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J Thorac Cardiovasc Surg 1994;108:467-476
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Effects of perfusion-induced edema on diastolic stress-strain relations in intact swine papillary muscle

New York, N.Y.

Supported in part by U.S. Public Health Service grants 1RO1HL41163 and 1F32HL07706.

Presented in part at the Thirty-ninth Annual Scientific Session of the American College of Cardiology.

Received for publication Aug. 25, 1993. Accepted for publication Jan. 9, 1994. Address for reprints: Henry M. Spotnitz, MD, Department of Surgery, Columbia University College of Physicians & Surgeons, 630 West 168th St., New York, NY 10032.

Abstract

The mechanism through which edema reduces left ventricular compliance has not been defined. Accordingly, diastolic properties of in situ left ventricular swine papillary muscles were studied in three groups: control (n= 6, 4°to 6°C), edematous (150 mOsm/L coronary perfusion, n= 6, 4°to 6°C), and ischemic contracture (n= 8, 28°C). Lagrangian stress () and strain () were calculated from slow stretch data and approximated by=(e^ß- 1). The natural logarithm of stress versus strain was linear over the physiologic range of 0.05 < strain < 0.40. Hypotonic perfusions (1 Lx3) progressively shifted the stress-strain relationship upward and to the left. Compared to baseline,increased significantly (p< 0.05) after perfusion 3 (6.7±2.1 baseline, 12.2±6.6 perfusion 1, 12.7±3.5 perfusion 2, and 42.9±16.3 gm/cm²perfusion 3). The constantßdid not change significantly (13.0±1.5 baseline, 13.1±1.6 perfusion 1, 13.2±1.6 perfusion 2, and 14.1±1.4 perfusion 3). Right ventricular water content increased after each perfusion (77.1%±1.4% baseline, 81.6%±1.3%, 84.7%±1.5%, and 86.9%±1.7%, p< 0.05). With ischemic contracture,increased from 61.9±17.8 to 173.1±61.5 gm/cm²(p> 0.05) andßincreased insignificantly from 6.5±0.6 to 10.6±1.8 (p= NS). In the control group all variables were unchanged after 210 minutes. We conclude that myocardial stiffness increases with myocardial edema. This may explain decreased compliance in the edematous left ventricle. (J THORACCARDIOVASCSURG1994;108:467-76)

Although myocardial edema has been demonstrated in clinical ¹ and experimental studies, ^2-4 detrimental hemodynamic effects of edema have been difficult to quantify. Studies suggesting that edema can decrease left ventricular (LV) compliance ^1,3,5,6 have recently been strengthened by data demonstrating a linear relationship between edema-induced increases in heart weight and decreased LV compliance. ⁷ The mechanism for edema-related changes in compliance has not been demonstrated and is controversial because of volume-displacement effects of edema. ⁸ Thus it has been argued that decreasing end-diastolic volume in the edematous LV simply reflects increased wall thickness caused by edema. ⁸ Studies of papillary muscle, ^9-12 especially in situ, ^13-15 might resolve this issue because effects of edema on length-tension properties could be studied independent of increases in ventricular wall thickness. Accordingly, in the present study we investigated the effects of coronary perfusion on the diastolic stress-strain relationship of the intact papillary muscle in the isolated heart. The study was designed to allow perfusion-induced alterations in papillary muscle stiffness to be distinguished from time-dependent effects, including ischemic contracture.

MATERIALS AND METHODS

Twenty domestic, specific pathogen–free swine, weighing 43 to 60 kg, were anesthetized with an intramuscular injection of ketamine (20 mg/kg), xylazine (1.6 mg/kg), and atropine (2 mg), intubated, and their lungs mechanically ventilated with ambient air. Anesthesia was maintained with intravenous sodium pentobarbitol (650 mg). A median sternotomy and longitudinal pericardiotomy were performed. The inferior vena cava, superior vena cava, and aorta were isolated with umbilical tapes. After systemic heparinization (1500 units), the inferior and superior venae cavae were ligated, the aorta was crossclamped, and artificial respiration was stopped. Hearts were arrested with simultaneous topical cooling and aortic injection of potassium chloride (80 mEq) and rapidly excised from the thorax. Fluid was evacuated from the ventricular and atrial chambers, the epicardial surface was blotted dry, and hearts were weighed on a triple-beam balance (Ohaus, DEC-O-GRAM, Florham, N.J.). Heart weight averaged 189 ± 9 gm (mean ± standard error). Transmural specimens were obtained from both the free wall of the right ventricle (RV) along the distal distribution of the right coronary artery and from the interventricular septum to determine myocardial water content. Hearts in control and perfusion groups were immersed in an iced Ringer's lactate bath (4° to 6° C). Hearts in the rigor group were maintained at room temperature. Myocardial temperature was monitored with a needle thermistor and digital thermometer (NTM-100, Wilton Webster Laboratories, Altedena, Calif.).

