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Acute myocardial infarction: a failure of timely, spontaneous thromholysis
1435
JACC Vol. 13. No. 6 May 1989: 1435-7
Acute Myocardial Infarction: A Failure of Timely, Spontaneous Thrombolysis* H.J.C.
SWAN,
Los Angeles.
MD, PHD, MACP,
FACC
Cal(fornia
Thrombosis in myocardial infarction and unstable angina.
Over the past 2 decades, a clearer understanding of the acute coronary syndromes has resulted in important progress in management strategies for atherosclerotic coronary artery disease. Whereas short- and longer-term prognosis in patients with acute myocardial infarction was found to relate to differing magnitudes of ventricular dysfunction (I), no common consensus as to the precipitating cause or causes was reached. In particular, a primary role for thrombosis was widely questioned (2). However, in 1980, the angiographic study by DeWood et al. (3) of patients with clinical myocardial infarction admitted for acute surgical revascularization demonstrated that 86% of patients who underwent cardiac catheterization within the first 4 h of symptom onset had diseased coronary arteries completely occluded by recent thrombus. These observations have been confirmed widely to allow for the general conclusion that acute myocardial infarction is due to a completely obstructive thrombus in a previously diseased coronary artery with, after an interval of 0.5 to 6 h, myocardial necrosis in the territory subserved by this vessel. This demonstration has provided a logical basis for current therapies providing acute coronary revascularization by injection or infusion of thrombolytic agents or by mechanical means. Thrombosis tively
has ulso been demonstrated
well defined
acute syndrome-unstable
in another relaangina pec-
Intraoperative angioscopic examination revealed intravascular ulceration with nonobstructive thrombus in patients with this clinical syndrome who had not responded to medical therapy (5). In contrast, patients operated on for severe but stable angina pectoris had an intact endothelial lining, even at the point of maximal luminal reduction, without observable thrombus. Patients categorized as having “unstable angina” must have a minimal level of blood flow through the culprit artery or collateral vessels, allowing for viability in the territory of distribution, thus providing a toris (4).
*Editorials published in the .k~na/ of The American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or of the American College of Cardiology. Manuscript received January 24, 1989;accepted February I, 1989. Add ess for reorinta: H.J.C. Swan, MD. 414 North Camden Drive. BeverlyrHills,
California
01989 by the American
90210.
College of Cardiology
negative serum enzyme test. A majority of patients studied weeks or months after completed acute myocardial infarction demonstrated patency of the culprit artery (6). Total coronary occlusion must have existed in these patients with transmural necrosis, yet later recanalization due to spontaneous thrombolysis had taken place. Ip these earlier reports of patients with acute transmural infarction or patients with unstable angina, thrombolytic agents or platelet inhibitors were not used, althou@ some patients had received heparin. The vascular pathology of atherosclerosis. This is complex and variable (7) and from time to time results in endothelial ulceration with exposure of the subendothelial material to flowing blood. Cholesterol, collagen, fibrous tissue, calcification--the lipid gruel-all affect the interaction between the exposed atherosclerotic lesion and blood components (8). Liberation of tissue thromboplastin and activation of platelets at the site of tissue damage are rapid. Absence of normal functioning endothelium results in a variety of effects, including the induction of thromboses and vasoconstriction, which tends to cause further obstruction in an already partly obstructed vessel. Primary thrombus forming deep fissures within the plaque itself (9) may prove to be resistant to lysis and favor formation of secondary thrombus, extending into the lumen of the vessel, that may be more susceptible to natural or induced lysis. A balance exists in which natural lytic substances ordinarily first oppose and then overcome the thrombotic processes and prothrombotic factors with plaque remodeling and final healing with endothelial repair. The severity of stable obstruction by the atherosclerotic lesion may be greater or less than that before ulceration (10). Acute coronary syndromes. These vary widely in their clinical presentation and acute myocardial infarction probably represents a distinct minority of events. The majorityunstable angina, prolonged myocardial ischemia and “ruled out” myocardial infarction-are by definition not associated with myocardial necrosis (negative serum enzymes) and are consistent with the concept of timely and effective spontaneous lysis of a partial or even completed thrombotic occlusion. Thus, unstable angina may represent a situation in which thrombotic occlusion is severe but does not progress to completion; in “prolonged myocardial ischemia,” chest pain and T wave changes persist beyond those that are usual 0735-1097/89/$3.50
