L. D. Hillis

Coronary-Artery Spasm

Detailed formal protocol with illustrations and extensive bibliography. Note: Some information has been redacted in the publicly-available version due to privacy issues. For questions, contact archives@utsouthwestern.edu.

Favorable Effects of Hyaluronidase on Electrocardiographic Evidence of Necrosis in Patients with Acute Myocardial Infarction

To evaluate hyaluronidases effect in reducing post-infarction myocardial necrosis, we randomized 91 patients with anterior infarction to control (45) or to hyaluronidase-treatment (46) groups. A 35-lead precordial electrocardiogram was recorded on admission and seven days later. Hyaluronidase was administered intravenously after the first electrocardiogram and every six hours for 48 hours. QRS-complex changes were analyzed to assess the drugs effect. Precordial sites with ST-segment elevation (larger than or equal to 0.15 mV) on the initial electrocardiogram that retained an R wave were considered vulnerable for the development of electrocardiographic signs of necrosis. The sum of R-wave voltages of vulnerable sites fell more in the control group than in the hyaluronidase group (70.9 +/- 3.6 per cent [+/- 1 S.E.M.] vs 54.2 +/- 5.0 per cent P less than 0.01). Q waves appeared in 59.3 +/- 4.9 per cent of the vulnerable sites in control versus 46.4 +/- 4.9 per cent in hyaluronidase-treated patients (P less than 0.05). Thus, hyaluronidase reduced the frequency of electrocardiographic signs of myocardial necrosis.

Use of changes in the epicardial QRS complex to assess interventions which modify the extent of myocardial necrosis following coronary artery occlusion.

SUMMARY The goal of this study was to determine if changes in the epicardial QRS complex after coronary artery occlusion (CAO) can be used to evaluate the efficacy of interventions designed to limit infarct size. Forty-one open-chest dogs with CAO were studied: 15 were controls, 18 received hyaluronidase and eight received propranolol starting 20 minutes after CAO. Epicardial ECGs were recorded at specific time intervals to analyze ST-segment elevation and changes in Q and R waves. Transmural specimens were obtained 24 hours after CAO from the same sites at which ECGs were recorded. Q wave development (ΔQ), R wave fall (ΔR), and their combination (ΔR + ΔQ) at 24 hours correlated with the extent of necrosis, as de- termined by myocardial creatine phosphokinase activity depression and histologic appearance. In the control group ST-segment elevation 15 minutes after CAO (ST18m) predicted changes in Q and R waves 24 hours later; in the treated groups, the same STism prior to drug administration resulted in significantly less QRS changes. Thus, I) Q wave development and R wave fall 24 hours after CAO accurately reflect myocardial necrosis. 2) ST18m predicts subsequent changes in Q and R waves. 3) The efficacy of hyaluronidase and propranolol, agents previously shown to reduce myocardial necrosis, can be detected by less Q wave development and a smaller fall in R wave voltage.

The influence of the time interval between coronary artery occlusion and the administration of hyaluronidase on salvage of ischemic myocardium in dogs.

SUMMARY The purpose of this study was to determine the time interval following coronary artery occlusion during which the administration of hyaluronidase exerts a significant protective effect on injured myocardium. Fortyeight open-chest dogs with coronary artery occlusion were studied. Fourteen were untreated (controls). Hyaluronidase (500 NF units/kg, iv) was administered 20 minutes (12 dogs), 3 hours (8 dogs), 6 hours (8 dogs), or 9 hours (6 dogs) after occlusion. Epicardial electrograms, recorded from 10 to 16 sites on the anterior surface of the left ventricle before, 15 minutes after, and 24 hours after coronary occlusion were analyzed for S-T segment elevation and changes in QRS morphology. Transmural specimens, excised 24 hours after occlusion from the sites at which the electrograms were recorded, were analyzed for creatine phosphokinase (CPK) activity and histological appearance. In all five groups, myocardial CPK depression, histological evidence of the extent of necrosis, and changes in QRS configuration correlated well with one another. In the controls, S-T segment elevation 15 minutes after occlusion (ST 15m) correlated well with myocardial CPK depression, histological extent of necrosis, and changes in the QRS complex 24 hours later. When hyaluronidase was given 20 minutes, 3 hours, or 6 hours after coronary occlusion, myocardial salvage was reflected in significantly less myocardial CPK depression for any given ST]5rn, less histological evidence of infarction, and less extensive changes in QRS configuration than in the untreated dogs, although there was a progressive reduction in tissue salvage as the time interval between occlusion and drug administration lengthened. Hyaluronidase administered 9 hours after occlusion had no demonstrable effect on the development of myocardial necrosis, suggesting that ischemic injury is totally irreversible by this time.