All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).

Heart preparation.
The left atrium was removed and weighed. The mitral valve leaflets were sutured together and dissected free of the anulus. Chordae tendineae connecting to the anterior papillary muscle were severed. The interventricular septum was exposed through the RV and opened with a longitudinal incision (4.0 cm) adjacent to the junction of the RV and the interventricular septum. A 2.5 cm diameter circular Teflon patch (USCI, C.R. Bard, Inc., Billerica, Mass.) was used to suture the apex of the heart to a rigid support plate.

Stress-strain apparatus.
The displacement mode apparatus is shown in Fig. 1. The support plate was bolted to the bottom of a test chamber, and hearts were immersed in isotonic saline to prevent myocardial desiccation and to control temperature. Lateral support of the heart was provided by 2-0 silk with pledgets connecting the free edges of the incised septum to eyelets attached to the wall of the chamber. The valve complex of the posterior LV papillary muscle was connected to a linear displacement syringe pump (model 351, Sage Instruments, Cambridge, Mass.) by preconditioned 0-0 silk joined to a spring-loaded alligator clip. A force transducer (FT-50-1-MM-W, Analog Devices, Norwood, Mass.) modified with right/angle brackets was connected in series with the displacement apparatus. Compliance of the experimental apparatus, 1.34 µm/gm, was found to vary linearly over the experimental range of force. Voltage differences from the transducer were filtered (f_c = 10 to 20 Hz) and amplified with a high-performance band-width strain-gauge signal conditioner (model 1B31, Analog Devices). The accuracy of the unit was 0.5 gm (0.1%) and the drift was ±0.25 µV/°C. Bridge excitation of the conditioner was maintained at 15 V with a triple-output power supply (model 6237B, Hewlett-Packard, Palo Alto, Calif.). Analog output from the signal conditioner was obtained with a dual-beam oscilloscope (model 2213, Tektronix, Beaverton, Ore.) and recorded on a digital computer (Apple Macintosh 512e, Apple Computer, Cupertino, Calif.). Starting from a small force (less than 120 gm), the extension of the papillary muscle was decreased to determine the position at which no force was discernible. This position was recorded from a ruler mounted on the syringe pump. Loading was initiated from this point by reversing the direction of linear displacement (L). Force samples (F) were recorded every 0.25 cm at a constant rate of 0.025 cm/sec. When a force of 2000 gm or a linear displacement of 2.5 cm was achieved, extension was terminated and loading was decreased to zero. Runs were repeated until the effects of hysteresis ^12,16 were resolved, that is, no detectable shift to a smaller force at given linear displacements of consecutive extensions (Fig. 2). At the conclusion of each experiment, the papillary muscle was released from the displacement apparatus and allowed to attain an unstressed geometry. Papillary length, major (d₁) and minor (d₂) papillary diameters, heart weight, and LV and RV water content samples were then measured.

View larger version (41K): [in this window] [in a new window]   Fig. 1. Apparatus for measurement of in situ stress-strain curves, myocardial water content (RV biopsy), and septal temperature (thermistor) in studies of the posterior papillary muscle in excised pig hearts. Reservoir allows gravity-induced constant-pressure coronary perfusion at 60 mm Hg via the aortic root. Ao, Aorta; LV, left ventricle; RV, right ventricle.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Representative example of hysteresis: Repeated stretching of the papillary muscle results in a shift of the stress-strain curve to the right. This shift becomes progressively smaller with each cycle, becoming insignificant after three to five cycles. Control data were not collected until this equilibration phase was complete and curves were reproducible. Only the loading phase is depicted.

