Modification of experimental myocardial infarct size by cardiac drugs

Modification of Experimental Myocardial Infarct Size by Cardiac Drugs

PRITPAL S. PUN, MD, FACC Detroit, Michigan

From the Department of Medicine, Wayne State University School of Medicine, and Division of Cardiology, Detroit General Hospital, Detroit, Mich. This work was supported by a grant from the Michigan Heart Association, the estate of Stanley E. Kaminski through Wayne State University School of Medicine and Detroit General Hospital Research Corporation, Detroit Mich. Manuscript accepted August 9, 1973. Address for reprints: P&pal S. Puri. MD, Department of Medicine, Wayne State University School of Medicine, 540 E. Canfield. Detroit, Mich. 48207.

After occlusion of a coronary artery in dogs, regknally ischemk myocardium was delineated by means of a strain gauge-tipped, two pronged catheter probe that measures myocardial fiber shortening. The curves of contraction were sensitive to the effects of &hernia. A central zone of complete ischemia was identified as the region in which fiber shortening was lost and replaced by passive fiber lengthening. As the probe was inched away from the center toward the periphery, an intermediate zone of incomplete ischemfa was defined as the region in which contractility was partially dimlnished but not lost. It was assumed that a shtft in oxygen balance induced by an intervention will be reflected as a change in contractflfty of the intermediate zone. Accordingly, the intermedlate zone was used as the test zone to evaluate effects of drugs on the extent of regionally ischemk myocardlum. lsoproterenol initially augmented contractility of ,the intermediate zone but, with continued infusion, a secondary reduction in coritractllity became evident at 30 to 45 minutes. Norepinephrlne augmented contractility of the intermediate zone and this effect persisted through the 1 hour observation period. Ouabain similarly increased the vekcfty of shortening of the intermediate zone. An increase in left ventricular afterload induced by methoxamine resulted in loss of contractility and Its replacement by fiber lengthening in the intermedlate zone. These findings indicate that lsoproterenol and methoxamine can fncrease the extent of noncontracting ischemic myocardium and, hence, infarct size. Norepinephrine and ouabain do not exert this effect.

Drugs that augment myocardial contractility or increase arterial pressure, or both, continue to be used to treat pump failure of the heart complicating acute myocardial infarction.1-5 But the increases in both myocardial contractile state6 and myocardial wall tension7 induce an increase in myocardial oxygen consumption. If coronary circulation is impaired, it is postulated that such an increase in oxygen demand may so exceed the rate of oxygen delivery as to accentuate the severity of ischemia and result in an extension of the infaict.8lg Maroko et al.9 recently reported that the severity and extent of ischemit injury after experimental coronary occlusion are increased by cardiac stimulating drugs that increase myocardial oxygen consumption. These observations, based on a study of the magnitude and distribution of S-T segment elevation in the epicardial electrogram, contrast with earlier data from Sayen et aLlo demonstrating that levarterenol has a favorable effect on the ischemic area. Earlier preliminary studies from this laboratorysJ1J2 indicated that changes in contractility of the zone of partial ischemia provide a method of evaluating the effect of drugs on the size of a myocardial infarct. The size of the infarct is delineated by means of a previously described strain gauge-tipped catheter probe that measures myocar-

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FfGURE 1. Deflnition of the intermediate zone. of partial ischemia after coronary occlusion. In the noninfarcted myocardium, the curve of fiber shortening is inscribed in an upward direction during systole. In the central zone of complete ischemia where contractility is lost. the curve of fiber shortening is replaced by the inverted curve of pas&e fiber lengthening. As the probe is inched away from the center toward the periphery, an intermediate zone is delineated as the regfon In which velocity of shortening is diminished by at least 50 percent of the control value. LAD = left anterior descending coronary artery; LCA = left circumflex artery.

dial fiber shortening.4J3 The probe is used to map segmental changes in myocardial contraction over the surface of the left ventricle.4J4 Curves of cardiac contraction obtained with the strain gauge probe are extremely sensitive to the effects of ischemia.4J1 Coronary occlusion results in a rapid loss of myocardial fiber shortening and its replacement by passive fiber lengthening in the center of the ischemic myocardium.4,8J2 By inching the probe away from the center toward the periphery, one can define an intermediate zone of partial ischemia, interposed between infarcted and noninfarcted myocardial zones, in which contractility is diminished but not lost.8J1J2 The intermediate zone is used as the test zone to evaluate the effects of drugs on the severity and extent of ischemia because it is assumed that a drug-induced shift in oxygen balance in this zone will be reflected as a primary change in contractility of this region.8J1J2 Four cardiac drugs with contractile and hemodynamic effects that result in an increase in myocardial oxygen consumption were studied.

