Myocardial oxygen utilization after reversible global ischemia

J

THORAC CARDIOVASC SURG

1990;100:210-20

Myocardial oxygen utilization after reversible global ischemia We tested in 20 sheep the hypothesis that oxygen consumption increases after reversible, global myocardial ischemia. Left ventricular oxygen consumption before and after 25 minutes of warm (370 C) global ischemia was linearly related to a function (integral) of left ventricular circumferential systolic waD stress, altered by changing afterload. The relation is expressed in the two regression equations: LVoz (preischemic) = 1.06 . SSI + 16.8 (n = 129; r = 0.79); LVoz (postischemic) = 4.35 . SSI + 5.6 (n = 89; r = 0.65). The fourfold increase in slope (4.35 versus 1.06) indicates (p = 0.0001) a massive increase of oxygen consumption in postischemic, globaUy "stunned" myocardium. The inferences are that g10baUy stunned myocardium causes severe impairment of oxygen utilization efficiency, and increased vulnerability to further ischemia if coronary vessels are diseased.

Joseph E. Bavaria, MD, Satoshi Furukawa, MD, Gerhard Kreiner, MD, Mark B. Ratcliffe, MD, James Streicher, BSE, Daniel K. Bogen, MD, PhD, and 1. Henry Edmunds, Jr., MD, Philadelphia, Pa.

h e term stunned myocardium describes reperfused myocardium that is noncontractile or poorly contractile after ischemia that does not cause necrosis. I The ischemic injury may be regional (temporary occlusion of one or more coronary arteries) or global. Heyndricks and associates/ showed that 5 minutes of warm, .regional ischemia in dogs causes immediate loss of myocardial systolic wall thickening for nearly 6 hours. Longer periods of reversible, regional ischemia may depress myocardial contractility for several days.' Global ischemia for periods insufficient to cause necrosis also profoundly reduces ventricular contractile force." Stunned myocardium is associated with reduced concentrations of myocardial high-energy phosphates and adenine nucleotides.v'' depression of sarcoplasmic reticulum function," and specific ultrastructural changes?that From the Division of Cardiothoracic Surgery and the Department of Bioengineering, Universityof Pennsylvania, Philadelphia, Pa. Supported by the National Heart, Lung and BloodInstitute, National Institutes of Health No. HL36308. Received for publicationApril 21, 1989. Accepted for publicationSept. 15, 1989. Address for reprints: Joseph E. Bavaria, MD, c/o L. Henry Edmunds, Jr., MD, Division of Cardiothoracic Surgery, Hospital of the Universityof Pennsylvania, 34th and Spruce Streets, Philadelphia, PA 19104.

12/1;'16833

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slowly resolve as adenosine triphosphate concentrations return to normal.3,6 Although reperfusion restores oxygensupplyand eventuallymyocardial function.t resultsof regional?"! and perfusedheart studies12-14 of postischemic myocardial oxygen utilization generally. indicate unchanged or modestly increased oxygen consumption. Data are not availablefor the working, globallyischemic heart in vivo. These studies tested the hypothesis that reversible global ischemia depresses myocardial contractility and increases myocardial oxygen consumption in the intact, working ovine heart. Methods Twenty healthy Dorsett sheep (mean 35.3 ± 5.4 kg) were studied in compliance with National Institutes of Health Publication No. 85-23 as revised in 1985. Two operations, both with thiopental sodium (25 mg/kg intravenously) and halothane (0.5%to 1.5%) anesthesia, were performed in all sheep. Animals were premedicated with atropine (1 mg intravenously), intubated, and their lungs mechanically ventilated at 12 to 20 cycles per minute with tidal volumes between 12 and 18 ml/kg with 100% oxygen (Harvard Model 607, Harvard Apparatus Co., Cambridge, Mass.). During operation, 5% dextrose in 0.9N saline was infused at 5 mljkg/hr and was used to replace shed

blood.

