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J Thorac Cardiovasc Surg 1995;109:457-465
© 1995 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
New York and Manhasset, N.Y.
Received for publication April 28, 1994. Accepted for publication July 19, 1994. Address for reprints: John D. Klemperer, MD, Department of Cardiothoracic Surgery, New York Hospital-Cornell University Medical College, Room A-827, 525 E. 68th St., New York, NY 10021.
Abstract
Cardiopulmonary bypass results in a "euthyroid sick" state. Recently, interest has focused on the relationship between low serum triiodothyronine levels and postoperative cardiovascular hemodynamics. The present study was undertaken to more clearly define the acute effects of triiodothyronine on myocardial mechanics and energetics after hypothermic global ischemia using an ex-vivo canine heart preparation to model the clinical condition. Experiments were performed on isolated hearts subjected to hyperkalemic arrest with 90 minutes of hypothermic (10° C) ischemia. Isolated hearts were cross-perfused by euthyroid support dogs in which triiodothyronine levels spontaneously deceased by 65% to 75% (p < 0.01) after the initiation of cross-perfusion. In nine heart preparations, triiodothyronine (Triostat) was given as a bolus dose (0.2µg/kg) after 1 hour of baseline data collection with a subsequent measurable rise in serum triiodothyronine levels (p < 0.01). In six postischemic hearts, reverse triiodothyronine was given as a 0.2µg/kg bolus. Triiodothyronine was also administered to a group of eight nonischemic, continuously perfused isolated hearts. Intrinsic myocardial contractility was assessed by analysis of the preload recruitable stroke work area, energetic efficiency from the myocardial oxygen consumption-pressure-volume area relationship, and coronary vascular resistance from analysis of coronary flow and perfusion pressure. Acute administration of triiodothyronine to postischemic hearts improved the preload recruitable stroke work area from 9.5 ± 1.42 to 14.9 ± 2.03 x 107 erg/ml, a 56% increase from baseline (p < 0.001), but had no effect on the preload recruitable stroke work area of the nonischemic hearts. The inotropic response resulting from triiodothyronine treatment did not alter the myocardial oxygen consumption-pressure-volume area relationship. Triiodothyronine treatment was associated with significantly decreased coronary resistance and increased coronary flow through a range of diastolic loading conditions in the postischemic hearts. The biologically inactive thyroid hormone metabolite reverse triiodothyronine was without effect on any of the measured parameters. On the basis of these results, we conclude that the low triiodothyronine state of cardiopulmonary bypass can be reproduced in this isolated heart model and that acute triiodothyronine treatment results in a unique inotropic action manifest only in the postischemic reperfused myocardium and is accomplished without oxygen wasting effects. (J THORACCARDIOVASCSURG1995; 109: 457-65)
Thyroid hormone has profound effects on the heart and cardiovascular system 
1-4 Although the sequelae of chronic hyperthyroid and hypothyroid states are well documented, the effects of acute alterations in serum hormone levels have been less thoroughly characterized. Cardiopulmonary bypass (CPB) results in a "euthyroid sick" state, 5,6 and interest has focused on the relationship between low serum triiodothyronine (T3) levels and postoperative cardiovascular hemodynamics. Accumulating experimental data suggest that pharmacologic T3 supplementation may improve hemodynamic parameters after ischemic injury in animal models of CPB 7-9 and in isolated heart studies. 10,11 Limited clinical data also suggest a benefit to short-term T3 supplementation in the peri-CPB period. 12,13 The mechanism of action of T3 in these settings remains uncharacterized, yet the rapid improvement in left ventricular function reveals the importance of extranuclear pathways. Because thyroid hormones are known to affect systemic vascular resistance, 14,15 direct cardiac effects of T3 are best measured with load-independent parameters of ventricular function. Published reports in which isolate heart models were used, however, have relied on severe warm ischemic injury and crystalloid perfusates and have not addressed the left ventricular pressure-volume area-oxygen consumption (PVA-MVO2 ) relationship. The present study was undertaken to delineate the acute effects of T3 on myocardial mechanics and energetics after hypothermic global ischemia with a canine ex vivo isolated heart model used to mimic the clinical condition.
METHODS
Operative procedures.
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 National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).
