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The significance of prolonged anginal pain (preinfarction angina)
Clinic al communications
The significance of prolonged angina1 pain William H. Resnik, Stamford, Conn.
angina)
M.D.
P
rolonged and severe attacks of angina1 pain may occur under three circumstances. In some patients, the ischemic myocardium may have imposed on it a greater than usual load, as by strenuous exertion or severe emotional stress, a hypoglycemic attack, or a sudden elevation of rate or blood pressure as in paroxysmal tachycardia or paroxysmal hypertension. In a second group, the prolonged angina is caused by conditions that are associated with a severe diminution of coronary flow. Examples of such conditions are shock caused by loss of extracellular fluid (hemorrhage, dehydration), massive pulmonary embolism, prolonged and intense tachycardia. In both of these categories, removal of the cause of either the increased metabolic demand or of the diminished coronary flow may restore the myocardium to its previous state, or, if the ischemia has been sufficiently prolonged and intense, result in the development of a mass of necrotic myocardial tissue. There is a third and far more common form of prolonged angina1 pain that occurs spontaneously, unassociated with a demonstrable cause for increased load or decline in coronary flow. This type is caused by atherosclerotic narrowing of a coronaq artery, usually enhanced either by the deposition of thrombus on a roughened intimal lining or by subintimal hemorrhage, or both. It is to this spontaneous11 From
(preinfarction
the Department oi Internal Medicine, ford Hospital, Stamford. Corm. Received for publication July 21, lWi1.
Yale
occurring form of prolonged angina1 pain that this discussion will be limited. If a patient has an attack of angina1 pain which lasts 10 to 15 minutes or longer, and particularly if there has been no obvious provoking cause, it is necessary to determine whether acute myocardial infarction or merely prolonged angina1 pain without myocardial necrosis has occurred. The graver forms of myocardial infarction usually present such characteristic features shortly after the onset of the attack that they do not enter into the problem under discussion. It is the milder forms of myocardial infarction that need to be differentiated from the type of ischemic heart disease that, by definition, is characterized by prolonged angina1 pain without evidence of myocardial necrosis. This latter condition has been designated by a number of terms: acute coronary insufficiency, preinfarction angina, impending infarction, the intermediate state, status anginosus. Although no designation thus far proposed is free of objections, the term preinfarction angina will be employed throughout this discussion. lJnti1 recently, the diagnosis of preinfarction angina and the separation from acute myocardial infarction were based primarily on failure of new and significant Q waves to develop, and on the absence of such signs of tissue necrosis as fever, leukocytosis, and elevated sedimentation rate. llniversity
School
of Medicine,
New
Haven,
Corm.,
and
the
Stan-
Signijcancc
Nevertheless, differentiation was often difficult, for even when infarction was present, pathognomonic electrocardiographic findings were often absent or obscured by previous abnormalities, such as left bundle branch block or those brought on by former infarctions. The introduction of the serum transaminase test has provided us with a method of detecting tissue necrosis which is far more accurate and sensitive than any the test previously available. I>2 Although is not specific for ml-ocardial necrosis, those conditions that are most likely to be confused clinically with acute myocardial infarction are either unassociated with a significant elevation in serum transaminase activit\r or are accompanied by other features that should lead to the correct diagnosis.“a Generally, in the presence of an acute chest pain consistent with that of myocardial ischemia, and in the absence of features that strongly point to some other diagnosis, the problem is primarily one of differentiating between preinfarctlon angina and acute myocardial infarction. For this purpose, serial determinations of the serum transaminase activity may usually be regarded as our single most reliable index of myocardial necrosis. Clinical
studies
The following discussion concerns observations made on serum glutamic oxaloacetic transaminase (SGOT) activity in patients who were considered to have preinfarction angina. It is commonly accepted that with this test a level of 40 represents the upper limit of normal, and that a peak level is attained within 24 to 48 hours after the onset of the chest pain. Hence, when a patient has experienced one or several closely recurrent bouts of chest pain, it is common practice to check the level of serum transaminase activity for 2 to 3 days. If the level has not risen above 40, and if there are no other unequivocal signs of infarction, the conclusion is usually drawn that the attack falls into the category of preinfarction angina. Over a period of 5 months, 31 patients presented the classic features of preinfarction angina: prolonged angina1 pain, often recurrent, sometimes associated with the of effort angina or with a appearance
oj prolongtd
anghial
pain
201
marked intensification of angina if previously present. Electrocardiograms taken serially revealed no new Q waves, although transient S-T-segment and T-wave abnormalities were occasionally observed. Serial transaminase tests failed to show figures above 40 during the first 3 days after the patients were hospitalized, and during this time there were no other signs of tissue necrosis, such as fever, leukoc\.tosis, or elevated sedimentation rate. L& normal transaminase levels, however, were observed frequently from the fourth day on, and, occasionally, a very brief and mild fever or leukocytosis or increased rate of sedimentation were also witnessed. Since reliance was placed principally on the transaminase test to provide evidence in regard to myocardial necrosis, daily leukocyte counts and determinations of the rate of erythrocyte sedimentation were not made, and details in regard to these tests are omitted. Because the primary purpose of these observations was to determine the frequency with which the SGOT level became abnormal after the third day, 4 patients who had a slight elevation of the transaminase level during the first 3 days after the last attack of pain were not included in this series. All patients were hospitalized for observation and management as soon as the diagnosis was suspected. The)- were placed on heparin therapy immediately, and dosages were adjusted to give a clotting time of 40 to 60 minutes just before the next injection of heparin. Almost invariably, ;uginal pain subsided within 24 to 36 hours after anticoagulant therapy was illstituted, and the patients were then encouraged to walk several times a day at a slow pace in the hospital corridors. Transaminase tests” were made each day for 7 to 10 days or more after the patients were hospitalized (see Table I ). Table I. SGOT cl~inical picture Patients
with
levels
ltwls in 31 patieds preinfarction angina
with
qf
over
40 units
Patients with levels above 28 units and with maximal variation of 10 u11its or more
23
74:;
29
9.1’,,’
292
ICesnik
much significance as a maximal level of 43 in denoting the presence of myocardial necrosis (Table 111). When the criterion of :I maximal level over 28 units, combined with a maximal variation greater thall 10 units, was employed, 29 patients (93 per cent) displayed abnormal results indicative of myocardial necrosis. No special significance is attached to the exact. percentages in which abnormal SGOT levels were witnessed. The total number of patients is rather small. The validity of the criterion of SGOT levels greater than 28 and a maximal variation greater than 10 needs to be established by more extended studies. Technical errors may conceivably h,ave accounted for some of the elevations barely above 40 units. Finally, by exclusion of patients who exhibited an elevated transaminase level during the first 3 days, picture some were omitted whose clinical was otherwise practically identical with that of those who were included in this series. \$Then the SGOT peak has been attained, it is usual for the transaminase level to fall sharply within the course of a fen- days and
Fig. f. Patient P.S. Daily trausaminase tests after an attack of preinfarction angina. The lirst abnormal figure, 42, occurred on the fifth day.