Coronary perfusion group.
Six cold (4° to 6° C) swine hearts were prepared as described earlier. Control force–linear displacement data and water content samples were obtained at 40 minutes of ischemia. The aorta was then clamped above the coronary ostia and 1 L of hypotonic perfusate at 4° to 6° C was infused into the aorta through a cardioplegia needle. The 150 mOsm/L hypotonic coronary perfusate was prepared from a commercial cardioplegic solution (Plegisol, Abbott Laboratories, Chicago, Ill.) and distilled water as reported previously. ⁷ Composition of the perfusate was as follows: Na 65⁺ mEq/L, K⁺ 8 mEq/L, Mg⁺⁺ 16 mEq/L, Ca⁺⁺ 1.2 mEq/L, Cl^-80 mEq/L, and HCO₃^- 10 mEq/L. Osmolarity was 150 mOsm/ L, and onconicity was 0 torr. The cut edges of the RV and LV served as sites for fluid egress. Global coronary perfusion was verified at the end of each experiment with perfusates containing dye (Evans blue dye, Fisher Scientific, Springfield, N.J.). Perfusion pressure was maintained at 60 mm Hg by a fluid reservoir located 32 inches above the heart (Fig. 1). After perfusion, force–linear displacement data and transmural myocardial samples for water content were obtained from the RV. The papillary muscles were studied immediately after coronary perfusion and were not subjected to any hydrostatic pressure during the acquisition of force-displacement data. At the conclusion of each experiment, myocardial samples for water content were obtained from both the RV and the LV papillary muscle used for stress-strain analysis. Perfusion was repeated three times. All studies were completed within 210 minutes.

Ischemic contracture group.
Eight swine hearts were prepared as described earlier, except for temperature, which was maintained at 28° C. Force–linear displacement data were obtained at 40 minutes and every hour thereafter until there was no change in force at a given linear displacement. Ischemic controls were not perfused. Water content was not determined.

Data analysis
Stress-strain relationship.
Force–linear displacement data were normalized to allow comparison of muscles of varying size. The cross section of the papillary muscle was treated as an ellipsoid of average diameter (d₁d₂). Cross-sectional area was found by d₁d₂/4. Force–linear displacement data were corrected to reflect the series compliance of the experimental apparatus (1.34 µm/gm) and chordae tendineae (0.20 µm/gm). The correct linear displacement was calculated by subtracting the displacement of the experimental apparatus and chordae tendineae at a measured force (1.54 µm/gm · F) from the measured linear displacement of the syringe pump. Lagrangian stress () was calculated as force/cross-sectional area. Lagrangian strain () was given by the ratio linear displacement/papillary length. The diastolic stress-strain relationship is nonlinear and can be modeled unidirectionally by the following equation ¹⁷:

=(e^ß- 1). (1)

where (grams per square centimeter) is a constant necessary to define the stress-strain relationship and ß is a dimensionless constant that categorizes the nonlinear elastic property. ¹⁴ Application of this constitutive equation for comparison of and ß values at different edematous states assumes that the myocardium remains incompressible. The physiologic range over which this equation applies was determined by plotting the natural logarithm of stress versus strain. ^11,14 The constants and ß were determined with commercially available regression software (Systat 5.0, SYSTAT Inc., Evanston, Ill.). Tests for statistical significance were also based on interval analysis. This included comparison of stresses observed at a strain of 0.3, abbreviated as (0.3), calculated from equation (1). In addition, data from the hypotonic perfusions were divided into five intervals of stress: 15 to 39.9, 40 to 99.9, 100 to 249.9, 250 to 649.9, and 650 to 1000 gm/cm². For each interval, a mean strain was calculated and mean results were compared by analysis of variance.

Myocardial water content and heart weight. Myocardial specimens from the RV and LV were blotted dry and the wet weight was obtained with an electronic analytic balance sensitive to 0.1 mg (XA Analytical Balance, Fisher Scientific). Dry weight was obtained after samples were dried to a constant weight for approximately 48 hours in an 80° C oven. Water content (WC) was calculated from this equation:

WC = ([Wet weight - Dry weight]/ [Wet weight]) x100% (2)

Satistical methods
Data were averaged and compared within each experimental group by the paired t test or by analysis of variance for repeated measures at the 5% significance level. Mean stress-strain plots for each state within experimental groups were generated from mean values of and ß by equation (1). The change in weight (percent) of each heart within the perfusion group was correlated with the corresponding difference in water content by linear regression.

RESULTS

Perfusion group
Representative stress-strain plots for papillary muscle subjected to stress-strain analysis after serial hypotonic (150 mOsm/L) coronary perfusion are presented in Fig. 3. The exponential curves fit the data very well. The natural logarithm of stress versus strain data are linear over the range 0.05 < strain < 0.40. After each perfusion, the stress-strain curve is shifted upward and to the left relative to preceding curves and the control curve. Heart weight and water content increased after each perfusion.

