American November,
Heart Journal
1975, Volume 90, Number
5
Editorial The advantages of a vasospastic myocardial infarction H. Richard Hellstrom, Pittsburgh, Pa.
cause of
M.D.
This editorial will renew the suggestion that it is likely myocardial infarctions are caused by vasospasm, a process which might be reversible. If this is true, proper and timely antispasmodic therapy might provide the most advantageous treatment for this disorder, and, ultimately, infarctions might be prevented. Such possibilities provide impetus for the clarification of any role of spasm in infarction. Practically all of the recent work in infarction has been in preserving ischemic myocardium (limiting infarction size) and improving hemodynamits after the acute attack.‘-6 This school assumes that, after an acute episode, ischemic myocardium can be separated into two classes: blighted myocardium, where necrosis is inevitable, and jeopardized muscle, which can be preserved by techniques which improve the myocardial oxygen supply-demand ratio. Contrariwise, there appears to be little interest in elucidating the pathogenesis of infarction. In fact, articles dealing with methods of improving the care of acute infarction generally skirt the issue of its pathogenesis. It probably is understood that stenotic atherosclerosis causes myocardial ischemia, but it is not always clear if it is assumed that this chronic arterial disorder is the From the Department of Pathology, University of Pittsburgh School Medicine, and the Veterans Administration Hospital, Pittsburgh. Received
for publication
July
23, 1974.
Reprint requests: Dr. H. Richard Hellstrom, Veterans Hospital, University Drive C.. Pittsburgh. Pa. 15240.
Administration
November, 1975, Vol. 90, No. 5, pp. 545-548
of
proximal cause of the acute attack.: If the acute episode is mentioned, it often is styled as a “coronary occlusion” or “acute event” without further comment. Possibly, it is assumed that efforts to clarify the cause of the acute &hernia of infarction would be unrewarding, and further, it most likely represents an irreversible fait accompli (?stenotic atherosclerosis), which, inevitably, results in some muscle necrosis. Such considerations and the promise of significant success in preserving ischemic myocardium probably have channeled efforts toward the pharmacologic manipulation of ischemic myocardium. However, there appears to be sufficient information available to build a case that the immediate cauSe of infarction is coronary artery vasospasm.* Excluding mechanical events as thrombosis, what else but spasm can initiate a sudden episode of ischemia? The very absence of a demonstrable anatomic cause for the dramatic onset of ischemia in infarction suggests an abnormal physiologic state, as spasm. Spasm has been indicted in variant or pre-infarction angina,+l’ yet its crescendic’2 culmination, e.g., infarction, only rarely’” is considered to have a spastic origin. Also, as vascular tone is related to the psyche, spasm can explain how psychological factors can be translated directly t.o chest pain. It seems that the evidence for spasm far outweighs the interest it evokes, and part of this neglect can be explained on historic grounds. Spasm, in one form or another, has been considered in ischemic heart disease-angina pecto-
American Heart Journal
545
Helldrom
LARGER
INFARCT
Fig. I. The injury vasospasm hypothesis considers coronary , arterial spasm to be secondary to myocardial injury. It is generally recognized that injury to vessels causes spasm, as after needle puncture, chemical irritation, physical trauma, or ischemia. Stenotic atherosclerosis causes chronic ischemic myocardial injury, which, in conjunction with emotional factors, initiates myocardial injury vasospasm. Variant angina represents spontaneously reversed spasm, and spasm might be reversed by appropriate vasodilators. If spasm persists. necrosis results, causing a vicious cycle and acute infarction. The fresh tissue injury perpetuates the spasm, which causes continuing ischemia during the acute phase of the infarction. Coronary artery stasis, secondary to spasm, may result. in a secondary thrombus and by totally obstructing the blood supply, causes infarction enlargement and, sometimes, cardiogenic shock.
