Peter R. Maroko

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.

Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs.

The time relationship for recovery of mechanical function, the intramyocardial electrogram and coronary flow after brief periods of regional myocardial ischemia, was studied in conscious dogs. Total left vemtricular (LV) function was assessed with measurements of LV systolic and diastolic pressures, rate of change of LV pressure (dP/dt), and dP/dt/P. Regional LV function was assessed with measurements of regional segment length and velocity of shortening. An implanted hydraulic occluder on either the left anterior descending or circumflex coronary artery was inflated for 5- and 15-min periods on separate days. A 5-min occlusion depressed overall LV function transiently, but just before release of occlusion overall function had nearly returned to control. At this time regional function in the ischemic zone was still depressed to the point of absent shorteining or paradoxical motion during systole and was associated with marked ST segment elevation (+ 10 +/- 2.2 mV) at the site where function was measured. With release of occlusion and reperfusion the intramyocardial electrogram returned to normal within 1 min, and reactive hyperemia subsided by 5-10 min. In contrast to the rapid return to preocclusion levels for coronary flow and the electrogram, regional mechanical function remained depressed for over 3 h. A 15-min coronary occlusion resulted in an even more prolonged (greater than 6 h) derangement of function in the ischemic zone. Thus, brief periods of coronary occlusion result in prolonged impairement of regional myocardial function which could not have been predicted from the rapid return of the electrogram and coronary flow. These observations indicate that brief interruptions of coronary flow result either in a prolonged period of local ischemia or that alterations of mechanical induced by ischemia far outlast the repayment of the oxygen debt.

Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first?

Both microvascular damage and myocardial cell injury occur after coronary occlusion, but the relationship of these two events is unclear; specifically, it is unknown whether microvascular damage causes myocardial cell injury. Dogs were subjected to coronary occlusion for 20, 40, 60, 90 or 180 minutes, after which subendocardial and subepicardial biopsies were obtained for electron and light microscopy of 1-, u sections. Of 312 biopsies of ischemic myocardium, 181 showed myocardial cell injury with no microvascular damage; 131 showed myocardial cell injury and microvascular damage; but none showed microvascular damage without myocardial cell injury. Although ultrastructural evidence of myocardial cell damage was present in the subendocardium after 20-40 minutes of ischemia, ultrastructural evidence of microvascular damage was not prominent until 60-90 minutes after coronary artery occlusion. Morphologic ultrastructural evidence of microvascular damage lagged behind myocardial cell injury, suggesting that ultrastructural microvascular damage is not a primary cause of ultrastructural myocardial cell injury.

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.

Comparison Between the Effects of Nitroprusside and Nitroglycerin on Ischemic Injury during Acute Myocardial Infarction

SUMMARY This clinical and experimental investigation was designed to delineate and compare the relative effects of sodium nitroprusside (NP) and nitroglycerin (TNG) on electrocardiographic ischemic injury following acute myocardial infarction in patients and following coronary artery occlusion in dogs. Accordingy, in ten patients with anterior acute myocardial infarction and ST-segment elevation stable for 60 min, the effects ofNP (average 95 4g/min i.v.) and TNG (average 0.48 mg sublingually) were studied. The hemodynamic actions of NP and TNG were directionally similar. However, NP increased average ST-segment elevation (ST) by 2.0 ± 0.2 mm, while TNG reduced ST by 1.4 ± 0.4 mm. In order to clarify this disparity, coronary artery occlusions were carried out in 14 open-chest dogs. During control, NP and TNG time periods, epicardial electrograms were recorded and regional myocardial blood flow (RMBF) determined by the microsphe te N side increased ST-egment elevation from 4.6 ± 0.6 to 5.7 ± 0.6 mV (P < 0.05) and reduced RMBF from 35± 3 to 27 ± 2 mI/uul/100 g (P < 0.01) in the ischemic zones. In contrs, TNG reced; STsegment elevation from 4.9 ± 0.7 to 3.0 ± 0.7 mV (P < 0.05), Wle increasing RMBF to 43 ± 4 ml/mi/100 g (P < 0.05) and the endo/ epicardial ratio from 0.57 ± 0.06 to 0.69 ± 0.07 (P < 0.01). Although TNG and NP exhibit similar hemodynamic effects, TNG reduced electrocardiographic ischemic injury, at least in part, by increasing perfusion of the ischemic areas and redistriutng it favorably, while NP increased electrocardiographic iscbemic injury, at least in part, by reducing perfusion. Therefore, TNG seems preferable to NP for reducing preload and afterload in ts during the early phase of acute myocardial infarction.

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.

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.

Modification of Myocardial Infarction Size After Coronary Occlusion

Abstract Several pharmacologic and hemodynamic interventions were found to alter acute ischemic injury of the myocardium and subsequent necrosis after coronary occlusion. Reduction in myocardial da...

