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Objectives of thrombolytic therapy in acute myocardial infarction
Objectives of Thrombolytic Therapy in Acute Myocardial Infarction
WILLIAM
BELL, M.D.
Baltimore,
Maryland
The objectives of thrombolytic therapy in acute myocardial infarction are to restore coronary artery patency, salvage myocardium, reduce infarct size, and facilitate coronary artery repair. Urokinase and streptokinase are the two most frequently used thrombolytic agents. Both dissolve thrombi by converting circulating plasminogen, an inert precursor, into plasmin. One possible advantage of urokinase and streptokinase over new clot-specific agents is that the former have systemic fibrinolytic effects. This reduces blood viscosity and prevents other thrombi from forming. Angiography is the most objective technique for assessing reestablished arterial patency, but being invasive, it presents disadvantages. Noninvasive criteria for coronary reperfusion include lowering of elevated STsegments, shifting creatine kinase isoenzyme MB curves, and the appearance of reperfusion arrhythmias. Techniques for assessing myocardial salvage include thallium uptake, assessment of wall motion and myocardial thickening, ejection fraction, and positron emission tomography to assess infarct size. The role and appropriate timing of coronary artery repair after thrombolytic therapy are being studied. In the years since 1910, when Herrick first described acute myocardial infarction (AMI) as a clinical entity, the main therapeutic objective was to make optimal use of the remaining cardiac myocytes. Bed rest, oxygen, opiates, nitroglycerin, beta blockers, and surgery were used [l]. Nevertheless, despite studying, refining, and reworking these various techniques, we continue to face a very grave problem in the United States. About 1 million patients have AMI annually [2]. Twenty percent of AMls occur before age 65, and 36 percent of all male deaths before age 65 are due to AMI. One year after infarction, mortality rates range as high as 10 to 15 percent, with half of those deaths being sudden. During the late 195Os, the thrombotic nature of coronary occlusion was becoming clear. In 1956, Fletcher, Sherry, and colleagues [3] were the first to employ thrombolytic therapy in dealing with AMI. Their pioneering work gave us a direct approach for dealing with coronary thrombotic obstruction. The ultimate objective in treating AMI is to reduce and, if possible, eliminate the extensive immediate mortality. Associated objectives are the preservation of myocardium and myocardial function. Thrombolytic therapy helps to achieve these aims by: (1) establishing coronary artery patency; (2) reducing infarct size; (3) salvaging myocardium; and, (4) facilitating coronary artery repair.
From the Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland. This work was supported, in part, by a grant (HL24696) from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Requests for reprints should be addressed to Dr. William Bell, Department of Medicine, Johns Hopkins Hospital, Blalock 1002, 600 North Wolfe Street, Baltimore, Maryland 21205.
August
24, 1987
The
Amerlcen
Journal
of Medicine
Volume
83 (suppl
2A)
11
SYMPOSIUM
ON THROMBOLYTlC
ESTABLISHING
CORONARY
THERAPY-BELL
ARTERY
PATENCY
Myocardial infarction fundamentally begins with progressive atherogenic narrowing of the lumen of a coronary artery. The acute infarction actually occurs when a superimposed thrombus is formed, thus obstructing the entire lumen. Thrombolytic therapy works by directly dissolving the thrombotic element, restoring patency of the lumen so that blood flow returns in the still living patient. Thrombolytic therapy activates the plasminogen/plasmin proteolytic enzyme system that produces circulating plasmin and dissolves the thrombus. Urokinase and streptokinase are two available agents that generate plasmin. Both dissolve thrombi by converting plasminogen, a circulating inert precursor, into plasmin. Plasminogen is a single-chain structure containing 690 amino acids. Urokinase introduces an enzymatic “clip,” creating a two-chain structure with a heavy and a light chain, joined by a single disulfide bridge. When that configurational change takes place, a serine nucleophilic center, having potent proteolytic capabilities, opens within the light chain. The agent generated, now called plasmin, acts on compounds containing an arginine-lysine amino acid sequence where that sequence is available for binding. Streptokinase generates plasmin in a slightly different