Burton E. Sobel

Factors Influencing Infarct Size Following Experimental Coronary Artery Occlusions

The purpose of this study was the determination of whether hemodynamic and pharmacologic factors influence the extent and severity of myocardial necrosis produced by coronary occlusion. In 48 dogs, 10 to 14 epicardial leads were recorded on the anterior surface of the left ventricle in the distribution and vicinity of the site of occlusion of a branch of the left anterior descending coronary artery. The average S-T segment elevation for each animal was determined at 5-min intervals after occlusion. This elevation was used as an index of the presence and severity of myocardial ischemic injury. The number of sites showing this elevation provided an additional measure of the size of the injured area. Occlusion alone raised the average S-T segment elevation from 0.22 ± 0.04 to 3.32 ± 0.37 mv (SEM). Isoproterenol, ouabain, glucagon, bretylium, and tachycardia given prior to a repeated occlusion increased the severity and extent of ischemic injury, while propranolol decreased it. Elevation of arterial pressure with methoxamine reduced the occlusion-induced S-T segment elevation, and lowering of the mean arterial pressure by hemorrhage had the opposite effect. In 19 additional experiments, propranolol, isoproterenol, and alterations in arterial pressure produced similar alterations in S-T segment elevation when these interventions were applied as long as 3 hr after ligation. In a third group of dogs, myocardial creatine phosphokinase (CPK) activity was determined 24 hr after occlusion at the same sites at which epicardial electrocardiograms were taken. Depression of myocardial CPK activity in injured portions of the left ventricle 24 hr after coronary artery ligation correlated well with S-T segment elevation in the same sites 15 min after ligation. Moreover, isoproterenol increased and propranolol decreased the area of depression of myocardial CPK activity. We conclude that the hemodynamic status and neurohumoral background at the time of occlusion and for up to 3 hr thereafter can alter the extent and severity of myocardial ischemic injury and myocardial necrosis.

Estimation of Infarct Size in Man and its Relation to Prognosis

Infarct size was assessed quantitatively in 33 patients with acute myocardial infarction with a new technic based on analysis of serial serum creatine phosphokinase (CPK) changes to determine its relationship to prognosis. We have recently measured infarct size in the conscious dog with this method which takes into account CPK distribution space, fractional disappearance rate, proportion degraded in myocardium, and proportion released into the circulation, and we have validated the method by measurement of myocardial CPK depletion in the same animals. In the present study, CPK activity (determined spectrophotometrically) and isoenzyme profiles (assayed electrophoretically) were measured in patient serum samples obtained every 2 hours. Infarct size was estimated by mathematical analysis of serial CPK changes utilizing the method previously developed in the conscious dog model. CPK isoenzyme profiles demonstrated prominent anodal bands, absent from normal serum, indicating that enzyme elevations reflected CPK released from heart rather than skeletal muscle. In 19 class I-II survivors (New York Heart Association) estimated infarct size was 31 ± 4 CPK-gram-equivalents (CPK-g-Eq). It was significantly larger (P < 0.01), 103 ± 14, in nine patients who died and in four class III or IV survivors (91 ± 8). Estimation of cumulative infarct size differentiated patients with electrocardiographic changes and clinical sequelae from complications such as pericarditis from those patients with extension of infarction. Thus, infarct size can be assessed quantitatively in patients with acute myocardial infarction and provide a useful diagnostic and prognostic index based on the extent of myocardial damage.

Precordial S-T segment elevation mapping: An atraumatic method for assessing alterations in the extent of myocardial ischemic injury