1436
SWAN EDITORIAL
in angina (I 1). Patients with “ruled out” myocardial infarction are characterized by even more prolonged or persistent pain and T wave abnormalities of greater magnitude, and they require in-hospital observation, normalization of the electrocardiogram and a negative enzyme test before categorization and discharge. However, 70% of such patients have important coronary artery disease. A significant proportion of patients with acute myocardial infarction not receiving thrombolytic agents or beta-adrenergic blockade demonstrated evidence for spontaneous reperfusion (12). Even in sudden death syndrome, angiographic studies performed on survivors have implicated plaque rupture, thrombosis and spontaneous lysis (13,14). Spontaneous thromholysis and reperfusion. In each of these syndromes, a rational model of complete coronary occlusion rapidly relieved by intrinsic thrombolytic mechanisms or by mechanical displacement due to a significant pressure gradient across the area of atherosclerosis is consistent with these facts and current knowledge. In unstable angina, occlusion is severe (or perhaps complete) but uncommonly persists for more than a very few minutes. Spontaneous reperfusion occurs in ~20 min in “prolonged myocardial ischemia,” in 30 to 40 min in “ruled out” myocardial infarction, in 60 to 90 min in “non-Q wave infarction” (a syndrome not dissimilar to induced thrombolysis) and for ~3 h in acute transmural myocardial infarction. As described (6), even in conventionally treated acute transmural myocardial infarction, late spontaneous lysis takes place in a significant proportion of patients including those with ventricular aneurysm (15). Reexamination of the placebo data from the various trials of thrombolytic agents in acute myocardial infarction supports this contention, In one study (16), reperfusion was demonstrated in >70% of patients who underwent catheterization 7 to 10 days after assignment to placebo or nitroglycerin while receiving anticoagulant therapy. In another study (17), the angiographic patency in patients receiving placebo with aspirin was 55% at 30 days. Thus, extensive myocardial necrosis in the clinical syndrome of acute myocardial infarction can be attributed to failure of timely spontaneous lysis. A reasonable estimate indicates that the number of patients with “ruled out” and “non-Q wave” infarction discharged from coronary care units is three times the number of patients discharged with “transmural” myocardial infarction. Unstable angina, prolonged ischemia and “ruled out myocardial infarction” with enzyme values within normal limits are more frequent than is non-Q or Q-wave infarction. Thus, spontaneous lysis must be the rule in acute thrombolytic coronary syndromes, perhaps by a factor of five or greater. Persistent thrombotic occlusion is, in fact, the exception. The data supporting spontaneous lysis in the ulcerationthrombosis syndromes (18) appear compelling in unstable angina (rapid) and in acute myocardial infarction (late and
JACC Vol. 13, No. 6 May 1989:1435-7
sometimes not at all). Data are unavailable in cases of prolonged myocardial ischemia. In non-Q wave infarction, persistent occlusion appears to be uncommon (19). In the latter syndrome, coronary collateral flow may limit the extent of myocardial damage. Clinical implications. The implications of this hypothesis are significant. First, spontaneous lytic processes are powerful biologic mechanisms that are deserving of at least as much investigation as pharmacologically induced lysis. Second, failure of spontaneous lysis may be due to overwhelming thrombogenicity of the ulcerated intracoronary plaque because of size, composition, location or an inadequate response of lytic mechanisms. This may be due either to lack of elements in the lytic chain or to excess of circulating plasminogen activator inhibitors (20). Evidence exists for increased levels of fibrinogen in patients with stable coronary disease (21) and in patients with acute myocardial infarction (22) and for a possible relation of these increased levels to hyperlipidemia. Major circadian fluctuations may be relevant to time of onset of acute myocardial infarction (23). However, rt-PA rapid-inhibitor levels vary widely in both patients with coronary artery disease and normal control subjects (24). The relation of thrombosis to coronary ulceration sod healing is well recognized; it is significant in the acute
coronary syndromes (25) and possibly in nonsymptomatic ischemia. The purpose of this editorial is to underscore the usual efficacy of natural lytic processes. Why do they fail, if only in a minority of thrombotic coronary events? Does the solution lie in newer, safer lytic agents (26), prehospital treatment strategies (27), prevention of increases of plasminogen activator inhibitors (20) or inhibition of the thrombogenie and vasoactive consequences of vascular ulceration? Do other mechanisms remain to be discovered? Whatever the cause, persistence of thrombus resulting in myocardial infarction is an uncommon outcome in the acute coronary syndromes.