Individual experiments involved the use of two adult mongrel dogs as previously described. 16 In each experiment, the heart of one animal was used as the ex vivo isolated heart preparation that was cross-perfused by the second dog as the support animal. The animals were allowed food and water ad libitum the night before the experiments to avoid acute alteration of thyroid hormone levels. Animals were sedated with acepromazine (0.1 mg/kg intramuscularly) and anesthesia was induced with pentobarbital (25 to 30 mg/kg intravenously) and maintained with isoflurane (0.4% to 1.5%). The animals were intubated and ventilated by a mechanical respirator. Cefazolin (Kefzol, 1 gm intravenously) and indomethacin (50 mg by suppository) was given to each support animal at the onset of surgical intervention. The electrocardiogram and mean arterial blood pressure were continuously monitored.
Support animal and cross-circulation.
An 8F catheter was placed in the left femoral vein for fluid and drug administration. The animal was fully heparinized (400 U/kg intravenous bolus, followed by a continuous infusion of 500 U/hr). The circuit has been described in detail in an earlier report. 16 In brief, the right femoral vessels were cannulated with 18F cannulas (Bard Vascular Systems, Billerica, Mass.) and connected to the circuit with 3/8 -inch tubing. A double roller head pump (Masterflex/Cole-Parmer Instrument Co., Chicago, Ill.) was used to pump bidirectional flows of arterial and venous blood in synchronous flow rates, which were controlled by a custom servo device to maintain constant coronary perfusion pressure (70 to 80 mm Hg) to the ex vivo heart. The circuit required a prime volume of 500 ml crystalloid solution before it was connected to the support animal. Hemodynamic stability was maintained by the infusion of fluids (crystalloid and dextran) when needed. Arterial pH was maintained within normal range by adjustment of the ventilator tidal volume and rate or the administration of sodium bicarbonate. Arterial inflow into the ex vivo heart's aorta and coronary sinus drainage were simultaneously measured by ultrasonic flow probes (Transonic, Ithica, N.Y.).
Ex vivo heart preparation/hypothermic ischemia model.
Through a sternotomy incision, a pericardial cradle was created. The great vessels were isolated and surrounded by sutures or tapes. After heparinization, the subclavian artery was cannulated with a catheter for monitoring of coronary perfusion pressure. The venae cavae and brachiocephalic artery were tied, followed by crossclamping of the descending aorta and ligation of the main pulmonary artery. Cardioplegic arrest was achieved by infusion of cold hyperkalemic crystalloid solution (750 ml of Normosol with 20 mEq potassium chloride, 5 ° C, adjusted to pH 7.5) into the previously placed subclavian arterial tubing. The heart was then excised and placed in 10 ° C Normosol solution.
During the 90-minute hypothermic arrest period, the heart was prepared for the ex vivo circuit. The brachiocephalic artery was cannulated for retrograde coronary perfusion and the right ventricle for coronary sinus drainage. A plastic O ring was sutured to the mitral anulus for mounting to the servo pump.
After 90 minutes of hypothermic ischemia, the heart was cleared of air in a basin of warm Normosol solution and reperfusion was begun at 40 mm Hg for the initial 10 minutes, then increased to 70 to 80 mm Hg for the remainder of the experiment. After being mounted on the servo apparatus, the left ventricular balloon was secured through an apical stab wound. Epicardial pacing wires were placed and pacing was maintained at 150 beats/min (Grass Instrument Co., Quincy, Mass.). The temperature of the blood in the circuit was maintained at 37° C by a heat exchanger.
Experimental protocol.
An outline of the experimental protocol is shown in Fig. 1. The postischemic hearts were reperfused with warm oxygenated blood from the support animal for 30 minutes before baseline data collection was begun. Data collection through a range of diastolic loading conditions was performed in 30-minute intervals. In nine heart preparations, T3 (Triostat, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.) was given as a 0.2 µg/kg bolus after 1 hour of baseline data collection. A 30-minute equilibration period was then allowed before resuming data collection every 30 minutes for a total period of 90 minutes. A second group of animals (n = 6) received reverse T3 (rT3, Sigma Chemical Co., St. Louis, Mo.) as a 0.2 µg/kg bolus dose and similar measurements were taken.
