Ann Thorac Surg 1995;60:1215-1218
© 1995 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Interaction of Thyroid Hormone and Heparin in Postischemic Myocardial Recovery
Michael G. Katz, MD, PhD,
Amram J. Cohen, MD,
Herzl Schwalb, PhD,
Joseph Segal, PhD,
Gideon Merin, MD,
Arie Schachner, MD
Joseph Lunenfeld Cardiac Surgery Research Center, Hadassah University Hospital, Jerusalem, Israel
Accepted for publication May 27, 1995.
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Abstract
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Background. Triiodothyronine (T3) administration can improve postischemic myocardial recovery. Heparin can interfere with cellular binding of T3. Introduction of heparin into an isolated heart model may interfere with this effect.
Methods. Four groups of 8 rat hearts were placed on a modified Langendorff apparatus. All groups underwent 15 minutes of perfusion with modified Krebs-Henseleit solution (KH), followed by 20 minutes of normothermic global ischemia and 30 minutes of reperfusion. Group I underwent reperfusion with KH. Group II underwent reperfusion with KH and 1 x 10-6 mol/L of T3. In group III, hearts underwent preischemic perfusion with heparinized KH (1,000 U/L) and reperfusion with KH containing 1 x 10-6 mol/L of T3 and 1,000 U/L of heparin. In group IV, rats were given heparin at 2,000 IU/kg 30 minutes before sacrifice, and isolated hearts were reperfused with KH and 1 x 10-6 mol/L of T3. A latex balloon in the left ventricle monitored hemodynamic variables.
Results. Left ventricular developed pressure throughout postischemic reperfusion was greater in all the groups receiving T3 when compared with group I. Group II showed significantly greater recovery than either group III (p < 0.05) or group IV (p < 0.05).
Conclusions. Addition of T3 to the reperfusate enhances postischemic myocardial recovery in the isolated heart model, whereas addition of heparin reduces this effect.
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Introduction
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Thyroid hormone (T3) has been shown to exert an acute extracellular stimulatory effect in various mammalian tissues, including the heart [1]. In an isolated perfused rat heart, we have demonstrated that the thyroid hormone produced a rapid and transient increase in cardiac inotropic activity, which was evident within 30 seconds of administration [2].
Recent evidence indicates that thyroid hormone can actively affect postischemic myocardial performance [3–7]. Novitzky and associates [6] have demonstrated that triiodothyronine (T3) administration can have salutary effects on organ integrity, including the heart. Further T3 supplementation has been used clinically during reperfusion of the heart to enhance myocardial recovery [4, 5].
Holland and co-workers [3] and Dyke and colleagues [7] previously used isolated heart models of rats and rabbits to evaluate the effect of T3 on postischemic myocardial recovery. Both groups showed a functional recovery of 63% to 99% with T3 administration, versus 60% in control animals. In preliminary work with comparable preparations, we have demonstrated a functional recovery of 120% to 130% after T3 administration. A significant difference between ours and previous studies is that their experimental animals were heparinized. Heparin is known to interact with thyroid hormone and is clinically present in patients undergoing revascularization of the myocardium [8–12]. The present study was designed to assess the effect of heparin treatment on isolated rat hearts given T3 during recovery from global ischemia.
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Material and Methods
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Male Sprague-Dawley rats with body weights of 320 ± 20 g were used for the experiment. The animals were treated in accordance with the ``Guide for the Care and Use of Laboratory Animals'' (National Institutes of Health publication 85-23, revised 1985). They were sacrificed, and their hearts were immediately removed and placed in ice-cold saline solution. The aorta was cannulated and the heart was mounted on a modified Langendorff perfusion apparatus. Retrograde aortic perfusion was maintained with modified Krebs-Henseleit (KH) solution (NaCl, 118 mmol/L; KCl, 4.9 mmol/L; MgSO4, 1.2 mmol/L; KH2PO4, 1.2 mmol/L; NaHCO3, 25.0 mmol/L; glucose, 1.1 mmol/L; and Ca, 1.25 mmol/L). The perfusate was aerated with a mixture of 95% oxygen and 5% carbon dioxide. The aortic perfusion was maintained at 37°C and a pressure of 850 mm H2O. The pulmonary artery was cut open to provide drainage and to measure coronary flow. Hearts were excluded from the study if during the first 2 minutes of perfusion one of the following events occurred: Arrhythmias developed, thrombus formed in the aorta, or left ventricular developed pressure was less than 45 mm Hg.
