THE PATHOGENESIS OF ANGINA
PECTORIS AND MYOCARDIAL
P. PRIORESCHI. Department of Physiology-Pharmacology, Street, Omaha, Nebraska 68178, U.S.A.
INFARCTION
Creighton University, School of Medicine, 2500 California
SUMMARY
A number of observations that have accumulated in the literature in the past several years cannot be explained by the classic pathogenetic hypothesis of angina pectoris and myocardial infarction. Experimental cardiac necroses of metabolic origin can be easily produced in the animal and if the classic pathogenetic hypothesis of angina pectoris and myocardial infarction is modified to include a metabolic factor, most of the unexplained observations become explainable.
INTRODUCTION
electrocardiographic abnormalities or abnormalities of myocardial lactate metabolism or both) associated with normal coronary angiograms have been described by several authors (7, 8, 9, 10, 11, 12). It is estimated that about 10% of all patients who have the clinical syndrome of angina pectoris are free of significant coronary artery disease (7: 10). To explain such cases, hypotheses have been advanced about the possibility of abnormal afhnity of hemoglobin for oxygen (“stingy” hemoglobin) or narrowing of small coronary arteries beyond the resolution of coronary arteriograms (13). However, it has been pointed out that patients with severe anoxemia (e.g. carbon monoxide poisoning) do not always exhibit angina and yet they must have myocardial anoxemia at least as severe as that conceivably occurring in the presence of “stingy” hemoglobin (13). The small coronary arteries disease (described in cases of “collagen” diseases, Marfan syndrome and some familial neuromyopathies) that would produce narrowing of the small vessels beyond the resolution of coronary angiogram has not been demonstrated in the cases under discussion (12). In addition, such a disease would have to be capable of spontaneous remission because Waxler et al (11) have reported that ten out of sixteen patients with chest pain, normal coronary arteriograms and ischemic S-T segment depression of more than 1.0 mm after exercise, had improvement or disappearance of their symptoms during a period of 6 months to 2.5 years. Abnormalities of lactate metabolism can be found in the absence of angina pectoris and cases of angina pectoris without abnormalities of lactate metabolism can also be found (14, 15). The presence of severe coronary artery disease at autopsy is not necessarily related to angina pectoris. Allison et al (16) have shown that in a series of 430 autopsies the majority of patients with severe coronary artery disease did not have a history of angina pectoris. Chest pain on effort is difficult to explain in cases of documented angina pectoris with normal coronary angiogram. In such cases ischemia could be produced by spasm of the coronary arteries, but ischemia itself is a very
When a scientific hypothesis becomes inadequate to explain a significantly large number of observations it must be modifled or replaced by a new one. The discarding of the old and the adoption of the new hypothesis are, however, hampered by the difficulty of establishing how large the number of unexplained observations should be and how precisely formulated the new theory must be. I suggest that there may be a sufficient number of unexplained observations to justify the modification of the classic pathogenetic hypothesis of angina pectoris and myocardial infarction. I will propose a modified hypothesis that may explain most of these observations.
ANGINA PECTORIS
It is usually assumed that angina pectoris is caused by absolute or relative ischemia of the myocardium due to inadequate blood flow through narrowed coronary arteries (coronary insufficiency) and that coronary atherosclerosis is the anatomical basis of the syndrome. The evidence rests on various observations, such as the S-T segment depression on the electrocardiogram indicating ischemia of the myocardium, abnormal coronary angiography, alterations of biochemical processes of the myocardium such as abnormal lactate metabolism, presence of severe coronary atherosclerosis at autopsy, and presence of chest pain related to effort. However, as underlined by Aronow (1) many observations are at variance with the ischemia hypothesis. He and his associates (2,3) have shown that a significant number (13%) of normal men developed at least 1.0 mm ischemic S-T segment depression after a maximal treadmill test and that a significant number (27%) of patients with angina pectoris due to documented coronary heart disease who developed angina pectoris after exercise (double Master’s test) did not have an ischemic S-T segment depression * 1.0 mm tier exercise. Other investigators have made similar observations (4, 5, 6). As afar as coronary angiography is concerned, many cases of angina pectoris (documented by 139
powerful coronary dilator (17, 18, 19) and, therefore, the reason why the spasm is not ~m~ately relieved is not apparent. If, on the other hand, we decide that such patients do not have angina pectoris, then we must explain the S-T depression and the abno~~ties of lactate metabolism observed in such cases (7, 8, 9, 10, 11, 12). All these observations seem to indicate that the hypothesis that coronary insufficiency produces angina pectoris cannot be applied to all cases. Although most of these observations are valid for only a minority of patients, any satisfactory pathogenetic hypothesis must take them into account. In the above-mentioned article (1) Aronow concludes: “Angina pectoris and coronary insu~cien~y are thus not interchangeable terms. Although it would appear that many patients with the the typical symptoms of angina pectoris on effort would probably show ischemic pattern after exercise and obstructive coronary artery disease on angiography, there is still a significant number of patients in whom such a correlation cannot be made”.