View larger version (26K): [in this window] [in a new window]   Fig. 3. Representative example of Lagrangian stress-strain data before (Control) and after each of three serial coronary perfusions (P1, P2, P3). Hypotonic perfusate (150 mOsm/L) caused progressive edema and progressive shifts upward and to the left of the stress-strain relationship (see Table I). Myocardial temperature was 4° to 6° C.

Tables I

Table I

View larger version (28K): [in this window] [in a new window]   Fig. 4. Effect of hypotonic (150 mOsm/L) coronary perfusion on stress-strain data for LV papillary muscle. Mean results are shown; standard errors are indicated by brackets. Each perfusion (P1, P2,P3) is followed by a shift of the stress-strain relation upward and to the left, indicating increased stiffness. Differences were statistically significant after P3 (see Table I).

Table II

Water content increased significantly after each perfusion (77% ± 1%, 82% ± 1%, 85% ± 2%, and 87% ± 2%, p < 0.05). After the third perfusion, water content in LV papillary muscle was not significantly different from RV water content (86.7% ± 3.0% versus 86.9% ± 2.9%, Fig. 5). Heart weight increased from 219 ± 11 gm in the control state to 313 ± 12 gm after perfusion 3 (p < 0.05). Increases in heart weight and water content were linearly related (r = 0.805, p < 0.05) when data from control, perfusion 1, perfusion 2, and perfusion 3 were examined (Fig. 6).

View larger version (16K): [in this window] [in a new window]   Fig. 5. Water content of LV papillary muscles, subjected to stress-strain analysis, versus water content of the RV of the same heart. Data, obtained after the third hypotonic perfusion, indicate that water content from the RV was also representative of the LV papillary muscle (r = 0.878).

View larger version (17K): [in this window] [in a new window]   Fig. 6. Percent change in heart weight versus percent change in myocardial water content after three hypotonic perfusions for six experiments in the perfusion group (p < 0.05). The correlation coefficient for least squares linear regression fitted to the data is r = 0.80.

View larger version (18K): [in this window] [in a new window]   Fig. 7. Lagrangian stress-strain curves demonstrating a significant increase in from 40 minutes of ischemia to ischemic contracture. The true stress at a physiologic strain of 0.3 increased by a factor of 20 between the two states. Myocardial temperature was maintained at 28° C in an isotonic bath. Data are summarized in Table I.

Table II

View larger version (16K): [in this window] [in a new window]   Fig. 8. Mean Lagrangian stress-strain curves for the control group at 40 and 210 minutes of ischemia. There was no detectable change in or ß (Table II). Myocardial temperature was maintained at 4° to 6° C. Data are summarized in Table I.

The present results extend previous studies of linear diastolic properties to demonstrate that perfusate-induced edema increases diastolic stiffness of papillary muscle. This is demonstrated as an increase in the constant for stress-strain curves. These data appear to resolve the controversy surrounding the mechanism of decreased ventricular compliance in the presence of edema. This observation supports the view that alterations in LV compliance caused by edema may be predicted from changes in water content or from measurement of changes in LV mass. ⁷

Although the present results demonstrate an increase in cellular stiffness provoked by edema, the mechanisms allowing edema to alter length-tension properties remain undefined. Steenbergen, Hill, and Jennings ¹⁸ demonstrated that a 5% increase in myocardial water content can increase intracellular water content by as much as 50%. Such expansion of intracellular volume could raise intracellular pressure sufficiently to increase cellular resistance to elongation beyond the unstressed diastolic length. Additional studies will be required to resolve this issue.

The present study is based on previous studies of the passive elastic properties of myocardium using stress-strain relationships determined experimentally from papillary muscle preparations, both isolated ^9,12,19,20 and intact. ^13,14 These properties have also been estimated from experimental pressure-volume data. ^11,21 Parameters in this relationship have detected differences between normal and abnormal cardiac states. ^10,11,16,17

Unidirectional Lagrangian stress () and strain () calculated from slow stretch data were found to vary exponentially in this study, approximated by the relationship = (eß- 1). The natural logarithm of stress versus strain was found to be linear over the physiologic range of 0.05 < strain < 0.40, consistent with the findings of Mirsky and Parmley ¹¹ and Kitabatake and Suga. ¹⁴ Mirsky and Parmley ¹¹ studied isolated cat papillary muscle and found to be 4.4 gm/cm ² and ß equal to 25.8. These values are comparable with the ß values in Table I for normal (10.5 to 10.7) and edematous papillary muscle (13.0 to 14.1). Kitabatake and Suga ¹⁴ reported a significant linear correlation between the papillary muscle stiffness constant and coronary perfusion pressure in the canine RV. In their study, ß (18.0 ± 1.0) for physiologic pressures was comparable with control and edematous values in the present study. The probability of edema formation under the cross-circulation conditions they used appears high, because postischemic coronary perfusion pressure above 50 mm Hg has been shown to cause myocardial edema. ^22,23

