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The stretched ventricle
The stretched ventricle Myocardial creep and contractile dysfunction after acute nonischemic ventricular distention The hypothesis that nonischemic distention of the arrested, flaccid ventricle causes myocardial creep and reduces ventricular contractile force was tested in 16 sheep. Left ventricular volume was calculated from ultrasonic dimension transducers spanning left ventricular major and minor axes and left ventricular waD thickness. Changes in left ventricular volume were plotted against left ventricular pressure, with and without temporary occlusion of both venae cavae before and after nonischemic distention of the continuously perfused, flaccid nonbeating left ventricle arrested with oxygenated, normothermic blood-potassium perfusate. During 12 minutes of cardiac arrest, an apical baDoon progressively distended the left ventricle to a peak pressure of 40 mm Hg in 11 sheep using a protocol designed to prevent subendocardial ischemia or mechanical injury. Coronary sinus lactate measurements and myocardial distribution of microspheres confirmed the absence of ischemia in 16 animals. In five control sheep the balloon was inserted but not inflated. Left ventricular volume at zero pressure increased from 5.9 ± 3.5 to 9.5 ± 4.4 ml (p < 0.05) after balloon inflation and did not change in the control animals. Mter maximum distention of the baDoon, static lett ventricular volumes at identical pressures were significantly greater. After passive distention, the slope of the end-systolic pressurevolume relationship, a measure of contractility, decreased significantly (p < 0.05) from 7.1 ± 2.8 to 3.5 ± 1.8 mm Hgjml and did not change in the control group. Passive distention ("stretching") of the nonischemic flaccid left ventricle thus causes myocardial creep and reduces ventricular contractility. (J THORAC CARDIOVASC SURG 1992;104:996-1005)
Stephen W. Downing, MD, Edward B. Savage, MD, James S. Streicher, MSE, Daniel K. Bogen, MD, PhD, George S. Tyson, MD, and L. Henry Edmunds, Jr., MD, Philadelphia, Pa.
CardiOPlegia, a condition unique to cardiac surgery, renders the heart flaccid and vulnerable to passivedistention. Outside the operating room, passivedistention of the nonbeating heart occurs only in association with regional or global ischemia. Heart muscle is viscoelastic1-5; passive stretching of excised papillary musclell- 6 or rabbit ventricle? exhibits time-dependent stress relaxation and From the Departments of Surgery and Bioengineering, University of Pennsylvania School of Medicine, Philadelphia, Pa. Supported by grant HL36308 from the National Heart, Lung, Blood Institute of the National Institutes of Health. Received for publication Jan. 24,1991. Accepted for publication Nov. 4, 1991. Address for reprints: L. Henry Edmunds, Jr., MD, Department of Surgery, Silverstein 4, Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
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996
creep. Myocardial creep is defined as an increase in unstressed ventricular volume or in the length of an unstressed segment of cardiac muscle. Reversible myocardial ischemia produces creep8-IO and an increase in myocardial stiffness,8-10 as well as reduced segment shortening and stroke work.8- 1OThe reduced contractility associated with ventricular distention is usually attributed to subendocardial ischemia. 11-13 We tested the hypothesis that distention of the nonischemic, flaccid ventricle causes creep and reduces myocardial contractile force. Methods Experimental protocol. In compliance with guidelines for humane care (NIH publication No. 85-23, revised 1985), nineteen Dorsett sheep (30 to 40 kg) were rendered unconscious with thiopental sodium (2 mg/kg administered intravenously), intubated, and anesthetized with halothane (0.8% to 1.5%) and oxygen (Drager Avek; North American Drager, Telford, Pa.).
Volume 104 Number 4 October 1992
Nonischemic ventricular distention
997
Table I. Balloon volumes before and after maximum distention to 40 mm Hg Pressure (mm Hg)
Volume before (ml)
Volume after (ml)
10 20 30
11.7 ± 3.7 29.6 ± 10.8 44.4 ± 13.7
39.9 ± 14.6* 56.2 ± 17.1* 63.9 ± 21.8*
*p < 0.05 compared with value before distention.
A clean median sternotomy was performed and both carotid arteries were exposed. A polytetrafluoroethylene catheter was inserted into the right common carotid artery. The preparation is shown in Fig. 1. Pneumatic occluders (In Vivo Metric, Healdsburg, Calif.) were placed around the superior and inferior vena cava. The left azygous vein was ligated. A polytetrafluoroethylene catheter was inserted into the left hemizygous vein so that the tip reached the coronary sinus but was several centimeters from the ostium of the coronary sinus." The hemiazygos vein was tied. Samples (10 ml) were withdrawn slowly during 30 seconds to prevent aspiration of right atrial blood. Prewarmed high-fidelity micromanometers (SPC-350; Millar Instruments, Inc., Houston, Texas) were placed in the aortic arch and directly into the left ventricular cavity. Two pairs of hemispheric ultrasonic dimension transducers (outer diameter 6.35 mm; Channel Industries Inc., Santa Barbara, Calif.) were sutured to the epicardium across the base-apex major (longitudinal) axis and the anterior-posterior minor axis of the left ventricle (LV). An identical hemispheric transducer was paired with a smaller disk (outer diameter 2 mm; Triton Technologies, San Diego, Calif.) placed on the endocardial surface to measure equatorial wall thickness. In five animals a pair of cylindrical transducers (outer diameter 2 mm, TritonTechnologies) was placed 1.5 em apart in the LV free wall. Dimension transducers were coupled to a multiplexed 4-channel sonomicrometer (Triton 120; Triton Technologies). Micromanometers were connected to pressure amplifiers (ES1200B; Gould, Inc., Test and Measurement Div., Cleveland, Ohio). Pressure and dimension data were digitized (Labmaster; Tecmar, Solon, Ohio) at 200 Hz and stored on floppy disk for subsequent analysis. Pressure and dimension data were recorded before and during occlusion of both venae cavae. Caval occlusion was maintained until steady-state conditions were achieved at end-diastolic pressure of 0 mmHg to obtain unstressed LV dimensions (20 to 30 seconds). Three to five sets of data during caval occlusion were obtained before and after bypass in each sheep. Changes in heart rate were less than 10% during caval occlusion. After initial data collection and heparinization (15,000 U administered intravenously), normothermic cardiopulmonary bypass was started. The perfusion circuit consisted of a twostage, 28F to 32F right atrial cannula (Sarns Inc./3M, Ann Arbor, Mich.), a 16 Fr carotid arterial cannula, a centrifugal pump (Medtronic Inc., Minneapolis, Minn.) with precalibrated electromagnetic flowmeter (VL-615; Biotronics, Kensington, Md.) and a hollow-fiber oxygenatorIheat exchanger (Maxima, Medtronic Blood Systems, Inc., Irvine, Calif.). The pulmonary artery was vented with a I OFcannula. During cardiopulmonary bypass, a phenylephrine infusion was used if needed to maintain the aortic pressure at 80 to 90 mm Hg.
Fig. 1. Pairs of hemispheric ultrasonic dimension transducers were implanted to measure the anterior-posterior minor axis and the base-apex major axis LV diameters. Wall thickness was measured across the LV free wall with a smaller endocardial disk paired with an epicardial hemisphere. L V and aortic pressures were measured with high-fidelity micrometers inserted into the aortic arch and directly into the L V cavity, respectively. Pneumatic occluders were placed around both venae cavae.
After the bypass had stabilized, the vented heart was electrically and mechanically arrested by clamping the ascending aorta and infusing 37° C, oxygenated, blood-potassium cardioplegia (potassium chloride 40 mliq/L) into the aortic root at 80 mm Hg or greater pressure delivered by a separate centrifugal pump system. When electromechanical silence occurred, the crossclamp was removed until atrial electrical activity returned. During this period the coronary arteries were perfused with pump blood at 80 mm Hg or greater pressure. With onset of atrial electrical activity, the aorta was again crossclamped and the aortic root was infused with cardioplegia. This repeating sequence created an electromechanically silent heart and a flaccid ventricle but avoided ischemia by constant perfusion of the aortic root with oxygenated blood at 80 mm Hg or greater. A large-volume (150 ml), noncompliant, custom-made, cylindric balloon (Datascope Corp., Paramus, N.J.) containing a micromanometer (SPC-350; Millar Industries) was introduced through a pursestring suture in the LV apex. Within its volume limit the balloon was capable ofexpanding in any direction and was sufficiently thin to conform to the topography of the endocardial surface. The ability of the distended balloon to conform uniformly to the endocardial surface was verified in
The Journal of Thoracic and Cardiovascular Surgery
9 9 8 Downing et al.