The effects of hyaluronidase on coronary blood flow following coronary artery occlusion in the dog.

In an attempt to determine the mechanism by which hyaluronidase reduces myocardial injury following coronary artery occlusion, myocardial blood flow was studied in 20 open-chest dogs with occlusion of the left anterior descending coronary artery. Ten dogs served as controls, and 10 received hyaluronidase (500 NF units/kg) intravenously 20 minutes after occlusion. At 15 minutes and at 6 hours after occlusion, regional myocardial blood flow in the epicardial and endocardial halves of both ischemic and nonischemic zones were determined with radiolabeled microspheres. Mean arterial pressure, heart rate, and cardiac output were similar in the untreated and treated dogs through the 6 hours of the experiment. Moreover, regional blood flow to nonischemic myocardium (areas without epicardial S-T segment elevation 15 minutes after occlusion) was similar in the two groups 15 minutes and 6 hours after occlusion. Fifteen minutes after occlusion, the flow to the ischemic myocardium subjacent to sites with S-T segment elevation exceeding 2 mV) in the untreated group was: transmural, 28.1 ± 2.2 (mean ± SE) ml/min per 100 g; endocardial, 20.7 ± 1.8; and epicardial, 38.5 ± 3.1. The endocardial-epicardial flow ratio was 0.56 ± 0.04. Six hours after occlusion, the untreated group demonstrated a further decrease in blood flow to the ischemic myocardium: transmural, 15.2 ± 1.4 ml/min per 100 g; endocardial, 6.8 ± 1.1; and epicardial, 24.3 ± 1.9. The endocardial-epicardial flow ratio fell to 0.28 ± 0.04. In contrast, the hyaluronidase-treated dogs showed no further reduction in blood flow to ischemic myocardium 6 hours after occlusion: transmural, 30.3 ± 3.1 ml/min per 100 g; endocardial, 21.3 ± 2.5; and epicardial, 38.8 ± 3.8. These regional myocardial flows were significantly higher than those of the untreated dogs 6 hours after occlusion. Thus, salvage of damaged myocardium by hyaluronidase might be explained by its beneficial effect on collateral blood flow to the ischemic tissue, though this effect on collateral flow could be the consequence rather than the cause of this salvage.

Assessment of the Efficacy of Interventions to Limit Ischemic Injury by Direct Measurement of Intramural Carbon Dioxide Tension after Coronary Artery Occlusion in the Dog

Although numerous interventions have been shown to exert a salutary effect on the ischemic myocardium, the severity of ischemia generally has been measured by indirect techniques. In the present investigation the effect of ischemia on intramural carbon dioxide tension (PmCO(2)) was measured directly in the open-chest, anesthetized dog with a mass spectrometer during repetitive 10-min coronary artery occlusions separated by 45-min periods of reflow; simultaneously, regional myocardial blood flow in the ischemic area was measured by (127)Xenon washout. In all dogs the increase in PmCO(2) from before to 10 min after the first occlusion (DeltaPmCO(2)) exceeded that during subsequent occlusions. In those dogs not receiving an intervention (controls), DeltaPmCO(2) during the third occlusion was similar to that during the second occlusion. When propranolol, hyaluronidase, and nitroglycerin were administered to different groups of dogs before the third occlusion, each caused significantly smaller elevations in DeltaPmCO(2) than those occurring during the control second occlusion, and the combination of all three interventions induced the smallest increase in DeltaPmCO(2). Regional myocardial blood flow rose with hyaluronidase and was unchanged with propranolol, nitroglycerin, and the three drugs in combination. In contrast to these beneficial interventions, isoproterenol infused with the third occlusion caused a higher DeltaPmCO(2) than during the control second occlusion. It is concluded, first, that interventions that modify the severity of ischemia can be evaluated by measuring intramural carbon dioxide tension; second, that propranolol, hyaluronidase, and nitroglycerin reduce ischemic injury, whereas isoproterenol increases it; and third, that the combination of propranolol, hyaluronidase, and nitroglycerin exerts an additive beneficial effect on ischemia.

The role of propranolol's negative chronotropic effect on protection of the ischemic myocardium.

Propranolol exerts a salutary effect on the ischemic myocardium. This beneficial influence is believed due mainly to a reduction in myocardial oxygen requirements, which, in turn, is caused by a decre