References 1. Forrester JS, Diamond GA, Chatterjee K, Swan HJC. Medical therapy of acute myocardial infarction by application of hemodynamic subsets. Parts I & II. N Engl J Med 1976;295:135&62,1404-13. 2. Roberts WC. Buja LM. The frequency and incidence of coronary arterial thrombi and other observations in fatal acute myocardial infarction. Am J Med 1972;52:42543. 3. DeWood MA, Spores J, Notske J, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980:303:897-902. 4. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;71:699-708. 5. Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 1986;315:913-9.
JACC Vol. 13. No. f May 1989: 1335-7
1437
SWAN Fl~l’l OKIAL~
6. Pichard AD. Ziff C. Rentrop P. Hold J. Blanke H. Smith H. Anglographlc study of the infarct-related coronary artery in the chronic stage of acute myocardial infarction. Am Heart J lY83:106:687-992.
17. White HD. Norris RM. Brow MA. et al. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987:317:X5&5.
7. Davies MJ. Thomas AC. Plaque fissuring-the cause of acute myocardial infarction. sudden itchaemic death. and crescendo angina, Br Heart J 198.5:53:363-73.
IX. Ridolf RL. Hutchins GM. The relalionship between coronary artery lwons and myocardial infarcts: ulceration of atherosclero:ic plaques precipitating coronary thrombosis. Am Heart J lY77;93:468-86.
X. Fuster V. Badimon L. Cohen M. Ambrose JA. Chesebro the pathogenesis ofacute ischemic syndromes. Circulation 20.
I9
J. Insights inro 198X:77: 1113-
9. I.am JT. Chesebro JH. Steele PM, Dewanjee hlK. et al. Deep arterial injury during experimental angloplasty: relation to a posmve indium-I I Ilabeled plafeler scintigram. quantitative platelet deposition and mural thombosis. J .Am Coil Cardiol 1986:8:138&6 IO. Crihrer A. Saoud~ N. Berland J. Letac B. Regression de la stenow coronaire residuellc apres recanalisation par fibrinolyce dans I’infarctus du myocarde. Arch Mal Coeur 1985:3:353-60.
Ii.
Hurst
II.
Ong L. Reiser P. Coromilas J. Scherr function and rapld release of creatine infarctlon. N Engl J Med lY83.3OY:l-6.
JW.
The Heart.
5th ed. Nevv York:
McGraw-Hill.
19X?: 1015.
L. Morrison J. Left ventrmular kinacr MB in acute myocardial
13. Lo Y-SA. Cutlel. JE. Blake K. Wright AM. Kron J. Suerdlow CD. Angiographlc coronary morphology in survivors of cardiac arrest. Am Heart J 1988:llS 7X1-5. 14. Frank RJ, Roomy PA. Trowbridge JO. Rose JP. Coronary thrombosis and platelet/fibrin microemboli in death associated unh acute myocardial infarction. Br Heart J 19X8:59: 19&-?00. 15. Forman MB. Collins HW. Kopelman HA. et al. Determinanrs of left ventricular aneurysm formation after anterior myocardial infarctlon: a clinical and angiographic study. J Am Coll Cardiol 19X6:6: 125662. 16. Rentrop KP. Feir F, Blanke H. et al. Effects of intracoronary streptokinate and intracoronary nitroglycerin infusion on coronary angiographic patterns and mortality in patients with acute myocardial infarction. N Engl J Med 1984 31 l:l45763.
