Limitation of infarct size

Editorial Board (clockwise from top): W. Proctor William C. Roberts, Robert A. O’Rourke. Frank de Leon.

Harvey, James J. Leonard, I. Marcus and Antonio C.

EDITOR’S PREFACE Doctors Braunwald and Maroko have provided us with informative and exciting reading in this overview of the research and treatment of one of the major problems in cardiovascular disease - that of myocardial infarction. Limiting the size of a myocardial infarction is, of course, a logical step in the treatment of and recovery from this serious complication. As the authors discuss the vast and varied research on this problem currently underway throughout the world, one cannot help but feel reassured as well as hopeful with regard to improved therapy and prevention. I have had the privilege of knowing Gene Braunwald for about 25 years, beginning when he was chief of clinical cardiology at the National Heart, Blood, and Lung Institute. He was also a member, of our faculty of the Division of Cardiology at Georgetown, and our Cardiology Fellows had one of their “rotations” under his supervision at the National Heart, Lung, and Blood Institute. It was evident immediately that he was a 2

unique, talented physician who organized and conducted many important aspects of research in cardiology. He has obviously continued to excel in his present position as physician-in-chief at the Peter Bent Brigham Hospital. The readers of CURRENT PROBLEMS IN CARDIOLOGY are indebted to Drs. Braunwald and Maroko for this up-to-date discussion.

Stephen E. Epstein, M.D., is Chief of Cardiology, National Heart, Lung, and Blood Institute, National Institutes of Health, Washington, D.C. He completed his medical training at Cornell University Medical College and his residency training at The New York Hospital. In 1963 he became a Clinical Associate at the National Heart, Lung, and Blood Institute and he became Chief of Cardiology in 1967. Over the years Dr. Epstein has conducted research in cardiac physiology, pharmacology and biochemistry. Most recently he has been involved in studies designed to develop interventions that can reduce ischemic injury occurring during acute myocardial infarction. He is on the editorial boards of Circulation and the Journal of Clinical Investigatiox

GUEST EDITOR’S COMMENTS Not so long ago the major function of the physician in treating the patient admitted to the hospital with acute myocardial infarction was to ameliorate pain, to treat arrhythmias whenever they occurred with specific antiarrhythmic agents, and if failure supervened, to bolster the weakened myocardium with positive inotropic agents. Over the past few years, however, the seeds of a therapeutic revolution have been sown and the fruits are already beginning to be harvested. It began with the working hypothesis that myocardial injury occurring during an acute myocardial infarction is not completed within the first few seconds, or even minutes, following the initiation of the acute event. Rather, it was postulated that myocardial necrosis is usually a relatively slow, evolving process that may take hours, and at times could even stutter on in an erratic progressive manner over the ensuing days. If this concept was correct, it would be possible to intervene therapeutically with the goal of reducing the quantity of infarcted myocardium that might have otherwise resulted if no therapy were instituted. Much of the pioneering work in this area was begun by Drs. Braunwald and Maroko and their colleagues several years ago. Their initial provocative results stimulated other investigators to enter this field, and over the past few years the number of studies designed to explore new modalities to reduce infarct size have mushroomed to impressive dimensions. As a result, there has been a virtual explosion of information relating to the treatment of acute myocardial infarction. Because of the numerous experiments that have been performed and the complex and often conflicting results, a review and apA

praisal of current information is now essential. Drs. Braunwald and Maroko, drawing on their broad personal investigative experience and knowledge of the field, have presented a comprehensive synthesis of the status of interventions designed to limit infarct size. They have also coupled this experience with their clinical insights to construct a viable and practical approach for the physician who is attempting to deliver the best possible care to the patient with acute myocardial infarction.

5

SELF-ASSESSMENT

QUESTIONS

1. It is likely that ischemia affects myocardial function by: a. Depolarizing the myocardial cells b. Altering the physical-chemical structure of cardiac contractile proteins c. Interfering with the release of calcium from the sarcoplasmic reticulum of the cardiac cell d. Interfering with the interaction between calcium and the regulatory protein tropomyosin 2. Myocardial ischemia has the following effects on the heart: a. Increases compliance b. Impairs ventricular relaxation c. Prolongs the isovolumic relaxation period d. Increases ejection fraction e. Elevates ventricular filling pressure 3. When an infarct occurs in the normal heart, how much myocardium must be lost before ventricular failure occurs? a. 10% b. 25% c. 40% 4. The following interventions have been shown to increase myocardial injury following coronary artery occlusion. Indicate whether each acts primarily by 1) increasing myocardial oxygen requirements, 2) decreasing myocardial oxygen supply, or 3) decreasing substrate availability. a. Anemia b. Isoproterenol c. Tachycardia d. Hemorrhage e. Hypoglycemia 5. Interventions that reduce myocardial injury after coronary artery occlusion are presumed to act by one of four mechanisms: (1) decreasing myocardial oxygen requirements, (2) increasing myocardial oxygen supply, (3) augmenting anaerobic metabolism and (4) protecting against autolytic and heterolytic processes. Indicate the presumed principal mechanisms of action of each of the following interventions: a. Ibuprofen b. Mannitol c. Intraaortic balloon counter-pulsation d. Elevating arterial oxygen tension e. Antilipolytic agents f. Nitroglycerin g. Beta-adrenergic blockade

6. In the experimental animal what is the upper limit of time, following coronary artery occlusion, during which an intervention must be applied to be effective? a. 1 hour b. 3 hours c. 6 hours d. 9 hours 7. Which of the following interventions has been shown to interfere with scar formation following myocardial infarction? a. Hyaluronidase b. Reserpines c. Cobra venom factor d. Glucocorticosteroids e. Ibuprofen 8. Each of the following statements should be answered True or False. a. In the routine management of acute myocardial infarction, atropine should be administered prophylactically. b. Digitalis glycosides should be administered prophylactically c. Heart failure should be treated first with diuretics rather than digitalis Answers are listed at the end of the article.

8

is Hersey Professor of Medicine and Head of Harvard’s Department of Medicine at the Peter Bent Brigham Hospital. He received his M.D. from the New York University School of Medicine and completed his internship, residency and fellowship training at the Mt. Sinai Hospital in New York, at Columbia University and at the Johns Hopkins Hospital. Doctor Braunwald has received the Research Achievement Award of the American Heart Association and the John J. Abel Prize of the American Society of Pharmacology and Experimental Therapeutics. He is a member of the National Academy of Sciences. His research interests have included many aspects of cardiovascular physiology, pharmacology and clinical cardiology.

is Associate Professor of Medicine at the Harvard Medical School and Peter Bent Brigham Hospital. He received his M.D. from the University of Sao Paulo, Sao Paulo, Brazil in 1960, and his Ph.D. in 1971. His research interests are in the area, of cardiovascular pharmacology and pathology. In recent years the main goal of his research has been the protection of ischemic myocardium.

1 1/ _ __ .P” ‘A

..

ISCHEMIC HEART DISEASE represents the most common serious health problem of contemporary Western society. It has been estimated that in the United States alone more than 675,000 patients die each year from ischemic heart disease and its complications; approximately 1,300,OOO patients develop myocardial infarction and countless more suffer from congestive heart failure secondary to ischemic myocardial damage. Acute Supported in part by Contract NG1 HV-53000 and Grant HL-20199 from the National Heart, Lung, and Blood Institut,e. 9

myocardial infarction thus remains the most common cause of in-hospital death in this country, indeed, in the Western world. In-hospital deaths of patients with acute myocardial infarction result mainly from primary arrhythmias and from pump failure. Although death due to arrhythmias has been reduced by modern monitoring techniques and more vigorous prophylaxis and treatment, the mortality following mechanical failure manifested by cardiogenic shock or pulmonary edema, or both, is still very high. These syndromes have been found to be associated with larger infarctions than those exhibited by patients who succumbed to myocardial infarction but who did not die as a consequence of pump failure.’ As a corollary, the prognosis for patients with larger infarcts is distinctly worse than it is in those with smaller infarcts.’

EFFECTS OF ISCHEMIA ON CARDIAC FUNCTION How does ischemia affect myocardial function? Although the fundamental basis of its effects has not been elucidated with certainty, most available evidence suggests that ischemia interferes with the release of Ca ++ from the sarcoplasmic reticulum of the cardiac cell and/or interferes with the interaction of Ca++ with the contractile proteins. There is considerable evidence that myocardial contraction is normally initiated by the rapid release of Ca++ from the sarcoplasmic reticulum and that this release is triggered by a rise in the Ca i-+ concentration near the sarcoplasmic reticulum. :( According to this concept, when the Ca++ concentration near the sarcoplasmic reticulum reaches a critical level, a massive release of Ca++ from the sarcoplasmic reticulum occurs. Once Ca + 1 is released from the sarcoplasmic reticulum, it combines with specific receptor sites on the regulator protein, troponin, which in turn allows the actin-myosin interaction to proceed, leading to muscle tension and shortening. Changes in intracellular pH may influence this Ca++ trigger mechanism; i.e., a fall in intracellular pH, as occurs in ischemia, may cause the sarcoplasmic reticulum to release a smaller quantity of Cah4. Also, the higher concentration of intracellular H+ induced by ischemia competes with Ca-+ for the receptors on the troponin molecules. As a result, the actin-myosin interaction is interfered with and contractility is impaired. This concept is supported by the observation that the functional changes induced by primary acidosis in the face of adequate myocardial oxygenation are almost identical to those produced by ischemia4; furthermore, the reversal of the acidosis of ischemia by the administration of alkali improves contractile performance.” In summary, it is likely that the abnormalities of contraction caused by ischemia result largely from the accumulation of intracellular Hi and its interference with the interaction between 10

Ca*- and contractile proteins. The effect of a reduction of intracellular PO, on stores of high energy phosphate compounds in critical locations within the myocardial cell requires further exploration. Myocardial ischemia and infarction alter not only the contractile properties of the heart, but the diastolic pressure-volume relationships of the left ventricle as well.(’ Myocardial ischemia and, in particular, recovery from ischemia, impair ventricular relaxation, as evidenced by both a decreased peak negative differential left ventricular pressure (dP/dt) and a prolonged isovolumic relaxation period. In turn, this impairment in ventricular relaxation increases the resistance to ventricular filling. Through its direct effects on contractility, ischemia causes incomplete ventricular emptying and an elevation of ventricular end-diastolic volume. The incomplete myocardial relaxation and depressed contractility combine to elevate ventricular filling pressures in patients with myocardial ischemia. When myocardial ischemia is prolonged and leads to infarction, distinct changes in the diastolic stiffness of the left ventricle also occur.7 At first, i.e., in the minutes to several hours following occlusion of a coronary artery, ventricular stiffness declines. Since the involved segment of myocardium does not contract, it is subjected to repetitive passive stretching by the adjacent normal myocardium. This paradoxical systolic expansion of the ischemic zone presumably not only decreases its stiffness, but also further reduces the ejection fraction, requiring further elevation of the end-diastolic volume to maintain stroke volume. With the passage of time, perhaps 6- 12 hours, edema and fibrocellular infiltration incrmse the stiffness of the infarcted myocardium back to and then above control. This change in stiffness may actually improve ventricular performance during recovery from acute myocardial infarction, since it reduces the paradoxical pulsation that occurs immediately after the infarction. If an area of myocardial ischemia is large, even transient asynergy, i.e., contraction, can lead to clinical evidence of heart failure. Hemodynamic evidence of left ventricular failure is apparent when contraction ceases or is seriously impaired in 20- 25% of the left ventricle. With the loss of 40% or more of the left ventricular myocardium, severe pump failure develops and, if this loss occurs acutely, cardiogenic shock usually supervenes.”

