SUMMARY The effect of propranolol (0.1 mg/kg intravenously followed by 320 mg given over 27 hour orally) on serum levels of creatine kinase enzyme was studied in a randomized trial involving 95 patients seen within 12 hours of onset of symptoms of uncomplicated myocardial infarction. In 15 patients who were treated with propranolol within 4 hours of onset, and who eventually developed pathological Q waves, peak measured enzyme levels were 27% (P < 0.0125) lower than in 19 control patients who were also seen THE WELL-KNOWN EFFICACY of beta-adrenergic blocking drugs for the treatment of angina pectoris53 suggests that these drugs should also be effective for the acute imbalance between oxygen supply and demand which occurs during the early stages of myocardial infarction. Apart from an encouraging report by Snow in 1965,4 however, a number of carefully randomized early clinical trials of beta blockers5-9 showed no effect on hospital mortality from infarction nor on the incidence of arrhythmias in treated patients compared with controls.A number of recent developments suggest, however, that the use of beta-adrenergic blocking drugs in the acute stage of myocardial infarction should be re-investigated. First, there is the evidence that long-term beta blockade prolongs life after myocardial infarction'0 11 and that this may be due in part to the prevention of new ischemic events.'2 Second, there is evidence that propranolol given prophylactically to experimental animals reduces myocardial infarct size;3-5 this suggests that measurements of infarct size should be used as an end-point for therapeutic trials in man. Third, doses of propranolol used in previous trials (40-80 mg per day) were comparatively low and were administered orally and comparatively late after the onset. Patients given this low dose do not develop blood levels within the therapeutic range for 24-48 hours after first administration of the drug. 16The present trial proposed to investigate the effect of highloading doses of propranolol given within 12 hours of onset of symptoms of infarction on serum creatine phosphokinase (CPK) levels.'7', Results show that CPK levels were reduced by propranolol if the drug was given within four hours of onset of the most severe chest pain.Patients and MethodsWe included in this study those infarctions which were of moderate severity since we postulated they would ultimately within 4 hours of the onset but had no specific treatment. Total calculated enzyme appearance was also lower in the treated patients (reduced 25%, P < 0.05) as was the calculated rate of appearance (33%, P < 0.005). No significant difference was found for treated compared with control patients entering the trial more than 4 hours after the onset of chest pain. This evidence suggests that propranolol may reduce the size of uncomplicated infarctiops if it is given intravenously within 4 hours of the onset.cause a moderately high enzyme release for which a reduction would be both easily measurable and clinically meaningful. At the same time it was r...

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The relationship between regional blood flow and epicardial S-T segment elevation was studied in 26 open-chest anesthetized dogs with left anterior coronary artery ligations. Changes in myocardial blood flow, measured with 15 plus or minus 5mu (diameter) microspheres labeled with 141-Ce, 85-Sr, and 169-Yb, were correlated with summated S-T segment elevations 15 minutes, 1 hour, and 2 hours after coronary artery occlusion. In normal areas, myocardial blood flow was 113 plus or minus 5 ml/min 100 g- minus 1 and summated S-T segment elevation was 0.3 plus or minus 0.2 mv. Fifteen minutes after coronary artery occlusion in 26 dogs, S-T segment elevation was 5.7 plus or minus 0.7 mv over the center of the infarct and myocardial blood flow was 10 plus or minus 1 ml/min 100 g- minus 1; over the border zone, myocardial blood flow was 63 plus or minus 4 ml/min 100 g- minus 1 and S-T segment elevation was 3.1 plus or minus 0.1 mv. One third of the areas with a myocardial blood flow of 10 ml/min 100 g- minus 1 or less had no S-T segment elevation. In the center and border zones of the infarct in 9 dogs, myocardial blood flow increased from 11 plus or minus 2 and 67 plus or minus 8 ml/min 100 g- minus 1 15 minutes after occlusion to 20 plus or minus 4 and 84 plus or minus 12 ml/min 100 g- minus 1, respectively, 2 hours after coronary artery occlusion. These increases were not associated with a significant reduction in summated S-T segment elevation. The results do not suggest a simple quantitative relationship between epicardial S-T segment elevation and myocardial blood flow following acute coronary artery occlusion.