thrombosis is much lower in cases of subendocardial necroses than in cases of ~~srnur~ infarcts (21, 23) it is dimcult to understand why fibrinoiytic activity would be more effective in the former cases. Several authors (23, 24, 25, 26, 27) have suggested that, in many cases, the thrombosis may be the result and not the cause of the necrosis. Spain and Bradess, in two series of similar observations made at an interval of a decade (24, 28) and Popper and Feiks (29) have found that the incidence of thrombosis increases with the time of survival after the attack. These findings strongly support the possibility that thrombosis, at least in some cases, may be the result and not the cause of the infarct and they also tend to disprove the hypothesis of postmortem lysis of thrombi. At this point it may be argued that even if the acute occlusion of a coronary artery is not necessary for the production of the infarct, the acute ischemic origin of the lesion is strongly suggested by the association of severe coronary atherosclerosis with infarct and the fact that the acute attacks most often follow states of increased oxygen requirement by the myocardium. There are observations, however, that contradict this assumption. Richart and Benirschke (30) have described two autopsy reports of myocardial infarctions in infants of 15 hours and 7 days of age with normal coronary arteries and no occlusion. Because of the extremely high incidence of some degree of coronary atherosclerosis at autopsy among adults and in view of the fact that myocardial infarction is rare in children, myocardial infarction with completely normal coronary arteries is very rare. However, autopsy reports of cases of infarct with “slight degree of atherosclerosis” and no occlusion are not as rare (31) and numerous cases of myocardial infarction in patients with normal coronary angiograms have been reported (12, 32, 33, 34, 35, 36). In addition, Master et al (37), in a series of 890 patients with myocardial infarction, found that in 73% of the cases the attack took place during sleep, rest or mild activity where we have no reason to suppose that there was an increased oxygen requirement by the myocardium. In conclusion, occlusion of a coronary artery can indeed produce a cardiac infarct (as shown by the numerous reported cases of coronary embolism and documented acute occlusions due to other causes), coronary atherosclerosis is almost invariably associated with myocardial infarction and the acute attack may follow severe exertion. Nevertheless there is ample evidence that myocardial infarct can occur without occlusion of atherosclerotic coronaries, with normal coronaries, and in situations in which increased oxygen requirement by the myocardium does not seem to be a factor. Any general hypothesis of the pathogenesis of myocardial infarction must explain both sets of observations.
MYOCARDIAL INFARCTION According to the classic pathogenetic hypothesis, myocardial infection is produced by a sudden occlusion (usually thrombotic) of a coronary artery previously damaged by atherosclerosis. The usual association of coronary a~erosclerosis with infarct is an indubitable fact. The same, however, cannot be said about coronary thrombosis and infarction. In a previous paper (20) I have reviewed the incidence of coronary thrombosis in cases of myocardial infarction reported in the literature from 1925 to 1967. Out of a total of 4020 cases of infarction, 115 1 (28.6%~ were reported as not having coronary occlusion, thrombotic or otherwise. The incidence of occlusion reported by individu~ authors varies from 0 to 100% (21, 22). Roberts (21) suggests that a major cause for the variation of the reported incidence could be the inclusion of cases of subend~ardi~ infarction in which the frequency of occlusion is s~~c~dy lower than in cases of transmural infarct. He reports nine cases of subendocardial necroses with no coronary thrombus and 74 cases of transmural infarcts of which 40 (54%) had a thrombus in a coronary artery (21). Similar observations have been reported by others (23). It would appear that the majority of authors agrees that in a significant number of myocardial infarcts a coronary occlusion cannot be found at autopsy. If we consider that in the review of 4020 cases cited above (20) the 71.4% of cases with occlusion included old occlusions associated with recent infarcts, nonocclusive thrombosis or su~clusions, and recent occlusions associated with old infarcts, we can safely assume that in about 30% cases the infarct could not have been caused by a sudden occlusion of a coronary artery. The idea that thrombi could have caused the infarct and subsequently disappeared by postmortem lysis as a result of excessive production of fibr~olysins has not been proven. The observations that autopsies performed within 15 minutes of death failed to disclose evidence of partially lysed thrombi (24) does not support such a hypothesis. In addition, in view of the fact that the incidence of