r&for 200 years without proof of its existence,8 and the biblical quotationI “Mene, mene, tekel ILpharsin” (you have been weighed in the balance and found wanting) may be applicable. A major objection t,o spasm has been that sclerotic arteries cannot coni?ract, and the recent assertion that nitroglycerin has a peripheral actionI has been a negative factor. While not verbalized, it probably has been assumed that coronary artery spasm is a short-lived event, as the ?spasm of variant angina, and the cerebral spasm of migraine headaches.ll Therefore, spasm cannot be a candidate for causing infarction, as the ischemia which initiates muscle necrosis is not an evanescent event, but continues on into the acute phase of the infarction. Several years ago, I found apparent vasospasm in experimental myocardial infarction,16 from which a hypothesis8 was developed which involves spasm in this disorder (Fig. 1). This injury vasospasm hypothesis provides an explanation for major events in infarction, and might obviate some of the objecGons to spasm. For example, the
546
hypothesis considers spasm to be primarily intramyocardial (although it probably extends to the main artery), permitting spasm to occur in spite of calcified coronary arteries. Instead of the usual adversary position between spasm and coronary artery atherosclerosis, the hypothesis reconciles them and presents spasm as an injury reaction to the chronic ischemia of at,herosclerosis. Also, the hypothesis holds that the spasm which initiates infarctions also continues during the acute phase of the infarction, and such spasm was observed experimentally.‘6 Recognition that there might be spasm during the acute course of clinical infarction should strengthen the case for spasm, considering that the preservation of ischemic myocardium school is based on the appreciation of continuing ischemia during acute infarction. If, indeed, infarctions are due to spasm, there are a number of avenues to consider. Antispasmodic therapy, if administered early, might abort the infarction, and this would be more advantageous than acceptance of limitation of infarction size. The reversal of spasm by antispasmodic agents prior to the onset of necrosis can be compared to variant angina, where ablation of spasm is considered to occur spontaneously. After infarction has supervened, vasodilaCve therapy should be more effective in dealing with the &hernia of acute infarction than non-specific attempts to improve the myocardial oxygen supply-demand ratio. The injury vasospasm hypothesis might provide some insight into cardiogenic shock, which has a mortality of over $5 per cent in most insGtuGons.3 Patients who die from cardiogenic shock have large infarction& Ii and there is evidence that the extensive loss of myocardium occurred in a stepwise pattern, with fresh necrosis occurring in close proximity to the onset of shock? Attempts to counter this devastating infarction enlargement have been by techniques to preserve ischemic myocardium. The vasospasm hypothesis considers infarction enlargement leading to cardiogenic shock to be due, in most cases, to secondary thrombosis. Although it has been known that thrombi are more frequent in cases with cardiogenic shock than in those without this complicaGon-71 per cent vs. 15 per cent”-thrombi had not been implicated as the cause of the shock. With spasm, there is some flow into the ischemic area,16 and with complete loss of flow subsequent to a complicating thrombus, the
November,
1975, Vol. 90, No. 5
l’asospastic
farction would enlarge. Such thrombus-induced farction enlargement has been noted experientally.” In the few cases of cardiogenic shock ithout thrombi, infarction enlargement prob,ly is due to extension or increased severity of ie original vasospasm. Also, if infarctions are due to spasm, it may be ossible to progress beyond effective treatment of le acute attack to the prevention of infarctions. ‘his might be possible in spite of the presence of he underlying cause of infarctions, i.e., coronary rtery atherosclerosis. Speculations might inlude ways to prevent or short circuit the psychic auses of vasospasm. Chronic vasodilator therapy nay be inappropriate as a prophylaxis, consid‘ring that angina, infarction, and sudden death iave followed withdrawal from chronic exposure o nitroglycerin in ammunition plants.‘” Such :ases also provide additional evidence that vasospasm can induce myocardial infarction. Fortuitously, it appears that therapeutic programs designed by the preservation of the ischemic myocardium school can be used to gain information about the role of vasospasm in infarction. Drugs’!‘-” have been used successfully in those programs which, according to the vasospasm hypothesis, are operative against coronary artery spasm. Intravenous nitroglycerin and sodium nitroprusside have been employed, assuming they cause peripheral vasodilation, which would then reduce end-diastolic pressure and cardiac overload, and thus help preserve ischemic myocardium. The injury vasospasm hypothesis considers the primary beneficial effects of these vasodilators to be. reduction of myocardial spasm and ischemia. That nitroglycerin can reverse coronary artery spasm was recently demonstrated at surgery by direct observation.” The improved cardiac action after vasodilative treatment’” suggests that ischemic and noncontractile myocardium became functional. The lessened chest pain,‘?’ arrhythmias,“’ and ischemia:’ appear to speak for themselves. A primary cardiac action for vasodilator treatment does not preclude the occurrence of helpful peripheral effects. Probably, only minor modification of intravenous vasodilator therapy designed to reduce enddiastolic pressure is needed to provide evidence about vasospasm. According to the injury vasospasm hypothesis,” therapy might (1) abort infarctions, (2) prevent cardiogenic shock, and (3)
American
Heart
Journal
cause of myocardia
f infarction
improve myocardial function by reducing ischemia. Evidence for the first two beneficial effects of vasodilators might be especially persuasive for vasospasm, as the third, improved myocardial function during infarction, has already been demonstrated, but is attributed to a peripheral effect. Vasodilative therapy should be started as early as possible, before necrosis supervenes, and continued until the danger of cardiogenic shock is passed. The preservation of ischemic: myocardium concept is growing in acceptance, which is expected, considering the wealth of propitious information which has been garnered. However, before treatment of infarction is completel>- harnessed to this philosophy, it is hoped that alternative views, such as vasospasm, which do not have the inherent attitude that the acute event in infarction is irreversible and that some muscle necrosis is inevitable, will be considered. REFERENCES 1.
