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Microcirculatory disturbances and human myocardial infarction
icrocirculatory man
myocardiai[
disturba infarc
yocardial infarction without significant coronary lesions or acute occlusion in man has frequently been reported in the literature.‘*” Furthermore, in many experimental studies an “infarctoid cardiopathy,” namely, a myocardial coagulative necrosis, has been obtained.5-6 Recently, the low incidence of acute occlusion in the human infarct has been empl-lasized,7-g and evidence has shown that in most of the human cases he cardiac infarct is not a true infarct, according to the general meaning of the term. It has been estimated that, in more than 90 per cent of these cases, only the dmbiguous term “myocardial infarction U,ith acute occlusion” applies. g Therefore, the different theories that have been proposed for “idiopathic myocardial coagulative necrosis” take on a particular significance. Among these theories, the most midley debated are those of acute or chronic coronary insufficiency of intracardiac or extracardiac origin,lO coronary spasm,11z12 intramural arterial lesions,13J4 metabolic disturbances by catecholamines,15 and ‘settling of blood cell masses.“16,17 This paper concerns the relationship of the myocardial alterations to the occlusive the small intramyocardial ‘esions of From
xanches. ‘These i&iOiltAit” :i.* 1 . 3 and widei) dissemmated in the hearts ‘,;f ;,atients who died from Mosi-hxwitz’s disease. Iysually referred -to as “tilrornbotic thrombocytopknic purpum” (?“!‘I~], this uisease is characterized, according to Singerand Bornstein,i8 by purpura, bleeding disorders, thrombocytopenia., severe hemolytic anemia, intermitterlt mental and neuroiogic disturbances, and myriads of “platelet” thrombi in the small arterioles and capillaries of almost all oi -tile orga.ns of the body. TTP offers a miqi!e opporI-unity in human pathology to evaluate rhe above-mentioned relationsh;p, since rbe widespread dissemination of x-asculx Lesions has its highest incidence in the heart. Thirty-nine
cases of thronr!x2t:C: thrompurpura collected d‘roin the files of the Armed Forces Imr.i:ute of Pathology were studied. The Sies of the AFIP include case material ir.orn the military, Veterans Administration, and civilian sources. In each case the c!inicaI an d autopsy records, blocks, wet tissue, and slides of all the main or-g:tns were available. Twenty-four cases were ma!e, and 1.5 were female. The age range was hocytopenic
the Institute of Morbid Anatomy, University ~1 %1&n, Milan, ita!y (Dr. Bmoidi), and :I(: i‘~lrdr~~vascu~~il Pathology Branch, Armed Forces Institute of Pathology, Washington, D.C. (Dr. Blanion aad Ik. j:aro!di). Kvceived for publication Sept. 12, 1966. *Address: Armed Forces Institute of Pathology, Washington. D.C., 20305.