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Fig. 2. A, These data illustrate the percentage of lactate extraction (mean ± standard deviation) for the control group (CON, n = 5) and the experimental group (DIST, n = 11) that underwent ventricular distention. There is no significant difference before (PRE), after (POST), or at sequential intervals (1,2, and 3) during cardiopulmonary bypass. Two experimental and one control sheep produced lactate, a sign of ischemia, and are excluded from data analysis. B, The ratio of epicardial to endocardial blood flow derived from microsphere data are shown before (PRE), during, and after (POST) cardioplegic arrest. Data from four experimental (DSTN) animals (mean ± standard deviation) do not appear to differ from data obtained from a single control experiment.
several excised hearts by ventriculography (pictures available on request). In the 13 animals comprising the experimental group the balloon was serially inflated with saline solution to internal pressures of 10, 20, 30, 40, 30, 20 and 10 mm Hg during asystole. The duration of balloon inflation was 5 seconds; the balloon was deflated for 10 seconds before the next inflation cycle. The balloon was inflated five times at each pressure before proceeding to the next level. The volume of fluid in the balloon was measured by calibrated syringe and recorded at each pressure. Additionally, in seven animals sonomicrometric dimension data and intraballoon pressures were recorded at 10,40, and 10 mm Hg during distention. The entire distention protocol was completed in less than 12 minutes and required 0.8 to 1.5 L cardioplegia to maintain a quiescent heart. The control group (n = 6) underwent nearly identical protocol, including insertion of the balloon but omitting balloon inflation. In these animals asystole was maintained for 12 minutes by intermittent cardioplegia infusion as described previously. Arterial and coronary sinus lactate concentrations were measured before, after, and three times during the asystolic period in all animals (Stat-Pack; Behring Diagnostics Inc., Somerville, N.J.). Arterial concentrations of potassium and ionized calcium were measured before and after the l2-minute period of asystole (Stat Profile 5; Nova Instruments, Needham, Mass.). In five animals (one control, four experimental), 106 colored microspheres (IS ILm; EZ Trac, Los Angeles, Calif.) were injected in the left atrium to determine myocardial blood flow before and after cardioplegia. A reference sample was drawn from the carotid artery at 15.3 ml/rnin, During cardioplegia, 105 colored microspheres were injected in the cardioplegia infusion line during asystole with or without balloon distention to examine myocardial blood flow distribution to epicardium and endocardium.
After resumption of ventricular contractions, ionized calcium and pH were corrected to prebypass levels as needed and the animal was separated from cardiopulmonary bypass and decannulated. The LV pressure and dimension data again were obtained at steady-state conditions and during three to fivevena caval occlusions. Arterial and coronary sinus lactate levels were obtained and myocardial blood flow was measured with microspheres in the same five animals. Blood potassium level remained less than 5.5 mfiq/L, Animals were killed with thiopental and potassium chloride. Hearts were excised without removing the crystals. Wall thickness beneath each epicardial crystal were measured and the position of the endocardial crystal was verified. Samples of myocardium (2 to 3 gm) were excised from the anterior, posterior, and free wall regions of the ventricle. Each sample was carefully divided into equal subendocardial and subepicardial portions. Weighed myocardial samples and reference blood samples were dissolved in potassium hydroxide and colored microspheres were visually counted in a hemocytometer.P Data analysis. Simultaneous arterial and coronary sinus lactate concentrations were compared and the percentage of myocardial lactate extracted from arterial blood was calculat-
ed."
To obtain true wall thickness measurements, measured displacements between epicardial and endocardial crystal pairs were calibrated at the end of the experiment after death in hearts by simultaneous caliper measurements of wall thickness. The ratio of caliper to crystal measurements was used as a scaling factor to correct all previous measurements obtained from crystal pairs. This correction assumed that measured crystal displacements were a fixed fraction of the postmortem caliper measurements. Endocardial diameter at the equator was obtained by subtraction of twice the wall thickness from the epicardial diameter. The ventricle was modeled as a prolate ellipsoid and volume was calculated according to the formula:
Volume 104 Number 4 October 1992
Nonischemic ventricular distention
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Balloon Volume (mls) Fig. 3. Static pressure-volume data from the experimental (DSTN) group (n = II) are illustrated before (PRE) and after (POST) distention to a maximum pressure of 40 mm Hg. Each data point represents the volume (mean ± standard deviation) obtained during five balloon inflations to a constant pressure. The volume at each pressure is significantly greater after maximum distention (see Table I).
Table II. Unstressed LV diameters, volumes, and wall thicknesses before and after cardiopulmonary bypass and nonischemic cardioplegic arrest Control group
Anterior-posterior minor axis diameter (em) Base-apex major axis diameter (em) LV volume (ml) Wall thickness (mm)
Distended group
Before
After
Before
After
1.43 ± 0.10
1.42 ± 0.20
1.31 ± 0.35
1.64 ± 0.24*
6.68 ± 1.82
6.18 ± 1.83
6.55 ± 1.95
6.53 ± 1.42
7.4 ± 2.7 10.6 ± 1.4
6.9 ± 3.0 10.8 ± 1.4
5.9 ± 3.5 9.9 ± 1.7
9.5 ± 4.4* 10.0 ± 2.1
'p < 0.05 compared with value before distention.
Table III. Diastolic function before and after nonischemic cardioplegic arrest* Control group
Mathematical descriptors of the diastolic pressure-volume relationship
ex (rnm Hg) {3
Distended group
Before
After
Before
After
7.5 ± 4.9 0.9 ± 0.4
6.5 ± 9.9 3.7 ± 4.3
3.3 ± 4.8 2.5 ± 2.3
3.4 ± 2.9 4.2 ± 1.4
'None of the changes in either control or distended groups are statistically significant.
V= (rr/6) ab 2 where V is the LY volume, a is the endocardial major axis diameter, and b is the anterior-posterior endocardial minor axis diameter.'? Means of five saline-inflated balloon volumes at each distending pressure were recorded in all animals in the experimental group. The end-systolic pressure-volume relationship (ESPYR )20-22 was derived from data obtained at a wide range of L Y volumes during vena caval occlusion. At maximal occlusion, the unstress-
ed value of each dimension was obtained and the unstressed ventricular volume (Va) was calculated. All dimension data were normalized as Lagrangian strain according to
where 2; is the strain, D is any instantaneous dimension or volume, and Do is the unstressed dimension obtained at maximal vena caval occlusion.v ' With only diastatic data (ld2;/dtl s
The Journal of Thoracic and Cardiovascular Surgery
Downing et al.
10 0 0
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104 Base- Apex Diameter
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(Vd) of the ESPVR and the descriptors of the diastolic P - ~ relationship (a and (1) were also analyzed by covariance discriminant analysis,
•
o L:...:..':"':"':-'-'--''"'--'JLlL.ll..JLJLlL Fig. 4. Hemodynamic data from one of the distention experiments are shown before and after maximum ventricular distention. In each case the animal is no longer undergoingcardiopulmonary bypass and steady-state data are followed by a vena caval occlusion. With the onset of caval occlusion, both long and short ventricular diameters decrease and reciprocal changes are seen in wall thickness. As the heart empties, LV pressure declines. For each ventricular dimension unstressed length is identified as the value obtained at maximum caval occlusion at an end-diastolic LV pressure of a mm Hg. After distention the ventricle operates across an increased range of end-diastolic and end-systolic volumes. The increase in unstresseddiameter for both diameters is evident.Time scale is 2 seconds. 0.05 sec") to minimize the effect of viscoelastic properties," diastolic LV pressure was plotted against the normalizedanteroposterior diameter and fit to the following equation: P= a
(~L-l)
when P is the diastolic LV pressure, ~ is the strain, and a and (1 are nonlinear elastic constants that describe the curve mathematically.v '
Midwallcircumferentialstresswascalculated during steadystate conditions before and after bypass in seven animals during balloon inflation as described by Mirsky-:': s = (Pb/h) (I -b 2/2a2 - h/2b
+ h2/8a2 )
where s is the stress, P is the intraventricular (or intraballoon) pressure, a is the midwall semimajor axis, b is the midwall semiminor axis, and h is the wall thickness. All data are expressedas mean ± standard deviation. Paired data were analyzed by dependent t tests; significance required a value of p < 0.05 unless otherwise noted. Unpaired groups werecompared by independent t test. The slopeand x -intercept
Two experimental and one control sheep produced lactate during cardioplegia and were excluded from further analysis. The percentage of lactate extracted by the myocardium did not differ between groups (Fig. 2, A). Myocardial blood flow increased from 113 ± 34 to 195 ± 55 mljhg per minute in four experimental sheep after potassium-blood cardioplegia and from 103 to 265 mljhg per minute in one control animal. The ratios of subepicardial to subendocardial blood flow did not differ between the four experimental and one control sheep (Fig. 2, B) and were not altered substantially during cardioplegic arrest. The volumes required to inflate the ventricular balloon to constant pressures are shown in Table I. After inflation to a maximum of 40 mm Hg, the volume required to achieve each constant pressure significantly increased. The static pressure-volume relationship thus shifted to the right (Fig. 3). The mean volume at maximum distention, 65.5 ± 15.7 ml, was significantly larger than the mean maximal end-diastolic volume observed before bypass, 26.0 ± 11.4 ml. Similarly, in the four animals with regional segment-length transducers the maximum enddiastolic length before bypass was 20.1 ± 2.7 mm and increased significantly to 22.1 ± 3.6 mm during maximum distention to 40 mm Hg. At a pressure of 10 mm Hg during balloon distention, the mean segment length increased, from 17.3 ± 1.8 before to 20.2 ± 4.1 mm after maximal distention. Raw hemodynamic data from a typical experimental animal are shown in Fig. 4. Control data before initiation of cardiopulmonary bypass are shown, followed by data obtained after the termination of bypass and restoration of unassisted circulation (and therefore after ventricular distention). In this data set, steady state conditions are followed by vena caval occlusion. With onset of vena caval occlusion, both ventricular diameters decrease to a stable minimum and reciprocal changes are seen in the wall thickness. The LV pressure declines as the ventricle empties. At the same end-diastolic pressure after ventricular distention, the ventricle is operating across a higher volume range. The increase in the unstressed diameters of the ventricle is evident at the end of vena caval occlusion. The mean unstressed diameters, wall thicknesses, and volumes derived from vena caval occlusions obtained before and after bypass in both groups are shown in Table II. The unstressed ventricular dimensions and wall thick-
Volume 104 Number 4 October 1992
Nonischemic ventricular distention
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Fig. 6. Pressure-volume loops during vena caval occlusions are shown before (A) and after (0 LV distention: For each cardiac cycle the point of maximum elastance was identified and these ESPVR data were fitted to a h~ear regression.The slopeofthe ESPVR is decreased after ventricular distention (D)in comparison with the slope obtained before distention (B).