Methods Experiments were performed in 47 mongrel dogs weighing 15 to 22 kg and anesthetized with sodium pentobarbital (25 mg/kg body weight) given intravenously. The trachea was intubated and artificial ventilation, using room air, was instituted by means of a Harvard respirator pump. Thoracotomy was performed in the left fifth intercostal space and the pericardium was opened anterior to the left phrenic nerve. The left anterior descending coronary artery or one of its major branches was mobilized by dissection and a rubber-sheathed curved arterial clamp described previous-

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19 was used to produce intermittent occlusion. Left ventricular pressure was monitored through a stiff-walled catheter directly connected to a Statham P23Db transducer system and an Electronics for Medicine recorder. Zero level for pressure measurements was set at the mid-chest position. The first derivative of left ventricular pressure pulse (dP/dt) was obtained by means of a resistance-capacitance differentiating circuit. Left ventricular end-diastolic pressure was recorded using higher sensitivity at the end expiratory phase of the respiratory cycle. Regional contractility: A strain gauge catheter probe that measures myocardial fiber shortening, previously described in detai1,4J3 was used to measure segmental changes in contractility. Briefly, the device consists of two strain gauge-bearing prongs mounted on a stylette. There is a linear relation between the spacing of the prongs and strain in the gauges. The distance between the prongs is 2.5 mm, thus permitting study of curves of contraction over small segments of myocardium. The prongs were extended to the outside of the catheter and were directly inserted into the subepicardial surface of the left ventricular wall. Only the terminal points of the prongs were engaged into the myocardium.4J3J4 As the prongs follow the course of fiber shortening during systole, curves of contraction are inscribed in an upward direction on a beat to beat basis. The velocity of shortening was measured by drawing a tangent at isolength points relating the height of the curve to time.13 All recordings were made during expiration. Regional ischemia: Medium-sized areas of ischemia were produced by occluding one of the major branches of the left anterior descending coronary artery. With use of the strain gauge probe, control curves of contraction were obtained from the region supplied by the artery to be occluded. The probe was positioned in the center of this area and recordings were made continuously as the artery was occluded. In this manner, the exact time course of changes in the curves of contraction was studied. In 15 animals, after a period of occlusion ranging from 5 to 45 minutes, the occlusion was released and recovery of contractility in the ischemic zone studied. The region immediately surrounding the occluded artery (Fig. l), in which contractility was lost and replaced by the inverted curve (inscribed downward) of passive fiber lengthening was referred to as the central zone of complete ischemia. As the probe was inched away from the center toward the periphery, an intermediate zone was delineated in which contractility (velocity of shortening) was diminished by at least 50 percent of the control values but not completely lost. This represented the zone of partial ischemia or intermediate zone interposed between infarcted and noninfarcted regions. Changes in contractility of this zone induced by various drugs were used to assess the effect of these agents on the severity and extent of regionally ischemic myocardium and, hence, infarct size. It is assumed that a drug-induced shift in myocardial oxygen balance will affect the severity of ischemia and, hence, contractility of the intermediate zone. For example, a cardiac stimulating drug is expected to augment contractility through its positive inotropic action. However, should the increase in myocardial oxygen consumption resulting from the increased contractility exceed the oxygen supply, then the resulting negative oxygen balance produced by the increased severity of ischemia may result in a decline of contractility in the intermediate zone. Interventions with an oxygen-sparing action will have an opposite effect. Protocol: The procedure followed in all experiments was identical. The intermediate zone was delineated 15 minutes

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FIGURE 2. Effect of coronary occlusion and release of occlusion on the curves of contraction in 15 dogs. In the control state the curve of myocardial contraction is inscribed in an upward direction. Two seconds after occlusion, the late systolic portion of the curve begins to show inversion. At 10 seconds most of the curve except for the initiil component is inverted. At 15 seconds the entire curve is inverted, indicating loss of fiber shortening and its replacement by passive fiber lengthening. After release of coronary occlusion at 30 minutes, the original upward inscription of the curve associated with an initiil overshoot is restored, indicating recovery of contractilii. P = left ventricular pressure.

