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Intracoronary infusion of streptokinase in patients with acute myocardial infarction: Effects of reperfusion on left ventricular performance
lntracoronary Infusion of Streptokinase in Patients With Acute Myocardial Infarction: Effects of Reperfusion on Left Ventricular Performance
LAWRENCE A. REDUTO, MD. FACC RICHARD W. SMALLING, MD, F’hD GREGORY C. FREUND K. LANCE GOULD, MD, CArr rnvv Houston, Texas
From the Division of Cardiology, Department of Medicine, University of Texas Health Science Center. Houston. Texas. Manuscript received October 27. 1980; revised manuscript received March 23, 1981, accepted Merch 31, 1981. Address for reprints: Lawrence A. Reduto. MD, FACC. Division of Cardldcgy. University of Texas Health Science Center at Houston, P.O. Box 20708, Houston, Texas 77025.
Cardiac catheterization and coronary anglography were performed on hospital admission in 32 consecutive patients with acute myocardial infarction. Twenty-six patlents had total occlusion of an infarct-related coronary artery and six had severe proximal steno&s wtth poor distal ftow. In 18 of the 28 patients with total occlusion, intracoronary infusion of streptokinase resulted in reperfusion of the distal coronary artery. Seventeen of these 18 patients had severe coronary arterial stenosis at the site of the previous total occlusion. Hemodynamlc indexes of left ventricular performance and ejection fraction determined by gated cardiac blood pool imaging did not change immediately afler reperfusion (p [probability] = not signfficant [NS]). The mean (f standard deviation) left ventricular ejection fraction increased significantly (p = 0.007) from admission (44 f 15 percent) to hospital discharge (55 f 7 percent) in patients evidencing reperfuslon of the occluded coronary artery. H dld not change (P = NS) in this tlme span In the patients wtth severe stenosis alone, in those with total occlusion not demonstrating reperfusion after administration of streptoklnase or In an additional 10 contrd patients with acute myocardlal infarctlon not evaluated with coronary anglography. These data suggest that (1) coronary arterial thrombus is frequent In acute myocardlal Infarction and can be lysed by lntracoronary streptoklnase; (2) reperfusion wlth lntracoronary streptoklnase in acute myocardial tnfarction results in Improved left ventricular performance between admission and hospital discharge.
The precise role of coronary arterial thrombosis in the pathogenesis of acute myocardial infarction is undefined. Postmortem studies of patients with acute myocardial infarction have demonstrated wide variations in the prevalence of such thrombosis and have not resolved the temporal relation of intracoronary clot to the onset of myocardial necrosis.’ Moreover, the relative roles of coronary arterial thrombosis, atherosclerotic plaque and coronary vasospasm in the initiation of acute myocardial infarction are complex and suggest a multifactorial origin. In clinical trials2-4 in patients with acute myocardial infarction intravenous thrombolytic agents were used in an attempt to lyse coronary thrombus and thereby restore regional myocardial blood flow. The results in the majority of these trials were equivocal, and few studies2-5 demonstrated reduced mortality and morbidity after acute myocardial infarction. Recent studieG7 using angiographic documentation of coronary thrombus in acute myocardial infarction have suggested that intracoronary infusion of streptokinase results in lysis ofcoronary thrombus with restoration of blood flow in the occluded coronary artery. However, the immediate and long-term effects of intracoronary thrombolytic therapy on preservation of ischemic myocardium in evolving acute myocardial infarction are unknown.
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The purposes of this investigation were to (1) define the prevalence of angiographically defined coronary arterial thrombosis in patients with evolving acute myocardial infarction, (2) assess the efficacy of intracoronary streptokinase in lysis of coronary arterial thrombus, and (3) determine the effects of coronary arterial reperfusion with intracoronary streptokinase on global left ventricular performance in patients with acute myocardial infarction.
Methods Study patients:
The study group consisted of 32 consecutive patients (13 women and 19 men) admitted to The University of Texas Health Science Center with acute myocardial infarction. Their mean age (ZJZ standard deviation) was 56 f 11 years. All patients had chest pain typical of acute myocardial infarction persisting for at least 30 minutes and electrocardiographic evidence of S-T segment elevation in at least two leads. Seventeen patients had S-T segment elevation in precordial leads and 15 patients demonstrated it in the inferior leads. At the time of presentation to the emergency room, 18 patients had electrocardiographic evidence of abnormal (greater than 0.04 second in duration) Q waves in the ieads with S-T segment elevation. Fifteen patients had an elevated serum creatine kinase level on admission. Eight patients had a history of angina pectoris treated with nitrates and propranolol and six had sustained a previous myocardial infarction. One patient had undergone aortocoronary bypass surgery for angina 3 years previously. Control patients: In addition, 10 patients (9 women and 1 man) with acute transmural myocardial infarction served as a control group to define the temporal course of left ventricular performance during the hospital phase of acute myocardial infarction. Patients in this group either refused angiography or met exclusion criteria. Their mean age was 65 f 14 years. Five patients had anterior wall and five had inferior wall myocardial infarction. On admission, five patients had abnormal Q waves in the electrocardiogram, and three had an elevated serum creatine kinase level. Six patients had a previous history of angina and two had a previous myocardial infarction. Protocol: In the emergency room, all subjects received the standard therapy at our institution for patients with acute myocardial infarction, including administration of opiates for pain, nasal oxygen and intravenous lidocaine and continuous electrocardiographic monitoring. Platelet count, prothrombin time, partial thromboplastin time, fibrinogen level and thrombin time were obtained in each patient. Informed consent for cardiac catheterization and intracoronary infusion of streptokinase was obtained directly from each patient by one of the investigators. Exclusion criteria were as follows: (1) cardiogenic shock, (2) history of streptokinase allergy, (3) previous cerebrovascular accident, (4) surgical procedure within the preceding 10 days, (5) significant valve disease, (6) abnormal coagulation profile, and (7) time interval more than 18 hours from the onset of chest pain. Before cardiac catheterization, all patients received aspirin, 300 mg orally and diphenhydramine, 50 mg intravenously. Right and left heart catheterization, left ventriculography and coronary angiography were performed utilizing either the femoral or branchial arterial approach. Cardiac output was determined with the thermodilution technique. Heparin, 5,000 units intravenously, was given to all patients before catheterization After hemodynamic measurements were made, left ventriculography was performed in the 30” right anterior oblique projection utilizing 40 to 60 cc of Renografin-76@.
