Dr. Alexis Carrel reported the first heterotopic transplantation (Table 4) of a canine heart connected to the neck vessels of another dog in 1905; the animal succumbed to massive clotting and survived for only 2 hours. Over the next 55 yr, Drs. Richard R. Lower and Norman E. Shumway ultimately perfected an orthotopic transplantation in the canine. In contrast to Carrel's original work, transplants in Shumway's laboratory research were placed orthotopically, and animals survived for up to 21 days before succumbing to rejection. Successful translation of this animal research to clinical practice was first accomplished by Dr. Christiaan N. Barnard in 1967; this required the further
use of animal models to provide a means to overcome the rejection by the host immune system that plagued previous attempts.
Today, the successful treatment of end-stage cardiac failure is now possible with either organ transplantation or mechanical assist devices (for those who may not initially qualify for transplantation). However, it is clear that too few suitable donor organs are available to meet the current needs (Fig. 11). It is also considered that the undersupply of organs will clearly worsen as the pool of potential donors is reduced further by the projected increased incidences of numerous factors that preclude heart donation, such as diabetes, hypertension, hypercholester-olemia, or infection with human immunodeficiency virus (HIV) or hepatitis B or C. This lack of a reliable and stable source of donor hearts serves as the main impetus for further research into expanding cardiac donor pools, the use of mechanical assist devices, and the potential for cellular-mediated transplantation.
Large amounts of research have been conducted in the field of cardiac transplantation (heterotopic or orthotopic) (Fig. 12). Orthotopic transplantation (the placement of the donor heart in the anatomically correct position) is considered the gold standard for the study of cardiac transplantation. This method of transplantation requires the use of cardiopulmonary bypass and was possible only after the pioneering efforts of Dr. C. Walton Lillehei (refer to ref. 35 for a complete discussion of the surgical technique). Orthotopic transplantation is technically feasible using available cardiopulmonary bypass circuits in both the canine and porcine animal models. The major disadvantage of orthotopic transplantation is that it requires a high level of surgical knowledge, and supportive technologies are usually found only in sophisticated research facilities (e.g., a university setting).
Furthermore, orthotopic transplantation has traditionally been chosen for the study of organ preservation, graft rejection immunology, immunosuppressive regimens, xenotransplan-tation, and ischemia/reperfusion injury (36-38). Heterotopic cardiac transplantation places the heart in an anatomical location other than the mediastinum. A heart transplanted into the
heterotopic position is connected by matching donor aorta to recipient aorta and donor pulmonary artery to recipient vena cava. As a result, blood flow is typically nonphysiological; normal patterns are limited to the coronary arterial and venous systems. Absence of significant flow in the ventricles, except for drainage of blood from the coronary sinus into its right ventricle, may promote clot formation and has been ultimately associated with failure of the model. An additional disadvantage of the heterotopic transplant model is the increased technical difficulty secondary to the donor/recipient aortic size mismatch, which also depends on the animal's age, weight, and species.
Heterotopic transplantation is generally used for studies of ischemia/reperfusion injury (39), prevention of rejection and immunosuppression (40), or coronary vascular pathology (41). Heterotopic heart transplantations can be performed using small mammal models such as the mouse, rat, hamster, guinea pig, or rabbit; yet, additional skills with microsurgical techniques are then required. A major advantage of this approach is that recipients may retain complete function of their native hearts whether or not the heterotopic donor hearts survive.
7.2. Specific Animal Models for Transplantation Research
The choice of an animal model for cardiac transplantation depends greatly on the area of physiological research. The following is a brief review to introduce the current models that have been used effectively to date in cardiac research laboratories around the world.
The development of microsurgical techniques has allowed for refinement of heart transplantation in the rodent model. Importantly, the use of rodents in transplantation research can dramatically reduce the costs associated with larger animal models. Typically, Lewis rats have been used for transplantation experiments related to ischemia and reperfusion, prevention of rejection, immunosuppression, and coronary vascular pathology. However, as long as the genetically bred rodent tissue types remain stable, they would also be suitable. Because of the small size of rodents, the technique of hetero-topic heart transplantation to the abdominal aorta and inferior vena cava, as described by Ono and Lindsey, has been used extensively (42).
Anatomically, the coronary artery blood flow in rodents differs somewhat from higher order mammals in that the left and right coronary arteries traverse the lateral wall of the right ventricle rather than the atrioventricular sulcus. In addition, the internal mammary arteries supply the atria with blood flow via the cardiomediastinal arteries. Some further disadvantages of the rodent model are that hemodynamic measurement of the transplanted hearts can be difficult, and transplantation uses microvascular surgical techniques requiring a surgical microscope.