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after coronary occlusion when hemodynamic variables were stable. Drugs were administered at a constant rate by means of a power-driven infusion pump. Curves of contraction in the intermediate zone were continuously monitored. Recordings were made at 5 minute intervals for 30 to 60 minutes. Measurements were made on the average of 8 to 10 beats for each period of observation with reproducible results; those obtained at the time of optimal response were utilized for statistical analysis using Student’s paired t test. Each of the four drugs studied was tested in eight dogs; no dog received more than one drug. The following drugs were administered intravenously: isoproterenol (0.25 to 0.50 pg/ kg per min), norepinephrine (4.0 pg/min), ouabain (0.5 mg) and methoxamine (1.0 mg/min). Results In the control state the systolic curve of myocardial contraction (fiber shortening) is inscribed upward. During diastole, corresponding to myocardial relaxation and fiber lengthening, the curve is inscribed downward (Fig. 1 to 6). Coronary occlusion resulted in an immediate decline in the amplitude of the curve of contraction in the central zone (Fig. 2). At 2 to 5 seconds, the late systolic portion of the curve was inverted and at 15 to 30 seconds the entire curve was inscribed downward, indicating loss of systolic fiber shortening and its replacement by dyskinetic passive fiber lengthening. If coronary occlusion was released and flow restored at any time up to 45 minutes, the original upward inscription of the curve returned, indicating recovery of contractility (Fig. 2). This sequence of events, in which the curve of contraction becomes inverted with coronary occlusion and returns to the original upward inscription with release of occlusion, could be

Release of occlusion 30 min 90/2

repeated several times in the same animal. Reproducibility of these changes was established in 15 animals, thereby demonstrating that the curve of contraction is extremely sensitive to the effects of ischemia resulting from coronary occlusion. Changes in the curve of contraction could therefore be used to indicate the presence of myocardial ischemia. After occlusion of a major branch of the anterior descending coronary artery (Fig. l), a central zone of ischemia was identified as the region in which fiber shortening was lost and replaced by the inverted curve of fiber lengthening. The intermediate zone of partial ischemia interposed between infarcted and noninfarcted myocardial regions was delineated as the region in which velocity of shortening was diminished by at least 50 percent of the control values. The stability of the curves of contraction in the intermediate zone was established 15 to 60 minutes after coronary occlusion. Zsoproterenol (0.25 to 0.5 pg/kg per min) was administered to eight animals. The means f standard errors of changes in various indexes were as follows: Heart rate increased from an average of 113 f 3 to 148 f 4 beats/min (P
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cent (P KO.001). Such an increase in contractility persisted during the first 15 to 20 minutes of infusion. Thereafter, a secondary decline in velocity of shortening occurred in the test zone (Fig. 3). Thirty minutes after the onset of infusion, velocity of shortening decreased to 0.56 f 0.02 mm/set, a decline of 72 percent (P CO.001). Norepinephrine was infused in a dose of 4.0 pg/ min to eight animals (Fig. 4). Heart rate declined from 116 f 2 to 104 f 5 beats/min (P CO.01). Left ventricular systolic pressure increased from 110 f 2 to 135 f 3 mm Hg (P <0.005), whereas left ventricular end-diastolic pressure decreased. Before infusion of norepinephrine, velocity of shortening in the noninfarcted myocardium was 1.75 f 0.12 mm/set; in the intermediate zone it was 0.60 f 0.02 mm/set representing a decline of 66 percent (P CO.001) from the control level. After infusion, velocity of shortening in the intermediate zone increased to 1.47 f 0.13 mm/ set, an increase of 145 percent (P CO.001). This increase in velocity of shortening persisted throughout the 60 minute observation period. Unlike isoproterenol, norepinephrine did not cause a secondary decline in contractility of the intermediate zone. Ouabain (0.5 mg) was administered intravenously to eight animals. Sixty minutes after administration, heart rate decreased from 124 f 2 to 119 f 2 beats/ min. Left ventricular systolic pressure did not change significantly, whereas left ventricular end-diastolic pressure decreased slightly. In the control state, velocity of shortening was 1.6 f 0.04 mm/set in the noninfarcted region and 0.60 f 0.03 mmlsec in the intermediate zone, a reduction of 62 percent (P
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FIGURE 3. Effect of isoproterenol in eight dogs. An inverted curve of fiber lengthening is inscribed in the central zone (center of infarct). In the intermediate zone the curve of contraction shows a 87 percent decline in velocity of shortening (V) compared to the control value. Fifteen minutes after infusion of isoproterenol, velocity of shortening increased by 352 percent. At 30 minutes, a secondary reduction in velocity of shortening of 71 percent occurred, indicating a possible increase in the severity of ischemia in the intermediate zone.

