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The Evolution of Heart Transplantation
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Heart Transplantation
The Evolution of Heart Transplantation Stephen D. Krau, PhD, RN
Of all of the medical advances that have taken place in the last century, none have caused more interest and extensive notice than the first human heart transplantation. Although the first human heart transplantation was performed on December 3, 1967, by Dr Christiaan Barnard of Cape Town, South Africa,2· 23 the success of the procedure was the result of the ideas and works of many brilliant scientists and surgeons over a long period. From ancient folklore of chimeric beings to preliminary experimentation on animals, heart transplantation has developed into a currently accepted therapeutic procedure for the treatment of end-stage cardiac disease. It is a superb example of a therapeutic technique whose development is the result of an extensive evolutionary process that continues to progress.
History of Cardiac Transplantation The history of cardiac transplantation is grounded in ideas of transplantation in general. The history of transplantation is exten-
From the School of Nursing, Middle Tennessee State University, Murfreesboro; and the Coronary care Unit, Vanderbilt University Medical Center, Nashville, Tennessee
sive and is divided into three parts: prehistory, experimental, and clinical eras. 34 Prehistory
The prehistory of transplantation closely aligns with the history of science and the development of knowledge and understanding of human anatomy and physiology. This era begins with ancient notions that extend to ideas of surgical considerations that were performed by humans, but were, more or less, subverted by divine intentions, and extends through a more sophisticated understanding of human anatomy and surgical interventions. This era starts before 500 BC and ends in the late 1800s AD. Notions of chimeric beings abound in mythology. The word chimera has a variety of meanings, but all of the meanings concur that a chimera is " . . . an often fantastic combination of incongruous parts. "40 In mythology, the creature that was a female monster with a goat's body, a lion's head, and a snake's tail was most often referred to as a chimera. The notion of different body parts in one being extends to mythologic creatures, such as a satyr or the Minotaur, the offspring of a human and bull, with the head of a bull and a human body. The conception of an exchange or change in body is well-illustrated in the Greek myth that focuses on Acteon, a great hunter. While hunting in the woods one day, Acteon became
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thirsty and came upon a grotto with crystal water. Unknowingly, he happened upon the favorite bathing place of Artemis. While preparing to bathe, Artemis, unaware of Acteon's presence, dropped her garments and stood at the water's edge. When she discovered Acteon, she furiously flung drops of water on him from her wet hand. On contact with the droplets, Acteon was transformed into a stagheaded creature. This transformation was not only an outward transformation as the myth recounts ". . . his heart became a deer's heart and he who had never known fear before was afraid and fled." 15 He was chased by his dogs, who caught him and tore him to pieces. It has been suggested that this tale constitutes an allegory for acute rejection. 34 The concept of heart transplantation was also familiar in ancient Judaic times. In sixth century BC, the prophet Ezekial illuminated: "A new heart also will I give you, and a new spirit will I put within you; and I will take away the stony heart out of your flesh, and I will give you an heart of flesh. "12 Chinese medicine in sixth century BC was separated from religion. Diseases were thought to be the result of a disequilibrium of energies within the body, often referred to as the yin and the yang. Legend has it that Pien Ch'iao, a physician in China born 430 BC, performed an exchange of hearts. 21 Pien Ch'iao was known for his ability to puncture vessels, create and use powerful drugs, and perform surgery. Two sick soldiers, Kung He of Lu, and Ch'i Ying of Choa sent for Pien Ch'iao to treat them. 42 After the doctor's ministration, both men recovered from the immediate illness but were told by Pien Ch'iao that there were other diseases forming within them and asked if they wanted to be treated. Pien Ch'iao explained that their energies were in disequilibrium. In Kung He, the will was strong, but the spirit was weak; the spirit of Ch'i Ying was strong, but the will was weak. Thus in one, the yin was too strong, and in the other, the yang dominated. Pien Ch'iao proposed that equilibrium would be restored if their two hearts were exchanged. Kung He and Ch'i Ying agreed to have surgery and were anesthetized by Pien Ch'iao and remained unconscious for 3 days. Pien Ch'iao is said to have been the first man to use a general anesthetic.21 He opened their chests and removed and exchanged their
hearts, thus bringing both men's yin and yang into balance. Both men returned to their homes feeling well, living the rest of their lives with the heart of the other. There are no other references to heart transplantation during this period and only a few references to any form of transplantation. Among miracles in Christian tradition is the miracle of the black leg, which is thought to have occurred around 348 AD and is attributed to the Saints Cosmas and Damian. 20 A church sacristan made a pilgrimage to Aesculapius to pray for his cancerous leg. During the night, Saints Cosmas and Damian replaced the sacristan's leg with the leg of a Moor gladiator who had died earlier that day. When the sacristan woke, he was pain free and discovered that where the cancerous leg had been was now a perfectly healthy black leg. He went to the cemetery with other townspeople to find that the gladiator's leg had been amputated, and next to him in the coffin was the sacristan's diseased leg. 20 Throughout subsequent centuries, the notion of transplantation was exuberantly denied by most physicians. A notable physician in the fifteenth century, Hieronymus Brunchweig, adamantly denied the possibility that appendages could ever be reattached to the body. He stated that if someone tried to reattach a part of the body, it would be equivalent to "a monkey becoming a philosopher" or a man "trying to fly in the air." 18 Experimental Era
By the eighteenth and nineteenth centuries, transplantation was a notion well-grasped by physicians and physiologists. 3 Because surgical asepsis had not yet been developed, the only form of transplantation that was taking place at this time was skin transplantation. The beginning of the experimental era of heart transplantation is closely associated with the work by Alexis Carrel, a visionary French surgeon.23• 34 • 36 Carrel was a vascular surgeon whose quest to develop the procedure of vascular anastomoses set the stage for organ transplantation. When the President of the French Republic, Sadi Carnot, was assassinated in 1894 by a stab wound that lacerated his portal vein, Carrel was deeply distressed that the best surgeons could not control Carnot's bleeding and save his life. Carrel was
THE EVOLUTION OF HEART TRANSPLANTATION