DISCUSSION AND CONCLUSION It seems evident that the classical pathogenetic hypothesis of angina pectoris and acute myocardial infarction fails to explain all the observed facts. On the other hand the evidence is indisputable that &hernia and coronary atherosclerosis play an important role in the development of the syndromes. I believe that the 140
introduction into the picture of another pathogenetic factor may help the formulation of a better hypothesis. We know that cardiac necroses can be produced in the animal by the administration of various drugs (38, 39). In some of these experimental cardiopathies (e.g. the one produced by 9n-fluorocortisol and sodium salts) the necroses resemble myocardial infarction although the coronary arteries are always normal and free of occlusion (38). The exact pathogenesis of such cardiac necroses is obscure, but it would appear that no ischemia is involved and that the lesions result from some derangement in the metabolic machinery of the myocardial cell (40, 41). This work shows that experimental metabolic necroses of the myocardium can easily be produced in the animal. As alloxan diabetes is considered an experimental model of diabetes mellitus, I suggest that such necroses be considered as models of the myocardial infarctions occuring with normal coronary arteries and with no ischemic component. In other words, I suggest that such clinical infarcts are produced by a non-ischemic metabolic derangement of the myocardial cell. If at one end of the spectrum we have the clinical infarcts produced by a metabolic disorder of the myocardium, at the other end we have the clinical cases in which the lesion was undoubtedly caused by sudden occlusion of a coronary artery (e.g. embolism). The experimental model for such cases is the cardiac infarct produced in the animal by ligature of a coronary artery. Between these two ends of the spectrum the majority of clinical myocardial infarctions would be produced, according to this hypothesis, by a mixture of the two pathogenetic mechanisms in various proportions according to the individual case. For example, in the infarct of the heart with very severe coronary atherosclerosis and multiple old occlusions of the coronary arteries, the ischemic component would be prominent and the metabolic one secondary. The reverse would be true in the infarct of a heart with modest coronary atherosclerosis and no ccrcnary occlusion. It must be emphasised at this point that 3 similar pathogenetic mixture can be produced in the animal. It has been shown that if the coronary arteries of the animal are previously made arteriosclerotic by small doses of dihydrotachysterol, then cardiotoxic agents, given at doses practi~~ly ineffective in normal animals, produce particularly extensive necroses (42). In addition, in this situation the necroses are often associated with obstructive changes of the coronary arteries (42). These observations suggest that ischemia caused by atherosclerosis “predisposes” the heart to coronary myocardial infarction and facilitates the development of the necroses even if the metabolic factor is minor. If the metabolic factor is sufficiently prominent, however, necrosis would develop even in the absence of atherosclerosis. Absence of the metabolic factor would result in absence of myocardial necrosis in cases of severe atherosclerosis, even with slow progressive obstruction of some of the coronary arteries (a not infrequent autopsy finding). An acute occlusion of a coronary artery would, of course, produce myocardial infarction in any case. As far as angina pectoris is concerned, we may assume that the same two pathogenetic factors are responsible for the syndrome. At one end of the spectrum are the purely
ischemic cases with severe atherosclerosis and, at the other end, the metabolic ones with normal coronary arteries. In between are the cases represen~g the mixtur? of the two. To explain the observed facts we will have to assume that the S-T segment depression is the electrocardiographic expression of ischemia and/or of the metabolic factor. Such an assumption may not be unwarranted if we consider that digitalis (which does not produce ischemia) produces depression of the S-T segment and may produce cardiac necroses in the experimentorl animal (38). If this assumption is correct, the metabolic factor would be present in the “normal” individuals with S-T depression although not in such a degree as to produce other symptoms. The metabolic factor alone, if sufhciently prominent, could produce angina pectoris in patients with normal coronary arteries, but in its absence only very severe atherosclerosis would produce angina pectoris. The mixture of the two pathogenetic factors in various proportions in the individual cases could explain the often observed lack of correlation between severity of coronary atherosclerosis and severity