A cold control group with no perfusion was used in our study to confirm that no alteration in stress-strain properties would be expected in the absence of perfusion. Ischemic contracture (rigor, see Table I) was also used to test the sensitivity of the preparation using an experimental state for which the effect on diastolic properties in the intact ventricle is well established. ²⁴ The effects of rigor and edema on the constant were similar, although control values in the rigor study were greater than in the edema group. Changes in ß were not statistically significant in either the edema group or the rigor group.

Little ¹⁶ hypothesized that the significance of changes in can be defined by means of a two-element model. The first element encompasses all elastic properties of the myocardium. The second element is not defined anatomically; however, it is suggested that it could represent the contractile element in Hill's initial model. ²⁵ When the papillary muscle is stretched to a given strain and then held constant, the stress experienced by the stretched elastic element will be inversely related to the length of the contractile unit. In this model, an increase in implies a decrease in the length of the contractile element. Barry and colleagues ²⁶ found that the y-intercept of the diastolic pressure-volume curve increased during attacks of angina. This increase was ascribed to impaired diastolic relaxation shifting the stress-strain curve to the left, thereby increasing .

The value of has been shown to be sensitive to errors encountered from the determination of muscle cross section. ²⁰ Because we normalized all force data by means of the cross-sectional area calculated at the completion of each experiment, errors caused by edema-related increases in major and minor papillary diameters may have occurred. Overestimation of papillary cross-sectional area affects the stress-strain relationship by underestimating ; the calculated value of ß is unaffected. However, edema-induced errors in papillary length could directly affect ß. This error was minimized by using an experimental model with a large papillary length. The coordinate at which the chordae tendineae and papillary muscle showed the first visual sign of stress was recorded to assess possible changes in papillary length attributable to edema. If changes occurred, they were smaller than 1 mm (corresponding to a strain of 0.02) and were not detected. Potential errors from damaged ends ¹⁹ were not categorized but are believed to be negligible because of the long length of the papillary muscles used. Contamination of the data by series elasticity is believed to be of minor importance in this system. Suga, Nakayama, and Sagawa ¹³ reported that errors in ß could be introduced by the series elastic extension of the chordae tendineae when the papillary muscle was loaded. They reported a compliance of 700 µm/300 gm for a single canine chordae tendineae. In the present study, force was distributed over approximately 10 chordae tendineae; thus extension attributable to chordae was estimated to be 0.2 µm/gm. System compliance was adjusted to 1.54 µm/gm to compensate for this effect.

Because the water content of the papillary muscles used for stress-strain analysis could not be determined after each perfusion, biopsy specimens from the RV were taken throughout the experiment. Water contents from the RV and the LV papillary muscle were compared at the completion of the third perfusion and are presented in Fig. 5. All six experimental points fell close to the line of identity (r = 0.878), and it is believed that water content determined from the RV is quantitatively representative of that in the experimental papillary muscle.

The hypotonic perfusate used (150 mOsm/L) was chosen because it had been shown to induce edema in the isolated LV and because its effects on the compliance of the excised LV are known. ⁷ The goal of this study was to demonstrate that increasing myocardial water content is associated with increases in diastolic myocardial stiffness. The present results are consistent with the view that the myocardium absorbed water on perfusion with the experimental solution and that the accumulation of water was responsible for the observed changes in the passive mechanical properties.

Because edema studies were conducted at 4° to 6° C, the effects of temperature on diastolic properties deserve some consideration. Prior studies from our laboratory have shown no effect of temperature variation in the range of 28° to 37° C on the diastolic pressure-volume relation of the isolated LV. Similarly, no effect of temperature was noted on the diastolic properties of the cooled heart allowed to assume a naturally reduced heart rate. ²⁷ In contrast, other investigators found that decreasing temperature reduced compliance of the intact heart when heart rate was increased by pacing. ²⁸ These results suggest that temperature influences diastolic properties primarily through viscous effects. The time constant of these viscous effects appears too long to influence the model presented here. In an elegant discussion of the effects of temperature on the diastolic properties of papillary muscle, Pinto and Fung ¹² demonstrated that slow cyclic loading and unloading at a constant strain rate produces a unique stress-strain relationship that is independent of temperature in the range 5° to 37° C.