Preliminary instrumentation. Two ultrasonic flow probes and one hemispheric piezoelectric crystal were placed through a left thoracotomy incision under sterile conditions. One 4 to 6 mm flow probe (Transonic Inc., Ithaca, N.Y.) was placed

Volume 100

Stress versus oxygen consumption in ischemic heart

Number 2 August 1990

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Fig. 1. Schematic drawing of experimental preparation illustrating placement of sonomicrometer crystals across two equatorial axes, the longitudinal axis, and across the ventricular wall. The aortic root occluder balloon and aortic flow probe are also illustrated. The preparation also included an ultrasonic flow probe around the left main coronary artery, an oximeter catheter in the coronary sinus, and a Millar catheter in the left ventricle. RV, Right ventricle. around the left main coronary artery at its origin from the aorta. A 16 to 20 mm flow probe (Transonic Inc.) was placed around the aorta downstream from the coronary ostia but upstream to the origin of the innominate artery. The left hemiazygos vein, which drains into the coronary sinus, was ligated at the pericardium. A 6 mm hemispheric crystal (3 mHz; model H25-C; Sonotek Inc., Delmar, Calif.) was sutured to the base of the heart between the aorta and the main pulmonary artery (Fig. I). The chest was closed with running sutures and drainage. Cloramphenicol (1 gm intravenously) was given before and once after operation. Further instrumentation. A chest roentgenogram was obtained I to 2 weeks after thoracotomy to verify the absence of pneumonia. After induction of anesthesia and endotracheal intubation, the heart was exposed through a median sternotomy incision. One apical and three pairs of sonomicrometry crystals were placed on the left ventricle (Fig. I). The longitudinal axis (base to apex) and two equatorial axes (anteroposterior; septum-free wall) at right angles to each other were measured with fivehemispheric crystals (6 mm, 3 mHz, model H25-C, Sonotek Inc.) and one plunge crystal (5 mHz, model 102 SL, Sonotek Inc.) placed onto the right ventricular, midequatorial surface of the interventricular septum." Wall thickness was measured by

one epicardial crystal disk (5 mm, 5 mHz, model lIOWT, Sonotek Inc.) and a plunge crystal placed against the endocardial surface between the septum and the anterior papillary muscle.P The surface electrocardiogram was continuously monitored (model ES-lOOOB, Gould Inc., Cleveland, Ohio). Micromanometer tip transducers (5F, mode SPC-350, Millar Instruments Inc., Houston, Tex.) were placed in the left ventricle through the ventricular apex, and in the descending aorta and right atrium. A temperature probe (Swan-Ganz, Edwards Critical Care, Santa Ana, Calif.) was inserted into the inferior vena cava. A flexible fiberoptic oxygen saturation catheter (P711 0, Oximextrix Co., Mountainview, Calif.) was introduced into the coronary sinus. A small (12 ml) intraaortic impedance balloon (Datascope Inc., Oakland, N.J.) was introduced through the right carotid artery" and positioned in the ascending aorta downstream to the flow probe to measure end-systolic elastance. A second small balloon (22 ml, Datascope Inc.) was inserted into the descending thoracic aorta through the left femoral artery to vary afterload. Experimental protocol. Data were obtained before and after 25 minutes of warm (37 0 C) myocardial ischemia. After instrumentation, afterload was randomly changed by partial

The Journal of Thoracic and Cardiovascular Surgery

2 1 2 Bavaria et al.

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inflation of the descending thoracic aortic impedance balloon. After each change in afterload, a 90-second stabilization interval preceded a 20-second period of recording data. Thus, for each change in afterload, left ventricular oxygen consumption (L Vo 2) and the dynamic changes in left ventricular pressure and dimensions were recorded. End-systolic elastance, a measure of contractile state, was determined by a series of four transient (one beat) inflations of the balloon during a lO-second interval in the aortic root!" while

the balloon in the descending aorta was deflated. These inflations were timed to produce a series of aortic occlusions at different points during ventricular ejection (Fig. 2). End-systolic elastance was measured once in each sheep before ischemia. After 5 to 13 measurements at different afterloads in the normal heart, heparin (15,000 U intravenously) was given and the animal was cannulated for cardiopulmonary bypass. The bypass circuit consisted of a venous reservoir (Johnson & Johnson Cardiovascular, Anaheim, Calif.), electromagnetic