Abstract A noninvasive technique for evaluating the extent of myocardial ischemic injury after experimental coronary artery occlusion was devised and applied to study alterations in the extent of injury produced by hemodynamic and pharmacologic interventions. The technique was then extended to the assessment of myocardial ischemic injury in patients with acute myocardial infarction. In 7 closed chest dogs, electrocardiograms were recorded from 15 sites on the chest wall before and after intermittent occlusions of the left anterior descending coronary artery. There was no S-T segment elevation before the occlusion; 15 minutes after occlusion the sum of S-T segment elevations (ΣS-T) averaged 15.0 ± 3.0 mm (SEM, 1 mm deflection = 0.1 mv), and an average of 4.2 ± 0.6 sites exhibited elevations exceeding 0.1 mv (NS-T). Occlusions occurring during administration of isoproterenol (0.25 μg/kg per min) increased ΣS-T to 51.0 ± 9.0 mm and NS-T to 10.6 ± 0.9, whereas occlusions occurring after administration of propranolol (1 mg/kg) decreased ΣS-T to 3.0 ± 1.5 mm and NS-T to 0.2 ± 0.2. In 8 dogs the extent of ischemic injury, manifested by S-T segment changes, was decreased by propranolol and norepinephrine and increased by hemorrhagic hypotension and isoproterenol, applied up to 6 hours after occlusion. Reproducible S-T segment maps, using 35 surface electrodes, were obtained in 19 patients with acute myocardial infarction. In 15 patients studied serially, ΣS-T decreased from 54.25 ± 7.00 to 38.50 ± 6.30 mm and NS-T from 18.7 ± 2.5 to 12.3 ± 2.8, respectively, during a 24 hour period. However, in 3 patients in whom ventricular fibrillation, arterial hypotension and further ischemic pain occurred, ΣS-T and NS-T increased whereas in another patient propranolol decreased ΣS-T and NS-T. Thus, precordial mapping, both in dogs and patients, shows changes parallel to those measured by the epicardial technique and should provide a useful clinical tool for determining acute changes in the extent of ischemic injury.

Coronary Artery Reperfusion: I. EARLY EFFECTS ON LOCAL MYOCARDIAL FUNCTION AND THE EXTENT OF MYOCARDIAL NECROSIS

The effects of coronary artery reperfusion 3 hr after coronary occlusion on contractile function and the development of myocardial damage at 24 hr was studied experimentally. In 14 control and 6 reperfused dogs, relationships between epicardial ST segment elevation 15 min after coronary occlusion and myocardial creatine phosphokinase activity (CPK) and histologic appearance 24 hr later were examined. The electrocardiograms were recorded from 10 to 15 sites on the left ventricular epicardium and transmural samples for CPK and histology were obtained from the same sites where epicardial electrocardiograms had been recorded. An inverse relation existed between ST segment elevation (mv) 15 min after occlusion and log CPK activity (IU/ mg of protein) 24 hr later, log CPK = - 0.06ST + 1.26. In dogs subjected to coronary artery reperfusion, there was significantly less CPK depression (log CPK = - 0.01ST + 1.31, [P < 0.01]) than that expected from the control group. In the control group 97% of specimens showing ST segment elevations over 2 mv at 15 min showed abnormal histology 24 hr later. In contrast, in the reperfused group 43% of sites exhibiting elevated ST segment at 15 min showed abnormal histology 24 hr later. In six additional dogs it was shown that the paradoxical movement of the left ventricular wall could be reversed within 1 hr of perfusion. Therefore, by enzymatic and histologic criteria, as well as by functional assessment, coronary artery reperfusion 3 hr after occlusion resulted in salvage of myocardial tissue.

An improved basis for enzymatic estimation of infarct size.

Infarct size has been estimated from serial serum creatine phosphokinase (CPK) changes, but the contribution of noncardiac CPK may interfere. Results would also be influenced if CPK disappearance varied with hemodynamic changes. Since MB CPK is a marker more specific to myocardium, infarct size was estimated from serum MB changes in 16 patients. In addition, 21 chronically instrumented conscious dogs subjected to tachycardia, decreased cardiac output or hepatic or renal ischemia were studied to evaluate the dependence of CPK disappearance on hemodynamics. MB CPK in human tissue extracts and serum was quantified with a new, rapid, glass bead-batch adsorption technique, verified with CPK isoenzymes prepared from human myocardium. Among tissues surveyed, only myocardium contained appreciable MB CPK. Infarct size estimated from MB correlated with total serum CPK in patients with uncomplicated myocardial infarction (r = 0.97, N = 12). In patients with infarction given intramuscular injections, total CPK curves were distorted but MB CPK curves were not apparently affected. Hemodynamic alterations in conscious dogs did not markedly affect the disappearance rate (kd) of intravenously injected, radioactively labeled, canine myocardial CPK, although kd was shown to depend on reticuloendothelial system activity. These findings suggest that estimation of the extent of infarction based on serum MB CPK should be useful despite hemodynamic deterioration associated with infarction or interference of noncardiac CPK.

Fast-Fourier transform analysis of signal-averaged electrocardiograms for identification of patients prone to sustained ventricular tachycardia.

