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J Thorac Cardiovasc Surg 1994;107:1050-1058
© 1994 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Charleston, S.C.
Supported by a grant-in-aid from the American Heart Association and National Institutes of Health grant R29-HL45024.
Received for publication May 11, 1993. Accepted for publication Sept. 7, 1993. Address for reprints: John R. Handy, MD, Division of Cardiothoracic Surgery, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425.
Abstract
Acute postoperative left ventricular dysfunction after hypothermic, crystalloid potassium cardioplegia occasionally occurs. This project examined myocyte contractility and inotropic responsiveness after hypothermic arrest with and without potassium cardioplegia. Isolated swine left ventricular myocytes were placed in a thermostatically controlled chamber (37° C) that contained a standard cell medium, pulse stimulated at 1 Hz, and steady-state contractions were measured by computer-assisted video microscopy with and without isoproterenol (25 nmol/L). After baseline measurements were taken the myocytes were randomly assigned to the following treatments: (1) control group with infusion of 37° C crystalloid solution and maintained at 37° C for 3 hours (n = 23), (2) hypothermia group with infusion of 4° C crystalloid without potassium and stored at 4° C for 3 hours (n = 22), (3) hypothermic cardioplegia group with infusion of a crystalloid cardioplegia (oxygenated, buffered 4° C Ringer's solution with 24 mEq/L K+) and then stored at 4° C for 3 hours (n = 35). After treatment the myocytes were then rewarmed to 37° C by infusion of medium, and contractile measurements were repeated. In the control group, the percent and velocity of shortening were identical to those in baseline measurements: 6.4% ± 0.4% and 53 ± 5µm/sec, respectively, and these values remained unchanged in the hypothermia group: 6.5% ± 0.4% and 51 ± 3µm/sec, respectively. However, in the hypothermic cardioplegia group, the percent and velocity of shortening were significantly lower with rewarming: 4.8% ± 0.4% and 35 ± 3µm/sec, respectively, p < 0.05). Isoproterenol caused increased percent and velocity of shortening in both the control and hypothermia groups: 10.0% ± 0.6% and 9.5% ± 0.9% and 81.6 ± 8µm/sec and 71.4 ± 8µm/sec, respectively. This response was significantly blunted in the cardioplegia group (8.9% ± 0.8% and 56.9 ± 7µm/sec, p < 0.05). With an isolated myocyte system that is independent of extracellular and perfusion effects, hyperkalemic cardioplegic solution resulted in depressed myocyte contractile performance after rewarming. Potassium cardioplegia also caused a blunted inotropic responsiveness on rewarming. A potential contributory factor for the depressed left ventricular function after the use of potassium cardioplegia is a direct depression in myocyte contractility. (J THORAC CARDIOVASC SURG1994;107:1050-8)
Melrose and associates 
1 first described elective potassium-induced cardiac arrest with resumption of cardiac activity on reperfusion in 1955. Concern about the cellular toxicity of potassium 2,3 delayed widespread clinical acceptance of chemically induced cardiac arrest until the 1973 report of Gay and Ebert. 4 Hypothermia as a myocardial protective strategy was introduced by Shumway, Lower, and Stofer 5 in 1959. Subsequently, hypothermia coupled with potassium-induced electromechanical cardiac arrest evolved into the primary pillars of myocardial protective techniques. 6
Multiple studies have examined the effects of hypothermia and cardioplegic arrest on global ventricular performance. 7,8 It remains unclear from these studies whether an inherent contractile deficit accompanies the early left ventricular (LV) dysfunction after rewarming from hypothermic cardioplegic arrest. Several previous studies have demonstrated that significant extracellular edema occurs after hypothermic arrest with cold potassium cardioplegia. 9-12 Other studies have suggested that alterations in myocardial metabolism contribute toward the perioperative LV dysfunction. 13,14 Thus results from past studies suggest that the mechanism for LV dysfunction after hypothermic arrest with crystalloid cardioplegia may be multifactorial.