the intermediate zone to 1.21 f 0.06 mm/set, an increase of 84 percent (P CO.001) (Fig. 5). Methoramine (1 mg/min) was administered to eight animals. Within 5 minutes left ventricular systolic pressure increased from 118 f 4 to 165 f 2 mm Hg (P
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FIGURE 4. Effect of norepinephrine in eight dogs. The intermediate zone showed a 71 percent reduction in velocity of shorten% compared to the control level. After infusion of norepinephrine, velocity of shortening increased by 80 percent at 30 minutes and 82 percent at 80 minutes. There was no secondary decline in contractilii.

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INTERMEDIATE ZONE PUABAIN (0 5mgm) (60min) (3Ominl

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FWURE 5. Effect of ouabain in eight dogs. In the intermediate zone velocity of shortening was 58 percent of the control value. Ouabain resulted in an increase in velocity of shortening of 25 percent at 30 minutes and 80 percent at 60 minutes. There was no secondary decline in contractility.

viable myocardial cells within the area of reversible ischemic injury. 18~22These cells constitute the twilight or intermediate zone bordering the infarcted myocardium. The ultimate fate of an ischemic myocardial cell is determined by several factors. With a mild degree of anoxia anaerobic glycolysis may occur and the myocardium may recover uneventfully.22,23 When ischemia is more severe, changes may occur in the mitochondria and reticulum. However, recovery is possible as long as nuclei and cell membranes are intact.22l24 The severity of ischemic injury is also determined by the state of the cells before injury, the level of endogenous glycogen stores, substrate availability25 and cellular environmental factors such as pH and ionic concentration.22,23

Pfmm

fig)

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n n

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lnturlon

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FfGURE S. Effect of methoxamine in eight dogs. The intermediate zone showed a 55 percent decline in velocii of shortening compared to the control value. After infusion of methoxamine, the curve became inverted, indicating loss of fiber shortening and its replacement by passive fiber lengthening. Loss of contractility in the intermediite zone suggests extension of the central zone.