To explore the possibility of a biphasic mechanical mechanism, ²⁹ we plotted the natural logarithm of force against the corresponding papillary length for control and after hypotonic perfusion of several muscles. For both control and edematous tissue, the relationship was found to be linear over the entire range of papillary extension. This suggests that the effects of edema on the passive diastolic properties are present at low as well as high strains. Appropriately, this study considers both and ß. Curve fits for the perfusion group by the equation = (eß- 1) had a mean r = 0.996. This relationship is attractive because the term eß approaches unity as (strain) approaches zero, ²⁰ forcing the stress-strain relationship to pass through the origin. Differentiation of this relationship with respect to strain yields d/d = ß( + ). Thus ß in the present study is the same as the elastic stiffness constant determined from the tangent modulus (d/d) as a function of (stress). ¹¹ The equation = e^ße + c has also been widely used. ^11,19,21 The constant c was determined analytically at known values of stress and strain. ^30,31 Both positive and negative values of c, not equal to -, have been reported. This method can predict a negligible offset of stress at zero strain. Equation (1) is generated from this equation by setting the constant c equal to -.

Myocardium is generally modeled as an incompressible tissue because changes in density, under most conditions, are negligible. It is possible in the present model that stretching the edematous papillary muscle extruded water from the intracellular and interstitial spaces. This effect could hinder interpretation of stress-strain data of each perfusion compared with control or another perfusion. If present, this phenomenon should be apparent in the most edematous state. As fluid is forced out of the myocardium, we would expect a shift in the stress-strain curve toward the control state and stress relaxation when displacement is ceased; neither was observed. If one assumes that no water is displaced from the muscle during stretching, the shift in myocardial density from 1.05 gm/cm³ toward the limit of 1.00 gm/cm³ with increasing edema is negligible. Finally, we measured serial pressure-volume curves 0, 10, and 50 minutes after hypotonic perfusion in the cold, excised rat heart and found no change in the pressure-volume data, suggesting fluid extrusion (Detwiler and associates, unpublished data).

The applicability of the present study in the pig to clinical problems in human beings requires further investigation. Specifically, the extent of ischemia-related myocardial edema and its effect on LV compliance in the human heart must be delineated. Ischemia has been shown to cause swelling of cellular elements in the rat kidney ³² and porcine ³³ and canine heart. ³⁴ The primary mechanism of ischemia-induced edema formation involves an increase in intracellular Na⁺ attributable to the breakdown of energy-dependent sodium extrusion. ³⁵ A secondary mechanism includes the anaerobic conversion of glycogen to lactate and the hydrolysis of high-energy phosphates, ³³ increasing intracellular oncotic pressure relative to the interstitium. Pine and associates ^36,37 found that simultaneous metabolic blockade and inhibition of Na^+-K⁺ exchange pump activity of papillary muscle prevented cell swelling over 60 minutes, suggesting that over the short time scale, oncotic pressure gradients created by anaerobic metabolites are more important than electrolyte-associated osmotic derangement. Cell membrane damage is a third mechanism. ^36,38 It is believed that the adenosine triphosphate depletion associated with membrane damage was avoided in this preparation by using hypothermic conditions and by limiting the experimental time.

The relevance of the present results to myocardial edema observed in vivo is also tempered somewhat by the fact that the mean water content we observed after the first perfusion, 81.6%, is commonly observed clinically and experimentally with injury or hemodilution, ^1-8,39-41 whereas the levels observed after the second and third perfusions are observed after severe stresses, including some crystalloid-based Langendorff preparations. Questions about the persistence and physiologic significance of perfusion-induced edema also require further investigation, because edema induced by hypotonic perfusion is partially reversed by subsequent perfusion with hypertonic solutes. ⁴¹ Recent studies from our laboratory indicate that perfusion-induced edema can resolve with as little as 15 minutes of blood reperfusion, if ischemic injury is limited. ⁴²

We conclude that myocardial edema increases diastolic stiffness of papillary muscle and that water content can be correlated with the slope of the stress-strain relationship. It appears that this mechanism explains the negative effect of edema on compliance of the intact LV.

ACKNOWLEDGEMENT

We express our appreciation to the following persons who have assisted in the preparation of this manuscript: Robert Sciacca, EngSci, for statistical consultation, Laura Pawlicky for editorial assistance, and Lars Weiss, Mark Bielefeld, MD, and Louis Vu, MS, for technical assistance.