THE CONCEPT OF LIMITATION

OF INFARCT SIZE

Death from cardiogenic shock may now be viewed as the end result of a vicious cycle (Fig I).!’ Coronary obstruction leads to myocardial ischemia, which, as we have already seen, impairs myocardial contractility and ventricular performance; this, in turn, reduces arterial pressure and therefore coronary perfusion

ObstructIon of Motor C~ono, y Artery 1 Myocordlol Ischenrca

4 LV. Function

LY Function

Fig l.-Diagram depicting the sequence of events in the vicious cycle in which coronary artery obstruction leads to cardiogenic shock and progressive circulatory deterioration. (Reproduced with permission from Braunwald, E.: Salvage of ischemic myocardium, in Lefer, A., Kelliher, G., and Rovetto, M. (eds.): Pathophysiology and Therapeutics of Myocardial lschemia [New York: Spectrum Publications, Inc., 19771.)

pressure, leading to further ischemia and extension of necrosis until the patient dies. Stasis in the smaller arteries and arterioles distal to a major proximal occlusion may result in secondfurther impairing myocardial ary microvascular obstruction, perfusion. b STEPHEN E. EPSTEIN: When the effects of &hernia are studied, attention is usually focused solely on the myocardium. However, as Drs. Braunwald, Maroko and their colleagues have shown, ischemia also affects the microvasculature, which, through further impairment of flow, may lead to greater myocardial damage. Interventions designed to minimize ischemia-induced vascular damage may be a fertile area for future investigations designed to reduce the myocardial damage caused by ischemia.

Accordingly, a treatment that could limit the extent of myocardial necrosis and by this mechanism decrease the frequency of intractable cardiogenic shock and pulmonary edema would be extremely useful, not only by reducing immediate mortality but also by leaving the patient who had suffered a coronary occlu12

sion with more viable myocardium. Such a patient would be less likely to develop chronic heart failure and would have a greater reserve of functioning myocardium should another coronary occlusion occur. There is considerable clinical evidence to suggest that factors influencing myocardial oxygen demands may aggravate or alleviate symptoms of myocardial ischemia. For example, in patients with angina and hyperthyroidism, treatment of the hypermetabolic state and the associated reduction of myocardial oxygen needs is often associated with relief of angina. Also, the reduction of myocardial oxygen needs by beta-adrenergic blockade or carotid sinus nerve stimulation reduces symptoms of myocardial ischemia. Conversely, treatment of hypothyroidism or the development of tachycardia (influences that augment myocardial oxygen needs) increases the frequency and severity of myocardial ischemia in patients with coronary artery disease. The importance of the decreased availability of oxygen is apparent in cases where arterial hypotension and acute anemia may cause infarction in patients with coronary artery disease even in the absence of coronary occlusion. The aforementioned clinical observations suggested to us, in 1967, that the ultimate size of a myocardial infarct is not determined irrevocably by the site of coronary occlusion and the pathoanatomy of the coronary vascular bed, but might be modified by other factors.to We proposed that when coronary occlusion occurs, the survival of the cardiac tissue normally perfused by the obstructed vessel may well depend on the balance between oxygen available to that segment of myocardium and its oxygen requirements, and that the survival of the patient with coronary occlusion could, in large measure, depend on the balance between myocardial oxygen supply and demand.“-‘” b STEPHEN E. EPSTEIN: This concept is based on the reasonable assumption that myocardial cell death depends not only on the net oxygen deficit of the cell, but also on a critical period of time during which reversible ischemic changes progress to irreversible damage. The time factor is presumably dependent on the intensity of the ischemic insult. Hence, the greater the net oxygen deficit, the shorter the critical period of time for irreversible myocardial damage to occur. Conversely, an intervention that leads to a decrease in oxygen deficit will prolong the time period leading to cell death and elimination of the oxygen deficit will prevent cell death even if oxygen availability is insufficient to restore contractile function.

METHODS FOR EVALUATING CHANGES IN MYOCARDIAL DAMAGE IN EXPERIMENTAL ANIMALS To test the hypothesis that acute myocardial ischemic injury can be modified by interventions applied following coronary oc13

elusion, we were forced to develop techniques for assessing the extent and severity of ischemic damage. Our initial efforts were in dogs in which electrographic S-T segments were recorded from multiple epicardial sites during repeated 20-minute coronary artery occlusions. I I- I3 Since all sequential electrographic recordings are made at the same epicardial sites on the same heart, the effect of the considerable variations in the distribution of the coronary arteries and in the extent of the intercoronary collaterals among different animals is eliminated by this technique, and each animal can serve as its own control. An alteration in the extent and magnitude of S-T segment elevation during one of these repeated occlusions suggests a change in acute myocardial ischemic injury. This approach, although simple and quite useful as a screening procedure, has two serious inherent disadvantages. First, it is possible that the intervention being evaluated has a nonspecific effect on the S-T segment and no effect on the ischemic injury itself. Second, it does not provide information about the relationship between ischemic injury occurring shortly after coronary occlusion and the final extent of myocardial necrosis.‘1 The 24-hour occlusion method in which S-T segments recorded soon (generally 15 minutes) after coronary occlusion are comFib 2.-Comparison of the effect of treatment on histology in areas with S-T segment elevations over 2 mV First column. control group; second column, glucose-insulin-potassium (G-I-K) group; third column, hyaluronidase group; fourth column, hydrocortisone group. Note that in all three treatment groups more than one third of the sites expected to show early signs of myocardial infarction were spared. Numbers at the bottom of each bar indicate the number of specimens in each group: the number of dogs in each group is shown in parentheses. (Reproduced with permission from Maroko, P. R.. and Braunwald, E.: Modification of myocardlal Infarct size after coronary occlusion, Ann. Intern. Med. 79:720 - 733.1973 )

G 40-

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59 (8) G-I-K

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82( 14) HYDROCORT.

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Fig 3. -Relationship between S-T segment elevatron 15 minutes after occlusion and log of CPK activity from the same specimens, obtained 24 hours later. Line A, control group (occlusion alone) (15 dogs. 101 biopsies); Line B, hyaluronidase (13 dogs, 94 biopsies); Irne C, propranolol; line 5, glucose 50% (6 dogs, 46 biopsies); line E. glucose-insulin-potassium infusion (13 dogs, 96 biopsies). All interventions started 30 mrnutes after coronary artery occlusion, i.e., 15 minutes after the epicardial mapping. There is a statistical difference (p <. 0.01) between the slope of ltne A and the slopes of the other lines showing less CPK depression after treatment. (Reproduced with permission from Maroko. P R , and Braunwald, E.: Effects of metabolic and pharmacologic interventions on myocardial infarct size followino coronary occlusion. Circulation (Suppl 1) 53.162-

168. 19’76.1

pared to the ultimate necrosis overcomes both of these lim itations. As with the first method, the coronary artery is occluded and the epicardial S-T segment m a p recorded 15 m inutes later. The occlusion is m a intained, the chest is closed for 24 hours, and the chest is reopened and transmural specimens are excised subjacent to sites from which epicardial electrograms had been recorded 24 hours earlier. The biopsy specimens are then analyzed for histologic evidence of necrosis and for tissue creatine kinase (CK) activity (Fig 2). In animals receiving no intervention, there is a predictable, significant inverse relationship between the height of the S-T segment 15 m inutes after occlusion and the tissue signs of necrosis, i.e.. the histologic, histochemical, elecI5

tron microscopic and biochemical (tissue CK activity) evidence of infarction 24 hours later’” 17(Figs 2 - 4). Thus, with this technique, the epicardial electrogram serves as a predictor of subsequent tissue viability or infarction, and the agent being evaluated is administered after the S-T segment map has been recorded. Therefore, a nonspecific effect of the intervention on the electrogram can be excluded. Agents that alter the relationship between the amount of necrosis predicted (from a control group of animals) and that observed following its administration can be said to alter the progression from ischemic injury to necrosis’“” (see Fig 2 - 4). These techniques have provided interesting and important results, but their value is limited by the fact that, as has been suggested elsewhere,14 S-T segment elevation is not specific for myocardial ischemia. Changes in local electrolyte concentrations (particularly of potassium) in the ischemic area, the adjacent normal tissue and the extracellular fluid, can markedly alter the height of S-T segment elevation. Pericarditis and local conduction defects as well as several commonly used cardiac drugs (including the cardiac glycosides) are also known to alter the height of the S-T segment elevation. Although these limitaFig 4.-Relationship between S-T segment elevation 15 minutes after occlusion with CPK activity and histologic changes 24 hours later, in an experiment in the control group. Left, schematic representation of the anterior surface of the heart LA., left atrial appendage; L.A.D., left anterior descending coronary artery. Area with diagonal lines, S-T segment elevation after occlusion. Circles, sites from which specimens were obtained. Right, comparison between S-T segment elevation with CPK activities and histologic analysis 24 hours later in the same sites. (Reproduced with permission from Maroko, P. Ft., and Braunwald, E.: Effects of metabolic and pharmacologic interventions on myocardial infarct size following coronary occlusion. Circulation (Suppl 1) 53:162-168. 1976.) B

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tions can be largely controlled in experimental investigations, all of these considerations prompted us to search for a technique of changes in the S-T segment and that would be independent that could assess the efficacy of an intervention in reducing acute ischemic myocardial damage. It was demonstrated that the relationship between regional myocardial blood flow (measured by the radioactive microsphere technique 15 minutes after coronary occlusion) and myocardial CK activity at the same sites 24 hours later, is useful for this purpose. Favorable interventions change this relationship so that the degree of myocardial damage, as reflected in myocardial CK activity, is reduced.‘8 In several experiments evidence for myocardial salvage was analyzed by correlating both the S-T segment and the regional blood flow with subsequent evidence of tissue damage, as reflected in the histologic and electron microscopic appearance of the tissue, as well as in tissue CK activity. The results strengthen the conclusions derived from the application of all of these techniques. More recently a rat model of coronary artery occlusion’9 has been utilized to quantify infarctions directly by serial histologic sections and by measuring total CK activity of the left ventricle. By this technique, a standard size infarct is produced in the left ventricles of Sprague-Dawley rats by occluding the left coronary artery 1 - 2 mm from its origin. The animals are killed either 48 hours or 21 days after occlusion. For the enzymatic studies, the CK activity of the homogenized whole left ventricle is measured and infarct size determined by comparing left ventricular CK in the occluded rats with that in sham-operated (unoccluded) rats. For the histologic measurement of infarct size the left ventricles are sectioned into slices in a plane parallel to the atrioventricular groove. Paraffin-embedded sections are prepared from each slice, stained with hematoxylin and eosin, projected onto a screen, and measured with a planimeter to determine the crosssectional area of the entire left ventricle and of the infarcted portion. The effects of an intervention are determined by comparing infarct size in treated and untreated rats with coronary occlusion.