2. 3.
4. 5.
6. 7.
8. 9.
10.
11. 12. 13.
14. 15. 16.
Braunwald, E., and Maroko, P. R.: Investigations on protection of the ischemic myocardium, Trans. Am. Clin. Climatol. Assoc. 84:80, 1972. Cohn. J. N.: Pharmacological manipulation of myocardial metabolism, Bull. N. Y. Acad. Med. 50:328, 1974. Scheidt, S.. Alonso, D. R., Wilner, G., and Killip, T.: New concepts of cardiogenic shock: preservation of ischemic myocardium. Bull. N. Y. Acad. Med. 50:247, 1974. Brachfeld, N.: Jschemic myocardial metabolism and cell necrosis, Bull. N. Y. Acad. Med. 50:261, 1974. Mueller, H., and Ayres, S. M.: Systemic and cardiac energetics in acute myocardial infarction and in cardiogenie shock in man: effects of therapeutic. interventions, Bull. N. Y. Acad. Med. 50:341, 1974. Sobel, B. E., and Shell, W. E.: Jeopardized, blighted, and necrotic myocardium, Circulation 42:215, 1973. Ayres, S. M.: Conference on cardiogenic shock: preservation of ischemic myocardium, introduction, Bull. N. Y. Acad. Med. 50:243, 1974. Hellstrom, H. R.: Vasospasm in ischemic heart disease-a hypothesis, Perspect. Biol. Med. 18:427. 1973. Hart. N. J.. Silverman, M. E., and King, S. B.: Variant angina pectoris caused by coronarv art.er.v spasm, Am. J. Med. 563269, 1974. Oliva, P. B., Potts, D. E., and Pluss, R. G.: Coronary arterial spasm in Prinzmetal angina. N. Engl. J. Med.288:745, 1973. Leon-Sotomayor, L. A.: Cardiac migraine-report of twelve cases, Angiology 25:161, 1974. Stowers, M., and Short, D.: Warning symptoms before major myocardial infarction, Br. Heart ,J. 32:833, 1970. Cheng, T. 0.. Bashour, T., Singh. B. K., and Kelser, G. A.: Myocardial infarction in the absence of c’oronary arteriosclerosis, Result of coronary spasm t?\. Am. J. Cardiol. 30:680. 1972. Daniel 5: 25-28. The New English Bible, New York, 1970, Oxford University Press, p, 1078. Robinson, B. F.: Mode of action of nitroglycerin in angina pectoris, Br. Heart 3. 30:295, 1968. Hellstrom. H. R.: Coronary artery stasis after induced
547
Hellstrom
myocardial infarction in the dog, Cardiovasc. Res. 5:371, 1971. 17. Roberts, W. C.: Relationship between coronary thrombosis and myocardial infarction, Mod. Concepts Cardiovast. Dis. 41:7, 1972. 18. Lange, R. L., Reid, M. S., Tresch, D. D., Keelan, M. H., Bernhard, V. M., and Coolidge, G.: Nonatheromatous ischemic heart disease following withdrawal from chronic industrial nitroglycerin exposure, Circulation 46:666, 1972. 19. Franciosa, J. A., Guiha, N. H., Limas, C. J., Rodriguera,
548
E., and Cohn, J. N.: Improved left ventricular functior during nitroprusside infusion in acute myocardial infarc. tion, Lancet 1:650, 1972. 20. Kent, K. M., Smith, E. R., Redwood, D. R., and Epstein. S. E.: Beneficial electrophysiologic effects of nitroglycerin during acute myocardial infarction, Am. J. Cardiol. 33:513,
1974.
21. Epstein, S. E.: Hypotension, nitroglycerin, and acute myocardial infarction, Circulation 47:217, 1973. 22. Medical News: Variant angina may result from arterial spasms, J. A. M. A. 227:1362, 1974.
