Myocardial necroses of coronary and noncoronary genesis

The American

Journal APRIL

VOLUME 13

of Cardiology

1063

NUMBER

4

EDITORIAL Myocardial

Necroses of Coronary ALEXANDER

and Noncoronary

Genesis*

L. MYASNIKOV, M.D.

Moscow,

Soviet

N

Union

of necrosis which occurs as the immediate result of an acute impairment of the blood supply to myocardial tissue caused by an interference with patency of a coronary artery. In other words, a myocardial infarct is a necrosis of the heart muscle of coronary origin-a coronarogenic necrosis. There are numerous types of myocardial necrosis whose origin is not connected with any disturbance of the coronary blood flow. One could designate such noncoronarogenic necroses as “primary” if this adjective would not have a general connotation of relativity and conditionality. (“Primariness” of a myocardial lesion is meant here merely as an alternative to its coronary genesis, while such “primarily” myocardial disturbances may, for their part, result from other, even more “primary” pathologic processes in the body) (Table I).

OT long ago, Selye’s book’ on necroses of the myocardium and their chemical prevention was published in Russian translation, and in recent years many attempts have been made to produce necroses of the heart muscle The findings of Raab2e3 conexperimentally. cerning the role of the catecholamines in the origin of myocardial necroses or infarcts are also of great interest. Under the impact of these investigations, clinicians of the Soviet Union are increasingly recognizing the necessity to reconsider the problem of the pathogenesis of myocardial infarction. Originally, myocardial infarction was regarded simply as the result of mechanical obstruction of a coronary artery (thrombosis, formation of atherosclerotic plaques or stenosis, etc.). Now one is beginning to interpret them from new viewpoints as sequelae of metabolic derangements in the heart muscle, connected with the influence of electrolytes, hormones, toxic products of metabolism, hypoxia and other factors. The present article deals with the classification of necrotic lesions of the heart muscle. We feel that, for clinical purposes, a differentiation of the various concepts will be more useful than their replacement by or confusion with others. The meanings of the terms “myocardial necrosis” and “ myocardial infarct,” respectively, coincide in certain instances; in others, they must be kept strictly apart. An infarct of the heart muscle consists, of course, of its necrosis; however, the term “necrosis” has a broader meaning than the term “infarct.” Not all necroses of the heart muscle are infarcts. The term “myocardial infarct” applies to that type

MYOCARDIAL INFARCTS (CORONAROGENIC NECROSES) Experimental Myocardial Infarcts: In turning to the coronarogenic necroses, i.e., myocardial infarcts, we have to consider first of all their customary experimental production by placing a ligature on one of the coronary arteries or on a major or minor branch. This model procedure has long been known,4 and to this day it is useful for the study of the pathology of the myocardial infarct. Naturally, it cannot be regarded as quite satisfactory from the clinical viewpoint: Under clinical conditions one seldom encounters infarcts elicited by external constriction of a coronary artery, with exception of the development of scars in the heart muscle or of periarteriitis nodosa. Nevertheless, this device still

* From the Institute of Therapy of the Academy of Medical Sciences of the USSR, Moscow. Translated from the Russian original by Wilhelm Raab, M.D., F.A.C.C., University of Vermont, College of Medicine, Burlington, Vt. 435

MyasnikoL

436 ‘rABLE

I

Classification of Myocardial

Nccroses

Cnronarogenic Nccroses (myocardial infarcts) .MMacrofocal, Microfocal Common types Atherosclerosis Overstrain of heart Arterial spasm Coronary thrombosis

muscle

Rare types Thromboangiitis and Embolism Mechanical constriction

angiitis (scars,

Anorcnk .4nrmia Hormonal Neurogenic Nutritional Toxic

Infectious-allergic in inflammatory myocardium:

(participating states of the myocarditis)

etc.)

