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Ann Thorac Surg 1996;62:78-82
© 1996 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Effect of Triiodothyronine on Graft Function in a Model of Heart Transplantation

Timothy V. Votapka, MD, David A. Canvasser, MD, D. Glenn Pennington, MD, Masaaki Koga, MD, Marc T. Swartz, BA

Division of Cardiothoracic Surgery, Department of Surgery, Saint Louis University Health Sciences Center, St. Louis, Missouri


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Brain death is associated with neuroendocrine changes that result in impaired metabolism, reduced myocardial energy stores, and deteriorating cardiac function. As a result of these changes, a substantial number of normal human hearts are not considered suitable for transplantation. In the hope of preventing these complications and stabilizing the condition of cardiac donors, we compared the function of transplanted hearts from brain-dead rats that received triiodothyronine (T3) (n = 6) with that of hearts from a group that received a placebo (n = 5).

Methods. This experiment was designed to be both blinded and randomized. Brain death was achieved by bilateral carotid ligation and inflation of an intracranial balloon. Triiodothyronine or placebo was administered in a blinded, randomized fashion. The brain-dead donors were then supported with conventional techniques for 2 hours after which time heterotopic transplantation was performed using hypothermic preservation and a working heart model. Hemodynamics of the transplanted hearts were assessed 48 hours postoperatively.

Results. The hearts from donors that had been pretreated with T3 were found to have a significantly higher (p < 0.005) peak left ventricular pressure than the hearts from the placebo-treated group (137 ± 17 mm Hg versus 115 ± 15 mm Hg). Left ventricular end-diastolic pressure was significantly lower (p < 0.01) in the T3-treated group (5.2 ± 2.2 mm Hg) compared with the placebo-treated group (6.9 ± 0.5 mm Hg). There was also a significantly higher (p = 0.03) maximal first derivative of left ventricular pressure in the T3-treated group compared with the placebo-treated group (4,876 ± 1,348 mm Hg/s versus 3,344 ± 1,016 mm Hg/s). Finally, the cardiac output in the group given T3 was 93 ± 16 mL/min compared with 61 ± 22 mL/min in the group given the placebo (p < 0.01).

Conclusions. Hearts from brain-dead rats that had received T3 before transplantation showed improved postoperative function. The experimental design of predonation brain death, cold immersion storage, and transplantation in a working heart model should make these data more relevant clinically than those previously reported.


   Introduction
Top
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 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
See also page 82.

Cardiac transplantation has become an established treatment of refractory heart failure. As transplant centers proliferate and as indications continue to broaden, there has been an increasing demand for donor organs. The desperate need of an expanded donor pool mandates that medical science improve the quality of readily available donor hearts and make available hearts not currently considered acceptable.

Trauma, in general, and brain death, in particular, are known to cause an acute and dramatic catecholamine release, and the resulting neuroendocrine changes affect multiple organ systems [1–5], often making the brain-dead donor a hostile environment for donor organs. Brain death in pigs has been shown to result in significantly depressed circulating levels of triiodothyronine (T3) [2]. In addition, brain death is associated with decreased intramyocardial high-energy phosphate stores [2, 3]. With the depletion of cellular high-energy phosphates, cellular respiration is shifted into anaerobic pathways with resultant lactic acid accumulation and deterioration in cardiac function. Improved cardiac performance after T3 administration has been documented both in animals [2, 3] and humans [1, 6]. Not only has T3 been shown to reverse cardiac dysfunction in brain-dead models, but in other studies [7–9], it has been demonstrated to improve postischemic cardiac performance.

In clinical transplantation, the net effect of the hypothyroid state in the organ donor is hemodynamic compromise, which becomes detrimental not only to the donor heart but also to other organs that are usually donated. It is not uncommon for organ donors to be maintained on high doses of inotropic agents while harvesting teams and organ recipients are being readied. The use of such inotropic drugs, particularly in high doses, has been shown to exacerbate myocardial ischemia [10–12] and may prolong myocardial recovery after the period of ischemia [13].

Administration of T3 to brain-dead donors in both animal models and clinical studies has been shown to improve hemodynamic status, reduce acidosis, and increase cellular high-energy phosphate content [1, 2, 5, 6]. Donor hearts that are aerobically metabolizing and have better energy stores should be better able to tolerate prolonged periods of ischemia. In addition, if predonation inotropic drug administration can be decreased, these hearts may return to normal function more rapidly. Thus, the donor pool can be expanded by making longer periods of cold storage safe and by improving performance in hearts that might otherwise seem too impaired for donation.

