Intensive Care Medicine
Intens. Care Med. 4, 21 - 27 (1978)
9 by Springer-Verlag1978
The Measurement and Control of Myocardial Infarct Size M.C.P. Apps and J. Tinker Intensive Therapy Unit, The Middlesex Hospital, London, England
Abstract. Direct, chemical, electrocardiographic and radio-isotopic methods are described for the estimation of myocardial infarct size in animals and man. Their relative points and failings are discussed. The effects of interventions, physical, metabolic and pharmacological, upon the size of myocardial infarcts, are examined and work attempting to reduce myocardial infarct size in man reviewed. Key words: Myocardial infarct size, Measurement, Chemical, Electrocardiographic, Radio-isotope, Treatment.
Introduction It is possible to measure the size of a myocardial infarct by a variety of techniques which are all more or less direct measures of myocardial cell death. Such measurement is useful in gauging the severity of an infarct and is essential for the assessment of any therapeutic intervention upon the course of infarct development. In the presence of obstruction to coronary blood flow, the supply of oxygen and nutrients to an area of myocardium may become insufficient and the cells die; this constitutes a myocardial infarct. In most instances the coronary arteries are found to be abnormal [1], although normal angiographic appearances have been seen after infarction [2]. Around the area of dead muscle there is an areawhose muscle has a poor blood supply; this muscle is ischaemic, and blighted. Page et al. [3] showed that at the periphery of myocardial infarcts in patients with cardiogenic shock, the muscle Showed a ragged appearance, with acute inflammation and some muscle ceils dead, some swollen, whereas further into the infarct there were only dead muscle cells.
The mortality for a myocardial infarct depends in part upon its size; in patients dying of cardiogenic shock a larger proportion o f the ventricular muscle has been destroyed than in those dying of rhythm disturbances [4 6]. The same applies to patients who have a low cardiac output, (cardiac index less than 2 1/min [7]). The acute prognosis and the likelihood of cardiac failure depends upon the size of the myocardial infarct and the long term prognosis is governed by the amount of functioning myocardium left after the infarct. Experimental work has correlated prognosis in animal models with the size of infarct produced, and similar work has been done in man. Myocardial cells contain proteins, enzymes and myoglobin, which are released when the cells die. The cell membranes show electrical activity, depolarisation and repolarisation, which are affected by ischaemia and cell death. The cells receive oxygen and nutrients via a blood supply and myocardial perfusion is affected in a myocardial infarct. It is these basic characteristics that are employed in the current methods of measuring infarct size.
Chemical Methods Heart muscle contains myoglobin [8] and a host of enzymes which are released at the time of cell death and which can be assayed in blood or urine to give a measure of the extent of muscle necrosis. Some of these enzymes are also present in tissues elsewhere in the body and so levels may be misleading. Measurement of infarct size by assessment of enzyme release has been used for many years; gradually the tests have become more specific and a better guide to the extent of myocardial cell death. Following cardiac surgery diagnosis of a myocardial infarct by chemical means may be difficult, as there is also enzyme release following cardiotomy.
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M.C.P. Apps and J. Tinker: The Measurement and Control of Myocardial Infarct Size
Lactate Dehydrogenase and the Aminotransferases Since the 1950's serum lactate dehydrogenase and aspartare aminotransferase levels have been used as a measure of infarct size. Kibe et al. [ 11 ] have correlated these results with the post mortem findings, and Helmers [12] has done the same with the prognosis after the second day. However these enzymes are relatively non specific, and more accurate enzyme component studies have been introduced. It is possible to separate the various dehydrogenase enzymes, according to their reactions with various substrates and also to separate the various isoenzymes. The levels of that dehydrogenase which reacts with hydroxybutyrate are more cardio-specific than the total dehydrogenase activity as are the levels of the isoenzymes and their ratios LDH1/LDHa [13]. Lactate dehydrogenase serum concentrations become abnormal approximately 6 - 12 h after a myocardial infarct and reach a peak 48 72 h later. Aspartate aminotransferase levels are elevated earlier, 6 - 8 h after a myocardial infarct and reach a peak at 24 - 48 hours and gradually fall over the next few days.
Creatine Phosphokinase Creatine phosphokinase is released from dead heart muscle, and serum levels become elevated within 4 - 6 h, earlier than those of lactate dehydrogenase or aspartate aminotransferase. It is a more specific enzyme, but not entirely so as it is present in muscle elsewhere in the body; levels in the serum are raised in muscle disease, following intramuscular injections, and after surgery [14]. The depletion of creatine phosphokinase from dead and ischaemic heart muscle has been studied in animals; a mathematical understanding of the dynamics of its release and its clearance from the blood has been obtained. This has enabled correlation of infarct size and enzyme levels in animals and man [15 - 18]. Sobel, Shell and others [19] have used this method to assess infarct size and to study the effect of intervention on that size, in animals and man. By taking samples hourly it is possible to draw a time/ concentration curve of creatine phosphokinase levels, and to quantify the infarction as CPK gram equivalents to predict its size. It is then possible to carry out some manoeuvre to alter the size of the infarct, and possible to measure its effect. The predicted size can be calculated after seven hours using hourly sampling. In the event of a successful intervention there is the possibility that the enzyme might be washed out of the dead muscle faster, giving a spurious measurement of a larger infarct size from less total destruction, and it has also been shown in animals that although most of the enzyme is cleared via the blood some escapes via the cardiac lymphatics [20]. In spite of these limitations creatine phosphokinase assay gives a reasonably reliable indication of infarct size in man. Because a total creatine phosphokinase measurement is not cardio-specific, assays of the cardiac iso-enzyme, CKMB can be used. This has proved a sensitive and more
specific indicator of heart muscle death, but it is not released if the cells are only ischaemic [21,22]. It is not absolutely cardio-specific [23], but when assayed in serial samples taken during the first 48 h after admission it provides a good measure of infarct size [24]. Roark et al. [25] have shown that CK-MB is the most specific and sensitive of the enzymatic methods for diagnosis of myocardial infarct, and have compared it with ECG findings. Separation of the various creatine phosphokinase iso-enzymes is a difficult procedure, but the technical problems are gradually being solved [26, 27]. All the enzyme methods of measurement take time, 7 h for the total creatine phosphokinase methods, and longer for the others.
Electrocardiographic Methods When heart muscle is ischaemic or dead, there are characteristic changes in the electrical activity which manifest in the ECG as Q waves, ST segment displacement or T wave changes. ST segment elevation occurs over an area of infarction as was first shown in animals by epicardial recording; it was also noted that these changes occurred within a few minutes of coronary artery occlusion [28]. Similar changes were noted with endocardial and praecordial recordings. The cause of ST segment elevation is uncertain, differing theories ascribe it to changes in either polarisation or depolarisation of the myocardial cell membrane. There is however a good correlation between it and transmural blood flow, but the association is not as strong with subendocardial blood flow. Epicardial ST segment elevation correlates well with the presence or extent of myocardial infarction. The intramyocardial ECG gives a better correlation, and the praecordial ECG gives one that is slightly less good [29] depending upon the size of electrical potential produced. Q waves are seen over the surface of an area of infarcted myocardium. There is no electrical activity over the infarcted tissue and it acts as a window through which the negative intraventricular potential is percieved on the surface of the heart. This gives rise to a pathological Q wave [30]. The size of an infarct can be assessed from changes in the electrical activity on the surface of the heart in animals, and on the surface of the chest in animals and man. ST segment elevation can be quantified to give a measure of infarct size. However ST segments can remain elevated if the infarct is extending, if there is pericarditis, or if there is development of a ventricular aneurysm; this lack of specificity limits its use. In addition, if there is bundle branch block, the ECG appearances of an infarct may be masked [31, 32].
