Ann Thorac Surg 2010;89:1518-1523. doi:10.1016/j.athoracsur.2010.02.008
© 2010 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Donor Heart Preservation in an Empty Beating State Under Mild Hypothermia
Hui Lin, MDa,c,*,*,
Ansheng Mo, MDa,*,
Fan Zhang, MDc,*,
Ailan Huang, MMb,
Zhaoke Wen, MMa,
Shengjin Ling, MMa,
Yanyan Hu, MMb,
Yifang Zhou, MMa,
Changchao Lu, MMa
a Department of Cardiothoracic Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning City, China
b Department of Anesthesia, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning City, China
c Department of Anesthesia, The People's Hospital of Wuhan University, Wuhan, China
Accepted for publication February 5, 2010.
* Address correspondence to Dr Lin, Department of Cardiothoracic Surgery, No 6 Taoyuan Rd, Nanning City, Guangxi Zhuang Autonomous Region 530021, China (Email: guangxixiongwai{at}yahoo.com.cn).
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Abstract
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Background: Cardiac surgery during an empty beating heart state has proven to be beneficial in myocardial protection. Based on this, we hypothesized that maintaining this state for donor heart preservation would have the same efficacy and a prolonged preservation period.
Methods: Part 1: 12 pigs were divided into two groups (n = 6 per group). Donor hearts were preserved in group A by perfusion with leukocyte-depleted blood in the beating state, and in group B, in the traditional hypothermic static state with University of Wisconsin solution. After 8 hours, myocardial samples were obtained to detect myocardial edema, adenosine triphosphate, and ultrastructure. Part 2: 12 donor-recipient swine pairs were randomly allocated to either beating heart preservation with perfusion (group C) or traditional static preservation (group D). Donor hearts were stored for 8 hours after isolation, followed by implantation into recipient animals. Implanted hearts recovered for 120 minutes in an empty and beating state followed by 30 minutes in a working state, after which cardiac function was measured.
Results: After preservation, myocardial adenosine triphosphate levels in group A were significantly higher than in group B. However, myocardial water content was not significantly different between these two groups. The damage of myocardial ultrastructure in group A was slight compared with that of group B. The experimental transplant group C showed excellent heart function after implantation when compared with group D.
Conclusions: Our study reveals greater effects of donor heart preservation in a beating state rather than simply with hypothermic storage in University of Wisconsin solution.
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Introduction
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Despite major achievements in heart transplantation, we still face the persistent problem of a shortage of donor hearts. An ideal situation would entail procurement of donor hearts in a manner that consumes no ischemic time. Unfortunately, current protocols for preserving donor hearts utilize hypothermic arrest and simple storage by a variety of crystalloid-based cardioplegic and preservation solutions. This is a suboptimal approach owing to the inevitable associated ischemia. Ischemic damage contributes to the risk of post-transplantation primary graft dysfunction and limits organ procurement and safe storage time to 4 to 6 hours. This time limit causes a significant obstacle for transporting a heart to distances whereby an otherwise well-matched recipient is in need of a timely transplantation. It has been suggested that on-pump empty beating heart surgery provides better myocardial protection [1–4]. Further, preserving the donor heart in a beating state ex vivo can safely prolong the preservation period [5–7].
Safely extending donor heart preservation time yields several benefits, including the opportunity for surgeons to evaluate the organ immediately before transplant, more comprehensive tissue matching, and adequate transport time. However, there are few studies addressing the technique of beating heart preservation, and the methods are not standardized. We therefore designed this study to compare continuous mild hypothermic perfusion of the isolated swine heart in the beating, resting state to standard hypothermic storage in the arrested state, to determine if a newer approach would extend the life-saving potential of the donor heart.
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Material and Methods
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This protocol was approved by our Institutional Animal Care Committee. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health publication 85-23, revised 1985).
Animal Preparation
All pigs were premedicated with intramuscular diazepam (1 mg/kg) and ketamine (30 mg/kg), followed by intubation, and mechanical ventilation. Anesthesia was maintained with 1% to 2% isoflurane. The right carotid artery and vein were cannulated for hemodynamic monitoring and support, and a median sternotomy was performed. After isolation of the great vessels outside the pericardium, animals were infused with 400 U/kg heparin. As a precautionary step, a blood cross-matching protocol was performed between donor and recipient before proceeding with blood transfusions and heart transplantation. No samples were positive for agglutination, confirming donor and recipients were appropriately matched.
Part 1, Preservation of Donor Hearts
Twelve pigs were randomly divided into two groups (n = 6 per group) comprising group A and group B.