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The Journal of Thoracic and Cardiovascular Surgery
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Calculated Volume (mls) Fig. 7. Data were available during balloon inflation in six experimentalanimals for comparisonof the LV volume, calculated from the dimension data measured by sonomicrometry, and the volume, measured as the fluid volume distending the LV. Linear regression of the measured volumeor the calculated volume revealed a high correlation (r = 0.89), with a slope of 1.02 and an intercept of -4.3. nesses did not change in the control group; there is therefore no change in unstressed volume. In the experimental group changes in unstressed major axis diameters were inconsistent (Fig. 4, Table II) but unstressed anteriorposterior minor axis diameters increased significantly, to produce a significant increase in the unstressed ventricular volume. Wall thickness did not change. Changes in the diastolic pressure-volume relationships obtained during vena caval occlusions before and after distention are similar to those observed in the static pressure-volume relationship during balloon inflation (Fig. 3). Specifically, the curve shifts to the right because of the increase in postdistention LV volumes. When the predistention volume data are normalized to the increased unstressed volume after distention, however, the pressure-strain relationship shifts upward and to the left (Fig. 5). This tendency is seen in all distention experiments. Because of the degree of variance in the data, however, comparison of the mathematic descriptors of the curves before and after bypass reveals no significant difference (Table III). There also is no change in the control group. The pressure-volume loops in Fig. 6 are derived from vena caval occlusions before and after bypass in another experimental animal. Again, at the same LV end-diastolic pressure during steady-state conditions before the vena
caval occlusion, the increased end-diastolic volume after distention is evident (Fig. 6, A and C). The ESPVR data from each vena caval occlusion are plotted as a linear regression. After distention (Fig. 6, D) the ESPVR is shifted down and to the right in comparison with the relationship before bypass (Fig. 6, B). As shown in Table IV, the mean slope of the ESPVR for each sheep decreased significantly after bypass in the experimental group, whereas there was no difference in the control group. There also was no difference between the groups before bypass. Before bypass the maximum midwall circumferential stress was 217.9 ± 55.9 dynes. ern? . 103 at a mean LV pressureofl02.8 ± 18.7mmHg(n = 6); maximal stress always occurred at the onset of ejection. In comparison, during maximal balloon distention at 43.6 ± 4.0 mm Hg midwall circumferential stress was significantly less, 148.8 ± 32.3 dynes. ern? . 103 (p < 0.05; n = 6). In six experimental animals, dimension data were available to compare the calculated volume with the measured volume infused into the balloon during balloon distention. As shown in Fig. 7, linear regression of calculated volume on measured volume revealed a high degree of correlation [r = 0.89; y(ml) = 1.02x - 4.3]. Discussion The stepwise distention protocol and the relatively brief and low distending pressures probably did not cause ventricular trauma. Distending pressures to 30 mm Hg only stretch collagen fibers/"; pressures as great as 70 to 100 mm Hg are required to disrupt these fibers and the collagen network.i" Sarcomeres are not stretched beyond 2.2 /-Lm until the collagen network is disrupted.i" Although the distending pressures in this study are above the normal diastolic range, they are below those associated with traumatic injury and calculated wall stresses are below those that normally occur during systole. The protocol also avoids regional and global ischemia. The heart receives continuous coronary arterial perfusion at 80 mm Hg or more throughout the 10 to 12 minutes of asytole. Cardiac arrestin diastole reduces myocardial oxygen demand. 25-28 Even when the ventricular balloon is inflated briefly, coronary perfusion pressure is always at least twice balloon pressure. As with the beating heart, balloon deflation ("diastole") is twice as long as balloon inflation ("systole"). Ventricular stretching does not change endocardial/epicardial flow ratios and the protocol does not initiate lactate production. Potassium is a powerful vasodilator that directly relaxes arteriolar smooth muscle in virtually every mammalian species tested.l? In dogs, a bolus injection of 40 /-Lmol of isosmotic potassium chloride reduces coronary vascu-
Volume 104 Number 4 October 1992
Nonischemic ventricular distention
1003
Table IV. ESPVR beforeand after nonischemic cardioplegic arrest Before arrest
Control I 2 3 4 5 Mean ± SEM
p Experimental I 2 3 4 5 6 7 8 9 10 II
p
Mean ± SEM
After arrest
n
Ees (mm Hg . ml'"]
Vd (ml)
2 3 3 5 2 15
7.4 1.7 1.8 3.7 16.1 5.1 ± 5.5
6.4 -41.1 -20.1 -15.3 3.5 -16.0
0.88 0.97 0.98 0.92 0.75
2 4 4 3 5 I 3 I I 2 2 28
4.5 6.6 8.0 2.4 7.4 3.2 9.3 7.2 9.2 11.9 7.6 7.1 ± 2.7
14.5 12.8 12.3 -7.9 11.7 10.5 4.9 -0.2 2.7 -0.7 6.2 -6.7
.93 .94 .98 .86 .99 .96 .99 .85 .91 .96 .95
Ees (mmHg ml- 1)
Vd (ml)
2 4 I 4 2 13
7.9 1.4 2.5 3.6 14.3 5.1 ± 4.9 0.69
4.3 -23.4 -9.3 -12.7 1.9 -10.9
0.97 0.97 0.81 0.93 0.95
3 3 4 2 2 I 4 2 I I 2 25
2.7 2.1 3.3 1.4 5.9 2.1 4.4 2.7 7.2 3.1 3.4 3.4 ± 1.6 0.0002
12.7 -18.4 -3.5 -25.8 -8.9 1.4 -5.9 -17.0 8.1 -17.1 -14.9 -6.4
0.93 0.98 0.98 0.96 0.83 0.97 0.98 0.81 0.85 0.97 0.96
n
A mixed-model analysis of variance was used to calculate tests of statistical significance between before and after arrest values for elastance only with the Satterthwaite approximation method. The p value refers to within-group before and after means for elastance. The between-group comparison was not made. Ees, Mean end-systolic elastance or slope of ESPVR; Vd- mean intercept of Ees at zero pressure or volume at zero pressure; r, regression coefficient of a single representative elastance from the one to five slopes obtained for each sheep before and after arrest. SEM, Standard error of the mean.
lar resistance 34% to 48%30; an infusion of 8 mmol potassium chloride per kilogram body weight in glucose and insulin increases coronary blood flow 98% but does not change myocardial oxygen uptake." Potassium-blood cardioplegia also increased coronary blood flow in both the distended and control groups in this study. The increase in postperfusion coronary blood flow thus probably represents a direct effect of potassium on the coronary vasculature rather than reactive hyperemia. Ventricular stretching increases ventricular volume at zero pressure and by definition produces myocardial creep. The observation that free wall segment lengths increase similarly argues against the possibility that volume increases are caused by better apposition between the balloon and ventricular wall with repeated inflation. Both the static pressure-volume relationship (Fig. 3) and raw end-diastolic pressure-volume data shift to the right and indicate an apparent increase in chamber compliance. When strains are calculated for the distended LV after adjusting for the increased unstressed volume, the pressure-strain relationship shifts upwards and to the left (Fig. 5). These results confirm the diastolic changes reported previously in isolated cardiac muscle- 6 and in the excised
rabbit heart.' This contradicts the work of Lucas and coworkers.l? who distended hearts after cardioplegic arrest (beating empty for 15 minutes). The injury resulting from ischemic arrest seen even in their control animals, however, may have masked the effect of mechanical distention. We expected the increase in LV volume after distention to be associated with a decrease in wall thickness. The expected decrease did not occur (Table 11). An increase in potassium-induced vascular volume is a possible explanation. We used the ESPVR to assess myocardial contractility and fitted the data, which were obtained in vivo across the physiologic range of end-systolic pressures, to a linear rather than a parabolic function. The linear fit across the full range of pressures measured during caval occlusion produced generally high correlation coefficients (Table IV). Others have shown that a quadratic ESPVR model provides a better fit of data obtained across a wider range of ventricular pressures and volumes, particularly when nonphysiologic low volumes and pressures are inc1uded. 32- 34 However, the curvilinear model does not facilitate comparisons of contractile state." In the physiologic range of pressures and volumes, end-systolic elastance
10 0 4
The Journal of Thoracic and Cardiovascular Surgery
Downing et al.
