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...

No abstract

Propranolol is a ,3-adrenergic blocking drug which reduces cardiac contractility and myocardial oxygen consumption (Folle and Aviado, 1965) and suppresses cardiac arrhythmias (Besterman and Friedlander, 1965). Snow (1965), in a study in which alternate patients with acute myocardial infarction were given propranolol, reported a mortality of 16% in treated patients and 35 % in control cases, the difference in mortality being statistically significant (P<0.02). The reduction in mortality in treated patients could have been due to the antiarrhythmic or the oxygen-sparing effect of propranolol.The present study was undertaken to test the hypothesis that propranolol lowers mortality or alters morbidity in acute myocardial infarction. A double-blind protocol was used, and over 500 patients were studied. Relevant details of past history, condition on admission to hospital, and subsequent progress were recorded in all cases, so that mortality and morbidity could be studied in detail. As no effect of propranolol on mortality was found, data from trial patients and from patients not admitted to the trial have been combined to form a study on the pattern of hospital mortality in infarction (Norris et al., 1968)

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 ...

In order to further define clinical and angiocardiographic predictors of long-term survival after myocardial infarction we followed 616 consecutive male patients under 60 years of age, survivors of a first (N = 455) or recurrent (N = 161) myocardial infarction, for 8.8 +/- 2.9 years. Patients had angiocardiography at 4-8 weeks after infarction; none had thrombolysis, but 33% had cardiac surgery, 14% on a clinical trial basis. Left ventricular end-systolic volume was the most powerful predictor of cardiac mortality; ejection fraction and end-diastolic volume added no further information. Myocardial score, a measure of the severity of coronary stenoses in relation to the amount of myocardium supplied, was of only borderline predictive value on multivariate analysis, possibly because any effect had been negated by coronary surgery. Administration of beta-blocker drugs had an independent effect of improving prognosis, while continued cigarette smoking worsened it. Age, status of index infarction (first or recurrent) and serum cholesterol did not affect survival. A trial of surgery, carried out in a subset of 200 of these patients who were relatively asymptomatic but had severe coronary disease, showed no survival advantage for intended surgical over non-surgical management. We conclude that a high left ventricular end-systolic volume remains the most important adverse prognostic factor after recovery from myocardial infarction.