Ambrose JA. Hjemdahl-Monaen CE. Borrico S. Gorlin R. Fuster V. Plnglographic demonstration of a common lurk bstvveen unstable angina pectoris and non-Q wave acute myocardial infal-coon. Am J Cardiol I%%:6 I -2-w:
10. Sprrngers
ED.
Kluft
C. Plasminogen
actlcalor
Inhibitors.
Blood
19872:
3x1-7. !I,
O‘Connor NTJ. Cederholm-Williams S. Cooper WS. Cotler L. Hypercoagulahihty and coronary artery disease. Br Heart J lY84:52:61&6.
22. V erhcugt FWA. ten Gate JW. Sturk A. et al. Tissue plasminogen activator a;twty and inhibition in acute myocardial mfarction and angiographically normal coronary arteries. .Am J Cardiol 19x7:s’): 1075-Y. 23. Andreotti librinol!rlc Infarction.
F. Davies GJ. Hackett DR. et al. Major circadian flucluations in tactors and possible relevance to tmle of onset of myocardial sudden cardiac death and stroke. .4m J Cardiol lY88:6?:635-7.
24. Hamsten A. Woman B. deFaire L. Blomback M. Increased plasma levels of a rapid mhmitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 19X5:31!: 1557-63. ?5 _.
Forrester JA. Litvack F. Grundfest W. Hickey A. A perspective of coronary disease seen through the arteries of living man. Circulation 19x7:75:505-13.
36. Verstraete theoretical II-?I-X.
M. New thrombolytic drugs in acute myocardial infarction: and practical considerations. Circulation 1987;7h(suppl 111:
27. Bower! LL. Demev HE, Colemont LJ. et al. Prehospital thrombolytic treatment of acute myocardial infarction with anisoylated plasminogen sireptokinase activator complex. Crit Care Med IOXX:lY:8?3-30.
JACC Vol. 13. No. 6 May 1989: 1435-7
Acute Myocardial Infarction: A Failure of Timely, Spontaneous Thrombolysis* H.J.C.
SWAN,
Los Angeles.
MD, PHD, MACP,
FACC
Cal(fornia
Thrombosis in myocardial infarction and unstable angina.
Over the past 2 decades, a clearer understanding of the acute coronary syndromes has resulted in important progress in management strategies for atherosclerotic coronary artery disease. Whereas short- and longer-term prognosis in patients with acute myocardial infarction was found to relate to differing magnitudes of ventricular dysfunction (I), no common consensus as to the precipitating cause or causes was reached. In particular, a primary role for thrombosis was widely questioned (2). However, in 1980, the angiographic study by DeWood et al. (3) of patients with clinical myocardial infarction admitted for acute surgical revascularization demonstrated that 86% of patients who underwent cardiac catheterization within the first 4 h of symptom onset had diseased coronary arteries completely occluded by recent thrombus. These observations have been confirmed widely to allow for the general conclusion that acute myocardial infarction is due to a completely obstructive thrombus in a previously diseased coronary artery with, after an interval of 0.5 to 6 h, myocardial necrosis in the territory subserved by this vessel. This demonstration has provided a logical basis for current therapies providing acute coronary revascularization by injection or infusion of thrombolytic agents or by mechanical means. Thrombosis tively
has ulso been demonstrated
well defined
acute syndrome-unstable
in another relaangina pec-
Intraoperative angioscopic examination revealed intravascular ulceration with nonobstructive thrombus in patients with this clinical syndrome who had not responded to medical therapy (5). In contrast, patients operated on for severe but stable angina pectoris had an intact endothelial lining, even at the point of maximal luminal reduction, without observable thrombus. Patients categorized as having “unstable angina” must have a minimal level of blood flow through the culprit artery or collateral vessels, allowing for viability in the territory of distribution, thus providing a toris (4).