Volume 100

Stress versus oxygen consumption in ischemic heart

Number 2 August 1990

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Fig. 3. Calibration of transonic (ultrasound) flow probe used to measure left main coronary blood against graduated cylinder measurements of flow in milliliters per minute. The probe was placed on carotid and superficial femoral arteries of separate sheep, and flow probe measurements (y) were plotted against collected volumes (x). The regression equation is: y = 1.02 (x) - 0.45; r = 0.994, N = 60. flow probe (model TX-20, Bio-Medicus Inc., Eden Prairie, Minn.), combined heat exchanger-hollow fiber membrane oxygenator (0.8 m Z, Maxima, Johnson & Johnson Cardiovascular), and centrifugal blood pump (model 520-C, Bio-Medicus Inc.). The circuit was primed with I L of Hetastarch (DuPont Critical Care Inc., Waukegan, III.) and 400 ml of 0.9N saline. A 32F to 40F two-stage venous cannula (Sarns, Inc., Ann Arbor, Mich.) was inserted into the right atrium; A 16F catheter (United States Catheter and Instrument Co., Glens Falls, N.Y.) was inserted into the right femoral artery. After initiation of cardiopulmonary bypass at 37° C, the aorta was clamped for 25 minutes. Recorded left main coronary flowfell to zero. The left ventricle was vented through the apex during both the ischemic and the reperfusion periods. Injury to the right ventricle was mitigated by placing a cold ice-slush pack on the right ventricular free wall during the ischemic period. After release of the aortic clamp, the heart was reperfused on bypass for 35 minutes. The heart was electrically defibrillated after 3 to 5 minutes of reperfusion. During reperfusion and weaning from bypass, epinephrine (0.35 ~g/kg/min) and lidocaine (1 mg/rnin) were infused. All drugs were stopped at least 10 minutes before the postischemic heart was studied. End-systolic elastance of postischemic hearts was measured once by a modification of the single beat method.v!" Postischemic measurements of LVo z and ventricular mechanics at

various left ventricular afterloads were made 47 to 165 minutes (mean 94 ± 13.7 SD*) after release of the aortic crossclamp and were continued until cardiac function deteriorated or arrhythmias developed. At that time the animal was exsanguinated and the heart was excised. The right ventricle was trimmed away and the left ventricle was weighed. Direct measurements of wall thickness at the apex, free wall, septum, and posterior wall were obtained and compared with the recorded anterior wall thickness signal. The base wall thickness calculation was 0.55 X anterior wall thickness signal.!? Calibration. Left ventricular axis measurements made from sonomicrometric crystals (Y) were calibrated against postmortem ventricular balloon measurements (X) as previously reported (Y = 4.85 ml + 0.85 X; r = 0.85; n = 101).4 Arterial blood flow measured with the 4 to 6 mm ultrasound transducer (Y) was calibrated against direct collection of blood from similar diameter carotid and superficial femoral arteries in separate sheep (Fig. 3). In sheep, the left coronary artery exclusively supplies the left ventricle and septum and the coronary sinus drains most of the left ventricle. 18 There is minimal overlap in the coronary circulations to the two ventricles's: thus measurements of the left main coronary blood represent total blood flow to the left ventricle. Fiberoptic oxygen saturations were cali*SD

= Standard deviation.

2 14

The Journal of Thoracic and Cardiovascular Surgery

Bavaria et al.

Table I. Hemodynamic and metabolic measurements in pre- and postischemic hearts Variable

Heart rate Systolic cycle length (msec) Diastolic cyclelength (msec) Peak LVP (mm Hg) ED LVP (mm Hg) LV ESV (mt) LV EDV (ml) Ees (mm Hg/rnl) (n = 26)* CAF (mljlOO gm/rnin) A-V 02 Diff. (rnl/dl) LV02 (ili/IOO gm/beat) LV SSI (mm Hg/sec) LV TSI (mm Hg/sec)

Preischemic In = 129)

Postischemic In = 89)

129 ± 310.7 ± 155.0 ± 72.9 ± 4.9 ± 18.2 ± 27.5 ± 8.3 ± 84.9 ± 5.3 ± 34.3 ± 16.5 ± 18.6 ±

92 ± 263.6 ± 390.0 ± 51.8 ± 5.3 ± 27.1 ± 33.9 ± 5.7 ± 109.9 ± 4.4 ± 50.0 ± 10.2 ± 13.8 ±