November,
1975, Vol. 90, No. 5
Heart Journal
1975, Volume 90, Number
5
Editorial The advantages of a vasospastic myocardial infarction H. Richard Hellstrom, Pittsburgh, Pa.
cause of
M.D.
This editorial will renew the suggestion that it is likely myocardial infarctions are caused by vasospasm, a process which might be reversible. If this is true, proper and timely antispasmodic therapy might provide the most advantageous treatment for this disorder, and, ultimately, infarctions might be prevented. Such possibilities provide impetus for the clarification of any role of spasm in infarction. Practically all of the recent work in infarction has been in preserving ischemic myocardium (limiting infarction size) and improving hemodynamits after the acute attack.‘-6 This school assumes that, after an acute episode, ischemic myocardium can be separated into two classes: blighted myocardium, where necrosis is inevitable, and jeopardized muscle, which can be preserved by techniques which improve the myocardial oxygen supply-demand ratio. Contrariwise, there appears to be little interest in elucidating the pathogenesis of infarction. In fact, articles dealing with methods of improving the care of acute infarction generally skirt the issue of its pathogenesis. It probably is understood that stenotic atherosclerosis causes myocardial ischemia, but it is not always clear if it is assumed that this chronic arterial disorder is the From the Department of Pathology, University of Pittsburgh School Medicine, and the Veterans Administration Hospital, Pittsburgh. Received
for publication
July
23, 1974.
Reprint requests: Dr. H. Richard Hellstrom, Veterans Hospital, University Drive C.. Pittsburgh. Pa. 15240.
Administration
November, 1975, Vol. 90, No. 5, pp. 545-548
of
proximal cause of the acute attack.: If the acute episode is mentioned, it often is styled as a “coronary occlusion” or “acute event” without further comment. Possibly, it is assumed that efforts to clarify the cause of the acute &hernia of infarction would be unrewarding, and further, it most likely represents an irreversible fait accompli (?stenotic atherosclerosis), which, inevitably, results in some muscle necrosis. Such considerations and the promise of significant success in preserving ischemic myocardium probably have channeled efforts toward the pharmacologic manipulation of ischemic myocardium. However, there appears to be sufficient information available to build a case that the immediate cauSe of infarction is coronary artery vasospasm.* Excluding mechanical events as thrombosis, what else but spasm can initiate a sudden episode of ischemia? The very absence of a demonstrable anatomic cause for the dramatic onset of ischemia in infarction suggests an abnormal physiologic state, as spasm. Spasm has been indicted in variant or pre-infarction angina,+l’ yet its crescendic’2 culmination, e.g., infarction, only rarely’” is considered to have a spastic origin. Also, as vascular tone is related to the psyche, spasm can explain how psychological factors can be translated directly t.o chest pain. It seems that the evidence for spasm far outweighs the interest it evokes, and part of this neglect can be explained on historic grounds. Spasm, in one form or another, has been considered in ischemic heart disease-angina pecto-
American Heart Journal
545
Helldrom
LARGER
INFARCT
Fig. I. The injury vasospasm hypothesis considers coronary , arterial spasm to be secondary to myocardial injury. It is generally recognized that injury to vessels causes spasm, as after needle puncture, chemical irritation, physical trauma, or ischemia. Stenotic atherosclerosis causes chronic ischemic myocardial injury, which, in conjunction with emotional factors, initiates myocardial injury vasospasm. Variant angina represents spontaneously reversed spasm, and spasm might be reversed by appropriate vasodilators. If spasm persists. necrosis results, causing a vicious cycle and acute infarction. The fresh tissue injury perpetuates the spasm, which causes continuing ischemia during the acute phase of the infarction. Coronary artery stasis, secondary to spasm, may result. in a secondary thrombus and by totally obstructing the blood supply, causes infarction enlargement and, sometimes, cardiogenic shock.