Footnotes

*Present address: Barrow NI Hospital, Phoenix, Ariz.

**Present address: Medical College of Wisconsin, Milwaukee, Wis.

***Present address: Veterans General Hospital, Taipei, Taiwan, Republic of China.

References

1. Cross CE, Rieben PA, Salisbury PF. Influence of coronary perfusion and myocardial edema on pressure-volume diagram of left ventricle. Am J Physiol 1961;201:102-8.[Abstract/Free Full Text]
   
2. Haasler GB, Rodigas PC, Collins RH, et al. Two-dimensional echocardiography in dogs: variation of left ventricular mass, geometry, volume, and ejection fraction on cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1985;90:430-40.[Abstract]
   
3. Geffin GA, Vasu MA, O'Keefe DD, et al. Ventricular performance and myocardial water content during hemodilution in dogs. Am J Physiol 1978;235:767-75.
   
4. Foglia RP, Buckberg GD, Lazar HL, Manganaro A, DeLand E. Effectiveness of mannitol after ischemic myocardial edema. Surg Forum 1978;29:320-3.[Medline]
   
5. Salisbury PF, Cross CE, Rieben PA. Distensibility and water content of heart muscle before and after injury. Circ Res 1960;8:788-93.[Abstract/Free Full Text]
   
6. Foglia RP, Partington MT, Buckberg GD, Leaf J. Iatrogenic myocardial edema with crystalloid primes. Curr Stud Hematol Blood Transfus 1986;53:53-63.
   
7. Weng Z-C, Nicolosi AC, Detwiler P, et al. Effects of crystalloid, blood, and UW perfusates on weight, water content, and left ventricular compliance in an edema-prone, isolated porcine heart model. J THORAC CARDIOVASC SURG 1992;103:504-13.[Abstract]
   
8. Schaff HV, Magee PG, Flaherty JT, Goldman RA, Gardner TJ, Gott VL. Are postischemic hearts really stiffer? Surg Forum 1978;29:265-7.
   
9. Hoffman BF, Bassett AL, Bartelstone HJ. Some mechanical properties of isolated mammalian cardiac muscle. Circ Res 1968;23:291-312.[Abstract/Free Full Text]
   
10. Wildenthal K, Skelton CL, Coleman HN III. Cardiac muscle mechanics in hyperosmotic solutions. Am J Physiol 1969;217:302-306.[Free Full Text]
    
11. Mirsky I, Parmley WW. Assessment of passive elastic stiffness for isolated heart muscle and the intact heart. Circ Res 1973;33:233-43.[Abstract/Free Full Text]
    
12. Pinto JG, Fung YC. Mechanical properties of the heart muscle in the passive state. J Biomech 1973;6:597-616.[Medline]
    
13. Suga H, Nakayama K, Sagawa K. Nonexcised papillary muscle preparation: force and length measurements and control. Am J Physiol 1977;233:H162-H167.
    
14. Kitabatake A, Suga H. Diastolic stress-strain relation of nonexcised blood-perfused canine papillary muscle. Am J Physiol 1978;234:H416-20.[Abstract/Free Full Text]
    
15. Endoh M, Koroku H. Frequency-force relationship in the blood-perfused canine papillary muscle preparation. Jpn J Physiol 1970;20:320-31.[Medline]
    
16. Little RC. The effect of acute hypoxia on the viscoelastic properties of the myocardium. Am Heart J 1976;92:609-14.[Medline]
    
17. Rabinowitz S, Radvany P, McMahon T, Abelmann W. Passive elastic properties of normal and infarcted myocardium. Circulation 1978;58:159.
    
18. Steenbergen C, Hill ML, Jennings RB. Volume regulation and plasma membrane injury in aerobic, anaerobic, and ischemic myocardium in vitro: effects of osmotic cell swelling on plasma membrane integrity. Circ Res 1985;57:864-75.[Abstract/Free Full Text]
    
19. Donald TC, Reeves DNS, Reeves RC, Walker AA, Hefner LL. Effect of damaged ends in papillary muscle preparations. Am J Physiol 1980;238:H14-23.
    