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Selective coronary angiography in multiple views was performed after ventriculography. On the basis of electrocardiographic site of infarction and regional dyssynergy, the coronary artery not deemed responsible for the acute infarction was studied first, followed by the infarct-related vessel. Intracoronary thrombus was presumed present if there was abrupt total occlusion of a vessel corresponding to the electrocardiographic infarct site and dyssynergy in the ventriculogram. The catheter was then left in the appropriate coronary ostium and 500 fig of nitroglycerin dissolved in saline solution was infused into the occluded coronary artery. Angiography was again performed 1 to 2 minutes later to exclude coronary spasm. If no change in the angiographic appearance of the vessel was noted, streptokinase (Streptasem, Hoechst-Roussel Pharmaceuticals) as a 10,000 unit bolus dose dissolved in 5 cc of saline solution was slowly infused into the occluded coronary artery. The bolus dose was immediately followed by a continuous regulated infusion of streptokinase dissolved in saline solution at a rate of 2,000 units/min through the coronary catheter. The mean interval from the onset of chest pain to infusion of streptokinase was 9.2 f 4 hours (range 2 to 18). Coronary angiography was repeated routinely at 15 minute intervals during the infusion of streptokinase, which was continued until complete reperfusion of the occluded coronary artery was achieved or 60 minutes of infusion had elapsed. If no angiographic evidence of reperfusion was noted after 30 minutes of infusion, a 0.032 inch (0.08/28 cm) movable core guide wire was advanced through the site of total occlusion in an attempt to improve local delivery of streptokinase. This procedure was performed in 11 patients without complications. After completion of infusion of streptokinase, measurements of hemodynamic variables and cardiac output and ventriculography were repeated in the initial 17 patients studied. Complications of angiography infusion: One patient with recurrent
and
streptokinase
chest pain but in hemodynamically stable condition at the start of coronary angiography experienced cardiogenic shock with a systolic blood pressure of 70 mm Hg refractory to pressor agents. Coronary angiography revealed 100 percent occlusion of the right and left circumflex coronary arteries and 99 percent stenosis of the proximal left anterior descending coronary artery. The patient died after 2 minutes of streptokinase infusion despite cardiopulmonary resuscitation and before intraaortic balloon insertion could be performed. No complications were noted in the remaining 31 patients, and all patients remained in clinically stable condition during cardiac catheterization. Subsequent treatment: After completion of cardiac catheterization, the patients were transferred to the coronary care unit and given a maintenance lidocaine infusion at a rate of 2 mglmin. All patients also received dipyridamole (150 mg/day), aspirin (300 mg/day), propranolol, 20 mg (orally every 6 hours), isosorbide dinitrate sublingually (5 mg every 4 hours) and heparin (5,000 units subcutaneously every 6 hours). The patients were observed in the coronary care unit for 3 days, gradually allowed to walk and discharged. In two patients hematomas developed at the site of the femoral arterial puncture but surgical evacuation was not required. Ten patients, with multivessel disease or repeated episodes of angina at rest, or both, underwent aortocoronary bypass surgery before hospital discharge. Radionuclide imaging technique: Gated cardiac blood pool imaging for determination of left ventricular ejection fraction was performed in each patient on three occasions. Admission studies were performed in the cardiac catheterization laboratory immediately before catheter placement. Additionally, a second gated cardiac blood pool scan was ob-
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THROMBOLYTlC TFERAPY IN ACUTE MYOCARDIAL INFARCTION--REM0
mined in the cardiac catheterization laboratory immediately after completion of the postinfusion ventriculogram in the initial 17 patients studied. A third study was performed before either hospital discharge or aortocoronary bypass surgery a mean of 10 days after admission. In the control group of patients with acute myocardial infarction, gated cardiac blood pool imaging was performed on hospital admission and on discharge. All studies were performed utilizing an OhioNuclear 420-550 mobile gamma camera and computer system. In vivo labeling of red blood cells was performed with 15 mg of stannous pyrophosphate followed by a second injection of 25 to 30 mCi of technetium pertechnetate. In our laboratory, ejection fraction determined by this technique correlated closely (r = 0.92) with angiographically determined left ventricular ejection fraction. Furthermore, the variability of the radionuclide technique in a separate group of 20 patients studied in this laboratory was determined to be f6 percent. Statistical analysis: Data are expressed as the mean f standard deviation. Statistical analysis was performed with paired t tests. Comparison of frequency distributions between groups was performed with Fisher’s exact or chi-square tests. Results Coronary Angiography and Left Ventriculography
Of the 32 consecutive patients with acute myocardial infarction studied, 26 had total occlusion of the in-
ET AL.
farct-related coronary artery (Table I). Of these 26 patients, 18 demonstrated reperfusion of the distal coronary artery after intracoronary infusion of streptokinase (Fig. 1 and 2). Seventeen of these 18 patients evidenced a severe (greater than 70 percent reduction in luminal diameter) stenosis at the site of the previously noted total occlusion. Seven patients with total occlusion failed to show angiographic improvement after either intracoronary nitroglycerin or streptokinase. In one patient with total occlusion, the distal coronary artery was visualized after intracoronary injection of nitroglycerin with no further improvement noted after infusion of streptokinase. Six patients demonstrated severe proximal stenosis of the infarct-related vessel with poor distal flow but without abrupt occlusion suggesting intracoronary thrombus. None of these six patients demonstrated angiographic improvement after nitroglycerin and streptokinase. In the entire group of patients studied, 15 patients had significant (greater than 50 percent reduction in luminal diameter) stenosis of one coronary vessel, five had double vessel coronary stenosis and 12 had triple vessel coronary artery disease (Table I). Eight patients demonstrated collateral vessels to the reperfused coronary artery. The mean interval from the onset of streptokinase infusion to angiographically assessed
TABLE I Anglographic Data In 32 Study Patlents (percent reduction In lumlnal dlametew)
Collateral
Case
LAD 50 100’ 95' 100’
sz . .
LCX
ACBG
RCA
.
100’ i&j 0 100’ 100’ io&
90 ...
ltiti
0
lk+
100’ ido'* 100’ 100’
ii i&j* 100’ i&j* 100’
.
‘9;5’. ... !8 70’ 100’
.. :I
. . ‘e’d
.
NC 80
No Yes
z: 90
Liz
2 NC 95
. ... .
No No Yes No No No Yes
..
No
.
No
NC
..
Yes
10-20
. ...
No Yes Yes
NC
. .
.. . . .
iii lb;6 100 lbb’ 100’ :x 100’ 1% 100’ 1b’d* 100’
1%
ii ... ...
;8
ix*
80
if
;"9
Yes No No
...
100’
95
E
. . LA6 ‘lbO*
95.
i&i*
After Streptokinase Infusion
...
:x ...
. .
Channels to Dccluded Coronary Artery
... ...
Liz
... .. .. ... ... .. ...
Ii No No
ti?G NC iz NC
:z NC
:I
k No Yes
NC NC NC 99 NC i!
Streptddnase-Infused coronary artery. ACBG = aortocoronary bypass graft; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; NC = no change; NTG = lntracoronary nitroglycerin; RCA = r&&t coronary artery. l
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FIGURE 1. Right coronary arteriogram (right anterior oblique projection) in a patient with an acute inferior wall myocardial infarction. Left, a pacing wire is in the apex of the right ventricle. Note the total occlusion (arrow) of the proximal to mid right coronary artery. Right, after intracoronary infusion of streptokinase. Arrow indicates a residual 70 percent stenosis at the site of previous total occlusion.
reperfusion of the distal coronary artery was 23 f 12 minutes (range 7 to 45). No significant differences were observed between patients evidencing coronary arterial reperfusion versus those not demonstrating reperfusion with respect to time from the onset of chest pain to study, serum creatine kinase level on admission, age, presence of Q waves in the admission electrocardiogram, severity of coronary artery disease or previous cardiac history (Table II). Left Ventricular Performance and Hemodynamic Data
Hemodynamic data (Table III): Cardiac catheterization data in the initial 17 patients evaluated are summarized in Table III. There were no significant changes in indexes of left ventricular performance obtained before and immediately after infusion of streptokinase either in patients demonstrating reperfusion
of an occluded coronary artery or in patients with severe coronary stenosis who showed no angiographic improvement after administration of nitroglycerin and streptokinase. However, systemic vascular resistance decreased significantly (p = 0.03) between the measurement obtained before streptokinase infusion and that obtained immediately after infusion. To minimize the time interval from the onset of chest pain to infusion of streptokinase and to reduce patient discomfort in the cardiac catheterization laboratory, hemodynamic measurements and ventriculography were not repeated in the subsequent 15 patients studied. Left ventricular ejection fraction (Table IV): Gated cardiac blood pool imaging performed before cardiac catheterization demonstrated abnormal left ventricular ejection fraction (less than 50 percent) in 11 patients. In patients demonstrating reperfusion of an
FIGURE 2. Left coronary arteriogram (right anterior oblique projection) in a 40 year old patient with an acute anteroseptal myocardial infarction. Left, arrow indicates site of total occlusion of the proximal left anterior descending coronary artery. Right, after a 30 minute intracoronary infusion of streptokinase. Arrow indicates a 95 percent stenosis in the left anterior descending coronary artery, at the previously noted site of total occlusion.
