Four decades of vascularized heterotopic cardiac transplantation in the mouse.

Since the first clinical heart transplant in 1967, there has been a heightened need to understand immune and inflammatory responses to "foreign" tissues. Research efforts in those early days were based on species that would now be considered "large" and were typically out-bred individuals. While this closely mirrors the clinical scenario, where genetic mismatches of donors and recipients can only be minimized in the selection process, these were not ideal models for studying the complexities and nuances of the immune system. Even when the rat was considered the standard model those early endeavors were limited by a small number of rat strains. The mouse model has provided us with an overwhelming array of strains, knockouts, knockins and transgenics that allow us to investigate the many layers of the innate and adaptive immune systems leading to a much greater understanding of immune responses. Fully vascularized heterotopic cardiac transplantation in the mouse has now been with us for four decades; the original papers describing this technique being published by Corry in 1973. In the subsequent 40 years, this technique has been used by many laboratories, including our own, and has become a powerful tool for the investigation of transplant immunity and ischemia reperfusion injury. Given the modern availability of mouse strains and mouse-related reagents, our current understanding of transplant immunity undoubtedly would not exist without such a technique.

The first human heart transplant and further advances in cardiac transplantation at Groote Schuur Hospital and the University of Cape Town - with reference to : the operation. A human cardiac transplant : an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town.

Christiaan (Chris) Barnard was born in 1922 and qualified in medicine at the University of Cape Town in 1946. Following surgical training in South Africa and the USA, Barnard established a successful open-heart surgery programme at Groote Schuur Hospital and the University of Cape Town in 1958. In 1967, he led the team that performed the world's first human-to-human heart transplant. The article describing this remarkable achievement was published in the South African Medical Journal just three weeks after the event and is one of the most cited articles in the cardiovascular field. In the lay media as well, this first transplant remains the most publicised event in world medical history. Although the first heart transplant patient survived only 18 days, four of Groote Schuur Hospital's first 10 patients survived for more than one year, two living for 13 and 23 years, respectively. This relative success amid many failures worldwide did much to generate guarded optimism that heart transplantation would eventually become a viable therapeutic option. This first heart transplant and subsequent ongoing research in cardiac transplantation at the University of Cape Town and in a few other dedicated centres over the subsequent 15 years laid the foundation for heart transplantation to become a well-established form of therapy for end-stage cardiac disease. During this period from 1968 to 1983, Chris Barnard and his team continued to make major contributions to organ transplantation, notably the development of the heterotopic ( 'piggy-back') heart transplants; advancing the concept of brain death, organ donation and other related ethical issues; better preservation and protection of the donor heart (including hypothermic perfusion storage of the heart; studies on the haemodynamic and metabolic effects of brain death; and even early attempts at xenotransplantation.

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[Mechanical cardiac assistance and artificial heart: historical perspectives]. / Histoire de l'assistance circulatoire mécanique et du coeur artificiel.

The impact of heart failure on patients and economical burden on health insurance resources is increasing. Cardiac transplantation is still the primary treatment for patients who are in end stage heart failure. The development of artificial hearts (total and partial) was implemented by the discrepancy between the scarcity of available donors and the importance of waiting lists for cardiac transplantation. The technical progresses achieved since the first works of Kolff in 1957 now allow these patients to have their circulation restored and go home to wait for their transplantation. The encouraging results of the artificial heart and the miniaturization of these devices allow them to be considered as a possible destination therapy for patients not eligible for cardiac transplantation.

The beginning of organ transplantation: Emerich Ullmann (1861-1937).

Between 1880 and 1930 there was a rapid surge in experiments with tissue transplantation, initially mainly of endocrine tissues (thyroid, parathyroid, testicles, ovary, adrenals etc.) with the aim of replacing endocrine function. Emerich Ullmann (1861-1937), who was born in Pecs, Hungary and worked his whole life as a surgeon in Vienna was the first to perform transplantations of solid organs in the modern sense of medicine. During 1899 and 1900 he conducted several experiments with intestinal transplantation and must be regarded as the father of intestinal transplantation--a hitherto unknown fact. He then moved to kidney transplantation and on March 7, 1902 he demonstrated a dog with a functioning kidney graft anastomized to the collar vessels with urine dripping off the ureter sutured to the skin of the neck in the lecture hall of the Society of Physicians in Vienna. Ullmann was the first to perform kidney auto-, homo- and heterotransplantations and in 1902 also tried--unsuccessfully--to perform the first human kidney transplantation using a pig kidney which he anastomized into the cubital region of a women with end stage renal disease. Ullmann also performed tissue transplantations (skin, testicles, ovaries) and made other scientific discoveries and described several novel surgical techniques. Finally, in 1914 he wrote the first monograph on the state of the art of transplantation medicine, a booklet on "Tissue and Organ Transplantation" summarizing the surprisingly extensive experience in transplantation medicine of his time. With the obvious immunologic barriers to transplantation, the first "technical surgical period" of transplantation came to an end around the times of Ullmann's death and clinical transplantation was not to be revived before effective means of immunosuppression became available in the 1950s.