agrees well with the linear coefficient of the quadratic equation.P End-systolic elastance in the physiologic range thus provides a reliable measure of contractile state. 33 If data from the low end of our ESPVR measurements are excluded (i.e., all pressures below 65 mm Hg) end-systolic elastance before distention changes little, whereas end-systolic elastance after distention decreases further (to 2.2 ± 1.3 mm Hg . ml") and more closely reflects the gross appearance of the poorly contractile hearts in situ. Previous work has shown that changes in the diastolic properties of heart muscle can affect the ESPVR. IO Our current studies show for the first time that mechanical distention of the nonischemic, flaccid LV alters the material properties of the myocardium (i.e., causes creep) and that this alteration causes a reduction in contractile force. This observation has important implications. The first for cardiac surgeons is obvious: even transient ventricular distention of the nonbeating heart (during cardioplegia or ventricular fibrillation) must be avoided. During cardiac operations the heart is vulnerable to both stunning35,36 and stretching; both reduce contractile function. A second implication involves possible regional creep when surgeons rearrange the geometry of the ventricle, as in repair of LV aneurysms'? or closure of ventriculotomies. Operations that alter the geometry of the ventricle also alter regional ventricular wall stresses. Although not proven, it is possible that a sustained increase in stress of a segment of the ventricular wall can induce nonischemic myocardial creep and reduced segment-length shortening. A third implication involves the halo of poorly contracting nonischemic myocardium that surrounds an acute infarction. The temporary loss of contractile function in this adjacent myocardium is obviously detrimental and has been ascribed to a "tethering effect" of the infarct. Bogen and colleagues.P' however, calculated that wall stresses increase in both the infarct and adjacent hypokinetic halo, and Ratcliffe and colleagues directly calculated increases in halo wall stresses from twodimensional sonoarray images in sheep with acute anteroapical infarcts (unpublished observations). The "tethering effect" may thus induce regional myocardial nonischemic creep. The changes in ventricular pressure-volume relationships associated with nonischemic and ischemic creep appear similar, but the morphologic features, minimal distending volumes, and reversibility may not be similar. Ischemic creep is associated with an increase in sarcomere length.!" disruption of the collagen network.V' 40 and myocyte slippage. 24,41,42 George? has shown that extremely small distending volumes within the physio-
logicrange produce creep in excisedventricles.7 Thisobservation raises the possibility that changes in diastolic viscoelastic function may occur independently of changes in systolic function. Glower and colleagues'? have shown that ischemic creep is reversible. In dogs, as long as 12 hours is needed to reverse the myocardial creep and decreased ejection shortening produced by 15 minutes of ischemia. Stroke work does not return to normal for days.43 This study provides no data regarding the morphologic characteristics, minimal distending pressures, or reversibility of nonischemic creep. It is therefore probably not wise to assume that recovery of the stretched ventricle is more rapid than is recovery of the stunned ventricle. We thank Brandon Claytor, Michelle Haywood, and Myra Monahan for their important contributions to this work and recognize the assistance of Datascope Corp., Paramus, N.J., in designing and producing the distending balloon. REFERENCES I. Fung YC. Stress-strain relations of soft tissues in simple elongation. In: Fung YC, Perine N, Anliker M, eds. Biomechanics: its foundations and objectives. Englewood Cliffs, New Jersey: Prentice Hall, 1972:181-208. 2. Pinto JG, Paititucci PJ. Creep in cardiac muscle. Am J Physiol 1977;232:H553-63. 3. Pinto JE, Fung yc. Mechanical properties of the heart muscle in the passive state. J Biomech 1973;6:597-616. 4. Rankin JS, Arentzen CE, McHale PA, Ling D, Anderson R W. Viscoelastic properties of the diastolic left ventricle in the conscious dog. Circ Res 1977;41:37-35. 5. Rankin JS, Arentzen CE, Ring WS, Edwards CH, McHale PA, Anderson RW. The diastolic mechanical properties of the intact left ventricle. Fed Proc 1980;39: 141-7. 6. Fish D, Orenstein J, Bloom S. Passive stiffness of isolated cardiac and skeletal myocytes in the hamster. Circ Res 1984;54:267-77. 7. George DT. The mechanics of cardiac edema [Dissertation]. Philadelphia: University of Pennsylvania, 1990. 8. Edwards CH, Rankin JS, Mchale PA, Ling D, Anderson R W. Effect of ischemia on left ventricular regional function in the conscious dog. Am J PhysioI1981;240:H413-20. 9. Visner MC, Arentzen CE, Parrish DG, et al. Effects of global ischemia on the diastolic properties of the left ventricle in the conscious dog. Circulation 1985;71:610-9. 10. Glower DD, Schaper J, Kabas JS, et al. Relation between reversal of diastolic creep and recovery of systolic function after ischemic myocardial injury in conscious dogs. Circ Res 1987;60:850-60. 11. Hottenrot C, Buckberg G. Studies ofthe effects ofventricular fibrillation on the adequacy of regional myocardial blood flow. II. Effects of ventricular distension. J THORAC CARDIOVASC SURG 1974;68:626-33. 12. Lucas SK, Gardner TJ, Elmer EB, Flaherty JT, Bulkley
Volume 104 Number 4 October 1992
BH, Gott VL. Comparison of the effects of left ventricular distension during cardioplegic-induced ischemic arrest and ventricular fibrillation. Circulation I980;62(Suppl):I42-9. 13. Lucas SK, SchaffHV, Flaherty JT, Gott VL, GardnerTJ. The harmful effects of ventricular distension during postischemic reperfusion. Ann Thorac Surg 1981;32:486-94. 14. Markovitz LJ, Savage EB, Ratcliffe MB, et al. A large animal model of left ventricular aneurysm. Ann Thorac Surg 1989;48:838-45. 15. Hale SL, Alker KJ, Kloner RA. Evaluation of non-radioactive colored microspheres for measurement of regional myocardial blood flowin dogs. Circulation 1988;78:428-34. 16. Jackson G. Laboratory diagnosis of myocardial ischemia. Cardiovasc Clin 1985;15:45-65. 17. Gertz EW, Wisnecki JA, Neese R, Houser A, Korte R, Bristow JD. Myocardial lactate extraction: multidetermined metabolic function. Circulation 1980;61:256-61. 18. Opie LH, Owen P, Thomas M, Sanson R. Coronary sinus lactate measurements in assessments of myocardial ischemia. Am J Cardiol 1973;32:295-305. 19. Rankin JS, McHale PA, Arentzen LE, Ling D, Greenfield JC Jr, Anderson RW. Three dimensional geometry of the left ventricle in the conscious dog. Circ Res 1976;39:304-13. 20. Suga H, Sagawa K, Shoukas AA. Load Independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973;32:314-22. 21. Sagawa K. The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use. Circulation 1981;63:1223-7. 22. Spratt JA, Tyson GS, Glower DD, et al. The end-systolic pressure-volumerelationship in conscious dogs. Circulation 1987;75:1295-309. 23. Yin FCP. Ventricular wall stress. Circ Res 1981;49:829-42. 24. Factor SM, Flomenbaun M, Zhao M-J, Eng C, Robinson TF. The effect of acutely increased ventricular cavity pressure on intrinsic myocardial connective tissue. J Am Coll CardioI1988;12:1582-9. 25. Bittl JA, Ingwall JS. The energetics of myocardial stretch. Circ Res 1986;58:378-83. 26. Nozawa T, Yasumura Y, FutakiS, Tanaka N,SugaH. No significantincrease in 02 consumption of KC I-arrested dog heart with filling and dobutamine. Am J Physiol 1988; 255(Suppl):H807-l2. 27. LoiselleDS, Gibbs CL. Factors affecting the metabolism of resting papillary muscle. Pflugers Arch 1983;396:285-91. 28. Sink JD, Hill RC, Atarian DE, Wechsler AS. Myocardial blood flowand oxygen consumption in the empty, beating, fibrillating and potassium-arrested hypertrophied canine heart. Ann Thorac Surg 1983;35:372-9. 29. Haddy FJ. Potassium effects on contraction in arterial smooth muscle mediated by Na+, K+-ATPase. Fed Proc 1983;42:239-45.
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30. Murray PA, Sparks HV. The mechanism of K+-induced vasodilation of the coronary vascular bed of the dog. Circ Res 1978;42:35-42. 31. Bronsveld W, van Lambaigen AA, van den Bos GC, Thijs LG, Koopman PAR. Effects of glucose-insulin-potassium (GIK) on myocardial blood flow and metabolism in canine endotoxin shock. Circ Shock 1984;13:325-40. 32. BurkhoffD, Sugiura S, Yue DT, Sagawa K. Contractilitydependent curvilinearity of end-systolic pressure-volume relations. Am J Physiol 1987;252(Suppl):HI218-27. 33. Kass DA, Beyar R, Lankford E, Heard M, Maughan WL, Sagawa K. Influence of contractile state on curvilinearity of in situ end-systolic pressure-volume relations. Circulation 1989;79:167-87. 34. Van der Velde ET, Burkhoff D, Steendijk P, Karsdon J, Sagawa K, Baan J. Nonlinearity and load sensitivity of end-systolic pressure-volume relation of canine left ventricle in vivo. Circulation 1991;83:315-27. 35. Bavaria JE, Furakawa S, Kreiner G, et al. Myocardial oxygen utilization after reversible global ischemia. J THORAC CARDIOVASC SURG 1990;100:210-20. 36. Furakawa S, Bavaria JE, Kreiner G, Edmunds LH Jr. Relationship between total mechanical energy and oxygen consumption in stunned myocardium. Ann Thorac Surg 1990;149:543-9. 37. Savage EB, Downing SW, Ratcliffe MB, et al. Repair of left ventricular aneurysm: changes in ventricular mechanics, hemodynamics, and oxygen consumption. J THORAC CARDIOVASC SURG 1992;104:752-63. 38. Bogen DK, Rabinowitz SA, Needleman A, McMahon TA, Abelmann WHo An analysis of the mechanical disadvantage of myocardial infarction in the canine left ventricle. Circ Res 1980;47:728-41. 39. Zhao M, Zhang H, Robinson TF,Factor SM, Sonnenblick EH, Eng C. Profound structural alterations of the extracellular collagen matrix in postischemic dysfunctional ("stunned") but viable myocardium. J Am Coll Cardiol 1987;10:1322-34. 40. Caulfield JB, Tao SB, Nachtigal M. Ventricular collagen matrix and its alterations. Adv MyocardioI1985;5:257-69. 41. Olivetti G, Capasso JM, Sonnenblick EH, Anversa P. Side to side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res 1990;67:23-34. 42. Ross JR, Sonnenblick EH, Taylor RR, Spotnitz HM, Covell JW. Diastolic geometry and sarcomere lengths in the chronically dilated canine left ventricle. Circ Res 1971; 28:49-61. 43. Matsuzak M, Gallagher KP, Kemper WS, White F, Ross J Jr. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion. Circulation 1983;68:170-82.