convinced that Carnot would have lived if the surgeons had the ability and technique to sew his vessels together. 34 Similarly, in 1896, a German surgeon, Ludwig Rehn, was the first surgeon to suture a cardiac laceration in a stab wound victim.6 Carrel left France and while working with Charles Claude Guthrie at the Hull Physiological Laboratory at the University of Chicago, performed the first cardiac transplant in 1905. In this experiment, the heart of a dog was transplanted into the neck of a recipient dog, and anastomoses to the jugular vein and carotid artery were created. When the second heart is inserted in tandem with the recipient heart the transplantation is referred to as heterotopic transplantation. The heart began to beat an hour after the procedure and maintained a rhythm for approximately 2 hours before coagulation occurred in the cavities of the heart, and the dog died.36 These experiments confirmed that the heart could be separated from its originating blood supply and reimplanted using vascular anastomoses while still maintaining heart function. In 1912, Carrel was the first scientist working in an American laboratory to be awarded the Nobel Prize in Medicine and Physiology.34 Together, Carrel and Guthrie published a landmark work in the history of transplantation. The Transplantation of Veins and Organi!' is the foundation of vascular surgery and organ transplantation. Shortly after this publication, Guthrie went to St. Louis and Carrel went to Rockefeller University of New York, where he became chief of the division of experimental surgery. There are few recorded subsequent experiments in heart transplantation until 1933, when Frank C. Mann, working at the Mayo Clinic, developed another heterotopic technique for transplanting the canine heart. 31• 37 Significant observations that Mann made to the evolution of heart transplantation included the necessity of avoiding ventricular distention and coronary air embolism, the importance of using heparin to prevent thrombosis, and the hypothesis that rejection was the result of some sort of graft failure. He suggested that the failure of the transplanted heart could possibly be attributed to "some biologic factor which is probably identical to that which prevents survival of the homotransplanted tissues and organs." 31 This obser-
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vation can currently be explained as immunologic rejection. The Mann technique for heterotopic transplantation provided a beneficial model that is still used for study of physiologic and immunologic components of transplantation. 36 Afterwards, Mann devoted his time to his interest in metabolic consequences of hepatectomy, and heart transplant research in the United States remained dormant for approximately 20 more years. In the Soviet Union, Vladimir Demikhov was conducting a series of experiments that significantly advanced the science of transplantation. Demikhov developed and implanted the first artificial canine heart in 1937. He also developed a method for intrathoracic heterotopic heart transplants and heart and lung transplants in canines. Demikhov devoted his life to experiments in transplantation and is credited with performing the first isolated lung transplantation in 1947, as well as experimental liver, heart, and lung transplants. 23 Demikhov's work was largely unnoticed in the United States because of the political relationship between the Soviet Union and the United States. Because South Africa did not experience political tensions with the Soviet Union during this time, Christiaan Barnard visited on several occasions to consult with Demikhov. Barnard learned the procedure from Demikhov. 24 Between 1951 and 1955, Demikhov performed 22 experiments involving heart replacement in canines. During the 1940s, there were simultaneous advances in other forms of cardiac surgery largely attributed to the development of a pump oxygenator created by John Gibbon.34 Gibbon developed the pump in response to a situation in which a woman died while receiving an embolectomy. Gibbon was certain that the woman would have lived had her circulatory system been supported during the surgery. The pump was used in the 1950s for several open heart procedures and was a catalyst for the era of open heart surgery. There were numerous surgeons and scientists in the experimental era whose works contributed to the success of heart transplantation. Many of their experiments led to the development of orthotopic transplantation, in which the recipient heart is removed and replaced by a donor heart. A brief outline of some of those people and their contributions is provided in Table 1. Although the experi-
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KRAU Table 1 LANDMARKS IN EXPERIMENTAL CARDIAC TRANSPLANTATION Scientist/Surgeon
Year
Contribution
Carrel & Guthrie 3· 36
1905
Performed the first reported heart transplant. The heart of a dog was heterotopically transplanted into the neck of a recipient canine. They created anastomoses to the carotid artery and jugular vein. The donor heart began to beat 1 hour after the procedure and did so for 2 hours. This seminal work indicated that a heart could be transplanted and maintain a stable rhythm.
Mann 31 • 36
1933
Developed a more sophisticated heterotopic technique for transplantation, still in use today for studies on physiologic and immunologic aspects of transplantation. First to identify the importance of using heparin to avoid thrombus formation, the importance of avoiding air embolism and ventricular distention, and the first to comment on the idea of immunologic rejection.
Demikhov23
1937
Implanted the first artificial heart into a canine .
Demikhov23
1939-50s
Downie 10· 34
1953
Heterotopic transplantation with maximal survival times of up to 10 days. Attributed the success of his experiments to the use of penicillin and improved suture materials. Ontario Veterinarian College, Canada.
Weslowski & Fennessey41
1953
By killing canine recipients on successive days posttransplantation and by examining histologic preparations of the myocardium, provided a cornerstone Billingham's (1980) grading system of transplant rejection through the use of biopsy.
Neptune, Cookson , & Bailey33
1953
First report in Western literature of total circulation provided by donor heart in a heart-lung transplant, by transplanting an entire heart-lung block and avoiding multiple pulmonary venous anastomoses. Performed procedures without the use of cardiopulmonary bypass using hypothermia. Hahnemann Medical College, Pittsburgh.
Webb & Howard 28 · 38
1957
Demonstrated that canine hearts can survive for prolonged periods at low temperatures (4°C) when heparinized and flushed with potassium citrate and return to adequate function when transplanted heterotopically. Experiments indicated that transplantation of the heart and both lungs is not practical. University of Mississippi.
Goldberg, Berman , & Akman 14
1958
Report of the first orthotopic heart transplant in experimental series . Used cardiopulmonary bypass and left direct atrial anastomoses to avoid anastomoses of the pulmonary veins . University of Maryland .
Cass & Brock4· 28
1959
Developed an orthotopic technique of heart transplant that leaves the right atrial cuff in the recipient, thus averting anastomoses with the vena cava. First description of the nowstandard practice of combining the multiple pulmonary venous and vena caval anastomoses into two atrial anastomoses. Also performed numerous experiments in autotransplantation in canines to study surgical and hemodynamic results of transplantation minus immunologic rejection. Guy's Hospital, London .
Multiple experiments that were done in the Soviet Union and somewhat obscure until his publication in 1962. Used more than 20 schemes for implanting a second heart, and in 1956 performed a transplant on a German Shepherd that returned to a normal state postoperatively.
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Table 1 LANDMARKS IN EXPERIMENTAL CARDIAC TRANSPLANTATION (Continued) . Scientist/Surgeon
Year
Contribution
Webb, Howard , & Neely39
1959
Accomplished 12 successful orthotopic cardiac transplants in canines by using the refrigeration technique to preserve the donor heart and the pump oxygenator to support the recipient.
Lower & Shumway9• 19· 29 · 30
1960-65
Perfected the method of preserving the recipient atrial cuffs . Advanced surgical technique of isotopic heart replacement. Identified electrocardiograph as a means to monitor rejection in canine transplants in lieu of previously used cardiac enzymes. They found that the administration of azathioprine and methylprednisolone restored normal electrocardiograph voltage , indicating that rejection can be controlled to an extent with immunosuppressives. The use of immunosupressive therapy resulted in the unprecedented survival of 250 days in an adult dog. Stanford University.
Kondo & Kantrowitz 25
1965
Performed experiments in which recipients were cooled to 16°C and underwent cardiac replacement while in a state of hypothermic circulatory arrest for a 60-minute period. One animal survived 213 days. Also conducted experiments on puppies without immunosuppressive agents and lengthy survival rates to immunologic immaturity.
Reitz, Burton , & Jamieson35
1980
Landmark publication documenting immunosuppressive regimen (cyclosporine and azathioprine) and operative technique resulted in long-term survival with normal pulmonary function in monkeys receiving heart-lung allotransplantation .