Of the 31 patients, 23 (73 per cent) first displayed an SGOT level over 40 units on the fourth to tenth days after the onset of pain or of the last bout of pain (Figs. 1 and 2; Table II). The peak transaminase levels ranged between 41 and 94; most of them were between 41 and 60. Although 40 units has been generalllr accepted as the upper limit of normal SGOT activity, there are studies which indicate that this figure is too high and that a more accurate figure is in the vicinit! of 28.5-7 Moreover, there is additional evidence that in normal individuals the maximal variation between the lowest and highest figures obtained over a period of da).s does not exceed 10 units.je7 This implies that the extent of variation in a series of daily transaminase tests as we11 as the absolute level of transaminase activity must be considered. For example, levels of 13 and 38 in the same patient may have as
Fig. 2. Patient :I.J. Daily transaminase tests ;tfter au attack of preinfarctiorx angina. The first almorm:~l ligure, 60. occurred on the seventh da!-.
Discussion
to remain at low levels thereafter. If another rise in SGOT activity occurs, new ittfarction is suspected. Such secondat-? rises were observed frequently itt this group of patients (Figs. 3 and 4). In no instance was there a corresponding appearance of ischemic pain or of any other clinical or electrocardiographic evidence to indicate a new cardiac injury. Z’ablc I I. Tmnsanzinase
A.Je. ‘I‘.J. A.K. A.Jn. J.F. hl .\Vll P.S. E.S. h1.S. H.B. \V.M. h1.N. ‘I‘.\V. N.7‘. T.L. G.F. T.P. L.bT.
rw. B.T. S.K. ED. F.R.
~--
~ -~ -
14 38
27 19 11 6 13 12
13 13 36
16 24 21 18 -_~ 33 -.-~ 12 24 19 15 27 22
21
11 19 25 17 13 17 18 21 21 19 18
27 18
levels in 23 patients
27
9 12 19 13 17 19 18 20 13 15
20 26 19
30 13 30 14 53 38 19 16 19 13 24 20 2.5 41
25
37
34
li 24 28 20 11
21 19 27 18 19
24
28
19 17
21 36
28 13 35 42 36 31 24 44
11
10
24 20 6 9 12
13 13 17 26
36
*Patients in whom the first abnormal Figures over 40 are set in boldiace
7bbla
YE.\\‘. LV. Hm. \V.B.S. I\.E. \V.Hn. L.L.
*Patients levels
II I. l‘ran~aminase
-~ 20 31 -.~-. 14
27 15 27 24 16 13
20 12 15 20 21 l-1
SGOT type.
22 33 34 17 17 94 42 33 26 20
34 31 42 41 25 54 34 32 51 48 38 51 46 level
60 39 35 15 19 82 56 45 41 28 28 38 67 18 44 44 48 44 32 41 47 18 54 (above
The results described above compel a revision of the generally accepted views in regard to the use of. the transaminase test in the diagnosis of acute tnyocardial infarction and a reconsideration of preinfarction angina. It is clear that a peak transantinase level does not ttecessarilv occur during the first 24 to 48 hours after the ouwith
48 46 20 28 11 54 67 37 53 33 45 45 60 17
34 45 51
34
36
32 54 48 19 17 58 19 12
17 21
preinfarction
40 53 41 42 35
11 19 31
32 16 21
48
40
17
3.l
16 43 41 45
11 29 3-i
32
38 39
30
32 32 17 17 22
13 19 20 47 18
24 28 2-l 15
45 19 46 28
38
40) appeared
angina*
18
1.5
20
19
19
21
29
-
-
34
--
51 -
15 41 45
19 16 26
15
19
13
30
36
20
23
26 28
19 -
-
21
17
19
22 .?O -
17 21
on the fourth
day or later
after
the last attack
ol angina1
pain.
levels in 6 patients*
33 17 15 15 17 28
17 19 9 15 15 3-l
11 19 19 20 37
13 38 1.5 19 22 16
13 36 23 26 29 19
26 2.5 31 13
15 29
31 25
12
in wllom the peak SGOT level exceeded 28 units and the maximal xxuiation were between 31 and 3X units. and the maximum variation was between
15
18
15
was greater than 16 and 26 units.
12
10 units.
Actually.
the peak
294
Am. firart J. March, 1962
liesnik
Fig. 3. Patient N.T. Daily angina. The first abnormal to 17, there was a secondary
transaminnse tests after an attack figure, 41, occurred on the fourth rise to 51 on the eighth day.