Christiaan Barnard and his contributions to heart transplantation.

Christiaan (Chris) Barnard was born in South Africa in 1922 and qualified in medicine at the University of Cape Town in 1946. Following surgical training in Cape Town and Minneapolis, Barnard established a successful open heart surgery program at Groote Schuur Hospital. In 1967, he led the team that performed the world's first human-to-human heart transplant. Although his first patient survived only 18 days, 4 of his first 10 patients survived for more than 1 year, 2 living for 13 and 23 years, respectively. With his junior colleague, Jaques Losman, Barnard then developed the operation of heterotopic heart transplantation. In 1981, his group was the first to successfully transport donor hearts using a hypothermic perfusion storage device. Several studies on the hemodynamic and metabolic sequelae of brain death were carried out in his department. Barnard retired from the University of Cape Town in 1983 at the age of 61. Now in his 79th year, he continues to pursue his interest in writing for the public. In the words of one of his former colleagues, he is a "surgical visionary and simply the most unforgettable character of the second generation of cardiac surgeons."

The development of cardiac transplantation.

The history of cardiac transplantation provides an excellent prototype for the development of a therapeutic technique. The first observations on cardiac transplantation were made in animal models in the early 20th century. Surgical problems were solved through a series of technologic advances, and problems associated with immune-mediated rejection were discovered and successfully addressed. By the late 1960s, cardiac transplantation in humans had become feasible. Since the first successful transplantation of a heart in a human in 1967, the management of rejection and infection has steadily progressed, and the long-term outcome after cardiac transplantation has improved dramatically. The success of cardiac transplantation has led to an expansion of the potential recipient pool to include children and adults in the eighth decade of life. Unfortunately, the growth of cardiac transplantation has resulted in an inadequate supply of suitable donor hearts. The limited supply of donor hearts has provided the impetus for further research in xenotopic cardiac transplantation and for the development of implantable circulatory assist devices.

New aspects of heterotopic liver transplantation.

In this report the history and clinical results of heterotopic liver transplantation (HLT) are reviewed and some special aspects of current research on HLT are high-lighted. The first laboratory experiments on liver transplantation were performed with auxiliary heterotopic grafts. The initial clinical results of HLT, however, were disappointing and orthotopic liver transplantation (OLT) evolved to be the procedure of choice. Of all the patients who received a heterotopic graft before 1980, only two survived. Since 1980, 50 HLTs are known to have been performed on 48 patients. Results of HLTs after 1986 are clearly better than earlier ones, and survival rates come within the range of those reported for OLT. Intraoperative fibrinolysis is found in the anhepatic phase of OLT, something which is absent in HLT. Tissue-type plasminogen activator (t-PA) is said to be responsible for this phenomenon, as well as for the postreperfusion hyperfibrinolysis. Parallel to the hemostatic changes, the intraoperative hemodynamic stability may be impaired by deleterious substances that arise during liver transplantation. Furthermore, the interaction between the two livers, the effect of HLT on portal pressure and hypersplenism, and the possible role of HLT in inborn errors of hepatic metabolism are described. Special attention is given to the treatment of acute hepatic failure. OLT, in an early phase of the disease, negates the possibility of spontaneous recovery, while delay of the decision to transplant may lead to further deterioration of the patient's clinical condition. As the procedure of HLT is reversible, the decision to transplant can be made more quickly. The clinical experience with HLT for acute liver failure is reported in detail.

The testis and tissue transplantation: historical aspects.

Transplantation experiments involving the testis have been performed since the days of John Hunter, who transplanted a testis into the belly of a hen. The first person to use the testis as a site of transplantation appears to have been Sand, who found in 1919 that an ovary transplanted into the substance of the testis developed follicles. By 1970, there was considerable evidence that the testis under some circumstances was a relatively favorable site for graft survival. However, much of the evidence was equivocal, and the immunological privilege was by no means complete.

The history of heart and heart-lung transplantation.

The current success of heart and heart-lung transplantation is grounded in a long progression of experimental and clinical advances. Beginning with an isolated heart transplant performed as a technical exercise in 1905, slowly accumulated experimental efforts yielded solutions to problems involving technique, recipient and graft protection, post-transplant function and immunology, and provided a foundation for subsequent clinical applications. Clinical studies augmented these observations and addressed legal and logistic issues involved in human transplantation.