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Am.HeavtI. August,1967
Baroldi and Manion
from 21 to 72 years in the men, averaging 36.1 years, and from 21 to 59 years, averaging 38 years, in the women. All of the main organs in these 39 cases were histologically examined, and the slides of each specimen were stained by hematoxylin and eosin, Movat, periodic acid-Schiff (PAS), Mallory’s phosphotungstic acid-hematoxylin, Luna’s canaliculi stain, and Rinehart-Abul-Haj stain for acid mucopolysaccharides. In 3 cases, hematoxylin-eosin-stained serial sections of two specimens from the right and left cardiac ventricular walls were studied. The frequency of the vascular lesions in each single slide has been evaluated as follows: 0 = no lesion found; 1+ = less than 5 lesions; 2+ = between 5 and 15 lesions; 3f = more than 15 lesions. Results
A complete discussion of TTP based on our own cases, as well as on a review of 220 cases from the literature, will be published in the near future. In this paper, however, we are concerned only with the obstructive or severely stenotic lesions of the arteriolar, precapillary intramural branches of the myocardium and the related myocardial damage. These vascular lesions were present in all of the hearts examined, with a frequency that was evaluated as l$- in 3 per cent of cases, 2+ in 37 per cent, and 3-i- in 60 per cent. The vascular lesions were not limited in location to any particular area of the heart but were disseminated throughout, chiefly involving the arterioles. The occlusive material is strongly PAS positive, even after digestion, showing little if any affinity for the collagen or acid mucopolysaccharide stains. In most of the cases it is possible to demonstrate an endothelial surface, and, very frequently, endothelium-like cells appear within the abnormal material. More rarely, there is a similar, more granular material on the endothelial surface of the obstructive neoformation. Frequently, the vessels appear to be highly dilated, showing a pattern resembling recanalization or glomeruli. In 29 cases (74.3 per cent) a focal myocarditis was present, consisting mainly of mild polymorphonuclear infiltration without damage to the myocardial cells. Focal
hemorrhages were found in 31 cases (79.5 per cent), and edema only was demonstrated in 20 cases (52.6 per cent). In only 4 cases (10.2 per cent) were rare, small foci of early coagulative necrosis present, without cellular reaction and apparently without any relationship to occluded arterioles. In 2 of these cases the right ventricle was involved, and in the other 2, the left ventricle. In 12 cases (31.5 per cent), scant, small foci of myocytolysis were found. Three out of 4 cases with focal early coagulative necrosis also showed myocytolysis. The terminal episodes in the 4 cases with focal early coagulative necrosis were coma in 3 and sudden death in 1. In all of the cases with focal myocytolysis the terminal episode was coma, with the exception of 2 cases in which death was due to shock after splenectomy. Conclusions
Acute focal myocardial necrosis has been reported in 33.3 per cent of 159 cases reviewed in the literature. Furthermore, most of these authors emphasized the disproportion between the limited extension of the necrotic damage and the diffuse dissemination of severe vascular lesions. In our material, however, the occurrence of extremely rare, minimal foci of coagulative necrosis of the myocardium was found in only 10.2 per cent of the cases. In none of these cases was there a direct relationship between the site of the vascular lesion and the location of the myocardial damage, as shown by serial sections; widespread dissemination of the vascular obstruction was maximal (Figs. l-3). Other myocardial alterations found, such as myocarditis, focal hemorrhage, focal myocytolysis, and edema, have no relationship to the coagulative necrosis typical of the myocardial infarct, and therefore they will not be considered in the present discussion. The finding of occasional focal coagulative necrosis of the myocardium in cases of TTP does not support the hypothesis that the obstructive involvement of the intramyocardial branches, even though extensive, may be the cause of the myocardial infarction in the absence of an effective acute occlusion of a main extramural branch. On the contrary, evidence
/-. .( lg. “. Some patterns of thrombotic thrombocytopenic purpura in the m~~ucC>rdluw, :mti sre~roi.c _+ :d 0: ,.iu>i\e lesions of the intramyocardial branches without myocardiai damage. L,‘i@+’ kjt.’ From 33-year-cid fe~nak Upper right: From 25.year-old lemale e^awasian patient. Hematoxylin-eosin, X 165. liFIP Keg. 6.54320, C’aucasian patient. Periodic acid-Schiff, x 115. AFIP Neg. 65.4240. Lowev lejf: From E-year-old male Caucka~~ patient. Hematoxylin-eosin, x210. AFIP Neg. 65-4340. LoBIer right: From 33-year-aid female Ca.wzasiari paCent. Hematoxylin-eosin, X350. AFIP Neg. 6.5-4332.
176
Baroldi and Manion
Fig. 2. U@er left: From 33-year-old female Caucasian Upper right: From 25year-old male Caucasian patient. From 33-year-old male Negro patient. Hematoxylin-eosin, year-old female Caucasian patient. Hematoxylin-eosin,
Am. Heart I. August, 1967
patient. Periodic acid-Schiff, X530. AFIP Neg. 65-4476. Hematoxylin-eosin, X 26.5. AFIP Neg. 65-4449. Lower left: X 180. AFIP Neg. 65-4480. Lowe7 right: From 33X.550. AFIP Neg. 65-4473.