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In this study, infarct size was delineated by means of a strain gauge-tipped catheter probe that measures myocardial fiber shortening.4J3 The probe records curves of myocardial contraction over localized segments of ventricular wa114J4; these curves of contractility are extremely sensitive to the effect of ischemia.4s8J4v26 After coronary occlusion, contractility immediately declines and the failure of contraction is complete within 15 to 30 seconds (Fig. 2). Inability to contract is associated with passive distension (fiber lengthening) as ischemic myocardium yields to intraventricular pressure. 27 This is reflected in the inversion or downward inscription of the curve in systole. If coronary occlusion is released and flow restored at any time within 45 minutes, myocardial contraction returns and the curve is restored to its original upward inscription (Fig. 2). This sequence of events is reproducible. The catheter probe can therefore be used to distinguish between the noncontracting central zone of complete ischemia and nonischemic myocardium on the basis of the direction in which the curve is inscribed in systole. The intermediate zone of partial ischemia that lies between infarcted and noninfarcted myocardium was defined as the region in which contractility was diminished but not completely lost (Fig. 1). Changes in contractility of the intermediate zone could therefore be used to evaluate the effect of cardiotonic drugs on the severity of ischemia. Thus, if a cardiac drug increases myocardial oxygen consumption in excess of oxygen delivery, then the resulting negative oxygen balance will lead to an increase in the degree of ischemia that, in the intermediate zone, will be reflected as an additional decline in contractility. The positive inotropic action of the cardiac stimulating drugs examined in our study-isoproterenol, norepinephrine and ouabain-initially augmented contractility of myocardial fibers in the intermediate zone, as indicated by increased velocity of shortening (Fig. 3 to 5). This effect was similar to that observed in the noninfarcted region. An increase in contractility of partially ischemic cells implies a concomitant increase in oxygen supply since enhanced contractility increases oxygen consumption.6 But during the 30 to 60 minute observation periods it became evident that these drugs had dissimilar effects.

minished coronary perfusion.2g The increase in heart rate that accompanied isoproterenol action also has an effect of increasing myocardial oxygen consumption.30 Other possible mechanisms are a direct effect whereby isoproterenol in large doses produces myocardial necrosis.31 This effect is unlikely with the doses used in our study. Increased lactate production by the drug may be a factor in depressing myocardial contractility.32 Maroko et a1.g reported that the additional myocardial sites showing S-T segment elevation after isoproterenol infusion also showed depression of myocardial creatine phosphokinase, and they attributed this finding to an increment in cell death. Such actions of isoproterenol on the myocardium of the intermediate zone will have the effect of extending the size of the infarct.

Norepinephrine

Norepinephrine did not result in a secondary decline in contractility of the intermediate zone (Fig. 4). The hemodynamic effects of this drug differed from those of isoproterenol since there was an increase in arterial pressure thereby insuring adequate coronary perfusion.33*34 Further, the decrease in heart rate permits an adequate diastolic filling period with its beneficial effect on cardiac output and coronary perfusion.35 Because of these actions of the drug, the increase in oxygen supply apparently kept pace with the increased myocardial oxygen consumption. These findings are consistent with the observations of Sayen et al.1° who reported that levarterenol results in an apparent shrinkage of the regionally ischemic myocardium. The difference in the effects of isoproterenol and norepinephrine on the severity of myocardial ischemia is also supported by the studies of Furuse et a1.,z8 who measured myocardial PO2 and PC02 by means of a mass spectrometer. They concluded that in the presence of coronary stenosis, isoproterenol failed to increase coronary flow enough to offset increased oxygen consumption and resulted in a marked reduction in myocardial PO2 and increase in PCO2. By contrast, norepinephrine led to an increase in coronary flow, augmentation of PO2 and a decrease in PCO2.

lsoproterenol

Ouabain

Continuous infusion of isoproterenol resulted in a secondary decline in contractility of the intermediate zone which became noticeable at 30 to 45 minutes (Fig. 3). The positive inotropic action of the drug was not diminished at this time, as was evident from changes in the nonischemic region, It is therefore reasonable to assume that the decline in contractility of the intermediate zone, despite the continued positive inotropic action of the drug, reflects an increase in the severity of ischemia of cells in this region.2s This increase may be due to either or both a progressive augmentation of oxygen consumption or decrease in oxygen supply due to decline in collateral flow or di-

Ouabain augmented contractility of the intermediate zone, and this effect persisted during the 60 minute observation period (Fig. 5). Unlike isoproterenol, ouabain did not produce a secondary decline in contractility. It is assumed therefore that digitalis does not induce a negative oxygen balance and consequently in situations comparable to our experiments may not have the effect of extending infarct size. The net effect of digitalis on myocardial oxygen consumption is determined by at least two opposing factors.36 In a failing heart it has an oxygen-sparing effect through its action in reducing myocardial wall tension. Further, by improving performance of the fail-

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ing ventricle it may increase coronary hence, oxygen delivery. An increase in contractility (V,,,) has the opposite effect ing oxygen consumption; in a nonfailing becomes the dominant effect of digitalis.