r&for 200 years without proof of its existence,8 and the biblical quotationI “Mene, mene, tekel ILpharsin” (you have been weighed in the balance and found wanting) may be applicable. A major objection t,o spasm has been that sclerotic arteries cannot coni?ract, and the recent assertion that nitroglycerin has a peripheral actionI has been a negative factor. While not verbalized, it probably has been assumed that coronary artery spasm is a short-lived event, as the ?spasm of variant angina, and the cerebral spasm of migraine headaches.ll Therefore, spasm cannot be a candidate for causing infarction, as the ischemia which initiates muscle necrosis is not an evanescent event, but continues on into the acute phase of the infarction. Several years ago, I found apparent vasospasm in experimental myocardial infarction,16 from which a hypothesis8 was developed which involves spasm in this disorder (Fig. 1). This injury vasospasm hypothesis provides an explanation for major events in infarction, and might obviate some of the objecGons to spasm. For example, the
546
hypothesis considers spasm to be primarily intramyocardial (although it probably extends to the main artery), permitting spasm to occur in spite of calcified coronary arteries. Instead of the usual adversary position between spasm and coronary artery atherosclerosis, the hypothesis reconciles them and presents spasm as an injury reaction to the chronic ischemia of at,herosclerosis. Also, the hypothesis holds that the spasm which initiates infarctions also continues during the acute phase of the infarction, and such spasm was observed experimentally.‘6 Recognition that there might be spasm during the acute course of clinical infarction should strengthen the case for spasm, considering that the preservation of ischemic myocardium school is based on the appreciation of continuing ischemia during acute infarction. If, indeed, infarctions are due to spasm, there are a number of avenues to consider. Antispasmodic therapy, if administered early, might abort the infarction, and this would be more advantageous than acceptance of limitation of infarction size. The reversal of spasm by antispasmodic agents prior to the onset of necrosis can be compared to variant angina, where ablation of spasm is considered to occur spontaneously. After infarction has supervened, vasodilaCve therapy should be more effective in dealing with the &hernia of acute infarction than non-specific attempts to improve the myocardial oxygen supply-demand ratio. The injury vasospasm hypothesis might provide some insight into cardiogenic shock, which has a mortality of over $5 per cent in most insGtuGons.3 Patients who die from cardiogenic shock have large infarction& Ii and there is evidence that the extensive loss of myocardium occurred in a stepwise pattern, with fresh necrosis occurring in close proximity to the onset of shock? Attempts to counter this devastating infarction enlargement have been by techniques to preserve ischemic myocardium. The vasospasm hypothesis considers infarction enlargement leading to cardiogenic shock to be due, in most cases, to secondary thrombosis. Although it has been known that thrombi are more frequent in cases with cardiogenic shock than in those without this complicaGon-71 per cent vs. 15 per cent”-thrombi had not been implicated as the cause of the shock. With spasm, there is some flow into the ischemic area,16 and with complete loss of flow subsequent to a complicating thrombus, the
November,
1975, Vol. 90, No. 5
l’asospastic
farction would enlarge. Such thrombus-induced farction enlargement has been noted experientally.” In the few cases of cardiogenic shock ithout thrombi, infarction enlargement prob,ly is due to extension or increased severity of ie original vasospasm. Also, if infarctions are due to spasm, it may be ossible to progress beyond effective treatment of le acute attack to the prevention of infarctions. ‘his might be possible in spite of the presence of he underlying cause of infarctions, i.e., coronary rtery atherosclerosis. Speculations might inlude ways to prevent or short circuit the psychic auses of vasospasm. Chronic vasodilator therapy nay be inappropriate as a prophylaxis, consid‘ring that angina, infarction, and sudden death iave followed withdrawal from chronic exposure o nitroglycerin in ammunition plants.‘” Such :ases also provide additional evidence that vasospasm can induce myocardial infarction. Fortuitously, it appears that therapeutic programs designed by the preservation of the ischemic myocardium school can be used to gain information about the role of vasospasm in infarction. Drugs’!‘-” have been used successfully in those programs which, according to the vasospasm hypothesis, are operative against coronary artery spasm. Intravenous nitroglycerin and sodium nitroprusside have been employed, assuming they cause peripheral vasodilation, which would then reduce end-diastolic pressure and cardiac overload, and thus help preserve ischemic myocardium. The injury vasospasm hypothesis considers the primary beneficial effects of these vasodilators to be. reduction of myocardial spasm and ischemia. That nitroglycerin can reverse coronary artery spasm was recently demonstrated at surgery by direct observation.” The improved cardiac action after vasodilative treatment’” suggests that ischemic and noncontractile myocardium became functional. The lessened chest pain,‘?’ arrhythmias,“’ and ischemia:’ appear to speak for themselves. A primary cardiac action for vasodilator treatment does not preclude the occurrence of helpful peripheral effects. Probably, only minor modification of intravenous vasodilator therapy designed to reduce enddiastolic pressure is needed to provide evidence about vasospasm. According to the injury vasospasm hypothesis,” therapy might (1) abort infarctions, (2) prevent cardiogenic shock, and (3)
American
Heart
Journal
cause of myocardia
f infarction
improve myocardial function by reducing ischemia. Evidence for the first two beneficial effects of vasodilators might be especially persuasive for vasospasm, as the third, improved myocardial function during infarction, has already been demonstrated, but is attributed to a peripheral effect. Vasodilative therapy should be started as early as possible, before necrosis supervenes, and continued until the danger of cardiogenic shock is passed. The preservation of ischemic: myocardium concept is growing in acceptance, which is expected, considering the wealth of propitious information which has been garnered. However, before treatment of infarction is completel>- harnessed to this philosophy, it is hoped that alternative views, such as vasospasm, which do not have the inherent attitude that the acute event in infarction is irreversible and that some muscle necrosis is inevitable, will be considered. REFERENCES 1.