Tig. 3. V~ippw: Fi-um /§-year-old .;oweu: From 25.year-old female
female Caucasian
Caucasian patient.
t:xists that the normal anastomotic circulation is capable of compensating efficiently !or this type of widespread involvement. TTP is, in most instances, a short-term Jisease; 82 per cent of the patients reported on in the literature and 90 per cent of our own patients died within 35 days irom the onset of the first symptoms and signs (42 and 52 per cent, respectively, within 14 days; 21 and 20 per cent, respectively, within 7 days). In view of the histologic pattern, it is difficult to evaluate the exact age of the obstructive lesion,
patient. Fleinato~yliil-eusIn, x 100. WI i- \r~?:g. ,,-:--...:,Oi. Hematoxy!in-eosin, X 130. AFlP LYeg. 6.54265,
the nature oi which is stil! deo,l :.eo. h:..JIIg the characteristic histologic featuri:s of this lesion are the absence of connective or reticular tissue, the absence of, or onl~~ minimal, inAammatory reaction, thy apparent proliferation of the endothe’?ial cell (which in most of the lesions covers the collected fibrinoid-like mater% and sometimes seems to penetrate into ti), and deposits of generally granular material superimposed on the more compact t&othelium-lined nodules. The usually short course of this disease and the app,Lrent
Am. Heart J. Aagust, 1967
Buroldi and AJarzion
178
endothelial proliferation would support the concept that the vascular lesions are definable as acute and recent in most cases. These vascular lesions are still old enwugh, however, to have produced myocardial necrosis if a direct relationship exists between them, since it has been well established by routine histologic procedures that, after its onset, the myocardial infarction cannot be demonstrated earlier than 8 to 12 hours. On the basis of our study, we conclude that the acute, recent occlusions of the intramyocardial artery do not induce myocardial coagulative necrosis.
6.
7.
A
8.
9.
10.
Summary
Thirty-nine cases of thrombotic thrombocytopenic purpura (Moschcowitz’s disease) were examined, and the severe, obstructive involvement of the intramyocardial arterial branches was compared to the myocardial condition. In only 4 cases (10.2 per cent) was an occasional microfocal coagulative necrosis present, despite the massive involvement of the intramural branches. The conclusion, therefore, is that the obstructive lesions of the intramyocardial arterial portion cannot be the cause of the so-called “myocardial infarction” without acute occlusion of the main extramural branches.
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16. 1.
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REFERENCES Gross, H., and Sternberg, W. H.: Myocardial infarction without significant lesions of coronary arteries, Arch. Int. Med. 64:249, 1939. Friedberg, C. K., and Horn, H.: Acute myocardial infarction not due to coronary artery occlusion. T.A.M.A. 112:1675. 1939. Selye, H.‘:“The chemical prevention of cardiac necrosis, New York, 1958, Ronald Press Company. Cannon, P. R., Frazier, L. E., and Hughes, R. H.: Sodium as a toxic ion in potassium dehciency, Metabolism 2:297, 1953. Rona, G., Chappel, C. I., Balasz, T., and Gaudry, R.: An infarct-like myocardial lesion
and other toxic manifestations produced by isoproterendl in rat, Arch. Path. 67:443, 1959. Thomas, W. A., and Hartroft, W. S.: Myocardial infarction in rats fed diets containing high fat, cholesterol, thiouracil and sodium cholate. Circulation 19:65, 1959. Ehrlich, J. C., and Shinohara, Y.: Low incidence of coronary thrombosis in myocardial infarction. A restudv bv serial block technioue. arch. Path. 78:432, i964. Baroldi, G., and Scomazzoni, G.: Coronary circulation in the normal and pathologic heart, Washington, D. C., 1965, Government Printing Office. Baroldi, G.: Acute coronary occlusion as a cause of myocardial infarct and sudden coronary heart death, Am. J. Cardiol. 