Praecordial ST segment elevation was measured at 35 electrode positions in each of 40 patients admitted to a coronary care unit after acute transmural anterior myocardial infarction. Serial praecordial electrocardiographic maps were recorded to determine (a) the time course as well as reproducibility of measurements of ST segment alterations, and (b) the degree of correlation between the magnitude of ST segment elevation and the severity of infarction, as assessed clinically or by sequential estimations of serum creatine kinase activity. Large variations in ST segment elevation were found in different patients with a comparable degree of myocardial damage, and at intervals of as little as four hours in the same patient. These variations were greater than could be explained by technicalfactors, and were not related to apparent changes in the patients' clinical status. The patterns of release of myocardial creatine kinase showed that the time course of ST segment elevation was longer than the period of myocardial necrosis. No correlation was found between the myocardial infarct size as determined by enzyme release and the highest levels of ST segment elevation recorded. Thefindings suggest that ST segment elevation as measured by praecordial electrocardiographic mapping does not constitute a reliable index of the size or severity of myocardial infarcts in man.Though elevation of the ST segment of the electro-kinase (CK) activity or histological changes 24 cardiogram has been recognized for many years as hours later. The possibility has thus arisen that one of the classical signs of acute myocardial in-quantification of praecordial ST segment elevation farction (Eppinger and Rothberger, 1909), the by a simple non-traumatic technique in patients electrophysiological correlates of ischaemic injury might prove of value for the assessment of size and were not established until intracellular potentials severity of the initial ischaemic damage (Maroko could be recorded from the intact heart. It is now et al., 1972a; Reid, Pelides, and Shillingford, 1971; known that ischaemia following coronary artery Neilsen, 1973; Maroko, 1974), and that serial occlusion leads to an acceleration of repolarization, measurements might be used to evaluate subsequent with loss of resting membrane potential, which progress (Reid et al., 1974) or test the effectiveness results in ST segment elevation in the surface of drugs in altering the extent of ischaemic injury electrocardiogram (Samson and Scher, 1960;(Pelides et al., 1972; Maroko et al., 1973

SUMMARY Myocardial creatine phosphokinase (CPK) activity and myocardial blood flow (MBF, 15 ± 5 ,u microspheres) were measured at 24 hours after ligation of the left anterior descending coronary artery in nine untreated anesthetized dogs, in eight dogs pretreated with intravenous propranolol 5 mg/kg and in eight which had both pretreatment as well as infusion of propranolol (1.25 mg/kg/hour) after occlusion. Loss of CPK activity from the border and center zones of the myocardial infarct was similar in extent in dogs which had pretreatment but no infusion of propranolol as it was in the control group. Loss of CPK from the center zone was greater REDUCTION OF MYOCARDIAL OXYGEN CON-SUMPTION with beta-adrenergic blocking drugs1 is of proven clinical value for the treatment of angina pectoris and might also be beneficial in the treatment of the acute imbalance between oxygen supply and demand which occurs during the early stages of myocardial infarction. In spite of an initially encouraging report,2 however, oral administration of propranolol in early randomized trials3 was not found to reduce mortality from myocardial infarction in patients.More recently, Maroko et al. suggested that propranolol could reduce the intensity of experimental myocardial ischemia, as judged by electrocardiographic as well as other criteria.5 The findings have been consistent with the results of histological studies of the posterior papillary muscle after circumflex coronary artery ligation in the dog6 and with the reports that propranolol used experimentally preserved high energy stores in infarcting myocardium'5 and reduced gross anatomic infarct size.t1 Moreover, a recent clinical study has shown that propranolol may improve myocardial oxygenation in patients with uncomplicated infarction.12The present study was designed to re-examine the effect of high doses of propranolol, using our previously described model for the measurement of myocardial blood flow, both at 15 min and 24 hours after coronary occlusion, and measurement of the intensity of creatine phosphokinase (CPK) depletion at 24 hours after onset of infarction.,3 The effects of propranolol on these parameters were correlated with the hemodynamic alterations produced by the drug in relation to its plasma concentrations. (P < 0.005) in dogs receiving pretreatment followed by constant infusion of the drug. Propranolol had no significant effect on collateral blood flow to the border or center zone of the infarct. In separate experiments, there was no important difference in hemodynamic measurements, except a slower heart rate (P < 0.01), when pretreated dogs were compared with control dogs up to 2 hours after coronary ligation. We conclude that propranolol given in this dose does not influence myocardial damage, on the basis of regional myocardial blood flow or tissue CPK depletion values at 24 hr after coronary occlusion. MethodsForty-eight mongrel dogs, weighing 18-32 kg (mean 24 kg) were divided into two groups.Group 1 (25 dogs), designated the survival group, was divided into ...