of angina. A further necessary assumption is that anginal pain may be caused by ischemia and/or by the metallic factor. We know that a non-ischemic metabolic alteration can produce cardiac necrosis in the experimental animal and it is not inconceivable that chest pain could be caused during the development of the heart necrosis. We may even speculate that, as in the case of ischemia, the metabolic factor would produce cellular damage by producing cellular hypoxia. In this case the common final pathogenetic pathway of the two factors would easily explain how S-T segment depression, anginal pain and abnormalities of lactate metabolism (all considered symptoms of cellular hypoxia) can be found in cases without ischemic factor. In short, I suggest that angina pectoris and myocardial ~f~~tion represent, respectively, the less and the more serious clinical manifestations of the same syndrome and that such syndrome is caused by the association of a metabolic and an ischemic factor. Although in the majority of cases the two factors would both be present (in different proportions in the individual cases), there would be cases at both ends of the spectrum in which the contribution of one or the other would be negligible or absent. A graphic representa~o~ of this concept is illustrated in Fig. 1, in which a normal distribution curve was chosen for simplicity and clarity and not because I have any reason to believe that the distribution of cases would follow a normal curve. The nature of the metabolic factor is unknown. Even in the case of experimental cardiac necroses our knowledge of the cellular metabolic iterations leading to the lesion is sketchy (40, 43). All these experimental syndromes, no matter which cardiotoxic agent is used, can be prevented by increasing the intracellular potassium content of the myocardium (39, 44, 45) and in some a decrease of the cellular level of this electrolyte seems to. be a condition necessary, but not sufficient, for the pr~u~tion of the lesions (40, 45). It is of interest that a decreased potassium concentration has been found in human hearts in cases of sudden cardiac death and myocardial infarction (47), but the significance of these findings cannot be assessed at present. 141
MTl’ABOLIC
FACTOR
ISCHEMIC
FACTOR
Figure 1 Graphic representation of the proposed pathogenetic hypothesis of angina pectoris and myocardial infarction. The relative importance of the two factors is indicated by the width of the bars parallel to the abscissa. Explanation in the text.
In any case, I think that the metabolic-ischemic hypothesis explains more observations than the purely ischemic one. I realize that the metabolic factor is not defined, but I feel that there is enough indirect evidence to justify the assumption of its existence. If this hypothesis is valid, the problem of the prevention of myocardial infarction would have a second approach: the identification and correction of the metabolic factor. After half a century of failure in the first approach (prevention of atheroscierosis and ischemia) a second one m;qy be rewarding.
10.
Proudfit W L, Shifey E K, Sones F M. Selective tine coronary arteriography. Correlation with clinical findings in 1000 patients. Circulation 33, 901, ,I966. 11. Waxier E B. Kimbms D. Dreifus L S. The fate of women with normal coronary arteriograms and chest pain resembling angina pectoris. Am J Cardiol. 28, 25, 19’71. 12. Eliot R S, Bratt G. The paradox of myocardial ischemia and necrosis in young women with normal coronary arteriograms. Relation to abnormal hemoglobin-oxygen dissociation. Amer J Cardiol. 23, 663., 1969. 13. {~1;7I. Angma without coronary disease (sic). Circulation 42, 14. 15. 16.
REFERENCES
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Popper L, Feiks F, K. Heart infarct and coronary thrombosis. Wien Klin Wschr. 73. 421. 1961. Richart R, Benirschke K. Myocardial infarction in the perinatal period. J Pediat. 55, 706, 1959. Gross H, ,Sternberg W H. Myocardial infarction without sign&qnt lesions of coronary arteries. Arch, Intern Med. 64, 249,
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Glancy D L, Marcus M L, Epstein S E. Myocardial infarction in young women with normal coronary arteriograms. Circulation 44, 495, 1971. Likoff. W.: Myocardial infarction in subjects with normal coronary arteriograms. Amer J Cardio. 28, 742, 1971. Nizet P M, Robertson L. Normal coronary arteriogram following myocardial infarction in a 17-year old boy. Amer J Cardiol. 28: 715. 1971. Dear H D. Russell R Q. Jones W B, Reeves T J. Myocardial infarction in the absence of coronary occlusion. Amer J Cardiol. 28, 718. 1971. Sidd J J. Kemp H G, Gorlin R. Acute myocardial infarction in a nineteen-year old student in the absence of coronary obstructive disease. New Eng J Med. 282, 1306, 1970. Master A M, Dack S, Jaffe H L. Activities associated with the onset of acute coronary artery occlusion. Amer Heart J. 18,434, 1939.