Stephen W. Downing, MD, Edward B. Savage, MD, James S. Streicher, MSE, Daniel K. Bogen, MD, PhD, George S. Tyson, MD, and L. Henry Edmunds, Jr., MD, Philadelphia, Pa.
CardiOPlegia, a condition unique to cardiac surgery, renders the heart flaccid and vulnerable to passivedistention. Outside the operating room, passivedistention of the nonbeating heart occurs only in association with regional or global ischemia. Heart muscle is viscoelastic1-5; passive stretching of excised papillary musclell- 6 or rabbit ventricle? exhibits time-dependent stress relaxation and From the Departments of Surgery and Bioengineering, University of Pennsylvania School of Medicine, Philadelphia, Pa. Supported by grant HL36308 from the National Heart, Lung, Blood Institute of the National Institutes of Health. Received for publication Jan. 24,1991. Accepted for publication Nov. 4, 1991. Address for reprints: L. Henry Edmunds, Jr., MD, Department of Surgery, Silverstein 4, Hospital of the University of Pennsylvania, Philadelphia, PA 19104.
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creep. Myocardial creep is defined as an increase in unstressed ventricular volume or in the length of an unstressed segment of cardiac muscle. Reversible myocardial ischemia produces creep8-IO and an increase in myocardial stiffness,8-10 as well as reduced segment shortening and stroke work.8- 1OThe reduced contractility associated with ventricular distention is usually attributed to subendocardial ischemia. 11-13 We tested the hypothesis that distention of the nonischemic, flaccid ventricle causes creep and reduces myocardial contractile force. Methods Experimental protocol. In compliance with guidelines for humane care (NIH publication No. 85-23, revised 1985), nineteen Dorsett sheep (30 to 40 kg) were rendered unconscious with thiopental sodium (2 mg/kg administered intravenously), intubated, and anesthetized with halothane (0.8% to 1.5%) and oxygen (Drager Avek; North American Drager, Telford, Pa.).
Volume 104 Number 4 October 1992
Nonischemic ventricular distention
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Table I. Balloon volumes before and after maximum distention to 40 mm Hg Pressure (mm Hg)
Volume before (ml)
Volume after (ml)
10 20 30
11.7 ± 3.7 29.6 ± 10.8 44.4 ± 13.7
39.9 ± 14.6* 56.2 ± 17.1* 63.9 ± 21.8*
*p < 0.05 compared with value before distention.
A clean median sternotomy was performed and both carotid arteries were exposed. A polytetrafluoroethylene catheter was inserted into the right common carotid artery. The preparation is shown in Fig. 1. Pneumatic occluders (In Vivo Metric, Healdsburg, Calif.) were placed around the superior and inferior vena cava. The left azygous vein was ligated. A polytetrafluoroethylene catheter was inserted into the left hemizygous vein so that the tip reached the coronary sinus but was several centimeters from the ostium of the coronary sinus." The hemiazygos vein was tied. Samples (10 ml) were withdrawn slowly during 30 seconds to prevent aspiration of right atrial blood. Prewarmed high-fidelity micromanometers (SPC-350; Millar Instruments, Inc., Houston, Texas) were placed in the aortic arch and directly into the left ventricular cavity. Two pairs of hemispheric ultrasonic dimension transducers (outer diameter 6.35 mm; Channel Industries Inc., Santa Barbara, Calif.) were sutured to the epicardium across the base-apex major (longitudinal) axis and the anterior-posterior minor axis of the left ventricle (LV). An identical hemispheric transducer was paired with a smaller disk (outer diameter 2 mm; Triton Technologies, San Diego, Calif.) placed on the endocardial surface to measure equatorial wall thickness. In five animals a pair of cylindrical transducers (outer diameter 2 mm, TritonTechnologies) was placed 1.5 em apart in the LV free wall. Dimension transducers were coupled to a multiplexed 4-channel sonomicrometer (Triton 120; Triton Technologies). Micromanometers were connected to pressure amplifiers (ES1200B; Gould, Inc., Test and Measurement Div., Cleveland, Ohio). Pressure and dimension data were digitized (Labmaster; Tecmar, Solon, Ohio) at 200 Hz and stored on floppy disk for subsequent analysis. Pressure and dimension data were recorded before and during occlusion of both venae cavae. Caval occlusion was maintained until steady-state conditions were achieved at end-diastolic pressure of 0 mmHg to obtain unstressed LV dimensions (20 to 30 seconds). Three to five sets of data during caval occlusion were obtained before and after bypass in each sheep. Changes in heart rate were less than 10% during caval occlusion. After initial data collection and heparinization (15,000 U administered intravenously), normothermic cardiopulmonary bypass was started. The perfusion circuit consisted of a twostage, 28F to 32F right atrial cannula (Sarns Inc./3M, Ann Arbor, Mich.), a 16 Fr carotid arterial cannula, a centrifugal pump (Medtronic Inc., Minneapolis, Minn.) with precalibrated electromagnetic flowmeter (VL-615; Biotronics, Kensington, Md.) and a hollow-fiber oxygenatorIheat exchanger (Maxima, Medtronic Blood Systems, Inc., Irvine, Calif.). The pulmonary artery was vented with a I OFcannula. During cardiopulmonary bypass, a phenylephrine infusion was used if needed to maintain the aortic pressure at 80 to 90 mm Hg.
Fig. 1. Pairs of hemispheric ultrasonic dimension transducers were implanted to measure the anterior-posterior minor axis and the base-apex major axis LV diameters. Wall thickness was measured across the LV free wall with a smaller endocardial disk paired with an epicardial hemisphere. L V and aortic pressures were measured with high-fidelity micrometers inserted into the aortic arch and directly into the L V cavity, respectively. Pneumatic occluders were placed around both venae cavae.
After the bypass had stabilized, the vented heart was electrically and mechanically arrested by clamping the ascending aorta and infusing 37° C, oxygenated, blood-potassium cardioplegia (potassium chloride 40 mliq/L) into the aortic root at 80 mm Hg or greater pressure delivered by a separate centrifugal pump system. When electromechanical silence occurred, the crossclamp was removed until atrial electrical activity returned. During this period the coronary arteries were perfused with pump blood at 80 mm Hg or greater pressure. With onset of atrial electrical activity, the aorta was again crossclamped and the aortic root was infused with cardioplegia. This repeating sequence created an electromechanically silent heart and a flaccid ventricle but avoided ischemia by constant perfusion of the aortic root with oxygenated blood at 80 mm Hg or greater. A large-volume (150 ml), noncompliant, custom-made, cylindric balloon (Datascope Corp., Paramus, N.J.) containing a micromanometer (SPC-350; Millar Industries) was introduced through a pursestring suture in the LV apex. Within its volume limit the balloon was capable ofexpanding in any direction and was sufficiently thin to conform to the topography of the endocardial surface. The ability of the distended balloon to conform uniformly to the endocardial surface was verified in
The Journal of Thoracic and Cardiovascular Surgery
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Fig. 2. A, These data illustrate the percentage of lactate extraction (mean ± standard deviation) for the control group (CON, n = 5) and the experimental group (DIST, n = 11) that underwent ventricular distention. There is no significant difference before (PRE), after (POST), or at sequential intervals (1,2, and 3) during cardiopulmonary bypass. Two experimental and one control sheep produced lactate, a sign of ischemia, and are excluded from data analysis. B, The ratio of epicardial to endocardial blood flow derived from microsphere data are shown before (PRE), during, and after (POST) cardioplegic arrest. Data from four experimental (DSTN) animals (mean ± standard deviation) do not appear to differ from data obtained from a single control experiment.
several excised hearts by ventriculography (pictures available on request). In the 13 animals comprising the experimental group the balloon was serially inflated with saline solution to internal pressures of 10, 20, 30, 40, 30, 20 and 10 mm Hg during asystole. The duration of balloon inflation was 5 seconds; the balloon was deflated for 10 seconds before the next inflation cycle. The balloon was inflated five times at each pressure before proceeding to the next level. The volume of fluid in the balloon was measured by calibrated syringe and recorded at each pressure. Additionally, in seven animals sonomicrometric dimension data and intraballoon pressures were recorded at 10,40, and 10 mm Hg during distention. The entire distention protocol was completed in less than 12 minutes and required 0.8 to 1.5 L cardioplegia to maintain a quiescent heart. The control group (n = 6) underwent nearly identical protocol, including insertion of the balloon but omitting balloon inflation. In these animals asystole was maintained for 12 minutes by intermittent cardioplegia infusion as described previously. Arterial and coronary sinus lactate concentrations were measured before, after, and three times during the asystolic period in all animals (Stat-Pack; Behring Diagnostics Inc., Somerville, N.J.). Arterial concentrations of potassium and ionized calcium were measured before and after the l2-minute period of asystole (Stat Profile 5; Nova Instruments, Needham, Mass.). In five animals (one control, four experimental), 106 colored microspheres (IS ILm; EZ Trac, Los Angeles, Calif.) were injected in the left atrium to determine myocardial blood flow before and after cardioplegia. A reference sample was drawn from the carotid artery at 15.3 ml/rnin, During cardioplegia, 105 colored microspheres were injected in the cardioplegia infusion line during asystole with or without balloon distention to examine myocardial blood flow distribution to epicardium and endocardium.