16:859, 1965. Master, A. M., Jaffe, H. L., and Field, L. E.: Acute coronary insufficiency; its importance in military medicine, U. S. Armed Forces M. J. 7:1, 1956. Zinck, K. H.: Sondervorrichtungen an Kranzgefassen und ihre Beziehung zu Coronarinfarkt und miliaren Nekrosen, Virchow’s Ardh. Path. Anat. 305:288, 1940. Sewell, W. H.: Coronary spasm as a primary cause of myocardial infarction. A preliminary report, Angiology 1’7:1, 1966. Linzbach, A. J.: Mikrometrische und histologische Analyse hypertropher menschlicher Herzen, Virchow’s Arch. Path. Anat. 314:534, 1947. Hirsch, S.: Le rBle des petites branches coronaires dans la pathogen&e de l’infarctus myocardique, Acta Med. Scandinav. 138:449, 19.50. Raab, W.: Key position of catecholamines in functional degenerative cardiovascular pathology, Am. J. Cardiol. 5:571, 1960. L&g, D. M., Myer, M. W., Brown, E. B., and Lillehei. C. W. : Mvocardial necrosis and electrocardiographic changes related to microcirculatory abnormalities, Am. J. Cardiol. 10:695, 1962. Knisely, M. H. : The settling of blood cell masses to the lower sides of vessels during life and the probable significance, ,in Henry Ford Hospital International Symposium: The etiology of myocardial infarction, Boston, 1963, Little, Brown Comaanv. DD. 557-585. Singer, K., and-Bo;nstein, F. P.: Thrombotic thrombocytopenic purpura: Hemorrhagic diathesis with generalized platelet thrombosis, Blood 2:542, 1947.
17.
18.
myocardiai[
disturba infarc
yocardial infarction without significant coronary lesions or acute occlusion in man has frequently been reported in the literature.‘*” Furthermore, in many experimental studies an “infarctoid cardiopathy,” namely, a myocardial coagulative necrosis, has been obtained.5-6 Recently, the low incidence of acute occlusion in the human infarct has been empl-lasized,7-g and evidence has shown that in most of the human cases he cardiac infarct is not a true infarct, according to the general meaning of the term. It has been estimated that, in more than 90 per cent of these cases, only the dmbiguous term “myocardial infarction U,ith acute occlusion” applies. g Therefore, the different theories that have been proposed for “idiopathic myocardial coagulative necrosis” take on a particular significance. Among these theories, the most midley debated are those of acute or chronic coronary insufficiency of intracardiac or extracardiac origin,lO coronary spasm,11z12 intramural arterial lesions,13J4 metabolic disturbances by catecholamines,15 and ‘settling of blood cell masses.“16,17 This paper concerns the relationship of the myocardial alterations to the occlusive the small intramyocardial ‘esions of From
xanches. ‘These i&iOiltAit” :i.* 1 . 3 and widei) dissemmated in the hearts ‘,;f ;,atients who died from Mosi-hxwitz’s disease. Iysually referred -to as “tilrornbotic thrombocytopknic purpum” (?“!‘I~], this uisease is characterized, according to Singerand Bornstein,i8 by purpura, bleeding disorders, thrombocytopenia., severe hemolytic anemia, intermitterlt mental and neuroiogic disturbances, and myriads of “platelet” thrombi in the small arterioles and capillaries of almost all oi -tile orga.ns of the body. TTP offers a miqi!e opporI-unity in human pathology to evaluate rhe above-mentioned relationsh;p, since rbe widespread dissemination of x-asculx Lesions has its highest incidence in the heart. Thirty-nine
cases of thronr!x2t:C: thrompurpura collected d‘roin the files of the Armed Forces Imr.i:ute of Pathology were studied. The Sies of the AFIP include case material ir.orn the military, Veterans Administration, and civilian sources. In each case the c!inicaI an d autopsy records, blocks, wet tissue, and slides of all the main or-g:tns were available. Twenty-four cases were ma!e, and 1.5 were female. The age range was hocytopenic
the Institute of Morbid Anatomy, University ~1 %1&n, Milan, ita!y (Dr. Bmoidi), and :I(: i‘~lrdr~~vascu~~il Pathology Branch, Armed Forces Institute of Pathology, Washington, D.C. (Dr. Blanion aad Ik. j:aro!di). Kvceived for publication Sept. 12, 1966. *Address: Armed Forces Institute of Pathology, Washington. D.C., 20305.