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TABLE II
TABLE Ill
Cllnlcal Characterlstlcs ot 32 Study Patlents
Hemodynamlc Data (mean f standard deviation) In lnltlal 17 Study Patlents
Age (yr) (mean f SD) Hours from onset of chest pain Admission CK (mlU) Patients (n) with: Q waves on admission History of angina History of previous MI Coronary artery disease Single Double Triple
Reperfusion (n = 19)
No Reperfusion (n = 13)
p
58f 10 9.0 f 3.2
53 f 13 10.1 f 5.3
NS NS
LVEDP
241 f 291
276 f 383
NS
LVSWI
11 4 3
NS NS NS
SVR
: 3
; 6
NS NS NS
10 :
CK = creatine kinase, MI = myocardial infarction: NS = not significant; p = probability: SD = standard deviation.
occluded coronary artery after intracoronary infusion of streptokinase, mean ejection fraction did not change (p = NS) from immediately before cardiac catheterization (44 f 15% range 22 to 59%) to after catheterization (46 f 14 percent). Similarly, both in patients with total occlusion but without angiographic reperfusion and in patients with severe proximal stenosis, mean ejection fraction did not change from before to after cardiac catheterization. It also did not change from before cardiac catheterization to discharge in patients with total occlusion not evidencing reperfusion or in patients with severe proximal stenosis alone (from 51 f 15 to 52 f 18 percent, p = NS) or in the 10 control patients with acute myocardial infarction not evaluated with coronary angiography (from 47 f 14 to 49 f 16 percent, p = NS). In contrast, ejection fraction increased significantly from before cardiac catheterization to discharge in patients demonstrating reperfusion of an occluded coronary artery after intracoronary infusion of streptokinase (from 44 f 15 to 55 f 7 percent, p = 0.007). An improvement (defined as a greater than 6 percent increase) in absolute left ventricular ejection fraction from before cardiac catheterization to discharge was seen in 7 of 18 patients demonstrating reperfusion of an occluded coronary artery after intracoronary infusion of streptokinase. In contrast, only
1 of the remaining 14 patients with no angiographic response to intracoronary infusion of streptokinase and only 1 of 10 control patients with myocardial infarction evidenced such improvement. The number of patients exhibiting an improvement in left ventricular systolic performance from admission through hospital discharge was significantly greater (chi-square test, p <0.05) in the group demonstrating coronary arterial reperfusion than in patients without angiographic evidence of reperfusion or the control group. There was no relation (r = 0.23) between the duration of chest pain and the absolute change in ejection fraction from before cardiac catheterization to discharge. Furthermore, within the group of 19 patients evidencing reperfusion of an occluded coronary after intracoronary nitroglycerin or
September
Before Streptokinase
Cl HR
28f 11 (range 15 to 48) 39 f 20 (range 17 to 87) 1979 f 612 (range 1,399 to 3,030) 2.19 f 0.28 (range 1.72 to 2.67) 83f 15 (range 50 to 118)
After Streptokinase
P
33 f 9
NS
35f
NS
12
1743 f 620
0.03
2.55 f 0.63
NS
82f
15
NS
Cl = cardiac index (literslmin per m*); HR = heart rate (beatslmin); LVEDP = left ventricular end-diastolicgressure (mm Hg); LVSWI = left ventricular stroke work index (g-m/m ); SVR = systemic vascular resistance (dynes.scm-5).
streptokinase, no significant differences (p = NS) could be discerned between the groups with or without improved left ventricular performance with respect to duration of chest pain, creatine kinase level on hospital admission, mean age, severity of coronary artery disease or duration of streptokinase infusion to lysis of thrombus. Discussion Role of coronary thrombus in initiating myocardial infarction: Our angiographic demonstration that intracoronary infusion of streptokinase resulted in reperfusion of an occluded coronary artery implies that coronary arterial thrombus is frequent in evolving acute myocardial infarction. Furthermore, intracoronary thrombus superimposed on a severe atherosclerotic coronary stenosis appeared to be the most commonly observed lesion responsible for acute myocardial infarction in this series. These data are in agreement with those of Rentrop et a1.s7 and are further supported by the findings of DeWood et al.,8 who noted that intracoronary thrombus was commonly present in the infarct-related coronary artery at the time of aortocoronary bypass surgery for evolving acute myocardial infarction.* Although the initiating mechanism for formation of coronary thrombus remains poorly under-
TABLE IV Radionucllde Election Fraction In 32 Study Patlents
Patient Croup
n
No angiography
10
No angiographic reperfusion after streptokinase Angiographic reperfusion after streptckinfse
14
1981
The American
18
Before Streptokinase (%) 47 f 14 23 to 51 f 15 21 to 44f
(range 70) (range 60)
lS(range 22 to 59)
Journal of CARDIOLOGY
On Discharge (%)
P
49 f
16
NS
52f
18
NS
55 f
7
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THROMBOLYTIC THERAPY IN ACUTE MYOCARDIAL INFARCTION-REDUTO
stood, it is conceivable that intimal disruption of the atherosclerotic plaque leads to platelet aggregation and precipitation of intracoronary clot. The observation by Oliva and Breckenridge9 that coronary arterial spasm is frequent in evolving acute myocardial infarction may be explained by the release of vasoactive substances during platelet aggregation.“’ Recent studies”J” in patients with myocardial infarction have suggested that platelet-inhibitory drugs such as dipyridamole or sulfinpyrazone may reduce subsequent coronary events and mortality. These data have important therapeutic implications in the management of patients undergoing intracoronary thrombolytic therapy for acute myocardial infarction. In our investigation, although no patient had clinical or electrocardiographic evidence of reocelusion while treated in the hospital with aspirin and dipyridamole, the long-term medical management and the role of aortocoronary bypass surgery in the prevention of reocclusion in these patients remain to he determined. Previous studies on interventions to reduce infarct size: Salvage of ischemic myocardium remains a prime goal of therapy in patients with acute myocardial infarction because infarct size is a major determinant of both in-hospital and late morbidity and mortality.13.14 Previous studies I5 have suggested that myocardial infarction is composed of a central area of necrosis surrounded by an ischemic “border zone.“‘” Many basic and clinical studies”‘Js have attempted to reduce the magnitude of evolving necrosis through a variety of pharmacologic interventions on this potentially reversible ischemic border zone. Although this concept has been questioned,‘; previous studies of experimental infarction have shown that the magnitude of myocardial necrosis is directly related to the duration of coronary arterial occlusion with little salvageable myocardium present after 6 hours of occlusion in acute experiments in the dog.ls In our investigation, there was a poor correlation between the duration of symptoms before initiation of thrombolytic therapy and change in ejection fraction from before infusion to discharge. The duration of time available for salvage of ischemic myocardium at risk after coronary occlusion in human beings is unknown and is likely to be more variable than in animal models of infarction because of differences in the degree of coronary stenosis, extent of collateral circulation and the effects of propranolol.lg Left ventricular performance after lysis of clot and reperfusion: Experimental models of acute myocardial infarction resulting from coronary arterial thrombus have demonstrated improvement in left ventricular performance after lysis with thrombolytic agents.20*21 In our investigation, left ventricular per-
ET AL.