*Editorials published in the .k~na/ of The American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or of the American College of Cardiology. Manuscript received January 24, 1989;accepted February I, 1989. Add ess for reorinta: H.J.C. Swan, MD. 414 North Camden Drive. BeverlyrHills,
California
01989 by the American
90210.
College of Cardiology
negative serum enzyme test. A majority of patients studied weeks or months after completed acute myocardial infarction demonstrated patency of the culprit artery (6). Total coronary occlusion must have existed in these patients with transmural necrosis, yet later recanalization due to spontaneous thrombolysis had taken place. Ip these earlier reports of patients with acute transmural infarction or patients with unstable angina, thrombolytic agents or platelet inhibitors were not used, althou@ some patients had received heparin. The vascular pathology of atherosclerosis. This is complex and variable (7) and from time to time results in endothelial ulceration with exposure of the subendothelial material to flowing blood. Cholesterol, collagen, fibrous tissue, calcification--the lipid gruel-all affect the interaction between the exposed atherosclerotic lesion and blood components (8). Liberation of tissue thromboplastin and activation of platelets at the site of tissue damage are rapid. Absence of normal functioning endothelium results in a variety of effects, including the induction of thromboses and vasoconstriction, which tends to cause further obstruction in an already partly obstructed vessel. Primary thrombus forming deep fissures within the plaque itself (9) may prove to be resistant to lysis and favor formation of secondary thrombus, extending into the lumen of the vessel, that may be more susceptible to natural or induced lysis. A balance exists in which natural lytic substances ordinarily first oppose and then overcome the thrombotic processes and prothrombotic factors with plaque remodeling and final healing with endothelial repair. The severity of stable obstruction by the atherosclerotic lesion may be greater or less than that before ulceration (10). Acute coronary syndromes. These vary widely in their clinical presentation and acute myocardial infarction probably represents a distinct minority of events. The majorityunstable angina, prolonged myocardial ischemia and “ruled out” myocardial infarction-are by definition not associated with myocardial necrosis (negative serum enzymes) and are consistent with the concept of timely and effective spontaneous lysis of a partial or even completed thrombotic occlusion. Thus, unstable angina may represent a situation in which thrombotic occlusion is severe but does not progress to completion; in “prolonged myocardial ischemia,” chest pain and T wave changes persist beyond those that are usual 0735-1097/89/$3.50
1436
SWAN EDITORIAL
in angina (I 1). Patients with “ruled out” myocardial infarction are characterized by even more prolonged or persistent pain and T wave abnormalities of greater magnitude, and they require in-hospital observation, normalization of the electrocardiogram and a negative enzyme test before categorization and discharge. However, 70% of such patients have important coronary artery disease. A significant proportion of patients with acute myocardial infarction not receiving thrombolytic agents or beta-adrenergic blockade demonstrated evidence for spontaneous reperfusion (12). Even in sudden death syndrome, angiographic studies performed on survivors have implicated plaque rupture, thrombosis and spontaneous lysis (13,14). Spontaneous thromholysis and reperfusion. In each of these syndromes, a rational model of complete coronary occlusion rapidly relieved by intrinsic thrombolytic mechanisms or by mechanical displacement due to a significant pressure gradient across the area of atherosclerosis is consistent with these facts and current knowledge. In unstable angina, occlusion is severe (or perhaps complete) but uncommonly persists for more than a very few minutes. Spontaneous reperfusion occurs in ~20 min in “prolonged myocardial ischemia,” in 30 to 40 min in “ruled out” myocardial infarction, in 60 to 90 min in “non-Q wave infarction” (a syndrome not dissimilar to induced thrombolysis) and for ~3 h in acute transmural myocardial infarction. As described (6), even in conventionally treated acute transmural myocardial infarction, late spontaneous lysis takes place in a significant proportion of patients including those with ventricular aneurysm (15). Reexamination of the placebo data