174
Am.HeavtI. August,1967
Baroldi and Manion
from 21 to 72 years in the men, averaging 36.1 years, and from 21 to 59 years, averaging 38 years, in the women. All of the main organs in these 39 cases were histologically examined, and the slides of each specimen were stained by hematoxylin and eosin, Movat, periodic acid-Schiff (PAS), Mallory’s phosphotungstic acid-hematoxylin, Luna’s canaliculi stain, and Rinehart-Abul-Haj stain for acid mucopolysaccharides. In 3 cases, hematoxylin-eosin-stained serial sections of two specimens from the right and left cardiac ventricular walls were studied. The frequency of the vascular lesions in each single slide has been evaluated as follows: 0 = no lesion found; 1+ = less than 5 lesions; 2+ = between 5 and 15 lesions; 3f = more than 15 lesions. Results
A complete discussion of TTP based on our own cases, as well as on a review of 220 cases from the literature, will be published in the near future. In this paper, however, we are concerned only with the obstructive or severely stenotic lesions of the arteriolar, precapillary intramural branches of the myocardium and the related myocardial damage. These vascular lesions were present in all of the hearts examined, with a frequency that was evaluated as l$- in 3 per cent of cases, 2+ in 37 per cent, and 3-i- in 60 per cent. The vascular lesions were not limited in location to any particular area of the heart but were disseminated throughout, chiefly involving the arterioles. The occlusive material is strongly PAS positive, even after digestion, showing little if any affinity for the collagen or acid mucopolysaccharide stains. In most of the cases it is possible to demonstrate an endothelial surface, and, very frequently, endothelium-like cells appear within the abnormal material. More rarely, there is a similar, more granular material on the endothelial surface of the obstructive neoformation. Frequently, the vessels appear to be highly dilated, showing a pattern resembling recanalization or glomeruli. In 29 cases (74.3 per cent) a focal myocarditis was present, consisting mainly of mild polymorphonuclear infiltration without damage to the myocardial cells. Focal
hemorrhages were found in 31 cases (79.5 per cent), and edema only was demonstrated in 20 cases (52.6 per cent). In only 4 cases (10.2 per cent) were rare, small foci of early coagulative necrosis present, without cellular reaction and apparently without any relationship to occluded arterioles. In 2 of these cases the right ventricle was involved, and in the other 2, the left ventricle. In 12 cases (31.5 per cent), scant, small foci of myocytolysis were found. Three out of 4 cases with focal early coagulative necrosis also showed myocytolysis. The terminal episodes in the 4 cases with focal early coagulative necrosis were coma in 3 and sudden death in 1. In all of the cases with focal myocytolysis the terminal episode was coma, with the exception of 2 cases in which death was due to shock after splenectomy. Conclusions
Acute focal myocardial necrosis has been reported in 33.3 per cent of 159 cases reviewed in the literature. Furthermore, most of these authors emphasized the disproportion between the limited extension of the necrotic damage and the diffuse dissemination of severe vascular lesions. In our material, however, the occurrence of extremely rare, minimal foci of coagulative necrosis of the myocardium was found in only 10.2 per cent of the cases. In none of these cases was there a direct relationship between the site of the vascular lesion and the location of the myocardial damage, as shown by serial sections; widespread dissemination