After resumption of ventricular contractions, ionized calcium and pH were corrected to prebypass levels as needed and the animal was separated from cardiopulmonary bypass and decannulated. The LV pressure and dimension data again were obtained at steady-state conditions and during three to fivevena caval occlusions. Arterial and coronary sinus lactate levels were obtained and myocardial blood flow was measured with microspheres in the same five animals. Blood potassium level remained less than 5.5 mfiq/L, Animals were killed with thiopental and potassium chloride. Hearts were excised without removing the crystals. Wall thickness beneath each epicardial crystal were measured and the position of the endocardial crystal was verified. Samples of myocardium (2 to 3 gm) were excised from the anterior, posterior, and free wall regions of the ventricle. Each sample was carefully divided into equal subendocardial and subepicardial portions. Weighed myocardial samples and reference blood samples were dissolved in potassium hydroxide and colored microspheres were visually counted in a hemocytometer.P Data analysis. Simultaneous arterial and coronary sinus lactate concentrations were compared and the percentage of myocardial lactate extracted from arterial blood was calculat-
ed."
To obtain true wall thickness measurements, measured displacements between epicardial and endocardial crystal pairs were calibrated at the end of the experiment after death in hearts by simultaneous caliper measurements of wall thickness. The ratio of caliper to crystal measurements was used as a scaling factor to correct all previous measurements obtained from crystal pairs. This correction assumed that measured crystal displacements were a fixed fraction of the postmortem caliper measurements. Endocardial diameter at the equator was obtained by subtraction of twice the wall thickness from the epicardial diameter. The ventricle was modeled as a prolate ellipsoid and volume was calculated according to the formula:
Volume 104 Number 4 October 1992
Nonischemic ventricular distention
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Balloon Volume (mls) Fig. 3. Static pressure-volume data from the experimental (DSTN) group (n = II) are illustrated before (PRE) and after (POST) distention to a maximum pressure of 40 mm Hg. Each data point represents the volume (mean ± standard deviation) obtained during five balloon inflations to a constant pressure. The volume at each pressure is significantly greater after maximum distention (see Table I).
Table II. Unstressed LV diameters, volumes, and wall thicknesses before and after cardiopulmonary bypass and nonischemic cardioplegic arrest Control group
Anterior-posterior minor axis diameter (em) Base-apex major axis diameter (em) LV volume (ml) Wall thickness (mm)
Distended group
Before
After
Before
After
1.43 ± 0.10
1.42 ± 0.20
1.31 ± 0.35
1.64 ± 0.24*
6.68 ± 1.82
6.18 ± 1.83
6.55 ± 1.95
6.53 ± 1.42
7.4 ± 2.7 10.6 ± 1.4
6.9 ± 3.0 10.8 ± 1.4
5.9 ± 3.5 9.9 ± 1.7
9.5 ± 4.4* 10.0 ± 2.1
'p < 0.05 compared with value before distention.
Table III. Diastolic function before and after nonischemic cardioplegic arrest* Control group
Mathematical descriptors of the diastolic pressure-volume relationship
ex (rnm Hg) {3
Distended group
Before
After
Before
After
7.5 ± 4.9 0.9 ± 0.4
6.5 ± 9.9 3.7 ± 4.3
3.3 ± 4.8 2.5 ± 2.3
3.4 ± 2.9 4.2 ± 1.4
'None of the changes in either control or distended groups are statistically significant.
V= (rr/6) ab 2 where V is the LY volume, a is the endocardial major axis diameter, and b is the anterior-posterior endocardial minor axis diameter.'? Means of five saline-inflated balloon volumes at each distending pressure were recorded in all animals in the experimental group. The end-systolic pressure-volume relationship (ESPYR )20-22 was derived from data obtained at a wide range of L Y volumes during vena caval occlusion. At maximal occlusion, the unstress-
ed value of each dimension was obtained and the unstressed ventricular volume (Va) was calculated. All dimension data were normalized as Lagrangian strain according to
where 2; is the strain, D is any instantaneous dimension or volume, and Do is the unstressed dimension obtained at maximal vena caval occlusion.v ' With only diastatic data (ld2;/dtl s
The Journal of Thoracic and Cardiovascular Surgery
Downing et al.
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(Vd) of the ESPVR and the descriptors of the diastolic P - ~ relationship (a and (1) were also analyzed by covariance discriminant analysis,
•
o L:...:..':"':"':-'-'--''"'--'JLlL.ll..JLJLlL Fig. 4. Hemodynamic data from one of the distention experiments are shown before and after maximum ventricular distention. In each case the animal is no longer undergoingcardiopulmonary bypass and steady-state data are followed by a vena caval occlusion. With the onset of caval occlusion, both long and short ventricular diameters decrease and reciprocal changes are seen in wall thickness. As the heart empties, LV pressure declines. For each ventricular dimension unstressed length is identified as the value obtained at maximum caval occlusion at an end-diastolic LV pressure of a mm Hg. After distention the ventricle operates across an increased range of end-diastolic and end-systolic volumes. The increase in unstresseddiameter for both diameters is evident.Time scale is 2 seconds. 0.05 sec") to minimize the effect of viscoelastic properties," diastolic LV pressure was plotted against the normalizedanteroposterior diameter and fit to the following equation: P= a
(~L-l)
when P is the diastolic LV pressure, ~ is the strain, and a and (1 are nonlinear elastic constants that describe the curve mathematically.v '
Midwallcircumferentialstresswascalculated during steadystate conditions before and after bypass in seven animals during balloon inflation as described by Mirsky-:': s = (Pb/h) (I -b 2/2a2 - h/2b
+ h2/8a2 )
where s is the stress, P is the intraventricular (or intraballoon) pressure, a is the midwall semimajor axis, b is the midwall semiminor axis, and h is the wall thickness. All data are expressedas mean ± standard deviation. Paired data were analyzed by dependent t tests; significance required a value of p < 0.05 unless otherwise noted. Unpaired groups werecompared by independent t test. The slopeand x -intercept
Two experimental and one control sheep produced lactate during cardioplegia and were excluded from further analysis. The percentage of lactate extracted by the myocardium did not differ between groups (Fig. 2, A). Myocardial blood flow increased from 113 ± 34 to 195 ± 55 mljhg per minute in four experimental sheep after potassium-blood cardioplegia and from 103 to 265 mljhg per minute in one control animal. The ratios of subepicardial to subendocardial blood flow did not differ between the four experimental and one control sheep (Fig. 2, B) and were not altered substantially during cardioplegic arrest. The volumes required to inflate the ventricular balloon to constant pressures are shown in Table I. After inflation to a maximum of 40 mm Hg, the volume required to achieve each constant pressure significantly increased. The static pressure-volume relationship thus shifted to the right (Fig. 3). The mean volume at maximum distention, 65.5 ± 15.7 ml, was significantly larger than the mean maximal end-diastolic volume observed before bypass, 26.0 ± 11.4 ml. Similarly, in the four animals with regional segment-length transducers the maximum enddiastolic length before bypass was 20.1 ± 2.7 mm and increased significantly to 22.1 ± 3.6 mm during maximum distention to 40 mm Hg. At a pressure of 10 mm Hg during balloon distention, the mean segment length increased, from 17.3 ± 1.8 before to 20.2 ± 4.1 mm after maximal distention. Raw hemodynamic data from a typical experimental animal are shown in Fig. 4. Control data before initiation of cardiopulmonary bypass are shown, followed by data obtained after the termination of bypass and restoration of unassisted circulation (and therefore after ventricular distention). In this data set, steady state conditions are followed by vena caval occlusion. With onset of vena caval occlusion, both ventricular diameters decrease to a stable minimum and reciprocal changes are seen in the wall thickness. The LV pressure declines as the ventricle empties. At the same end-diastolic pressure after ventricular distention, the ventricle is operating across a higher volume range. The increase in the unstressed diameters of the ventricle is evident at the end of vena caval occlusion. The mean unstressed diameters, wall thicknesses, and volumes derived from vena caval occlusions obtained before and after bypass in both groups are shown in Table II. The unstressed ventricular dimensions and wall thick-