M.C.P. Apps and J. Tinker: The Measurement and Control of MyocardialInfarct Size In animals the size of an infarct can be assessed with epicardial or praecordial mapping. There is good correlation between the histological size of an infarct produced in the dog by occlusion of a coronary artery, and the ECG mapping. ST segment mapping also correlates well with enzyme levels in the serum, and with creatine phosphokinase depletion from the heart muscle [33]. In the dog there is a good correlation between ST segment changes measured on the epicardium with an open chest, and those recorded on the praecordium. In man, however, the interpretation of ST segment mapping is much more controversial. It has the advantage of being reasonably easy to do, and of giving an estimate of infarct size quickly. It can be used to study the extension of an infarct and also the effect of interventions upon the infarct size. ST segment elevation of greater than 2 mm is seen in extending infarcts, and is associated with increased complications [32]. Reid et al. [35] found that ST segment mapping and summation were useful in transmural anterior infarcts, but that the posterior and inferior infarcts did not show up as well. There are difficult technical problems associated with mapping, with recording being carried out via multiple single points [36], straps contained several electrodes [37], and harnesses carrying an array of electrodes [38 ]. Analysis of the data has been done either manually or by computer. Early work on the quantification of the ST segment changes, the ST suggested that this was a good way of measuring infarct size. The ST is a measure of the summation of ST segment changes across the chest [39]. More recent work has however been unable to correlate either the clinical outcome or the enzyme levels with the ST carried out by praecordial mapping [40 - 42]. In animals the ST is a good indication of the size of a myocardial infarct using epicardial or praecordial leads. Man has a chest with high electrical resistance, which is large and thick, and perhaps not surprisingly, enzymatic methods are still more accurate measures of infarct size than is praecordial ST segment mapping. More recently mapping techniques have been extended to the study of Q waves, the RS ratio, and to mapping throughout the cardiac cycle. These may become feasible but as yet only a limited amount of work has been done [43].
Isotopic Methods In some patients the ECG cannot be used to diagnose the presence of myocardial infarct, or to assess its size, and in others recent surgery may abscure changes in enzyme release. Radionucleotide imaging may be of particular use in these patients. Several techniques are possible, with the infarct presenting as either a hot or a cold spot. Some radioisotopes (Technetium, bound to pyrophosphate, tetracycline, or glucoheptonate) are selectively concentrated in the area of infarcted muscle [44]. The infarct
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appears as a hot spot on a dark field but does n o t show for approximately six hours. Anterior infarcts show up better than inferior infarcts. If there is a large transmural infarct this may show as a doughnut shape; there is no blood flow to the centre of the infarct, the isotope is sequestered by the tissue at the edge of the infarct but little reaches the middle. Technetium is also concentrated in bones, and the pictures of the heart were initially affected by uptake into the rib cage. Now with better imaging techniques this is less noticeable. Some compounds show the infarct as a cold spot, the isotope shows that part of the myocardium which is perfused. Potassium, Thallium, and Caesium salts give this sort of picture. In animals radio-actively myosin antibodies have been used [45]. The infarct does not show for six hours, and is at its maximum positivity for 24 - 28 hours. In animals the size of infarct shown by scanning has been shown to correlate well with the weight of infarcted muscle, [46] the creatine phosphokinase release and depletion, [47] and the distribution of radioactively labelled microsperes injected into the coronary circulation to show up areas of non perfusion [48]. In man the size of the infarct as measured by radionucleotide imaging has been correlated with the presence or absence of complications, [51] and the overall difference between death and survival; the larger infarct seen on scanning is associated with a higher mortality [52]. Scans carried out with "cold spot" imaging cannot differentiate between an area of old or new infarction [53]. As with ECG mapping radio-isotope methods are good for anterior infarcts, but not so good for inferior or posterior infarcts [54, 55]. Scanning is possible by a combination of both "hot" and "cold" spot methods, using *K and *Technetium, to improve the quality of the picture [48]. It is also possible to study the movement of the ventricular wall, with cineangiography, and also to use gated scintiphotography to study myocardial function [52]. A further method that has been tried is that of emission computerized tomography using *C labelled glucose, fatty acids, and *N labelled amino acids to study myocardial metabolism. This is only experimental at present [56]. Indirect Methods The size of a myocardial infarct can be measured directly at post mortem, or indirectly by methods described. A more indirect way of measuring the infarct size is to study its effect upon the overall myocardial function [57]. If the infarct involves 30 - 40% of the myocardium, the patient is in danger of death from pump failure, as not enough myocardium is left to provide an adequate cardiac output. The prognostic indices of Peel [58], Killip [59], Norris [60] and Helmers [12] have been used as measures of infarct size and used in some studies of the effect of intervention on prognosis. In these the blood pressure, pulse, presence or absence of cardiac failure or shock and other measures of the cardiac output give a measure of myo-
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M.C.P. Apps and J. Tinker: The Measurement and Control of MyocardialInfarct Size
cardial function, and therefore indirectly of the degree of damage sustained by the heart. They are only crude measures of infarct size, but easy to use in practice.
Control of Infarct Size Most of the work done on this problem has been carried out in animals, in whom an infarct has been produced by direct occlusion of a coronary artery. Both direct and indirect measures of its size have been employed. Much less work has been done on man, because of ethical and technical difficulties. In a myocardial infarct there is an area of muscle which has a very tenuous blood supply; this muscle is ischaemic, and in danger of death. There is evidence that the area of dead muscle increases in size, as the infarct extends. It is the objective of all therapeutic interventions to protect this threatened muscle and so prevent an increase of infarct size. Oxygen supply to the ischaemic muscle is limited; the extent of muscle death in this region depends upon the balance of oxygen supply and the requirements of the muscle cells. The extent of cell death is related to the myocardial oxygen consumption, the MVO2. In the experimental animal the size of infarct can be increased by increasing the oxygen requirements of the blighted muscle, by fever, by reducing the oxygen supply, with hypoxia, anaemia, or severe hypotension, or by increasing the metabolic requirements of the cells by infusing isoprenaline or pacing to increase the heart rate. In animals it is possible to prevent the extension of an infarct, and to reduce its size, by reducing oxygen requirements, increasing oxygen supply, and by protecting the cells by a variety of means [33]. In man some of these techniques have been used, with variable success. To study the effect of interventions on myocardial infarct size, a good indirect measure of the size is essential. This needs to be accurate, repeatable, easy to do, and preferably quick to carry out. Other more crude measures, morbidity and mortality, are not as good for studies of this kind. Large numbers of patients are necessary, in properly controlled trials, to find which therapeutic measures are useful.