mental era merged into the clinical era, heralded by human transplantation, experiments with animals continue to refine techniques and trial immunosuppressives. Clinical Era
The first human heart transplantation was performed by James D. Hardy at the University of Mississippi in January of 1964. 16· 28· 34·36 Hardy, a year before this event, began assembling a team to perform human heart-to-heart transplant. 28 At the time, there were many issues that had not been pioneered, especially ethical issues related to the donor and the notion of brain death. With this scenario, a human heart-to-heart transplant would mandate that a person sustain a total cardiopulmonary arrest for the heart to be harvested. Because the technique was experimental and eminently life-threatening, a recipient with a failing heart and a donor who is essentially dead with a heart suitable for donation would need to be in close proximity. Hardy, aware of the slight probability of this circumstance, considered xenograft transplantation with the heart of a chimpanzee. 16
In January of 1964, a 68-year-old comatose man with ischemic heart disease and no detectable blood pressure was admitted to the University of Mississippi Medical Center. In spite of numerous attempts and inotropes to maintain a blood pressure, the man remained hypotensive. It was concluded that the only potentially life-saving intervention for this man would be a cardiac transplant. Cardiopulmonary bypass was instituted while a suitable donor was sought. With no donor heart available, the transplant team elected to transplant the heart of a chimpanzee into the patient. The heart was harvested and implanted using the technique developed by Lower and Shumway. Unable to handle the large venous return of the recipient, the transplanted heart stopped an hour after transplantation and the patient died.16• 34 The episode was a landmark in the evolution of heart transplantation. This case led Hardy to several conclusions including: (1) the sutures he used were acceptable for this type of surgery; (2) a heart could be preserved for an hour and still function; (3) once transplanted, the heart would beat after defibrillation ; and (4) the size of the heart was
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an important consideration. In this case, the heart of a lower primate was not large enough to support the circulation of an adult human. 16 Hardy ceased his experiments, and for 3 years cardiac transplantation on humans was not attempted again. Several North American centers during this time were preparing to perform transplants and developing cardiac programs. Several distinguished medical centers throughout the world were planning cardiac transplantation programs, which is why "the cardiovascular community was shocked when, on December 3, 1967, the location of the first human-to-human heart transplantation was announced." 34 The recipient of the first human-to-human heart transplant was a 54-year-old grocer, Louis Washkansky. Because of repeated myocardial infarctions, Washkansky lay dying of intractable heart failure at Groote Schuur Hospital in Capetown, South Africa. The donor came from Denise Darvall, a 24-year-old woman killed in a motor vehicle accident. 11 The surgeon who performed the transplantation was Christiaan Barnard; the chief cardiologist at Groote Schuur was Val Shrire, and the anesthetist was]. Ozinsky.11 As with all transplants, there were many who contributed to this successful operation. Using cardiopulmonary bypass, arterial perfusion, hypothermia of Darvall's heart, and the surgical technique of Lower and Shumway, the heart was successfully implanted into Washkansky. He received immunosuppressive therapy with steroids, azathioprine, radiation, and actinomycin C, and did well for 18 days. 34 On the eighteenth day, he succumbed to Pseudomonas pneumonia and died. The first human-to-human heart transplantation in the United States took place on December 6, 1967 by a team led by Adrian Kantrowitz. This was also the first pediatric transplant; the recipient was a 1-month-old infant who had previously undergone an operation to ameliorate tricuspid atresia. The infant died 6. 5 hours after transplantation. 22 This was, in actuality, Kantrowitz's team's second attempt performing a human heart transplant. The first attempt took place on June 30, 1966 on a cyanotic male infant born at Maimonides Medical Center and was aborted in the operating room when the donor heart of a male anacephalic stopped and would not resuscitate.
The transplants performed by Barnard and Kantrowitz provided the media with a new and opportunely controversial focus. Transplantation as a new technology brought with it many new issues and resurrected issues that had been left dormant up to this time. Medical journals discussed multiple ethical issues, issues of expertise and readiness, and in many cases, were critical of transplantation attempts. Several dilemmas brought to the medical forefront during this time remain controversial and unresolved to this day. For example, problems over the definition of death and issues such as anacephalic infant as donor continue to be discussed and debated. 22 In spite of the many opinions and public debates over transplantation, within 1 year of Barnard's success, 102 heart transplantations were performed in over 17 different countries. 28· 36 By the end of 1968, most of the transplant recipients had died, with a mean survival of 29 days. 7 This outcome was costly, attracted unfavorable recognition, and resulted in many heart transplant centers being closed. By 1971, the number of heart transplantations performed decreased to 10, and transplant centers throughout the world were closing or had closed. 34 Largely owing to the commitment and obstinacy of Norman Shumway, Stanford University became the premiere heart transplant center in the United States. Simultaneously, Harvard Medical School was making progress in the definition of brain death, which brought about an increased ability to harvest organs while protecting surgeons from accusations of immorality and murder. 34 During the 1970s, the team at Stanford University made several notable advances in the evolution of heart transplantation. The use of right ventricular endomyocardial biopsy for detecting graft rejection was developed by Phillip Caves during this time. 5 Margaret Billingham, another member of the Stanford team, developed the currently used grading system of rejection based on biopsy sampling. Other advances that came from the Stanford University Medical Center include the development of antithymocyte immunoglobulin and a refined method of cold potassium cardioplegia and topical cooling for effective preservation of donor organs. 36
THE EVOLUTION OF HEART TRANSPLANTATION
Immunosuppression was attempted with the use of corticosteroids and azathioprine during the 1970s. Cyclosporine A was used in experimental heart transplantation and used for the first time clinically in 1983. The use of cyclosporine A resulted in better rejection control, decreased infection rates, and increased survival rates to an unprecedented 80% to 90% at 1 year and a 5-year survival rate of 60%.36 Later in the 1980s, immunosuppression methods were improved with the development of the monoclonal antibody OKT3, which inhibits allograft rejection by interfering with T-cell antigen recognition sites bound to CD3 antigen. 13 Management of refractory rejection was improved by the use of total lymphoid irradiation and methotrexate.1s, 36 During the 1980s, transplant candidate criteria and donor criteria became more refined and explicit. Because of improved heart transplant survival rates, transplant centers proliferated in the United States. In 1986, the federal government contracted with the United Network for Organ Sharing (UNOS) to operate the Organ Procurement and Transplantation Network in the development of an effective organ allocation system. Also in 1986, the Health Care Financing Administration (HCFA), which oversees the United States Medicare program, approved coverage and payment for heart transplantation for Medicare recipients. 17 Although many heart transplant candidates are not eligible for Medicare, this reform brought about a more stringent set of guidelines for donors, recipients, and transplant centers. In 1992, a study demonstrated lower mortality rates among heart transplant recipients that were transplanted in Medicare-approved transplant centers than those who received transplants in centers that were not Medicare approved. 27
Current and Future Issues in Heart Transplantation There are many ongoing facets of heart transplantation that continue to be addressed and studied. Newer drugs for immunosuppression with fewer toxic effects, including a lesser incidence of cardiac allograft vasculopathy, are currently being explored in animal models. Many transplant surgeons and cardiologists have been encouraged by the immuno-
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suppressive effects of CTLA4-IG and antiCD40 ligand in animals. 26 A perpetual condition in the evolution of clinical heart transplantation is the lack of donor hearts available to meet the demands of the many potential candidates who desperately need them. There are numerous initiatives to increase the general population's understanding of organ donation, and there are alternatives to human donor transplantations being investigated. Xenotransplantation, transplantation of the heart from another species, although continually under ethical, scientific, and popular debate, remains an option. A landmark case of xenotransplantation is the case of Baby Fae, in which Leonard Bailey used a baboon heart to transplant into a neonate with hypoplastic left heart syndrome.34 Currently, there are studies and experiments in genetic technology to produce transgenic animals with important epitopes that will inhibit the production of complement in the donor animal against human antibodies to ameliorate the incidence of hyperacute rejection once transplanted.32 There are multiple ethical and medical issues concerning xenotransplantation that remain unresolved. Not the least of which is the issue of xenoses. Xenoses occurs when some microbes that are not necessarily pathogenic in their hosts change when transmitted to a new species and potentially cause serious transmittable diseases when transplanted along with the donor organ. A public health concern is the potential for subsequent transmission of an infectious agent not previously endemic to humans to the recipient's contacts and the general population. The potential risks to public health have caused some prominent leaders to advocate for a moratorium on xenotransplantation until risks are better understood and defined and policies are in place to address the issue at a societal level. 1 Permanent mechanical support is another alternative to the current insufficient heart donor pool. Satisfactory implantable circulatory support devices, including artificial hearts and left ventricular assist devices, continue to evolve. Although typically used as a bridge to transplantation, to restore moribund patients to a better physiologic state and to create much better candidacy for transplantation, clinical trials are underway to explore the use of these devices as a permanent alternative
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therapy for patients who are not transplant candidates.17 The advantages of mechanical devices over transplantation include the potential availability and the lack of the need to immunosuppress the patient. Disadvantages
of the current devices include the need to keep the patient anticoagulated, the incidence of infection caused by its transcutaneous insertion, and, as with any mechanical device, the potential for malfunction.