formance was assessed both in the immediate postreperfusion period and at hospital discharge, utilizing both hemodynamic and radionuclide techniques. Previous experimental studies 22 of coronary occlusion and reperfusion have shown that left ventricular function in the horder zone may require several weeks to return to normal after a 2 hour period of occlusion. Such data are in agreement with those of our investigation. Despite a decrease in systemic vascular resistance, presumably due to the vasodilating effects of contrast medium, radionuclide ejection fraction and additional indexes of left ventricular performance did not change from preinfusion to immediate postinfusion measurements in the initial group of 17 patients studied. However, patients evidencing reperfusion of an occluded coronary artery after intracoronary infusion of streptokinase demonstrated a significant increase (p <0.05) in ejection fraction from before infusion to hospital discharge. In contrast, in patients without angiographic evidence of reperfusion and in 10 control patients, mean left ventricular ejection fraction did not change from admission to hospital discharge (p = NS). These data are in agreement with several previous hemodynamic and radionuclide studies’“-“” demonstrating that left ventricular systolic performance does not change during the hospital phase of acute myocardial infarction. Although the number of patients in our series is small, the increase in left ventricular ejection fraction shown in our study may suggest a beneficial effect of intracoronary thrombolytic therapy on left ventricular performance in evolving acute myocardial infarction. The clinical and laboratory features of patients likely to benefit from intracoronary thrombolytic therapy could not be identified in this preliminary investigation. Further studies using this therapeutic technique will be required to differentiate at hospital admission between patients with intracoronary thrombus and patients with severe atherosclerotic lesions and poor distal flow. Therapeutic implications: Our preliminary data suggest that intracoronary infusion of thrombolytic agents such as streptokinase may be safely performed in evolving acute myocardial infarction; it results in reperfusion of the occluded coronary artery and may improve left ventricular performance by the time of hospital discharge. Moreover, this technique may provide an alternative to aortocoronary bypass surgery in the reestablishment of coronary blood flow to ischemic myocardium in acute myocardial infarction.H,26 Acknowledgment We express our gratitude to Kathryn Rainbird for secretarial assistance and to Diane Bennett, RN and Linda Elder for technical assistance.
References 1. Chandkr AB, Chapman I, Ether& LE, St al. Coronary thrombosis in myocardial infarction. Report of a workshop on the role of corotlat’y thfornbosis in the pathogenesis of acute myocardial infarction. Am J Cardiol 1974;34:823-33. 2. Aber CP, Bare NM, Berry LL, et al. Streptokinase in acute myocardial infarction: a controlled multicentre study in the United
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Kingdom. Br Med J 1976;2: 1100-4. 3. European Working Party. Streptokinase in recent myocardial infarction: a controlled multicentre trial. Br Med J 1971;3:325-31. 4. European Collaborative Study. A controlled trial of urokinase in myocardial infarction. Lancet 1975;2:624-6. 5. European Cooperative St&y Group for Streptokinase Treatment
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8.
7.
8.
9.
10.
11.
12.
13.
14. 15. 16.
in Acute Myocardial Infarction. Streptokinase in acute myocardial infarction. N Erg1 J Med 1979;301:797-803. Rentrop P, Blanke H, K6aterlng K, Karach KR. Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase in combination with transluminal recanalization. Clin Cardiol 1979;2:354-83. Rentrop P, Blanke H, Karsch KR, Katser Ii, Kdstertng H, Lettz K. Selective intraccronary thrornbotysis in acute myocardttl infarctit and unstable angina pectoris. Circulation 1981;83:307-18. BeWood MA, Spores J, Notake R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897-901. Ollva PB, Breckenrklge JC. Arteriographic evidence of coronary spasm in acute myocardial infarction. Circulation 1977;56: 366-76. Heedfaman P, Kulharnl PS, Raz A. Coronary tone modulation: formation and actions of prostaglandins, endoperoxides and thromboxanes. Science 1977; 195409-l 1. Persantine-Aspirin Reinfarction Study Research Croup. Persantine and aspirin in coronary heart disease. Circulation 1980;62: 449-60. Antwane Reinfarction Trial Research Croup. Sulfinpyrazone in the prevention of sudden death after myocardial infarction. N Engl J Med 1980;302:250-6. Weber KT, Ratshln RA, Jankkl JS, Rackley CB, Russell RO. Left ventricular dysfunction following acute myocardial infarction. Am J Med 1973;54:697-705. Caulflekf JB, Lekrbach R, Gokt H. The relationship of myocardial infarct size and prognosis. Circulation 1978;53:Suppl l:l-141-4. Mar&o PR, Braunwdd E. Modification of myocardial infarction size after coronary occlusion. Ann Intern Med 1973;79:720-33. Mar&o PR, BraunwakJ B. Effects of metabolic and pharmacologic interventions on myocardial infarct size following coronary occlusion. Circulation 1976;53:Suppl l:l-182-8.
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ET AL.
17. Hlrzel HO, Borwtenbllck EH, Klrk ES. Absence of a lateral border zone of intermediate creatina phosph&inase depletion surounding a central infarct 24 hours after acute coronary occlusion in the dog. Circ Res 1977;41:673-83. 18. Relmer KA, Lowe JE, Rasmussen MM, Jennlqs RB. The wavefront phenomenon of ischemic cell death. Circ 1977;58:78693. 19. Raam~sen MM, Rekner KA, Ktover RA, Jemfngs RB. Infarct size reduction by prcpranotol before and after coronary ligation in dogs. Circulation 1977;56:794-8. 20. Moschos LB, Burke WM, Lehan PH, Oklewurtel HA, Regan TJ. Thrombolytic agents and lysis of coronary artery thrombosis. Cardiovasc Res 1970;4:228-34. 2 1, Kcrdsnat RK, Kezdt P. Experimental intraccxonary thrombosis and selective in situ lysis by catheter technique. Am J Cardiol 1972; 30:640-5. 22. Ross J, Theroux P, Sasayama S, McKown D, Franklln D. Late recovery of cardiac function after coronary artery reperfusion (abstr). Circulation 1975;51:Suppl ll:ll-21. 23. Kupper W, Blelfleld W, Hanroth P, Mathey D, Effert S. Left ventricutar he-t and furtctii in acute myocardial infarction: studies during the acute phase, convalescence and later recovery. Am J Cardiol 1977;40:900-5. 24. Reduto LA, Berger HJ, Cohen LS, BoRschelk A, Zaret BL. Sequential radionuclide assessment of left and right ventricular performance after acute transmural myocardial infarction. Ann Int Med 1978;89:441-7. 25. Schelbert HR, Henning H, Ashbum WL, Verba JW, Karllnar JS, O’Rourke RA. Serial measurements of left ventricular ejection fraction by radicnuclids angiogaphy earty and late after myocardbl infarction. Am J Cardiol 1976;38:407-15. 26. Phllllp BJ, Kougtahworn C, Zeff RH, et al. Emergency coronary artery revascularization: a possible therapy for acute myocardial infarction. Circulation 1979;60:241-6.
