visit Arumugam Page ---------------------------------------------------------------------------- Heart transplantation - Historical view Sarasa Bharati Arumugam, MD, Phd, FICP K.M.Cherian, MS, FRACS Within 16 years of the statement made by Marcus that "Heart transplantation remains a fantastic speculation for the future" (Marcus 1951) the first full heart transplantation from man to man was performed by Christiaan Barnard in 1967, much to the amazement of the entire world of doctors, surgeons and the lay public. Man has, from time immemorial, toyed from time to time, with ideas of `rejuvenation' : transplant of organs and complete transformation to youth (Yayathi). Thus the ideas are not new but society had to await results of research into, not only the adoption of proper surgical techniques, skill and expertise, but also obtain knowledge regarding recipient protection and heart preservation during transfer, in addition to physiology of the transplanted heart, reaction of the recipients tissues to the new heart ie, the numerous immunological reactions which might occur, leading to rejection phenomenon and equally importantly, legal and logistic problems. These led multiple groups of scientists to get seized of these problems which had not been foreseen and had to be grappled with as needs arose. Thus, heart transplantation had to undergo various prolonged diligent research before it became thoroughly practical and is now accepted as a common therapeutic procedure in the Western world. If we look into the origin of the procedure, it is not surprising to note that the earliest of experiments were with animals for obvious reasons and the most common animal chosen, was the dog, since the dogs heart is closest to man as far as anatomical considerations are concerned. Later the hearts of chimpanzees were used. The first cardiac transplant in dogs was performed by Alexis Carrel and CC Guthrie at the University of Chicago in 1905 when they extirpated the heart of a small dog and transplanted it into the chest of a larger one by anastomosing the cut ends of the jugular vein and the carotid artery to the aorta, pulmonary artery,one of the vena cava and the pulmonary vein. One hour 15 minutes after cessation of the heart beat, circulation was re-established through the heart and 20 minutes after re-establishment of circulation, blood was actively circulating through the coronary system. Since this was an experiment and no special aseptic techniques were adopted, the dog died after 2 hrs. However this experiment, at once demonstrated that cardiac transplant was possible and that the heart could be separated from its blood supply and sutured into the circulation of a second animal when it recovered its ability to contract. Further, this experiment threw up a number of questions at the same time, such as, myocardial preservation of the donor heart during transfer period and various other physiological phenomena, requiring further research to be undertaken on these issues. Thus the next major step was seen only 28 yrs later when Mann, Priestley, Markowitx and Yater (1933) working at the Mayo Clinic and George Town University after a systematic study of all technical aspects of transplanting the dogs heart into the carotid jugular circulation,were able to achieve a mean post operative survival of 4 days with a longest survival of 8 days in their dogs. Mann and Colleagues caused innovative change in the anastomoses whereby the right ventricle functioned as a pump. Here the aorta was anastomosed to either the proximal or distal cut end of the carotid artery establishing arterial inflow into the coronary circulation while the pulmonary artery was anastomosed to the receipient's jugular vein, establishing venous outflow via the coronary sinus. Thus the problem of coronary perfusion was solved: even with this techniques, however the longest survival was still 8 days only. Studying the autopsies performed on these dogs, Mann et al (1933) were horrified to see massive mononuclear cell aggregates in the muscle which led them to write " that it is readily seen that the failure of the transplanted heart to survive, is not due to the technique of transplantation, but to some biological factor". Immunological rejection was understood only years later. Thus it was, that further advances got bogged down till 1951 when Marcus, Wong and Luisada working at the Chicago Medical School, attempted a modified Mann preparation calling it the Marcus I technique. Here there were attempts to answer questions such as, "can accommodation of highly specialised tissues be grafted in an animal ?, can such a graft live in an homologous environment ?, can such a graft actually function by receiving and delivering blood ?". These questions led to the conclusion that "heart transplant remained a fantastic speculation for the future". The surgeons however were persistent in their attempts and performed 22 more experiments though 10 only of these were successful and had a maximum