retains its value for research concerning the evolution of this particular type of cardiac lesion, especially in combination with other influences which either accentuate or inhibit necrotization. The experimental use of ligatures whose ends are left exposed on the outside of the body, makes it possible to reduce the coronary flow by different degrees, i.e., to create an adaptable stenosis of a coronary artery. This corresponds, without doubt, more closely to clinical conditions.5 Another method to produce a mechanical interference with coronary artery passz bility is the introduction of glass beads or lycopodium seeds into the lumen of a coronary artery to obstruct it from the inside. This technic is even more comparable to clinic21 conditions because it creates a genuine obstruction resemIt corresponds to the bling a thrombotic plug. pathogenesis of that rare type of myocardial infarction elicited by an embolus (as in cases of bacterial endocarditis or detachment of thromHere we botic material from the left auricle). may also mention experiments with injection of mercury into a coronary artery.‘j Due to the radio-opaqueness of mercury, its localization can However, this be ascertained radiographically. method, too, has major shortcomings; e.g., the inconstancy of the development and location of infarcts, irregular dimensions of the resulting foci of necrosis, and injurious pentration of the material into other organs. The most natural way to obtain experimental myocardial infarctions would be the creation of those lesions of the coronary arteries which constitute the common prerequisite for the ocIt is currence of myocardial infarction in man. well known that, in the overwhelming majority of cases, atherosclerosis of the coronary arteries Numerous appears to be a causative factor. experiments have been performed with the induction of atherosclerosis by feeding choles-

to various anild species according to the method of Anitchkov.7 They pro\-e that it is possible in prolonged experiments to produce atherosclerosis not only of the aorta but also However, experiof the coronary arteries. mental coronary atherosclerosis per se is not accompanied by the appearance of any major necrotic foci in the heart muscle, comparable to the features of clinical myocardial infarction. At the Institute of Therapy, we applied a new principle for the provocation of myocardial infarctions in experimental atherosclerosisxrg We reasoned that coronary atherosclerosis serves merely as the most important predisposing factor for the development of myocardial infarction. To reproduce the latter in the it is presence of coronary atherosclerosis, necessary to add, as a supplement, one of the main pathogenic mechanisms which form the causal basis of myocardial infarction: (a) functional overstrain of the heart muscle; (b) a supervening coronary spasm; (c) a supervening thrombosis. Evidently, there exist also other pathologic processes which can complicate atherosclerosis and can lezd to the development of a myocardial infarction, such as hemorrhage in a plaque and obstruction of a coronary lumen by atheromatous masses. However, in our opinfactors z re ion, the three above-mentioned particularly significant for the occurrence of myocardial infarction on the grounds of atherosclerosis. Their importance was clearly demonstrated by studies of Kipshidze and Chazov at the Institute of Therapy. Kipshidze’O showed th2.t it is possible to obtain extensive experimental myocardial necroses by first producing cholesterol atherosclerosis, followed by the imposition of physical stress. Chazov” elicited similar changes in experiments in which induction of relatively moderate atherosclerosis was combined with the injection of pituitrin, which causes a spasm of the coronary arteries, or with the administration of thrombin, which markedly increases the coagulability of the Recently we have investigated the role blood. of nervous influences in the origin of experimental coronarogenic necroses of the myocardium. * * I. K. Shkhvatsabaya12 and I. K. Shkhvatsabaya and terol

V. V. MenshikoG found that central nervous stimulation by air insufflation into the lateral brain ventricles is followed by a marked accumulation of catecholamines in the heart muscle, electrocardiographic signs of myocardial ischemia, and focal necroses in the subendocardium, sometimes even expanding transmurally. THE

AMERICAN

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Editorial For dqno.~tic distinction of the intrwtwdic~te t~je from angina pectoris on the one hand and from myocardial infarction on the other, \VCllse the following clinical criteria (Table 11) : (1) angina pectoris dccubitus (stenocardic attacks at night, especially in the early morning hours); (2) attacks of angina on effort \vhich persist for more than 10 to 15 minutes but less than 45 to 50 minutes, and which are refractor), to coronary dilator drugs, rest, and the like. (.4ttacks of shorter duration fit rather into the angina1 syndrome, and longer ones into the syndrome of arbimyocardial infarction ; but a certain trariness of such a differentiation is obvious); (3) electrocardiographic signs of coronary insufficiency (depression of the S-T segment and alterations of the T wave), if they remain for one to two days after an attack of pain and then disappear ; (4) a slight elevation of temperature several hours after the pain or during the following day: (5) a moderate neutrophile leucocytosis (10,000 to 12,000 for one to two days after the attack); (6) occasionally a slight elevation of transaminase activity in the blood during the first days after the painful attack. -4s mentioned before, the category of intermediary forms includes two stages or types of lesions: (a) foci of ischemic dystrophy, and (b) microfocal necroses. Their clinical differentiation is at present still extremely difficult. With some reservations, one may assume that only the first 3 of the enumerated criteria in the absence of the last 3 are to be attributed to the firstnamed clinical type. Presence of the second type is suggested by the coincidence of all six criteria, or at least by that of some criteria from both subgroups. Evaluation of the real significance of the pro-