Volume 104 Number 4 October 1992
Nonischemic ventricular distention
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20 0
10
o
0
0
10
20
30
40
50
60
70
80
Calculated Volume (mls) Fig. 7. Data were available during balloon inflation in six experimentalanimals for comparisonof the LV volume, calculated from the dimension data measured by sonomicrometry, and the volume, measured as the fluid volume distending the LV. Linear regression of the measured volumeor the calculated volume revealed a high correlation (r = 0.89), with a slope of 1.02 and an intercept of -4.3. nesses did not change in the control group; there is therefore no change in unstressed volume. In the experimental group changes in unstressed major axis diameters were inconsistent (Fig. 4, Table II) but unstressed anteriorposterior minor axis diameters increased significantly, to produce a significant increase in the unstressed ventricular volume. Wall thickness did not change. Changes in the diastolic pressure-volume relationships obtained during vena caval occlusions before and after distention are similar to those observed in the static pressure-volume relationship during balloon inflation (Fig. 3). Specifically, the curve shifts to the right because of the increase in postdistention LV volumes. When the predistention volume data are normalized to the increased unstressed volume after distention, however, the pressure-strain relationship shifts upward and to the left (Fig. 5). This tendency is seen in all distention experiments. Because of the degree of variance in the data, however, comparison of the mathematic descriptors of the curves before and after bypass reveals no significant difference (Table III). There also is no change in the control group. The pressure-volume loops in Fig. 6 are derived from vena caval occlusions before and after bypass in another experimental animal. Again, at the same LV end-diastolic pressure during steady-state conditions before the vena
caval occlusion, the increased end-diastolic volume after distention is evident (Fig. 6, A and C). The ESPVR data from each vena caval occlusion are plotted as a linear regression. After distention (Fig. 6, D) the ESPVR is shifted down and to the right in comparison with the relationship before bypass (Fig. 6, B). As shown in Table IV, the mean slope of the ESPVR for each sheep decreased significantly after bypass in the experimental group, whereas there was no difference in the control group. There also was no difference between the groups before bypass. Before bypass the maximum midwall circumferential stress was 217.9 ± 55.9 dynes. ern? . 103 at a mean LV pressureofl02.8 ± 18.7mmHg(n = 6); maximal stress always occurred at the onset of ejection. In comparison, during maximal balloon distention at 43.6 ± 4.0 mm Hg midwall circumferential stress was significantly less, 148.8 ± 32.3 dynes. ern? . 103 (p < 0.05; n = 6). In six experimental animals, dimension data were available to compare the calculated volume with the measured volume infused into the balloon during balloon distention. As shown in Fig. 7, linear regression of calculated volume on measured volume revealed a high degree of correlation [r = 0.89; y(ml) = 1.02x - 4.3]. Discussion The stepwise distention protocol and the relatively brief and low distending pressures probably did not cause ventricular trauma. Distending pressures to 30 mm Hg only stretch collagen fibers/"; pressures as great as 70 to 100 mm Hg are required to disrupt these fibers and the collagen network.i" Sarcomeres are not stretched beyond 2.2 /-Lm until the collagen network is disrupted.i" Although the distending pressures in this study are above the normal diastolic range, they are below those associated with traumatic injury and calculated wall stresses are below those that normally occur during systole. The protocol also avoids regional and global ischemia. The heart receives continuous coronary arterial perfusion at 80 mm Hg or more throughout the 10 to 12 minutes of asytole. Cardiac arrestin diastole reduces myocardial oxygen demand. 25-28 Even when the ventricular balloon is inflated briefly, coronary perfusion pressure is always at least twice balloon pressure. As with the beating heart, balloon deflation ("diastole") is twice as long as balloon inflation ("systole"). Ventricular stretching does not change endocardial/epicardial flow ratios and the protocol does not initiate lactate production. Potassium is a powerful vasodilator that directly relaxes arteriolar smooth muscle in virtually every mammalian species tested.l? In dogs, a bolus injection of 40 /-Lmol of isosmotic potassium chloride reduces coronary vascu-
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Table IV. ESPVR beforeand after nonischemic cardioplegic arrest Before arrest
Control I 2 3 4 5 Mean ± SEM
p Experimental I 2 3 4 5 6 7 8 9 10 II
p
Mean ± SEM
After arrest
n
Ees (mm Hg . ml'"]
Vd (ml)
2 3 3 5 2 15
7.4 1.7 1.8 3.7 16.1 5.1 ± 5.5
6.4 -41.1 -20.1 -15.3 3.5 -16.0
0.88 0.97 0.98 0.92 0.75
2 4 4 3 5 I 3 I I 2 2 28
4.5 6.6 8.0 2.4 7.4 3.2 9.3 7.2 9.2 11.9 7.6 7.1 ± 2.7
14.5 12.8 12.3 -7.9 11.7 10.5 4.9 -0.2 2.7 -0.7 6.2 -6.7
.93 .94 .98 .86 .99 .96 .99 .85 .91 .96 .95
Ees (mmHg ml- 1)
Vd (ml)
2 4 I 4 2 13
7.9 1.4 2.5 3.6 14.3 5.1 ± 4.9 0.69
4.3 -23.4 -9.3 -12.7 1.9 -10.9
0.97 0.97 0.81 0.93 0.95
3 3 4 2 2 I 4 2 I I 2 25
2.7 2.1 3.3 1.4 5.9 2.1 4.4 2.7 7.2 3.1 3.4 3.4 ± 1.6 0.0002
12.7 -18.4 -3.5 -25.8 -8.9 1.4 -5.9 -17.0 8.1 -17.1 -14.9 -6.4
0.93 0.98 0.98 0.96 0.83 0.97 0.98 0.81 0.85 0.97 0.96
n
A mixed-model analysis of variance was used to calculate tests of statistical significance between before and after arrest values for elastance only with the Satterthwaite approximation method. The p value refers to within-group before and after means for elastance. The between-group comparison was not made. Ees, Mean end-systolic elastance or slope of ESPVR; Vd- mean intercept of Ees at zero pressure or volume at zero pressure; r, regression coefficient of a single representative elastance from the one to five slopes obtained for each sheep before and after arrest. SEM, Standard error of the mean.
lar resistance 34% to 48%30; an infusion of 8 mmol potassium chloride per kilogram body weight in glucose and insulin increases coronary blood flow 98% but does not change myocardial oxygen uptake." Potassium-blood cardioplegia also increased coronary blood flow in both the distended and control groups in this study. The increase in postperfusion coronary blood flow thus probably represents a direct effect of potassium on the coronary vasculature rather than reactive hyperemia. Ventricular stretching increases ventricular volume at zero pressure and by definition produces myocardial creep. The observation that free wall segment lengths increase similarly argues against the possibility that volume increases are caused by better apposition between the balloon and ventricular wall with repeated inflation. Both the static pressure-volume relationship (Fig. 3) and raw end-diastolic pressure-volume data shift to the right and indicate an apparent increase in chamber compliance. When strains are calculated for the distended LV after adjusting for the increased unstressed volume, the pressure-strain relationship shifts upwards and to the left (Fig. 5). These results confirm the diastolic changes reported previously in isolated cardiac muscle- 6 and in the excised
rabbit heart.' This contradicts the work of Lucas and coworkers.l? who distended hearts after cardioplegic arrest (beating empty for 15 minutes). The injury resulting from ischemic arrest seen even in their control animals, however, may have masked the effect of mechanical distention. We expected the increase in LV volume after distention to be associated with a decrease in wall thickness. The expected decrease did not occur (Table 11). An increase in potassium-induced vascular volume is a possible explanation. We used the ESPVR to assess myocardial contractility and fitted the data, which were obtained in vivo across the physiologic range of end-systolic pressures, to a linear rather than a parabolic function. The linear fit across the full range of pressures measured during caval occlusion produced generally high correlation coefficients (Table IV). Others have shown that a quadratic ESPVR model provides a better fit of data obtained across a wider range of ventricular pressures and volumes, particularly when nonphysiologic low volumes and pressures are inc1uded. 32- 34 However, the curvilinear model does not facilitate comparisons of contractile state." In the physiologic range of pressures and volumes, end-systolic elastance
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The Journal of Thoracic and Cardiovascular Surgery
Downing et al.