2.1 5 5 2.4 0.6 0.7 1.0 1.7

2.3 0.1 1.0 0.8 0.8

p

0.001 0.001 0.001 0.001 0.73 0.0001 0.0001 0.19 0.001 0.01 0.0001 0.0001 0.001

7.8 7 21 1.2 0.7 0.8 0.9 0.9 5.8 0.1 2.9 0.4 0.6

Data from all experiments (n = ZO sheep) in both preischemic (16 sheep) and postischemic (10 sheep) states. Values expressed as mean ± standard error of the mean. LV. left ventricle; LVP, left ventricular pressure; ED, end-diastolic; E5V, end-systolic volume; EDV, end-diastolic volume; Ees, end-systolic elastance; CAF, left main coronary arterial blood flow; A-V 02 Diff., left ventricular oxygen arteriovenous difference; LVo z, left ventricular oxygen consumption; 551, systolic stress integral; T51, total (throughout the cardiac cycle) stress integral. • n, Preischemic = 16; n, postischemic = 10.

bra ted against oximeter readings (model 168, Corning Medical Inc., Medfield, Mass.) before and several times during experiment. All pressure transducers were calibrated immediately before experiments and checked for drift during the studies. Verification of steady state. In six additional sheep, measurements of oxygen consumption and the integral of systolic stress were obtained during a 5-minute period after a change in afterload both before and after 25 minutes of warm (37 0 C) ischemia. For preischemic hearts, the mean differences between the 9Q-second measurements and five to nine (total 35) measurements after 90 seconds in each sheep were -0.8 ± 3.2 (p = NS*) for LVo 2 and -0.1 ± 0.7 (p = NS) for systolic stress integral (SSI). For postischemic hearts, the mean differences between the 9Q-second measurements and four to seven (total 29) measurements in each sheep made after 90 seconds were -2.8 ± 8.3 (p = NS) and -0.8 ± 2.2 (p = NS). Data collection. During each 2Q-second collection period, four left ventricular dimension signals, left ventricular pressure, right atrial pressure, aortic pressure, aortic and left main coronary flow, electrocardiograph, and coronary sinus oxygen saturation'? were simultaneously recorded on a 16-channel analog electrostatic strip-chart recorder (Gould ES-I000B). Data were digitally sampled every 10 msec with a 12-pit, 16-channel analog to digital converter (Tecmar Lab Master, Solon, Ohio) in a Sperry PC/AT computer. Calculations. Stresses were calculated along various axes with use of the generalized ellipsoidal model.v17,20-23,+ SSIs and total stress integrals (TSIs) were calculated by integrating stress throughout systole (SSI) and the entire cardiac cycle (TSI). End-systole and end-diastole were determined as previously reported.t" Oxygen consumption of the left ventricle was calculated as the product of steady state (10 seconds) aorta-left coronary sinus oxygen difference (milliliters of oxygen per deciliter) and mean left main coronary arterial blood flow measured over 10 *NS = Not significant. tRadcliffe MB, Bogen OK. Personal communication.

seconds (ml/rnin). Hemoglobin concentration and aortic blood oxygen saturation were measured intermittently before, during, and after data collection periods (model 168, Corning Medical Inc.). Oxygen content (Co) in arterial and coronary sinus blood was calculated as follows: Co (rnl/dl) = Hemoglobin (gm) X K X Oxygen saturation (%). K (1.35) is the oxyhemoglobin coefficient for sheep blood (hemoglobin 11.5 gm, 37 0 C sea leve!).25 Plasma oxygen is ignored. LVo 2 is normalized to microliters per 100 gm per beat by dividing by postmortem left ventricular weight and heart rate and multiplying by 105. Maximal end-systolic elastance (Ees), which is the slope of the end-systolic pressure-volume relationship.P is calculated according to the Grossman-? equation, Pes

= Ees (Ves -

Vo)

where Pes and Ves are end-systolic pressure and end-systolic volume, respectively. Ees, the slope of the end-systolic pressurevolume relationship, is calculated from four pressure-volume loops at different afterloads with use of a shooting point numerical iterative method.P' Vo, volume at zero pressure, is determined by extrapolation of Ees. Statistics. Statistical analysis of preischemic and postischemic data was performed with the use of standard commercially available software (BBN Software RS / I). Standard tests for normality and Student's t tests were employed. Correlation coefficients (r) were calculated by RS/l regression routines. Confidence limits of 95% on the regression equations were performed by means of Systat (Systat, Inc., Evanston, III.). Regression equations were compared using Fisher's Z transformation.