Physical Intervention Myocardial infarcts occur in patients who have obstructed coronary arteries, and may be associated withhypotension severe enough to compromise the remaining coronary arterial flow. For these reasons mechanical methods of assistance have been tried [61 ]. Intra-aortic balloon pumping (counterpulsation) has been used to support the heart. Its use improves coronary artery blood flow, and perfusion of the brain and kidneys. In some patients with cardiogenic shock intra-aortic balloon counterpulsation has been
shown to improve the blood pressure, the cardiac output, and the urinary output. There is evidence in animals that this kind of support may reduce myocardial infarct size, but no comparable work has been done in man. Since the blood supply to the myocardium is compromised in patients with myocardial infarction, emergency revascularisation has been attempted to improve blood flow to the ischaemic areas [62]. Direct implantation of vessels into the ischaemic area has been tried, and more recently coronary artery vein grafting has been done to bypass stenosed vessels and to improve the distal blood supply. In dogs revascularisation reduces the size of a myocardial infarct produced after coronary artery occlusion; in man the operation has been carried out, but there are few patients in whom sequential measurement of infarct size has been performed.
Metabolic Intervention Myocardial muscle cells obtain energy from the breakdown of fatty acids and glucose. In the presence of ischaemia fatty acid oxidation is impaired, and glucose becomes the principal source of energy [63]. There is increased production of lactic acid and increased fatty acid levels which may be toxic and lead to dysrhythmias [64]. To improve the state of the ischaemic muscle, oxygen can be given; this can reduce the size of infarcts in animals [65]; many patients with acute myocardial infarction are hyproxic and may benefit from oxygen therapy [66]. Glucose and insulin solutions can be given to improve cardiac function and to reduce the extent of myocardial necrosis in experimental animals [67]. In man there is a suggestion that it may reduce the mortality of myocardial infarction, but little controlled work has been done [68, 69]. Sodium dichloroacetate stimulates the utilisation of glucose in myocardial cells and this protects the cells in the dog from ischaemia, and reduce the amount of lactic acid produced [701.
Pharmacological Interventions The ischaemic myocardial cell is in jeopardy and oxygen and glucose and insulin help to provide increased energy for the cell to maintain its stabil,ityl Hyaluronidase, given by infusion, seems to protect in the dog and to improve collateral blood flow to the area of ischaemia, allowing a better diffusion of nutrients; in the dog the 'size of myocardial infarction can be reduced. It is a reasonably nontoxic compound and has been tested on patients, causing a reduction in ST segment elevation [71 ].Mannitolprotects the ischaemic myocardium presumably by reducing oedema at the site of the infarct and allowing better oxygenation [72]. The role of corticosteroids in protecting the ischaemic moycardium is controversial. They may stabilise lysozomal and other cell membranes and therefore reduce the number
M.C.P. Apps and J. Tinker: The Measurement and Control of Myocardial Infarct Size of ceils that die. They may also increase blood flow to the ischaemic myocardium. They slow healing, preventing the production of a firm scar [73]. The size of infarct is reduced in animals given steroids both before and after coronary artery occlusion [74, 75] but in man results are inconclusive. In some studies steroids are of benefit, in others they are associated with a higher mortality [76, 77]. There is always the risk that healing may be affected and that cardiac rupture or the production of an aneurysm may occur. Only small numbers of patients have been involved in the trials. It is possible to reduce the size of myocardial infarcts in animals by improving the oxygen and nutrient supply and by reducing the amount of work done by the myocardium. Myocardial work can be reduced by beta-blockade, antagonizing the actions of endogenous catecholamines. This has the effect of reducing heart rate and contractility. In animals propranolol, practolol, and other beta-blockers are effective in reducing infarct size, measured directly and indirectly by many methods [78]. In patients treated with beta-blockade in the period immediately following a myocardial infarct, Pelides and his colleagues first showed that practolol caused a reduction in ST segment elevation in the praecordial ECG [79]. Since then work has suggested that chest pain may be alleviated by blockade in the patient who has had a myocardial infarct [80]. Barber et al showed that the mortality of myocardial infarction was reduced in patients who had a tachycardia of greater than 100, and no evidence of failure. These are the patients who presumably have a high level of endogenous circulating catecholamines, in the absence of pump failure. They point out that the size of trial necessary for statistical confirmation of their results would require approximately 2,000 patients and would need to be carried out on a multicentre basis. Other trials to date have consisted of only limited numbers of patients [81 ]. The myocardial muscle pumps blood out of the heart against peripheral resistance. If this resistance can be reduced whilst leaving an adequate blood pressure for coronary artery perfusion, the work done by the heart is reduced. Sobel and Shell gave trimetaphan to patients with hypertension and a myocardial infarct [19], and noted a reduction in the release of creatine phosphokinase suggesting a reduction in infarct size. In animals reduction of the peripheral resistance with nitroglycerine and nitroprusside has been tried. As long as adequate coronary artery perfusion was maintained, there was a reduction in ischaemic injury [82, 83]. In man nitroglycerine infusion was shown by Flaherty et al. [84] to reduce ST segment elevation in doses which did not significantly affect the blood pressure. Many patients with myocardial infarcts are anxious, and may have high levels of catecholamines, free fatty acids and cortisol, as seen in other stress situations. Sedation with diazepam has been tried [85] to reduce "stress" and therefore catecholamines release [86]. A reduction in
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catecholamine release would lead to decreased drive to the heart and thus decreased myocardial oxygen consumption, and might help to protect ischaemic myocardium, but this has not been shown as yet. In animals isoprenaline and other catecholamines increase cardiac output, but at the cost of increasing infarct size [78]. The cost of increased cardiac output is an increased oxygen requirement and this causes the demise of muscle that is already in jeopardy. In man catecholamines are most commonly used in patients with myocardial infarcts when there is a very poor cardiac output. They increase the cardiac output and probably the coronary artery blood flow, but there is no evidence of their effect upon myocardial infarct size. Digoxin is another agent which can increase cardiac output, myocardial oxygen requirements, and myocardial infarct size in animals [78], but there is no evidence of any effect on infarct size in man.
Conclusion Whilst increasingly more acceptable methods of measurement are being developed, at the present time enzyme studies are perhaps the most accurate. Much work on the effect of therapeutic interventions on the size of myocardial infarct has been done in animals but less to date in man [87, 88]. Only small numbers of patients have been studied, often without adequate controis. From animals work it seems likely that the reduction of myocardial work with beta-blockade and nitroglycerine, and the improvement of nutrient availability to the ischaemic muscle with glucose and insulin, hyaluronidase, and oxygen therapy are valuable in limiting infarct size. In man beta-blockade reduces pain after infarction and may reduce myocardial infarct size in some patients. Because of the lack of data no firm recommendations for the treatment of patients with myocardial infarcts along these lines can be made. Further studies to elucidate the effect of beta-blockade, hyaluronidase, glucose and insulin and oxygen therapy would be valuable but must await the development of an accurate, rapid and clinically acceptable method of quantifying infarct size. Until there is such a method it will be impossible to assess critically the effect of any therapeutic intervention on the control of infarct size.