Group A
The pericardium was separated from surrounding tissue. Next, the aorta was clamped, and the heart was arrested with 1 L University of Wisconsin solution [8] through a brachiocephalic artery cannula, completing the donor cardiectomy and maintaining the intact pericardium. After harvesting, a catheter was introduced into the left ventricle through the pulmonary vein and mitral valve for decompression. The donor hearts were connected to the perfusion circuit (Figs 1 and 2)
and stored in an empty and beating state (resting mode) with continuous perfusion of leukocyte-depleted blood at 32° to 34°C.
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Fig 1. Schematic of perfusion device and the cardiopulmonary bypass for the heart. The perfusion device consisted of a roller pump, small heat exchanger, gas blender, oxygenator of infant and blood reservoir, self-design heart preservation chamber, filtration system, and tubing system. Blood circulation flowed from ascending aortic cannula to coronary ostia to coronary sinus to blood reservoir to pump to membrane oxygenator to filter, and back to ascending aortic cannula.
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Fig 2. Perfusion the heart and decompression of the heart chambers. A cannula for perfusion was inserted through the brachiocephalic artery, and a catheter for decompression was introduced into the left ventricle through the pulmonary vein and mitral valve.
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The perfusion device consisted of a roller pump, heat exchanger, gas blender and tubes, oxygenator and blood reservoir, heart preservation chamber, filtration system, tubing system, and leukocyte-depleted blood. The associated pump was nonpulsatile, in which rate and volume could be controlled and measured. The mean perfusion pressure was maintained at 30 to 60 mm Hg with a flow rate of 60 to 80 mL/min. Continuous perfusion pressure readings were obtained with a pressure transducer attached to the arterial inflow line.
The perfusion solution (Table 1) consisted of 675 ± 93.54 mL heparinized leukocyte-depleted, dilute blood, supplemented with red cell storage solution (sodium citrate, citric acid, glucose, sodium dihydrogen phosphate, adenine, sodium chloride, mannitol [Changchun Terumo Medical Products, China]), fructose-1,6-diphosphate, penicillin, methylprednisolone, and epinephrine. Blood in the perfusion circuit was oxygenated with 95% oxygen/5% carbon dioxide at a rate of 100 mL/min and warmed to 32° to 34°C with a hollow-fiber membrane oxygenator. The blood of perfusate was collected into siliconized collecting bags containing heparin from a second swine under anesthesia.
Group B
The donor hearts of group B were harvested in conventional method. After exposure of the heart, the aorta was clamped and the heart was arrested with 1 L University of Wisconsin solution at 4°C through an ascending aortic cannula, completing the donor cardiectomy. Donor hearts were preserved for 8 hours in University of Wisconsin solution at 4°C.
Obtaining samples
After donor hearts from both groups were stored for 8 hours and hearts from group A were arrested with University of Wisconsin solution at 4°C, myocardial samples were obtained from the 12 donor hearts and analyzed for adenosine triphosphate, myocardial edema, and ultrastructure.
Myocardial adenosine triphosphate
Biopsies (1 mm in diameter) were obtained from both left ventricular free walls and rapidly frozen (approximately 1 s). Biopsy specimens were stored at –80°C in liquid nitrogen. Adenosine triphosphate levels were measured using biochemical methods following the manufacturer's instructions (Nanjing Institute of Jiancheng Biological Engineering, Nanjing, China).
Measurement of myocardial water content
After donor hearts from both groups were stored for 8 hours and donor hearts from group A were arrested with University of Wisconsin solution at 4°C, the specimen wet weight was obtained from both groups. Each specimen was then dried in an 80°C oven for 48 hours to obtain dry weight measurements. Myocardial water content was calculated as follows: myocardial water content = ([wet weight – dry weight]/[wet weight]) x 100%.
Myocardial ultrastructure
After 8 hours of preservation and cardioplegic arrest, 2 donor hearts from each group (A or B) were taken from the left ventricular free walls. Processing of tissue into blocks for transmission electron microscopy was by the method of Medeiros and colleagues [9], using gluteraldehyde and osmium tetroxide as fixatives and spurr as resin. Ultrastructural findings of biopsies were examined using a transmission electron microscope.
Part 2, Preservation and Implantation of Donor Hearts
Twenty-four Guangxi Bama miniature pigs weighing 25 to 30 kg were divided into 12 donor-recipient pairs and randomly allocated to hypothermic state with beating preservation (group C) or University of Wisconsin solution (group D) for 8 hours, as described above.