from the various trials of thrombolytic agents in acute myocardial infarction supports this contention, In one study (16), reperfusion was demonstrated in >70% of patients who underwent catheterization 7 to 10 days after assignment to placebo or nitroglycerin while receiving anticoagulant therapy. In another study (17), the angiographic patency in patients receiving placebo with aspirin was 55% at 30 days. Thus, extensive myocardial necrosis in the clinical syndrome of acute myocardial infarction can be attributed to failure of timely spontaneous lysis. A reasonable estimate indicates that the number of patients with “ruled out” and “non-Q wave” infarction discharged from coronary care units is three times the number of patients discharged with “transmural” myocardial infarction. Unstable angina, prolonged ischemia and “ruled out myocardial infarction” with enzyme values within normal limits are more frequent than is non-Q or Q-wave infarction. Thus, spontaneous lysis must be the rule in acute thrombolytic coronary syndromes, perhaps by a factor of five or greater. Persistent thrombotic occlusion is, in fact, the exception. The data supporting spontaneous lysis in the ulcerationthrombosis syndromes (18) appear compelling in unstable angina (rapid) and in acute myocardial infarction (late and
JACC Vol. 13, No. 6 May 1989:1435-7
sometimes not at all). Data are unavailable in cases of prolonged myocardial ischemia. In non-Q wave infarction, persistent occlusion appears to be uncommon (19). In the latter syndrome, coronary collateral flow may limit the extent of myocardial damage. Clinical implications. The implications of this hypothesis are significant. First, spontaneous lytic processes are powerful biologic mechanisms that are deserving of at least as much investigation as pharmacologically induced lysis. Second, failure of spontaneous lysis may be due to overwhelming thrombogenicity of the ulcerated intracoronary plaque because of size, composition, location or an inadequate response of lytic mechanisms. This may be due either to lack of elements in the lytic chain or to excess of circulating plasminogen activator inhibitors (20). Evidence exists for increased levels of fibrinogen in patients with stable coronary disease (21) and in patients with acute myocardial infarction (22) and for a possible relation of these increased levels to hyperlipidemia. Major circadian fluctuations may be relevant to time of onset of acute myocardial infarction (23). However, rt-PA rapid-inhibitor levels vary widely in both patients with coronary artery disease and normal control subjects (24). The relation of thrombosis to coronary ulceration sod healing is well recognized; it is significant in the acute
coronary syndromes (25) and possibly in nonsymptomatic ischemia. The purpose of this editorial is to underscore the usual efficacy of natural lytic processes. Why do they fail, if only in a minority of thrombotic coronary events? Does the solution lie in newer, safer lytic agents (26), prehospital treatment strategies (27), prevention of increases of plasminogen activator inhibitors (20) or inhibition of the thrombogenie and vasoactive consequences of vascular ulceration? Do other mechanisms remain to be discovered? Whatever the cause, persistence of thrombus resulting in myocardial infarction is an uncommon outcome in the acute coronary syndromes.
References 1. Forrester JS, Diamond GA, Chatterjee K, Swan HJC. Medical therapy of acute myocardial infarction by application of hemodynamic subsets. Parts I & II. N Engl J Med 1976;295:135&62,1404-13. 2. Roberts WC. Buja LM. The frequency and incidence of coronary arterial thrombi and other observations in fatal acute myocardial infarction. Am J Med 1972;52:42543. 3. DeWood MA, Spores J, Notske J, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980:303:897-902. 4. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;71:699-708. 5. Sherman CT, Litvack F, Grundfest W, et al. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 1986;315:913-9.
JACC Vol. 13. No. f May 1989: 1335-7
1437
SWAN Fl~l’l OKIAL~
6. Pichard AD. Ziff C. Rentrop P. Hold J. Blanke H. Smith H. Anglographlc study of the infarct-related coronary artery in the chronic stage of acute myocardial infarction. Am Heart J lY83:106:687-992.
17. White HD. Norris RM. Brow MA. et al. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med 1987:317:X5&5.
7. Davies MJ. Thomas AC. Plaque fissuring-the cause of acute myocardial infarction. sudden itchaemic death. and crescendo angina, Br Heart J 198.5:53:363-73.