and less direct way. It initially must form a complex with some of the circulating plasminogen. This complex then acts upon other plasminogen; the enzymatic “clip” is introduced at the identical anatomic site as by urokinase, and plasmin is formed. Plasmin has appreciable affinity for fibrin, and acts on fibrin, the architectural essence of all endogenously formed thrombi. Because streptokinase and urokinase activate plasminogen already circulating in the blood, a considerable amount of circulating plasmin is generated, and systemic fibrinolysis takes place. Some of the newer thrombolytic agents being studied are considered to be clot-specific rather than systemic in their lysing activity. Tissue plasminogen activator (t-PA), for example, activates plasminogen that is already bound up in the fibrin thrombus [4]. Other agents that have an affinity for fibrin depend on the fibrin for their activation. No thrombolytic agent is completely clot-specific; there is some systemic lysis even with t-PA. And clot-specific agents may not be the best therapy in AMI if a systemic fibrinolytic state is required to prevent other thrombi from forming. When a vessel is occluded, the flow of blood distal to the thrombus is completely interrupted. The consequence is death and dropout of myocytes in the myocardium. Microscopically, we know that the number of myocytes that are disturbed is considerably greater than the number of vessels that are disturbed distal to the obstruction. We also know that as ischemia continues, the microcirculation within the myocardium is disturbed. Although there may be no thrombus distally in the microcirculation of the myocardium, the endothelial cells swell and obstruct the 12
August
24, 1987
The
American
Journal
of Medicine
Volume
lumen if ischemia is allowed to continue for an appreciable period of time. Thus, the objective of returning blood flow as soon as possible also prevents ischemia in areas where vessels do not contain a thrombus. An important point about using urokinase or streptokinase is that these agents not only dissolve thrombi in the occluded vessel, but their systemic effects actually reduce blood viscosity. In its normal state, blood has non-Newtonian properties. Streptokinase and urokinase, as studies have shown, can reduce blood viscosity so that the blood has the characteristic properties of a Newtonian fluid [5]. With viscosity lowered, blood requires less force to flow through the microcirculation where, even without thrombi, there may still be some degree of obstruction from swollen endothelial cells. Improving blood flow through the microcirculation as thoroughly and quickly as possible can be accomplished more easily with a fluid that requires less force than the normal non-Newtonian state of blood. This added ease of flow is important even though patency has been restored to the artery. Since the newer clot-specific agents act primarily at the site of the thrombus, they have relatively fewer systemic effects. They therefore lack the significant advantage of urokinase and streptokinase, both of which improve blood viscosity by changing fluid flow dynamics. It should be remembered that thrombolytic therapy is efficacious, at least in part, because it can change the viscosity of blood to enable flow that requires less force. Studies from the mid-1970s showed that the longer blood flow is obstructed in the coronary vessels, the greater the cell damage; injury is progressive over minutes, hours, and days [6,7]. If reperfusion is established within hours, death of cardiac myocytes and endothelial cells in the microcirculation of the myocardium is reduced. If blood flow returns very quickly, within minutes, cellular death may be eliminated and there may be no obstruction in the microcirculation of the myocardium. Does this mean that if thrombolytic therapy cannot be instituted early it should not be attempted? The answer is not clear. We shall have to await the outcome of further research before we know whether, and the extent to which, a patient may benefit by improved circulation, even though there is a long delay before thrombolytic therapy can be instituted. For now, however, it is reasonable to state that the earlier we are able to dissolve the thrombus and reperfuse the coronary vessels, the more likely we are to have more extensive myocardial salvage, a smaller infarction, and a greater ease of coronary repair. TECHNIQUES FOR ASSESSING CORONARYARTERY
PATENCY
OF THE