MECHANISM

OF ACTION OF VARIOUS INTERVENTIONS

It was proposed that because the blood supply and therefore oxygen delivery to the ischemic zone surrounding the infarct is markedly reduced, the survival of this tissue may depend on its oxygen consumption. Is According to this concept, when the coronary artery is occluded at any specific site and the oxygen consumption of the myocardium is stimulated by factors such as increased rate, tension and/or contractility, the viability of the ischemic border zone may be reduced and the size of the infarct 17

IMPROVES

DEPR

--.

\ REGIONAL ISCHEMIA

-

O2

REQU

( LAPLACE’S

LAW)

Fig B.-Schema showing changes In circulatory regulation in ischemic heart disease. DEPR. L.V. FUNCT., depressed left ventricular function; S.V., stroke volume; DILATAT.. dilatation; and 0, REQU., oxygen requirements. Solid lines produce or intensify the effect, whereas a broken line diminishes it (Reproduced with permission from Braunwald, E.: Regulation of the circulation. N. Engl. J Med. 290,1124-1129.1420-1425.1974.)

enlarged. Furthermore, such unfavorable alterations in the relationship between myocardial oxygen supply and demand could impair the contractile function of the ischemic myocardium at the margin of the infarct (see Fig 1). This depression of left ventricular function could then result in enlargement of this chamber which, in accord with Laplace’s law, will result in an augmentation of tension at any level of ventricular pressure.“” An elevation of tension, in turn, leads to even higher levels of oxygen consumption, which could further impair myocardial function and lead to the vicious cycle of cardiogenic shock referred to earlier (Figs 1 and 5). b STEPHEN E. EPSTEIN: There is currently much debate concerning whether or not a border zone of any magnitude exists along the lateral margins of a zone of ischemia. This debate is largely irrelevant to the concept offered by Drs. Braunwald and Maroko. Even if the border zone located along the lateral perimeter of the ischemic zone is small, the epicardium constitutes an important “border” zone, because, although it is underperfused during acute occlusion, it is less so than the endocardium. Thus, increasing the oxygen demands of the zone of myocardium that is marginally underperfused, whether it involves the epicardium, the lateral perimeter of the infarct, or both, can lead to extension of ischemic injury and the vicious cycle described by the authors.

EFFECTS OF ALTERING

MYOCARDIAL

OXYGEN

BALANCE

Using the technique of recording epicardial S-T segments it was found that a variety of interventions, notably those that increase myocardial oxygen consumption (e.g., isoproterenol, digitalis, glucagon, bretylium tosylate and pacing-induced atria1 18

TABLE

1. -INTERVENTIONS THAT INCREASE MYOCARDIAL AFTER CORONARY ARTERY OCCLUSION

Increases myocardial oxvgen rrymremrnts Isoproterenol Digitalis (in the nonfailing heart; Glucagon Bretylium tosylate Tachycardia Hyperthermia Decreases myocardial oxygen wpply Directly Hypoxemia Anemia Through collateral vessels. reducing coronary Hemorrhage Sodium nitroprusside Minoxidil Decreases substrate availability Hypoglycemia

perfusion

INJURY

pressure

tachycardia), increase the severity and extent of myocardial injury (Table l).lZ1 Other investigators, using subepicardial electrodes for recording S-T segments or serum creatine kinase disappearance curves as an index of myocardial damage, studied the influence of atropine and pacing-induced tachycardia in conscious dogs, and found similar increases in myocardial injury. b STEPHEN E. EPSTEIN: It should be noted that any intervention having the capacity to increase myocardial oxygen requirements could also theoretically reduce blood flow to ischemic myocardium. The mechanism that would lead to such a deleterious result is based on a coronary steal. Thus, arterioles supplying ischemic tissue are maximally dilated as a Arterioles supplying nonresult of the metabolic products of &hernia. ischemic tissue still have the potential to dilate. If oxygen demands of normal myocardium increase, its arterioles will dilate through autoregulatory mechanisms. This may cause a decrease in perfusion pressure supplying collateral vessels, which arise more proximally and which supply the ischemic zone. This drop in collateral perfusion pressure would lead to an unfavorable redistribution of blood flow from ischemic tissue to normal nonischemic mvocardium.

If the were in induced achieved sumption

increases in infarct size produced by these interventions fact related to the increased myocardial oxygen needs by their application, then the opposite effect should be with interventions that reduce myocardial oxygen con(Table 2).

b STEPHEN E. EPSTEIN: Likewise, an intervention that reduces myocardial oxygen demands could increase the flow of blood to ischemic myocardium by a mechanism opposite to that debscribedabove.

Therefore,

two

beta-adrenergic

blocking

agents

that

exert 19

TABLE 2. -INTERVENTIONS THAT REDUCE MYOCARDIAL INJURY AFTER CORONARY ARTERY OCCLUSION Decreases myocardial oxygen requirements Beta-adrenergic blockade+ Digitalis (in the failing heart) Counterpulsation Intraaortic balloon’External* Nitroglycerin* Decreasing afterload in patients with hypertension* Reducing intracellular free fatty acid levels Antilipolytic agents-&pyridylcarbinol Lipid-free albumin infusions Glucose-insulin-potassium* (presumed) Pentobarbital Increases myocardial oxygen supply Directly Coronary artery reperfusion* Elevating arterial oxygen tension* Thrombolytic agents Heparin* (presumed ) Through collateral vessels Elevation of coronary perfusion pressure by methoxamine, phenylephrine, norepinephrine Intraaortic balloon counterpulsation” External counterpulsation” Hyaluronidase* Increasing plasma osmolality Mannitol Hypertonic glucose Augments anaerobic metabolism (presumed) Glucose-insulin-potassium* Hypertonic glucose I-Carnitine Sodium dichloroacetate Protects against autolytic and heterolytic processes (presumed) Corticosteroids* Cobra-venom factor Aprotinin Ibuprofen *Intervention

has been applied to patients.

such an effect, propranolol and practolol, were studied and were found to decrease myocardial injury after coronary artery occlusion both in open- and closed-chest animals (Fig 6). Using histologic techniques, Sommers and Jennings have also observed smaller infarctions following coronary occlusion after pretreatment with propranolol. In recent experiments in our laboratory, Kloner has shown that beta-adrenergic blockade reduces not only ischemic injury of myocardial cells, but microvascular injury as well. Electron microscopic observations in untreated dogs following coronary occlusion revealed that in addition to swollen 20

60 0

OCCLUSION ALONE

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OCCL + ISOPROTERENOL

a

OCCL + PROPRANOLOL

1

45 -iIf i

i

15

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1 d.

- El *

-dbp-

Fig 6.-Changes in average ZS-T (left) and average number of sites with S-T elevations (NSTJ (right) 15 minutes after occlusion alone (whife bars), after occlusion during infusion of isoproterenol (diagonal bars) and after occlusion following administration of propranoiol (crossed bars) in closed-chest dogs. (Reproduced with permission from Maroko, P. R.. Libby, P., Covell, J. W., Sobel, B. E., Ross. J.. Jr., and Braunwald. E: Precordial S-T segment elevation mapping. an atraumatic method for assessing alteration In the extent of myocardial ischemic injury, Am. J. Cardiol 29 223.-239 1972 )

myocardial cells, there were endothelial gaps, blebs and swelling. All of these changes were reduced in propranolol-treated dogs. Experiments by Mueller and associates in patients with acute myocardial infarction have shown that although the infusion of isoproterenol resulted in either increased lactate production or a shift from lactate extraction to production (i.e., biochemical evidence of worsening of ischemiai, the administration of proprano101 shifted lactate production to extraction or increased lactate extraction, i.e., lessening of ischemia.2’ Thus, these observations, which show the detrimental metabolic effects of isoproterenol and the beneficial effects of propranolol, also support the hypothesis that myocardial oxygen consumption is important in determining the fate of myocardial tissue subjected to ischemia. b STEPHEN E. EPSTEIN: Table 2 indicates that nitroglycerin acts mainly by decreasing myocardial oxygen requirements. It should be noted, however, that we, as well as others, have demonstrated that nitroglyc-

erin may also be of benefit in reducing myocardial injury by increasing blood flow delivered

to ischemic myocardium

by collateral

vessels.

The effects of digitalis on the extent and magnitude of ischemic injury were extended to studies in the failing heart.22 Although this drug increases oxygen consumption and ischemic injury in 21

the nonfailing heart, it may reduce the oxygen consumption of the failing heart by lowering wall tension consequent to the reduction of ventricular volume, which overrides the augmentalion of myocardial oxygen consumption resulting from increases in contractility. Thus, in the failing heart, digitalis reduced myocardial ischemic injury after coronary occlusion. To study the importance of the oxygen supply to the ischemic myocardium, either hemorrhagic hypotension or arterial hypertension was induced after coronary occlusion13, l6 Arterial hypotension increased the area of myocardial ischemic injury, whereas raising arterial pressure by infusions of methoxamine or phenylephrine reduced myocardial ischemic injury. In these experiments the effect of arterial pressure on coronary blood flow and, therefore, on myocardial oxygen delivery appeared to be more important than the changes induced in myocardial oxygen demand as a consequence of altering wall tension. In addition, the inhalation of 40% oxygen significantly reduced electrocardiographic evidence of acute myocardial ischemic injury and the extent of subsequent myocardial necrosiP; the inhalation of 10% oxygen had the opposite effect (Fig 7). The effect of altering the balance between oxygen supply and demand by causing a redistribution of coronary blood flow was Fig 7.-An example of the effects of hyperoxia and hypoxia on acute myocardial ischemic injury. Right, schematrc representation of the heart and its arteries. The section with diagonal lines represents the area of S-T segment elevation following coronary occlusion with FIO, of 0.10. The cross-hatched section represents the area of injury FIO, of 0.20. The section with horizontal lines represents the area of injury with FIO, of 0.40. Left, average S-T segment elevation (ST) 15 minutes following occlusion with FIO, of 0.10 (diagonal lines), with FIO, of 0.20 (cross-hatched bar) and with FIO, of 0.40 (horizontal lines). (Reproduced with permission from Braunwald, E.: Salvage of ischemic myocardium, in Lefer, A., Kelliher, G., and Rovetto, M. (eds.): Pathophysiology and Therapeutics of Myocardial lschemia [New York: Spectrum Publications, Inc., 19771.)