SUMMARY
Now that heart transplantation is a common therapeutic modality, it has lost much of its earlier mystique. Numerous issues related to donor allocation, immunosuppression, quality-of-life of the recipient, patient selection, costeffectiveness, and a myriad of ethical considerations remain. Current policies, procedures, legislation, and techniques are the result of a long progression of experimental and clinical advances and public reaction. Current practices and legislation are a part of heart transplantation's evolutionary process. The process can change and advance as rapidly as it did on December 3, 1967, with the announcement of the first successful human-to-human heart transplantation.
REFERENCES 1. Bach FH, Fishman JA, Daniels N, et al: Uncertainty in xenotransplantation: Individual benefit versus collective risk. Nat Med 4:141-144, 1998 2. Barnard CN: A human cardiac transplant: An interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J 41:12711274, 1967 3. Carrel A, Guthrie CC: The transplantation of veins and organs. Am J Med 10:1101-1102, 1905 4. Cass MH, Brock R: Heart excision and replacement. Guys Hosp Rep 108:285- 290, 1959 5. Caves PK, Billingham ME, Shulz WP, et al: Transvenous biopsy from canine orthotopic heart allografts. Am Heart J 85:525-530, 1973 6. Cooley DA: A brief history of heart transplants and mechanical assist devices. In Frazier OH Ced): Support and Replacement of the Failing Heart. Philadelphia, Lippincott, 1996, p 5 7. Cooley DA, Bloodwell RD, Hallman GL, et al: Organ transplantation for advanced cardiopulmonary disease. Ann Thorac Surg 8:30- 46, 1969 8. Danilevicius Z: SS. Cosmas and Damian: The patron saints of medicine in art. JAMA 210:1021-1025, 1967 9. Dong E, Hurley EJ, Lower RR, et al: Performance of the heart two years after autotransfusion. Surgery 56: 270-273, 1964 10. Downie HG: Homotransplantation of the dog heart. Arch Surg 66:624-636, 1953 11. Dubb A: The first human-to-human heart transplant. lsr J Med Sci 32:1051, 1996 12. Ezekial 36:26 (Authorized King James Version) 13. Gilbert EM, Dewitt CW, Eiswirth CC, et al: Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 82:202-206, 1987 14. Goldberg M, Berman EF, Akman LC: Homologus transplantation of the canine heart. J Internat Coll Surg 30:575-586, 1958
15. Hamilton E: Mythology. Boston, Little, Brown & Company, 1942, p 374 16. Hardy J, Chavez CM, Kurrus FD, et al: Heart transplantation in man. JAMA 188:1132-1140, 1964 17. Hunt SA: Current status of cardiac transplantation. JAMA 280:1692-1698, 1998 18. Hunt SA, Strober S, Hoppe RT, et al: Total lymph irradiation for the treatment of intractable cardiac allograft rejection. J Heart Lung Transplant 10:211216, 1991 19. Hurley EJ, Dong E, Stofer RC, et al: Isotopic replacement of the totally excised canine heart. ] Surg Res 2:90-94, 1962 20. Kahan BD: Cosmas and Damian revisited. Transplant Proc 15(suppl 1):2211-2216, 1983 21. Kahan BD: Preface: Pien Ch'iao, the legendary exchange of hearts, traditional Chinese medicine, and the modern era of cyclosporine. Transplant Proc 20(suppl 2): 3-12, 1988 22. Kantrowitz A: America's first human heart transplantation: The concept, the planning, the furor. ASAIO J 44:244-251, 1998 23. Kapoor AS, Schroeder JS: Historical perspective of cardiac transplantation. In Kapoor AS, Laks H, Schroeder JS, et al (eds): Cardiomyopathies and HeartLung Transplantation. New York, McGraw-Hill, 1991, p 135 24. Kaye MP: Pioneer award.Journal of Heart Transplantation 8:427-429, 1989 25. Kondo Y, Grundel FO, Chaptal PA, et al: Immediate and delayed orthotopic homotransplantation of the heart. J Thorac Cardiovasc Surg 50:781-789, 1965 26. Kirk AD, Harlan DM, Armstrong NN, et al: CT-DLA4Ig and anti-CD40 prevent renal allograft rejection in primates. Proc Natl Acad Sci U S A 94:8789-8794, 1997 27. Krakuer H, Shakur SS, Kaye MP: The relationship of clinical outcomes to status as a Medicare approved heart transplantation center. Transplantation 59:840846, 1995
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28. Lansman SL, Ergin MA, Griepp RB: History of heart and heart-lung transplantation. In Thompson ME Ced): Cardiac Transplantation. Philadelphia, FA Davis, pp 3-19, 1990 29. Lower RR, Shumway N: Studies on the orthotopic homotransplantation of the canine heart. Surgical Forum 11:18-19, 1960 30. Lower RR, Dong E, Shumway NE: Suppression of rejection crisis in the cardiac homograft. Ann Thorac Surg 1:645-649, 1965 31. Mann FC, Priestly JT, Markowitz], et al: Transplantation of the intact mammalian heart. Arch Surg 26:219224, 1933 32. McCurry KR, Kooyman DL, Alvarado CH: Human complement regulatory proteins protect swine-toprimate cardiac xenografts from humoral injury. Nat Med 1:423-427, 1995 33. Neptune WB, Cookson BA, Bailey CP, et al: Complete homologous heart transplantation. Arch Surg 66: 174178, 1953 34. Patterson C, Patterson KB: The history of heart transplantation. Am J Med Sci 314:190-197, 1997
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35. Reitz BA, Burton NA, Jamieson SW, et al: Heart and lung transplantation. J Thorac Cardiovasc Surg 80:360-372, 1980 36. Rodeheffer RJ, McGregor CG: The development of cardiac transplantation. Mayo Clin Proc 67:480484, 1992 37. Sterioff S, Rucker-Johnson N: Frank C. Mann and transplantation at the Mayo Clinic. Mayo Clin Proc 62:1051-1055, 1987 38. Webb WR, Howard HS: Restoration of function of the refrigerated heart. Surgical Forum 8:302-306, 1957 39. Webb WR, Howard HS, Neely WA: Practical methods of homologous cardiac transplantation. Journal of Thoracic Surgery 37:361-366, 1959 40. Webster's Third New International Dictionary. P. Babcock (ed): Springfield, MA, Merriam-Wester Inc, 1986, p 389 41. Wesolowski SA, Fennessey JF: Pattern of failure of the homografted canine heart. Circulation 8:750755, 1953 42. Wong KC, Lien-Teh W: History of Chinese Medicine, ed 2. New York, AMS Press, 1973, pp 21-27
Address reprint requests to Stephen D. Krau , PhD, RN School of Nursing Middle Tennessee State University 1500 Greenland Drive Murfreesboro, TN 37132
Heart Transplantation
The Evolution of Heart Transplantation Stephen D. Krau, PhD, RN
Of all of the medical advances that have taken place in the last century, none have caused more interest and extensive notice than the first human heart transplantation. Although the first human heart transplantation was performed on December 3, 1967, by Dr Christiaan Barnard of Cape Town, South Africa,2· 23 the success of the procedure was the result of the ideas and works of many brilliant scientists and surgeons over a long period. From ancient folklore of chimeric beings to preliminary experimentation on animals, heart transplantation has developed into a currently accepted therapeutic procedure for the treatment of end-stage cardiac disease. It is a superb example of a therapeutic technique whose development is the result of an extensive evolutionary process that continues to progress.