flow and, myocardial of increasheart this

DRUGS AND WJFARCT SIZE-PtJRI

Clinical Implications

Methoxamine Methoxamine led to inversion of the curve of contractility in the intermediate zone; that is, it resulted in loss of fiber shortening and its replacement by passive fiber lengthening (Fig. 6). Methoxamine stimulates alpha adrenergic receptors, resulting in vasoconstriction. The increase in arterial pressure may increase coronary perfusion.33 At the same time the increase in left ventricular afterload and, hence, myocardial wall tension increases myocardial oxygen consumption. The increase in oxygen demand was apparently greater than that which could be offset by the possible improved coronary perfusion. This led to worsening of the severity of ischemia in the intermediate zone. A marked increase in afterload may therefore extend the size of myocardial infarction. These findings are in contrast to the conclusions of Maroko et a1.,g who reported that methoxamine results in a decrease in the extent of ischemic injury.

Although one must be cautious in extrapolating the results of canine experiments to man, our observations have important clinical implications. Among cardiac stimulating drugs used in the treatment of pump failure in acute myocardial infarction, isoproterenol seems most likely to induce negative oxygen balance of a magnitude that may further reduce the already impaired contractility of partially ischemic myocardial fibers. This will have the effect of extending the nonfunctioning zone of ischemia. Norepinephrine and digitalis, when administered in doses comparable to those used in our study, are not likely to exert such deleterious effects. An excessive increase in left ventricular afterload such as that induced by methoxamine may result in extension of infarct. An increase in the noncontracting ischemic myocardium is likely to accentuate cardiac dysfunction and thereby set up a vicious cycle of decreasing coronary flow and enlarging infarct size. Acknowledgment I thank Ralph Williams and H. S. Buttar assistance.

for technical

References

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Gunnar RM, Loeb HS: Use of drugs in cardiogenic shock due to acute myocardial infarction. Circulation 45: 111 l-l 124, 1972 Work MJ, Schektt S, Klllip T: Heart failure complicating acute myocardbl infarction. Circulation 45: 1125-l 138, 1972 Swan HJC, Forrester JS, Danzlc R, et al: Power failure in acute mvocardiil infarction. Proc Cardiovasc Dis 12:578-599. 1970 Purl PS, Btng RJ: Effect of drugs on myocardial contractility in the intact dog and in experimental myocardial infarction. Basis for their use in cardiogenic shock. Am J Cardiol 21:888-893, 1988 Purl PS: Heart failure and shock in acute myocardial infarction. J Am Coll Emergency Physicians 2: 108- 110, 1973 Sonnenbllck EH, Ross J Jr, Covell JW, et al.: Velocity of contraction as a determinant of myocardial oxygen consumption. Am J Physiol209:919-927, 1985 Sarnoff SJ, Braunwakf E, Wekh GH Jr, et al: Hemodynamic determinants of the oxygen consumption of the heart with spe ctal reference to the tension-time index. Am J Physiol 192: 148-158, 1958 Purl PS, Buttar HS: Regional changes in myocardial contractility after coronary occlusion (abstr). Fed Proc 30:288, 197 1 Maroke PR, Kjekshus JK, Sobel BE, et al: Factors influencing infarct size following experimental coronary artery occlusions. Circulation 43:87-82, 1971 Sayen JJ, Katcher AH, Sheldon WF, et al: The effect of levarterenol on polarographic myocardial oxygen, the epicardial electrogram and contraction in non-ischemic dog hearts and experimental acute regional ischemia. Circ Res 8:109-128, 1980 Purl PS: Studiis on contractility in the zone of partial ischemia as a means of evaluating effects of cardiotonic drugs on the size of myocardial infarction (abstr). Clin Res 19:848, 197 1 Puri PS, Buttar HS: Recovery of myocardial contractility and high energy phosphates after extended periods of coronary occlusion followed by restoration of blood flow (abstr). Circulation 44: suppl lkll-213, 1971 Purl PS, Bing RJ: Evaluation of myocardial force-velocity relation in closed-chest dogs. Am J Physiol214:1273-1279, 1988 Purl PS. Blng RJ: Effects of glucagon on myocardttl contractility and hemodynamics in acute experimental myocardial infarction. Basis for its possible use in cardiogenic shock. Am Heart J 78: 880-888,1989 Page DL, Cauffleld JB, Kastor JA, et al: Myocardial changes