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Volume 49
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LAWRENCE A. REDUTO, MD. FACC RICHARD W. SMALLING, MD, F’hD GREGORY C. FREUND K. LANCE GOULD, MD, CArr rnvv Houston, Texas
From the Division of Cardiology, Department of Medicine, University of Texas Health Science Center. Houston. Texas. Manuscript received October 27. 1980; revised manuscript received March 23, 1981, accepted Merch 31, 1981. Address for reprints: Lawrence A. Reduto. MD, FACC. Division of Cardldcgy. University of Texas Health Science Center at Houston, P.O. Box 20708, Houston, Texas 77025.
Cardiac catheterization and coronary anglography were performed on hospital admission in 32 consecutive patients with acute myocardial infarction. Twenty-six patlents had total occlusion of an infarct-related coronary artery and six had severe proximal steno&s wtth poor distal ftow. In 18 of the 28 patients with total occlusion, intracoronary infusion of streptokinase resulted in reperfusion of the distal coronary artery. Seventeen of these 18 patients had severe coronary arterial stenosis at the site of the previous total occlusion. Hemodynamlc indexes of left ventricular performance and ejection fraction determined by gated cardiac blood pool imaging did not change immediately afler reperfusion (p [probability] = not signfficant [NS]). The mean (f standard deviation) left ventricular ejection fraction increased significantly (p = 0.007) from admission (44 f 15 percent) to hospital discharge (55 f 7 percent) in patients evidencing reperfuslon of the occluded coronary artery. H dld not change (P = NS) in this tlme span In the patients wtth severe stenosis alone, in those with total occlusion not demonstrating reperfusion after administration of streptoklnase or In an additional 10 contrd patients with acute myocardlal infarctlon not evaluated with coronary anglography. These data suggest that (1) coronary arterial thrombus is frequent In acute myocardlal Infarction and can be lysed by lntracoronary streptoklnase; (2) reperfusion wlth lntracoronary streptoklnase in acute myocardial tnfarction results in Improved left ventricular performance between admission and hospital discharge.
The precise role of coronary arterial thrombosis in the pathogenesis of acute myocardial infarction is undefined. Postmortem studies of patients with acute myocardial infarction have demonstrated wide variations in the prevalence of such thrombosis and have not resolved the temporal relation of intracoronary clot to the onset of myocardial necrosis.’ Moreover, the relative roles of coronary arterial thrombosis, atherosclerotic plaque and coronary vasospasm in the initiation of acute myocardial infarction are complex and suggest a multifactorial origin. In clinical trials2-4 in patients with acute myocardial infarction intravenous thrombolytic agents were used in an attempt to lyse coronary thrombus and thereby restore regional myocardial blood flow. The results in the majority of these trials were equivocal, and few studies2-5 demonstrated reduced mortality and morbidity after acute myocardial infarction. Recent studieG7 using angiographic documentation of coronary thrombus in acute myocardial infarction have suggested that intracoronary infusion of streptokinase results in lysis ofcoronary thrombus with restoration of blood flow in the occluded coronary artery. However, the immediate and long-term effects of intracoronary thrombolytic therapy on preservation of ischemic myocardium in evolving acute myocardial infarction are unknown.
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The purposes of this investigation were to (1) define the prevalence of angiographically defined coronary arterial thrombosis in patients with evolving acute myocardial infarction, (2) assess the efficacy of intracoronary streptokinase in lysis of coronary arterial thrombus, and (3) determine the effects of coronary arterial reperfusion with intracoronary streptokinase on global left ventricular performance in patients with acute myocardial infarction.
Methods Study patients:
The study group consisted of 32 consecutive patients (13 women and 19 men) admitted to The University of Texas Health Science Center with acute myocardial infarction. Their mean age (ZJZ standard deviation) was 56 f 11 years. All patients had chest pain typical of acute myocardial infarction persisting for at least 30 minutes and electrocardiographic evidence of S-T segment elevation in at least two leads. Seventeen patients had S-T segment elevation in precordial leads and 15 patients demonstrated it in the inferior leads. At the time of presentation to the emergency room, 18 patients had electrocardiographic evidence of abnormal (greater than 0.04 second in duration) Q waves in the ieads with S-T segment elevation. Fifteen patients had an elevated serum creatine kinase level on admission. Eight patients had a history of angina pectoris treated with nitrates and propranolol and six had sustained a previous myocardial infarction. One patient had undergone aortocoronary bypass surgery for angina 3 years previously. Control patients: In addition, 10 patients (9 women and 1 man) with acute transmural myocardial infarction served as a control group to define the temporal course of left ventricular performance during the hospital phase of acute myocardial infarction. Patients in this group either refused angiography or met exclusion criteria. Their mean age was 65 f 14 years. Five patients had anterior wall and five had inferior wall myocardial infarction. On admission, five patients had abnormal Q waves in the electrocardiogram, and three had an elevated serum creatine kinase level. Six patients had a previous history of angina and two had a previous myocardial infarction. Protocol: In the emergency room, all subjects received the standard therapy at our institution for patients with acute myocardial infarction, including administration of opiates for pain, nasal oxygen and intravenous lidocaine and continuous electrocardiographic monitoring. Platelet count, prothrombin time, partial thromboplastin time, fibrinogen level and thrombin time were obtained in each patient. Informed consent for cardiac catheterization and intracoronary infusion of streptokinase was obtained directly from each patient by one of the investigators. Exclusion criteria were as follows: (1) cardiogenic shock, (2) history of streptokinase allergy, (3) previous cerebrovascular accident, (4) surgical procedure within the preceding 10 days, (5) significant valve disease, (6) abnormal coagulation profile, and (7) time interval more than 18 hours from the onset of chest pain. Before cardiac catheterization, all patients received aspirin, 300 mg orally and diphenhydramine, 50 mg intravenously. Right and left heart catheterization, left ventriculography and coronary angiography were performed utilizing either the femoral or branchial arterial approach. Cardiac output was determined with the thermodilution technique. Heparin, 5,000 units intravenously, was given to all patients before catheterization After hemodynamic measurements were made, left ventriculography was performed in the 30” right anterior oblique projection utilizing 40 to 60 cc of Renografin-76@.