set of the attack. In this series, in about 75 per cent of the patients who were ordinarily classified as having sustained an attack of preinfarction angina, a transaminase level of over 40 units was first observed on the fourth to tenth days after the attack. If the criterion of a level above 28 combined with a maximal variation greater than 10 units is employed, over 90 per cent of such patients showed evidence of myocardial necrosis. Thus, a high percentage of all patients presumed to have had attacks of preinfarction angina have actually sustained areas of myocardial necrosis sufficiently large to give rise to abnormal levels of transaminase activitv. Such an inference is based on the premise that an abnormal transaminase level denotes cellular death. There are observations, however, that demonstrate that ischemia of certain degrees of intensity may injure the cell sufficiently to liberate transaminase without necessarily leading to immediate death. Whether such damaged cells can remain viable and be re-
of preinfarction day. After a fall
stored to normal function is not known. Since none of the patients of this series died, it is impossible to know whether abnormal transaminase figures were an expression of cellular death or whether cellular damage without death existed. Consethroughout this discussion, the quently, use of the term necrosis in cases of preinfarction angina is made with the understanding that it may mean histologic cellular necrosis or severe cellular damage short of being lethal to the involved rnyocardial mass. Similar observations in regard to increased transaminase levels in preinfarction angina have been described previously.’ Nydick8 reported SGOT elevations in about 30 per cent of a group of 50 patients, and about 50 per cent of the abnormal figures occurred after the third day. Employing the criterion of SGOT levels greater than 28 and maximal variations over 10 units ill the same person to constitute evidence of myocardial necrosis, Goble and O’Brien6
Signijicance
observed abnormal transaminase levels in 50 to 87 per cent of patients who otherwise exhibited all the features of L‘acute coronary insufficiency.” But even before the transaminase test had been introduced, evidence less decisive but nevertheless highly suggestive had led to the statement: “The distinction between the two conditions (myocardial infarction and preinfarction angina) is somewhat artificial, because careful study indicates that manq patients with typical preinfarction angina reveal clear evidence of necrosis (transient leucocytosis, minimal fever, elevation of the sedimentation rate), even though other manifestations of infarction are absent. In such instances one is presumably dealing with a small area of necrosis surrounded by a large zone of ischeniia.“3’1 The present observations with the transaminase test used as a sign of myocardial necrosis full>* confirm this view. What is the significance of these observations which indicate the presence of myocardial necrosis or damage bordering on necrosis in a high percentage of all patients with preinfarction angina? Careful subsequent study of these patients has failed
of prolongd
angina1 pain
205
to reveal any detectable diminution of cardiac reserve as manifested by their capacity to perform work loads similar to those undertaken prior to the attack. This is not altogether surprising since the slight elevation of the peak transaminase levels signilies that only a small mass of myocardium has been destroyed or injured. Nevertheless, the destruction of so small and clinically insignificant a segment of m)-ocardial tissue should not be construed as evidence that the patient has merely sustained a disagreeable, but fortunately benign, episode of pain. The fact that in many patients with preinfarction angina a small area of myocardial necrosis may occur means that the anatomic lesion responsible for the obstruction has probably already reduced coronary flow to the involved area to a critical level. Since by Poiseuille’s law, flow through a tube at a given pressure is proportional to the fourth power of the diameter of the tube, a further and onlv very slight narrowing of an already criticall) narrowed blood vessel, as by the deposition of a small amount of additional thrombus, could bring about so serious a reduction in blood flow as to cause frank infarction.
Fig. 4. Patient M.W. Daily transaminase tests after an attack of preinfarction angina. The first abnormal figure, 94, occurred on the fifth day. After a fall to 17 on the ninth day, a secondary rise to 51 occurred on the sixteenth day.
296
l&n
ik
Obviously, such a diminution in coronaq flow could take place either in the coronaq artery primarily responsible for blood flow to the affected tnyocardium or in a coronary vessel supplying important collaterals to this area. In this series, the ischemia responsible for the attack of preinfarction angina resulted in a delayed rise, with peak levels lower than those usually witnessed in frank infarction, and the occasional occurrence of the secondary rise in SGOT. Why should the transaminase peak appear as late as 5 to 10 days after the attack of preinfarction angina when it appears almost invariably within 24 to 72 hours after frank infarction? One explanation could be that no transaminase elevation resulted from the ischemia responsible for the preinfarctional pain, but that, after a variable number of days, a painless exacerbation of the ischemia caused the delayed increase in transaminase. A painless intensification of the ischemia occurring in each of the patients with a delayed rise seems to be a gratuitous assumption, particularly since there were no other clinical phenomena to indicate a worsening of the patient’s cottdition. A more probable explanation for the delayed rise would be that the intensit). of the ischemia in preinfarction angina was sufficient to cause severe damage in a small mass of myocardium, but insufficient to cause protnpt cellular death. Only after a number of days did cellular disintegration reach that level which is associated with the liberation of transaminase. Essentially the same explanation may be invoked to account for the secondary rise in transaminase. During the attack of preinfarction angina the involved myocardiutn is comprised of confluent areas which are variously affected by the ischemia, depending primarily on variations in the richness of collateral blood flow. The foci of necrosis must be small to account for the low peak of transatninase levels. Moreover, more than one focus of necrosis may be present in the same mass of ischemic myocardium. Thus, one small area may have been subjected to an intensity of ischemin sufficient to cause cellular death and disorganization responsible for a peak of 41 on the fourth da\-. Another slightly larger area may have been destroyed but b\. a