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Selye H. The Pluricuusal Cardiopathies. Charles C. Thomas, Publisher. Sorinafield. Illinois, 1961. Prioreschi P. Eiperimental cardiac necroses and potassium. A review, Canad Med Assoc J. 96, 1221, 1967. Prioreschi P. Chlorides, potassium and experimental cardiac necroses. Circulation Res. 12, 55, 1963. Proireschi P. Experimental cardiac necroses. Biochem Clin. 1’ 149, 1963. Selye H. The humoral production of cardiac infarcts. Brit Med J. I. 599. -_--. 1968. _, ___, Prioreschi P. Heart phospholipids in the electrolyte-steroid cardiooathv. Brit J Pharmacol. 26: 723, 1966. Prioreschi P. Protection of the myocardium by potassium. Exper Med Surg. 22, 60, 1964. Prioreschi P, Sullivan R, Grinnell E. Potassium, cardiac necroses and amiloride. Eur J Pharmacol. 10, 319. 1970. Prioreschi P. The role of potassium in the pathogenesis of the ;leetr$;;-steriod cardiopathy with necrosis. Circulation Res. 10, Zug?lbe F T, Bell P,, Conley T, Standish M L. Determination of myocardial alterations at autopsy in the absence of gross and microscopic changes. Arch Path. 81, 409. 1966.
PECTORIS AND MYOCARDIAL
P. PRIORESCHI. Department of Physiology-Pharmacology, Street, Omaha, Nebraska 68178, U.S.A.
INFARCTION
Creighton University, School of Medicine, 2500 California
SUMMARY
A number of observations that have accumulated in the literature in the past several years cannot be explained by the classic pathogenetic hypothesis of angina pectoris and myocardial infarction. Experimental cardiac necroses of metabolic origin can be easily produced in the animal and if the classic pathogenetic hypothesis of angina pectoris and myocardial infarction is modified to include a metabolic factor, most of the unexplained observations become explainable.
INTRODUCTION
electrocardiographic abnormalities or abnormalities of myocardial lactate metabolism or both) associated with normal coronary angiograms have been described by several authors (7, 8, 9, 10, 11, 12). It is estimated that about 10% of all patients who have the clinical syndrome of angina pectoris are free of significant coronary artery disease (7: 10). To explain such cases, hypotheses have been advanced about the possibility of abnormal afhnity of hemoglobin for oxygen (“stingy” hemoglobin) or narrowing of small coronary arteries beyond the resolution of coronary arteriograms (13). However, it has been pointed out that patients with severe anoxemia (e.g. carbon monoxide poisoning) do not always exhibit angina and yet they must have myocardial anoxemia at least as severe as that conceivably occurring in the presence of “stingy” hemoglobin (13). The small coronary arteries disease (described in cases of “collagen” diseases, Marfan syndrome and some familial neuromyopathies) that would produce narrowing of the small vessels beyond the resolution of coronary angiogram has not been demonstrated in the cases under discussion (12). In addition, such a disease would have to be capable of spontaneous remission because Waxler et al (11) have reported that ten out of sixteen patients with chest pain, normal coronary arteriograms and ischemic S-T segment depression of more than 1.0 mm after exercise, had improvement or disappearance of their symptoms during a period of 6 months to 2.5 years. Abnormalities of lactate metabolism can be found in the absence of angina pectoris and cases of angina pectoris without abnormalities of lactate metabolism can also be found (14, 15). The presence of severe coronary artery disease at autopsy is not necessarily related to angina pectoris. Allison et al (16) have shown that in a series of 430 autopsies the majority of patients with severe coronary artery disease did not have a history of angina pectoris. Chest pain on effort is difficult to explain in cases of documented angina pectoris with normal coronary angiogram. In such cases ischemia could be produced by spasm of the coronary arteries, but ischemia itself is a very
When a scientific hypothesis becomes inadequate to explain a significantly large number of observations it must be modifled or replaced by a new one. The discarding of the old and the adoption of the new hypothesis are, however, hampered by the difficulty of establishing how large the number of unexplained observations should be and how precisely formulated the new theory must be. I suggest that there may be a sufficient number of unexplained observations to justify the modification of the classic pathogenetic hypothesis of angina pectoris and myocardial infarction. I will propose a modified hypothesis that may explain most of these observations.