of the vascular obstruction was maximal (Figs. l-3). Other myocardial alterations found, such as myocarditis, focal hemorrhage, focal myocytolysis, and edema, have no relationship to the coagulative necrosis typical of the myocardial infarct, and therefore they will not be considered in the present discussion. The finding of occasional focal coagulative necrosis of the myocardium in cases of TTP does not support the hypothesis that the obstructive involvement of the intramyocardial branches, even though extensive, may be the cause of the myocardial infarction in the absence of an effective acute occlusion of a main extramural branch. On the contrary, evidence
/-. .( lg. “. Some patterns of thrombotic thrombocytopenic purpura in the m~~ucC>rdluw, :mti sre~roi.c _+ :d 0: ,.iu>i\e lesions of the intramyocardial branches without myocardiai damage. L,‘i@+’ kjt.’ From 33-year-cid fe~nak Upper right: From 25.year-old lemale e^awasian patient. Hematoxylin-eosin, X 165. liFIP Keg. 6.54320, C’aucasian patient. Periodic acid-Schiff, x 115. AFIP Neg. 65.4240. Lowev lejf: From E-year-old male Caucka~~ patient. Hematoxylin-eosin, x210. AFIP Neg. 65-4340. LoBIer right: From 33-year-aid female Ca.wzasiari paCent. Hematoxylin-eosin, X350. AFIP Neg. 6.5-4332.
176
Baroldi and Manion
Fig. 2. U@er left: From 33-year-old female Caucasian Upper right: From 25year-old male Caucasian patient. From 33-year-old male Negro patient. Hematoxylin-eosin, year-old female Caucasian patient. Hematoxylin-eosin,
Am. Heart I. August, 1967
patient. Periodic acid-Schiff, X530. AFIP Neg. 65-4476. Hematoxylin-eosin, X 26.5. AFIP Neg. 65-4449. Lower left: X 180. AFIP Neg. 65-4480. Lowe7 right: From 33X.550. AFIP Neg. 65-4473.
Tig. 3. V~ippw: Fi-um /§-year-old .;oweu: From 25.year-old female
female Caucasian
Caucasian patient.
t:xists that the normal anastomotic circulation is capable of compensating efficiently !or this type of widespread involvement. TTP is, in most instances, a short-term Jisease; 82 per cent of the patients reported on in the literature and 90 per cent of our own patients died within 35 days irom the onset of the first symptoms and signs (42 and 52 per cent, respectively, within 14 days; 21 and 20 per cent, respectively, within 7 days). In view of the histologic pattern, it is difficult to evaluate the exact age of the obstructive lesion,
patient. Fleinato~yliil-eusIn, x 100. WI i- \r~?:g. ,,-:--...:,Oi. Hematoxy!in-eosin, X 130. AFlP LYeg. 6.54265,
the nature oi which is stil! deo,l :.eo. h:..JIIg the characteristic histologic featuri:s of this lesion are the absence of connective or reticular tissue, the absence of, or onl~~ minimal, inAammatory reaction, thy apparent proliferation of the endothe’?ial cell (which in most of the lesions covers the collected fibrinoid-like mater% and sometimes seems to penetrate into ti), and deposits of generally granular material superimposed on the more compact t&othelium-lined nodules. The usually short course of this disease and the app,Lrent
Am. Heart J. Aagust, 1967
Buroldi and AJarzion
178
endothelial proliferation would support the concept that the vascular lesions are definable as acute and recent in most cases. These vascular lesions are still old enwugh, however, to have produced myocardial necrosis if a direct relationship exists between them, since it has been well established by routine histologic procedures that, after its onset, the myocardial infarction cannot be demonstrated earlier than 8 to 12 hours. On the basis of our study, we conclude that the acute, recent occlusions of the intramyocardial artery do not induce myocardial coagulative necrosis.