Yet, an advantage of this model is its use for xenotransplantation experiments with grafts from mouse to rat, hamster to rat, guinea pig to rat, or hamster to guinea pig. In addition, preservation solutions can be fairly easily evaluated for the end points of survival, histology, and high-energy phosphate analysis. The heterotopic rat transplant model has been extensively used in the pharmaceutical industry to evaluate the effectiveness of antirejection medications. The availability of transgenic or "knockout" rodents will likely dramatically further the use of rodents in this area of research.
The anatomy of the canine heart is similar to that of the human heart (for more details, see Chapter 5). As mentioned in Section 6.3, the dog heart has an extensive collateral circulation connecting the left and right coronary circulation. In contrast, nonathletic humans elicit few bridging collaterals. This collateral circulation in the dog is considered theoretically advantageous in heart transplantation experiments because it may protect marginal areas of the heart from ischemia.
From the perspective of an easy-to-employ model, dogs have a minimal amount of adipose tissue, and their skin is loose, allowing tunneling of catheters if vascular access is needed postoperatively. Furthermore, the dog's relatively large thorax and mediastinum allow clear visualization of the heart and great vessels. Thus, the canine model for heart transplantation is generally considered most readily employable for animal stud ies of organ preservation, reperfusion injury, rejection studies, and posttransplant organ monitoring.
The porcine heart is often considered the most anatomically similar to the human heart (see Chapter 5). Specifically, the porcine heart has few collateral vessels, and an end-artery coronary anatomy predominates. Yet, cannulation for cardiopulmo-nary bypass may be difficult, and the right atrial tissue has typically been described as friable (2). In addition, a surgical cutdown for venous and arterial access may be required secondary to the thick subcutaneous layer of adipose tissue. The pig transplantation model is also prone to postoperative wound infections, necessitating strict sterile techniques during cardiac surgery. Furthermore, juvenile pigs have a tremendous capacity for somatic growth, which can challenge long-term foreign body implantations.
Physiologically, the porcine heart is considered prone to arrhythmia and is sensitive to physical manipulation. Bre-tylium tosylate can be given to limit such arrhythmias; however, ventricular fibrillation can be a recurrent problem following cardiopulmonary bypass (43). The swine model is considered appropriate for heart transplantation, but is often described as more suited to acute or short-term survival studies (44). Ongoing transgenic breeding projects to create a porcine heart with compatible tissue antigens (to be used as a substitute for the human donor heart) are exciting areas of research that will make the increased use of the swine model more likely.
Researchers in the field of cardiac transplantation have used the nonhuman primate model extensively in developing both the technique of transplantation and the scientific background necessary for the survival of the donor heart (45,46). Numerous programs have successfully used the nonhuman primate in small and large cardiac transplant studies (47-49). Yet, particular problems with the use of primates have been primarily associated with their veterinary care.
Specifically, specialized care is necessary during preopera-tive and postoperative times, and thus established facilities are required for appropriate holding and colony breeding. Furthermore, nonhuman primates are extremely susceptible to Myco-bacterium tuberculosis, and appropriate precautions must be taken to minimize the risk of infection. It should be noted that baboons are sensitive to stress and are apt to develop gastroenteritis and bacteremia after surgery; handling of the baboon typically requires sedation (Fig. 13).
Nevertheless, the use of baboons and other nonhuman primates has many advantages as an experimental model in transplant research. First, the size and anatomy of the baboon is very similar to human anatomy. Second, the growth of the baboon can be controlled, and adult weights in the range of20-30 kg are maintained for 20-30 yr. In addition, cardiac physiological characteristics of the baboon are similar to humans, allowing for the use of standard operative instrumentation.
Yet, cardiac anatomy differs somewhat from humans; the baboon heart has only two aortic arch vessels compared to the three found in humans. From a technical standpoint, the cardiac tissue of the nonhuman primate is not considered as friable or prone to serious arrhythmias as in the swine.
Adverse immunological responses in the primate are a main concern with xenotransplantation and with antirejection treatments. Interestingly, the human ABO blood-type system is applicable with simian tissue and saliva, but not with simian blood (50). Tissue typing with the major histocompatibility class system using primate tissue is also possible. Hyperacute rejection is inherent to xenotransplantation in this model because of the preexisting antibodies in the recipient; the donor antigens on the surface of the endothelium of the donor's heart that are present to the recipient's intact immune system cause rejection to ensue with subsequent activation of compliment (51). Fortunately, depletion of compliment factors in hetero-topic heart transplantation is possible in the primate model, as was performed at the University of Minnesota (Minneapolis, MN) (52).
Heterotopic (nonanatomic and nonfunctional) heart transplantation in the nonhuman primate is an established surgical procedure appropriate for investigation of immunosuppressive drug therapies and study of immune reactions between the donor heart and recipient. Typical locations for hetrotopic implantation of the donor heart include the neck or abdomen of the primate (53).
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