History of Cardiac Transplantation The history of cardiac transplantation is grounded in ideas of transplantation in general. The history of transplantation is exten-
From the School of Nursing, Middle Tennessee State University, Murfreesboro; and the Coronary care Unit, Vanderbilt University Medical Center, Nashville, Tennessee
sive and is divided into three parts: prehistory, experimental, and clinical eras. 34 Prehistory
The prehistory of transplantation closely aligns with the history of science and the development of knowledge and understanding of human anatomy and physiology. This era begins with ancient notions that extend to ideas of surgical considerations that were performed by humans, but were, more or less, subverted by divine intentions, and extends through a more sophisticated understanding of human anatomy and surgical interventions. This era starts before 500 BC and ends in the late 1800s AD. Notions of chimeric beings abound in mythology. The word chimera has a variety of meanings, but all of the meanings concur that a chimera is " . . . an often fantastic combination of incongruous parts. "40 In mythology, the creature that was a female monster with a goat's body, a lion's head, and a snake's tail was most often referred to as a chimera. The notion of different body parts in one being extends to mythologic creatures, such as a satyr or the Minotaur, the offspring of a human and bull, with the head of a bull and a human body. The conception of an exchange or change in body is well-illustrated in the Greek myth that focuses on Acteon, a great hunter. While hunting in the woods one day, Acteon became
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thirsty and came upon a grotto with crystal water. Unknowingly, he happened upon the favorite bathing place of Artemis. While preparing to bathe, Artemis, unaware of Acteon's presence, dropped her garments and stood at the water's edge. When she discovered Acteon, she furiously flung drops of water on him from her wet hand. On contact with the droplets, Acteon was transformed into a stagheaded creature. This transformation was not only an outward transformation as the myth recounts ". . . his heart became a deer's heart and he who had never known fear before was afraid and fled." 15 He was chased by his dogs, who caught him and tore him to pieces. It has been suggested that this tale constitutes an allegory for acute rejection. 34 The concept of heart transplantation was also familiar in ancient Judaic times. In sixth century BC, the prophet Ezekial illuminated: "A new heart also will I give you, and a new spirit will I put within you; and I will take away the stony heart out of your flesh, and I will give you an heart of flesh. "12 Chinese medicine in sixth century BC was separated from religion. Diseases were thought to be the result of a disequilibrium of energies within the body, often referred to as the yin and the yang. Legend has it that Pien Ch'iao, a physician in China born 430 BC, performed an exchange of hearts. 21 Pien Ch'iao was known for his ability to puncture vessels, create and use powerful drugs, and perform surgery. Two sick soldiers, Kung He of Lu, and Ch'i Ying of Choa sent for Pien Ch'iao to treat them. 42 After the doctor's ministration, both men recovered from the immediate illness but were told by Pien Ch'iao that there were other diseases forming within them and asked if they wanted to be treated. Pien Ch'iao explained that their energies were in disequilibrium. In Kung He, the will was strong, but the spirit was weak; the spirit of Ch'i Ying was strong, but the will was weak. Thus in one, the yin was too strong, and in the other, the yang dominated. Pien Ch'iao proposed that equilibrium would be restored if their two hearts were exchanged. Kung He and Ch'i Ying agreed to have surgery and were anesthetized by Pien Ch'iao and remained unconscious for 3 days. Pien Ch'iao is said to have been the first man to use a general anesthetic.21 He opened their chests and removed and exchanged their
hearts, thus bringing both men's yin and yang into balance. Both men returned to their homes feeling well, living the rest of their lives with the heart of the other. There are no other references to heart transplantation during this period and only a few references to any form of transplantation. Among miracles in Christian tradition is the miracle of the black leg, which is thought to have occurred around 348 AD and is attributed to the Saints Cosmas and Damian. 20 A church sacristan made a pilgrimage to Aesculapius to pray for his cancerous leg. During the night, Saints Cosmas and Damian replaced the sacristan's leg with the leg of a Moor gladiator who had died earlier that day. When the sacristan woke, he was pain free and discovered that where the cancerous leg had been was now a perfectly healthy black leg. He went to the cemetery with other townspeople to find that the gladiator's leg had been amputated, and next to him in the coffin was the sacristan's diseased leg. 20 Throughout subsequent centuries, the notion of transplantation was exuberantly denied by most physicians. A notable physician in the fifteenth century, Hieronymus Brunchweig, adamantly denied the possibility that appendages could ever be reattached to the body. He stated that if someone tried to reattach a part of the body, it would be equivalent to "a monkey becoming a philosopher" or a man "trying to fly in the air." 18 Experimental Era
By the eighteenth and nineteenth centuries, transplantation was a notion well-grasped by physicians and physiologists. 3 Because surgical asepsis had not yet been developed, the only form of transplantation that was taking place at this time was skin transplantation. The beginning of the experimental era of heart transplantation is closely associated with the work by Alexis Carrel, a visionary French surgeon.23• 34 • 36 Carrel was a vascular surgeon whose quest to develop the procedure of vascular anastomoses set the stage for organ transplantation. When the President of the French Republic, Sadi Carnot, was assassinated in 1894 by a stab wound that lacerated his portal vein, Carrel was deeply distressed that the best surgeons could not control Carnot's bleeding and save his life. Carrel was
THE EVOLUTION OF HEART TRANSPLANTATION
convinced that Carnot would have lived if the surgeons had the ability and technique to sew his vessels together. 34 Similarly, in 1896, a German surgeon, Ludwig Rehn, was the first surgeon to suture a cardiac laceration in a stab wound victim.6 Carrel left France and while working with Charles Claude Guthrie at the Hull Physiological Laboratory at the University of Chicago, performed the first cardiac transplant in 1905. In this experiment, the heart of a dog was transplanted into the neck of a recipient dog, and anastomoses to the jugular vein and carotid artery were created. When the second heart is inserted in tandem with the recipient heart the transplantation is referred to as heterotopic transplantation. The heart began to beat an hour after the procedure and maintained a rhythm for approximately 2 hours before coagulation occurred in the cavities of the heart, and the dog died.36 These experiments confirmed that the heart could be separated from its originating blood supply and reimplanted using vascular anastomoses while still maintaining heart function. In 1912, Carrel was the first scientist working in an American laboratory to be awarded the Nobel Prize in Medicine and Physiology.34 Together, Carrel and Guthrie published a landmark work in the history of transplantation. The Transplantation of Veins and Organi!' is the foundation of vascular surgery and organ transplantation. Shortly after this publication, Guthrie went to St. Louis and Carrel went to Rockefeller University of New York, where he became chief of the division of experimental surgery. There are few recorded subsequent experiments in heart transplantation until 1933, when Frank C. Mann, working at the Mayo Clinic, developed another heterotopic technique for transplanting the canine heart. 31• 37 Significant observations that Mann made to the evolution of heart transplantation included the necessity of avoiding ventricular distention and coronary air embolism, the importance of using heparin to prevent thrombosis, and the hypothesis that rejection was the result of some sort of graft failure. He suggested that the failure of the transplanted heart could possibly be attributed to "some biologic factor which is probably identical to that which prevents survival of the homotransplanted tissues and organs." 31 This obser-