Earlier studies [2, 3] of the effect of T3 on donor heart function in animal models did not use cold immersion storage as is done in clinical transplantation. In addition, graft function was measured in an ex vivo setting only. An animal model that more closely approximates clinical transplantation is necessary. The purpose of this study is to analyze the effect of administering T3 prior to donation on donor heart function after heterotopic heart transplantation in a loaded working heart model.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Male inbred Lewis rats weighing 270 to 320 g were used as recipients and donors. The basic techniques were the same as those prescribed for heterotopic heart and heart-lung transplantation, and all procedures were performed in a sterile manner [14–16]. The animals received humane care in compliance with 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 85-23, revised 1985).

The donor rat was anesthetized with an intraperitoneal injection of sodium pentobarbital (30 mg/kg). Intravenous access was established, and systemic blood pressure was monitored with an indwelling catheter placed in the femoral artery. Heparin sodium (300 U/kg) was administered intravenously. A longitudinal cervical incision was made. The trachea was isolated and cannulated with a 14-gauge catheter. Ventilation was begun with a Harvard ventilator.

Brain death was induced in donor animals by combining modifications of two different, well-described models of brain death [17, 18]. Bilateral ligation of the carotid arteries was performed, and the cervical musculature was divided in the midline and retracted laterally to expose the underlying clivus. A dental drill was used to create a 3-mm midline craniotomy, thus exposing the dura and underlying basilar artery. A balloon-tipped catheter was placed extradurally and inflated with 0.5 mL of saline solution. The accompanying hypertensive response was blunted with an infusion of Arfonad (trimethaphan camsylate) (Roche Laboratories, Nutley, NJ). Inflation was maintained for 20 minutes to produce brain death and then was released. The 6 animals in the study group received an intravenous dose of T3 (0.1 µg), and the control group (n = 5) received a saline placebo. All injections were coded in prefilled syringes and administered in a blinded, randomized fashion.

After 2 hours of ventilatory support, the donors were replaced in a supine position. Heparin (300 mg/kg) was administered, and a small midline abdominal incision was made followed by a median sternotomy. A 14-gauge cannula was introduced into the right atrium through the suprahepatic inferior vena cava for infusion of cardioplegia. For these experiments, we used 10 mL of cold (4°C) saline solution with 20 mEq/L of potassium to arrest the heart. At the same time, cold saline solution was applied to the heart for topical cooling. After ligation and division of both the superior vena cava and the azygos vein with 5-0 silk, the aorta was transected just distal to the origin of the brachiocephalic artery. The heart and lungs were again flushed with 5 mL of cold saline solution through the previously placed inferior vena cava cannula, and then the inferior vena cava was ligated and divided. The right lower and postcaval lobes were ligated at the hilum and resected. The main bronchi were divided and left open to allow drainage of secretions. The heart-lung block was freed by resection of the esophagus. The block was stored in an iced saline solution until the time of transplantation into the recipient.

Anesthesia was induced in the recipient in the same manner as in the donor. The recipient was placed in a supine position, and a midline abdominal incision was used to expose the infrarenal aorta. A 2-cm segment of the infrarenal aorta was isolated by placing microvascular clips proximally and distally. Two longitudinal incisions corresponding to the size of the donor aorta and the size of the distal left pulmonary artery were made in the aorta.

The donor heart was wrapped in cold, wet gauze and placed in the abdominal cavity of the recipient. Topical cooling of the graft was maintained with an occasional application of iced saline solution. The donor aorta was anastomosed to the proximal incision in the recipient aorta in an end-to-side fashion. The donor left pulmonary artery was ligated and transected at its takeoff from the main pulmonary artery. The distal portion of the left pulmonary artery was anastomosed to the smaller distal aortotomy (Fig 1Go).



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  		Fig 1. . Working heart model of heterotopic heart-lung transplantation. (Abd. = abdominal; CS = coronary sinus; IVC = inferior vena cava; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.)

 
After completion of the anastomosis, a microvascular clamp was placed on the left pulmonary artery prior to reperfusion of the graft. The microvascular clamps were removed from the recipient aorta, and the donor heart resumed beating spontaneously within several minutes. After 20 minutes of reperfusion in an unloaded condition, the clamp on the left pulmonary artery of the donor heart-lung block was slowly released to introduce blood into the graft. The abdominal incision was then closed, and the animal was allowed to recover. Graft viability was monitored by palpation of the beating heart.

Hemodynamic measurements were made 48 hours after transplantation to minimize any discrepancies that might have resulted from rejection-related complications. All physiologic measurements were performed while the animals were still coded, and thus all measurements were performed in a blinded fashion. Anesthesia was induced and maintained by inhalation of minimal concentrations (0.8% to 1%) of isoflurane (Forane) (Anaquest, Inc, Madison, WI). Body temperature was kept constant by the use of a warming plate. The left carotid artery was exposed and cannulated with a 22-gauge cannula connected to a standard pressure transducer. The donor left ventricular (LV) pressure was measured with a 3F high-fidelity catheter-tipped microtransducer (Millar Instruments, Houston, TX), which was inserted into the LV cavity through the apex. Ejected flow from the donor heart was measured using an ultrasonic transit-time flow probe (Transonic Systems, Ithaca, NY) placed around the donor ascending aorta. Blood pressure in the recipient carotid artery was standardized to a mean of 80 mm Hg by saline solution infusion.