Despite the large number of studies that have examined the effects of hypothermic arrest and crystalloid potassium cardioplegia, the direct effects on myocyte contractile function have remained unclear. Measurements of the contractile properties of isolated adult myocytes have been recently done in several pathologic conditions and have offered distinct advantages. 15-20 Specifically, these studies allow (1) examination of contraction and relaxation properties of myocytes independent from the effects of the extracellular matrix, (2) the removal of in vivo hemodynamic and neurohormonal influences, (3) independence from coronary perfusion and capillary diffusion capacity, and (4) careful control of the extracellular milieu to examine specific aspects of myocyte function. Through the use of isolated myocyte function studies, the effects of hypothermic arrest and crystalloid potassium cardioplegia on myocyte contractility can be directly examined. Accordingly, the present study was designed to accomplish the following specific objectives: (1) to determine the effects of hypothermia and rewarming on myocyte contractile performance, (2) to examine the potential additive effects of hypothermia and potassium cardioplegic arrest on myocyte contractile performance, and (3) to examine whether myocyte inotropic responsiveness is affected after hypothermia and cardioplegic arrest.
METHODS
Myocyte isolation
Six Yorkshire swine (25 to 30 kg) were anesthetized with 2% isoflurane and 1.5 L/min oxygen and the lungs ventilated through a nonrecirculating anesthesia circuit. All animals were treated and cared for in accordance with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals" (NIH Publication No. 86-23). Under a plane of surgical anesthesia, a sternotomy was done and the heart quickly extirpated and placed in an oxygenated Krebs solution. The great vessels were rapidly removed at the aortic and pulmonary valves, and the region of the LV free wall incorporating the circumflex artery (5 by 5 cm) was excised and used for myocyte isolation. This region was isolated to obtain isolated myocytes strictly from the LV free wall. The left circumflex coronary artery was cannulated, distal branches ligated, and the tissue rinsed free of blood with 35 ml of a modified Kraft-Bruhe (KB) solution (80 mmol/L KCl, 30 mmol/L K2HPO4, 5 mmol/L MgSO4, 10 mmol/L glucose, 5 mmol/L Na2-adenosine triphosphate, 20 mmol/L taurine, 5 mmol/L creatine, 5 mmol/L succinate, and 5 mmol/L HEPES, supplemented with 5 mmol/L nitrilotriacetic acid and 0.1% salt-free bovine serum albumin. 18 Collagenase (0.5 mg/ml, Worthington Biochemical Corp., Freehold, N.J., type II; 146 U/mg) was then added to 75 ml of the modified KB solution and the tissue perfused with the collagenase solution for 35 minutes. All perfusion procedures were done with the tissue being maintained at 37° C and perfusion solutions continuously aerated with 95% O2 and 5% CO2. Aeration was done from the bottom of the solution vessels, which prevented foam formation. The tissue was then minced into 2 mm sections and added to an oxygenated trituration solution of fresh KB solution containing 2% bovine serum albumin, deoxyribonuclease II (51 Kunitz units/ml, type IV, Sigma, St. Louis, Mo.), 300 µmol/L CaCl2, and collagenase (0.5 mg/ml). The tissue and trituration solution was transferred to a centrifuge tube and gently agitated. After 15 minutes, the supernatant was removed, filtered, and the cells allowed to settle. The myocyte pellet was then resuspended in Dulbecco's modified Eagle medium (nutrient mixture F-12, pH 7.4, 2.0 mmol/L Ca2+, Gibco Laboratories, Grand Island, N.Y.).
The number of viable myocytes were counted at 100x magnification with the use of a hemocytometer (Reichert-Jung, Cambridge Instruments Inc., Buffalo, N.Y.) and resuspended to a final concentration of (5 x 10 4 cells/ml). Viable myocytes were defined as those cells that maintained a rod shape and were quiescent in culture. We have previously shown that these myocytes exclude trypan blue, are Ca+2 tolerant, respond to electric stimulation, and are stable in culture. 18 An aliquot (2 ml) of the isolated myocyte suspension was then plated on coverslips previously coated with a laminin/fibronectin matrix (Matrigel, Collaborative Research Inc., Bedford, Mass.) and incubated at 37° C for 1 hour.