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associated with cardiogenic shock. N Engl J Med 285: 133-137, 1971 Harnaryan C, Bennett MA, Pentecost BL, et al: Quantitative study of infarcted myocardium in cardiogenic shock. Br Heart J 32:728-732, 1970 Sobel BE, Bresnahan OF, Shell WE, et al: Estimation of infarct size in man and its relation to prognosis. Circulation 48:840848, 1972 COX JL, McLaughlin WV, Flowers NC, et al: The ischemic zone surrounding acute myocardial infarction. Its morphology as detected by dehydrogenase staining. Am Heart J 78:850-859, 1988 Maroko PR, Libby P, Bloor CM, et al: Reduction by hyaluronk&se of myocardial necrosis following coronary artery occlusion. Circulation 48~430-437. 1972 Maroko PR, Libby P, Sobel BE, et al: Effects of glucose-insulinpottassium infusion on myocardial infarction following experimental coronary artery occlusion. Circulation 45: 1180-l 175, 1972 Maroko PR, Bernsteln EF, Libby P, et al: Effects of intraaortic balloon counterpulsation on the severity of myocardial ischemic injury following acute coronary occlusion. Circulation 45: 11501159,1972 Brachfeld N: Maintenance of cell viability. Circulation 40: suppl IV:IV-202-IV-215, 1989 Olson RE: Metabolic interventions in the treatment of infarcting myocardium. Circulation 40: suppl IV:IV-195-IV-20 1, 1989 Jennings RB, Sommers HM, Herdson PB, et al: lschemic injury of myocardium. Ann NY Acad Sci 158:81-78, 1989 Welsster AM, Kruger FA, Baba N, et al: Role of anaerobic metabolism in the preservation of functional capacity and structure of anoxic myocardium. J Clin Invest 47:403-418, 1988 Sayen JJ, Pelrce G, Katcher AH, et al: Correlation of intramyocardlal electrocardiograms with polarographic oxygen and contractility in the non-ischemic and regionally ischemic left ventricle. Circ Res 9:1288-1279, 1981 Tennant R, Wtggers CJ: The effect of coronary occlusion on myocardtl contraction. Am J Physiol 112:35 l-38 1, 1935 Furuse A, Brawley RK, Gott VL: Effects of isoproterenol, I-norepinephrine and glucagon on myocardial gas tensions in animals with coronary artery stenosis (abstr). Circulation 48: suppl ll:ll101.1972

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29. Kattue AA, Major MC, Gregg DE: Some determinants of coronary collateral blood flow in the open-chest dog. Circ Res 7: 828-842, 1959 3Q. Braunwald E: Control of myocardial oxygen consumption: physiologii and clinical considerations. Am J Cardiol 27:418-432, 1971 31. Rona G, Chappell CL, Balazs T, et al: An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. Arch Pathol87:443-455, 1959 32. Kuhn LA, Kline HJ, Goodman P, et al: Effects of isoproterenol on hemodynamic alterations, myocardhl metabolism, and coronary flow in experimental acute myocardial infarctlon with shock. Am Heart J 77:772-783, 1989

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33. Braunwald E, Sarnotf SJ, Case RB, et al: Hemodynamic determinants of coronary flow: effects of changes in aortic pressure and cardiic output on the relationship between myocardiil oxygen consumption and coronary flow. Am J Physiol 192: 157183.1958 34. W@ers CF: The interplay of coronary vascular resistance and myocardial compression in regulating coronary flow. Circ Res 2:271-279, 1954 35. De&on AB, Green HD: Effects of autonomic nerves and their mediators on the coronary circulation and myocardial contraction. Circ Res 8833-843, 1958 38. Braunwakl E: Thirteenth Bowdiich lecture. The determinants of myocardlal oxygen consumption. Physiologist 12:85-93, 1989

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