Recipient protocol
After a median sternotomy was performed, the recipients were placed on standard cardiopulmonary bypass with a membrane oxygenator at a nasopharyngeal temperature of 28°C. Recipient heart excision was timed to coincide with the end of the donor heart storage interval. After the pericardium of donor heart was excised, the aorta and pulmonary artery were separated from each other with sharp dissection, the pulmonary vein openings were connected, creating one large left atrial cuff, and the excess atrium, aorta and pulmonary artery were trimmed. Then, the donor hearts were implanted into recipients using standard orthotopic heart transplantation procedures (Lower and Shumway) [10]. During implantation, topical cooling was applied to the hearts in both groups. Once the anastomoses of the left atrium and aorta were completed, partial anastomoses of the pulmonary artery and right atrium was performed, the animals' temperature was returned to 35°C, a venting catheter was inserted into the left ventricle cavity through the apex, and animals received 500 mg of methylprednisolone to prevent hyperacute rejection of cardiac allografts from preformed recipient antibodies. Finally, the cross clamp was released, and continuous anastomoses were performed on the beating heart during reperfusion. After removal of the aortic clamp, hearts were defibrillated with 10 to 30 J, if necessary. If necessary, an intravenous infusion of dobutamine was given at 5 µg · kg–1 · min–1 and an infusion of isoproterenol was instituted at a dose of 0.02 µg · kg–1 · min–1 to achieve a heart rate of 100 to 120 beats per minute.
Measurement of ventricular performance
Intracavity pressures of the right and left ventricle were measured at 2 hours after reperfusion in an empty and beating state with a physiological recorder. After weaning off cardiopulmonary bypass for 30 minutes, hemodynamics was monitored by a Swan-Ganz catheter.
Statistical Analysis
Data are expressed as mean ± SD. Groups were compared with a two-sided independent samples t test, and the paired samples test was used in hematocrit comparison using the Statistical Package for the Social Sciences (SPSS Inc, Chicago, IL). Significance was set at p less than 0.05.
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Results
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Preservation
Group A
During the preservation phase, the coronary flow of 60 to 80 mL/min had a coronary perfusion pressure of 39 to 62 mm Hg, the partial pressure of oxygen from coronary venous blood was 56.62 ± 6.93 mm Hg, and no arrhythmia occurred except 1 case that presented with a brief 2:1 atrioventricular conduction. Hematocrit was 18.00 ± 2.83 at the beginning and 15.33 ± 1.97 in the end of preservation (p = 0.022).
Comparison of two groups
Adenosine triphosphate levels were significantly lower in group B (0.83 ± 1.02 nmol/mg pro) compared with group A (37.83 ± 9.02 nmol/mg pro; p < 0.05). But there was no difference in the myocardial water content between the two groups (group B 79.51% ± 2.73% versus group A 80.04% ± 0.73%, p = 0.65). Myocardial ultrastructural analysis revealed that there was less ultrastructural damage in group A compared with group B (Fig 3).
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Fig 3. Electron microscopic findings. Group A: (1) Normal mitochondria and sarcolemma; (2) mitochondria are seen in myofibril and sarcomeres are neatly arranged. (Original magnification, both, x20,000.) Group B: (3) Focal myofibrillar lysis and fragmentation, and vacuolar degeneration of mitochondria; (4) myocardial sarcolemma, swollen and fingerlike protrusions, and myocardial degeneration. (Original magnification, both, x10,000.)
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Reperfusion
The weight differences between donor and recipient, time of cardiopulmonary bypass, and anastomotic time are listed in Table 2. Upon reperfusion, all hearts in group D required direct-current shock to convert to sinus rhythm, whereas all hearts in group C returned to normal sinus rhythm without pacing or direct-current shock. Left ventricular systolic pressure and right ventricular systolic pressure of donor hearts in an empty and beating state at 2 hours after reperfusion are higher in group C (Table 2). The cardiac output, cardiac index, and dobutamine levels 30 minutes after weaning off cardiopulmonary bypass are listed in Table 2.
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Comment
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The main goal of donor heart preservation is to maintain myocardial ultrastructure and cardiac function. Historically, ischemia-reperfusion injury is inevitable in hypothermic arrest and simple storage of donor hearts. In contrast to cold storage, the underlying principle of beating heart preservation is to provide a near-physiologic environment for the heart by continuously perfusing it with a warm, oxygen-rich medium. Thus, nutrients were continuously supplied and waste products continuously removed, resulting in a more optimal preservation. Moreover, there was reduction of ischemic or reperfusion injury to potentially impair graft function. In addition, damage induced by low temperature and hyperkalemia was also avoided. In our study, we observed significant differences in both of these variables between the two techniques. Adenosine triphosphate levels, cardiac output, cardiac index, and left ventricular systolic pressure were higher in the groups using the beating preservation technique than in the groups using an arresting preservation technique. Further, a stronger ultrastructure preservation was observed in the beating preservation group A. The potential mechanisms for myocardial protection of beating heart technique are described below.
To decrease ischemia and reperfusion injury, the donor hearts were continuously perfused physiologically through the aortic root and allowed uninterrupted coronary blood flow. Thus, nourishment derived from continuous perfusion was adequate to diminish ischemia and reperfusion injury and prevent acidosis by continuously removing waste products.