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Selective coronary angiography in multiple views was performed after ventriculography. On the basis of electrocardiographic site of infarction and regional dyssynergy, the coronary artery not deemed responsible for the acute infarction was studied first, followed by the infarct-related vessel. Intracoronary thrombus was presumed present if there was abrupt total occlusion of a vessel corresponding to the electrocardiographic infarct site and dyssynergy in the ventriculogram. The catheter was then left in the appropriate coronary ostium and 500 fig of nitroglycerin dissolved in saline solution was infused into the occluded coronary artery. Angiography was again performed 1 to 2 minutes later to exclude coronary spasm. If no change in the angiographic appearance of the vessel was noted, streptokinase (Streptasem, Hoechst-Roussel Pharmaceuticals) as a 10,000 unit bolus dose dissolved in 5 cc of saline solution was slowly infused into the occluded coronary artery. The bolus dose was immediately followed by a continuous regulated infusion of streptokinase dissolved in saline solution at a rate of 2,000 units/min through the coronary catheter. The mean interval from the onset of chest pain to infusion of streptokinase was 9.2 f 4 hours (range 2 to 18). Coronary angiography was repeated routinely at 15 minute intervals during the infusion of streptokinase, which was continued until complete reperfusion of the occluded coronary artery was achieved or 60 minutes of infusion had elapsed. If no angiographic evidence of reperfusion was noted after 30 minutes of infusion, a 0.032 inch (0.08/28 cm) movable core guide wire was advanced through the site of total occlusion in an attempt to improve local delivery of streptokinase. This procedure was performed in 11 patients without complications. After completion of infusion of streptokinase, measurements of hemodynamic variables and cardiac output and ventriculography were repeated in the initial 17 patients studied. Complications of angiography infusion: One patient with recurrent
and
streptokinase
chest pain but in hemodynamically stable condition at the start of coronary angiography experienced cardiogenic shock with a systolic blood pressure of 70 mm Hg refractory to pressor agents. Coronary angiography revealed 100 percent occlusion of the right and left circumflex coronary arteries and 99 percent stenosis of the proximal left anterior descending coronary artery. The patient died after 2 minutes of streptokinase infusion despite cardiopulmonary resuscitation and before intraaortic balloon insertion could be performed. No complications were noted in the remaining 31 patients, and all patients remained in clinically stable condition during cardiac catheterization. Subsequent treatment: After completion of cardiac catheterization, the patients were transferred to the coronary care unit and given a maintenance lidocaine infusion at a rate of 2 mglmin. All patients also received dipyridamole (150 mg/day), aspirin (300 mg/day), propranolol, 20 mg (orally every 6 hours), isosorbide dinitrate sublingually (5 mg every 4 hours) and heparin (5,000 units subcutaneously every 6 hours). The patients were observed in the coronary care unit for 3 days, gradually allowed to walk and discharged. In two patients hematomas developed at the site of the femoral arterial puncture but surgical evacuation was not required. Ten patients, with multivessel disease or repeated episodes of angina at rest, or both, underwent aortocoronary bypass surgery before hospital discharge. Radionuclide imaging technique: Gated cardiac blood pool imaging for determination of left ventricular ejection fraction was performed in each patient on three occasions. Admission studies were performed in the cardiac catheterization laboratory immediately before catheter placement. Additionally, a second gated cardiac blood pool scan was ob-
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mined in the cardiac catheterization laboratory immediately after completion of the postinfusion ventriculogram in the initial 17 patients studied. A third study was performed before either hospital discharge or aortocoronary bypass surgery a mean of 10 days after admission. In the control group of patients with acute myocardial infarction, gated cardiac blood pool imaging was performed on hospital admission and on discharge. All studies were performed utilizing an OhioNuclear 420-550 mobile gamma camera and computer system. In vivo labeling of red blood cells was performed with 15 mg of stannous pyrophosphate followed by a second injection of 25 to 30 mCi of technetium pertechnetate. In our laboratory, ejection fraction determined by this technique correlated closely (r = 0.92) with angiographically determined left ventricular ejection fraction. Furthermore, the variability of the radionuclide technique in a separate group of 20 patients studied in this laboratory was determined to be f6 percent. Statistical analysis: Data are expressed as the mean f standard deviation. Statistical analysis was performed with paired t tests. Comparison of frequency distributions between groups was performed with Fisher’s exact or chi-square tests. Results Coronary Angiography and Left Ventriculography
Of the 32 consecutive patients with acute myocardial infarction studied, 26 had total occlusion of the in-
ET AL.
farct-related coronary artery (Table I). Of these 26 patients, 18 demonstrated reperfusion of the distal coronary artery after intracoronary infusion of streptokinase (Fig. 1 and 2). Seventeen of these 18 patients evidenced a severe (greater than 70 percent reduction in luminal diameter) stenosis at the site of the previously noted total occlusion. Seven patients with total occlusion failed to show angiographic improvement after either intracoronary nitroglycerin or streptokinase. In one patient with total occlusion, the distal coronary artery was visualized after intracoronary injection of nitroglycerin with no further improvement noted after infusion of streptokinase. Six patients demonstrated severe proximal stenosis of the infarct-related vessel with poor distal flow but without abrupt occlusion suggesting intracoronary thrombus. None of these six patients demonstrated angiographic improvement after nitroglycerin and streptokinase. In the entire group of patients studied, 15 patients had significant (greater than 50 percent reduction in luminal diameter) stenosis of one coronary vessel, five had double vessel coronary stenosis and 12 had triple vessel coronary artery disease (Table I). Eight patients demonstrated collateral vessels to the reperfused coronary artery. The mean interval from the onset of streptokinase infusion to angiographically assessed
TABLE I Anglographic Data In 32 Study Patlents (percent reduction In lumlnal dlametew)
Collateral
Case
LAD 50 100’ 95' 100’
sz . .
LCX
ACBG
RCA
.
100’ i&j 0 100’ 100’ io&
90 ...
ltiti
0
lk+
100’ ido'* 100’ 100’
ii i&j* 100’ i&j* 100’
.
‘9;5’. ... !8 70’ 100’
.. :I
. . ‘e’d
.
NC 80
No Yes
z: 90
Liz
2 NC 95
. ... .
No No Yes No No No Yes
..
No
.
No
NC
..
Yes
10-20
. ...
No Yes Yes
NC
. .
.. . . .
iii lb;6 100 lbb’ 100’ :x 100’ 1% 100’ 1b’d* 100’
1%
ii ... ...
;8
ix*
80
if
;"9
Yes No No
...
100’
95
E
. . LA6 ‘lbO*
95.
i&i*
After Streptokinase Infusion
...
:x ...
. .
Channels to Dccluded Coronary Artery
... ...
Liz
... .. .. ... ... .. ...
Ii No No
ti?G NC iz NC
:z NC
:I
k No Yes
NC NC NC 99 NC i!
Streptddnase-Infused coronary artery. ACBG = aortocoronary bypass graft; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; NC = no change; NTG = lntracoronary nitroglycerin; RCA = r&&t coronary artery. l
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FIGURE 1. Right coronary arteriogram (right anterior oblique projection) in a patient with an acute inferior wall myocardial infarction. Left, a pacing wire is in the apex of the right ventricle. Note the total occlusion (arrow) of the proximal to mid right coronary artery. Right, after intracoronary infusion of streptokinase. Arrow indicates a residual 70 percent stenosis at the site of previous total occlusion.
reperfusion of the distal coronary artery was 23 f 12 minutes (range 7 to 45). No significant differences were observed between patients evidencing coronary arterial reperfusion versus those not demonstrating reperfusion with respect to time from the onset of chest pain to study, serum creatine kinase level on admission, age, presence of Q waves in the admission electrocardiogram, severity of coronary artery disease or previous cardiac history (Table II). Left Ventricular Performance and Hemodynamic Data
Hemodynamic data (Table III): Cardiac catheterization data in the initial 17 patients evaluated are summarized in Table III. There were no significant changes in indexes of left ventricular performance obtained before and immediately after infusion of streptokinase either in patients demonstrating reperfusion
of an occluded coronary artery or in patients with severe coronary stenosis who showed no angiographic improvement after administration of nitroglycerin and streptokinase. However, systemic vascular resistance decreased significantly (p = 0.03) between the measurement obtained before streptokinase infusion and that obtained immediately after infusion. To minimize the time interval from the onset of chest pain to infusion of streptokinase and to reduce patient discomfort in the cardiac catheterization laboratory, hemodynamic measurements and ventriculography were not repeated in the subsequent 15 patients studied. Left ventricular ejection fraction (Table IV): Gated cardiac blood pool imaging performed before cardiac catheterization demonstrated abnormal left ventricular ejection fraction (less than 50 percent) in 11 patients. In patients demonstrating reperfusion of an
FIGURE 2. Left coronary arteriogram (right anterior oblique projection) in a 40 year old patient with an acute anteroseptal myocardial infarction. Left, arrow indicates site of total occlusion of the proximal left anterior descending coronary artery. Right, after a 30 minute intracoronary infusion of streptokinase. Arrow indicates a 95 percent stenosis in the left anterior descending coronary artery, at the previously noted site of total occlusion.