somewhat less intense ischemia, so that cellular disorganization with liberation of transaminase to a level of 51 does not take place until the eighth day (Fig. 3). The rest of the ischemic m~~ocardium retnains viable, although some portions of it must have barely escaped necrosis. These interpretations of the behavior of the transaminase test after an attack of preinfarction angina are supported by histologic studies that show within the same ischemic myocardium all stages of death and healing, from earliest- necrosis to early fibrosis . .8-l:! It seems clear that the basic difference in the behavior of the transaminase after frank infarction and that after preinfarction angina is simply one of intensity of ischemia. In the former, the severit?. of the ischetnia is such as to cause immediate and fait-l>- uniform necrosis of a macroscopic tnass of myocardium, \vith prompt liberation of transaminase. In the latter, the ischetnia suffices only to cause variable degrees of cellular injury. Only small a~td possibly microscopic patches of necrosis appear, cellular death and disorganization proceeding more slowI>. and at different rates. The potentially serious nature of an attack of preinfarction angina rests on more than theoretical considerations. Although there are some writers who regard anticoagulant therapy as either unttecessary or a matter of little urgency, there are others whose reports indicate that 25 to 93 per cent of patients with preinfarctiott allgina develop frank and serious infarction within 4 to 12 weeks after t-he onset of the attack if anticoagulant therapy is not used. On the other hand, frank infarction is reduced to 3 to 10 per cent during the same period of time if anticoagulants are given for at least 6 weeks.13-t5 All of the patients in the present series were given anticoagulants for 5 or more months after the attack. In only one did frank infarction develop during this time. Although the value of anticoagulant therapy, as judged by the above figures, appears to be convincing, one must bear in mind the possibility that it ma>- actually be less effective than it seems to be. .\nticoagulant therapy m~11d h:tve value onI!. if ;I thrombus were respottsible for the es-
Signijicuncc~ qf prolonged angiml
acerbation of myocardial ischemia. However, the latter may also be caused by progressive atherosclerotic narrowing, with or without subintimal hemorrhage, but without formation of thrombi. Consequently, in an undetermined but small percentage of patients in this and other series reported upon in the literature, anticoagulant therapy could have played no significant role in preventing frank infarction. Moreover, there is abundant evidence that patients suffering from myocardial ischemia are not immune to the placebo influence of otherwise ineffective forms of therapy. I6 It is possible, therefore, that management of the patient, including anticoagulant therapy, may have done nothing more than reassure an anxious patient. The resultant diminution in heart rate and in the endogenous formation of excessive quantities of catecholamines” could conceivably reduce myocardial oxygen requirement enough to prevent frank infarction. This possibility could be answered only by a well-controlled double-blind study. Despite these considerations and until there is unequivocal evidence that anticoagulant therapy is ineffective, the management of the patient with preinfarction angina should be based on an appreciation of the fact that blood flow to the affected nlvocardium has already been reduced to a critical level. ,Ylthough one can never be certain that thrombotic occlusion is present, this type of lesion is present in so high a percentage of patients that one is justified in administering anticoagulant therap\ promptly and continuing it for 6 weeks or longer. Ph\-sic-al activity should be sharplyrestricted for at least 2 to 3 weeks. The purpose of this regimen is to reduce the metabolic needs of the heart, to prevent further narrowing of the coronary lumen b>, formation of thrombi, and to afford time for the development of collaterals sufficient to increase blood flow to the affected area above its presently precarious level. It is evident that there should be no sharp distinction betweet) preinfarction angina and frank infarction. All ischemic heart disease should be considered to be a continuous spectrum of increasing severit!, of ischeinia, ranging from the mildest ai)gina of effort without necrosis to the most
pain
207
massive infarction. In a high percentage of patients with preinfarction angina, evidences of necrosis can be detected, and the more severe forms of preinfarction angina merge insensibl>r with the milder forms of frank infarction. Regardless of the terminology one prefers-preinfarction angina, coronary insuficienc)-, impending infarction, status anginosus, or the intermediate state-it is important to recognize that necrosis has already occurred in mang., and that far more serious infarction is likely to develop if appropriate therapy is not instituted promptl>.. Summary
and
conclusion
Necrosis of the myocardium takes place in a high percentage of all persons who have spontaneous attacks of preinfarction angina. Abnormal transaminase levels ma? first appear on the fourth to tenth days after the attack, and not during the first 2 days as is now generally considered to be the case. =\ secondary rise in transaminase may not be the result of a ne\v occlusion or the propagation of the original thrombus. It may be caused only by the slow and uneven death and tlisorganizatioli of small areas of myocardiunl subsequent to the original attack of ischemia. The importance of spontaneous preinfarction angina conies from the fact that diminution in blood flow to an area of the myocardium has alread!. reached a critical and dangerously loa level, and appropriate measures, pi-imarilv anticoagulant therapy and restriction 01 activity, should be instituted promptly. to prevent, so far as possible, the development of a larger and niore serious frank iiifarction. 1. ;Igress. C. M.: Evaluation of transaminase test, Am. J. Cnrdiol. 3:71, 1959. 2. Hamolsky, hl. IV., and Kaplan, N. 0.: Measurements of enzymes in the diagnosis of acute III!-ocardial infarction, Circulation 23:102, 1961. AI. Iiesnik, \\:. H., and Harrison, T. Ii.: In Harrison, ‘1‘. I<., editor: Principles of internal medicine, ed. 3, New York, 1958. iLlcGra\v-Hill Book Compall~. p. -I-.?. 3b. Ibid., p. 1264. 4. Keitman, S., and Frankel, S.: .\ calorimetric method for the detcrminatio~~ of serum glutanlic osalacetic. and glutatnlc pyruvic tr;L11silfillli;lSe~, .\m. J, Clin. Path. 2856, 1957. 5. I)ewar, II. .A., 12o~vell, N. I<., and Smith. A. J.: Sernni ~lutamic: omlacetic t r;tnsaminitbe ill
208
Am Hrurt J. March, 1962
Iiesnik
acute myocardial infarction, Brit. M. J. 2:1121, 19.58. 6. Goble, A. J., and O’Brien, E. N.: Acute myocardial ischemia: significance of plasma-transaminase activity, Lancet 2:373, 19.58. 7. Russell, N. R., and Smith, A. J.: Multiple serial enzyme studies in acute myocardial infarction, Brit. M. J. 2:4.59, 19.59. 8. Nydick, I., Ruegsegger, P., Wroblewski, F., and LaDue, J. S.: Variations in serum glutamic oxalacetic transaminase activity in experimental and clinical coronary insufficiency, pericarditis, and pulmonary infarction, Circulation 15:324, 1957. 9. Horn, H., Field, L. E., Dack, S., and Master, A. M.: Acute coronary insufficiency: pathological and physiological aspects, AM. HICAFX J. 40:63, 1950. 10. Mounsey, P.: Prodromal symptoms in myocardial infarction, Brit. Heart J. 13:21.5, 19.51. 11. Schlesinger, M. J., and Reiner, L.: Focal myo-
12.
13. 14.
15.
16. 17.
cytolysis of heart, Am. J. Path. 31:443, 1955. Haldersleben, D.: Value of T-wave abnormalities in the diagnosis, prognosis, and treatment of coronary arteriosclerotic heart disease, M. Ann. District of Columbia 28:477, 1959. Wood, I’.: Acute and subacute coronary insufficiency, Brit. M. J. 1:1779, 1961. Nichol, E. S., Phillips, W. C., and Casten, G. G.: Virtue of prompt anticoagulant therapy in impending myocardial infarction: experiences with 318 patients during a 10 year period, Ann. Int. Med. 50:1158, 1959. Beamish, R. E., and Storrie, V. M.: Impending myocardial infarction. Recognition and management, Circulation 21:1107, 1960. Beecher, H. K.: Surgery as placebo. A quailtitative study of bias, J.A.M.A. 176:1102, 1961. Elmadjian, F., Hope, J. M., and Lamson, E. T.: Excretion of epinephrine and norepinephrine in various emotional states, J. Clin. Endocrinol. 17:608, 1957.