Electrocardiograms obtained from patients during arrhythmia-free intervals do not identify those prone to sustained ventricular tachycardia (VT) despite the occult delayed activation that is presumably present. To determine whether frequency-domain analysis facilitates detection of this hallmark of predisposition to VT, fast-Fourier transform analysis (FFTA) procedures were developed and tested with a computer-generated mathematical model. The FFTA approach developed allows inherent limitations of high-gain amplification and a priori filtering used commonly for time-domain analysis to be avoided. After demonstrating that FFTA detected low-amplitude oscillatory waveforms in signal-averaged recordings in the frequency domain, the procedure was applied to signal-averaged X, Y, and Z lead recordings from the following three groups of patients: group I, patients with prior myocardial infarction and episodic sustained VT (n = 16); group II, patients with prior myocardial infarction without overt sustained VT (n = 35); and group III, normal control subjects (n = 10). Results of FFTA demonstrated significant (p less than .0001) differences in the decibel drop at 40 Hz and the area under the curve from the fundamental frequency to the frequency at which the spectral amplitude was decreased by 60 dB for both the terminal 40 msec of the QRS and ST segment in patients in group I compared with those in groups II and III, in whom results were similar. Results were independent of QRS duration (r = .2), left ventricular ejection fraction (r = .19), and complexity of spontaneous ventricular ectopy. Thus, patients known to manifest sustained VT also exhibited relatively greater high-frequency content in arrhythmia-free intervals in the terminal QRS and ST segment than those without VT (88%, 15%, and 0% in groups I through III, respectively). FFTA offers promise for the noninvasive detection of patients at risk for the development of sustained VT.

Effect of Glucose-Insulin-Potassium Infusion on Myocardial Infarction following Experimental Coronary Artery Occlusion

The effects of glucose-insulin-potassium (GIK) infusion and glucose (G) infusion started 30 min after experimental coronary occlusion and the combination of GIK and propranolol (P) started 3 hours after coronary occlusion on the development of myocardial infarction were studied in 37 dogs. Fifteen minutes after the coronary occlusion, epicardial electrocardiograms were recorded at 10-15 sites; 24 hours later transmural specimens were obtained from the same sites for determination of myocardial creatine phosphokinase (CPK) activity and the evaluation of morphologic changes. In the control group (normal saline infusion) the relationship between S-T-segment elevation (mv) 15 min after occlusion and CPK activity (IU/mg of protein) 24 hours later was: log CPK = −0.064 S-T + 1.24; r = 0.81. In the GIK group, the infusion was begun 15 min following epicardial mapping, and sites with the same S-T-segment elevations showed less CPK depression than did the control group: log CPK = −0.022 S-T + 1.25. The G group also showed less CPK depletion than the control group but to a somewhat lesser extent than the GIK group (log CPK = −0.030 S-T + 1.20). The group receiving GIK and P 3 hours after occlusion also showed less CPK depression than did the control group (log CPK = −0.034 S-T + 1.26). Histologic analysis in 24-hour specimens showed that sites which exhibited S-T-segment elevation 15 min after occlusion showed normal histology in 3% of specimens obtained from control dogs, while the other 97% showed early signs of myocardial infarction. However, in the GIK group, 36% of the specimens with S-T-segment elevation prior to the infusion were histologically normal 24 hours later, while in the G group 30% were normal, and in the GIK and P group 17% were normal. Electron microscopy confirmed the morphologic changes observed by light microscopy. Thus, in the presence of experimental coronary occlusion, GIK exerts a protective effect against myocardial ischemia and reduces the extent of myocardial necrosis. G alone acts similarly but to a lesser degree, while a beneficial effect can also be demonstrated when GIK and P are started 3 hours after the onset of coronary occlusion.

Coronary Artery Reperfusion: II. REDUCTION OF MYOCARDIAL INFARCT SIZE AT 1 WEEK AFTER THE CORONARY OCCLUSION

The question of whether or not the size of an area of myocardial infarction, measured at 1 wk after coronary occlusion, can be influenced by coronary artery reperfusion was examined in dogs. In seven control experiments the anterior descending coronary artery was ligated, while in seven other studies the occlusion was released after 3 hr. In all animals calibrated photographs were used to assess the zone of hypoperfusion and the acutely injured area of epicardial ST segment elevation, as well as the extent of damage at postmortem 1 wk later. In control dogs, the gross infarct size at postmortem averaged 63.8+/-7.3% of that predicted from the acutely injured zone. However, in reperfused hearts the average gross infarct size at 1 wk was only 10.2+/-4.4% of that predicted. Transmural specimens were obtained at autopsy for histology and measurement of myocardial creatine phosphokinase (CPK) activity from sites initially used for epicardial electrocardiography. In control animals, there was a direct relationship between the degree of ST segment elevation and the degree of cell necrosis in transmural histologic sections. ST segment elevation also predicted myocardial CPK (international units per milligram protein): log CPK = - 0.0613 ST + 1.17 (r = 0.66, n = 56 sites). In the reperfused animals, log CPK = - 0.166 ST + 1.36 (r = 0.69, n = 46 sites) showing almost complete preservation of CPK activity at 1 wk, sparing being most prominent in the epicardial zone. Similarly, there was a good correlation between myocardial CPK activity and the histological assessment of cell destruction, the degree of cell damage = - 0.152 CPK + 3.86 (r = 0.86; n = 102 sites). Thus, control dogs showed severe myocardial CPK depletion and histologic evidence of extensive cell destruction, whereas animals subjected to coronary artery reperfusion had little CPK depletion and much less evidence of myocardial cell necrosis 1 wk later.