\,Vith Clinictrlhlyocardinl Infarcts and .Vecroses: regard to the clinical coronarogenic necroses of the ulyocardium, we shall limit ourselves to a brief discussion of only one question of classificathat concerning the so-called tion, namely, intermediary form (between angina pectoris and lnyocardial infarction), as described by Lang,14 Vovsi,‘” Shestakov’” and many others. For some time we have endeavored to show that there exist all stages of transition between arteriosclerotic coronary insufficiency, manifested as angina pectoris on the one hand, and myocardial infarction on the other. Both occur on the basis of the same pathogenic mechanism. Morphologically, the intermediate forms are characterized by small focal necroses which are usually multiple, even though often concentrated within the supply territor) of an individual coronary arterv or its branches. By contrast, a myocardial infarct is characterized by a large area of necrosis, sometimes composed of a number of confluent foci. With this in mind, one can speak of microfocal necroses (or infarctions) and of macrofocal necroses (infarcts). There remains the question as to whether one may classify as intermediate forms those focal lesions found in the myocardium along with coronary insufficiency as a result of local ischemia, without having progressed to the stage of necrotization. The difficulty of differentiating between ischemic-dystrophic lesions and foci of ischemic necrosis is illustrated by the fact that frequently both types of lesions are found in the same heart, largely depending on the stage and duration of the process, in particular on the length of time during which the causative coronary insufficiency had prevailed.

TABLE II Differentiation

of Types of Coronary Clinical

Type Angina pectoris Focal dystrophy of myocardium Microfocal necroses (microfocal infarctions) Myocardial infarct (macrofocal)

APRIL 1964

Character Pain

of

Duration Pain

of

Insufficiency

ECG Changes

Up to 10 min.

None

15-45

min.

Same

15-45

min.

Depression S-T, T changes Same

SUS

angino-

1 hr. or more

Heart Disease)

Manifestations

On physical effo1t The same, also at rest

Status

(Ischemic

Typical changes

Fever

of

Leucocytosis

Enzyme Reactions

None

None

Normal

None

None

Normal

Slight, l-2 days after pain

Moderate, l-2 days after pain For several days For longer period

Slightly increased Markedly increased

Myasnikov posed differentiation is hampered by- two facts: (1) Coronary disturbances often take place at intervals and repetitively, blurring the criteria for estimation of the time of their occurrence and of their duration ; (2) acute coronary disturbances supervene frequently on the basis of old chronic coronary vascular lesions. This disturbs the interpretation, especially of electrocardiographic signs. The recognition of other etiologic types of coronarogenic necroses (Table I), apart from those caused by atherosclerosis, constitutes a most arduous clinical problem, partly due to the nonavailability of adequate methods for the detection of the early phases of coronary atherosclerosis. NONCORONAROGENICNECROSES Noncoronarogenic necroses of the heart muscle have been produced by various experimental procedures. Clinically, they have been investigated to a lesser extent. Anoxic Necroses: The first group of this category consists of myocardial necroses provoked by interferences in the composition of the blood gases. Necrotization of the heart muscle was observed under conditions of anoxemia17, carbon monoxide poisoning,18 and experimental exposure of animals to low atmospheric pressures.rg Clinical equivalents of these anoxemic myocardial necroses in man have not been studied extensively. They may be expected to occur in states of pulmonary insufficiency (pulmonary fibrosis or emphysema, severe bronchial asthma), and also under certain industrial occupational conditions. The factor of anoxemia is particularly important for mountain climbers and aviators. Anemic Necroses: A second group, related to the first one, concerns anemic necroses of the They are observed both under heart muscle. experimental and clinical conditions. Similarly as in the case of coronary atherosclerosis, necroses originate in the presence of anemia if additional supplementary circumstances, such Biichner’s experias physical stress, arise. ments2’J*21 in which necroses of the heart muscle developed in bled animals after running on a treadmill are well known. Clinical observations have also shown that anemia aggravates the tendency toward necrotic lesions in the atherosclerotic heart. Necroses Due to Mechanical Stress: A third group consists of small foci of necrosis in the myocardium which occur under excessive me-