To monitor heart hemodynamic variables, we inserted a latex balloon through the left atrium into the left ventricle. The balloon was connected through a pressure transducer to a recording system (Hewlett Packard 7758B, Andover, MA). The balloon was inflated and equilibrated to give an end-diastolic pressure of 0 mm Hg. With the balloon in place, hemodynamic indices were measured. Coronary flow was measured by collecting the effluent from the pulmonary artery.
Experimental Design
Hearts from the different experimental groups (8 hearts each) were mounted on the isolated heart apparatus. Individual experiments were randomized within the four groups. Hearts from group I underwent 15 minutes of perfusion with KH, followed by 20 minutes of global ischemia. The hearts were then reperfused for 30 minutes with KH. Hearts from group II were subjected to 15 minutes of perfusion with KH, followed by 20 minutes of global ischemia. Reperfusion was performed with KH and 1 x 10-6 mol/L of T3 (Henning, Berlin, Germany) for 30 minutes. Hearts from group III were subjected to 15 minutes of perfusion with KH and 1,000 U/L of sodium heparin (Leo Pharmaceutical Products, Ballerup, Denmark), followed by 20 minutes of global ischemia. Reperfusion was performed with the heparinized KH and 1 x 10-6 mol/L of T3. Animals from group IV received 2,000 IU/kg of sodium heparin intraperitoneally 30 minutes before excision of the heart. Once the heart was mounted, it was perfused for 15 minutes with KH followed by 20 minutes of global ischemia. The hearts were then reperfused with KH and 1 x 10-6 mol/L of T3 for 30 minutes. In all four groups during recovery, hearts were discarded after 5 minutes if they displayed persistent arrhythmia or if they had no systolic pressure. This included 2 hearts from the control group and 1 each from groups III and IV.
Measurements
Hemodynamic measurements included left ventricular systolic and diastolic pressures and time derivatives of pressure at contraction (+dP/dt) and at relaxation (-dP/dt). Coronary flow was measured during the same period. Left ventricular developed pressure was calculated from the difference between the systolic and diastolic pressures. Preischemic hemodynamic values were measured 1 minute before global ischemia. Recovery for each index during reperfusion at any given time was compared with the preischemic value and expressed as a percentage of this value.
Statistical analysis of the data included an analysis of variance, which was applied for comparisons of the groups' postischemic recovery of left ventricular developed pressure, +dP/dt, -dP/dt, coronary flow, and heart rate. The results are expressed as means ± standard deviation.
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Results
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Left Ventricular Developed Pressure
The results for the percentage recovery of left ventricular developed pressure are depicted in Table 1
. In the postischemic period, there was an increase throughout the recovery period in groups receiving T3 as compared with the control group (group I). Throughout the recovery period, hearts that received T3 alone demonstrated a significant increase in postischemic recovery when compared with the other groups (p < 0.05).
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Table 1. . Effect of Triiodothyronine and Heparin on Recovery of Left Ventricular Developed Pressure During Postischemic Reperfusiona
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Time Derivatives of Pressure at Contraction and Relaxation
The results for +dP/dt and -dP/dt are shown in Tables 2 and 3, respectively. In all hearts treated with T3 during the postischemic period, there was an increase in +dP/dt values throughout this period. Similarly, there was better relaxation throughout the postischemic recovery period in the groups receiving T3 when compared with the control group. Among the groups receiving T3 in the postischemic reperfusion period, group II, not receiving heparin, showed a significantly better recovery of +dP/dt values. Group II also exhibited significantly better relaxation (-dP/dt) throughout the recovery period (p < 0.05). In all groups, throughout the reperfusion period, the changes in +dP/dt and -dP/dt were comparable to the changes found in left ventricular developed pressure.