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vation can currently be explained as immunologic rejection. The Mann technique for heterotopic transplantation provided a beneficial model that is still used for study of physiologic and immunologic components of transplantation. 36 Afterwards, Mann devoted his time to his interest in metabolic consequences of hepatectomy, and heart transplant research in the United States remained dormant for approximately 20 more years. In the Soviet Union, Vladimir Demikhov was conducting a series of experiments that significantly advanced the science of transplantation. Demikhov developed and implanted the first artificial canine heart in 1937. He also developed a method for intrathoracic heterotopic heart transplants and heart and lung transplants in canines. Demikhov devoted his life to experiments in transplantation and is credited with performing the first isolated lung transplantation in 1947, as well as experimental liver, heart, and lung transplants. 23 Demikhov's work was largely unnoticed in the United States because of the political relationship between the Soviet Union and the United States. Because South Africa did not experience political tensions with the Soviet Union during this time, Christiaan Barnard visited on several occasions to consult with Demikhov. Barnard learned the procedure from Demikhov. 24 Between 1951 and 1955, Demikhov performed 22 experiments involving heart replacement in canines. During the 1940s, there were simultaneous advances in other forms of cardiac surgery largely attributed to the development of a pump oxygenator created by John Gibbon.34 Gibbon developed the pump in response to a situation in which a woman died while receiving an embolectomy. Gibbon was certain that the woman would have lived had her circulatory system been supported during the surgery. The pump was used in the 1950s for several open heart procedures and was a catalyst for the era of open heart surgery. There were numerous surgeons and scientists in the experimental era whose works contributed to the success of heart transplantation. Many of their experiments led to the development of orthotopic transplantation, in which the recipient heart is removed and replaced by a donor heart. A brief outline of some of those people and their contributions is provided in Table 1. Although the experi-
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KRAU Table 1 LANDMARKS IN EXPERIMENTAL CARDIAC TRANSPLANTATION Scientist/Surgeon
Year
Contribution
Carrel & Guthrie 3· 36
1905
Performed the first reported heart transplant. The heart of a dog was heterotopically transplanted into the neck of a recipient canine. They created anastomoses to the carotid artery and jugular vein. The donor heart began to beat 1 hour after the procedure and did so for 2 hours. This seminal work indicated that a heart could be transplanted and maintain a stable rhythm.
Mann 31 • 36
1933
Developed a more sophisticated heterotopic technique for transplantation, still in use today for studies on physiologic and immunologic aspects of transplantation. First to identify the importance of using heparin to avoid thrombus formation, the importance of avoiding air embolism and ventricular distention, and the first to comment on the idea of immunologic rejection.
Demikhov23
1937
Implanted the first artificial heart into a canine .
Demikhov23
1939-50s
Downie 10· 34
1953
Heterotopic transplantation with maximal survival times of up to 10 days. Attributed the success of his experiments to the use of penicillin and improved suture materials. Ontario Veterinarian College, Canada.
Weslowski & Fennessey41
1953
By killing canine recipients on successive days posttransplantation and by examining histologic preparations of the myocardium, provided a cornerstone Billingham's (1980) grading system of transplant rejection through the use of biopsy.
Neptune, Cookson , & Bailey33
1953
First report in Western literature of total circulation provided by donor heart in a heart-lung transplant, by transplanting an entire heart-lung block and avoiding multiple pulmonary venous anastomoses. Performed procedures without the use of cardiopulmonary bypass using hypothermia. Hahnemann Medical College, Pittsburgh.
Webb & Howard 28 · 38
1957
Demonstrated that canine hearts can survive for prolonged periods at low temperatures (4°C) when heparinized and flushed with potassium citrate and return to adequate function when transplanted heterotopically. Experiments indicated that transplantation of the heart and both lungs is not practical. University of Mississippi.
Goldberg, Berman , & Akman 14
1958
Report of the first orthotopic heart transplant in experimental series . Used cardiopulmonary bypass and left direct atrial anastomoses to avoid anastomoses of the pulmonary veins . University of Maryland .
Cass & Brock4· 28
1959
Developed an orthotopic technique of heart transplant that leaves the right atrial cuff in the recipient, thus averting anastomoses with the vena cava. First description of the nowstandard practice of combining the multiple pulmonary venous and vena caval anastomoses into two atrial anastomoses. Also performed numerous experiments in autotransplantation in canines to study surgical and hemodynamic results of transplantation minus immunologic rejection. Guy's Hospital, London .
Multiple experiments that were done in the Soviet Union and somewhat obscure until his publication in 1962. Used more than 20 schemes for implanting a second heart, and in 1956 performed a transplant on a German Shepherd that returned to a normal state postoperatively.
THE EVOLUTION OF HEART TRANSPLANTATION
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Table 1 LANDMARKS IN EXPERIMENTAL CARDIAC TRANSPLANTATION (Continued) . Scientist/Surgeon
Year
Contribution
Webb, Howard , & Neely39
1959
Accomplished 12 successful orthotopic cardiac transplants in canines by using the refrigeration technique to preserve the donor heart and the pump oxygenator to support the recipient.
Lower & Shumway9• 19· 29 · 30
1960-65
Perfected the method of preserving the recipient atrial cuffs . Advanced surgical technique of isotopic heart replacement. Identified electrocardiograph as a means to monitor rejection in canine transplants in lieu of previously used cardiac enzymes. They found that the administration of azathioprine and methylprednisolone restored normal electrocardiograph voltage , indicating that rejection can be controlled to an extent with immunosuppressives. The use of immunosupressive therapy resulted in the unprecedented survival of 250 days in an adult dog. Stanford University.
Kondo & Kantrowitz 25
1965
Performed experiments in which recipients were cooled to 16°C and underwent cardiac replacement while in a state of hypothermic circulatory arrest for a 60-minute period. One animal survived 213 days. Also conducted experiments on puppies without immunosuppressive agents and lengthy survival rates to immunologic immaturity.
Reitz, Burton , & Jamieson35
1980
Landmark publication documenting immunosuppressive regimen (cyclosporine and azathioprine) and operative technique resulted in long-term survival with normal pulmonary function in monkeys receiving heart-lung allotransplantation .