There are both invasive and noninvasive techniques for evaluating whether therapy has reestablished the patency of the occluded coronary artery. Invasive Techniques. Angiography, although imperfect, 83 (suppl
2A)
SYMPOSIUM
ON THROMBOLMIC
THERAPY-BELL
is the best of the invasive techniques, as all investigators will agree. It is the most objective technique; it allows one to actually see the return of blood flow. Even so, cannulating the coronary vessels carries some associated problems: it is time-consuming; the logistics are sometimes difficult; it is somewhat uncomfortable for the patient; it is expensive; and risk to the patient, although minimal, nevertheless exists. Noninvasive Techniques. There are several noninvasive techniques for evaluating patency of the coronary arteries. All of them, although less objective than angiography, do not have the latter’s disadvantages. 1. Reduction of pain. Although reduction of ischemic cardiac pain is clearly subjective, many investigators find it a reasonably reliable indication of restoration of coronary blood flow. 2. Lowering of elevated ST-segments. Electrocardiographic observation of reduction of elevated ST-segments is an excellent technique. In some situations, however, the electrocardiogram may show some persistent STsegment elevation even though other tests of patencyangiography, for example-show an excellent result in an open lumen. Some lag time may account for the difference in these cases, or perhaps the electrocardiogram does not accurately reflect the status of the electrical conduction currents through the myocytes in these instances. 3. Creatine kinase isoenzyme MB (CK-MB) curves. When coronary arterial patency is restored, both the appearance and the peak in the circulation are fairly prompt [8]. Early reperfusion is associated with earlier and higher CK-MB curves. 4. Reperfusion arrhythmia. Reperfusion arrhythmias are often seen during restoration of patency of the coronary artery. They may indicate patency, and usually are not particularly difficult to deal with medically. With reperfusion of the left coronary artery, there may be an increased number of premature ventricular contractions, and even slow ventricular bradyarrhythmias. If the obstruction was in the right coronary artery and was associated with heart block, sinus pause, or delay in the conduction system, reestablishing patency abolishes the abnormalities. Rapid supraventricular arrhythmias or ventricular arrhythmias may also occur.
tion. The test can be repeated fairly often. Although with the initial injection some of the cells that are viable but still ischemic will not take up the thallium, repeating the test several hours later may show uptake by cells that are no longer ischemic. Later in the patient’s course, exercise stress, right atrial pacing, or administration of chronotropic drugs can show further benefit. Living non-ischemic myocytes will redistribute the isotope, thus indicating that viable myocardium was salvaged. Wail Motion. Multiple gated image acquisition analysis (MUGA scans), contrast ventriculography, and echocardiography can be used to assess wall motion. If myocytes are dead, then that area of the myocardium will not display motion. Wall motion abnormalities vary from hypokinesis to akinesis to dyskinesis, depending on the amounts of infarcted, ischemic, and normal myocardial tissue. Ejection Fraction. Contrast ventriculography, MUGA scans, and echocardiography can all evaluate the fraction of blood volume ejected from the left ventricle. The assessment can be done either globally, looking at the entire left ventricle, or regionally, focusing only on certain areas. Global ejection fraction may be normal or near-normal, even though some regional abnormalities exist. In these cases, non-ischemic and non-infarcted tissues are compensating, resulting in a normal global ejection fraction. Evaluation of regional function becomes more subjective when one attempts to evaluate a small area in the left ventricular wall. Myocardial Thickening. Muscle normally thickens as it contracts. There is no thickening of the myocardium where the myocytes are severely ischemic or dead. Where myocardial cells are not salvaged, there may actually be myocardial thinning. Infarct Size. Infarct size can be determined by several techniques. Positron emission tomography seems to be the most genuine indicator of myocardial salvage, but it is expensive and time-consuming [lo]. A variety of computerized techniques can analyze the extent of thallium uptake initially and subsequently, and can then indicate how many of the myocytes in the left ventricle have been saved.