Isolated myocyte function
Isolated myocytes were placed in a thermostatically controlled chamber (37° C) fitted with a coverslip on the bottom for imaging on an inverted microscope (Axiovert IM35, Zeiss Inc., Oberkochen, Germany). The volume of the chamber was 2.5 cc and the chamber contained two stimulating platinum electrodes and a miniature thermocouple (CN7100; Omega Engineering, Stamford, Conn.). The medium within the chamber was preoxygenated before it entered a miniature pump system (733100 Reglo; Ismatec, Cole-Palmer, Inc., Chicago, Ill.) that changed the medium within the chamber every 15 minutes. The myocytes were imaged by a 20x long-working-distance Hoffmann modulation contrast objective (Modulation Optics Inc., Greenvale, N.Y.) with a final magnification of x1100. Myocyte contractions were elicited by field-stimulating the tissue chamber at 1 Hz (S11, Grass Instruments, Quincy, Mass.) with current pulses of 5 msec duration and voltages 10% higher than the contraction threshold. The polarity of the stimulating electrodes was alternated at every pulse to prevent the buildup of electrochemical by-products. 15,17 Myocyte contractions were imaged by a charge-coupled device with a noninterlaced scan rate of 240 Hz (GPCD60, Panasonic, Secaucus, N.J.). Myocyte motion signals were captured with the cell parallel to the video raster lines and this video signal input through an edge detector system (Crescent Electronics, Sandy, Tex.). The changes in light intensity at the myocyte edges were used to track myocyte motion. 18,20 The distance between the left and right myocyte edges was converted into a voltage signal, digitized, and input to a computer (80286; ZBV2526, Zenith Data Systems, St. Joseph, Mich.) for subsequent analysis.
Stimulated myocytes were allowed a 5-minute stabilization period after electric stimulation, and contraction data for each myocyte were recorded from a minimum of 20 consecutive contractions. Parameters computed from the digitized contraction profiles included percentage shortening, velocity of shortening (in micrometers per second), velocity of relengthening (in micrometers per second), total contraction duration (in milliseconds), and time to peak contraction (in milliseconds). Myocyte percent shortening was determined as the percentage difference between maximum and minimum cell length for each contraction. Myocyte velocity computations were obtained by differentiating the digitized contraction profiles. The time to peak contraction was computed by calculating the time required for the differentiated velocity profile to reach zero velocity after the start of contraction. These parameters were calculated for each contraction and the results averaged for the 20 contractions.
Hypothermia and cardioplegia protocol
After collection of measurements of baseline myocyte contractile performance, the myocytes were then randomly assigned to the following treatment protocols: control group received infusion with 37° C Ringer's solution containing 30 mmol/L/L HCO3- (pH 7.8, 280 mOsm) and was then stored for 3 hours at 37° C; hypothermia group received infusion with 4° C Ringer's solution as described previously and was stored at 4° C for 3 hours; hypothermia and cardioplegia group received infusion with 4° C Ringer's solution containing 24 mEq/L potassium and 30 mEq/L HCO3-, then was stored at 4° C for 3 hours. During the performance of each of the treatment protocols, there was no oxygenation of the myocyte bath, thus simulating the clinical situation of aortic crossclamping. After the respective treatment protocol was completed, the myocytes were transferred to the stimulation chamber and infused with warm, oxygenated medium until the bath temperature returned to 37° C. Once the myocytes had been rewarmed, electric stimulation was initiated and steady-state contractile measurements were obtained as described in the previous section. The pH, carbon dioxide tension, and oxygen tension of the media were checked at the beginning and end of each experimental protocol and were not significantly different for any of the treatment groups (pH, 7.45 to 7.50; carbon dioxide tension, 30 to 35 torr; oxygen tension, 150 to 200 torr; p > 0.45). Further, the concentrations of Na+ and K+ in the media were 129 ± 1 and 4.9 ± 0.1 mEq/ L, respectively, and did not change with any experimental protocol (p > 0.45). All measurements were done immediately after the 3-hour incubation period.
In addition to examining steady-state contractile performance, a beat-to-beat analysis of myocyte contractions was done with the initiation of electric stimulation. In these studies, the cell was stimulated from a quiescent state, and individual contraction profiles were measured after the initiation of electric stimulation. In this manner, the positive staircase effect, which results in a beat-by-beat increase in the extent and velocity of shortening, could be examined between groups. 21 Finally, steady-state and beat-by-beat myocyte contraction profiles were examined in the three groups of myocytes in the presence of 25 nmol/L (–) isoproterenol.
Data analysis
Changes in indices of myocyte function between the control, hypothermia alone, and cardioplegia groups were examined by multiway analysis of variance. If the analysis of variance revealed significant differences, pairwise tests of individual group means were compared by Tukey's procedure. 22 In the beat-by-beat analysis (staircase phenomenon), the relationship between the extent of shortening and the velocity of relengthening was examined by linear regression. The slope of the line obtained from this linear regression analysis was compared among the three groups by the t distribution. All statistical analyses were done with the use of standard statistical software programs (BMDP Statistical Software Inc., University of California Press, Los Angeles, Calif.). Results are presented as mean plus or minus the standard error of the mean. Values of p < 0.05 were considered to be statistically significant.