agrees well with the linear coefficient of the quadratic equation.P End-systolic elastance in the physiologic range thus provides a reliable measure of contractile state. 33 If data from the low end of our ESPVR measurements are excluded (i.e., all pressures below 65 mm Hg) end-systolic elastance before distention changes little, whereas end-systolic elastance after distention decreases further (to 2.2 ± 1.3 mm Hg . ml") and more closely reflects the gross appearance of the poorly contractile hearts in situ. Previous work has shown that changes in the diastolic properties of heart muscle can affect the ESPVR. IO Our current studies show for the first time that mechanical distention of the nonischemic, flaccid LV alters the material properties of the myocardium (i.e., causes creep) and that this alteration causes a reduction in contractile force. This observation has important implications. The first for cardiac surgeons is obvious: even transient ventricular distention of the nonbeating heart (during cardioplegia or ventricular fibrillation) must be avoided. During cardiac operations the heart is vulnerable to both stunning35,36 and stretching; both reduce contractile function. A second implication involves possible regional creep when surgeons rearrange the geometry of the ventricle, as in repair of LV aneurysms'? or closure of ventriculotomies. Operations that alter the geometry of the ventricle also alter regional ventricular wall stresses. Although not proven, it is possible that a sustained increase in stress of a segment of the ventricular wall can induce nonischemic myocardial creep and reduced segment-length shortening. A third implication involves the halo of poorly contracting nonischemic myocardium that surrounds an acute infarction. The temporary loss of contractile function in this adjacent myocardium is obviously detrimental and has been ascribed to a "tethering effect" of the infarct. Bogen and colleagues.P' however, calculated that wall stresses increase in both the infarct and adjacent hypokinetic halo, and Ratcliffe and colleagues directly calculated increases in halo wall stresses from twodimensional sonoarray images in sheep with acute anteroapical infarcts (unpublished observations). The "tethering effect" may thus induce regional myocardial nonischemic creep. The changes in ventricular pressure-volume relationships associated with nonischemic and ischemic creep appear similar, but the morphologic features, minimal distending volumes, and reversibility may not be similar. Ischemic creep is associated with an increase in sarcomere length.!" disruption of the collagen network.V' 40 and myocyte slippage. 24,41,42 George? has shown that extremely small distending volumes within the physio-
logicrange produce creep in excisedventricles.7 Thisobservation raises the possibility that changes in diastolic viscoelastic function may occur independently of changes in systolic function. Glower and colleagues'? have shown that ischemic creep is reversible. In dogs, as long as 12 hours is needed to reverse the myocardial creep and decreased ejection shortening produced by 15 minutes of ischemia. Stroke work does not return to normal for days.43 This study provides no data regarding the morphologic characteristics, minimal distending pressures, or reversibility of nonischemic creep. It is therefore probably not wise to assume that recovery of the stretched ventricle is more rapid than is recovery of the stunned ventricle. We thank Brandon Claytor, Michelle Haywood, and Myra Monahan for their important contributions to this work and recognize the assistance of Datascope Corp., Paramus, N.J., in designing and producing the distending balloon. REFERENCES I. Fung YC. Stress-strain relations of soft tissues in simple elongation. In: Fung YC, Perine N, Anliker M, eds. Biomechanics: its foundations and objectives. Englewood Cliffs, New Jersey: Prentice Hall, 1972:181-208. 2. Pinto JG, Paititucci PJ. Creep in cardiac muscle. Am J Physiol 1977;232:H553-63. 3. Pinto JE, Fung yc. Mechanical properties of the heart muscle in the passive state. J Biomech 1973;6:597-616. 4. Rankin JS, Arentzen CE, McHale PA, Ling D, Anderson R W. Viscoelastic properties of the diastolic left ventricle in the conscious dog. Circ Res 1977;41:37-35. 5. Rankin JS, Arentzen CE, Ring WS, Edwards CH, McHale PA, Anderson RW. The diastolic mechanical properties of the intact left ventricle. Fed Proc 1980;39: 141-7. 6. Fish D, Orenstein J, Bloom S. Passive stiffness of isolated cardiac and skeletal myocytes in the hamster. Circ Res 1984;54:267-77. 7. George DT. The mechanics of cardiac edema [Dissertation]. Philadelphia: University of Pennsylvania, 1990. 8. Edwards CH, Rankin JS, Mchale PA, Ling D, Anderson R W. Effect of ischemia on left ventricular regional function in the conscious dog. Am J PhysioI1981;240:H413-20. 9. Visner MC, Arentzen CE, Parrish DG, et al. Effects of global ischemia on the diastolic properties of the left ventricle in the conscious dog. Circulation 1985;71:610-9. 10. Glower DD, Schaper J, Kabas JS, et al. Relation between reversal of diastolic creep and recovery of systolic function after ischemic myocardial injury in conscious dogs. Circ Res 1987;60:850-60. 11. Hottenrot C, Buckberg G. Studies ofthe effects ofventricular fibrillation on the adequacy of regional myocardial blood flow. II. Effects of ventricular distension. J THORAC CARDIOVASC SURG 1974;68:626-33. 12. Lucas SK, Gardner TJ, Elmer EB, Flaherty JT, Bulkley
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BH, Gott VL. Comparison of the effects of left ventricular distension during cardioplegic-induced ischemic arrest and ventricular fibrillation. Circulation I980;62(Suppl):I42-9. 13. Lucas SK, SchaffHV, Flaherty JT, Gott VL, GardnerTJ. The harmful effects of ventricular distension during postischemic reperfusion. Ann Thorac Surg 1981;32:486-94. 14. Markovitz LJ, Savage EB, Ratcliffe MB, et al. A large animal model of left ventricular aneurysm. Ann Thorac Surg 1989;48:838-45. 15. Hale SL, Alker KJ, Kloner RA. Evaluation of non-radioactive colored microspheres for measurement of regional myocardial blood flowin dogs. Circulation 1988;78:428-34. 16. Jackson G. Laboratory diagnosis of myocardial ischemia. Cardiovasc Clin 1985;15:45-65. 17. Gertz EW, Wisnecki JA, Neese R, Houser A, Korte R, Bristow JD. Myocardial lactate extraction: multidetermined metabolic function. Circulation 1980;61:256-61. 18. Opie LH, Owen P, Thomas M, Sanson R. Coronary sinus lactate measurements in assessments of myocardial ischemia. Am J Cardiol 1973;32:295-305. 19. Rankin JS, McHale PA, Arentzen LE, Ling D, Greenfield JC Jr, Anderson RW. Three dimensional geometry of the left ventricle in the conscious dog. Circ Res 1976;39:304-13. 20. Suga H, Sagawa K, Shoukas AA. Load Independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 1973;32:314-22. 21. Sagawa K. The end-systolic pressure-volume relation of the ventricle: definition, modifications and clinical use. Circulation 1981;63:1223-7. 22. Spratt JA, Tyson GS, Glower DD, et al. The end-systolic pressure-volumerelationship in conscious dogs. Circulation 1987;75:1295-309. 23. Yin FCP. Ventricular wall stress. Circ Res 1981;49:829-42. 24. Factor SM, Flomenbaun M, Zhao M-J, Eng C, Robinson TF. The effect of acutely increased ventricular cavity pressure on intrinsic myocardial connective tissue. J Am Coll CardioI1988;12:1582-9. 25. Bittl JA, Ingwall JS. The energetics of myocardial stretch. Circ Res 1986;58:378-83. 26. Nozawa T, Yasumura Y, FutakiS, Tanaka N,SugaH. No significantincrease in 02 consumption of KC I-arrested dog heart with filling and dobutamine. Am J Physiol 1988; 255(Suppl):H807-l2. 27. LoiselleDS, Gibbs CL. Factors affecting the metabolism of resting papillary muscle. Pflugers Arch 1983;396:285-91. 28. Sink JD, Hill RC, Atarian DE, Wechsler AS. Myocardial blood flowand oxygen consumption in the empty, beating, fibrillating and potassium-arrested hypertrophied canine heart. Ann Thorac Surg 1983;35:372-9. 29. Haddy FJ. Potassium effects on contraction in arterial smooth muscle mediated by Na+, K+-ATPase. Fed Proc 1983;42:239-45.
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30. Murray PA, Sparks HV. The mechanism of K+-induced vasodilation of the coronary vascular bed of the dog. Circ Res 1978;42:35-42. 31. Bronsveld W, van Lambaigen AA, van den Bos GC, Thijs LG, Koopman PAR. Effects of glucose-insulin-potassium (GIK) on myocardial blood flow and metabolism in canine endotoxin shock. Circ Shock 1984;13:325-40. 32. BurkhoffD, Sugiura S, Yue DT, Sagawa K. Contractilitydependent curvilinearity of end-systolic pressure-volume relations. Am J Physiol 1987;252(Suppl):HI218-27. 33. Kass DA, Beyar R, Lankford E, Heard M, Maughan WL, Sagawa K. Influence of contractile state on curvilinearity of in situ end-systolic pressure-volume relations. Circulation 1989;79:167-87. 34. Van der Velde ET, Burkhoff D, Steendijk P, Karsdon J, Sagawa K, Baan J. Nonlinearity and load sensitivity of end-systolic pressure-volume relation of canine left ventricle in vivo. Circulation 1991;83:315-27. 35. Bavaria JE, Furakawa S, Kreiner G, et al. Myocardial oxygen utilization after reversible global ischemia. J THORAC CARDIOVASC SURG 1990;100:210-20. 36. Furakawa S, Bavaria JE, Kreiner G, Edmunds LH Jr. Relationship between total mechanical energy and oxygen consumption in stunned myocardium. Ann Thorac Surg 1990;149:543-9. 37. Savage EB, Downing SW, Ratcliffe MB, et al. Repair of left ventricular aneurysm: changes in ventricular mechanics, hemodynamics, and oxygen consumption. J THORAC CARDIOVASC SURG 1992;104:752-63. 38. Bogen DK, Rabinowitz SA, Needleman A, McMahon TA, Abelmann WHo An analysis of the mechanical disadvantage of myocardial infarction in the canine left ventricle. Circ Res 1980;47:728-41. 39. Zhao M, Zhang H, Robinson TF,Factor SM, Sonnenblick EH, Eng C. Profound structural alterations of the extracellular collagen matrix in postischemic dysfunctional ("stunned") but viable myocardium. J Am Coll Cardiol 1987;10:1322-34. 40. Caulfield JB, Tao SB, Nachtigal M. Ventricular collagen matrix and its alterations. Adv MyocardioI1985;5:257-69. 41. Olivetti G, Capasso JM, Sonnenblick EH, Anversa P. Side to side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res 1990;67:23-34. 42. Ross JR, Sonnenblick EH, Taylor RR, Spotnitz HM, Covell JW. Diastolic geometry and sarcomere lengths in the chronically dilated canine left ventricle. Circ Res 1971; 28:49-61. 43. Matsuzak M, Gallagher KP, Kemper WS, White F, Ross J Jr. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion. Circulation 1983;68:170-82.