TECHNIQUES FOR ASSESSING MYOCARDIAL SALVAGE
During the course of coronary artery obstruction, a number of myocytes are in a viable although metabolically abnormal state. As reperfusion returns blood nutrients to these myocytes, the abnormal metabolic pathways give rise to certain cellular metabolic by-products, known as free radicals, that may severely disturb normal cellular metabolism. To prevent further injury to the partially ischemic but still viable myocytes, some researchers have administered substances that scavenge these free radicals. Among the more well-known scavengers are superoxide dismutase, mannitol, vitamin E, and desferrioxamine. The scavengers envelop and nullify the free radicals
Commonly employed techniques and measurements for assessing myocardial salvage include thallium uptake, wall motion, ejection fraction (regional and global), myocardial thickening, and infarct size. Thallium Uptake. lntracoronary injection of thallium-201 assesses the immediate effect of thrombolysis on myocardial salvage because only viable non-ischemic myocytes can extract and concentrate the isotope from the restored coronary flow [9]. Initially, one can use this technique to assess whether there is flow to the area of infarcAugust
24, 1987
REPERFUSION INJURY
The American
Journal
of Medicine
Volume
83 (suppl
2A)
13
SYMPOSIUM
ON THROMBOLYTIC
THERAPY-BELL
without additional injury to the cells, thus further reducing infarct size and diminishing the total amount of myocardial necrosis. FACILITATING
CORONARY
REPAIR
Once the lumen of the cornonary artery is patent, the size of the infarct has been reduced, the myocardium has been salvaged, and viability has been restored to myocytes distal to the obstruction, we have the opportunity of dealing with the area of the coronary artery that initiated the thrombus. Among techniques being used and studied are bypass
surgery and direct repair of narrowed or distorted areas in the coronary artery [l 11. Angioplasty, even without prior thrombolytic therapy, is also being done. This technique may be effective in patients who do not have a thrombus, but if there is a thrombotic aspect to the acute condition, angioplasty alone will usually not be sufficient for dealing with the problem. The optimal time for coronary repair is uncertain. Some of the early studies of thrombolytic therapy concluded that coronary repair should not be attempted until the patient’s condition stabilizes [7,12]. Currently, the trend is to initiate repair very close to the time that patency of the artery is restored.
REFERENCES 1. 2.
3.
4.
5.
8.
14
Braunwald E: The aggressive treatment of acute myocardial infarction. Circulation 1985; 71: 1087-l 092. U. S. Department of Health and Human Services, National Institutes of Health: Report of the director-National Heart, Lung, and Blood Institute (NIH publication). Washington: NIH 1988; 86-2643: l-10. Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S: The treatment of patients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Physicians 1958; 71: 287-288. Sobel B, Geltman E, Tiefenbrunn A, et al: Improvement of regional myocardial metabolism after coronary thrombolysis induced with tissue-type plasminogen activator or streptokinase. Therapy and Prevention 1984; 69: 983-990. Bell WR: Defibrinogenation with Atvin in thrombotic disorders. in: Sherry S, Scriabine A, eds. Platelets and thrombosis. Baltimore: University Park Press, 1974; 274-298. MacKawa K, Liang C-S, Hood WB: Comparison of dobutamine and dopamine in acute Ml: effects of systemic hemodynamits, plasma catecholamines, and blood flow and infarct size. Circulation 1983; 87: 750-758.
August
24, 1987
The American
Journal
of Medlclne
7.
8.
9.
10.
11. 12.
Volume
Laffel GL, Braunwald E: Thrombolytic therapy: a new strategy for the treatment of acute myocardial infarction. N Engl J Med 1984; 311: 710-717, 770-776. Roberts R: Enzymatic estimation of infarct size during reperfusion. Circulation 1983; 68 (suppl): I-1. Cited in: Sirnes P, Cverskeid K, Pedersen T, et al: Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: The Norwegian Nifedipine Multicenter Trial. Circulation 1984; 70: IV-638. Markis J, Malagold M, Parker JA, et al: Myocardial salvage after intra-coronary thrombolysis with streptokinase in acute myocardial infarction. N Engl J Med 1981; 305: 777-782. Bergmann SR, Fox KAA, Pozossian NM, Sobel BE: Colt-selective coronary thrombolysis with tissue-type plasminogen activator. Science 1983; 220: 1181-l 183. Spann J, Sherry S: Coronary thrombolysis for evolving myocardial infarction, Drugs 1984; 28: 465-483. O’Neill W, Timmis GC, Bourdillon PD, et al: A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 1986; 314: 812-818.