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t

f

Fig 8.-Simultaneous changes In average S-T segment elevation (ST) and transmural - flow in dogs. Flow decreased with nitroprusside (NP), causing elevation in ST. After nitroglycerin (NTGI, flow increased and m decreased. (Reproduced with permission from Chiariello. fvl., Gold, H. K., Leinbach, R. C.. Davis. M. A., and Maroko, P. R. Comparison between the effects of nitroprusside and nitroglycerin on ischemic Injury duriny acute myocardial infarction. Circulation 54.766. 1976.)

also studied with minoxidil and sodium nitroprusside, two potent vasodilators. Despite a marked increase in the delivery of blood to the nonischemic myocardium, the regional blood flow, both to the border zone and to the center of the ischemic zone, declined with both drugs. This effect caused an increase in ischemit injury, showing the detrimental effect of this type of intervention.24 On the other hand, nitroglycerin and methoxamine were found to redistribute the flow to the ischemic area and thereby to reduce myocardial damage (Fig 8). ~.__--.-..~--.--b STEPHEN E. EPSTEIN: These studies, as well as those from other laboratories, emphasize the very important point that vasodilator drugs cannot be considered agents with homogenous effects and, therefore, cannot be used interchangeably. Although nitroglycerin favorably alters the flow to ischemic tissue and reduces ischemic injury, several laboratories have now demonstrated that in the absence of left ventricular failure, nitroprusside reduces the flow to ischemic tissue, and can result in an increase in ischemic injury. These results must still be considered experimental, since deleterious effects of nitroprusside may not occur often in the clinical setting when left ventricular failure is present. However, the clinician must be aware of the fact that beneficial effects during acute infarction inherent in one vasodilator cannot necessarily be ascribed to other vasodilators. The reason for this is that different vasodilators affect various vascular beds differently. Nitroprusside is a very potent dilator of arterioles as compared to nitroglycerin, but nitroglycer-

in is a more potent dilator of veins and of the coronary collateral circulation. Another more direct method of preserving myocardial cells would be to increase oxygen supply by restoring blood flow to the obstructed vessel. This method is not only of theoretical importance, but is the basis of the surgical restoration of blood flow in patients with evolving myocardial infarction. Using the same method as that employed for the studies already discussed, and reperfusing the coronary artery three hours after occlusion, it was found that an acute fall in S-T segment elevation occurred after the release of the coronary occlusion. More importantly, CK activity and histologic examination, 24 hours and seven days later, showed preservation of extensive portions of the myocardium otherwise expected to have lost their viability.zs In addition, ventricular function was investigated using radioopaque beads implanted in the inner third of the left ventricular wall. The paradoxical movements of the ventricle, which were present after coronary occlusion, ceased or were reversed onehalf hour after reperfusion. Thus, not only was there a reduction in myocardial damage anatomically, but the ultimate aim of restoring viable, normally functioning myocardium was achieved. Smith et al.*‘j reversibly occluded a coronary artery of primates for varying periods of time and observed, by histologic examination seven days following coronary occlusion, that reperfusion four hours after occlusion resulted in salvage of myocardium and that the extent of this salvage varied inversely with the duration of the occlusion. It should be noted, however, that reports from several investigators have shown conflicting results using different methods for assessing the viability of myocardial tissue after coronary artery reperfusion, and after variable time intervals from the onset of coronary artery reperfusion and after variable time intervals from the onset of coronary artery occlusion. Indeed, in some studies, reperfusion resulted in a hemorrhagic infarct larger than would have been expected from simple coronary occlusion. Presumably, ischemic damage to the microvasculature can result in the extravasation of blood during reperfusion. Despite these deleterious results in some experiments, the clear-cut demonstration in others of myocardial salvage after several hours of ischemia indicates the clinical potential of myocardial salvage, at least under certain circumstances. Another series of related experiments was performed using intraaortic balloon counterpulsation. This intervention has the advantage of reducing the heart’s need for oxygen while simultaneously increasing its supply. I2 As anticipated, with this intervention there was also a striking reduction in myocardial ischemit injury (Fig 9). These experiments, taken as a group, show that the balance 24

-

OCCLUSION

5

10

m

ALONE

‘!,

‘?

AREA OF INJURY AFTER OCCLUSION ALONE

:i

MlNU?ES

Fig 9. -Effects of aortic balloon counterpulsation. Left, average S-T segment elevation (%i) during occlusion alone (closed circles) and during occlusion with counterpulsation (open crrcles). Right, schematic representation of the heart, with circles indicating sites where epicardial electrocardiograms were obtained. The area of ischemic injury after occlusion alone (S-T > 2 mV) is depicted by the diagonal lines and, during occfusion with counterpulsation by the crosshatched area. Note the reduction of the Injured zone by counterpulsation. LA, left atrial appendage, LAD, left anterior descending coronary artery. (Reproduced with permission from Maroko. P. R., Bernstein. E. F., Libby, P., DeLaria, G. A., Covell, J. W., Ross, J., Jr and Braunwald E.: Effects of intra-aortic balloon counterpulsation on the severity of myocardial ischemic injury following acute coronary occlusion Circulatton 45 11
between myocardial oxygen supply and demand is an important factor in determining infarct size following coronary occlusion. They suggest that tachycardia or arterial hypotension, or both, in a patient with an acute coronary occlusion might extend the size of the ischemic zone and the ultimate size of the infarct, thereby further impairing left ventricular function and resulting in a vicious cycle (see Figs 1 and 5). They also point to the potentially deleterious effects of the administration of positive inotropic agents, such as isoproterenol, digitalis glycosides or other agents that exert a positive inotropic action in patients with acute myocardial infarction, but without heart failure. All of these positive inotropic agents augment myocardial oxygen demands in the nonfailing heart, but do not necessarily exert such an effect in the presence of heart failure.22 GLUCOSE-INSULIN-POTASSIUM Analysis quirements

of the relationship between myocardial energy reand its supplv was then extended to anaerobic myo25

cardial metabolism. Normally, the heart derives all of its energy from the oxidation of various substrates in the Kreb’s cycle. However, in the absence of oxygen, the myocardium possesses the capacity to derive significant energy from anaerobic glycolysis provided the tissue is not totally ischemic, since severe intracellular acidosis inhibits anaerobic glycolysis.y Experiments were, therefore, conducted to determine whether anaerobic glycolysis could provide sufficient energy to limit the extent of myocardial necrosis after coronary occlusion. It was reasoned that if the size of a myocardial infarct is dependent on the balance between the availability and the demand for the various compounds involved in energy production, then the anatomic and functional integrity of cardiac muscle in the border zone surrounding the infarct, in which perfusion is present but reduced, might be preserved by increasing anaerobic glycolysis. Accordingly, we examined the effects of the infusion of glucose-insulinpotassium.“’ It was found that when administration was begun 30 minutes after coronary occlusion, glucose-insulin-potassium substantially decreased the quantity of necrosis, as reflected in myocardial creatine kinase activity and histologic (see Figs 2 and 3) and electron microscopic appearance 24 hours later. The beneficial effects of the glucose-insulin-potassium mixture on myocardial ischemic damage have also been demonstrated by Opie and collaborators in the baboon with experimentally induced coronary occlusion. These investigators noted that the hearts of glucose-insulin-potassium treated animals exhibited higher concentrations of adenosine triphosphate, creatine phosphate and glycogen, as well as higher K+/Na+ and lower lactatepyruvate ratios than those of untreated baboons.‘x HYALURONIDASE

This enzyme, which depolymerizes mucopolysaccharides, is also very effective in reducing the acute S-T segment elevation. It also reduces necrosis 24 hours after occlusion, as reflected in myocardial CK depression, histologic examination and epicardial S-T segment changes 27 (Figs 2, 3 and 10). Moreover, following left coronary artery occlusion in the rat, infarct size is substantially smaller in hyaluronidase-treated rats than in nontreated rats, when analyzed either by serial histologic sections or by total left ventricular CK activity.‘” This is evident both after 2 and after 21 days, thus demonstrating that not only is the necrosis less at the peak of the process but that hyaluronidase administration does more than simply delay the necrotic process. It reduces the ultimate extent of necrosis and, therefore, results in a larger quantity of normally contracting myocardium when the infarct has healed (Fig 11). The beneficial results obtained with 26

Fig lO.-An example of the effect of hyaluronidase administration on the sum of S-T segment elevations (ZST). Right, schematic representation of the heart. Diagonal lines, area of S-T segment elevation 15 minutes following occlusion alone; cross-hatched section, area of S-T segment elevation 15 minutes following occlusion alone preceded by hyaluronidase administration. LA., left atrium: L.A.D., left anterior descending coronary artery; closed circles, sites where epicardial electrocardiograms were obtained. Left, comparison between the sums of S-T segment elevations (ZST) rn the same animal after the two occlusions. Continuous line, XT just before and after the control occlusion; broken line, CST just before and after occlusion with hyaluronidase pretreatment; Time = minutes after occlusion. (Reproduced with permission from Maroko, P. Pi., Libby, P.. Bloor, C. M., Sobel. B. E. and Braunwafd, E.: Reduction by hyaluronidase of myocardial necrosis following coronary artery occlusion. Crrculation 46:430-437. 1972 )

this drug during the first 48 hours exceeded those produced by the other interventions tested in the rat model; by the CK method there was approximately 50% more residual myocardium in the hyaluronidase-treated than in the untreated control rats at the peak of the necrotic process. The mechanism of action of hyaluronidase is still not fully understood. Hyaluronidase has been shown to penetrate the ischemit zone, depolymerizing the mucopolysaccharides even in the center of the infarct. This action may facilitate either the transport of nutrients to, or the washout of potentially harmful metabolites from, the ischemic zone. The electron microscopic observation that glycogen is abundant even in the center of the ischemic zone in hyaluronidase-treated rats may support the postulate that the transport of nutrients such as glucose is facilitated.‘” In addition, it was found that hyaluronidase prevents the fall in collateral blood flow to the ischemic zone, which normally occurs between 15 minutes and six hours after coronary artery occlusion. This may be explained by a reduction in edema and, therefore, in compression of the microvasculature. 27

Fig ll.-Htstologic sections (top) and dragrams (bottom) of transverse slices of hearts of rats killed 21 days after occlusion of the left main coronary artery with (right side) and without (left side) hyaluronidase treatment. LV, left ventricle; RV, right ventricle: VS, ventricular septum: I, infarcted myocardium. The borders of the infarctions are shown by the broken lines and their areas by the diagonal lines in the diagrams. Note that In the rat with an occlusion alone the infarction involved 54.1% of the endocardial circumference of the left ventricle, whereas in the hyaluronidase-treated rat it involved only 20.1%. (Reproduced with permissron from Maclean, D., Fishbein. M. C., Maroko, P. R. and Braunwald, E.: Hyaluromdase-induced reductions in myocardial infarct size. Direct quantification of infarction following coronary artery occlusion in the rat, Science 194.199. 1976.)