Depressed Myocardial Creatine Phosphokinase Activity Following Experimental Myocardial Infarction in Rabbit

Since creatine phosphokinase (CPK) is found predominantly in myocardial and skeletal muscle cells, in contrast to cells participating in the inflammatory response, it was considered likely that measurement of activity of this enzyme in the heart would provide a sensitive and relatively specific index of the extent of ischemic injury following acute coronary artery occlusion. Accordingly, CPK activity was measured serially following coronary artery occlusion in extracts from rabbit myocardium with gross infarction and from normal rabbit left ventricle. In addition, myocardial CPK activity was assayed in extracts from various portions of dog hearts 24 hours after ligation of the coronary artery. CPK activity of rabbit myocardium with infarction was uniformly depressed within 6 hours following coronary occlusion. After 24 hours, activity declined from 15.5±0.9 (mean±SE) to 3.4±0.3. CPK activity in whole left ventricular extracts was depressed and in general, the extent of depression was proportional to the size of the gross infarct. CPK depression in various regions of the dog heart 24 hours after coronary occlusion correlated with the extent of reduction of blood flow determined with the use of radioactively labeled microspheres. Results suggest that depression of myocardial CPK activity may be useful in estimating the extent of tissue damage following experimental coronary artery occlusion and the effect of prophylactic and therapeutic measures on the survival of myocardium in this setting.

Prognostic significance of location and type of myocardial infarction: Independent adverse outcome associated with anterior location

To determine the relative prognostic significance of location (anterior or inferior) and type (Q wave or non-Q wave) of infarction, the hospital course and follow-up outcome (mean duration 30.8 months) of 471 patients with a first infarction were analyzed. Analyses were performed grouping the patients according to infarct location (anterior, n = 253; inferior, n = 218), infarct type (Q wave, n = 323; non-Q wave, n = 148), and both location and type (inferior non-Q wave, n = 85; inferior Q wave, n = 133; anterior non-Q wave, n = 63; and anterior Q wave, n = 190). Patients with anterior infarction had a substantially worse in-hospital and follow-up clinical course compared with those with inferior infarction, evidenced by a larger infarct size (21.2 versus 14.9 g Eq/m2 creatine kinase, MB fraction [MB CK], p less than 0.001), lower admission left ventricular ejection fraction (38.1 versus 55.3%, p less than 0.001) and higher incidence of heart failure (40.7 versus 14.7%, p less than 0.001), serious ventricular ectopic activity (70.2 versus 58.9%, p less than 0.05), in-hospital death (11.9 versus 2.8%, p less than 0.001) and total cumulative cardiac mortality (27 versus 11%, p less than 0.001). Patients with Q wave infarction similarly experienced a worse in-hospital course compared with patients with non-Q wave infarction, evidenced by a larger infarct size (20.7 versus 12.7 MB CK g Eq/m2, p less than 0.001), lower admission left ventricular ejection fraction (43.7 versus 50.6%, p less than 0.001), and a higher incidence of heart failure (31.9 versus 21.6%, p less than 0.05) and in-hospital death (9.3 versus 4.1% p less than 0.05). However, there was no increased rate of reinfarction or mortality in hospital survivors with non-Q wave infarction compared with those with Q wave infarction, and total cardiac mortality was similar (16 versus 21%, p = NS). To evaluate the role of infarct location and type independent of infarct size, patients were grouped according to quartile of infarct size, and outcome was reanalyzed within each group. Patients with anterior infarction demonstrated a lower left ventricular ejection fraction on admission and after 10 days than did patients with inferior infarction, even after adjustment for infarct size, as well as a higher incidence of congestive heart failure and cumulative cardiac mortality.(ABSTRACT TRUNCATED AT 400 WORDS)