62 (suppl
2A)
WILLIAM
BELL, M.D.
Baltimore,
Maryland
The objectives of thrombolytic therapy in acute myocardial infarction are to restore coronary artery patency, salvage myocardium, reduce infarct size, and facilitate coronary artery repair. Urokinase and streptokinase are the two most frequently used thrombolytic agents. Both dissolve thrombi by converting circulating plasminogen, an inert precursor, into plasmin. One possible advantage of urokinase and streptokinase over new clot-specific agents is that the former have systemic fibrinolytic effects. This reduces blood viscosity and prevents other thrombi from forming. Angiography is the most objective technique for assessing reestablished arterial patency, but being invasive, it presents disadvantages. Noninvasive criteria for coronary reperfusion include lowering of elevated STsegments, shifting creatine kinase isoenzyme MB curves, and the appearance of reperfusion arrhythmias. Techniques for assessing myocardial salvage include thallium uptake, assessment of wall motion and myocardial thickening, ejection fraction, and positron emission tomography to assess infarct size. The role and appropriate timing of coronary artery repair after thrombolytic therapy are being studied. In the years since 1910, when Herrick first described acute myocardial infarction (AMI) as a clinical entity, the main therapeutic objective was to make optimal use of the remaining cardiac myocytes. Bed rest, oxygen, opiates, nitroglycerin, beta blockers, and surgery were used [l]. Nevertheless, despite studying, refining, and reworking these various techniques, we continue to face a very grave problem in the United States. About 1 million patients have AMI annually [2]. Twenty percent of AMls occur before age 65, and 36 percent of all male deaths before age 65 are due to AMI. One year after infarction, mortality rates range as high as 10 to 15 percent, with half of those deaths being sudden. During the late 195Os, the thrombotic nature of coronary occlusion was becoming clear. In 1956, Fletcher, Sherry, and colleagues [3] were the first to employ thrombolytic therapy in dealing with AMI. Their pioneering work gave us a direct approach for dealing with coronary thrombotic obstruction. The ultimate objective in treating AMI is to reduce and, if possible, eliminate the extensive immediate mortality. Associated objectives are the preservation of myocardium and myocardial function. Thrombolytic therapy helps to achieve these aims by: (1) establishing coronary artery patency; (2) reducing infarct size; (3) salvaging myocardium; and, (4) facilitating coronary artery repair.
From the Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland. This work was supported, in part, by a grant (HL24696) from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Requests for reprints should be addressed to Dr. William Bell, Department of Medicine, Johns Hopkins Hospital, Blalock 1002, 600 North Wolfe Street, Baltimore, Maryland 21205.
August
24, 1987
The
Amerlcen
Journal
of Medicine
Volume
83 (suppl
2A)
11
SYMPOSIUM
ON THROMBOLYTlC
ESTABLISHING
CORONARY
THERAPY-BELL
ARTERY
PATENCY
Myocardial infarction fundamentally begins with progressive atherogenic narrowing of the lumen of a coronary artery. The acute infarction actually occurs when a superimposed thrombus is formed, thus obstructing the entire lumen. Thrombolytic therapy works by directly dissolving the thrombotic element, restoring patency of the lumen so that blood flow returns in the still living patient. Thrombolytic therapy activates the plasminogen/plasmin proteolytic enzyme system that produces circulating plasmin and dissolves the thrombus. Urokinase and streptokinase are two available agents that generate plasmin. Both dissolve thrombi by converting plasminogen, a circulating inert precursor, into plasmin. Plasminogen is a single-chain structure containing 690 amino acids. Urokinase introduces an enzymatic “clip,” creating a two-chain structure with a heavy and a light chain, joined by a single disulfide bridge. When that configurational change takes place, a serine nucleophilic center, having potent proteolytic capabilities, opens within the light chain. The agent generated, now called plasmin, acts on compounds containing an arginine-lysine amino acid sequence where that sequence is available for binding. Streptokinase generates plasmin in a slightly different and less direct way. It initially must form a complex with some of the circulating plasminogen. This complex