IX. Ridolf RL. Hutchins GM. The relalionship between coronary artery lwons and myocardial infarcts: ulceration of atherosclero:ic plaques precipitating coronary thrombosis. Am Heart J lY77;93:468-86.
X. Fuster V. Badimon L. Cohen M. Ambrose JA. Chesebro the pathogenesis ofacute ischemic syndromes. Circulation 20.
I9
J. Insights inro 198X:77: 1113-
9. I.am JT. Chesebro JH. Steele PM, Dewanjee hlK. et al. Deep arterial injury during experimental angloplasty: relation to a posmve indium-I I Ilabeled plafeler scintigram. quantitative platelet deposition and mural thombosis. J .Am Coil Cardiol 1986:8:138&6 IO. Crihrer A. Saoud~ N. Berland J. Letac B. Regression de la stenow coronaire residuellc apres recanalisation par fibrinolyce dans I’infarctus du myocarde. Arch Mal Coeur 1985:3:353-60.
Ii.
Hurst
II.
Ong L. Reiser P. Coromilas J. Scherr function and rapld release of creatine infarctlon. N Engl J Med lY83.3OY:l-6.
JW.
The Heart.
5th ed. Nevv York:
McGraw-Hill.
19X?: 1015.
L. Morrison J. Left ventrmular kinacr MB in acute myocardial
13. Lo Y-SA. Cutlel. JE. Blake K. Wright AM. Kron J. Suerdlow CD. Angiographlc coronary morphology in survivors of cardiac arrest. Am Heart J 1988:llS 7X1-5. 14. Frank RJ, Roomy PA. Trowbridge JO. Rose JP. Coronary thrombosis and platelet/fibrin microemboli in death associated unh acute myocardial infarction. Br Heart J 19X8:59: 19&-?00. 15. Forman MB. Collins HW. Kopelman HA. et al. Determinanrs of left ventricular aneurysm formation after anterior myocardial infarctlon: a clinical and angiographic study. J Am Coll Cardiol 19X6:6: 125662. 16. Rentrop KP. Feir F, Blanke H. et al. Effects of intracoronary streptokinate and intracoronary nitroglycerin infusion on coronary angiographic patterns and mortality in patients with acute myocardial infarction. N Engl J Med 1984 31 l:l45763.
Ambrose JA. Hjemdahl-Monaen CE. Borrico S. Gorlin R. Fuster V. Plnglographic demonstration of a common lurk bstvveen unstable angina pectoris and non-Q wave acute myocardial infal-coon. Am J Cardiol I%%:6 I -2-w:
10. Sprrngers
ED.
Kluft
C. Plasminogen
actlcalor
Inhibitors.
Blood
19872:
3x1-7. !I,
O‘Connor NTJ. Cederholm-Williams S. Cooper WS. Cotler L. Hypercoagulahihty and coronary artery disease. Br Heart J lY84:52:61&6.
22. V erhcugt FWA. ten Gate JW. Sturk A. et al. Tissue plasminogen activator a;twty and inhibition in acute myocardial mfarction and angiographically normal coronary arteries. .Am J Cardiol 19x7:s’): 1075-Y. 23. Andreotti librinol!rlc Infarction.
F. Davies GJ. Hackett DR. et al. Major circadian flucluations in tactors and possible relevance to tmle of onset of myocardial sudden cardiac death and stroke. .4m J Cardiol lY88:6?:635-7.
24. Hamsten A. Woman B. deFaire L. Blomback M. Increased plasma levels of a rapid mhmitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 19X5:31!: 1557-63. ?5 _.
Forrester JA. Litvack F. Grundfest W. Hickey A. A perspective of coronary disease seen through the arteries of living man. Circulation 19x7:75:505-13.
36. Verstraete theoretical II-?I-X.
M. New thrombolytic drugs in acute myocardial infarction: and practical considerations. Circulation 1987;7h(suppl 111:
27. Bower! LL. Demev HE, Colemont LJ. et al. Prehospital thrombolytic treatment of acute myocardial infarction with anisoylated plasminogen sireptokinase activator complex. Crit Care Med IOXX:lY:8?3-30.