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17 uses a computerized servo pump equipped with a mock circulatory system to collect a set of pressure-volume loops under a constant afterload and a range of increasing diastolic filling pressures set by the investigator. The left ventricular pressure, left ventricular volume, coronary perfusion pressure, and coronary sinus outflow were measured simultaneously and collected at 250 Hz by custom data software. Blood samples were collected at the same time for determination of the MVO2. The heart was allowed to equilibrate for 3 to 5 minutes at each preload setting before data collection. A minimum of four loading conditions was measured for each data set. Blood was taken for measurement of serum T3 levels during placement of intravenous lines (baseline) from both support and donor animals. Support animals had subsequent blood withdrawal via the circuit at the end of baseline data collection and then 1 hour after drug administration. Whole blood was centrifuged and the serum was stored at -5° C. Hormone levels were determined by radioimmunoassay at a commercial animal laboratory (Animal Medical Center, New York, N.Y.).
Measurement of parameters.
Analysis of left ventricular function and PVA.
The left ventricular performance was derived from analysis of the stroke work/end-diastolic volume relationship, which yielded an x intercept, slope, and the preload recruitable stroke work area (PRSWA) extrapolated to an end-diastolic volume of 100 ml 18 at each data interval.
Total mechanical energy production was measured as the PVA for each preloading condition with the use of custom software modeled after the method of Sagawa and colleagues 19 These PVAs are plotted against the corresponding MVO2 values to generate the PVA-MVO2 relationship.
MVO2.
Aortic and coronary sinus oxygen tension (Po2), oxygen saturation, and hemoglobin (HgB) were measured by a blood gas/pH analyzer and a Co-Oximeter device (Instrumentation Laboratory Inc., Lexington, Mass.). MVO2 per cardiac cycle was calculated as ([Cao2 - Cvo2] x coronary flow)/wet left ventricular weight x heart rate. Cao2 and Cvo2 denote arterial and venous oxygen content, respectively. Oxygen content was calculated as (1.38 x Hgb x percent saturation of Hgb) + (0.003 x Po2). MVO2 in milliliters of oxygen per 100 gm · beat was converted into mm Hg · ml/100 gm · beat by multiplying 20 joules/ml of oxygen and 7502 mm Hg · ml/joule.
Coronary resistance.
The resistive component (mm Hg · min/ml) of the coronary vascular impedance was calculated as the mean coronary perfusion pressure divided by the mean coronary flow after 3 to 5 minutes of equilibration at each diastolic loading condition.
Diastolic constant.
Diastolic function is expressed in terms of the diastolic stiffness constant (kD) of the exponential equation describing the end-diastolic pressure-volume relationship P = bekv , where P and V represent end-diastolic pressure and volume, respectively, and b is the left ventricular pressure extrapolated to zero volume. 20
Statistical methods.
All values are expressed as the mean plus and minus the standard error. For each individual experiment, the two baseline data sets were averaged as were the three posttreatment data sets. Baseline data were then pooled for statistical comparison to pooled posttreatment data. Comparisons within and between experimental groups were performed with paired and two-sample t tests, respectively. Coronary resistance and flow data were analyzed by analysis of variance with repeated measures. A p value of less than 0.05 was considered statistically significant.
RESULTS
T3 levels.
Total serum T3 levels were normal in both donor and support animals at the onset of the experiment. After the initiation of cross-perfusion, mean serum T3 levels in the support animals decreased from 0.55 ± 0.07 to 0.13 ± 0.01 µg/dl (p < 0.01). This decrease was associated with an average drop in hemoglobin value from 13 to 9.8 gm/dl. Mean T3 levels subsequently rose to 0.58 ± 0.05 µg/dl (p < 0.01) 60 minutes after the T3 bolus. In the experiments in which rT3 was used, serum T3 levels dropped to a mean value of 0.10 ± 0.01 µg/dl (p < 0.01) and did not rise after the rT3 bolus.
Contractility.
The changes in intrinsic myocardial contractility were evaluated by analysis of the PRSWA before and after T3 or rT3 administration. Data collected during the pre-T3 period (baseline) were pooled, as were the post-T3 data (Fig. 2). Administration of T3 to postischemic hearts improved the PRSWA from 9.5 ± 1.42 to 14.9 ± 2.03 x 107 erg/ml, a 56% increase over baseline that was highly significant (p < 0.001). Administration of the biologically inactive metabolite rT3 did not change contractility compared with baseline (8.82 ± 1.40 to 8.16 ± 1.31 x 107 erg/ml). The hearts treated with T3 and rT3 in this set of experiments did not differ significantly at baseline with respect to PRSWA. Prior analysis of a group of untreated postischemic as well as continuously perfused, nonischemic hearts revealed no significant change in PRSWA over a 3-hour time period (manuscript in preparation). Administration of T3 to the nonischemic, normal hearts was without significant effect on contractility (9.79 ± 1.15 to 8.42 ± 0.97 x 107 erg/ml).