then acts upon other plasminogen; the enzymatic “clip” is introduced at the identical anatomic site as by urokinase, and plasmin is formed. Plasmin has appreciable affinity for fibrin, and acts on fibrin, the architectural essence of all endogenously formed thrombi. Because streptokinase and urokinase activate plasminogen already circulating in the blood, a considerable amount of circulating plasmin is generated, and systemic fibrinolysis takes place. Some of the newer thrombolytic agents being studied are considered to be clot-specific rather than systemic in their lysing activity. Tissue plasminogen activator (t-PA), for example, activates plasminogen that is already bound up in the fibrin thrombus [4]. Other agents that have an affinity for fibrin depend on the fibrin for their activation. No thrombolytic agent is completely clot-specific; there is some systemic lysis even with t-PA. And clot-specific agents may not be the best therapy in AMI if a systemic fibrinolytic state is required to prevent other thrombi from forming. When a vessel is occluded, the flow of blood distal to the thrombus is completely interrupted. The consequence is death and dropout of myocytes in the myocardium. Microscopically, we know that the number of myocytes that are disturbed is considerably greater than the number of vessels that are disturbed distal to the obstruction. We also know that as ischemia continues, the microcirculation within the myocardium is disturbed. Although there may be no thrombus distally in the microcirculation of the myocardium, the endothelial cells swell and obstruct the 12
August
24, 1987
The
American
Journal
of Medicine
Volume
lumen if ischemia is allowed to continue for an appreciable period of time. Thus, the objective of returning blood flow as soon as possible also prevents ischemia in areas where vessels do not contain a thrombus. An important point about using urokinase or streptokinase is that these agents not only dissolve thrombi in the occluded vessel, but their systemic effects actually reduce blood viscosity. In its normal state, blood has non-Newtonian properties. Streptokinase and urokinase, as studies have shown, can reduce blood viscosity so that the blood has the characteristic properties of a Newtonian fluid [5]. With viscosity lowered, blood requires less force to flow through the microcirculation where, even without thrombi, there may still be some degree of obstruction from swollen endothelial cells. Improving blood flow through the microcirculation as thoroughly and quickly as possible can be accomplished more easily with a fluid that requires less force than the normal non-Newtonian state of blood. This added ease of flow is important even though patency has been restored to the artery. Since the newer clot-specific agents act primarily at the site of the thrombus, they have relatively fewer systemic effects. They therefore lack the significant advantage of urokinase and streptokinase, both of which improve blood viscosity by changing fluid flow dynamics. It should be remembered that thrombolytic therapy is efficacious, at least in part, because it can change the viscosity of blood to enable flow that requires less force. Studies from the mid-1970s showed that the longer blood flow is obstructed in the coronary vessels, the greater the cell damage; injury is progressive over minutes, hours, and days [6,7]. If reperfusion is established within hours, death of cardiac myocytes and endothelial cells in the microcirculation of the myocardium is reduced. If blood flow returns very quickly, within minutes, cellular death may be eliminated and there may be no obstruction in the microcirculation of the myocardium. Does this mean that if thrombolytic therapy cannot be instituted early it should not be attempted? The answer is not clear. We shall have to await the outcome of further research before we know whether, and the extent to which, a patient may benefit by improved circulation, even though there is a long delay before thrombolytic therapy can be instituted. For now, however, it is reasonable to state that the earlier we are able to dissolve the thrombus and reperfuse the coronary vessels, the more likely we are to have more extensive myocardial salvage, a smaller infarction, and a greater ease of coronary repair. TECHNIQUES FOR ASSESSING CORONARYARTERY
PATENCY
OF THE
There are both invasive and noninvasive techniques for evaluating whether therapy has reestablished the patency of the occluded coronary artery. Invasive Techniques. Angiography, although imperfect, 83 (suppl