6.
7.
A
8.
9.
10.
Summary
Thirty-nine cases of thrombotic thrombocytopenic purpura (Moschcowitz’s disease) were examined, and the severe, obstructive involvement of the intramyocardial arterial branches was compared to the myocardial condition. In only 4 cases (10.2 per cent) was an occasional microfocal coagulative necrosis present, despite the massive involvement of the intramural branches. The conclusion, therefore, is that the obstructive lesions of the intramyocardial arterial portion cannot be the cause of the so-called “myocardial infarction” without acute occlusion of the main extramural branches.
11.
12.
13.
14.
15.
16. 1.
2.
3.
4.
5.
REFERENCES Gross, H., and Sternberg, W. H.: Myocardial infarction without significant lesions of coronary arteries, Arch. Int. Med. 64:249, 1939. Friedberg, C. K., and Horn, H.: Acute myocardial infarction not due to coronary artery occlusion. T.A.M.A. 112:1675. 1939. Selye, H.‘:“The chemical prevention of cardiac necrosis, New York, 1958, Ronald Press Company. Cannon, P. R., Frazier, L. E., and Hughes, R. H.: Sodium as a toxic ion in potassium dehciency, Metabolism 2:297, 1953. Rona, G., Chappel, C. I., Balasz, T., and Gaudry, R.: An infarct-like myocardial lesion
and other toxic manifestations produced by isoproterendl in rat, Arch. Path. 67:443, 1959. Thomas, W. A., and Hartroft, W. S.: Myocardial infarction in rats fed diets containing high fat, cholesterol, thiouracil and sodium cholate. Circulation 19:65, 1959. Ehrlich, J. C., and Shinohara, Y.: Low incidence of coronary thrombosis in myocardial infarction. A restudv bv serial block technioue. arch. Path. 78:432, i964. Baroldi, G., and Scomazzoni, G.: Coronary circulation in the normal and pathologic heart, Washington, D. C., 1965, Government Printing Office. Baroldi, G.: Acute coronary occlusion as a cause of myocardial infarct and sudden coronary heart death, Am. J. Cardiol. 16:859, 1965. Master, A. M., Jaffe, H. L., and Field, L. E.: Acute coronary insufficiency; its importance in military medicine, U. S. Armed Forces M. J. 7:1, 1956. Zinck, K. H.: Sondervorrichtungen an Kranzgefassen und ihre Beziehung zu Coronarinfarkt und miliaren Nekrosen, Virchow’s Ardh. Path. Anat. 305:288, 1940. Sewell, W. H.: Coronary spasm as a primary cause of myocardial infarction. A preliminary report, Angiology 1’7:1, 1966. Linzbach, A. J.: Mikrometrische und histologische Analyse hypertropher menschlicher Herzen, Virchow’s Arch. Path. Anat. 314:534, 1947. Hirsch, S.: Le rBle des petites branches coronaires dans la pathogen&e de l’infarctus myocardique, Acta Med. Scandinav. 138:449, 19.50. Raab, W.: Key position of catecholamines in functional degenerative cardiovascular pathology, Am. J. Cardiol. 5:571, 1960. L&g, D. M., Myer, M. W., Brown, E. B., and Lillehei. C. W. : Mvocardial necrosis and electrocardiographic changes related to microcirculatory abnormalities, Am. J. Cardiol. 10:695, 1962. Knisely, M. H. : The settling of blood cell masses to the lower sides of vessels during life and the probable significance, ,in Henry Ford Hospital International Symposium: The etiology of myocardial infarction, Boston, 1963, Little, Brown Comaanv. DD. 557-585. Singer, K., and-Bo;nstein, F. P.: Thrombotic thrombocytopenic purpura: Hemorrhagic diathesis with generalized platelet thrombosis, Blood 2:542, 1947.
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