With an empty beating heart state, cardiac workload is dramatically reduced, which led to greatly decreased myocardial metabolism. Thus, the perfusion pressure of 39 to 62 mm Hg, together with precise left ventricle venting, results in an optimal balance of myocardial oxygen supply and demand. In addition, a low perfusion pressure of 39 to 62 mm Hg has the advantage of preventing increased myocardial bleedings and edemas [6], as well as blood cell damage. Supporting this, a previous study [11] demonstrated that oxygen demand saturated by adequate oxygen delivery at 30 mm Hg, and an increasing coronary flow or oxygen delivery does not increase myocardial oxygen consumption in an empty beating heart state.
With a mild hypothermic cardiopulmonary bypass, adenosine triphosphate synthase was less impaired and oxyhemoglobin levels shifted slightly to the left on the dissociation curve, favoring dissociation of oxygen from the heme and efficient oxygen use by the myocardium [12]. This is important, because if adequate oxygen is not provided to the tissue, there would be a need for additional energy support systems. This energy would be derived from glycolysis or anaerobic metabolism, consequently increasing lactate levels, and increasing base deficits and acidosis. Mild hypothermia is beneficial for energy production and consumption. Similarly, Kaukoranta and coworkers [13] proposed that mild hypothermia, instead of normothermia, was a preferred means to obtain better heart protection.
We used leukocyte-depleted blood in our perfusion protocol. This provides a better substrate, improves oxygen delivery and oncotic pressure, and contains endogenous free-radical scavengers and potent buffers [14–19]. The oncotic pressure helps alleviate unwanted edema, and continuous delivery of oxygen and substrates maintains cellular adenosine triphosphate content by allowing ongoing aerobic metabolism. Leukocyte-depleted, endogenous free-radical scavengers and potent buffers attenuated inflammatory reactions and acid-base disturbances [20–26].
Another key feature of the techniques presented in the current study is that myocardial lymph flow is maintained in the beating preservation group. Previous research demonstrated that machine perfusion maintained donor heart metabolism during static storage and led to superior reperfusion function [27–30]. However, this resulted in increased myocardial edema, leading to impaired diastolic cardiac function, compared with conventional static preservation methods [27–30]. Therefore, myocardial contraction is very important for maintaining normal myocardial lymph flow and myocardial fluid balance [31–33]. In our study, the beating heart group maintained electromechanical activity and lymph flow, unlike the arrested heart group. Consequently, there was no statistically significant difference in the myocardial water content between group A and group B.
Finally, it is known that the pericardium prevents overdilation of the heart, facilitates the hemodynamic interdependence of ventricles [34–36], lubricates heart surfaces, keeps myocardial surface moist, and secretes immunologic mediators. Furthermore, the pericardium carries the weight of the heart in the Langendorff model. As a result, the pericardium is expected to play an important role in restraint of acute volume overload and prevention of myocardial surface friction injury during preservation. Conversely, there are reports [37, 38] that pericardiotomy could improve the pump function of the heart by blood volume expansion according to the Frank-Starling mechanism. However, preload above a certain value will result in damage to the myocardium. Thus, in group A and group C, myocardium injury may take place during the procedures of donor heart excision and in the initiation of preservation. During the procedures of donor heart excision, the left ventricle would dilate because of increase in aortic resistance once the aorta was cross-clamped. In the initiation of preservation, the left ventricle may dilate for the decreased ventricular function, and the blood of cardiac ventricles that was pumped out through the decompression tube and pulmonary artery would decline. Therefore, keeping the pericardium intact appears to be more reasonable in the beating heart preservation method.
Our study shows that donor hearts kept in a beating state, whereby the intact pericardium is preserved, extend the preservation time and improve recovery of heart function. This technique has the potential to be a promising protective strategy for minimizing heart injury. Compared with the working heart state, donor heart preservation in the empty beating state under conditions of mild hypothermia is associated with simpler surgical procedures. The flow rate of 60 to 80 mL/min provides adequate tissue perfusion and minimizes edema development caused by low perfusion pressure. An intact pericardium prevents myocardial surface from friction injury, keeps myocardial surface moist, and facilitates the hemodynamic interdependence of ventricles. Donor heart preservation with these techniques also has several disadvantages, including the more technically challenging, like risk of infection, probably higher risk of air embolism, and greater costs than the traditional hypothermic static state. But these shortcomings would be gradually resolved with the development of science and technology.
This study has the limitation that the study has a small sample size, and the reperfusion interval was limited to 150 minutes. Further, larger studies will be required to test this technique under longer preservation and reperfusion intervals.
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Acknowledgments
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The study was supported by a grant from the Natural Science Foundation of Guangxi Zhuang Autonomous Region (0235024-1). We wish to thank the operating room nurses at The People's Hospital of Guangxi Zhuang Autonomous Region for making this study possible.
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Footnotes
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* These authors contributed equally to this work. 
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Abstract
Introduction