2A)
SYMPOSIUM
ON THROMBOLMIC
THERAPY-BELL
is the best of the invasive techniques, as all investigators will agree. It is the most objective technique; it allows one to actually see the return of blood flow. Even so, cannulating the coronary vessels carries some associated problems: it is time-consuming; the logistics are sometimes difficult; it is somewhat uncomfortable for the patient; it is expensive; and risk to the patient, although minimal, nevertheless exists. Noninvasive Techniques. There are several noninvasive techniques for evaluating patency of the coronary arteries. All of them, although less objective than angiography, do not have the latter’s disadvantages. 1. Reduction of pain. Although reduction of ischemic cardiac pain is clearly subjective, many investigators find it a reasonably reliable indication of restoration of coronary blood flow. 2. Lowering of elevated ST-segments. Electrocardiographic observation of reduction of elevated ST-segments is an excellent technique. In some situations, however, the electrocardiogram may show some persistent STsegment elevation even though other tests of patencyangiography, for example-show an excellent result in an open lumen. Some lag time may account for the difference in these cases, or perhaps the electrocardiogram does not accurately reflect the status of the electrical conduction currents through the myocytes in these instances. 3. Creatine kinase isoenzyme MB (CK-MB) curves. When coronary arterial patency is restored, both the appearance and the peak in the circulation are fairly prompt [8]. Early reperfusion is associated with earlier and higher CK-MB curves. 4. Reperfusion arrhythmia. Reperfusion arrhythmias are often seen during restoration of patency of the coronary artery. They may indicate patency, and usually are not particularly difficult to deal with medically. With reperfusion of the left coronary artery, there may be an increased number of premature ventricular contractions, and even slow ventricular bradyarrhythmias. If the obstruction was in the right coronary artery and was associated with heart block, sinus pause, or delay in the conduction system, reestablishing patency abolishes the abnormalities. Rapid supraventricular arrhythmias or ventricular arrhythmias may also occur.
tion. The test can be repeated fairly often. Although with the initial injection some of the cells that are viable but still ischemic will not take up the thallium, repeating the test several hours later may show uptake by cells that are no longer ischemic. Later in the patient’s course, exercise stress, right atrial pacing, or administration of chronotropic drugs can show further benefit. Living non-ischemic myocytes will redistribute the isotope, thus indicating that viable myocardium was salvaged. Wail Motion. Multiple gated image acquisition analysis (MUGA scans), contrast ventriculography, and echocardiography can be used to assess wall motion. If myocytes are dead, then that area of the myocardium will not display motion. Wall motion abnormalities vary from hypokinesis to akinesis to dyskinesis, depending on the amounts of infarcted, ischemic, and normal myocardial tissue. Ejection Fraction. Contrast ventriculography, MUGA scans, and echocardiography can all evaluate the fraction of blood volume ejected from the left ventricle. The assessment can be done either globally, looking at the entire left ventricle, or regionally, focusing only on certain areas. Global ejection fraction may be normal or near-normal, even though some regional abnormalities exist. In these cases, non-ischemic and non-infarcted tissues are compensating, resulting in a normal global ejection fraction. Evaluation of regional function becomes more subjective when one attempts to evaluate a small area in the left ventricular wall. Myocardial Thickening. Muscle normally thickens as it contracts. There is no thickening of the myocardium where the myocytes are severely ischemic or dead. Where myocardial cells are not salvaged, there may actually be myocardial thinning. Infarct Size. Infarct size can be determined by several techniques. Positron emission tomography seems to be the most genuine indicator of myocardial salvage, but it is expensive and time-consuming [lo]. A variety of computerized techniques can analyze the extent of thallium uptake initially and subsequently, and can then indicate how many of the myocytes in the left ventricle have been saved.