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M.C.P. Apps and J. Tinker: The Measurement and Control of Myocardial Infarct Size
2.Kahn, A.H., Haywood, L.J.: Myocardial Infarction in nine patients with radiologically patent coronary arteries. New Engl. J. Med. 291,427 (1974) 3.Page, D.L., Caulfield, J.B., Kastor, J.A., De Sanctis, R.W., Sanders, C.A.: Myocardial changes associated with cardiogenic shock. New Engl. J. Med. 285,133 (197i) 4.Walston, A., Hackel, D.B., Estes, E.H.: Acute coronary occlusion and the power-failure syndrome. Amer. Heart J. 79, 613 (1970) 5.Alonso, D.R., Scheidt, S., Post, M., Killip, T.: Pathophysiology of cardiogenic shock; quantification of myocardial necrosis, clinical, pathologic and electrocardiographic correlation. Circulation 48, 588 (1973) 6.Harnarayan, C., Bennett, M.A., Pentecost, B.L., Brewer, D.B.: Quantitative study of infarcted myocardium in cardiogenic shock. Brit. Heart J. 32,728 (1970) 7.Lundy, E.G., Davidson, R.M., Hackel, D.B., Radcliffe, N.R., Wallace, A.G.: Relation of infarct size to cardiac index in patients with acute myocardial infarction. Circulation 41, 742 (1971) 8.Saranchak, H.J., Berstein, S.I-I.: A New diagnostic test for acute myocardial infarction. The detection of myoglobinuria by radioimmunodiffusion assay. J. Amer. med. Ass. 228, 1251 (1974) 9.Nydick, I., Wroblewski, F., La Due, J.S.: Evidence for increased serum glutamic oxaloacetic transaminase activity following graded myocardial infarcts in dogs. Circulation 12, 161 (1955) 10.Thygesen, K., Lyager Nielsen, B., Straede Nielson, J.: Enzymes and long term survival after first myocardial infarct. Acta med. scand. 199, 75 (1976) ll.Kibe, O., Nilsson, N.J.: Observations on the diagnostic and prognostic values of some enzyme tests in myocardial infarction. Acta med. seand. 182,597 (1967) 12.Helmers, C.: Short and long term prognostic indices in acute myocardial infarction. Acta reed. scand. Suppl. 555 (1974) 13. Auvinen, S.: Evaluation of serum enzyme tests in the diagnosis of acute myocardial infarction. Acta med. scand. Suppl. 539 (1972) 14.Nevins, M.A., Saran, M., Bright, M., Lyon, L.J.: Pitfalls in interpreting serum creatine phosphokinase activity. J. Amer. med. Ass. 224, 1382 (1973) 15.Sobel, B.E., Bresnahan, G.F., Shell, W.E., Yoder, R.D.: Estimation of infarct size in man and its relation to prognosis. Circulation 46,646 (1972) 16.Smith, A.F.: Diagnostic value of serum creatine kinase in a coronary care unit. Lancet 1967 1I, 178 17.Mathey, D., Bleifield, W., Buss, H. Hanrath, P.: Creatine kinase release in acute myocardial infarction; correlation with clinical electrocardiographic and pathological findings. Brit. Heart J. 37, 1161 (I975) 18.Norris, R.M., Whitlock, R.M.L., Barratt-Boyes, C., Small, C.W.: Clinical Measurement of myocardial infarct size. Circulation 51,614 (1975) 19.Shell, W.E., Sobel, B.E.: Protection of jeopardized ischaemic myocardium by reduction of ventricular afterload. New Engl. J. Med. 291,481 (1974) 20.Roe, C.R., Starmer, C.F.: A sensitivity analysis of enzymatic estimations of infarct size. Circulation 52, 1 (1975) 21.Blomberg, D.I., Kimber, W.D., Burke, M.D.: Creatine Kinase isoenzymes. Predictive values in the early diagnosis of acute myocardial infarction. Amer. J. Med. 59, 464 (1975) 22.Wagner, G.S., Roe, C.R., Limbird, L.E., Rosati, R.A., Wallace, R.A.: The importance of identification of the myocardial specific isoenzyme of creatine phosphokinase (MB form) in the diagnosis of acute myocaxdial infarction. Circulation 47, 263 (1973) 23.Smith, A.F., Radford, D., Wong, C.P.: Creatine kinase isoenzyme studies in myocardial infarction. Clin. Chem. 21, 975 (1975) 24.Roberts, R., Henry, P.D., Sobel, B.E.: An improved basis for enzymatic estimation of infarct size. Circulation 52, 743 (1975) 25.Roark, S.F., Wagner, G.S., Izlar, H.L., Roe, C.R.: Diagnosis of
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M.C.P. Apps and J. Tinker: The Measurement and Control of Myocardial Infarct Size technecium 99m Stannous pyrophosphate imaging of acute myocardial infarcts in dogs. Circulation 53,411 (1976) 48.Zaret, B.L., Di Cola, V., Konabedian, R.K., Purl, S., Wolfson, S., Freeman, G.S., Cohen, L.S.: Dual Radionucleotide study of myocardial infarction. Circulation 53, 411 (1976) 49.Rossman, D.J., Rouleau, J., Strauss, H.W., Pitt, B.: Detection and size estimation of acute myocardial infarction using 99Tc glueoheptonate. J. nucl. Med. 16, 980 (1975) 50.Holman, B.L., Lesch, M. Zweiman, F.G., Temte, J., Lown, B., Gallin, R.: Detection and sizing of acute myocardial infarcts with 99TcSn Tetracycline. New Engl. J. Med. 291,159 (1974) 51.Harris, R.A., Parkey, R.W., Bonte, F.J., Stokely, E. M., Buja, L.W., Willerson, J.T.: Sizing acute myocardial infarction utilizing technetium stannous pyrophosphate scintigrams. Clin. Res. 23, 3A (1975) 52.Rig_o, P., Murray, M., Strauss, H.W., Taylor, D., Kelly, D., Weisfeld, M., Pitt, B.: Left ventricular function in acute myocardial infarction evaluated by gated scintiphotography. Circulation 50, 678 (1974) 53.Gorten, R.J.: Evaluation of radioactive K+ and its analogues for imaging myocardial infarcts. Sem. nucl. Med. 7, 15 (1977) 54.Wackers, F.J.T., Lie, K.I., Liem, K.L., Wellens, H.J.J., Sokole, E.B., Samoson, G., Schoot, J.B.: Value and limitations of thallium 2~ scintigraphy in the acute phase of myocardial infarction. New Engl. J. Med. 295, 1 (1976) 55.Strauss, H.W., Pitt, B.: Thallium 2~ as a myocardial imaging agent. Sere. nucl. Med. 7, 49 (1977) 56.Ter Pogossian, M.M.: Limitations of present radionucleotide methods in the evaluation of myocardial ischaemia and infarction. Circulation 52, 53 (1976) 57.Leading article: Prognosis in myocardial infarction. Lancet 1977 I, 179 58.Peel, A.A.F., Semple, T., Wang, T., Lancaster, W.M., Dall, J.L.G.: A coronary prognostic index for grading the severity of infarction. Brit. Heart J. 24, 745 (1962) 59.Killip, T., Kimball, J.T.: Treatment of myocardial infarction in a coronary care unit. Amer. J. Cardiol. 