Reduction of Experimental Myocardial Infarct Size by Corticosteroid Administration

The influence of the administration of pharmacologic doses of hydrocortisone on the extent and severity of acute myocardial ischemic injury and on subsequent necrosis after acute coronary occlusion was investigated in 28 dogs. In order to study acute myocardial injury, repeated epicardial electrocardiograms were recorded from 10 to 15 sites on the anterior surface of the left ventricle. Average ST segment elevation (ST) and the number of sites in which ST segment elevation exceeded 2 mV (NST), indices of the magnitude and extent of myocardial injury, respectively, were analyzed at 30 and 60 min after coronary occlusion. In the control group ST and NST did not change significantly in this time interval while in the treated group, which received 50 mg/kg hydrocortisone just after the 30 min recording, ST fell from 3.5+/-0.8 to 1.1+/-0.4 mV (P<0.01) and NST was reduced from 6.7+/-1.1 to 1.4+/-0.8 (P<0.01). In order to study the influence of hydrocortisone on necrosis, epicardial ST segment elevation 15 min after coronary occlusion was compared to myocardial creatine phosphokinase activity (CPK) and histologic appearance 24 h later in each site. In a control group (14 dogs) a relationship was established between ST segment elevation at 15 min (in millivolts) and CPK activity (in international units per milligram of protein) 24 h later: log CPK = -0.0611ST + 1.26 (N = 102 specimens, r = -0.79). In the treated groups, hydrocortisone (50 mg/kg i.v.) was given either at 30 min after occlusion (seven dogs) or at 6 h after occlusion (six dogs). Both groups received supplementary doses of hydrocortisone (25 mg/kg) 12 h after occlusion. The two treated groups exhibited less CPK depression than that expected from ST segment elevation at each site, with slopes of the regression lines which were significantly less steep: log CPK = -0.0288ST + 1.26 (N = 48, r = -0.71) and log CPK = -0.0321ST + 1.31 (N = 48, r = -0.76) in the (1/2) h and 6 h groups, respectively. Histologically, sites with ST segment elevations of less than 2 mV at 15 min after occlusion exhibited normal appearance 24 h later. Sites with ST segment elevations (> 2 mV) in the control group showed histologic changes compatible with early myocardial infarction in 96% of specimens, while this occurred only in 61% and 63% of specimens, respectively, in the treated groups, showing that over one third of the sites were protected from undergoing necrosis due to the intervening hydrocortisone treatment. Thus pharmacological doses of hydrocortisone prevent myocardial cells from progressing to ischemic necrosis even when administration is initiated 6 h after coronary occlusion.

Reduction by Cobra Venom Factor of Myocardial Necrosis after Coronary Artery Occlusion

Components of the complement system are known to play an important role in the cytolytic process and in chemotaxis of leukocytes. Cobra venom factor specifically cleaves C3 activity via activation of the alternative (properdin) complement pathway. It does not act directly on C3. If C3 is involved in tissue necrosis after ischemic injury, cobra venom factor might reduce tissue damage after acute coronary occlusion. Accordingly, in 14 control dogs occlusion of the left anterior descending artery was carried out for 24 h. Epicardial electrograms were recorded 15 min after occlusion, and 24 h later transmural specimens for creatine phosphokinase activity (CPK) and for histological analysis were obtained from the same sites. In another 14 experimental dogs, 20 U/kg cobra venom factor was given intravenously 30 min after occlusion. Serum complement levels fell within 2-4 h to <20% of normal. In the control dogs, the relationship between ST-segment elevation and CPK activity 24 h later was: log CPK = -0.06 ST + 1.48 (n = 111 specimens, 14 dogs, r = 0.77). In the experimental dogs, log CPK = -0.024 ST + 1.46 (n = 111 specimens, 14 dogs, r = 0.60), showing significantly different slopes (P < 0.001), i.e., less CPK depression for any level of ST-segment elevation. Histologically, 69 of 71 sites (97%) with ST-segment elevation exceeding 2 mV in the control dogs showed signs of necrosis 24 h later, whereas in the experimental group only 43 of 79 sites (54%) with abnormal ST-segment elevations showed signs of necrosis (P < 0.0005). At the same time, it was shown that the administration of cobra venom factor did not alter cardiac performance, collateral blood flow to the ischemic myocardium or the clotting system, but infiltration of polymorphonuclear leukocytes into the myocardium was decreased. It is concluded that cobra venom factor, by reducing the amount of C3 and C5 substrate available for chemotactic factor generation, or other as yet undefined mechanisms, protects the ischemic myocardium from undergoing necrosis, as judged by histology and local CPK activity. Hence, a new approach to limiting the extent of myocardial infarcts after experimental coronary occlusion, based upon inhibition of complement-dependent inflammatory processes, is demonstrated.