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Table I). Although compliance decreased in both groups, neither change was statistically significant.
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Table II). These were arbitrary settings corresponding to end-diastolic ventricular pressures in the range of 4 to 20 mm Hg. T3 significantly reduced coronary resistance throughout the range of loading conditions in the ischemic reperfused hearts. This reduction in coronary vascular resistance in the T3 -treated hearts resulted in a significant increase in blood flow at each diastolic pressure setting, as shown in Table III. rT3 did not alter coronary vascular resistance or flow rate.
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Recently, interest has focused on the effects of an acute deficiency of circulating total and free T3 arising as a consequence of CPB 5,6,21 on postoperative cardiac performance. Several studies have suggested that T3 repletion in this setting has hemodynamic benefits. Novitzky and colleagues reported an improvement in postischemic left ventricular function after experimental CPB and cardioplegic arrest in pigs 7 and dogs 8 that had received T3 after removal of the aortic crossclamp. These studies, however, used load-dependent parameters of ventricular function that do not accurately reflect primary cardiac effects. Dyke and associates, 11 using an isolated rabbit heart model, found that T3 treatment administered immediately at the time of reperfusion restored peak developed pressure after ischemia. A more recent report from this group describes improved load-independent ventricular function (using the stroke work-end-diastolic volume relationship) in response to T3 treatment in an experimental model of CPB. 9 Both studies, however, involved severe warm ischemic injury and did not investigate the relationship between cardiac work and MVO2 .
The goal of this study was to characterize the effects of T3 administered immediately on load-independent parameters of left ventricular function and on myocardial energetics in a model of hypothermic global ischemia designed to mimic the clinical situation encountered in the peri-CPB or transplantation period. The ex vivo isolated heart preparation eliminates variability in left ventricular loading conditions and establishes a hormonal environment that approximates clinical CPB.
The observed 65% to 75% drop in the total serum T3 levels of the support animals correlates with clinical experience. 5,6 Although the mechanism underlying this decrease was not addressed, it could not be completely attributed to the hemodilution related to the preparation. An acute stress response resulting from the inherent trauma of extracorporeal circulation and the added work imposed by the ex vivo heart on the support dog may have contributed to the low T3 state in this model as a result of decreased peripheral conversion of thyroxine (T4 ) to T3 , shortened half-life of T3 , and/or altered volume of distribution for the hormone.
Our isolated heart preparation is similar to previously described animal models of hyperkalemic cardioplegic arrest followed by a period of global, hypothermic ischemia in which systolic function is preserved. 22-24 However, whether T3 could affect the performance of hearts subjected to a period of protected hypothermic ischemia followed by reperfusion has not been tested in a setting where loading conditions are carefully controlled.
In the present study, T3 treatment resulted in a 56% increase in PRSWA in the postischemic hearts. In agreement with an earlier report, 11 no inotropic response to T3 was observed in the nonischemic, continuously perfused hearts. Similar to the myocardium injured by normothermic ischemia, 9-11 T3 augmented ventricular performance in the hypothermic arrested myocardium. This is consistent with data reported by Novitzky and associates, 7 in which T3 treatment in a porcine model of CPB, with protected cardioplegic arrest, resulted in a peak developed pressure greater than baseline. The PRSWA is an index of intrinsic myocardial contractility independent of loading conditions and is recognized as a more sensitive measure of ventricular performance. 25,26
One emphasis of this study was to characterize the effects of T3 on myocardial energetics in terms of efficiency, namely, the ratio of total mechanical energy production to total myocardial energy consumption. The linearity of the PVA-MVO2 relationship has been well described. 27 The slope of this regression is inversely proportional to the efficiency of energy use, and the extrapolated y intercept represents the energy requirement of the unloaded contracting ventricle. Traditional ß-agonist inotropic agents such as dobutamine 16,21 and epinephrine 28 shift the PVA-MVO2 regression line upward. This elevation of the y intercept represents an "oxygen wasting effect" in which an increased amount of energy is required in the enhanced state compared with the normal state for the same level of total work. T3, in the dose of 0.2 µg/kg, restored serum T3 to physiologic levels and produced a significant inotropic effect without incurring additional oxygen debt. The PVA-MVO2 relationship was similar before and after T3 administration. The PVA-MVO2 relationship was unaffected by rT3 treatment, which showed no inotropic effect. Conflicting, though perhaps species-dependent, descriptions of the PVA-MVO2 relationship in the chronically hyperthyroid left ventricle have been reported. 29,30 The acute effects of T3 treatment in a hormonally depleted environment represent a fundamentally different situation, and this report is the first to directly characterize myocardial energetics in this setting.