mental era merged into the clinical era, heralded by human transplantation, experiments with animals continue to refine techniques and trial immunosuppressives. Clinical Era
The first human heart transplantation was performed by James D. Hardy at the University of Mississippi in January of 1964. 16· 28· 34·36 Hardy, a year before this event, began assembling a team to perform human heart-to-heart transplant. 28 At the time, there were many issues that had not been pioneered, especially ethical issues related to the donor and the notion of brain death. With this scenario, a human heart-to-heart transplant would mandate that a person sustain a total cardiopulmonary arrest for the heart to be harvested. Because the technique was experimental and eminently life-threatening, a recipient with a failing heart and a donor who is essentially dead with a heart suitable for donation would need to be in close proximity. Hardy, aware of the slight probability of this circumstance, considered xenograft transplantation with the heart of a chimpanzee. 16
In January of 1964, a 68-year-old comatose man with ischemic heart disease and no detectable blood pressure was admitted to the University of Mississippi Medical Center. In spite of numerous attempts and inotropes to maintain a blood pressure, the man remained hypotensive. It was concluded that the only potentially life-saving intervention for this man would be a cardiac transplant. Cardiopulmonary bypass was instituted while a suitable donor was sought. With no donor heart available, the transplant team elected to transplant the heart of a chimpanzee into the patient. The heart was harvested and implanted using the technique developed by Lower and Shumway. Unable to handle the large venous return of the recipient, the transplanted heart stopped an hour after transplantation and the patient died.16• 34 The episode was a landmark in the evolution of heart transplantation. This case led Hardy to several conclusions including: (1) the sutures he used were acceptable for this type of surgery; (2) a heart could be preserved for an hour and still function; (3) once transplanted, the heart would beat after defibrillation ; and (4) the size of the heart was
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an important consideration. In this case, the heart of a lower primate was not large enough to support the circulation of an adult human. 16 Hardy ceased his experiments, and for 3 years cardiac transplantation on humans was not attempted again. Several North American centers during this time were preparing to perform transplants and developing cardiac programs. Several distinguished medical centers throughout the world were planning cardiac transplantation programs, which is why "the cardiovascular community was shocked when, on December 3, 1967, the location of the first human-to-human heart transplantation was announced." 34 The recipient of the first human-to-human heart transplant was a 54-year-old grocer, Louis Washkansky. Because of repeated myocardial infarctions, Washkansky lay dying of intractable heart failure at Groote Schuur Hospital in Capetown, South Africa. The donor came from Denise Darvall, a 24-year-old woman killed in a motor vehicle accident. 11 The surgeon who performed the transplantation was Christiaan Barnard; the chief cardiologist at Groote Schuur was Val Shrire, and the anesthetist was]. Ozinsky.11 As with all transplants, there were many who contributed to this successful operation. Using cardiopulmonary bypass, arterial perfusion, hypothermia of Darvall's heart, and the surgical technique of Lower and Shumway, the heart was successfully implanted into Washkansky. He received immunosuppressive therapy with steroids, azathioprine, radiation, and actinomycin C, and did well for 18 days. 34 On the eighteenth day, he succumbed to Pseudomonas pneumonia and died. The first human-to-human heart transplantation in the United States took place on December 6, 1967 by a team led by Adrian Kantrowitz. This was also the first pediatric transplant; the recipient was a 1-month-old infant who had previously undergone an operation to ameliorate tricuspid atresia. The infant died 6. 5 hours after transplantation. 22 This was, in actuality, Kantrowitz's team's second attempt performing a human heart transplant. The first attempt took place on June 30, 1966 on a cyanotic male infant born at Maimonides Medical Center and was aborted in the operating room when the donor heart of a male anacephalic stopped and would not resuscitate.
The transplants performed by Barnard and Kantrowitz provided the media with a new and opportunely controversial focus. Transplantation as a new technology brought with it many new issues and resurrected issues that had been left dormant up to this time. Medical journals discussed multiple ethical issues, issues of expertise and readiness, and in many cases, were critical of transplantation attempts. Several dilemmas brought to the medical forefront during this time remain controversial and unresolved to this day. For example, problems over the definition of death and issues such as anacephalic infant as donor continue to be discussed and debated. 22 In spite of the many opinions and public debates over transplantation, within 1 year of Barnard's success, 102 heart transplantations were performed in over 17 different countries. 28· 36 By the end of 1968, most of the transplant recipients had died, with a mean survival of 29 days. 7 This outcome was costly, attracted unfavorable recognition, and resulted in many heart transplant centers being closed. By 1971, the number of heart transplantations performed decreased to 10, and transplant centers throughout the world were closing or had closed. 34 Largely owing to the commitment and obstinacy of Norman Shumway, Stanford University became the premiere heart transplant center in the United States. Simultaneously, Harvard Medical School was making progress in the definition of brain death, which brought about an increased ability to harvest organs while protecting surgeons from accusations of immorality and murder. 34 During the 1970s, the team at Stanford University made several notable advances in the evolution of heart transplantation. The use of right ventricular endomyocardial biopsy for detecting graft rejection was developed by Phillip Caves during this time. 5 Margaret Billingham, another member of the Stanford team, developed the currently used grading system of rejection based on biopsy sampling. Other advances that came from the Stanford University Medical Center include the development of antithymocyte immunoglobulin and a refined method of cold potassium cardioplegia and topical cooling for effective preservation of donor organs. 36
THE EVOLUTION OF HEART TRANSPLANTATION
Immunosuppression was attempted with the use of corticosteroids and azathioprine during the 1970s. Cyclosporine A was used in experimental heart transplantation and used for the first time clinically in 1983. The use of cyclosporine A resulted in better rejection control, decreased infection rates, and increased survival rates to an unprecedented 80% to 90% at 1 year and a 5-year survival rate of 60%.36 Later in the 1980s, immunosuppression methods were improved with the development of the monoclonal antibody OKT3, which inhibits allograft rejection by interfering with T-cell antigen recognition sites bound to CD3 antigen. 13 Management of refractory rejection was improved by the use of total lymphoid irradiation and methotrexate.1s, 36 During the 1980s, transplant candidate criteria and donor criteria became more refined and explicit. Because of improved heart transplant survival rates, transplant centers proliferated in the United States. In 1986, the federal government contracted with the United Network for Organ Sharing (UNOS) to operate the Organ Procurement and Transplantation Network in the development of an effective organ allocation system. Also in 1986, the Health Care Financing Administration (HCFA), which oversees the United States Medicare program, approved coverage and payment for heart transplantation for Medicare recipients. 17 Although many heart transplant candidates are not eligible for Medicare, this reform brought about a more stringent set of guidelines for donors, recipients, and transplant centers. In 1992, a study demonstrated lower mortality rates among heart transplant recipients that were transplanted in Medicare-approved transplant centers than those who received transplants in centers that were not Medicare approved. 27
Current and Future Issues in Heart Transplantation There are many ongoing facets of heart transplantation that continue to be addressed and studied. Newer drugs for immunosuppression with fewer toxic effects, including a lesser incidence of cardiac allograft vasculopathy, are currently being explored in animal models. Many transplant surgeons and cardiologists have been encouraged by the immuno-
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suppressive effects of CTLA4-IG and antiCD40 ligand in animals. 26 A perpetual condition in the evolution of clinical heart transplantation is the lack of donor hearts available to meet the demands of the many potential candidates who desperately need them. There are numerous initiatives to increase the general population's understanding of organ donation, and there are alternatives to human donor transplantations being investigated. Xenotransplantation, transplantation of the heart from another species, although continually under ethical, scientific, and popular debate, remains an option. A landmark case of xenotransplantation is the case of Baby Fae, in which Leonard Bailey used a baboon heart to transplant into a neonate with hypoplastic left heart syndrome.34 Currently, there are studies and experiments in genetic technology to produce transgenic animals with important epitopes that will inhibit the production of complement in the donor animal against human antibodies to ameliorate the incidence of hyperacute rejection once transplanted.32 There are multiple ethical and medical issues concerning xenotransplantation that remain unresolved. Not the least of which is the issue of xenoses. Xenoses occurs when some microbes that are not necessarily pathogenic in their hosts change when transmitted to a new species and potentially cause serious transmittable diseases when transplanted along with the donor organ. A public health concern is the potential for subsequent transmission of an infectious agent not previously endemic to humans to the recipient's contacts and the general population. The potential risks to public health have caused some prominent leaders to advocate for a moratorium on xenotransplantation until risks are better understood and defined and policies are in place to address the issue at a societal level. 1 Permanent mechanical support is another alternative to the current insufficient heart donor pool. Satisfactory implantable circulatory support devices, including artificial hearts and left ventricular assist devices, continue to evolve. Although typically used as a bridge to transplantation, to restore moribund patients to a better physiologic state and to create much better candidacy for transplantation, clinical trials are underway to explore the use of these devices as a permanent alternative
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therapy for patients who are not transplant candidates.17 The advantages of mechanical devices over transplantation include the potential availability and the lack of the need to immunosuppress the patient. Disadvantages
of the current devices include the need to keep the patient anticoagulated, the incidence of infection caused by its transcutaneous insertion, and, as with any mechanical device, the potential for malfunction.