ANGINA PECTORIS
It is usually assumed that angina pectoris is caused by absolute or relative ischemia of the myocardium due to inadequate blood flow through narrowed coronary arteries (coronary insufficiency) and that coronary atherosclerosis is the anatomical basis of the syndrome. The evidence rests on various observations, such as the S-T segment depression on the electrocardiogram indicating ischemia of the myocardium, abnormal coronary angiography, alterations of biochemical processes of the myocardium such as abnormal lactate metabolism, presence of severe coronary atherosclerosis at autopsy, and presence of chest pain related to effort. However, as underlined by Aronow (1) many observations are at variance with the ischemia hypothesis. He and his associates (2,3) have shown that a significant number (13%) of normal men developed at least 1.0 mm ischemic S-T segment depression after a maximal treadmill test and that a significant number (27%) of patients with angina pectoris due to documented coronary heart disease who developed angina pectoris after exercise (double Master’s test) did not have an ischemic S-T segment depression * 1.0 mm tier exercise. Other investigators have made similar observations (4, 5, 6). As afar as coronary angiography is concerned, many cases of angina pectoris (documented by 139
powerful coronary dilator (17, 18, 19) and, therefore, the reason why the spasm is not ~m~ately relieved is not apparent. If, on the other hand, we decide that such patients do not have angina pectoris, then we must explain the S-T depression and the abno~~ties of lactate metabolism observed in such cases (7, 8, 9, 10, 11, 12). All these observations seem to indicate that the hypothesis that coronary insufficiency produces angina pectoris cannot be applied to all cases. Although most of these observations are valid for only a minority of patients, any satisfactory pathogenetic hypothesis must take them into account. In the above-mentioned article (1) Aronow concludes: “Angina pectoris and coronary insu~cien~y are thus not interchangeable terms. Although it would appear that many patients with the the typical symptoms of angina pectoris on effort would probably show ischemic pattern after exercise and obstructive coronary artery disease on angiography, there is still a significant number of patients in whom such a correlation cannot be made”.
thrombosis is much lower in cases of subendocardial necroses than in cases of ~~srnur~ infarcts (21, 23) it is dimcult to understand why fibrinoiytic activity would be more effective in the former cases. Several authors (23, 24, 25, 26, 27) have suggested that, in many cases, the thrombosis may be the result and not the cause of the necrosis. Spain and Bradess, in two series of similar observations made at an interval of a decade (24, 28) and Popper and Feiks (29) have found that the incidence of thrombosis increases with the time of survival after the attack. These findings strongly support the possibility that thrombosis, at least in some cases, may be the result and not the cause of the infarct and they also tend to disprove the hypothesis of postmortem lysis of thrombi. At this point it may be argued that even if the acute occlusion of a coronary artery is not necessary for the production of the infarct, the acute ischemic origin of the lesion is strongly suggested by the association of severe coronary atherosclerosis with infarct and the fact that the acute attacks most often follow states of increased oxygen requirement by the myocardium. There are observations, however, that contradict this assumption. Richart and Benirschke (30) have described two autopsy reports of myocardial infarctions in infants of 15 hours and 7 days of age with normal coronary arteries and no occlusion. Because of the extremely high incidence of some degree of coronary atherosclerosis at autopsy among adults and in view of the fact that myocardial infarction is rare in children, myocardial infarction with completely normal coronary arteries is very rare. However, autopsy reports of cases of infarct with “slight degree of atherosclerosis” and no occlusion are not as rare (31) and numerous cases of myocardial infarction in patients with normal coronary angiograms have been reported (12, 32, 33, 34, 35, 36). In addition, Master et al (37), in a series of 890 patients with myocardial infarction, found that in 73% of the cases the attack took place during sleep, rest or mild activity where we have no reason to suppose that there was an increased oxygen requirement by the myocardium. In conclusion, occlusion of a coronary artery can indeed produce a cardiac infarct (as shown by the numerous reported cases of coronary embolism and documented acute occlusions due to other causes), coronary atherosclerosis is almost invariably associated with myocardial infarction and the acute attack may follow severe exertion. Nevertheless there is ample evidence that myocardial infarct can occur without occlusion of atherosclerotic coronaries, with normal coronaries, and in situations in which increased oxygen requirement by the myocardium does not seem to be a factor. Any general hypothesis of the pathogenesis of myocardial infarction must explain both sets of observations.