The three channels of continuous data (recipient carotid pressure, donor LV pressure, and donor aortic output) were digitized at 250 samples per second per channel for 6-second epochs every minute. The raw data and resultant computed hemodynamic values were stored every minute, and average values were reported for the 10 minutes of measurement. Data analysis was done using the XYZ program for data manipulation and SYSTAT Statistics program for statistics and graphic output. SYSTAT subroutines were used to evaluate t tests.

At the completion of these measurements, the animal was sacrificed and the transplanted heart was removed.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
The hemodynamic measurements made 2 days postoperatively in both groups are shown in Table 1Go. All of the variables related to function of the transplanted hearts were significantly better in the T3-treated group than in the placebo-treated group. There were no significant differences in systolic, diastolic, or mean arterial pressures between groups, as the carotid artery pressure was a cooperative effort of both the donor and recipient hearts. A representative tracing of the measured hemodynamic variables is shown in Figure 2Go.


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  		Table 1. . Hemodynamic Measurements in the Two Groupsa
 


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  		Fig 2. . Hemodynamic tracings from a heart in the triiodothyronine-treated group. (LV dP/dt = first derivative of left ventricular pressure; LVP = left ventricular pressure.)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The exact mechanism of the effect of T3 is incompletely understood, but it probably has both direct and indirect effects. Triiodothyronine exerts much of its influence on the cell at the nuclear level. The net effect of this nuclear interaction is an increase in mitochondrial protein synthesis. This protein synthesis results in an increase in various adenosine triphosphatase systems including Na+-K+, Ca+, and myosin-troponin adenosine triphosphatases [19, 20]. Extranuclear effects include alterations in the myocyte membrane that affect the transport of amino acids, glucose, and calcium [21]. Thyroid hormone also affects the peripheral vasculature so as to result in a reduction of systemic vascular resistance [22] and thus secondarily improves cardiac output.

We found significantly improved performance of T3-treated donor hearts by all the indices of myocardial function that we measured. Peak first derivative of LV pressure is thought to be largely independent of changes in afterload but can be modestly influenced by changes in preload and by changes in muscle mass produced by ventricular hypertrophy [23]. By controlling abdominal aortic pressure in the recipient rat and thereby controlling for pulmonary artery pressure in the donor heart, we attempted to control for LV loading. The hemodynamic measurements were made on posttransplantation day 2, and therefore there would be negligible LV hypertrophy to confound the first derivative of LV pressure measurements.

The reliable and reproducible production of brain death in rats was problematic and is worthy of mention. In early experiments, we tried to induce brain damage by four-vessel occlusion as described by Pulsinelli and Brierly [17]. Although the animals were clearly impaired, they still demonstrated spontaneous respiration and pain response. We then adapted the porcine model of brain death described by Schwartz and colleagues [18] to the rat. By combining bilateral carotid artery ligation and intracranial Fogarty balloon inflation, we were able to reliably produce brain death confirmed by apnea and absence of deep pain reflexes. In early experiments to further confirm the presence of brain death, triphenyltetrazolium chloride was administered intravenously 1 hour after balloon inflation. In no animal studied was there evidence of triphenyltetrazolium chloride staining on cross section of the brain.

We acknowledge that the results of this study could be questioned because of the small sample size, and we were disappointed by the paucity of complete data points available for analysis. Several technical aspects of this experiment made it difficult to have a completely studied animal at end point and should be mentioned. The induction of brain death in these anesthetized and ventilated rats resulted in such severe hemodynamic compromise that many donor animals died before the mandatory 2 hours of support could be completed. Donor hearts from animals that died before the time of organ harvest were discarded. Such animals typically experienced a period of extreme hypertension at the time of balloon inflation followed by progressive hypotension refractory to dopamine hydrochloride infusions. After heterotopic transplantation, almost all donor hearts began to beat (both study and control hearts), but many animals did not survive the required 2 days to undergo hemodynamic measurements. Any animal that was not subjectively vigorous on posttransplantation day 2 was excluded from hemodynamic analysis. A total of 12 animals were excluded from analysis on the basis of this consideration (7 in the placebo-treated group and 5 in the T3-treated group).