Results

Five to 13 simultaneous measurements of LVoz and left ventricular systoliccircumferential wall stress (SSI) were made in each of 20 sheep. In 16sheep,a total of 129 measurements were made in preischemichearts. In sixof these sheep and in four additional sheep, a total of 89

Volume 100 Number 2 August 1990

Stress versus oxygen consumption in ischemic heart

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Fig. 4. Linear regression plots with 95% confidence limits for left main coronary arterial blood flow (CAF) and arteriovenous oxygen difference (AV-02 difference) as a function of circumferential SSI in preischemic and postischemic hearts. For preischemic hearts, regression equations are (A) CAF (ml/rnin) = 63.9 + 1.27 SSI; n = 129; r = 0.41; and (B)AV-o z difference (ml/dl/l00 gm) = 0.45 + 0.0048 SSI; n = 129;r = 0.42. For postischemic hearts (C), CAF = 31.0 + 7.72 SSI; n = 89; r = 0.57; and (D) AV-Oz difference = 0.48 - 0.0034 SSI; n = 89; r = 0.34.

measurements were made after 25 minutes of warm ischemia. Thus, in six sheep, 53 preischemic and 56 postischemic measurements were made in the same sheep. Mean left ventricular weight of 20 sheep was

115.4 ± 12.8gm. Heart rate decreased significantlyfrom a mean of 129 before ischemia to 92 afterward (Table I). The duration of systole actually decreased in postischemic hearts; however, the duration of diastole more than doubled and increased from 33% of the cardiac cycle to

2 16

The Journal of Thoracic and Cardiovascular Surgery

Bavaria et al.

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Fig. 5. Linear regression plots with 95% confidence limits for left ventricular oxygen consumption (LVo2) as a function of circumferential SSI in preischemic (A) and postischemic hearts (B). A, LVo 2 = 16.8 + 1.06 SSI; n = 129; r = 0.79. B, LVo 2 = 5.6+ 4.35 SSI; n = 89; r = 0.65.; p = 0.006; p = 0.0001 for regression slopes by two-tailed Fisher's Z transformation; p = not significant for intercepts. An exponential curve (ae- bx) fitted to preischemic data produces: LVo2 = 21.4 * exp(0.027 SSJ);n = 129;r = 0.97. Forpostischemicdata, LVo2 = 23.7 * exp (0.0697 SSI); n = 89; r = 0.92; P = 0.0001.

60%.Both systolicand total cyclelength did not vary with changes in afterload but varied significantly between preischemic and postischemichearts and between sheep. As previously observed,"warm ischemia increased left ventricular end-systolic and end-diastolic volumes and reduced peak left ventricular systolic pressure without significantlyincreasing left ventricular end-diastolicpressure (Table I). Measurements of Ees indicate that warm ischemia reduced ventricular contractility. In pooled studies, the difference in Ees before and after ischemia was not statistically significant. As expected, mean SSI and mean TSI decreased in postischemichearts (Table I). Mean coronary blood flowincreased and mean arteriovenous oxygen difference decreased in postischemic hearts (Table I). When these measurements are related to SSI (Fig. 4), striking differences between preischemic and postischemic hearts are evident. In preischemic hearts, both coronary blood flow and arteriovenous oxygen difference increased gradually with increasing left ventricular stress. The data are more scattered in postischemic hearts, but the most striking change is the steep increase in coronary bloodflow (reactive hyperemia) with increasing SSI.

Mean LVo 2 increasedin postischemichearts (Table I). The magnitude of the increase is not apparent until LV02 is plotted against SSI, however, as Fig. 5 shows, the slope of the LVo2/SSI linear regression increased by a factor of four. The difference in slopes between preischemic experiments (n = 16) and postischemic experiments (n = 10) is highly significant (p = 0.00(1). Regression equations relating left ventricular oxygen consumption and left ventricular wall stress during the entire cardiac cycle for preischemic and postischemic hearts have been calculated, as have regressionequations relating LVo 2 and end-diastolic volume and peak ventricular pressure (data not shown). Correlation coefficients do not improve over LV02/SSI. Also, integrating variously derived equations for left ventricular stress21-23,* during systole in the circumferential and meridional directions does not improve correlation coefficientsmore than those obtained with the use of the Falsetti equation-" for circumferential SSI. The relationshipsbetween LV02consumptionand circumferential SSI for individual sheep are presented in *Radcliffe MD, Bogen DK. Personal communication.