chanical strain of the respective section of the heart. Such necrotic lesions are sometimes observed in the right ventricle after embolization of the pulmonary artery. They can be elicited experimentallyby introduction of glass beads into the right ventricle of animals to create an embolism of the pulmonary artery.2Z Clinical identification of such necroses in one or another section of the heart as being caused by mere overstrain remains questionable, but in conjunction with other factors, the role of this element in the origin of microfocal changes in the heart muscle appears to be a reality (e.g., in connection with severe acute physical overexertion of sportsmen). Necroses Due to Shock: The fourth group comprises necroses induced by shock, which occur under the conditions of vascular collapse. It is quite probable that the collapse which so frequently accompanies an acute infarction of the heart muscle may exert an unfavorable influence on the predamaged myocardium and cause additional necrotic foci which expand the area of the infarct. Essentially, all of these four groups of focal necroses are closely akin to the coronarogenic focal necroses through their common denominator, myocardial anoxia. Metabolic Necroses: The fifth group is composed of metabolic myocardial necroses deriving from nutritional abnormalities. In animal experiments such necroses could be elicited by diets deficient in proteinP or thiamine,24 or vitamin E.25ses On the other hand, rats consuming excessive amounts of fat developed necroses in the left ventricle of the heart even before the appearance of coronary atheroIt is assumed that these “fatty” sclerosisZ7 necroses result from a reduction of the fibrinolytic properties of the blood under the influence of animal fats. Myocardial necroses from lack of potassium in the food should also be mentioned here.28*2g Clinical necroses of the heart muscle are known to occur frequently in cases of nutritional dystrophy and also in vitamin B, deficiency. Hormonal Necroses: The sixth group is directly It concerns connected with the preceding one. hormonal necroses, caused by an excess of thyroxine in clinical cases of hyperthyroidism as well as in numerous experiments,28-30 and by desoxycorticosterone.31 ss2 The investigations of myocardial necroses Selye’ 3 who obtained through administration of steroid hormones, especially in combination with electrolytes THE

AMERICAN

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OF CARDIOLOGY

Editorial \“electrolyte-steroid-necroses”), are generally known. In his monograph Selye describes of these cardiac chemical prevention the necroscs by means of potassium and magnesium salts, sodium-poor diet, and the 1ike.l These observations are also related to the role of the catecholamines in the origin of cardiac nccroses.K:’ At this time, it is still difficult to evaluate the significance of the electrolyteand steroidinduced necroses for clinical practice, but we feel that the importance of this investigative approach, also for clinical medicine, cannot be denied. Finally, the seventh and Toxic Xecroses: eighth groups of noncoronarogenic necroses consist of toxic and infectious-allergic lesions. Cardiac necroses resulting from intoxication with digitalis have been described in the past.34 Furthermore, necroses have been produced by the administration of arsenic, chloroform, plasmocid and other chemical and pharmacologic The mechanism of their action on the agents. It may be conmyocardium is not yet clear. nected with disturbances of metabolism, especially in the domain of the enzymatic systems. Allergic-Infectious Necroses: The question of allergic necroses is of great clinical importance. Not infrequently, small necroses of the myocardium are observed in the post-infectious stage of influenza and tonsillitis, and also with rheumatic fever, collagen diseases and scarlet fever. The problem of necroses of infectious and infectious-allergic origin is closely related to that of the inflammatory reactions which take place in the heart muscle under these circumstances. In such cases, the necroses often appear to be only a secondary feature, resulting from the inflammatory processes. SUMMARY