The significance of prolonged angina1 pain William H. Resnik, Stamford, Conn.
angina)
M.D.
P
rolonged and severe attacks of angina1 pain may occur under three circumstances. In some patients, the ischemic myocardium may have imposed on it a greater than usual load, as by strenuous exertion or severe emotional stress, a hypoglycemic attack, or a sudden elevation of rate or blood pressure as in paroxysmal tachycardia or paroxysmal hypertension. In a second group, the prolonged angina is caused by conditions that are associated with a severe diminution of coronary flow. Examples of such conditions are shock caused by loss of extracellular fluid (hemorrhage, dehydration), massive pulmonary embolism, prolonged and intense tachycardia. In both of these categories, removal of the cause of either the increased metabolic demand or of the diminished coronary flow may restore the myocardium to its previous state, or, if the ischemia has been sufficiently prolonged and intense, result in the development of a mass of necrotic myocardial tissue. There is a third and far more common form of prolonged angina1 pain that occurs spontaneously, unassociated with a demonstrable cause for increased load or decline in coronary flow. This type is caused by atherosclerotic narrowing of a coronaq artery, usually enhanced either by the deposition of thrombus on a roughened intimal lining or by subintimal hemorrhage, or both. It is to this spontaneous11 From
(preinfarction
the Department oi Internal Medicine, ford Hospital, Stamford. Corm. Received for publication July 21, lWi1.
Yale
occurring form of prolonged angina1 pain that this discussion will be limited. If a patient has an attack of angina1 pain which lasts 10 to 15 minutes or longer, and particularly if there has been no obvious provoking cause, it is necessary to determine whether acute myocardial infarction or merely prolonged angina1 pain without myocardial necrosis has occurred. The graver forms of myocardial infarction usually present such characteristic features shortly after the onset of the attack that they do not enter into the problem under discussion. It is the milder forms of myocardial infarction that need to be differentiated from the type of ischemic heart disease that, by definition, is characterized by prolonged angina1 pain without evidence of myocardial necrosis. This latter condition has been designated by a number of terms: acute coronary insufficiency, preinfarction angina, impending infarction, the intermediate state, status anginosus. Although no designation thus far proposed is free of objections, the term preinfarction angina will be employed throughout this discussion. lJnti1 recently, the diagnosis of preinfarction angina and the separation from acute myocardial infarction were based primarily on failure of new and significant Q waves to develop, and on the absence of such signs of tissue necrosis as fever, leukocytosis, and elevated sedimentation rate. llniversity
School
of Medicine,
New
Haven,
Corm.,
and
the
Stan-
Signijcancc
Nevertheless, differentiation was often difficult, for even when infarction was present, pathognomonic electrocardiographic findings were often absent or obscured by previous abnormalities, such as left bundle branch block or those brought on by former infarctions. The introduction of the serum transaminase test has provided us with a method of detecting tissue necrosis which is far more accurate and sensitive than any the test previously available. I>2 Although is not specific for ml-ocardial necrosis, those conditions that are most likely to be confused clinically with acute myocardial infarction are either unassociated with a significant elevation in serum transaminase activit\r or are accompanied by other features that should lead to the correct diagnosis.“a Generally, in the presence of an acute chest pain consistent with that of myocardial ischemia, and in the absence of features that strongly point to some other diagnosis, the problem is primarily one of differentiating between preinfarctlon angina and acute myocardial infarction. For this purpose, serial determinations of the serum transaminase activity may usually be regarded as our single most reliable index of myocardial necrosis. Clinical
studies
The following discussion concerns observations made on serum glutamic oxaloacetic transaminase (SGOT) activity in patients who were considered to have preinfarction angina. It is commonly accepted that with this test a level of 40 represents the upper limit of normal, and that a peak level is attained within 24 to 48 hours after the onset of the chest pain. Hence, when a patient has experienced one or several closely recurrent bouts of chest pain, it is common practice to check the level of serum transaminase activity for 2 to 3 days. If the level has not risen above 40, and if there are no other unequivocal signs of infarction, the conclusion is usually drawn that the attack falls into the category of preinfarction angina. Over a period of 5 months, 31 patients presented the classic features of preinfarction angina: prolonged angina1 pain, often recurrent, sometimes associated with the of effort angina or with a appearance
oj prolongtd
anghial
pain
201
marked intensification of angina if previously present. Electrocardiograms taken serially revealed no new Q waves, although transient S-T-segment and T-wave abnormalities were occasionally observed. Serial transaminase tests failed to show figures above 40 during the first 3 days after the patients were hospitalized, and during this time there were no other signs of tissue necrosis, such as fever, leukoc\.tosis, or elevated sedimentation rate. L& normal transaminase levels, however, were observed frequently from the fourth day on, and, occasionally, a very brief and mild fever or leukocytosis or increased rate of sedimentation were also witnessed. Since reliance was placed principally on the transaminase test to provide evidence in regard to myocardial necrosis, daily leukocyte counts and determinations of the rate of erythrocyte sedimentation were not made, and details in regard to these tests are omitted. Because the primary purpose of these observations was to determine the frequency with which the SGOT level became abnormal after the third day, 4 patients who had a slight elevation of the transaminase level during the first 3 days after the last attack of pain were not included in this series. All patients were hospitalized for observation and management as soon as the diagnosis was suspected. The)- were placed on heparin therapy immediately, and dosages were adjusted to give a clotting time of 40 to 60 minutes just before the next injection of heparin. Almost invariably, ;uginal pain subsided within 24 to 36 hours after anticoagulant therapy was illstituted, and the patients were then encouraged to walk several times a day at a slow pace in the hospital corridors. Transaminase tests” were made each day for 7 to 10 days or more after the patients were hospitalized (see Table I ). Table I. SGOT cl~inical picture Patients
with
levels
ltwls in 31 patieds preinfarction angina
with
qf
over
40 units
Patients with levels above 28 units and with maximal variation of 10 u11its or more
23
74:;
29
9.1’,,’
292
ICesnik
much significance as a maximal level of 43 in denoting the presence of myocardial necrosis (Table 111). When the criterion of :I maximal level over 28 units, combined with a maximal variation greater thall 10 units, was employed, 29 patients (93 per cent) displayed abnormal results indicative of myocardial necrosis. No special significance is attached to the exact. percentages in which abnormal SGOT levels were witnessed. The total number of patients is rather small. The validity of the criterion of SGOT levels greater than 28 and a maximal variation greater than 10 needs to be established by more extended studies. Technical errors may conceivably h,ave accounted for some of the elevations barely above 40 units. Finally, by exclusion of patients who exhibited an elevated transaminase level during the first 3 days, picture some were omitted whose clinical was otherwise practically identical with that of those who were included in this series. \$Then the SGOT peak has been attained, it is usual for the transaminase level to fall sharply within the course of a fen- days and
Fig. f. Patient P.S. Daily trausaminase tests after an attack of preinfarction angina. The lirst abnormal figure, 42, occurred on the fifth day.