24, 745 (1967) 60.Norris, R.M., Brandt, P.W.T., Caughey De Lee, A.J., Scott, P.J.: A new coronary prognostic index. Lancet 1969 I, 274 61.Bourdarias, J.P., Gourgon, R., Bardet, J.: Mechanical circulatory assistance by intra-aortic balloon pumping for the treatment of cardiogenic shock. Intens. Care Med. 4, 29 (1978) 62.Dubost, C., Carpenter, A., Sellier, P., Pinnica, A., Deloche, A., Relland, J., Vial, F., Fabianij, N.: Emergency myocardial revascularisation: Postgrad. med. J. 52,743 (1976) 63.Kjekshus, J.K., MjCs, O.D.: Effect of free fatty acids on myocardial function and metabolism in the ischaemic dog heart. J. clin. Invest. 51, 1767 (1972) 64.Oliver, M.F., Kurien, V.A., Greenwood, T.W.: Relation between serum free fatty acids and arrhythmias and death after acute myocardial infarction. Lancet 1968 I, 710 65.Radvany, P., Maroko, P.R., Braunwald, E.: Effects of hypoxaemia on the extent of myocardial necrosis after experimental coronary occlusion. Amer. J. Cardiol. 35,795 (1975) 66. Madias, J.E., Madias, N.E., Hood, W.B.: Praecordial ST segment mapping 2. Effects of oxygen inhalation on ischaemic injury in patients with acute moycardial infarction. Circulation 53, 411 (1975) 67.Maroko, P.R., Libby, P., Sobel, B.E., Bloor, C.M. Sybers, H.D., Shell, W.E., Covell, J.W., Braunwald, E.: Effect of glucose insulin potassium infusion on myocardial infarction following experimental coronary artery occlusion. Circulation 45, 1160 (1972) 68.Rogers, W.J., Stanley, A.W., Breinig, J.B., Prather, J.W., McDaniel, H.G., Moraski, R.E., Mantle, J.A., Russell, R.O., Rackley, C.E.: Reduction of hospital mortality rate of acute myocardial infarction with glucose insulin potassium infusion. Amer. Heart J. 92, 441 (1976) 69.Kernohan, R.J.: Potassium glucose and insulin in myocardial infarction. Lancet 1967 I, 620 70.Mj6s, O.D., Miller, N.E., Riemersma, R.A., Oliver, M.F.: Effects of dichloroacetate on myocardial substrate extraction, epi-
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cardial ST segment elevation and ventricular blood flow following coronary artery occlusion in dogs. Cardiovasc. Res. 10, 427 (1976) 71.Braunwald, E., Maroko, P.R.: The use of hyaluronidase and hydrocortisone in the reduction of myocardial infarct size following coronary occlusion. Acta med. scand. Suppl. 589, 169 (1976) 72.Powell, W.J., Dibona, D.R., Flores, J., Leaf, A.: The protective effect of hyperosmolar mannitol in myocardial ischaemia and necrosis. Circulation 54, 603 (1976) 73.Green, R.M., Cohen, J., Deweese, J.A.: Short term use of cortieosteroids after experimental infarction. Effects on ventricular function and infarct healing. Circulation 50, Suppl. 3, 103 (1974) 74.Masters, T.N., Harbold, N.B., Hall, D.G.: Beneficial results of methylprednisolone sodium succinate in acute myocardial ischaemia. Circulation 50, Suppl. 3,119 (1974) 75.Spath, J.A., Lefer, A.M.: Effects of dexamethasone on myocardial cells in the early phase of myocardial infarction. Amer. Heart J. 90, 50 (1975) 76.Roberts, R., Demello, V., Sobel, B.E.: Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation 53, Suppl. 1,204 (1976) 77.Morrison, J., Reduto, L., Pizzarello, R.: Modification of myocardial injury in man by cortieosteroid administration. Circulation 53, 200 (1976) 78.Maroko, P.R., Kjekshus, J.K., Sobel, B.E., Watenabe, T., Covell, J.W., Ross, J., Braunwald, E.: Factors influencing infarct size following experimental coronary artery occlusion. Circulation 43, 67 (1971) 79.Pelides, L.J., Reid, D.S., Thomas, M., Shillingford, J.P.: Inhibition by Beta-blockade of the ST segment elevation after acute myocardial infarction. Cardiovase. Res. 65, 295 (1972) 80.Waagstein, F., Hjalmarson, A.C.: Double blind study of the effect of cardioselective beta blockade on chest pain in acute myocardial infarction. Acta reed. scand. Suppl. 587,201 (1976) 8i.Barber, J.M., Boyle, D.McC, Cheturveds, N.C., Singh, N., Walsh, M.J.: Practolol in acute myocardial infarction. Acta med. scand. Suppl. 587,213 (1976) 82.Redwood, D.R., Smith, E.R., Epstein, S.E.: Coronary artery occlusion in the conscious dog. Effects of alteration of heart rate and arterial pressure on the degree of myocardial ischaemia. Circulation 46,323 (1972) 83.Hirschfield, J.W., Borer, J.S., Gotdstein, R.S., Barrett, M., Epstein, S.E.: Reduction in severity and extent of myocardial infarction when nitroglycerin and methoxamine are administered during coronary occlusion. Circulation 49, 291 (1974) 84.Flaherty, J.T., Reid, P.R., Kelly, D.T., Taylor, D.R., Weisfeldt, M.L., Pitt, B.: Intravenous nitroglycerin in acute myocardial infarction. Circulation 51, 132 (1975) 85.Melsom, M., Andreassen, P., Melsom, H., Hanson, T., Grendahl, H., Hillestad, L.K.: Diazepam in acute myocardial infarction. Clinical effects and effects on catecholamines, free fatty acids and cortisol. Brit. Heart. J. 38, 804 (1976) 86.Jewitt, D.E., Mercer, C.J., Reid, D., Valori, C., Thomas, M., Shillingford, J.P.: Free noradrenaline and adrenaline excretion in relation to the development of cardiac arrhythmias and heart failure in patients with acute myocardial infarction. Lancet 1969 I, 635 87.Hillis, L.D., Braunwald, E.: Myocardial ischaemia (second of three parts). New Engl. J. Meal. 296, 1034 (1977) 88.Hillis, L.D., Braunwald, E.: Myocardial ischaemia (third of three parts). New Engl. J. Med. 296, 1093 (1977)
Dr. J. Tinker Director of Intensive Therapy Unit The Middlesex Hospital Mortimer Street London WIN 8AA England
Intens. Care Med. 4, 21 - 27 (1978)
9 by Springer-Verlag1978
The Measurement and Control of Myocardial Infarct Size M.C.P. Apps and J. Tinker Intensive Therapy Unit, The Middlesex Hospital, London, England
Abstract. Direct, chemical, electrocardiographic and radio-isotopic methods are described for the estimation of myocardial infarct size in animals and man. Their relative points and failings are discussed. The effects of interventions, physical, metabolic and pharmacological, upon the size of myocardial infarcts, are examined and work attempting to reduce myocardial infarct size in man reviewed. Key words: Myocardial infarct size, Measurement, Chemical, Electrocardiographic, Radio-isotope, Treatment.