MYOCARDIAL INFARCTION According to the classic pathogenetic hypothesis, myocardial infection is produced by a sudden occlusion (usually thrombotic) of a coronary artery previously damaged by atherosclerosis. The usual association of coronary a~erosclerosis with infarct is an indubitable fact. The same, however, cannot be said about coronary thrombosis and infarction. In a previous paper (20) I have reviewed the incidence of coronary thrombosis in cases of myocardial infarction reported in the literature from 1925 to 1967. Out of a total of 4020 cases of infarction, 115 1 (28.6%~ were reported as not having coronary occlusion, thrombotic or otherwise. The incidence of occlusion reported by individu~ authors varies from 0 to 100% (21, 22). Roberts (21) suggests that a major cause for the variation of the reported incidence could be the inclusion of cases of subend~ardi~ infarction in which the frequency of occlusion is s~~c~dy lower than in cases of transmural infarct. He reports nine cases of subendocardial necroses with no coronary thrombus and 74 cases of transmural infarcts of which 40 (54%) had a thrombus in a coronary artery (21). Similar observations have been reported by others (23). It would appear that the majority of authors agrees that in a significant number of myocardial infarcts a coronary occlusion cannot be found at autopsy. If we consider that in the review of 4020 cases cited above (20) the 71.4% of cases with occlusion included old occlusions associated with recent infarcts, nonocclusive thrombosis or su~clusions, and recent occlusions associated with old infarcts, we can safely assume that in about 30% cases the infarct could not have been caused by a sudden occlusion of a coronary artery. The idea that thrombi could have caused the infarct and subsequently disappeared by postmortem lysis as a result of excessive production of fibr~olysins has not been proven. The observations that autopsies performed within 15 minutes of death failed to disclose evidence of partially lysed thrombi (24) does not support such a hypothesis. In addition, in view of the fact that the incidence of
DISCUSSION AND CONCLUSION It seems evident that the classical pathogenetic hypothesis of angina pectoris and acute myocardial infarction fails to explain all the observed facts. On the other hand the evidence is indisputable that &hernia and coronary atherosclerosis play an important role in the development of the syndromes. I believe that the 140
introduction into the picture of another pathogenetic factor may help the formulation of a better hypothesis. We know that cardiac necroses can be produced in the animal by the administration of various drugs (38, 39). In some of these experimental cardiopathies (e.g. the one produced by 9n-fluorocortisol and sodium salts) the necroses resemble myocardial infarction although the coronary arteries are always normal and free of occlusion (38). The exact pathogenesis of such cardiac necroses is obscure, but it would appear that no ischemia is involved and that the lesions result from some derangement in the metabolic machinery of the myocardial cell (40, 41). This work shows that experimental metabolic necroses of the myocardium can easily be produced in the animal. As alloxan diabetes is considered an experimental model of diabetes mellitus, I suggest that such necroses be considered as models of the myocardial infarctions occuring with normal coronary arteries and with no ischemic component. In other words, I suggest that such clinical infarcts are produced by a non-ischemic metabolic derangement of the myocardial cell. If at one end of the spectrum we have the clinical infarcts produced by a metabolic disorder of the myocardium, at the other end we have the clinical cases in which the lesion was undoubtedly caused by sudden occlusion of a coronary artery (e.g. embolism). The experimental model for such cases is the cardiac infarct produced in the animal by ligature of a coronary artery. Between these two ends of the spectrum the majority of clinical myocardial infarctions would be produced, according to this hypothesis, by a mixture of the two pathogenetic mechanisms in various proportions according to the individual case. For example, in the infarct of the heart with very severe coronary atherosclerosis and multiple old occlusions of the coronary arteries, the ischemic component would be prominent and the metabolic one secondary. The reverse would be true in the infarct of a heart with modest coronary atherosclerosis and no ccrcnary occlusion. It must be emphasised at this point that 3 similar pathogenetic mixture can be produced in the animal. It has been shown that if the coronary arteries of the animal are previously made arteriosclerotic by small doses of dihydrotachysterol, then cardiotoxic agents, given at doses practi~~ly ineffective in normal animals, produce particularly extensive necroses (42). In addition, in this situation the necroses are often associated with obstructive changes of the coronary arteries (42). These observations suggest that ischemia caused by atherosclerosis “predisposes” the heart to coronary myocardial infarction and facilitates the development of the necroses even if the metabolic factor is minor. If the metabolic factor is sufficiently prominent, however, necrosis would develop even in the absence of atherosclerosis. Absence of the metabolic factor would result in absence of myocardial necrosis in cases of severe atherosclerosis, even with slow progressive obstruction of some of the coronary arteries (a not infrequent autopsy finding). An acute occlusion of a coronary artery would, of course, produce myocardial infarction in any case. As far as angina pectoris is concerned, we may assume that the same two pathogenetic factors are responsible for the syndrome. At one end of the spectrum are the purely