Of the 31 patients, 23 (73 per cent) first displayed an SGOT level over 40 units on the fourth to tenth days after the onset of pain or of the last bout of pain (Figs. 1 and 2; Table II). The peak transaminase levels ranged between 41 and 94; most of them were between 41 and 60. Although 40 units has been generalllr accepted as the upper limit of normal SGOT activity, there are studies which indicate that this figure is too high and that a more accurate figure is in the vicinit! of 28.5-7 Moreover, there is additional evidence that in normal individuals the maximal variation between the lowest and highest figures obtained over a period of da).s does not exceed 10 units.je7 This implies that the extent of variation in a series of daily transaminase tests as we11 as the absolute level of transaminase activity must be considered. For example, levels of 13 and 38 in the same patient may have as
Fig. 2. Patient :I.J. Daily transaminase tests ;tfter au attack of preinfarctiorx angina. The first almorm:~l ligure, 60. occurred on the seventh da!-.
Discussion
to remain at low levels thereafter. If another rise in SGOT activity occurs, new ittfarction is suspected. Such secondat-? rises were observed frequently itt this group of patients (Figs. 3 and 4). In no instance was there a corresponding appearance of ischemic pain or of any other clinical or electrocardiographic evidence to indicate a new cardiac injury. Z’ablc I I. Tmnsanzinase
A.Je. ‘I‘.J. A.K. A.Jn. J.F. hl .\Vll P.S. E.S. h1.S. H.B. \V.M. h1.N. ‘I‘.\V. N.7‘. T.L. G.F. T.P. L.bT.
rw. B.T. S.K. ED. F.R.
~--
~ -~ -
14 38
27 19 11 6 13 12
13 13 36
16 24 21 18 -_~ 33 -.-~ 12 24 19 15 27 22
21
11 19 25 17 13 17 18 21 21 19 18
27 18
levels in 23 patients
27
9 12 19 13 17 19 18 20 13 15
20 26 19
30 13 30 14 53 38 19 16 19 13 24 20 2.5 41
25
37
34
li 24 28 20 11
21 19 27 18 19
24
28
19 17
21 36
28 13 35 42 36 31 24 44
11
10
24 20 6 9 12
13 13 17 26
36
*Patients in whom the first abnormal Figures over 40 are set in boldiace
7bbla
YE.\\‘. LV. Hm. \V.B.S. I\.E. \V.Hn. L.L.
*Patients levels
II I. l‘ran~aminase
-~ 20 31 -.~-. 14
27 15 27 24 16 13
20 12 15 20 21 l-1
SGOT type.
22 33 34 17 17 94 42 33 26 20
34 31 42 41 25 54 34 32 51 48 38 51 46 level
60 39 35 15 19 82 56 45 41 28 28 38 67 18 44 44 48 44 32 41 47 18 54 (above
The results described above compel a revision of the generally accepted views in regard to the use of. the transaminase test in the diagnosis of acute tnyocardial infarction and a reconsideration of preinfarction angina. It is clear that a peak transantinase level does not ttecessarilv occur during the first 24 to 48 hours after the ouwith
48 46 20 28 11 54 67 37 53 33 45 45 60 17
34 45 51
34
36
32 54 48 19 17 58 19 12
17 21
preinfarction
40 53 41 42 35
11 19 31
32 16 21
48
40
17
3.l
16 43 41 45
11 29 3-i
32
38 39
30
32 32 17 17 22
13 19 20 47 18
24 28 2-l 15
45 19 46 28
38
40) appeared
angina*
18
1.5
20
19
19
21
29
-
-
34
--
51 -
15 41 45
19 16 26
15
19
13
30
36
20
23
26 28
19 -
-
21
17
19
22 .?O -
17 21
on the fourth
day or later
after
the last attack
ol angina1
pain.
levels in 6 patients*
33 17 15 15 17 28
17 19 9 15 15 3-l
11 19 19 20 37
13 38 1.5 19 22 16
13 36 23 26 29 19
26 2.5 31 13
15 29
31 25
12
in wllom the peak SGOT level exceeded 28 units and the maximal xxuiation were between 31 and 3X units. and the maximum variation was between
15
18
15
was greater than 16 and 26 units.
12
10 units.
Actually.
the peak
294
Am. firart J. March, 1962
liesnik
Fig. 3. Patient N.T. Daily angina. The first abnormal to 17, there was a secondary
transaminnse tests after an attack figure, 41, occurred on the fourth rise to 51 on the eighth day.