Heart Rate and Coronary Flow
The results for heart rate and coronary flow are shown in Tables 4 and 5, respectively. Postischemic recoveries for both were not significantly different among any groups.
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Comment
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After open heart surgery in both adult and pediatric patients, low levels of free T3 develop, which have been associated with poor cardiac function [13–15]. Clinical studies have demonstrated that administration of T3 is associated with improved hemodynamic indices in this patient population [4, 5]. Laboratory data from isolated heart models have shown that T3 enhances the function of hearts recovering from an ischemic insult [3, 7]. However, the magnitude of this recovery varies widely, and complete recovery has not been demonstrated.
Thyroid hormone affects the heart indirectly by influencing the sympathoadrenal system and by increasing peripheral oxygen consumption, and directly by acting on cardiac cells [16]. The direct effect of T3 on cardiac cells can be of a nuclear or extranuclear nature. Nuclear effects are delayed in onset (30 to 60 minutes), require ongoing protein synthesis, and are brought about by binding of thyroid hormone to nuclear thyroid hormone receptors [16]. Extranuclear effects of thyroid hormone are rapid in action and are executed after thyroid hormone binds to plasma membrane receptors. This effect is mediated by an increase in Ca2+ influx into the myocytes [17].
Heparin is known to interact with thyroid hormone both in vivo and in vitro. Hollander and co-workers [18] demonstrated a rise in serum free thyroxine in patients receiving intravenous heparin. Shatz and associates [8] reported elevation of free thyroxine after injection of heparin into both euthyroid and hypothyroid patients. Schwartz and colleagues [10] confirmed Shatz's work and inferred that heparin interferes with cellular as well as plasma protein binding of thyroxine. Robuschi and associates [15] demonstrated a rise in free thyroxine levels with heparin administration before cardiopulmonary bypass. The hypothesis of our study was that the presence of heparin interferes with the extranuclear effects of T3 on myocytes and thus attenuates the effect of T3 on myocardium recovering from an ischemic injury.
We designed our experiments such that the effect of T3 was measured immediately after T3 administration and continued for 30 minutes. Thus, temporally the nuclear effects of T3 on the myocytes were negligible [16]. We were able to demonstrate that heparin significantly reduces the effect of T3 on developed myocardial pressure. We have also shown that T3 affects both systolic contraction and diastolic relaxation and that the presence of heparin interferes with both of these functions. The ability of T3 to affect these cardiac functions is known [3, 19, 20]; the ability of heparin to interfere with these T3-induced functions is being reported for the first time.
Our experiments were performed on the isolated heart using KH as a perfusate medium. Thus, we may infer that the effect of heparin on T3 is exerted, at least in part, at the level of the myocyte. The time frame of the effect measured here suggests that the effect occurs at the extranuclear level. Most likely, heparin interferes with the increased calcium uptake at the plasma membrane caused by T3 [17]. This speculation is being investigated presently.
This finding, that heparin interferes with the effect of T3 on the recovering myocardium, has clinical significance. Patients receiving T3 after cardiopulmonary bypass will be those who fail to wean from bypass or are weaned from bypass with low cardiac output. Such patients will still be heparinized. It may be that to achieve a clinical effect in this setting, the T3 dose must be altered. Also, when possible, the heparin will need to be neutralized with protamine before administration of T3. This hypothesis requires further investigation.
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Acknowledgments
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Supported by a grant from the Milton Polinger Fund of the United Jewish Endowment Fund of the UJA Federation of Greater Washington, DC. The manuscript was prepared in consultation with Eliezer Jucha, who performed the statistical calculations, and with the technical assistance of Sally Esakov.
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Footnotes
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Address reprint requests to Dr Cohen, Department of Cardiovascular Surgery, Edith Wolfson Medical Center, PO Box 5, Holon 58100, Israel.
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References
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Abstract
Introduction
