AND CONCLUSIONS 1. The coronary arteries from 100 consecutive autopsies have been studied by a special technique and 22 coronary deaths subjected to particular scrutiny. The initiating and fatal mechanisms were investigated. 2. Judged by this small series, a patient who experiences the abrupt onset of "ischaemic cardiac pain", with or without the classical infarction syndrome, has sustained a coronary thrombosis in over half of the cases coming to autopsy. 3. Persons who had experienced one bout of thrombosis in these fatal cases are frequently shown to have suffered a recurrence of thrombosis leading to death before the myocardial lesions from the initial occlusion have healed (about two-thirds of the thrombosis group in this series).
4. Acute coronary insufficiency in this series has been defined as an acute inadequacy of coronary flow, precipitated by altered cardiac output, in the presence of narrowing of coronary arteries. Pathological confirmation of such a state may or may not be found in disseminated foci of myocardial necrosis. 5. In clinical practice, one may suspect acute coronary insufficiency as an underlying mechanism in a minority of cases, where one or more episodes of low cardiac output are known to have preceded the onset of the episode of ischoemia, and particularly if aggravating factors (e.g., anemia or aortic stenosis) are present. However, in the absence of such factors, thrombosis should be assumed. 6. Acute coronary insufficiency as a principal cardiac disturbance is distinguished from the same state occurring as a purely secondary phenomenon in sudden death. RESUME Dans une serie de cent autopsies consecutives, les arteres coronaires ont ete etudiees avec une technique speciale, et les causes de 22 deces par maladie coronarienne ont ete particulierement recherchees. Les mecanismes initial et final furent etudies. D'apres cette courte s6rie, une personne qui ressent une attaque soudaine de "douleur isch6mique cardiaque" accompagnee, ou non, du syndrome classique de l'infarctus, a subi une thrombose coronaire, dans environ 70% des cas passant a l'autopsie. Parmi ces cas fatals, on trouve fr6quemment que les malades qui, ayant de6ja subi une premiere attaque de thrombose, avaient ensuite succombe a une autre attaque portaient des lesions du myocarde causees par la premiere occlusion et qui n'avaient pas eu le temps de guerir (environ 70% du groupe des thromboses de la serie).
En pratique, on peut soupconner une insuffisance coronarienne aigue comme le mecanisme fondamental dans un petit nombre de cas o"u une diminution passagere du d6bit cardiaque a pr6cede le debut de la manifestation d'ischemie, surtout s'il existe des facteurs aggravants, comme de l'anemie, ou un retr6cissement aortique. Toutefois, en l'absence de ces facteurs, on doit incriminer la thrombose comme diagnostic probable. L'insuffisance coronarienne aigue comme affection cardiaque primordiale n'est pas confondue avec le meme etat se presentant comme ph6nom'ne secondaire dans la mort subite. THE SPLEEN HAS BEEN removed in cases of leukiemia and lymphoma sporadically since Billroth removed one in 1866 for "leukosarcoma". Some 53 splenectomies were performed for leukhemia at the Mayo Clinic up to 1928.' The results were not reported in detail but some of the patients appeared to benefit. Scott2 reported two instances of haemolytic aneemia, one in Hodgkin's disease and one in reticulosarcoma, with relief of haemolysis in each case after splenectomy. A case of Hodgkin's disease and one of myeloid leukiemia3 had a fair amelioration of haemolysis after splenectomy. Five patients with leukaemia (briefly reported by Hunter and Kiernan4) who underwent splenectomy for varying degrees of haemolysis included one with chronic granulocytic leukeemia in whom the reticulocytes returned to normal after operation. Hagen and Watson5 had experience with eight cases of leukeemia with haemolytic anemia. In four, all with chronic lymphocytic leukemia, results were good, while the other four had indifferent or slight improvement. Those in whom the reticulocyte count was highest had the best response.
In a series of 11 cases of Hodgkin's disease splenectomy did not seem to accelerate the couirse of the disease.6 Nine cases had improve-*FIom the Department of Medicine, University of British Columbia. ment in haemolytic anaemia, neutropenia or thrombocytopenia. A fall in white cell count has been noted after operation in chronic granulocytic leukemia.4' 7 Fisher, Welch and Dameshek8 reported 18 cases of leukhemia or leukosarcoma with splenectomy; 14 operations were intentional and four were performed before diagnosis was made. Eleven benefited to some degree in that haemolytic anaemia or thrombocytopenia or pancytopenia was controlled for a "reasonable period". Of the 11 cases that responded well, nine were cases of lymphocytic or lymphoblastic disease. To observe the effect of splenectomy on the course of Hodgkin's disease itself Sykes et al.9 operated upon five cases, none with benefit. They reviewed the literature and could find no report of a case of Hodgkin's disease apparently confined to the spleen at the time of operation and so cured. In 16 instances in the literature, the spleen was removed from patients with Hodgkin's disease thought to have haemolytic anaemia. Ten of these were improved for periods ranging from 8 weeks to 41/2 years.
It was noted that thrombocytopenia, independent of general depression of the bone marrow, was rare in Hodgkin's disease but that there were two reports in the literature of thrombocytopenia relieved by splenectomy. Reinhard and Loeb'0 had experience with 21 cases and found excellent results in significant numbers of cases of chronic lymphocytic leuktemia and of Hodgkin's disease with haemolytic aneemia and thrombocytopenia or both.
In the last six years we have treated upwards of 450 cases of leukaemia and lymphoma.