set of the attack. In this series, in about 75 per cent of the patients who were ordinarily classified as having sustained an attack of preinfarction angina, a transaminase level of over 40 units was first observed on the fourth to tenth days after the attack. If the criterion of a level above 28 combined with a maximal variation greater than 10 units is employed, over 90 per cent of such patients showed evidence of myocardial necrosis. Thus, a high percentage of all patients presumed to have had attacks of preinfarction angina have actually sustained areas of myocardial necrosis sufficiently large to give rise to abnormal levels of transaminase activitv. Such an inference is based on the premise that an abnormal transaminase level denotes cellular death. There are observations, however, that demonstrate that ischemia of certain degrees of intensity may injure the cell sufficiently to liberate transaminase without necessarily leading to immediate death. Whether such damaged cells can remain viable and be re-
of preinfarction day. After a fall
stored to normal function is not known. Since none of the patients of this series died, it is impossible to know whether abnormal transaminase figures were an expression of cellular death or whether cellular damage without death existed. Consethroughout this discussion, the quently, use of the term necrosis in cases of preinfarction angina is made with the understanding that it may mean histologic cellular necrosis or severe cellular damage short of being lethal to the involved rnyocardial mass. Similar observations in regard to increased transaminase levels in preinfarction angina have been described previously.’ Nydick8 reported SGOT elevations in about 30 per cent of a group of 50 patients, and about 50 per cent of the abnormal figures occurred after the third day. Employing the criterion of SGOT levels greater than 28 and maximal variations over 10 units ill the same person to constitute evidence of myocardial necrosis, Goble and O’Brien6
Signijicance
observed abnormal transaminase levels in 50 to 87 per cent of patients who otherwise exhibited all the features of L‘acute coronary insufficiency.” But even before the transaminase test had been introduced, evidence less decisive but nevertheless highly suggestive had led to the statement: “The distinction between the two conditions (myocardial infarction and preinfarction angina) is somewhat artificial, because careful study indicates that manq patients with typical preinfarction angina reveal clear evidence of necrosis (transient leucocytosis, minimal fever, elevation of the sedimentation rate), even though other manifestations of infarction are absent. In such instances one is presumably dealing with a small area of necrosis surrounded by a large zone of ischeniia.“3’1 The present observations with the transaminase test used as a sign of myocardial necrosis full>* confirm this view. What is the significance of these observations which indicate the presence of myocardial necrosis or damage bordering on necrosis in a high percentage of all patients with preinfarction angina? Careful subsequent study of these patients has failed
of prolongd
angina1 pain
205
to reveal any detectable diminution of cardiac reserve as manifested by their capacity to perform work loads similar to those undertaken prior to the attack. This is not altogether surprising since the slight elevation of the peak transaminase levels signilies that only a small mass of myocardium has been destroyed or injured. Nevertheless, the destruction of so small and clinically insignificant a segment of m)-ocardial tissue should not be construed as evidence that the patient has merely sustained a disagreeable, but fortunately benign, episode of pain. The fact that in many patients with preinfarction angina a small area of myocardial necrosis may occur means that the anatomic lesion responsible for the obstruction has probably already reduced coronary flow to the involved area to a critical level. Since by Poiseuille’s law, flow through a tube at a given pressure is proportional to the fourth power of the diameter of the tube, a further and onlv very slight narrowing of an already criticall) narrowed blood vessel, as by the deposition of a small amount of additional thrombus, could bring about so serious a reduction in blood flow as to cause frank infarction.
Fig. 4. Patient M.W. Daily transaminase tests after an attack of preinfarction angina. The first abnormal figure, 94, occurred on the fifth day. After a fall to 17 on the ninth day, a secondary rise to 51 occurred on the sixteenth day.
296
l&n
ik
Obviously, such a diminution in coronaq flow could take place either in the coronaq artery primarily responsible for blood flow to the affected tnyocardium or in a coronary vessel supplying important collaterals to this area. In this series, the ischemia responsible for the attack of preinfarction angina resulted in a delayed rise, with peak levels lower than those usually witnessed in frank infarction, and the occasional occurrence of the secondary rise in SGOT. Why should the transaminase peak appear as late as 5 to 10 days after the attack of preinfarction angina when it appears almost invariably within 24 to 72 hours after frank infarction? One explanation could be that no transaminase elevation resulted from the ischemia responsible for the preinfarctional pain, but that, after a variable number of days, a painless exacerbation of the ischemia caused the delayed increase in transaminase. A painless intensification of the ischemia occurring in each of the patients with a delayed rise seems to be a gratuitous assumption, particularly since there were no other clinical phenomena to indicate a worsening of the patient’s cottdition. A more probable explanation for the delayed rise would be that the intensit). of the ischemia in preinfarction angina was sufficient to cause severe damage in a small mass of myocardium, but insufficient to cause protnpt cellular death. Only after a number of days did cellular disintegration reach that level which is associated with the liberation of transaminase. Essentially the same explanation may be invoked to account for the secondary rise in transaminase. During the attack of preinfarction angina the involved myocardiutn is comprised of confluent areas which are variously affected by the ischemia, depending primarily on variations in the richness of collateral blood flow. The foci of necrosis must be small to account for the low peak of transatninase levels. Moreover, more than one focus of necrosis may be present in the same mass of ischemic myocardium. Thus, one small area may have been subjected to an intensity of ischemin sufficient to cause cellular death and disorganization responsible for a peak of 41 on the fourth da\-. Another slightly larger area may have been destroyed but b\. a