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Stress versus oxygen consumption in ischemic heart

217

Table II. Regression slopes LVoJ/SSI (Y/Xj calculated for individual preischemic and postischemic hearts Experiment No. 1 2 3 4 5 6 Subtotal

7 8 9 10 11 12 13 14 15 16 17 18 19 20 Total

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Postischemia

n

Y-intercept

LVo2/SS1

r

n

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LVol/SSI

r

7 10 13 5 7 _1_1 53 7 7 7 8 5 9 9 8 7 9

-27.6 -1.8 26.9 18.1 1.5 18.0 5.9 ± 8.0 12.9 7.9 13.3 -4.8 10.8 -23.4 25.8 13.8 7.1 27.2

4.37 2.87 0.81 0.45 1.43 1.14 1.85 ± 0.61 1.20 3.11 1.80 3.54 3.58 4.93 0.57 0.81 1.21 1.00

0.98 0.97 0.67 0.71 0.95 0.86

11 9 13 9 7

3.23 5.67 4.86 9.12 1.67 7.83 5.40 ± 0.61

0.85 0.74 0.59 0.98 0.74 0.87

56

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5 11 9 8 89

7.1 -6.3 -12.2 40.9 3.1 ± 6.6

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129

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Preischemic and postischemic data were obtained in experiments I to 6. LVo z, Left ventricular oxygen consumption ("II I00 grrr/beat); 55I, circumferential systolic stress-integral (mm Hg . sec); n. number of measurements; r, correlation coefficient. Mean ± standard error of the mean.

Table II. Slopes for individual sheep vary widely both before and after ischemia, but with one exception in each group, all data within individual sheep are strongly correlated. Six sheep had measurements made before and after ischemia. The mean Ees of these six sheep before ischemia was 11.02 ± 3.64 mm Hg/rnl (range 5.50 to 29.02) and was 4.41 ± 0.97 (range 1.99 to 6.79) after ischemia (p = 0.13). Separate linear regression equations and pooled data for these six sheep are presented in Table II and Fig. 6 and confirm the results obtained from all studies.

Discussion Many variables affect myocardial oxygen consumption, but the most important are stroke work, contractile state, and heart rate. In these studies, the effect of heart rate is removed by calculating oxygen consumption per beat. Weber and Janicki?" demonstrated the close correlation between myocardial oxygen consumption and the integral of systolic force in isolated canine hearts at different developed pressures and shortening loads. Suga and associates'P: 3I showed that myocardial oxygen consumption in excised, normal, cross-circulated canine hearts correlates most closely with systolic pressurevolume area, which is defined as the area within the pres-

sure-volume loop (external work) and a triangular area to the left of this loop that relates to end-systolic potential energy. However, neither estimate of left ventricular systolic energy output is established in poorly contracting, diseased ventricles nor has. been studied in hearts with impaired oxygen utilization. Calculation of systolic pressure volume area requires determination of volume at zero pressure from extrapolation of the end-systolic elastance line; in poorly contracting hearts, this extrapolation produces widely varying zero pressure volumes. Therefore we chose to relate LVo 2 to the SSI, with the realization that this measure of ventricular energy output is also untested in poorly contracting ventricles. In sheep, 25 minutes of warm, global ischemia probably produces a heterogeneous injury of mostly reversibly injured cells and some irreversibly damaged myocytes. Jennings-' and DeBoer33 and their associates found the first evidence of irreversible necrosis in dogs 18 to 22 minutes after occlusion of the nutrient coronary artery. Reversibility of ischemic damage has not been assessed after global ischemia; however, the fact that the ovine heart recovers after 25 minutes of warm ischemia and sustains the circulation without exogenous pharmacologic or mechanical support shows that the injury is reversible and that the myocardium was "stunned" and not killed.

The Journal of Thoracic and Cardiovascular Surgery

2 1 8 Bavaria et af.

150

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Fig. 6. Linear regression plots with 95% confidence limits for LV0 2 as a function of SSI before (A)and after ischemia (B)in six sheep. A,LVo 2 = 14.2 + 1.21 SSI;n = 53;r = 0.81;B,LVo2 = 9.83 + 4.17 SSI;n = 56,r = 0.58;p = 0.001 for regression slopes by two-tailed Fisher's Z transformation; p = not significant for intercepts.