The administration of hyaluronidase to patients offers several potential advantages compared with other interventions that reduce infarct size in experimental animals after coronary occlusion: (1) Its application is simple and does not require any special equipment, as does intraaortic balloon counterpulsation. (2) It does not depress cardiac contractility or cause hypotension, as does propranolol. (3) It does not have the intrinsic property of changing S-T segments as does glucose-insulin-potassium, and thus the electrocardiographic monitoring of ischemic injury may be used for monitoring the extent and severity of ischemic injury. (4) Most importantly, hyaluronidase has been used widely clinically for a variety of purposes and its toxicity is extremely low. Allergic reactions are rare (O.OS%), generally occurring after frequent exposure, and may be avoided if a skin test is performed. Finally, in terms of effectiveness in reducing myocardial 28

necrosis in the dog after coronary occlusion, hyaluronidase compared favorably with other interventions, such as propranolol and glucose-insulin-potassium. ANTIINFLAMMATORY

INTERVENTIONS

Following the initial damage caused directly by ischemia, many additional factors are responsible for myocardial cell injury. These include an increase in capillary permeability, interstitial edema, leukotaxis, phagocytosis and nonspecific injury to cell membranes. Presumably, the boundary of the necrotic zone is defined not only by the ischemic stimulus per se, but also by many other influences that may result either in definite irreversible damage or the sparing of these cells in the border zone. Accordingly, the influences of interventions that can limit these inflammatory reactions have been examined. The activation of the complement system, which may occur during ischemic damage, results in the release of leukotactic factors, may be responsible for increases in capillary permeability and interstitial edema and may contribute substantially to the injury to cell membranes. The action of cobra venom factor, a protein that enzymatically cleaves C3 and thus inhibits the action of the complement system, has been investigated. Also, the effects on infarct size of aprotinin, an inhibitor of the kallikrein system, have been studied, as activation of the kallikrein system may also enhance leukotactic activity, capillary permeability, interstitial edema and proteolytic activity. Moreover, the effects on myocardial ischemic injury of pharmacologic doses of glucocorticoids, which may stabilize lysosomal and other cellular membranes, were examined. All three of these interventions, i.e., cobra venom factor, aprotinin and glucocorticoids, were shown to be beneficial, limiting substantially the extent of myocardial ischemic injury following experimental coronary artery occlusion in the dog.‘” Studies in the rat model have confirmed the effectiveness not only of these drugs in limiting infarct size, but also of ibuprofen, a nonsteroidal antiinflammatory drug, which appears to act by inhibiting prostaglandin synthesis. It may be postulated that by interfering with the inflammatory responses of the organism to ischemic injury, additional damage to myocardial cells is avoided. Because the development of the collateral circulation occurs relatively soon after the ischemic stimulus provided by coronary occlusion, the cells, which are only reversibly damaged, may recover. b STEPHEN E. EPSTEIN: Although several experimental studies have demonstrated a beneficial effect of glucocorticoids, other studies have suggested a potential deleterious effect. Hence, as the authors emphasize 29

later on, the precise role of these agents in acute myocardial still uncertain.

infarction

is

OTHER INTERVENTIONS

Munnitol reduces the extent of ischemic injury and improves the function of the ischemic myocardium. This hyperosmotic agent reduces cell swelling and, as a result, presumably improves collateral blood flow to the ischemic myocardium. Elevations of serum osmolality are associated with improved performance of ventricular papillary muscle and, in addition to its effect on collateral blood flow, mannitol exerts a direct beneficial effect on myocardial function. Since mannitol must greatly increase serum osmolality to be effective, its administration usually causes major shifts of fluid to the intravascular space; as a result, it carries certain potential clinical hazards.:“) b STEPHEN E. EPSTEIN: In addition to the cautionary authors, most recent studies using mannitol under conditions than the original experiments, have failed beneficial effect on either collateral flow to ischemic parameters reflecting ischemic iniurv.

note raised by the more physiologic to demonstrate a myocardium or on

In the open-chest dog with acute coronary occlusion, infusions of high doses of heparin have been reported to reduce myocardial ischemic injury, as measured by epicardial S-T segment elevation, myocardial CK depletion and histologic evidence of necrosis. In patients with acute myocardial infarction treated with heparin, precordial S-T segment elevations 24 hours after administration were reduced compared to untreated patients. The mechanism by which heparin reduces myocardial necrosis has not been established; it may prevent thrombosis of the microvasculature by its well-known anticoagulant effect, thereby improving collateral flo~.:~’ EFFECTS OF DELAYED

INTERVENTIONS

Unless the above-cited interventions are effective several hours after-coronary occlusion, their direct clinical effectiveness in reducing infarct size will be limited to patients who had experienced an infarct under observation in the hospital, or those treated for impending myocardial infarction. It was found in scattered experiments that isoproterenol, propranolol, methoxamine, phenylephrine, norepinephrine, the combination of glucose-insulin-potassium and propranolol, hydrocortisone and intraaortic balloon counterpulsation’:‘, I53Ifi, Z7 can change the extent and magnitude of myocardial ischemic injury when administered 3-6 hours after coronary occlusion. However, more systematic studies were recently carried out with hyaluronidase.:” 30

40 30 F 20 ( IU/mg

CPK24h PROTEIN) 15 -

10 5-.A0

I 8

4

ST,5m

I 12

J 16

in mV

Fig lP.-The relationship between S-T segment elevation 15 minutes after coronary artery occlusion (ST15,) and log CK values of specimens obtained from the same sites 24 hours later Group A, occlusion alone (--); group B, hyaluronidase given 20 minutes after occlusron (- - -); group C, hyaluronidase given 3 hours after occlusion (--- - -); group D, hyaluronidase given 6 hours after occlusion (- - .). group E, hyaluronidase given 9 hours after occlusion (- - - - - - -). Note that for any ST,,,. hyaluronidase given 20 minutes, 3 hours or 6 hours after occlusion results in significantly greater myocardial CK activity. In contrast, hyaluronidase administered 9 hours after occlusion has no such effect. *= p cc 0.025; *’ = p < 0.025: ‘* = p < 0.0005 in comparison to control; ? = p i 0.025; ?t = p < 0.0005 in comparison to hyaluronidase at 20 minutes. (Reproduced with permissron from Hillis, L. D., Fishbein, M. C., Braunwald, E.. and Maroko, P R.: The influence of the time interval between coronary artery occlusion and the administration of hyaluronidase on salvage of ischemic myocardium in dogs. Circ. Res. 41.26-31. 1977.) l

When this agent was administered 20 minutes, 3 and 6 hours after coronary occlusion, myocardial salvage was reflected by less CK depletion for any degree of S-T segment elevation than was observed in control (untreated) dogs (Fig 12). However, this effect decreased progressively with time after coronary occlusion; when administered nine hours after coronary occlusion hyaluronidase had no detectable effect, suggesting irreversible injury at this time. EFFECT OF INTERVENTIONS

ON THE HEALING

PROCESS

The healing process following infarction, i.e., the formation of a scar, is distinct from that of the development of myocardial necrosis per se. It was considered possible that drugs exerting a protective effect on the ischemic myocardium may have a detrimental effect on scar formation In the rat model, the thickness of the scar was examined three weeks after the occlusion. Hy31

Fig 13.-Scar thinning resulting from administration of 50 mg/kg of methylprednisolone (MP) 5 minutes and 3, 6 and 24 hours after occlusion (MPx4). A representative histologic section from a nontreated occluded rat at 21 days postocclusion is shown in (A) and one with an MPx4-treated rat in (B). Note that for a scar of comparable size, that from the MPx4-treated rat is abnormally thin (Masson’s trichrome, x3). (Reproduced with permission from Maclean, D., Fishbein, M. C., Braunwald. E.. and Maroko, P. R.: Long-term preservation of ischemic myocardium after experimental coronary artery occlusion, J. Clin. Invest. 61 :541 1978.)

aluronidase, reserpine, cobra venom factor, ibuprofen and single doses of hydrocortisone or methylprednisolone did not result in thinner scars. However, when multiple doses of methylprednisolone were administered during the 24 hours after coronary artery occlusion the scars were excessively thinner (Fig 13). At the time of killing, 21 days after coronary occlusion, these abnormally thin scars had already developed into prominent ventricular aneurysms. Interestingly, it has been suggested that in man multiple dos32

es of methylprednisolone following acute myocardial infarction may increase the incidence of ventricular rupture, although this has not yet been substantiated. The present controversy about the role glucocorticoids should play in the treatment of myocardial infarction may be related, at least in part, to their opposing effects on necrosis and healing.

CLINICAL OBSERVATIONS One of the most formidable barriers to the clinical application of the information that has been obtained in the laboratory is the lack of a suitable technique to assess the efficacy, or lack thereof, of these interventions. The ideal technique for assessing the effectiveness of interventions designed to protect injured, but potentially salvageable myocardium in patients would be: (1) safe and noninvasive; (2) capable of predicting the extent of necrosis to be expected if no interventions were employed; (3) capable of assessing the extent of necrosis that actually develops; (4) capable of providing the data in items 2 and 3 accurately and in quantitative terms, i.e., in grams; (5) effective if applied immediately upon the patient’s admission, so that the intervention under study can be promptly applied, since delay in treatment may be expected to reduce the population of injured cells that are salvageable; (6) relatively simple, easy to apply and inexpensive, so that its use would not be limited to specialized centers; and (7) applicable to all patients with acute myocardial infarction. Items 2 and 3 are of particular importance, since they would allow each patient to be used as his own control. At present, myocardial ischemic injury in the clinical setting can be assessed by the following methods: (1) radionuclide scintigraphy by gamma imaging of the myocardium; (2) release of enzymes from the injured myocardium (CK disappearance curves); and (3) precordial S-T segment and QRS mapping. The application of the radionuclide techniques has great potential, but their use for monitoring changes in the extent of an ischemic zone depends on the development of cameras with higher resolution and the availability of an imaging agent that would specifically identify injured cells and that could be used serially. The CK disappearance curves offer the possibility of predicting “infarct size” following at least 7 hours of sampling (i.e., at least 10 hours from the onset of pain), but they are, therefore, of less value in studies carried out in the early hours of ischemia when the population of reversibly injured cells is maximal. The experimental foundation for the use of S-T segment elevations recorded from multiple precordial leads was established in 1972 in experiments in dogs with coronary artery occlusion.‘“, Ifi Interventions that caused an increase or decrease in epicardial S-T segment elevations produced similar directional changes in 33

Fig 14.~Schematic representation of the 35electrode map on a patient’s chest. (Reproduced with permission from Maroko. P. R.. Libby, P., Covell, J. W.. Sobel, B. E., Ross, J.. Jr., and Braunwald. E.: Precordial S-T segment elevation mapping: an atraumatic method for assessing alteration in the extent of myocardial ischemic injury, Am. J. Cardiol 29:223. 1972.)

precordial maps. A 35lead electrode blanket was devised to record precordial maps from patients with acute infarction (Fig 14). Several interventions, such as propranolol or intraaortic balloon counterpulsation, resulted in rapid resolution of the precordial S-T segment elevation. Recently, studies in dogs with simultaneously recorded epicardial and precordial maps have confirmed the presence of an extremely close relationship between changes in epicardial and precordial S-T segment elevations.14 In turn, epicardial.S-T segment elevation correlates well with changes in myocardial PO,, in myocardial CK activity and, most importantly, it accurately predicts the areas of necrosis, as defined by light and electron microscopy.‘q The clinical relationship between precordial S-T segment elevation and the reversible damage to myocardial cells is well illustrated by patients with Prinzmetal’s “variant” angina. In these patients there is a temporary occlusion of a major coronary artery, most often as a result, at least in part, of coronary arterial spasm. The relief of coronary spasm and subsequent disap34

pearance of ischemic injury is reflected by cessation of pain and ventricular irritability and the fall of the S-T segment elevation. However, in patients in whom the coronary blood flow fails to return, the ischemic injury progresses, the S-T segments remain elevated and a frank infarction develops. In view of the apparent lack of toxic effects from hyaluronidase and the impressive experimental results with this agent, a pilot study was undertaken to examine its effectiveness in patients with acute myocardial infarction.“” Twenty-four patients who had suffered a typical transmural myocardial infarction, as determined.by history, enzyme changes and electrocardiographic Fig 15.-l, The sum of S-T segment elevations (XST) In controls and in hyaluronidase-treated patients at zero time (before treatment) and at 2 and 24 hours after treatment. Note that before treatment both groups had similar values of more rapidly X-T. However, in the treated group XS-T dropped significantly than in the control group. II, number of electrodes showing S-T segment elevations exceeding 1 m m (NST) In control patients and in hyaluronidase-treated patients at zero time (before treatment) and at 2 and 24 hours after treatment. Note that before treatment both groups had similar values of NST. However, in the treated group NST dropped sigmficantly more rapidly than in the control group. (Reproduced with permission from Maroko. P. R., Davidson, D. M., Libby, P.. Hagan. A. D., and Braunwald. E. Effects of hyaluronidase administration on myocardial ischemic injury in acute infarction. A preliminary study in 24 patients Ann Intern Med 82:516-520 1975 i CONTROL HYALURONlD4SE

;,

i 0

CONTROL HYALURONIDASE

35

BEFORE

AFTER

2 hrs.