Introduction It is possible to measure the size of a myocardial infarct by a variety of techniques which are all more or less direct measures of myocardial cell death. Such measurement is useful in gauging the severity of an infarct and is essential for the assessment of any therapeutic intervention upon the course of infarct development. In the presence of obstruction to coronary blood flow, the supply of oxygen and nutrients to an area of myocardium may become insufficient and the cells die; this constitutes a myocardial infarct. In most instances the coronary arteries are found to be abnormal [1], although normal angiographic appearances have been seen after infarction [2]. Around the area of dead muscle there is an areawhose muscle has a poor blood supply; this muscle is ischaemic, and blighted. Page et al. [3] showed that at the periphery of myocardial infarcts in patients with cardiogenic shock, the muscle Showed a ragged appearance, with acute inflammation and some muscle ceils dead, some swollen, whereas further into the infarct there were only dead muscle cells.
The mortality for a myocardial infarct depends in part upon its size; in patients dying of cardiogenic shock a larger proportion o f the ventricular muscle has been destroyed than in those dying of rhythm disturbances [4 6]. The same applies to patients who have a low cardiac output, (cardiac index less than 2 1/min [7]). The acute prognosis and the likelihood of cardiac failure depends upon the size of the myocardial infarct and the long term prognosis is governed by the amount of functioning myocardium left after the infarct. Experimental work has correlated prognosis in animal models with the size of infarct produced, and similar work has been done in man. Myocardial cells contain proteins, enzymes and myoglobin, which are released when the cells die. The cell membranes show electrical activity, depolarisation and repolarisation, which are affected by ischaemia and cell death. The cells receive oxygen and nutrients via a blood supply and myocardial perfusion is affected in a myocardial infarct. It is these basic characteristics that are employed in the current methods of measuring infarct size.
Chemical Methods Heart muscle contains myoglobin [8] and a host of enzymes which are released at the time of cell death and which can be assayed in blood or urine to give a measure of the extent of muscle necrosis. Some of these enzymes are also present in tissues elsewhere in the body and so levels may be misleading. Measurement of infarct size by assessment of enzyme release has been used for many years; gradually the tests have become more specific and a better guide to the extent of myocardial cell death. Following cardiac surgery diagnosis of a myocardial infarct by chemical means may be difficult, as there is also enzyme release following cardiotomy.
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M.C.P. Apps and J. Tinker: The Measurement and Control of Myocardial Infarct Size
Lactate Dehydrogenase and the Aminotransferases Since the 1950's serum lactate dehydrogenase and aspartare aminotransferase levels have been used as a measure of infarct size. Kibe et al. [ 11 ] have correlated these results with the post mortem findings, and Helmers [12] has done the same with the prognosis after the second day. However these enzymes are relatively non specific, and more accurate enzyme component studies have been introduced. It is possible to separate the various dehydrogenase enzymes, according to their reactions with various substrates and also to separate the various isoenzymes. The levels of that dehydrogenase which reacts with hydroxybutyrate are more cardio-specific than the total dehydrogenase activity as are the levels of the isoenzymes and their ratios LDH1/LDHa [13]. Lactate dehydrogenase serum concentrations become abnormal approximately 6 - 12 h after a myocardial infarct and reach a peak 48 72 h later. Aspartate aminotransferase levels are elevated earlier, 6 - 8 h after a myocardial infarct and reach a peak at 24 - 48 hours and gradually fall over the next few days.
Creatine Phosphokinase Creatine phosphokinase is released from dead heart muscle, and serum levels become elevated within 4 - 6 h, earlier than those of lactate dehydrogenase or aspartate aminotransferase. It is a more specific enzyme, but not entirely so as it is present in muscle elsewhere in the body; levels in the serum are raised in muscle disease, following intramuscular injections, and after surgery [14]. The depletion of creatine phosphokinase from dead and ischaemic heart muscle has been studied in animals; a mathematical understanding of the dynamics of its release and its clearance from the blood has been obtained. This has enabled correlation of infarct size and enzyme levels in animals and man [15 - 18]. Sobel, Shell and others [19] have used this method to assess infarct size and to study the effect of intervention on that size, in animals and man. By taking samples hourly it is possible to draw a time/ concentration curve of creatine phosphokinase levels, and to quantify the infarction as CPK gram equivalents to predict its size. It is then possible to carry out some manoeuvre to alter the size of the infarct, and possible to measure its effect. The predicted size can be calculated after seven hours using hourly sampling. In the event of a successful intervention there is the possibility that the enzyme might be washed out of the dead muscle faster, giving a spurious measurement of a larger infarct size from less total destruction, and it has also been shown in animals that although most of the enzyme is cleared via the blood some escapes via the cardiac lymphatics [20]. In spite of these limitations creatine phosphokinase assay gives a reasonably reliable indication of infarct size in man. Because a total creatine phosphokinase measurement is not cardio-specific, assays of the cardiac iso-enzyme, CKMB can be used. This has proved a sensitive and more
specific indicator of heart muscle death, but it is not released if the cells are only ischaemic [21,22]. It is not absolutely cardio-specific [23], but when assayed in serial samples taken during the first 48 h after admission it provides a good measure of infarct size [24]. Roark et al. [25] have shown that CK-MB is the most specific and sensitive of the enzymatic methods for diagnosis of myocardial infarct, and have compared it with ECG findings. Separation of the various creatine phosphokinase iso-enzymes is a difficult procedure, but the technical problems are gradually being solved [26, 27]. All the enzyme methods of measurement take time, 7 h for the total creatine phosphokinase methods, and longer for the others.
Electrocardiographic Methods When heart muscle is ischaemic or dead, there are characteristic changes in the electrical activity which manifest in the ECG as Q waves, ST segment displacement or T wave changes. ST segment elevation occurs over an area of infarction as was first shown in animals by epicardial recording; it was also noted that these changes occurred within a few minutes of coronary artery occlusion [28]. Similar changes were noted with endocardial and praecordial recordings. The cause of ST segment elevation is uncertain, differing theories ascribe it to changes in either polarisation or depolarisation of the myocardial cell membrane. There is however a good correlation between it and transmural blood flow, but the association is not as strong with subendocardial blood flow. Epicardial ST segment elevation correlates well with the presence or extent of myocardial infarction. The intramyocardial ECG gives a better correlation, and the praecordial ECG gives one that is slightly less good [29] depending upon the size of electrical potential produced. Q waves are seen over the surface of an area of infarcted myocardium. There is no electrical activity over the infarcted tissue and it acts as a window through which the negative intraventricular potential is percieved on the surface of the heart. This gives rise to a pathological Q wave [30]. The size of an infarct can be assessed from changes in the electrical activity on the surface of the heart in animals, and on the surface of the chest in animals and man. ST segment elevation can be quantified to give a measure of infarct size. However ST segments can remain elevated if the infarct is extending, if there is pericarditis, or if there is development of a ventricular aneurysm; this lack of specificity limits its use. In addition, if there is bundle branch block, the ECG appearances of an infarct may be masked [31, 32].