The slopesof both the LVo 2/SSI relationshipand Ees vary widelybetweenpreischemicand postischemic sheep. Weber and Janicki" also observed marked variation in the myocardial oxygen consumption/total force integral between normal dogs. In both studies the correlation between oxygen consumption and myocardial force or stress within individual animals is high, however. Variations between animals are most likelydue to variationsin contractile state and internal work or potential energy.30. 31 The heterogeneous injury producedby warm ischemia, a period of bypass, and several hours of anesthesia and surgical exposureexplain the variations in LVo 2/SSI slopes of postischemic hearts. Anesthesia, operations, instrumentation, and manipulation of the heart probably alter the contractile state in the preischemic hearts as well. Nevertheless, our ability to make multiple measurements at different afterloads during relatively short periods permits calculation of regression equations with reasonably small confidence limits and good correlation coefficients. Most likely the LV02/SSI slope of the normal ovineheart is even lessthan the 1.06 SSI that wefind in the surgicallymanipulated preischemic heart. Our postischemicmeasurements were made 47 to 165 (mean 94) minutes after the aortic crossclamp was

released.We were not able to obtain serial measurements after ischemia in these sheep and therefore do not know when the LVo 2/SSI slope begins to decrease. Since reversible ischemia appears to impair energy utilization, recovery of the LVo 2/SSI slopemay parallel recovery of contractile function; however, no data are available. Regional studies of oxygen consumption of stunned myocardium have produced mixed results ranging from minus 25% of control10 to no change!' to an 8% to 13% increase." In the excised perfused isovolumic rat heart, myocardial oxygen consumption after 18 minutes of ischemia at 37° C ranges from -8% to +26% of control measurements at equivalent rate-pressure-products.!' After 20 minutes of global ischemia at 37° C during full cardiopulmonary bypass, Ward and associates!" did not observean increasein myocardialoxygenconsumption of the empty, beating canine heart, but did find a 179% increase in oxygen consumption in the postischemic workingheart compared with the preischemic nonworking heart. Thirty minutes after 2 hours of potassiumcardioplegic arrest at 28° C, Krukenkamp and associates'? observeda 39%increasein myocardial oxygenconsumption at equivalentpeak developed pressuresof isovolumic canine hearts. None of these previous studies measured the relationshipbetweenmyocardialoxygenconsumption

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and systolic load after global ischemia in the in situ, ejecting heart at different afterloads. Thus none observed the magnitude of the increase in oxygen consumption and loss of oxygen utilization efficiency that we found in the postischemic ovine heart. The biochemical mechanism of the reversible ischemic injury is not clear. Reimer," DeBoer,5 and Kloner 3 and their associates observe depletion of adenosine triphosphate and purine nucleotides in reperfused stunned myocardium, but the magnitude of depletion is not sufficient to explain the profound functional loss.34, 35 Sako and colleagues13 find that the rate ratios of adenosine triphosphate synthesis to oxygen consumption do not change after 20 minutes of 370 C ischemia in rat hearts and conclude in agreement with Hoffmeister, Mauser, and Schaper'? and Kusuoka, Inoue, and Marban '? that inefficiency of adenosine triphosphate utilization rather than mitochondrial uncoupling is involved. Others observe accumulation of calcium and lactate and other glycolytic products within ischemic myocytes 34,38 and find that reperfusion with low calcium perfusates attenuates the depression in function. 35,38 Other biochemical mechanisms to explain the prolonged loss of contractile function are proposed,39,40 and it is possible that more than one mechanism is involved. The steep increase in the LVo 2/ SS 1 relationship in postischemic hearts has important implications for cardiac surgeons. Perioperative ischemic injury despite myocardial protection is a major risk in virtually all heart operations. Although the L Vo2/SSI slope probably varies with the magnitude of the reversible ischemic injury, any degree of ischemia increases oxygen demand for an equivalent amount of myocardial work after release of the aortic crossclamp. In patients with extensive coronary disease, the vascular system may be unable to supply the additional oxygen required by the inefficient stunned myocardium. It is not known whether this causes more ischemic damage or further reduces contractility. Unfortunately, neither event favors recovery. We thank Dr. Robert Wenger, Bernie McHugh, Ross Bauer, Sandra Royer, Myra Monahan, and Mary Wittrock for their contributions to this study. REFERENCES I. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-9. 2. HeyndricksGR, Millard RW, McRitchieRJ, MarokoPR, Vatner SF. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest 1975;56:978-85.

Stress versus oxygen consumption in ischemic heart 2 I 9

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