ischemic cases with severe atherosclerosis and, at the other end, the metabolic ones with normal coronary arteries. In between are the cases represen~g the mixtur? of the two. To explain the observed facts we will have to assume that the S-T segment depression is the electrocardiographic expression of ischemia and/or of the metabolic factor. Such an assumption may not be unwarranted if we consider that digitalis (which does not produce ischemia) produces depression of the S-T segment and may produce cardiac necroses in the experimentorl animal (38). If this assumption is correct, the metabolic factor would be present in the “normal” individuals with S-T depression although not in such a degree as to produce other symptoms. The metabolic factor alone, if sufhciently prominent, could produce angina pectoris in patients with normal coronary arteries, but in its absence only very severe atherosclerosis would produce angina pectoris. The mixture of the two pathogenetic factors in various proportions in the individual cases could explain the often observed lack of correlation between severity of coronary atherosclerosis and severity of angina. A further necessary assumption is that anginal pain may be caused by ischemia and/or by the metallic factor. We know that a non-ischemic metabolic alteration can produce cardiac necrosis in the experimental animal and it is not inconceivable that chest pain could be caused during the development of the heart necrosis. We may even speculate that, as in the case of ischemia, the metabolic factor would produce cellular damage by producing cellular hypoxia. In this case the common final pathogenetic pathway of the two factors would easily explain how S-T segment depression, anginal pain and abnormalities of lactate metabolism (all considered symptoms of cellular hypoxia) can be found in cases without ischemic factor. In short, I suggest that angina pectoris and myocardial ~f~~tion represent, respectively, the less and the more serious clinical manifestations of the same syndrome and that such syndrome is caused by the association of a metabolic and an ischemic factor. Although in the majority of cases the two factors would both be present (in different proportions in the individual cases), there would be cases at both ends of the spectrum in which the contribution of one or the other would be negligible or absent. A graphic representa~o~ of this concept is illustrated in Fig. 1, in which a normal distribution curve was chosen for simplicity and clarity and not because I have any reason to believe that the distribution of cases would follow a normal curve. The nature of the metabolic factor is unknown. Even in the case of experimental cardiac necroses our knowledge of the cellular metabolic iterations leading to the lesion is sketchy (40, 43). All these experimental syndromes, no matter which cardiotoxic agent is used, can be prevented by increasing the intracellular potassium content of the myocardium (39, 44, 45) and in some a decrease of the cellular level of this electrolyte seems to. be a condition necessary, but not sufficient, for the pr~u~tion of the lesions (40, 45). It is of interest that a decreased potassium concentration has been found in human hearts in cases of sudden cardiac death and myocardial infarction (47), but the significance of these findings cannot be assessed at present. 141
MTl’ABOLIC
FACTOR
ISCHEMIC
FACTOR
Figure 1 Graphic representation of the proposed pathogenetic hypothesis of angina pectoris and myocardial infarction. The relative importance of the two factors is indicated by the width of the bars parallel to the abscissa. Explanation in the text.
In any case, I think that the metabolic-ischemic hypothesis explains more observations than the purely ischemic one. I realize that the metabolic factor is not defined, but I feel that there is enough indirect evidence to justify the assumption of its existence. If this hypothesis is valid, the problem of the prevention of myocardial infarction would have a second approach: the identification and correction of the metabolic factor. After half a century of failure in the first approach (prevention of atheroscierosis and ischemia) a second one m;qy be rewarding.
10.
Proudfit W L, Shifey E K, Sones F M. Selective tine coronary arteriography. Correlation with clinical findings in 1000 patients. Circulation 33, 901, ,I966. 11. Waxier E B. Kimbms D. Dreifus L S. The fate of women with normal coronary arteriograms and chest pain resembling angina pectoris. Am J Cardiol. 28, 25, 19’71. 12. Eliot R S, Bratt G. The paradox of myocardial ischemia and necrosis in young women with normal coronary arteriograms. Relation to abnormal hemoglobin-oxygen dissociation. Amer J Cardiol. 23, 663., 1969. 13. {~1;7I. Angma without coronary disease (sic). Circulation 42, 14. 15. 16.
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