20. Yin FCP. Ventricular wall stress. Circ Res 1981;49:829-42.[Free Full Text]
    
21. Glantz SA, Kernoff RS. Muscle stiffness determined from canine left ventricular pressure-volume curves. Circ Res 1975;37:787-94.[Abstract/Free Full Text]
    
22. Engelman RM, Alder S, Gouge TH, Chandra R, Boyd AD, Baumann FG. The effect of normothermic anoxic arrest and ventricular fibrillation on coronary blood flow distribution of the pig. J THORAC CARDIOVASC SURG 1975;69:858-69.[Abstract]
    
23. Swanson DK, Myerowitz PD. Effect of reperfusion temperature and pressure on the functional and metabolic recovery of preserved hearts. J THORAC CARDIOVASC SURG 1983;86:242-51.[Abstract]
    
24. Griggs DM Jr, Holt PR, Case RB. Serial pressure-volume studies in the excised canine heart. Am J Physiol 1960;198:336-40.[Abstract/Free Full Text]
    
25. Hill AV. The mechanics of active muscle. Proc R Soc Lond Ser 1971;B141:104-17.
    
26. Barry WH, Brooker JZ, Alderman EL, Harrison DC. Changes in diastolic stiffness and tone of the left ventricle during angina pectoris. Circ Res 1974;34:255-63.
    
27. Haasler GB, Rodigas PC, Spotnitz HM. The absence of temperature effects on end-diastolic pressure-volume relations in the canine left ventricle determined by two-dimensional echocardiography. J THORAC CARDIOVASC SURG 1982;83:878-90.[Abstract]
    
28. Braunwald E, Frye RL, Ross J Jr. Studies on Starling's law of the heart: determinants of the relationship between left ventricular end-diastolic pressure and circumference. Circ Res 1960;8:1254-63.[Abstract/Free Full Text]
    
29. Pinto JG, Fung YC. Mechanical properties of heart muscle in the passive state. J Biomech 1973;6:597-616.
    
30. Gordon AM, Huxley AF, Julian FJ. The variation in isometric tension with sarcomere length in vertebral muscle fiber. J Physiol Lond 1966;184:170-92.[Abstract/Free Full Text]
    
31. Diamond G, Forrester JS, Hargis J, Parmley WW, Danzig R, Swan HJC. Diastolic pressure-volume relationship in the canine left ventricle. Circ Res 1971;29:267-75.[Abstract/Free Full Text]
    
32. Flores J, DiBona DR, Beck CH, Leaf A. The role of swelling in ischemic renal damage and the protective effect of hypertonic solute. J Clin Invest 1972;51:118-26.
    
33. Tranum-Jensen J, Janse MJ, Fiolet JWT, Krieger WJG, D'Alnoncourt CN, Durrer D. Tissue osmolality, cell swelling, and reperfusion in acute regional myocardial ischemia in the isolated porcine heart. Circ Res 1981;49:364-81.[Free Full Text]
    
34. DiBona DR, Powell WJ. Quantitative correlation between cell swelling and necrosis in myocardial ischemia in dogs. Circ Res 1980;47:653-65.[Free Full Text]
    
35. Leaf A. Regulation of intracellular fluid volume and disease. Am J Med 1970;49:291-5.[Medline]
    
36. Pine MB, Bing OHL, Abelmann WH. Comparisons of changes in tissue water and electrolytes after metabolic blockade and after inhibition of the NA-K exchange pump in heart and kidney slices. Am J Cardiol 1977;39:313.
    
37. Pine MB, Bing OHL, Brooks WW, Abelmann WH. Changes in in vitro myocardial hydration and performance in response to transient metabolic blockade in hypertonic, isotonic, and hypotonic media. Cardiovasc Res 1978;12:569-77.[Medline]
    
38. Jennings RB, Reimer KA. Lethal myocardial ischemic injury. Am J Pathol 1981;102:241-55.[Medline]
    
39. Gross H. Water content of the myocardium in hypertrophy and chronic congestive failure. J Lab Clin Med 1940;25:899-911.
    
40. Spotnitz HM, Hsu DT. Myocardial edema: importance in the study of left ventricular function. Adv Cardiac Surg 1994;5:1-25.[Medline]
    
41. Hsu DT, Weng Z-C, Nicolosi AC, Detwiler PW, Sciacca R, Spotnitz HM. Quantitative effects of myocardial edema on the left ventricular pressure-volume relation in the isolated stored pig heart. J THORAC CARDIOVASC SURG 1993;106:651-7.[Abstract]
    
42. Takoudes T, Amirhamzeh MR, Hsu DT, Wise BR, Odeh S, Spotnitz HM. Time course of resolution of perfusion-induced myocardial edema in the rat heart. J Surg Res [In press].
    

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