One effect of thyroid hormones is a decrease in peripheral vascular resistance. 14,15 Recent studies suggest that T3 may act as a direct vasodilator on arterial smooth muscle cells, 15,31 yet its influence on coronary arterial tone has not been established. Our data suggest that T3 may substantially increase blood flow to the coronary bed. Coronary resistance is determined by perfusion pressure and flow. Flow is most dependent on the demand of the myocardium, which is strongly influenced by the loading conditions and contractile activity of the heart. The isolated heart model, in which coronary perfusion pressure and afterload can be kept constant, is well suited for examining changes in vascular tone. Although it is difficult to distinguish a primary vasodilatory effect from a response to the enhanced contractile state, the finding that the augmentation of contractility occurred without additional oxygen requirement supports such an effect. Kadletz and coworkers 32 have recently reported that T3 did not increase coronary flow in a rat heart Langendorff preparation involving warm ischemia. Several differences in method may account for the discrepancy. The two models differ in type of injury, perfusate, and sampling time relative to reperfusion. We have noted that during the initial period of reperfusion, the postischemic hearts are markedly hyperemic. If data collection is obtained before a sufficient interval of stabilization after reperfusion is completed, it is possible that an already dilated coronary vasculature may not be additionally influenced by T3 administration.
Although the present model does not provide a molecular basis for the effects of T3 on left ventricular function, the rapidity of onset of the effect suggests an extranuclear mechanism. Despite intensive investigation into the interaction with several cell membrane and enzyme systems, 33 the mechanism(s) responsible for the acute action of T3 are not well defined. The inotropic action of T3 on the postischemic myocardium may relate to alterations in intracellular and transcellular calcium handling after injury. Ischemia-reperfusion may result in profound disturbances in intracellular calcium 34 andsodium 35 balance, along with depression of key enzyme systems such as calcium adenosinetriphosphatase in the sarcoplasmic reticulum. 36,37 The known effects of T3 on myocardial calcium handling 38-40 and sodium channel activity 41 suggest potential routes through which the postischemic myocardium may be acutely responsive to T3 treatment. Although T3 is known to affect left ventricular diastolic function, 2,42 we did not observe significant change after T3 administration. This analysis, however, did not measure the rate of diastolic relaxation.
Some interesting comparisons between T3 and bipyridine phosphodiesterase inhibitors can be made. At a biochemical level, T3 and milrinone were reported to display structural and functional homologies. 43 In addition, the relationship between inotropic effect and oxygen utilization efficiency observed with T3 is similar to that reported for amrinone. 16 Finally, Caldarone and associates 44 have described an inotropic specificity of milrinone for the postischemic reperfused heart with no effect on normal hearts.
In summary, the ex vivo isolated heart preparation cross-circulated by a support dog was found to be a useful model for evaluating the effects of acute T3 administration in a hormonal environment that mimics the clinical condition of CPB. Specificity for the postischemic myocardium has been suggested by earlier experimental literature, and, despite preservation of left ventricular contractility in our model, the ischemic interval followed by reperfusion allowed an inotropic effect of T3 to be manifest. This report is the first to characterize the acute effects of T3 on the postischemic heart with respect to the PVA-MVO2 relationship and clearly shows that T3 augmentation of postischemic left ventricular function occurs without oxygen wasting effects. In addition, T3 appears to have a vasodilatory effect on the coronary vasculature. Together, these findings lend additional support for repleting T3 levels in the setting of myocardial ischemia-reperfusion.
Acknowledgments
We thank Howard Thaler, PhD for statistical consultation We also thank SmithKline Beecham Pharmaceuticals, Philadelphia, for the generous supply of triiodothyronine (Triostat).
Footnotes
From the Department of Cardiothoracic Surgery, New York Hospital-Cornell University Medical College,a New York, N.Y., and the Department of Medicine/Division of Endocrinology, North Shore University Hospital-Cornell University Medical College,b Manhasset, N.Y. 
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