RESULTS
Myocyte contractile properties after hypothermia and cardioplegia infusion
Rod-shaped, Ca2+-tolerant myocytes that were mechanically quiescent and responded to field stimulation were used in these experiments. All of the myocytes included in the study were responsive to field stimulation and were identical with respect to contractile performance before they were entered into the study protocol. A total of 80 myocytes were successfully examined at baseline and were randomized to the three treatment groups: control (n = 23), hypothermia alone (n = 22), and hypothermia and cardioplegia (n = 35). The resting length of the myocytes was 123 ± 3 µm and did not significantly change with any treatment protocol (p > 0.38). A summary of steady-state contractile performance for these three groups is shown in Table I. In the control group, myocyte contractile parameters as measured after 3 hours of normothermic storage without additional oxygenation of the bath were unchanged from baseline conditions and were very similar to those reported previously for swine myocytes. 18 There were no significant differences in contractile performance of myocytes after 3 hours of hypothermia and rewarming compared with results in the control cells. However, the contractile performance of myocytes that had been rewarmed after 3 hours of hypothermic storage in the cardioplegic solution was significantly affected compared with values obtained from control myocytes and myocytes after hypothermia alone. Specifically, myocyte percent shortening fell by 26% and the velocity of shortening fell by 35% in the hypothermic cardioplegia group compared with the values in control myocytes. The total duration of contraction and the time to peak contraction remained unchanged in all three groups. Thus steady-state myocyte contractile performance remained unchanged from control values after 3 hours of hypothermia alone. However, hypothermia and potassium cardioplegia resulted in a depression in steady-state contractile performance from control values with rewarming.
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21 In control myocytes, the slope of this relationship was 5.7 seconds -1 and remained unchanged with hypothermia alone (5.2 seconds -1, p > 0.85). Though a significant positive linear relationship persisted in the hypothermia and cardioplegia group, the slope of the regression line was significantly lower than that of the control or hypothermia alone groups (3.4 seconds -1, p < 0.05). Thus potassium infusion and hypothermic storage of isolated myocytes followed by rewarming resulted in a significant reduction in the myocyte contractile performance after electric stimulation from a quiescent state.
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Table II. In control myocytes, the percent shortening increased by 58% and the velocity of shortening increased by 53% from basal values. Similarly, in myocytes subjected to hypothermia alone, the percent and velocity of shortening increased from basal values by 46% and 39%, respectively. However, a blunted response to isoproterenol was observed in myocytes subjected to both hypothermia and cardioplegia (Table II). Specifically, in myocytes infused with a hypothermic cardioplegic solution and stored at 4° C for 3 hours, the percent shortening was reduced by 26% and velocity of shortening was reduced by 34% compared with values in control cells. Thus the contractile dysfunction observed after rewarming of myocytes stored for 3 hours in a potassium cardioplegic solution was associated with diminished inotropic responsiveness.
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Table III In both the control and hypothermia alone groups, the slope of this linear relationship increased from basal values (9.8 and 9.5 seconds -1, p < 0.05, respectively). In the myocytes treated with both hypothermia and potassium cardioplegia, the slope of the linear relationship between the extent of shortening and the velocity of relengthening also increased from basal values but remained significantly lower than that for the control or hypothermia alone groups (6.5 seconds -1, p < 0.05). Thus though isoproterenol increased the contractile performance of myocytes after hypothermia and potassium cardioplegia administration, this response was significantly blunted as compared with that in control cells and those treated with hypothermia alone.
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Adequate preservation of the myocardium through the use of hypothermic delivery of cardioplegic solutions has been a primary focus of the cardiac surgeon for decades. 23 In attempts to minimize the LV dysfunction that can occur in the early postoperative period, the type and method of delivery of the hypothermic cardioplegic solution have been areas of intense investigation. 24-27 Although it has been clearly established that hypothermic arrest through the use of a potassium cardioplegic solution may cause transient LV dysfunction, 7,8 the cellular basis for this phenomenon has remained unclear. In the present study, isolated myocyte function was examined after the use of hypothermia alone and after hypothermia with potassium crystalloid cardioplegia. The most significant findings of this study were (1) hypothermic storage of myocytes for 3 hours with subsequent rewarming had no effect on contractile performance or inotropic responsiveness, (2) hypothermic storage with a potassium cardioplegic solution caused a depression in myocyte contractile performance after rewarming, and (3) this depression in contractile performance of myocytes subjected to hypothermic potassium cardioplegia was associated with blunted inotropic responsiveness.