In the past, necroses of the heart muscle were attributed merely to obstructive lesions of the coronary arteries. However, more recently it has become quite clear that various nonvascular noxious influences directly interfering in myocardial metabolism (such as anoxemic, hormonal and neurogenic) are of outstanding importance in the origin of myocardial necroses, either as This applies primary or as contributory factors. in particular to the multiple, microfocal type of necroses, frequently developing by coincidence with, or aggravation of, the pathogenic effects of primarily vascular disturbances. APRIL

1964

.\ clinical differentiation of the pathogenic mechanisms involved in the formation 01’ mvocardial infarcts or of multiple nccroses, rcspectively, although difficult, is feasible to some extent. REFERENCES 1. SI:.LYE. H. The Chemical Prevention of Myocardial Necroses. New York, 1958. Ronald Press Co. 2. KAAB, W. The adrenergic-cholinergic control of and function. .4dunllcP$ cardiac metabolism Card&., 1: 65, 1956. 3. RAAB, W. The nonvascular metabolic myocardial vulnerability factor in “coronary heart disease.” Am. Heart J., 66: 685, 1963. Moscow, 1920. 4. FOKH~, A. B. Patologiya syerdtsa. 5. USVATOVA,I. N. Unpublished. 6. VINOGRADOV,S. A. K metodike y sravneetel’noy otsenke razlitchnykh eksperimental’nykh mod&y infarkta miokarda u zhivotnykh. :Irk-hiopntol., 1 :

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Moscow, 1957. 15. Vovst, M. S. Klinika y patogenez ostroy koronarnoy nyedostatotchnosti (grudnoy zhaby), Trudy 14-go vsyesoyuznogo syezda terapevtov, p. 127. Moscow, 1958. 16. SHESTAKOV,S. V. 0 razlitchnom tetcheniy y klineecheskoy karteenyl infarkta miokarda y nyekotorykh yego formakh, Trudy 14x0 vsyesoyuznogo syezda terapevtov, p. 336. Moscow, 1958. 17. LUFT, U. C. Irreversible hypoxamische Organverlnderungen bei alten und jungen Tieren im Unterdruck. Beitr. path. Amt., 99: 351, 1937. 18. CHRIST, C. Experimentelle Kohlenoxydvergiftung, Herzmuskelnekrosen und Elektrokardiogramm. Beitr. path. Amt., 94: 111, 1934. 19. GRUNDMANN, E. Histologische Untersuchungen iiber die Wirkungen experimentellen Sauerstoffmangels auf das Katzenherz. BP&. path. Amt., 111: 36, 1950. 20. B~~CHNER,F. Relative Durchblutungsnot des Herzmuskels, Akute Koronarinsuffizienz. Deutsche

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cholesterol, thiouracil and sodium cholatc-. <,i,_culntiotr, 19: 65. 1959. SCIIRADER. G. A., PRICKETT, C. 0. and SALMON, W. D. Symptomatology and pathology of potassium and magnesium deficiencies in rats. .J. ,Vutrition. 14: 85, 1937. THOMAS, W. A., HAKTROPT, W. S. and O’NBAI.. R. M. Modifications of diets responsible for induction of coronary thrombosis and myocardial infarcts in rats. .J. h’utrition, 69: 325, 1959. FARRANT, R. Hyperthyroidism; its experimental production in animals. Brit. M. J.. 22: 1363, 1913. DARROW, D. C. and MILLER, H. C. The production of cardiac lesions by repeated injections of desoxycorticosterone acetate. J. C/in. Znotst.,21: 601, 1942. ZALKA, E. Herzmuskelverlnderungen bei experimentellem Hyperthyreoidismus. Beitr. path. Anat. 95: 590, 1935. SELYE, H. The Pluricausal Cardiopathies. Springfield, Ill., 1961. Charles C Thomas. RADNAI, P. and PILTER, A. Ueber die experimentelle Jodmyokarditis. Ztschr. f. d. grv. Pxper. Med., 85: 501, 1932.

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