M.C.P. Apps and J. Tinker: The Measurement and Control of MyocardialInfarct Size In animals the size of an infarct can be assessed with epicardial or praecordial mapping. There is good correlation between the histological size of an infarct produced in the dog by occlusion of a coronary artery, and the ECG mapping. ST segment mapping also correlates well with enzyme levels in the serum, and with creatine phosphokinase depletion from the heart muscle [33]. In the dog there is a good correlation between ST segment changes measured on the epicardium with an open chest, and those recorded on the praecordium. In man, however, the interpretation of ST segment mapping is much more controversial. It has the advantage of being reasonably easy to do, and of giving an estimate of infarct size quickly. It can be used to study the extension of an infarct and also the effect of interventions upon the infarct size. ST segment elevation of greater than 2 mm is seen in extending infarcts, and is associated with increased complications [32]. Reid et al. [35] found that ST segment mapping and summation were useful in transmural anterior infarcts, but that the posterior and inferior infarcts did not show up as well. There are difficult technical problems associated with mapping, with recording being carried out via multiple single points [36], straps contained several electrodes [37], and harnesses carrying an array of electrodes [38 ]. Analysis of the data has been done either manually or by computer. Early work on the quantification of the ST segment changes, the ST suggested that this was a good way of measuring infarct size. The ST is a measure of the summation of ST segment changes across the chest [39]. More recent work has however been unable to correlate either the clinical outcome or the enzyme levels with the ST carried out by praecordial mapping [40 - 42]. In animals the ST is a good indication of the size of a myocardial infarct using epicardial or praecordial leads. Man has a chest with high electrical resistance, which is large and thick, and perhaps not surprisingly, enzymatic methods are still more accurate measures of infarct size than is praecordial ST segment mapping. More recently mapping techniques have been extended to the study of Q waves, the RS ratio, and to mapping throughout the cardiac cycle. These may become feasible but as yet only a limited amount of work has been done [43].
Isotopic Methods In some patients the ECG cannot be used to diagnose the presence of myocardial infarct, or to assess its size, and in others recent surgery may abscure changes in enzyme release. Radionucleotide imaging may be of particular use in these patients. Several techniques are possible, with the infarct presenting as either a hot or a cold spot. Some radioisotopes (Technetium, bound to pyrophosphate, tetracycline, or glucoheptonate) are selectively concentrated in the area of infarcted muscle [44]. The infarct
23
appears as a hot spot on a dark field but does n o t show for approximately six hours. Anterior infarcts show up better than inferior infarcts. If there is a large transmural infarct this may show as a doughnut shape; there is no blood flow to the centre of the infarct, the isotope is sequestered by the tissue at the edge of the infarct but little reaches the middle. Technetium is also concentrated in bones, and the pictures of the heart were initially affected by uptake into the rib cage. Now with better imaging techniques this is less noticeable. Some compounds show the infarct as a cold spot, the isotope shows that part of the myocardium which is perfused. Potassium, Thallium, and Caesium salts give this sort of picture. In animals radio-actively myosin antibodies have been used [45]. The infarct does not show for six hours, and is at its maximum positivity for 24 - 28 hours. In animals the size of infarct shown by scanning has been shown to correlate well with the weight of infarcted muscle, [46] the creatine phosphokinase release and depletion, [47] and the distribution of radioactively labelled microsperes injected into the coronary circulation to show up areas of non perfusion [48]. In man the size of the infarct as measured by radionucleotide imaging has been correlated with the presence or absence of complications, [51] and the overall difference between death and survival; the larger infarct seen on scanning is associated with a higher mortality [52]. Scans carried out with "cold spot" imaging cannot differentiate between an area of old or new infarction [53]. As with ECG mapping radio-isotope methods are good for anterior infarcts, but not so good for inferior or posterior infarcts [54, 55]. Scanning is possible by a combination of both "hot" and "cold" spot methods, using *K and *Technetium, to improve the quality of the picture [48]. It is also possible to study the movement of the ventricular wall, with cineangiography, and also to use gated scintiphotography to study myocardial function [52]. A further method that has been tried is that of emission computerized tomography using *C labelled glucose, fatty acids, and *N labelled amino acids to study myocardial metabolism. This is only experimental at present [56]. Indirect Methods The size of a myocardial infarct can be measured directly at post mortem, or indirectly by methods described. A more indirect way of measuring the infarct size is to study its effect upon the overall myocardial function [57]. If the infarct involves 30 - 40% of the myocardium, the patient is in danger of death from pump failure, as not enough myocardium is left to provide an adequate cardiac output. The prognostic indices of Peel [58], Killip [59], Norris [60] and Helmers [12] have been used as measures of infarct size and used in some studies of the effect of intervention on prognosis. In these the blood pressure, pulse, presence or absence of cardiac failure or shock and other measures of the cardiac output give a measure of myo-
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M.C.P. Apps and J. Tinker: The Measurement and Control of MyocardialInfarct Size
cardial function, and therefore indirectly of the degree of damage sustained by the heart. They are only crude measures of infarct size, but easy to use in practice.
Control of Infarct Size Most of the work done on this problem has been carried out in animals, in whom an infarct has been produced by direct occlusion of a coronary artery. Both direct and indirect measures of its size have been employed. Much less work has been done on man, because of ethical and technical difficulties. In a myocardial infarct there is an area of muscle which has a very tenuous blood supply; this muscle is ischaemic, and in danger of death. There is evidence that the area of dead muscle increases in size, as the infarct extends. It is the objective of all therapeutic interventions to protect this threatened muscle and so prevent an increase of infarct size. Oxygen supply to the ischaemic muscle is limited; the extent of muscle death in this region depends upon the balance of oxygen supply and the requirements of the muscle cells. The extent of cell death is related to the myocardial oxygen consumption, the MVO2. In the experimental animal the size of infarct can be increased by increasing the oxygen requirements of the blighted muscle, by fever, by reducing the oxygen supply, with hypoxia, anaemia, or severe hypotension, or by increasing the metabolic requirements of the cells by infusing isoprenaline or pacing to increase the heart rate. In animals it is possible to prevent the extension of an infarct, and to reduce its size, by reducing oxygen requirements, increasing oxygen supply, and by protecting the cells by a variety of means [33]. In man some of these techniques have been used, with variable success. To study the effect of interventions on myocardial infarct size, a good indirect measure of the size is essential. This needs to be accurate, repeatable, easy to do, and preferably quick to carry out. Other more crude measures, morbidity and mortality, are not as good for studies of this kind. Large numbers of patients are necessary, in properly controlled trials, to find which therapeutic measures are useful.