2. 3.
4. 5.
6. 7.
8. 9.
10.
11. 12. 13.
14. 15. 16.
Braunwald, E., and Maroko, P. R.: Investigations on protection of the ischemic myocardium, Trans. Am. Clin. Climatol. Assoc. 84:80, 1972. Cohn. J. N.: Pharmacological manipulation of myocardial metabolism, Bull. N. Y. Acad. Med. 50:328, 1974. Scheidt, S.. Alonso, D. R., Wilner, G., and Killip, T.: New concepts of cardiogenic shock: preservation of ischemic myocardium. Bull. N. Y. Acad. Med. 50:247, 1974. Brachfeld, N.: Jschemic myocardial metabolism and cell necrosis, Bull. N. Y. Acad. Med. 50:261, 1974. Mueller, H., and Ayres, S. M.: Systemic and cardiac energetics in acute myocardial infarction and in cardiogenie shock in man: effects of therapeutic. interventions, Bull. N. Y. Acad. Med. 50:341, 1974. Sobel, B. E., and Shell, W. E.: Jeopardized, blighted, and necrotic myocardium, Circulation 42:215, 1973. Ayres, S. M.: Conference on cardiogenic shock: preservation of ischemic myocardium, introduction, Bull. N. Y. Acad. Med. 50:243, 1974. Hellstrom, H. R.: Vasospasm in ischemic heart disease-a hypothesis, Perspect. Biol. Med. 18:427. 1973. Hart. N. J.. Silverman, M. E., and King, S. B.: Variant angina pectoris caused by coronarv art.er.v spasm, Am. J. Med. 563269, 1974. Oliva, P. B., Potts, D. E., and Pluss, R. G.: Coronary arterial spasm in Prinzmetal angina. N. Engl. J. Med.288:745, 1973. Leon-Sotomayor, L. A.: Cardiac migraine-report of twelve cases, Angiology 25:161, 1974. Stowers, M., and Short, D.: Warning symptoms before major myocardial infarction, Br. Heart ,J. 32:833, 1970. Cheng, T. 0.. Bashour, T., Singh. B. K., and Kelser, G. A.: Myocardial infarction in the absence of c’oronary arteriosclerosis, Result of coronary spasm t?\. Am. J. Cardiol. 30:680. 1972. Daniel 5: 25-28. The New English Bible, New York, 1970, Oxford University Press, p, 1078. Robinson, B. F.: Mode of action of nitroglycerin in angina pectoris, Br. Heart 3. 30:295, 1968. Hellstrom. H. R.: Coronary artery stasis after induced
547
Hellstrom
myocardial infarction in the dog, Cardiovasc. Res. 5:371, 1971. 17. Roberts, W. C.: Relationship between coronary thrombosis and myocardial infarction, Mod. Concepts Cardiovast. Dis. 41:7, 1972. 18. Lange, R. L., Reid, M. S., Tresch, D. D., Keelan, M. H., Bernhard, V. M., and Coolidge, G.: Nonatheromatous ischemic heart disease following withdrawal from chronic industrial nitroglycerin exposure, Circulation 46:666, 1972. 19. Franciosa, J. A., Guiha, N. H., Limas, C. J., Rodriguera,
548
E., and Cohn, J. N.: Improved left ventricular functior during nitroprusside infusion in acute myocardial infarc. tion, Lancet 1:650, 1972. 20. Kent, K. M., Smith, E. R., Redwood, D. R., and Epstein. S. E.: Beneficial electrophysiologic effects of nitroglycerin during acute myocardial infarction, Am. J. Cardiol. 33:513,
1974.
21. Epstein, S. E.: Hypotension, nitroglycerin, and acute myocardial infarction, Circulation 47:217, 1973. 22. Medical News: Variant angina may result from arterial spasms, J. A. M. A. 227:1362, 1974.
November,
1975, Vol. 90, No. 5