Fig l&-Three enlarged leads from a 35-lead precordial map in a patient with acute myocardial infarction, showing S-Tsegment elevations in these leads before hyaluronidase administration (left), and the striking reduction of S-T segment elevation two hours after its administration (right). (Reproduced with permission from Maroko. P R., Davidson, D. M.. Libby, P.. Hagan, A. D.. and Braunwald, E: Effects of hyaluronidase administration on myocardial ischemic injury in acute infarction. A preliminary study in 24 patients, Ann Intern Med. 82516-520. 1975.)

criteria, were studied. The 11 patients who did not receive hyaluronidase served as controls and the 13 patients who received the drug constituted the experimental group. Although these patients were not assigned to one of the two groups in a randomized manner and the design of the study was not blind, there was no attempt to preselect the patients on the basis of the severity of their disease. All patients had acute myocardial infarction involving the anterior or lateral walls of the left ventricle, and the onset of chest pain occurred less than eight hours before the beginning of the study. Patients more than 75 years of age and others with disease of kidney or liver, pregnancy, neoplasms or infections were excluded. Patients received hyaluronidase, 500 National Formulary units/kg intravenously in a bolus injection, folJowed by additional identical doses after 2 and 6 hours, and then every 6 hours until 42 hours after the initial dose. The precordial electrocardiograms were recorded with 35 unipolar leads. The precordial leads were in a fixed position in a blanket covering the precordium, distributed in five rows of seven electrodes each (see Fig 14). Average levels of XS-T and of the number of electrodes showing S-T elevations greater than 0.1 mv (NST) before administration of hyaluronidase in this group were not statistically different from values in the control group. However, at all times after treatment with hyaluronidase, average 36

XS-T and NST were significantly lower (p< 0.05) than in the control group (Fig 15 and 161. The precordial S-T segment mapping technique as described above, or some variation, has been used to show that several other interventions reduce precordial ST segment elevation in patients more rapidly than expected; this implies that these interventions effectively reduce myocardial injury while it is still in the reversible phase. These interventions include propranolo134 (Fig 171, nitroglycerin and the inhalation of high concentrations of oxygen.” However, as already pointed out, precordial, like epicardial, S-T segment elevation can result from other causes, such as pericarditis, changes in ionic concentrations (i.e., hyperkalemia) and normal early repolarization. Moreover, S-T segment changes at best reflect alterations in myocardial ischemic injury and not necrosis. Accordingly, there has been considerable interest in finding a noninuasiue marker of myocardial viability. One such measure that is readily available clinically is the precordial QRS complex. A reduction in the electromotive force of the epicardial R wave within hours of experimental coronary occlusion was demonstrated in 1933 by Wilson and his associates. Later it was demonstrated that a reduction in epicardial R wave voltage was found at sites in which ischemia produced a mixture of viable and necrotic myocardium, as determined by histologic study. To apply this method clinically, we have proposed the use of the precordial S-T segment soon after the onset of the clinical event as a predictor of the ultimate fate of the tissue, in a manner analogous to the epicardial ST segment in the experimental animal, as described earlier. This precordial S-T segment may then be compared to the changes in the QRS complex that subsequently occur, such as the development or deepening of Q waves and the reduction of R wave potential; these changes in the QRS complex could then be employed in a manner analogous to the alterations in CK activity or histologic appearance of the myocardium subjacent to the epicardial electrode in the experimental animal. Recent experiments have confirmed the existence of a very close correlation between changes in the QRS complex of epicardial leads and myocardial CK activity.“J In these experiments, unipolar electrograms recorded from epicardial sites in open-chest dogs were analyzed for S-T segment elevation 15 minutes after coronary occlusion and changes in Q and R waves 24 hours later. Transmural myocardial specimens were then obtained 24 hours after occlusion from the same sites from which the ECGs had been recorded. Both in control (untreated) dogs and in dogs treated with hyaluronidase or propranolol, the 37

i-

6’ !.

3

AFTER PROPRANOLOL (7.29 PM) : ,, I 1~0101 on the reduction In S-T segment elevation ::, Q

2 18: scads depicted are from the V,. V, and V, posiq !lrl’ ,I!C?S are one intercostal space above and below I‘ I;- ‘ht- marked reduction in S-T segment elevations 5, jr.- -,

developltic nt 11 *J waves. the fall in R waves and their combinaticin iLli + hl~ I ;$a:24 hours correlated well with the final depression 0:’:n> xard,;tl CK activity (Figs 18 and 19). In addition (AR 4 IQ) correiatetl well with the extent of necrosis present on histologic ex: mi nation cFig 20). From these investigations we concluded t h: t: i 1 Q wave development and R wave fall 24 hours after OCCIL sion accurately reflect myocardial necrosis, as measured by C:K activity and by histologic appearance; (2) S-T segment elcvltion 15 minutes after occlusion predicts subsequent changes ir: Q and R waves: (3) the efficacy of hyaluronidase and propranolol. agents shown by a variety of other techniques (including direct anatomic measurements of infarct size) to reduce myol:ardial necrosis following coronary artery occlusion, can be detected by a diminution in the changes in QRS morphology (i.e.. !ess Q wave development and smaller fall in R wave voltage,. This method of electrocardiographic mapping can be adapted for clinical use as a predictor of the ultimate fate of the myocardium, in a manner analogous to that of the epicardial S-T segment in the experimental animal. S-T segment elevation is recorded in the precordial leads, utilizing the special 35-lead system or some variation thereof, when the patient is first admitted to the cormary care unit The evolution of the QRS complex in 38

Fig 18.-A (left side), a schematic representation of the heart and its arteries. The left anterior descending coronary artery (LAD) was occluded at its midportion (occl). Diagonal bars, the zone of S-T segment elevation 15 minutes after occlusion. Right side, examples of eprcardial electrograms. myocardial CPK values (in IU/mg protein) and hrstologic grades from a control dog. Site A (from nonischemic myocardium) exhrbited no S-T segment elevation at 15 minutes. At 24 hours it had no changes rn QRS configuration and normal CPK activity. and it appeared normal hrstologically. Site 5 (border zone) showed moderate ST,,, while at 24 hours there was a significant Q wave and partial loss of R wave voltage. The CPK activity was moderately depressed, and the histologic section was graded 3+ (51-75%) necrosis. Site C (center of the ischemic zone) had marked ST,,, and at 24 hours rt demonstrated a total loss of R wave with a QS complex. The myocardial CPK activity was greatly depressed, and the histologic section was graded 4’ (;75%) necrosis. B, examples of epicardial electrograms. myocardial CPK activity and histologic grades rn a dog that received hyaluronidase 20 minutes after occlusion Site A (from nonischemic myocardium) exhibited no S-T segment elevation at 15 minutes. and at 24 hours there were no changes In QRS configuration The myocardial CPK was normal, and the specimen appeared normal histologrcally. Site 8 (border zone) showed moderate ST,,,. at 24 hours. the specimen did not exhibtt the expected loss of CPK activity. was graded 1 _ (1 -25% necrosis) hrstologically, and did not show extensive changes in QRS configuratron, rndicatrng that hyaluronidase acted to reduce necrosis in the border zone. Site C (center of the ischemic zone) had marked ST,,,, while at 24 hours the QRS configuration and CPK activity were moderately altered; the hrstologrc sectton was graded 3’ (51-75% necrosis). Note. in comparing sites 5 and C in thts figure with those in A, for similar degrees of S-T segment elevation, hyaluronidase reduces necrosis, as measured electrically (QRS complex), brochemically (CPK activity) and histologically. (Reproduced with permission from Hrllis. L. D., Askenazi, J.. Braunwald, E., Radvany, P.. Muller. J. E., Fishbein. M. C.. and Maroko. P. R.: Use of changes In epicardial QRS complex to assess interventions which modify the extent of myocardial necrosis following coronary artery occlusion, Circulation 54:591598. 1976.)

the leads that demonstrate initial ST segment elevation can then be compared with those in a control and a treated group of patients. These changes in the QRS complex in precordial leads can be used as a replacement for the analysis of changes in CK activity and histologic appearance of myocardial specimens obtained in experimental animals. Thus, this electrocardiographic analysis, although not capable of expressing the mass of infarcted myocardium in quantitative terms, would appear to be: (1) capable of predicting the surface representation of the extent of necrosis to be expected when much of the myocardial injury is still in a reversible phase, i.e., at a time of S-T segment elevation prior to the development of 39

Fig lg.-The relationship between S-T segment elevation at 15 minutes following occlusion (ST,,,) and changes in QRS configuration at 24 hours [(AR + AQ),,,]. The regression line for eight controls (continuous line) is: (AR + AQ),,, = 3.39 t 0.75) ST, 5Ill *- (8.8 +- 1.9); N = 8, r = 0.81 -t 0.06. The regression line for eight hyaluronidase-treated dogs (dotted line) is: (AR + = (1.35 2 0.37) ST,,, + A%, (5.4 f 1.7); N = 8, r = 0.60 t 0.14. The regression line for the eight propranolol-treated dogs (dashed line) is (AR + AQ),., = (1.79 i 0.4i) sr,,, + (9.0 2 2.5); N = 8. r = 0 68 ? 0.08. Note that for any level of ST,,,, (AR + AQ),,, is less in the treated dogs than in the controls (p i 0.05). reflecting less myocardial necrosis. The R values, which range from .81 to .60. indicate that the use of the technique should be confined to comparisons of groups of animals. (Reproduced with permission from Hillis, L. D., Askenazl, J., Braunwald. E., Radvany, P.. Muller. J. E., Fishbein. M. C.. and Maroko, P. R.: Use of changes in epicardial QRS complex to assess interventions which modify the extent of myocardial necrosis followrng coronary artery occlusion, Circulation 54594, 1976.) c...

changes in the QRS complex; (2) capable of assessing the surface representation of the extent of necrosis that actually develops, as reflected by the change in the QRS complexes; (3) capable of being applied immediately so as not to delay therapy; (4) safe and atraumatic and (5) simple to apply, easy to interpret and inexpensive. Using* this technique the effects of hyaluronidase have been assessed.3” Ninety-one patients with anterior infarction were randomly placed in control (45 patients) or in hyaluronidasetreatment (46 patients) groups. A 35lead precordial electrocardiogram was recorded on admission and seven days later. Hyaluronidase was administered intravenously after the first electrocardiogram and every 6 hours for 48 hours. The sum of R wave voltages of vulnerable sites fell more in the control group than in the hyaluronidase group (70.9 5 3.6% I? 1 SEMI VS. 54.2 2 5.0%, p < 0.01). Q waves appeared in 59.3 k 4.9% of the vulnerable sites in control vs. 46.4 k 4.9% in hyal40