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TABLE II
TABLE Ill
Cllnlcal Characterlstlcs ot 32 Study Patlents
Hemodynamlc Data (mean f standard deviation) In lnltlal 17 Study Patlents
Age (yr) (mean f SD) Hours from onset of chest pain Admission CK (mlU) Patients (n) with: Q waves on admission History of angina History of previous MI Coronary artery disease Single Double Triple
Reperfusion (n = 19)
No Reperfusion (n = 13)
p
58f 10 9.0 f 3.2
53 f 13 10.1 f 5.3
NS NS
LVEDP
241 f 291
276 f 383
NS
LVSWI
11 4 3
NS NS NS
SVR
: 3
; 6
NS NS NS
10 :
CK = creatine kinase, MI = myocardial infarction: NS = not significant; p = probability: SD = standard deviation.
occluded coronary artery after intracoronary infusion of streptokinase, mean ejection fraction did not change (p = NS) from immediately before cardiac catheterization (44 f 15% range 22 to 59%) to after catheterization (46 f 14 percent). Similarly, both in patients with total occlusion but without angiographic reperfusion and in patients with severe proximal stenosis, mean ejection fraction did not change from before to after cardiac catheterization. It also did not change from before cardiac catheterization to discharge in patients with total occlusion not evidencing reperfusion or in patients with severe proximal stenosis alone (from 51 f 15 to 52 f 18 percent, p = NS) or in the 10 control patients with acute myocardial infarction not evaluated with coronary angiography (from 47 f 14 to 49 f 16 percent, p = NS). In contrast, ejection fraction increased significantly from before cardiac catheterization to discharge in patients demonstrating reperfusion of an occluded coronary artery after intracoronary infusion of streptokinase (from 44 f 15 to 55 f 7 percent, p = 0.007). An improvement (defined as a greater than 6 percent increase) in absolute left ventricular ejection fraction from before cardiac catheterization to discharge was seen in 7 of 18 patients demonstrating reperfusion of an occluded coronary artery after intracoronary infusion of streptokinase. In contrast, only
1 of the remaining 14 patients with no angiographic response to intracoronary infusion of streptokinase and only 1 of 10 control patients with myocardial infarction evidenced such improvement. The number of patients exhibiting an improvement in left ventricular systolic performance from admission through hospital discharge was significantly greater (chi-square test, p <0.05) in the group demonstrating coronary arterial reperfusion than in patients without angiographic evidence of reperfusion or the control group. There was no relation (r = 0.23) between the duration of chest pain and the absolute change in ejection fraction from before cardiac catheterization to discharge. Furthermore, within the group of 19 patients evidencing reperfusion of an occluded coronary after intracoronary nitroglycerin or
September
Before Streptokinase
Cl HR
28f 11 (range 15 to 48) 39 f 20 (range 17 to 87) 1979 f 612 (range 1,399 to 3,030) 2.19 f 0.28 (range 1.72 to 2.67) 83f 15 (range 50 to 118)
After Streptokinase
P
33 f 9
NS
35f
NS
12
1743 f 620
0.03
2.55 f 0.63
NS
82f
15
NS
Cl = cardiac index (literslmin per m*); HR = heart rate (beatslmin); LVEDP = left ventricular end-diastolicgressure (mm Hg); LVSWI = left ventricular stroke work index (g-m/m ); SVR = systemic vascular resistance (dynes.scm-5).
streptokinase, no significant differences (p = NS) could be discerned between the groups with or without improved left ventricular performance with respect to duration of chest pain, creatine kinase level on hospital admission, mean age, severity of coronary artery disease or duration of streptokinase infusion to lysis of thrombus. Discussion Role of coronary thrombus in initiating myocardial infarction: Our angiographic demonstration that intracoronary infusion of streptokinase resulted in reperfusion of an occluded coronary artery implies that coronary arterial thrombus is frequent in evolving acute myocardial infarction. Furthermore, intracoronary thrombus superimposed on a severe atherosclerotic coronary stenosis appeared to be the most commonly observed lesion responsible for acute myocardial infarction in this series. These data are in agreement with those of Rentrop et a1.s7 and are further supported by the findings of DeWood et al.,8 who noted that intracoronary thrombus was commonly present in the infarct-related coronary artery at the time of aortocoronary bypass surgery for evolving acute myocardial infarction.* Although the initiating mechanism for formation of coronary thrombus remains poorly under-
TABLE IV Radionucllde Election Fraction In 32 Study Patlents
Patient Croup
n
No angiography
10
No angiographic reperfusion after streptokinase Angiographic reperfusion after streptckinfse
14
1981
The American
18
Before Streptokinase (%) 47 f 14 23 to 51 f 15 21 to 44f
(range 70) (range 60)
lS(range 22 to 59)
Journal of CARDIOLOGY
On Discharge (%)
P
49 f
16
NS
52f
18
NS
55 f
7
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THROMBOLYTIC THERAPY IN ACUTE MYOCARDIAL INFARCTION-REDUTO
stood, it is conceivable that intimal disruption of the atherosclerotic plaque leads to platelet aggregation and precipitation of intracoronary clot. The observation by Oliva and Breckenridge9 that coronary arterial spasm is frequent in evolving acute myocardial infarction may be explained by the release of vasoactive substances during platelet aggregation.“’ Recent studies”J” in patients with myocardial infarction have suggested that platelet-inhibitory drugs such as dipyridamole or sulfinpyrazone may reduce subsequent coronary events and mortality. These data have important therapeutic implications in the management of patients undergoing intracoronary thrombolytic therapy for acute myocardial infarction. In our investigation, although no patient had clinical or electrocardiographic evidence of reocelusion while treated in the hospital with aspirin and dipyridamole, the long-term medical management and the role of aortocoronary bypass surgery in the prevention of reocclusion in these patients remain to he determined. Previous studies on interventions to reduce infarct size: Salvage of ischemic myocardium remains a prime goal of therapy in patients with acute myocardial infarction because infarct size is a major determinant of both in-hospital and late morbidity and mortality.13.14 Previous studies I5 have suggested that myocardial infarction is composed of a central area of necrosis surrounded by an ischemic “border zone.“‘” Many basic and clinical studies”‘Js have attempted to reduce the magnitude of evolving necrosis through a variety of pharmacologic interventions on this potentially reversible ischemic border zone. Although this concept has been questioned,‘; previous studies of experimental infarction have shown that the magnitude of myocardial necrosis is directly related to the duration of coronary arterial occlusion with little salvageable myocardium present after 6 hours of occlusion in acute experiments in the dog.ls In our investigation, there was a poor correlation between the duration of symptoms before initiation of thrombolytic therapy and change in ejection fraction from before infusion to discharge. The duration of time available for salvage of ischemic myocardium at risk after coronary occlusion in human beings is unknown and is likely to be more variable than in animal models of infarction because of differences in the degree of coronary stenosis, extent of collateral circulation and the effects of propranolol.lg Left ventricular performance after lysis of clot and reperfusion: Experimental models of acute myocardial infarction resulting from coronary arterial thrombus have demonstrated improvement in left ventricular performance after lysis with thrombolytic agents.20*21 In our investigation, left ventricular per-
ET AL.