somewhat less intense ischemia, so that cellular disorganization with liberation of transaminase to a level of 51 does not take place until the eighth day (Fig. 3). The rest of the ischemic m~~ocardium retnains viable, although some portions of it must have barely escaped necrosis. These interpretations of the behavior of the transaminase test after an attack of preinfarction angina are supported by histologic studies that show within the same ischemic myocardium all stages of death and healing, from earliest- necrosis to early fibrosis . .8-l:! It seems clear that the basic difference in the behavior of the transaminase after frank infarction and that after preinfarction angina is simply one of intensity of ischemia. In the former, the severit?. of the ischetnia is such as to cause immediate and fait-l>- uniform necrosis of a macroscopic tnass of myocardium, \vith prompt liberation of transaminase. In the latter, the ischetnia suffices only to cause variable degrees of cellular injury. Only small a~td possibly microscopic patches of necrosis appear, cellular death and disorganization proceeding more slowI>. and at different rates. The potentially serious nature of an attack of preinfarction angina rests on more than theoretical considerations. Although there are some writers who regard anticoagulant therapy as either unttecessary or a matter of little urgency, there are others whose reports indicate that 25 to 93 per cent of patients with preinfarctiott allgina develop frank and serious infarction within 4 to 12 weeks after t-he onset of the attack if anticoagulant therapy is not used. On the other hand, frank infarction is reduced to 3 to 10 per cent during the same period of time if anticoagulants are given for at least 6 weeks.13-t5 All of the patients in the present series were given anticoagulants for 5 or more months after the attack. In only one did frank infarction develop during this time. Although the value of anticoagulant therapy, as judged by the above figures, appears to be convincing, one must bear in mind the possibility that it ma>- actually be less effective than it seems to be. .\nticoagulant therapy m~11d h:tve value onI!. if ;I thrombus were respottsible for the es-
Signijicuncc~ qf prolonged angiml
acerbation of myocardial ischemia. However, the latter may also be caused by progressive atherosclerotic narrowing, with or without subintimal hemorrhage, but without formation of thrombi. Consequently, in an undetermined but small percentage of patients in this and other series reported upon in the literature, anticoagulant therapy could have played no significant role in preventing frank infarction. Moreover, there is abundant evidence that patients suffering from myocardial ischemia are not immune to the placebo influence of otherwise ineffective forms of therapy. I6 It is possible, therefore, that management of the patient, including anticoagulant therapy, may have done nothing more than reassure an anxious patient. The resultant diminution in heart rate and in the endogenous formation of excessive quantities of catecholamines” could conceivably reduce myocardial oxygen requirement enough to prevent frank infarction. This possibility could be answered only by a well-controlled double-blind study. Despite these considerations and until there is unequivocal evidence that anticoagulant therapy is ineffective, the management of the patient with preinfarction angina should be based on an appreciation of the fact that blood flow to the affected nlvocardium has already been reduced to a critical level. ,Ylthough one can never be certain that thrombotic occlusion is present, this type of lesion is present in so high a percentage of patients that one is justified in administering anticoagulant therap\ promptly and continuing it for 6 weeks or longer. Ph\-sic-al activity should be sharplyrestricted for at least 2 to 3 weeks. The purpose of this regimen is to reduce the metabolic needs of the heart, to prevent further narrowing of the coronary lumen b>, formation of thrombi, and to afford time for the development of collaterals sufficient to increase blood flow to the affected area above its presently precarious level. It is evident that there should be no sharp distinction betweet) preinfarction angina and frank infarction. All ischemic heart disease should be considered to be a continuous spectrum of increasing severit!, of ischeinia, ranging from the mildest ai)gina of effort without necrosis to the most
pain
207
massive infarction. In a high percentage of patients with preinfarction angina, evidences of necrosis can be detected, and the more severe forms of preinfarction angina merge insensibl>r with the milder forms of frank infarction. Regardless of the terminology one prefers-preinfarction angina, coronary insuficienc)-, impending infarction, status anginosus, or the intermediate state-it is important to recognize that necrosis has already occurred in mang., and that far more serious infarction is likely to develop if appropriate therapy is not instituted promptl>.. Summary
and
conclusion
Necrosis of the myocardium takes place in a high percentage of all persons who have spontaneous attacks of preinfarction angina. Abnormal transaminase levels ma? first appear on the fourth to tenth days after the attack, and not during the first 2 days as is now generally considered to be the case. =\ secondary rise in transaminase may not be the result of a ne\v occlusion or the propagation of the original thrombus. It may be caused only by the slow and uneven death and tlisorganizatioli of small areas of myocardiunl subsequent to the original attack of ischemia. The importance of spontaneous preinfarction angina conies from the fact that diminution in blood flow to an area of the myocardium has alread!. reached a critical and dangerously loa level, and appropriate measures, pi-imarilv anticoagulant therapy and restriction 01 activity, should be instituted promptly. to prevent, so far as possible, the development of a larger and niore serious frank iiifarction. 1. ;Igress. C. M.: Evaluation of transaminase test, Am. J. Cnrdiol. 3:71, 1959. 2. Hamolsky, hl. IV., and Kaplan, N. 0.: Measurements of enzymes in the diagnosis of acute III!-ocardial infarction, Circulation 23:102, 1961. AI. Iiesnik, \\:. H., and Harrison, T. Ii.: In Harrison, ‘1‘. I<., editor: Principles of internal medicine, ed. 3, New York, 1958. iLlcGra\v-Hill Book Compall~. p. -I-.?. 3b. Ibid., p. 1264. 4. Keitman, S., and Frankel, S.: .\ calorimetric method for the detcrminatio~~ of serum glutanlic osalacetic. and glutatnlc pyruvic tr;L11silfillli;lSe~, .\m. J, Clin. Path. 2856, 1957. 5. I)ewar, II. .A., 12o~vell, N. I<., and Smith. A. J.: Sernni ~lutamic: omlacetic t r;tnsaminitbe ill
208
Am Hrurt J. March, 1962
Iiesnik
acute myocardial infarction, Brit. M. J. 2:1121, 19.58. 6. Goble, A. J., and O’Brien, E. N.: Acute myocardial ischemia: significance of plasma-transaminase activity, Lancet 2:373, 19.58. 7. Russell, N. R., and Smith, A. J.: Multiple serial enzyme studies in acute myocardial infarction, Brit. M. J. 2:4.59, 19.59. 8. Nydick, I., Ruegsegger, P., Wroblewski, F., and LaDue, J. S.: Variations in serum glutamic oxalacetic transaminase activity in experimental and clinical coronary insufficiency, pericarditis, and pulmonary infarction, Circulation 15:324, 1957. 9. Horn, H., Field, L. E., Dack, S., and Master, A. M.: Acute coronary insufficiency: pathological and physiological aspects, AM. HICAFX J. 40:63, 1950. 10. Mounsey, P.: Prodromal symptoms in myocardial infarction, Brit. Heart J. 13:21.5, 19.51. 11. Schlesinger, M. J., and Reiner, L.: Focal myo-
12.
13. 14.
15.
16. 17.
cytolysis of heart, Am. J. Path. 31:443, 1955. Haldersleben, D.: Value of T-wave abnormalities in the diagnosis, prognosis, and treatment of coronary arteriosclerotic heart disease, M. Ann. District of Columbia 28:477, 1959. Wood, I’.: Acute and subacute coronary insufficiency, Brit. M. J. 1:1779, 1961. Nichol, E. S., Phillips, W. C., and Casten, G. G.: Virtue of prompt anticoagulant therapy in impending myocardial infarction: experiences with 318 patients during a 10 year period, Ann. Int. Med. 50:1158, 1959. Beamish, R. E., and Storrie, V. M.: Impending myocardial infarction. Recognition and management, Circulation 21:1107, 1960. Beecher, H. K.: Surgery as placebo. A quailtitative study of bias, J.A.M.A. 176:1102, 1961. Elmadjian, F., Hope, J. M., and Lamson, E. T.: Excretion of epinephrine and norepinephrine in various emotional states, J. Clin. Endocrinol. 17:608, 1957.