20 -

(AR+AQ& in mV

T

HISTOLOGIC

GRADE

Fig 20.-The

relationship between 0 wave development and R wave fall 24 hours after coronary artery occlusion [(AC! + AR),,,/ and the extent of necrosis demonstrated histologically at the same time in myocardial biopsy specimens. Histologic grade 0 = no visible necrosis; grade l+ = l-25% necrosis; grade 2* = 26-50% necrosis; grade 3- = 51-75% necrosis; and grade 41 = >75% necrosis. Note that [(AQ + AR),,,] increases progressively as necrosis becomes more pronounced. The standard error of the mean is indicated. (Reproduced with permission from Hillis. L. D., Askenazi. J., Braunwald, E., Radvany, P., Muller, J. E., Fishbein, M. C., and Maroko. P. R.: Use of changes in epicardial QRS complex to assess interventions which modify the extent of myocardial necrosis following coronary artery occlusion. Circulation 54:591, 1976.)

uronidase-treated patients (,D c: 0.05) (Figs 21,22 and 23). Thus, the findings in this study demonstrate the hyaluronidase, when administered within the first eight hours after the onset of the clinical event, reduces the extent of electrocardiographic evidence of myocardial necrosis in patients with acute myocardial infarction. Although the differences in these electrocardiographic changes between the two groups were approximately 20%, it should be noted that this type of analysis indicates a directional change in the extent of myocardial infarction, but does not provide quantitative information. When considered together, the observations of the effects of hyaluronidase on the extent of myocardial necrosis in dogs*‘, 32,:E and rats’!’ with experimentally produced coronary occlusion, the two pilot clinical trials demonstrating the effects of this agent on the rate of resolution of abnormally elevated precordial S-T segments”” and the development of electrocardiographic changes indicative of necrosis in the QRS complex”” all point to the conclusion that this agent may be effective in reducing the quantity of myocardium that eventually becomes 41

Fig 21.-Changes in scores for S-T segment elevation In hyaluronidase-treated and control groups. Left, the percentage of precordial sites with S-T segment elevations 2 0.15 mV on the admission electrocardiogram, with at least minor changes in QRS complex, i.e., a score of 1 or more, in the tracing recorded on the 7th day. Numbers in the columns represent the number of patients in each group. Bars represent 21 SEM. The 45 control patients had 635 sites with S-T segment elevations, and the 46 hyaluronidase-treated patients had 591 sites. Note that the control patients had significantly more sites in which the QRS morphology changed at least slightly, i.e., a score of 1 or more, than the hyaluronidase-treated patients (’ = p c 0.05). Center, the percentage of precordial sites with S-T segment elevations > 0.15 mV on the admission electrocardiogram with at least moderate changes in the QRS complex, i.e., a score of 2 or more, in the tracing recorded on the 7th day. In the 45 control patients the total number of vulnerable sites was 575, and in the hyaluronidase-treated patients it was 494. Right, the percentage fall in total R-wave voltage (ZR) in the sites with S-T segment elevation ?I 0.15 mV on the inttial electrocardiogram. Note that the controls had a significantlygreaterfall in R-w,avevoltage than the hyaluronidasetreated patients (” = p c 0.05. ** : p c 0.01). (Reproduced by permissioh from Maroko, P. R., Hillis, L. D., Muller, J. E., Tavazzi, L., Heyndrickx. G. R., Ray, M., Chiariello. M., Distante. A.. Askenazi. J., Salerno, J.. Carpentier, J., Reshetnaya, N. I., Radvany, P., Libby, P.. Raabe, D. S., Chazov, E. I., Bobba, P., and Braunwald, E.: Favorable effects of hyaluronidase on electrocardiographic evidence of necrosis in patients with acute myocardial infarction, N. Engl. J. Med. 296:898-903, 1977.)

necrotic after coronary occlusion. Its low level of toxicity and its ease of administration suggest that expanded and rigorous clinical trials with hyaluronidase should now be undertaken. A number of other pilot studies in patients with acute myocardial infarction have supported the hope that significant myocardium can be salvaged by the application of an intervention several hours after the clinical event (see Table 2). As already noted, several studies have demonstrated that beta-adrenergic blockade relieves pain and reduces myocardial ischemia in patients with acute myocardial infarction (see Fig 17).‘34 In addition, the beta blockers stabilize cardiac rhythm in patients with myocardial ischemia and infarction independent of their salutary effect on infarct size. The cardiac depressant effects of beta blockade do, however, limit the potential value of these agents to patients who are not in heart failure. Until recently, nitroglycerin was avoided in patients with acute myocardial infarction because nitroglycerin-induced re42

ductions in systemic arterial pressure and concomitant reflex increases in heart rate were believed to intensify ischemic injury. However, the use of this drug has recently been reassessed. Studies in dogs by Myers et al. have shown that intravenous nitroglycerin given at a rate sufficient to cause a mild reduction in systemic arterial pressure reduces the magnitude and extent of ischemic injury, and that this injury can be further reduced if the blood pressure decrease and reflex tachycardia induced by nitroglycerin are abolished by the simultaneous infusion of methoxamine.“’ In addition, the administration of nitroglycerin shortly after coronary artery occlusion partially reverses the ventricular fibrillation threshold lowered by coronary occlusion, whereas nitroglycerin and phenylephrine in combination return this threshold to normal. ___-_----.-. _---____ ___..___ b STEPHEN E. EPSTEIN: Most importantly, it, was demonstrated in our laboratory that nitroglycerin, adminislered with methoxamine, diminishes the incidence of ventricular fibrillation and death occurring sponmyocardial infarction in the dog. taneously within 30 minutes of acute __-..~--_--.--_-

A6 B5 c4

-c--

B2 7 days c3 D3

Fig 22. - Examples of the electrocardiographic evolution in seven days. Left, three leads from admission tracings; right, leads from the same sites one week later. The three top leads are taken from a patient in the control group. Note that after seven days all complexes exhibited a QS pattern (i.e., score of 4) The three bottom leads are from a patient treated with hyaluronidase. All leads show only moderate declines in the R waves. Each letter and number patr identifies the position of the electrode in the 35lead mat. The letter identifies the horizontal row. and the number the vertical one. (Reproduced with permission from Maroko, P. R.. Hillis, L. D., Muiier. J. E.. Tavazzi, L., Heyndrickx. G R Ray, M.. Chiariello, M.. Distante, A.. Askenazi. J., Salerno, J., Carpentier, J.. Reshetnaya, N. I., Fladvany. P.. Libby, P., Raabe, D. S.. Chazov, E. I.. Bobba, P., and Braunwald, E.: Favorable effects of hyaluronidase on electrocardiographic evidence of necrosis in patients with acute myocardial infarction, N. Engl. J Med %96:f396-903 1977.1 43

._. ; I

j

II

III

M

%+ZR=lW.O

8vL

avF al

I

%ASCOlt3Z1dXO

II

Ill

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avF Cal

%Asauu~2=lOO.O

Fig 23.-An example of the use of 354ead precordial electrocardiographic mapping to evaluate the development of myocardial necrosis in a patient with an anterior myocardial infarction. The sites with S-T segment elevation of 0.15 m V on admission are outlined. Note the unfavorable progression from the ischemit injury to necrosis with 100% loss of R wave voltage by one week of sites within the outline.

Nitroglycerin, either alone or in combination with phenylephrine or methoxamine, reduces myocardial ischemic injury in patients with acute myocardial infarction, as reflected in precordial S-T segment elevations. It has been proposed that sublingual nitroglycerin alone can exert a salutary effect in patients with left ventricular failure, whereas a combination of nitroglycerin and phenylephrine is more beneficial in patients without left ventricular failure.3 Others have demonstrated that nitroglycerin administered intravenously reduces ischemic injury in all patients, whereas phenylephrine counteracts this beneficial effect.3R These divergent conclusions may be based on the different effects of nitroglycerin and of the nitroglycerin-phenylephrine combination in patients with and without left ventricular failure.g Nitroglycerin reduces myocardial ischemic injury, whereas sodium nitroprusside may intensify it. In patients with acute myocardial infarction, nitroprusside and nitroglycerin caused similar hemodynamic changes; with sublingual nitroglycerin precordial S-T segment elevation decreases, whereas with nitroprusside, S-T segment elevation increases.“” As mentioned earlier, in the dog, nitroprusside or nitroglycerin were each admin44

istered at a rate sufficient to cause a modest fall in systemic arterial pressure. Nitroprusside reduced transmural coronary blood flow, whereas nitroglycerin increased it (see Fig 8). Therefore, although these two drugs cause similar hemodynamic changes, they apparently exert opposite effects on myocardial blood flow and may produce substantially different effects on ischemic injury. Derrida et al. randomly placed 74 patients with acute myocardial infarction into control and nitroglycerintreated gr0ups.w The latter received nitroglycerin intravenously at an average rate of 51 pg/minute. Using the precordial QRS mapping technique described above for the study of hyaluronidase36 (see Figs 21, 22 and 23) the extent of electrocardiographic evidence of myocardial necrosis was found to be significantly reduced by nitroglycerin. Furthermore, in the nitroglycerin fibrillation and ventricular tachycardia group, ventricular were less frequent and the hospital mortality was significantly lower. Intraaortic balloon counterpulsation has also been used extensively in the treatment of patients with cardiogenic shock resulting from acute myocardial infarction. In this setting, the effect of balloon pumping has been temporary in most cases, without improvement in long-term survival. The best clinical results have been obtained when temporary circulatory assistance is combined with urgent reestablishment of blood flow to the injured myocardium, i.e., revascularization performed within 2- 4 hours following the onset of symptoms. However, it is obviously useless to apply an intervention that is accompanied by significant risk such as emergency surgical revascularization in patients in whom the infarction is already, or almost, complete. At present, it is not possible to identify the specific intervention likely to be most effective in reducing infarct size. Indeed, there may not be one single best treatment. Rather, it seems more likely to us that in the future patients will be carefully but rapidly subdivided and categorized according to their clinical, electrocardiographic and hemodynamic states, and the interventions given will be tailored appropriately. In hypertensive patients and/or those with heart failure nitroglycerin may be a very effective intervention; in patients without any evidence of myocardial depression, cardiospecific beta-adrenergic blockade may be the treatment of choice; in hypotensive patients with pump failure, mechanical circulatory support may be in order. Moreover, all patients with acute infarction, regardless of their hemodynamic state, may benefit from the administration of an anti-inflammatory agent, such as hydrocortisone, methylprednisolone, ibuprofen or aprotinin. and a drug such as hyaluronidase. 45