Hypothermia has long been used as an effective myocardial protective technique. 28 Hypothermia diminishes myocardial oxygen consumption in excess of that provided by electromechanical arrest. Buckberg and associates 29 found oxygen consumption of 1.1ml O2/100 gm LV weight in the arrested normothermic heart versus 0.3 ml O2/100 gm LV weight in the arrested heart at 22° C. Chitwood and associates 30 have shown normothermic, potassium-induced arrest decreases myocardial oxygen utilization approximately 65% and cooling to 15° C decreases oxygen uptake an additional 82%. The University of Toronto group has developed interest in the administration of warm cardioplegic solutions because of the marked effect that electromechanical arrest alone has on myocardial oxygen consumption and the supposed detrimental effects of hypothermia. 31,32 Our data clearly show no decrease in postreperfusion myocyte contractility or inotropy because of hypothermia alone.
Extracellular potassium provides electromechanical cardiac arrest by inactivating the fast sodium channel of the myocyte and thus reducing the resting membrane potential, causing it to become unexcitable and rendering diastolic arrest. 6 Electromechanical arrest alone accounts for a marked decrease in myocardial oxygen consumption compared with that of a normothermic, empty, beating heart. Buckberg and associates 29 demonstrated oxygen consumption of 5.6 ml O2/100 gm LV weight in the empty, beating heart. This decreased to 1.1 ml O2/100 gm LV weight with potassium-induced electromechanical arrest. Potassium as a means of achieving cardioplegic arrest is, therefore, very beneficial. However, elevated concentrations of potassium have been shown to be clinically detrimental by increasing coronary vascular resistance 33 and increasing cardiac arrhythmias. 34 This study shows increased extracellular potassium to have a negative effect on contractility and inotropy in the isolated cardiac myocyte after reperfusion.
The transient LV dysfunction that has been observed on rewarming after hypothermic, hyperkalemic cardiac arrest has been well described. 7,8 In past in vivo studies, the mechanism or mechanisms responsible for the LV dysfunction after cardioplegic arrest remained unclear inasmuch as LV pump function is altered by changes in load and inotropic state. Accordingly, a large number of past studies have examined the effects of hypothermic arrest with use of isolated heart models. In these isolated heart studies, abnormalities in myocardial water content, extracellular pH, and Ca+2 metabolism have all been identified after hypothermic cardioplegic arrest. 9,10,35,36 Furthermore, isolated heart studies have demonstrated that cardioplegic arrest is associated with decreased LV chamber compliance. 36 These past studies suggest that significant changes in the extracellular milieu occur after cardioplegic arrest and may be an important determinant in the LV dysfunction observed in the postoperative period. However, other studies that used isolated heart models of cardioplegic arrest and isovolumic indices of LV contractile performance have suggested that fundamental abnormalities exist in myocardial contractile function. 36,37 Thus it appears that the LV dysfunction associated with cardioplegic arrest may be multifactorial in that changes in both intracellular and extracellular processes may be affected. 38 To more carefully define the fundamental changes in myocardial contractile performance that may occur with cardioplegic arrest and rewarming, an isolated myocyte system was used in the present study. With this myocyte system, the extracellular milieu could be carefully controlled and the direct effects of hypothermia and cardioplegic arrest on myocyte contractile performance directly determined. The baseline contractile function of porcine myocytes used in the present study was very similar to that reported previously for myocytes isolated from canine, 16,19 feline, 15,17 and human 39 hearts. Results from the present study suggest that hypothermic storage of isolated myocytes with subsequent rewarming did not significantly affect steady-state contractile function. However, exposure of the myocytes to hyperkalemic cardioplegic arrest followed by rewarming caused a significant reduction in steady-state myocyte contractile function.