SUMMARY
Now that heart transplantation is a common therapeutic modality, it has lost much of its earlier mystique. Numerous issues related to donor allocation, immunosuppression, quality-of-life of the recipient, patient selection, costeffectiveness, and a myriad of ethical considerations remain. Current policies, procedures, legislation, and techniques are the result of a long progression of experimental and clinical advances and public reaction. Current practices and legislation are a part of heart transplantation's evolutionary process. The process can change and advance as rapidly as it did on December 3, 1967, with the announcement of the first successful human-to-human heart transplantation.
REFERENCES 1. Bach FH, Fishman JA, Daniels N, et al: Uncertainty in xenotransplantation: Individual benefit versus collective risk. Nat Med 4:141-144, 1998 2. Barnard CN: A human cardiac transplant: An interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. S Afr Med J 41:12711274, 1967 3. Carrel A, Guthrie CC: The transplantation of veins and organs. Am J Med 10:1101-1102, 1905 4. Cass MH, Brock R: Heart excision and replacement. Guys Hosp Rep 108:285- 290, 1959 5. Caves PK, Billingham ME, Shulz WP, et al: Transvenous biopsy from canine orthotopic heart allografts. Am Heart J 85:525-530, 1973 6. Cooley DA: A brief history of heart transplants and mechanical assist devices. In Frazier OH Ced): Support and Replacement of the Failing Heart. Philadelphia, Lippincott, 1996, p 5 7. Cooley DA, Bloodwell RD, Hallman GL, et al: Organ transplantation for advanced cardiopulmonary disease. Ann Thorac Surg 8:30- 46, 1969 8. Danilevicius Z: SS. Cosmas and Damian: The patron saints of medicine in art. JAMA 210:1021-1025, 1967 9. Dong E, Hurley EJ, Lower RR, et al: Performance of the heart two years after autotransfusion. Surgery 56: 270-273, 1964 10. Downie HG: Homotransplantation of the dog heart. Arch Surg 66:624-636, 1953 11. Dubb A: The first human-to-human heart transplant. lsr J Med Sci 32:1051, 1996 12. Ezekial 36:26 (Authorized King James Version) 13. Gilbert EM, Dewitt CW, Eiswirth CC, et al: Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 82:202-206, 1987 14. Goldberg M, Berman EF, Akman LC: Homologus transplantation of the canine heart. J Internat Coll Surg 30:575-586, 1958
15. Hamilton E: Mythology. Boston, Little, Brown & Company, 1942, p 374 16. Hardy J, Chavez CM, Kurrus FD, et al: Heart transplantation in man. JAMA 188:1132-1140, 1964 17. Hunt SA: Current status of cardiac transplantation. JAMA 280:1692-1698, 1998 18. Hunt SA, Strober S, Hoppe RT, et al: Total lymph irradiation for the treatment of intractable cardiac allograft rejection. J Heart Lung Transplant 10:211216, 1991 19. Hurley EJ, Dong E, Stofer RC, et al: Isotopic replacement of the totally excised canine heart. ] Surg Res 2:90-94, 1962 20. Kahan BD: Cosmas and Damian revisited. Transplant Proc 15(suppl 1):2211-2216, 1983 21. Kahan BD: Preface: Pien Ch'iao, the legendary exchange of hearts, traditional Chinese medicine, and the modern era of cyclosporine. Transplant Proc 20(suppl 2): 3-12, 1988 22. Kantrowitz A: America's first human heart transplantation: The concept, the planning, the furor. ASAIO J 44:244-251, 1998 23. Kapoor AS, Schroeder JS: Historical perspective of cardiac transplantation. In Kapoor AS, Laks H, Schroeder JS, et al (eds): Cardiomyopathies and HeartLung Transplantation. New York, McGraw-Hill, 1991, p 135 24. Kaye MP: Pioneer award.Journal of Heart Transplantation 8:427-429, 1989 25. Kondo Y, Grundel FO, Chaptal PA, et al: Immediate and delayed orthotopic homotransplantation of the heart. J Thorac Cardiovasc Surg 50:781-789, 1965 26. Kirk AD, Harlan DM, Armstrong NN, et al: CT-DLA4Ig and anti-CD40 prevent renal allograft rejection in primates. Proc Natl Acad Sci U S A 94:8789-8794, 1997 27. Krakuer H, Shakur SS, Kaye MP: The relationship of clinical outcomes to status as a Medicare approved heart transplantation center. Transplantation 59:840846, 1995
THE EVOLUTION OF HEART TRANSPLANTATION
28. Lansman SL, Ergin MA, Griepp RB: History of heart and heart-lung transplantation. In Thompson ME Ced): Cardiac Transplantation. Philadelphia, FA Davis, pp 3-19, 1990 29. Lower RR, Shumway N: Studies on the orthotopic homotransplantation of the canine heart. Surgical Forum 11:18-19, 1960 30. Lower RR, Dong E, Shumway NE: Suppression of rejection crisis in the cardiac homograft. Ann Thorac Surg 1:645-649, 1965 31. Mann FC, Priestly JT, Markowitz], et al: Transplantation of the intact mammalian heart. Arch Surg 26:219224, 1933 32. McCurry KR, Kooyman DL, Alvarado CH: Human complement regulatory proteins protect swine-toprimate cardiac xenografts from humoral injury. Nat Med 1:423-427, 1995 33. Neptune WB, Cookson BA, Bailey CP, et al: Complete homologous heart transplantation. Arch Surg 66: 174178, 1953 34. Patterson C, Patterson KB: The history of heart transplantation. Am J Med Sci 314:190-197, 1997
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35. Reitz BA, Burton NA, Jamieson SW, et al: Heart and lung transplantation. J Thorac Cardiovasc Surg 80:360-372, 1980 36. Rodeheffer RJ, McGregor CG: The development of cardiac transplantation. Mayo Clin Proc 67:480484, 1992 37. Sterioff S, Rucker-Johnson N: Frank C. Mann and transplantation at the Mayo Clinic. Mayo Clin Proc 62:1051-1055, 1987 38. Webb WR, Howard HS: Restoration of function of the refrigerated heart. Surgical Forum 8:302-306, 1957 39. Webb WR, Howard HS, Neely WA: Practical methods of homologous cardiac transplantation. Journal of Thoracic Surgery 37:361-366, 1959 40. Webster's Third New International Dictionary. P. Babcock (ed): Springfield, MA, Merriam-Wester Inc, 1986, p 389 41. Wesolowski SA, Fennessey JF: Pattern of failure of the homografted canine heart. Circulation 8:750755, 1953 42. Wong KC, Lien-Teh W: History of Chinese Medicine, ed 2. New York, AMS Press, 1973, pp 21-27
Address reprint requests to Stephen D. Krau , PhD, RN School of Nursing Middle Tennessee State University 1500 Greenland Drive Murfreesboro, TN 37132