LIMITATION OF INFARCT SIZE AND THE ROUTINE MANAGEMENT OF ACUTE MYOCARDIAL INFARCTION The recognition that the ultimate size of a myocardial infarct is not depend.ent solely on the pathoanatomy of the coronary vascular bed, but also on a variety of physiologic determinants, suggests that a number of “common sense” rules in the management of acute myocardial infarction deserve particular emphasis. First and foremost, it is mandatory to maintain an optimal balance between myocardial oxygen supply and demand so that as much of the jeopardized zone of the myocardium surrounding the center of the infarct can be salvaged. This can be accomplished by maintaining the patient at rest; mild sedation and a quiet atmosphere may reduce anxiety and thereby lower heart rate, a major determinant of myocardial oxygen consumption. b STEPHEN E. EPSTEIN: The point that an intrinsic part of optimal treatment is to have the patient resting in a quiet atmosphere with attempts made to reduce anxiety, is an important one. This is to be emphasized particularly because of the possibility that the therapeutic pendulum may be swinging too far toward aggressive approaches designed to reduce infarct size. Take the patient who, after admission to the coronary care unit, is pain-free, hemodynamically stable and resting comfortably. If that patient is approached to give informed consent for his physicians to apply a new form of therapy, if he is instrumented to obtain a pulmonary capillary wedge pressure, or if the intimidating 35lead precordial ECG blanket is applied to his chest, it is entirely possible that the

patient will experience anxiety-induced augmentation of cardiac catecholamine stimulation, thereby contributing paradoxically to a possible increase in infarct size. As the authors wisely emphasize, each patient must be evaluated individually. ___If the patient was receiving a beta-adrenergic blocking agent at the time the clinical manifestations of the infarct commenced, the drug should not be discontinued, unless a specific contraindication develops, such as left ventricular failure or a bradyarrhythmia. Marked sinus bradycardia (heart rate less than approximately 45 per minute) should be treated by postural maneuvers and atropine or by electrical pacing. However, the routine administration of atropine, with the resultant increase in heart rate, to patients without serious bradycardia seems unwise. All forms of tachyarrhythmias require prompt and direct treatment. Drugs that exert a positive inotropic effect, such as the digitalis glycosides and cardioactive sympathomimetics, should be administered only if there is evidence of ventricular failure - and should not be given prophylactically. Of the various sympathomimetic amines available, isoproterenol with its chronotropic and vasodilator effects is the least desirable. Dopamine or Dobutamine, which have less effect on heart rate and systemic vascular resistance, are more desirable when it is nec46

essary to augment cardiac contractility. Obviously, diuretics are also indicated in the presence of heart failure and might, in fact, be used to the exclusion of cardiac stimulants unless the patient is already hypovolemic or unresponsive to their administration. All patients should receive inhalation of oxygen-enriched air by mask and/or nasal prongs for the first 8- 12 hours. Particular attention must be paid to preserving arterial oxygenation in patients with hypoxemia, such as occurs in patients with chronic pulmonary disease, pneumonia or left ventricular failure. Severe anemia, which can also extend the area of ischemic injury, should be corrected by the cautious administration of packed red cells, sometimes accompanied by a diuretic. Associated conditions, particularly infections and the accompanying tachycardia and elevated myocardial oxygen needs, require immediate attention. Systolic arterial pressure should not be allowed to deviate by more than 25-30 mm Hg from the patient’s usual level. In regard to the effect of changes in arterial pressure on myocardial injury, it is likely that each patient has an optimum level of perfusion pressure. As coronary perfusion (aortic diastolic) pressure is elevated toward this level, the perfusion of, and therefore oxygen delivery to, the peri-infarction zone increases more than do the oxygen needs of this tissue. The more favorable balance between oxygen supply and demand that ensues will reduce the extent of ischemic injury. However, as coronary perfusion pressure is elevated above this optimum level, the increasing oxygen delivery does not keep pace with the increase in oxygen needs, and ischemic injury increases. In the normal dog, this optimum pressure level is relatively high and was not exceeded in the previously described studies. ‘3 In patients with acute myocardial infarction, this optimum level appears to be much lower, and is probably dependent on the extent of collateral vessels. Thus, in a patient with a highly developed collateral circulation this level would be higher than in a patient with poorly developed collaterals between the normal and ischemic zones; in the latter each increment in arterial pressure will only increase the afterload as well as the myocardial oxygen needs without further increasing the collateral blood flow and the oxygen delivery to the ischemic zone. Moreover, the presence of heart failure may further complicate the influence of changes in aortic pressure on the peri-infarction zone. When the heart is dilated, the myocardial tension and therefore oxygen consumption are elevated (a consequence of LaPlace’s law, which states that myocardial tension is related to the product of intraventricular pressure and radius). A reduction of arterial pressure (through its effect on both ventricular pressure and radius) could favorably alter the balance between myocardial oxygen supply and demand, thereby reducing ischemic injury following coronary occlusion. 4.7

CONCLUSIONS Recognition of the importance of the mass of myocardium undergoing necrosis as a determinant of prognosis and the efforts to preserve ischemic tissue may drastically alter the therapeutic approach to acute myocardial infarction. Rather than simply maintaining the patient’s vital signs, the physician’s attention may now be directed toward preserving the myocardium as well as maintaining perfusion of peripheral organs. However, these two objectives may sometimes conflict. In the first hours following the onset of the clinical event, when the ultimate size of the infarct is not yet established, myocardial preservation might be given the highest priority. Later, once the size of the infarct is fixed and if heart failure supervenes, it may be more appropriate to stimulate the heart with positive inotropic agents and to reduce afterload, i.e., to employ interventions that may increase infarct size if given at an earlier time. The observations of Reid, et al.41 suggest that significant extensions of myocardial necrosis occur during apparently uneventful convalescence in a large fraction of patients with acute myocardial infarction. Also, in many patients previously classified as having acute myocardial infarction, tissue damage occurs in a slow, “stuttering” manner, rather than abruptly, a condition that might more properly be termed subacute infarction. These considerations greatly expand the horizon for what can be accomplished by techniques to prevent myocardial necrosis, since the interventions designed to limit infarct size could then be applied prophylactically, when they are most likely to be effective. The interesting observation by Cox, et a1.42that the incidence of ventricular arrhythmia is a function of the size of the infarct, adds yet another dimension to the benefit that can potentially be derived from protection of jeopardized myocardium. Acute myocardial infarction continues to be the most common cause of death in the United States today, and of those patients who survive the infarct, the quantity of viable, contracting myocardium with which they are left is critical to their well being Considering the frequency of ischemic heart disease, the potential benefits from interventions designed to salvage ischemic tissue and-the encouraging preliminary results obtained thus far, continued intensive research in this field appears to be especially desirable. REFERENCES 1. Page, D. L., Caulfield, J. B., Kastor, J. A., DeSanctis, R. W., and Sanders, C. A.: Myocardial changes associated with cardiogenic shock, N. Engl. J. Med. 285133, 1971. 2. Sobel, B. E., Bresnahan, G. F., Shell, W. E., and Yoder, R. D.: Estimation of infarct size in man and its relation to prognosis, Circulation 46:640, 1972. 3. Braunwald, E., Ross, J., ,Jr., and Sonnenblick, E. H.: Mechanism of 48

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Contraction in the Normai and Fultlng Heart (2d ed; Boston: Little, Brown, 1976),357-397. Williamson, J. R., Schaffer, S. W., Ford, C., and Safer, B.: Contribution of tissue acidosis to ischemic injury in the perfused rat heart, Circulation 53 (Suppl 1):3, 1976. Regan, T. J., Effros, R. M., Haider. B., Oldewurtel, H. A., Ettinger, P. O., and Ahmecl, S. S.: Myocardial ischemia and cell acidosis: modification by alkali and the effects of ventricular funct.ion and cation comwsition. Am. .J. Cardiol. 37501, 1976. Barry, W. H., Brooker, J. Z., Alderman, E. L., and Harrison, D.: Changes in diastolic stiffness and tone of the left ventricle during angina pectoris, Circulation 49:255, 1974. Forrester, J. S., Diamond. G.. Parmlev. W. W.. and Swan. H. J. C.: Earlv* increase in left’ventricular compliance after mvocardial infarction, J. Clin. Invest. 51:598, 1972. Amsterdam, E. A.: Function of the hypoxic myocardium: Experimental and clinical aspects, Am. J. Cardiol. 32:461, 1973. Braunwald, E.: Symposium on protection of the ischemic myocardium. Circulation 53 (Suppl 3):1, 1976. Braunwald, E.: The pathogenesis and treatment of shock in myocardial infarction, Johns Hopkins Med. ,J. 121:421, 1967. Maroko, P. R., Braunwald, E., Covell, J. W.. and Ross, J., Jr.: Factors influencing the severity of myocardial &hernia following experimental coronary occlusion, Circulation 39/40 (Suppl31:111,1969 (abstract). Braunwald, E., Covell, J. W., Maroko, P. R., and Ross, J., Jr.: Effects of drugs and of counterpulsation on myocardial oxygen consumption. Circulation 40 (Suppl4):220, 1969. Maroko, P. R., Kjekshus, J. K., Sobel, B. E., Watanabe, T., Covell, J. W., Ross, J., Jr.. and Braunwald, E.: Factors influencing infarct size following coronary artery occlusions, Circulation 43:67, 1971. Muller, J. E., Maroko, P. R., and Braunwald, E.: Precordial electrocardiographic mapping: A technique to assess the efficacy of interventions designed to limit infarct size, Circulation 57:1, 1978. Maroko, P. R., and Braunwald, E.: Effects of metabolic and pharmacologic interventions on myocardial infarct size following coronary occlusion, Circulation 53 (Suppl 1):162, 1976. Maroko, P. R., Libby, P.. Covell, J. W., Sobel, B. E., Ross, J., Jr., and Braunwald, E.: Precordial S-T segment elevation mapping: an atraumatic method for assessing alterations in the extent of myocardial ischemic injury, Am. J. Cardiol. 29:223, 1972. Smith, E. R., Redwood, D. R., McCarron, W. E., and Epstein, S. E.: Coronary artery occlusion in the conscious dog. Effects of alterations in arterial hemorrhage, and alpha-adrenergic pressure produced by nitroglycerin, agonists on the degree of myocardial &hernia, Circulation 47:51, 1973. Ribeiro, L. G. T., Hillis, L. D., Fishbein, M. C., Davis, M. A., Maroko, P. R., and Braunwald, E.: A new technique for demonstrating the efficacy of interventions designed to limit infarct size following coronary occlusion: beneficial effect of hyaluronidase, Clin. Res. 25:248, 1977. Maclean, D., Fishbein, M. C., Maroko, P. R., and Braunwald, E.: Hyaluronidase-induced reductions in myocardial infarct size. Direct quantification of infarction following coronary artery occlusion in the rat, Science 194: 199,1976. Braunwald, E.: Regulation of the circulation, N. Engl. J. Med. 290:1124, 1974. Mueller, H. S., Ayres, S. M., Religa, A., and Evans, R. G.: Propranolol in the treatment of acute myocardial infarction, Circulation 49:1078, 1974. Watanabe, T., Covell, J. W., Maroko, P. R., Braunwald, E., and Ross, J., Jr.: Effects of increased arterial pressure and positive inotropic agents on the ”

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39. Chiariello,

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ANSWERS 1. 2. 3. 4.

c,d b, c, e b a: 2 b: 1,2 c: 1 d: 3

5. a: b: c: d: e: f: g:

4 2 1,2 2 1 1,2 1

6. I: 7. d 8. a: False b: False c: True

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