In the present study, the extent of shortening and the velocity of relengthening were significantly affected by hyperkalemic cardioplegic arrest followed by rewarming. Maximal shortening depends on the rate of cross-bridge formation and sarcoplasmic reticular Ca2+ release. The velocity of relengthening is determined by adenosine triphosphate–dependent processes and the restoring forces of the myocyte. To determine whether the decrease in the velocity of relengthening was a result of an associated decrease in the extent of shortening or a basic impairment of the relaxation process itself, the relationship between the extent of shortening and the velocity of relengthening was examined. Exposure of the myocytes to a hypothermic and hyperkalemic environment caused a decrease in the slope of the extent of shortening–velocity of relengthening relationship, which suggests that the reduction in the velocity of relengthening may be caused by abnormalities intrinsic to the relaxation process. 40 Thus results from the present study suggest that hyperkalemic cardioplegic arrest affects both contractile properties and relaxation properties of the myocyte. Future studies that examine the mechanisms by which hyperkalemic cardioplegic arrest influences myocyte relaxation properties would be appropriate.
To more closely examine the extent in which myocyte contractile function was affected by hypothermia and cardioplegic arrest, myocyte contractile performance was examined on a beat-by-beat basis in the presence and absence of isoproterenol. In this series of experiments, the inotropic responsiveness of isolated myocytes could be determined after cardioplegic arrest and rewarming. Results from this portion of the study demonstrated the inotropic responsiveness of myocytes subjected to the potent ß-receptor agonist isoproterenol. Normal activation of the ß-adrenergic system is through binding of ß-agonists to the receptor, stimulation of adenylate cyclase to produce cyclic adenosine monophosphate, and subsequent increased intracellular Ca+2 concentration during myocyte depolarization. 41 Although the present study demonstrated abnormalities in myocyte ß-adrenergic responsiveness after hypothermic, hyperkalemic arrest, the mechanism responsible for this finding remains unclear. Potential mechanisms include internalization of ß-adrenergic receptors because of the hyperkalemic environment, abnormalities in the ß-receptor transduction system itself, and reduced responsiveness of the contractile apparatus to increased intracellular Ca+2. Future studies aimed at addressing this issue would be appropriate. Nevertheless, the findings from the present study demonstrated for the first time that hyperkalemic cardioplegic storage causes reduced inotropic responsiveness with subsequent rewarming. These findings suggest that treatment of LV dysfunction in the acute postoperative period with ß-adrenergic agonists may not be maximally effective.
In the present study, an isolated myocyte system was used to examine the direct effects of hypothermia and hyperkalemic cardioplegic arrest. Although this system has the advantages of obtaining direct measurements of myocyte contractile performance, it has several limitations. First, the buffering and osmotic influences of the extracellular matrix, which may play an important role in vivo, have been removed. Thus the hyperkalemic solution used in the present study was not buffered by extracellular proteins that may exist in vivo. Second, this isolated system provides maximal solute diffusion capacity between the cytosol and the extracellular space. This is not the case in vivo where the coronary vasculature and capillary diffusion distances are affected by coronary artery disease, hypertrophy, and other pathologic states. However, these limitations also define the strength of this model, inasmuch as questions can be asked concerning the direct effects of cardioplegic arrest on the basic functional unit of the heart, the cardiac myocyte.
In summary, the present study demonstrates that myocyte contractile function and inotropic responsiveness are preserved with hypothermia alone. However, the transient extracellular hyperkalemia of cardioplegia is shown to have a significant negative impact on myocyte contractile function after rewarming. These results suggest that myocardial protective techniques should incorporate the least amount of potassium to cause and maintain electromechanical arrest.
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J. L. Zellner, L. Hebbar, F. A. Crawford Jr, R. Mukherjee, and F. G. Spinale Beneficial Effects of Myocyte Preconditioning on Contractile Processes After Cardioplegic Arrest Ann. Thorac. Surg., February 1, 1996; 61(2): 558 - 564. [Abstract] [Full Text]
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J. D. Walker, F. A. Crawford Jr., R. Mukherjee, and F. G. Spinale THE DIRECT EFFECTS OF 3,5,3'-TRIIODO-L-THYRONINE (T3) ON MYOCYTE CONTRACTILE PROCESSES: Insights into mechanisms of action J. Thorac. Cardiovasc. Surg., November 1, 1995; 110(5): 1369 - 1380. [Abstract] [Full Text]
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J. D. Walker, F. A. Crawford, and F. G. Spinale PRETREATMENT WITH 3,5,3' TRIIODO-L-THYRONINE (T3): Effects on myocyte contractile function after hypothermic cardioplegic arrest and rewarming J. Thorac. Cardiovasc. Surg., August 1, 1995; 110(2): 315 - 327. [Abstract] [Full Text]
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