The experimental design of this study more closely duplicates the actual clinical setting of heart transplantation than previous studies of the effect of T3 on donor heart function. We recognize that complex proclivities of each individual experiment make it difficult to control for all variables. Nonetheless, we believe that the results overwhelmingly demonstrate improved myocardial function in donor hearts treated with T3. It is hoped that T3 will not only allow more donor hearts to become available but also will improve the function of currently "suitable" hearts, thereby resulting in improved posttransplantation survival. These findings argue for a large multiinstitutional clinical trial to determine the effects of T3 in the human transplant setting.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
Supported in part by a grant from Smith Kline-Beechum, Philadelphia, PA.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Presented at the Forty-second Annual Meeting of the Southern Thoracic Surgical Association, San Antonio, TX, Nov 9–11, 1995.

Address reprint requests to Dr Votapka, Division of Cardiovascular and Thoracic Surgery, The Evanston Hospital, 2650 Ridge Ave, Evanston, IL 60201.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Novitzky D, Cooper DKC, Reichart B. Hemodynamic and metabolic responses to hormonal therapy in brain-dead potential organ donors. Transplantation 1987;43:852–4.[Medline]
  2. Novitzky D, Wicomb WN, Cooper DKC, Tjaalgard MA. Improved cardiac function following hormonal therapy in brain dead pigs: relevance to organ donation. Cryobiology 1987;24:1–10.[Medline]
  3. Wicomb WN, Cooper DKC, Lanza RP, Novitzky D, Isaacs S. The effects of brain death and 24 hours' storage by hypothermic perfusion on donor heart function in the pig. J Thorac Cardiovasc Surg 1986;91:896–909.[Abstract]
  4. Burch GE, Meyers R, Abildskov JA. A new electrocardiographic pattern observed in cerebrovascular accidents. Circulation 1954;9:719–23.[Medline]
  5. Wicomb WN, Novitzky D, Cooper DKC, Wells M, Hill JD. Early extranuclear effect of triiodothyronine (T3) on tissue slices: relevance to organ donor viability. Transplant Proc 1989;21:1263–4.[Medline]
  6. Novitzky D, Cooper DKC, Chaffin JS, Greer AE, DeBault LE, Zuhdi N. Improved cardiac allograft function following triiodothyronine therapy to both donor and recipient. Transplantation 1990;49:311–6.[Medline]
  7. Holland FW II, Brown PS Jr, Clark RE. Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg 1992;54:301–5.[Abstract]
  8. Novitzky D, Cooper DKC, Barton CI, et al. Triiodothyronine as an inotropic agent after open heart surgery. J Thorac Cardiovasc Surg 1989;98:972–8.[Abstract]
  9. Novitzky D, Matthews N, Shawley D, Cooper DKC, Zuhdi N. Triiodothyronine in the recovery of stunned myocardium in dogs. Ann Thorac Surg 1991;51:10–7.[Abstract]
  10. Lazar HL, Buckberg GD, Foglia RP, Manganaro AJ, Maloney JV. Detrimental effects of premature use of inotropic drugs to discontinue cardiopulmonary bypass. J Thorac Cardiovasc Surg 1981;82:18–25.[Abstract]
  11. DaLuz P, Forrester JS, Wyatt HL, Water D, Swan HJC. Divergent effects of dopamine upon ischemic myocardium with partial and total coronary occlusion [Abstract]. Am J Cardiol 1976;37:130.
  12. Mueller HS, Evans R, Ayres SM. Effect of dopamine on hemodynamics and myocardial metabolism in shock following acute myocardial infarction in man. Circulation 1978;57:361–5.[Abstract/Free Full Text]
  13. Kabas JS, Spratt JA, Davis JW, Rankin JS, Glower DD. The effects of dopamine on myocardial functional recovery after reversible ischemic injury. J Thorac Cardiovasc Surg 1990;100:715–23.[Abstract]
  14. Maruyama T, Swartz MT, McBride LR, Pennington DG. Working heart model of heterotopic heart-lung transplantation in rats. J Thorac Cardiovasc Surg 1994;107:210–5.[Abstract/Free Full Text]
  15. Konertz W, Semik M, Bernhard A. Heart, lung and heart-lung transplantation in rats. J Heart Transplant 1985;4: 426–30.[Medline]
  16. Ding M, Dyke CM, Kadletz M, et al. A working heterotopic heart transplantation model. Surg Forum 1992;43:241–3.
  17. Pulsinelli WA, Brierly JP. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 1979;10:267–72.[Abstract/Free Full Text]
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  20. Guernsy DL, Edelman IS. Regulation of thermogenesis by thyroid hormones. In: Oppenheimer JH, Samuels HH, eds. Molecular basis of thyroid hormone action. New York: Academic Press 1983:298.
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  22. Klein I. Thyroid hormone and the cardiovascular system. Am J Med 1990;88:631–7.[Medline]
  23. Braunwald E. Heart disease: a textbook of cardiovascular medicine. Vol 1. 4th ed. Philadelphia: Saunders, 1992:419–43.

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