formance was assessed both in the immediate postreperfusion period and at hospital discharge, utilizing both hemodynamic and radionuclide techniques. Previous experimental studies 22 of coronary occlusion and reperfusion have shown that left ventricular function in the horder zone may require several weeks to return to normal after a 2 hour period of occlusion. Such data are in agreement with those of our investigation. Despite a decrease in systemic vascular resistance, presumably due to the vasodilating effects of contrast medium, radionuclide ejection fraction and additional indexes of left ventricular performance did not change from preinfusion to immediate postinfusion measurements in the initial group of 17 patients studied. However, patients evidencing reperfusion of an occluded coronary artery after intracoronary infusion of streptokinase demonstrated a significant increase (p <0.05) in ejection fraction from before infusion to hospital discharge. In contrast, in patients without angiographic evidence of reperfusion and in 10 control patients, mean left ventricular ejection fraction did not change from admission to hospital discharge (p = NS). These data are in agreement with several previous hemodynamic and radionuclide studies’“-“” demonstrating that left ventricular systolic performance does not change during the hospital phase of acute myocardial infarction. Although the number of patients in our series is small, the increase in left ventricular ejection fraction shown in our study may suggest a beneficial effect of intracoronary thrombolytic therapy on left ventricular performance in evolving acute myocardial infarction. The clinical and laboratory features of patients likely to benefit from intracoronary thrombolytic therapy could not be identified in this preliminary investigation. Further studies using this therapeutic technique will be required to differentiate at hospital admission between patients with intracoronary thrombus and patients with severe atherosclerotic lesions and poor distal flow. Therapeutic implications: Our preliminary data suggest that intracoronary infusion of thrombolytic agents such as streptokinase may be safely performed in evolving acute myocardial infarction; it results in reperfusion of the occluded coronary artery and may improve left ventricular performance by the time of hospital discharge. Moreover, this technique may provide an alternative to aortocoronary bypass surgery in the reestablishment of coronary blood flow to ischemic myocardium in acute myocardial infarction.H,26 Acknowledgment We express our gratitude to Kathryn Rainbird for secretarial assistance and to Diane Bennett, RN and Linda Elder for technical assistance.
References 1. Chandkr AB, Chapman I, Ether& LE, St al. Coronary thrombosis in myocardial infarction. Report of a workshop on the role of corotlat’y thfornbosis in the pathogenesis of acute myocardial infarction. Am J Cardiol 1974;34:823-33. 2. Aber CP, Bare NM, Berry LL, et al. Streptokinase in acute myocardial infarction: a controlled multicentre study in the United
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Kingdom. Br Med J 1976;2: 1100-4. 3. European Working Party. Streptokinase in recent myocardial infarction: a controlled multicentre trial. Br Med J 1971;3:325-31. 4. European Collaborative Study. A controlled trial of urokinase in myocardial infarction. Lancet 1975;2:624-6. 5. European Cooperative St&y Group for Streptokinase Treatment
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8.
7.
8.
9.
10.
11.
12.
13.
14. 15. 16.
in Acute Myocardial Infarction. Streptokinase in acute myocardial infarction. N Erg1 J Med 1979;301:797-803. Rentrop P, Blanke H, K6aterlng K, Karach KR. Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase in combination with transluminal recanalization. Clin Cardiol 1979;2:354-83. Rentrop P, Blanke H, Karsch KR, Katser Ii, Kdstertng H, Lettz K. Selective intraccronary thrornbotysis in acute myocardttl infarctit and unstable angina pectoris. Circulation 1981;83:307-18. BeWood MA, Spores J, Notake R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897-901. Ollva PB, Breckenrklge JC. Arteriographic evidence of coronary spasm in acute myocardial infarction. Circulation 1977;56: 366-76. Heedfaman P, Kulharnl PS, Raz A. Coronary tone modulation: formation and actions of prostaglandins, endoperoxides and thromboxanes. Science 1977; 195409-l 1. Persantine-Aspirin Reinfarction Study Research Croup. Persantine and aspirin in coronary heart disease. Circulation 1980;62: 449-60. Antwane Reinfarction Trial Research Croup. Sulfinpyrazone in the prevention of sudden death after myocardial infarction. N Engl J Med 1980;302:250-6. Weber KT, Ratshln RA, Jankkl JS, Rackley CB, Russell RO. Left ventricular dysfunction following acute myocardial infarction. Am J Med 1973;54:697-705. Caulflekf JB, Lekrbach R, Gokt H. The relationship of myocardial infarct size and prognosis. Circulation 1978;53:Suppl l:l-141-4. Mar&o PR, Braunwdd E. Modification of myocardial infarction size after coronary occlusion. Ann Intern Med 1973;79:720-33. Mar&o PR, BraunwakJ B. Effects of metabolic and pharmacologic interventions on myocardial infarct size following coronary occlusion. Circulation 1976;53:Suppl l:l-182-8.
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ET AL.
17. Hlrzel HO, Borwtenbllck EH, Klrk ES. Absence of a lateral border zone of intermediate creatina phosph&inase depletion surounding a central infarct 24 hours after acute coronary occlusion in the dog. Circ Res 1977;41:673-83. 18. Relmer KA, Lowe JE, Rasmussen MM, Jennlqs RB. The wavefront phenomenon of ischemic cell death. Circ 1977;58:78693. 19. Raam~sen MM, Rekner KA, Ktover RA, Jemfngs RB. Infarct size reduction by prcpranotol before and after coronary ligation in dogs. Circulation 1977;56:794-8. 20. Moschos LB, Burke WM, Lehan PH, Oklewurtel HA, Regan TJ. Thrombolytic agents and lysis of coronary artery thrombosis. Cardiovasc Res 1970;4:228-34. 2 1, Kcrdsnat RK, Kezdt P. Experimental intraccxonary thrombosis and selective in situ lysis by catheter technique. Am J Cardiol 1972; 30:640-5. 22. Ross J, Theroux P, Sasayama S, McKown D, Franklln D. Late recovery of cardiac function after coronary artery reperfusion (abstr). Circulation 1975;51:Suppl ll:ll-21. 23. Kupper W, Blelfleld W, Hanroth P, Mathey D, Effert S. Left ventricutar he-t and furtctii in acute myocardial infarction: studies during the acute phase, convalescence and later recovery. Am J Cardiol 1977;40:900-5. 24. Reduto LA, Berger HJ, Cohen LS, BoRschelk A, Zaret BL. Sequential radionuclide assessment of left and right ventricular performance after acute transmural myocardial infarction. Ann Int Med 1978;89:441-7. 25. Schelbert HR, Henning H, Ashbum WL, Verba JW, Karllnar JS, O’Rourke RA. Serial measurements of left ventricular ejection fraction by radicnuclids angiogaphy earty and late after myocardbl infarction. Am J Cardiol 1976;38:407-15. 26. Phllllp BJ, Kougtahworn C, Zeff RH, et al. Emergency coronary artery revascularization: a possible therapy for acute myocardial infarction. Circulation 1979;60:241-6.
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