Physical Intervention Myocardial infarcts occur in patients who have obstructed coronary arteries, and may be associated withhypotension severe enough to compromise the remaining coronary arterial flow. For these reasons mechanical methods of assistance have been tried [61 ]. Intra-aortic balloon pumping (counterpulsation) has been used to support the heart. Its use improves coronary artery blood flow, and perfusion of the brain and kidneys. In some patients with cardiogenic shock intra-aortic balloon counterpulsation has been
shown to improve the blood pressure, the cardiac output, and the urinary output. There is evidence in animals that this kind of support may reduce myocardial infarct size, but no comparable work has been done in man. Since the blood supply to the myocardium is compromised in patients with myocardial infarction, emergency revascularisation has been attempted to improve blood flow to the ischaemic areas [62]. Direct implantation of vessels into the ischaemic area has been tried, and more recently coronary artery vein grafting has been done to bypass stenosed vessels and to improve the distal blood supply. In dogs revascularisation reduces the size of a myocardial infarct produced after coronary artery occlusion; in man the operation has been carried out, but there are few patients in whom sequential measurement of infarct size has been performed.
Metabolic Intervention Myocardial muscle cells obtain energy from the breakdown of fatty acids and glucose. In the presence of ischaemia fatty acid oxidation is impaired, and glucose becomes the principal source of energy [63]. There is increased production of lactic acid and increased fatty acid levels which may be toxic and lead to dysrhythmias [64]. To improve the state of the ischaemic muscle, oxygen can be given; this can reduce the size of infarcts in animals [65]; many patients with acute myocardial infarction are hyproxic and may benefit from oxygen therapy [66]. Glucose and insulin solutions can be given to improve cardiac function and to reduce the extent of myocardial necrosis in experimental animals [67]. In man there is a suggestion that it may reduce the mortality of myocardial infarction, but little controlled work has been done [68, 69]. Sodium dichloroacetate stimulates the utilisation of glucose in myocardial cells and this protects the cells in the dog from ischaemia, and reduce the amount of lactic acid produced [701.
Pharmacological Interventions The ischaemic myocardial cell is in jeopardy and oxygen and glucose and insulin help to provide increased energy for the cell to maintain its stabil,ityl Hyaluronidase, given by infusion, seems to protect in the dog and to improve collateral blood flow to the area of ischaemia, allowing a better diffusion of nutrients; in the dog the 'size of myocardial infarction can be reduced. It is a reasonably nontoxic compound and has been tested on patients, causing a reduction in ST segment elevation [71 ].Mannitolprotects the ischaemic myocardium presumably by reducing oedema at the site of the infarct and allowing better oxygenation [72]. The role of corticosteroids in protecting the ischaemic moycardium is controversial. They may stabilise lysozomal and other cell membranes and therefore reduce the number
M.C.P. Apps and J. Tinker: The Measurement and Control of Myocardial Infarct Size of ceils that die. They may also increase blood flow to the ischaemic myocardium. They slow healing, preventing the production of a firm scar [73]. The size of infarct is reduced in animals given steroids both before and after coronary artery occlusion [74, 75] but in man results are inconclusive. In some studies steroids are of benefit, in others they are associated with a higher mortality [76, 77]. There is always the risk that healing may be affected and that cardiac rupture or the production of an aneurysm may occur. Only small numbers of patients have been involved in the trials. It is possible to reduce the size of myocardial infarcts in animals by improving the oxygen and nutrient supply and by reducing the amount of work done by the myocardium. Myocardial work can be reduced by beta-blockade, antagonizing the actions of endogenous catecholamines. This has the effect of reducing heart rate and contractility. In animals propranolol, practolol, and other beta-blockers are effective in reducing infarct size, measured directly and indirectly by many methods [78]. In patients treated with beta-blockade in the period immediately following a myocardial infarct, Pelides and his colleagues first showed that practolol caused a reduction in ST segment elevation in the praecordial ECG [79]. Since then work has suggested that chest pain may be alleviated by blockade in the patient who has had a myocardial infarct [80]. Barber et al showed that the mortality of myocardial infarction was reduced in patients who had a tachycardia of greater than 100, and no evidence of failure. These are the patients who presumably have a high level of endogenous circulating catecholamines, in the absence of pump failure. They point out that the size of trial necessary for statistical confirmation of their results would require approximately 2,000 patients and would need to be carried out on a multicentre basis. Other trials to date have consisted of only limited numbers of patients [81 ]. The myocardial muscle pumps blood out of the heart against peripheral resistance. If this resistance can be reduced whilst leaving an adequate blood pressure for coronary artery perfusion, the work done by the heart is reduced. Sobel and Shell gave trimetaphan to patients with hypertension and a myocardial infarct [19], and noted a reduction in the release of creatine phosphokinase suggesting a reduction in infarct size. In animals reduction of the peripheral resistance with nitroglycerine and nitroprusside has been tried. As long as adequate coronary artery perfusion was maintained, there was a reduction in ischaemic injury [82, 83]. In man nitroglycerine infusion was shown by Flaherty et al. [84] to reduce ST segment elevation in doses which did not significantly affect the blood pressure. Many patients with myocardial infarcts are anxious, and may have high levels of catecholamines, free fatty acids and cortisol, as seen in other stress situations. Sedation with diazepam has been tried [85] to reduce "stress" and therefore catecholamines release [86]. A reduction in
25
catecholamine release would lead to decreased drive to the heart and thus decreased myocardial oxygen consumption, and might help to protect ischaemic myocardium, but this has not been shown as yet. In animals isoprenaline and other catecholamines increase cardiac output, but at the cost of increasing infarct size [78]. The cost of increased cardiac output is an increased oxygen requirement and this causes the demise of muscle that is already in jeopardy. In man catecholamines are most commonly used in patients with myocardial infarcts when there is a very poor cardiac output. They increase the cardiac output and probably the coronary artery blood flow, but there is no evidence of their effect upon myocardial infarct size. Digoxin is another agent which can increase cardiac output, myocardial oxygen requirements, and myocardial infarct size in animals [78], but there is no evidence of any effect on infarct size in man.
Conclusion Whilst increasingly more acceptable methods of measurement are being developed, at the present time enzyme studies are perhaps the most accurate. Much work on the effect of therapeutic interventions on the size of myocardial infarct has been done in animals but less to date in man [87, 88]. Only small numbers of patients have been studied, often without adequate controis. From animals work it seems likely that the reduction of myocardial work with beta-blockade and nitroglycerine, and the improvement of nutrient availability to the ischaemic muscle with glucose and insulin, hyaluronidase, and oxygen therapy are valuable in limiting infarct size. In man beta-blockade reduces pain after infarction and may reduce myocardial infarct size in some patients. Because of the lack of data no firm recommendations for the treatment of patients with myocardial infarcts along these lines can be made. Further studies to elucidate the effect of beta-blockade, hyaluronidase, glucose and insulin and oxygen therapy would be valuable but must await the development of an accurate, rapid and clinically acceptable method of quantifying infarct size. Until there is such a method it will be impossible to assess critically the effect of any therapeutic intervention on the control of infarct size.
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M.C.P. Apps and J. Tinker: The Measurement and Control of Myocardial Infarct Size
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Dr. J. Tinker Director of Intensive Therapy Unit The Middlesex Hospital Mortimer Street London WIN 8AA England