TECHNIQUES FOR ASSESSING MYOCARDIAL SALVAGE
During the course of coronary artery obstruction, a number of myocytes are in a viable although metabolically abnormal state. As reperfusion returns blood nutrients to these myocytes, the abnormal metabolic pathways give rise to certain cellular metabolic by-products, known as free radicals, that may severely disturb normal cellular metabolism. To prevent further injury to the partially ischemic but still viable myocytes, some researchers have administered substances that scavenge these free radicals. Among the more well-known scavengers are superoxide dismutase, mannitol, vitamin E, and desferrioxamine. The scavengers envelop and nullify the free radicals
Commonly employed techniques and measurements for assessing myocardial salvage include thallium uptake, wall motion, ejection fraction (regional and global), myocardial thickening, and infarct size. Thallium Uptake. lntracoronary injection of thallium-201 assesses the immediate effect of thrombolysis on myocardial salvage because only viable non-ischemic myocytes can extract and concentrate the isotope from the restored coronary flow [9]. Initially, one can use this technique to assess whether there is flow to the area of infarcAugust
24, 1987
REPERFUSION INJURY
The American
Journal
of Medicine
Volume
83 (suppl
2A)
13
SYMPOSIUM
ON THROMBOLYTIC
THERAPY-BELL
without additional injury to the cells, thus further reducing infarct size and diminishing the total amount of myocardial necrosis. FACILITATING
CORONARY
REPAIR
Once the lumen of the cornonary artery is patent, the size of the infarct has been reduced, the myocardium has been salvaged, and viability has been restored to myocytes distal to the obstruction, we have the opportunity of dealing with the area of the coronary artery that initiated the thrombus. Among techniques being used and studied are bypass
surgery and direct repair of narrowed or distorted areas in the coronary artery [l 11. Angioplasty, even without prior thrombolytic therapy, is also being done. This technique may be effective in patients who do not have a thrombus, but if there is a thrombotic aspect to the acute condition, angioplasty alone will usually not be sufficient for dealing with the problem. The optimal time for coronary repair is uncertain. Some of the early studies of thrombolytic therapy concluded that coronary repair should not be attempted until the patient’s condition stabilizes [7,12]. Currently, the trend is to initiate repair very close to the time that patency of the artery is restored.
REFERENCES 1. 2.
3.
4.
5.
8.
14
Braunwald E: The aggressive treatment of acute myocardial infarction. Circulation 1985; 71: 1087-l 092. U. S. Department of Health and Human Services, National Institutes of Health: Report of the director-National Heart, Lung, and Blood Institute (NIH publication). Washington: NIH 1988; 86-2643: l-10. Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S: The treatment of patients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Physicians 1958; 71: 287-288. Sobel B, Geltman E, Tiefenbrunn A, et al: Improvement of regional myocardial metabolism after coronary thrombolysis induced with tissue-type plasminogen activator or streptokinase. Therapy and Prevention 1984; 69: 983-990. Bell WR: Defibrinogenation with Atvin in thrombotic disorders. in: Sherry S, Scriabine A, eds. Platelets and thrombosis. Baltimore: University Park Press, 1974; 274-298. MacKawa K, Liang C-S, Hood WB: Comparison of dobutamine and dopamine in acute Ml: effects of systemic hemodynamits, plasma catecholamines, and blood flow and infarct size. Circulation 1983; 87: 750-758.
August
24, 1987
The American
Journal
of Medlclne
7.
8.
9.
10.
11. 12.
Volume
Laffel GL, Braunwald E: Thrombolytic therapy: a new strategy for the treatment of acute myocardial infarction. N Engl J Med 1984; 311: 710-717, 770-776. Roberts R: Enzymatic estimation of infarct size during reperfusion. Circulation 1983; 68 (suppl): I-1. Cited in: Sirnes P, Cverskeid K, Pedersen T, et al: Evolution of infarct size during the early use of nifedipine in patients with acute myocardial infarction: The Norwegian Nifedipine Multicenter Trial. Circulation 1984; 70: IV-638. Markis J, Malagold M, Parker JA, et al: Myocardial salvage after intra-coronary thrombolysis with streptokinase in acute myocardial infarction. N Engl J Med 1981; 305: 777-782. Bergmann SR, Fox KAA, Pozossian NM, Sobel BE: Colt-selective coronary thrombolysis with tissue-type plasminogen activator. Science 1983; 220: 1181-l 183. Spann J, Sherry S: Coronary thrombolysis for evolving myocardial infarction, Drugs 1984; 28: 465-483. O’Neill W, Timmis GC, Bourdillon PD, et al: A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 1986; 314: 812-818.
62 (suppl
2A)