survival of 48 hrs. Working further on these problems, the same group within 2 years modified, once agian the original Mann procedure (Marcus II technique) where the proximal end of the divided recipients common carotid artery was anastomosed to the donors left atrium and the recipients distal common carotid to the innominate artery. The innovation here was that the donors left ventricle supplied blood to the coronary arteries and the recipients cerebral circulation. However, here again the maximum survival was still 48 hrs only. At the same time (1953) Downie working at the Ontario Veterenary College produced excellent results with the original Mann technique, which he attributed to the use of pencillin the first antibiotic to be used in cardiac transplant. However, Downie noted that "in the present state of knowledge, it is not likely that homotransplantation will achieve great prominance clinically, since it has a melancholy record of failure in surgery". He further noted that this was the results of destruction of cells (rejection) and he queried loudly as to the cause of cell destruction. 3 years later Reemtsma reported graft survival using amethopterin or azathioprine immunosuppression drugs in a subsequent series and cases. The same group documented maintenance of circulation of the donors heart for 4 hrs. By this time, the technical feasibility of cardiac transplant was well established and Neptune and his colleagues (1953) attempted a complete homologous heart transplant. Here they attempted to simplify the procedure by transplanting an entire heart - lung block, for the first time, thus avoiding the multiple pulmonary venous anastomoses; further, both the animals were placed in a cooler for production of hypothermia, which would reduce metabolic demands of the heart muscle. These proved successful and the problems of donor myocardial protection and recipient preservation were solved simultaneously. Though the results of this experiment were successfuls, the survival period of the heart lung tranplant in dogs was only 6 hrs. However, an important fall out of this experiment was the introduction of hypothermia which has remained indispensable during cardiac pulmonary bypass for recipient protection and during ischaemic period for donor graft preservation. The canine hearts can survive for prolonged periods at low temperature (4 degree C) if heparinized and flushed with potassium citrate. This experiment also showed that cardiac transplant was completely feasible though other problems such as immunology still remained. The next improvement in technique was the introduction 'left atrial' cuff procedure by Goldberg, Berman and Akman from the University of Maryland. In 1958 they demonstrated the first 3 experimental orthotopic cardiac transplants with the modified technique which involved transection of the left auricle to circumvent the anastomoses of the several pulmonary veins. Here the recipients heart was excised so as to leave the posterior cuff of the left atrium containing the openings of the multiple pulmonary veins, thus requiring one large, relatively simple, left atrial anastomosis rather than multiple small pulmonary venous anastomosis. The cavae were reconnected with methyl methacrylate tubes and the aorta and pulmonary arteries were reanastomosed. The recipients circulation was maintained with caridac pulmonary bypass during the transfer and the donar heart was arrested with potassium citrate prior to excision but hypothermia was not employed. These experiments were also successful but the post op survival was still too short. A year later Webb, Howard and Neely (1959) reported successful cases of Orthotopic transplants experimentally. The aortic and pulmonary anastomoses were sutured but the individual pulmonary veins were joined using vascular couplers and the operation was performed in hypothermia. The same year Cass and Brock from Guys Hospital, London described 6 different methods of cardiac excision and replacement. While the first 5 were autotransplants, the 6th was an orthotopic transplant. Here, the surgeons, for the first time,described a method in which the native heart was seperated from the vena cavae and pulmonary veins by dividing through the walls of the atria thus forming both the right and left atrial cuffs. This has now become a routine practice of combining the multiple pulmonary venous and vena caval anastomosis into two atrial anastomoses. Lower and Shumway in 1960 brought out a cardinal paper in Orthotopic transplantation in which all previously described advances in techniques, recipient support and donor preservation were all integrated into a single approach.Receipient protection during the transfer period was provided by cardiac pulmonary bypass under moderate hypothermia (30 degree C). Hypothermia was also employed for donor heart preservation. The heart was then implanted using suture anastomoses into the two atrial cuffs anastomosis. 5 of the 8 dogs survived 6-21 days eating and exercising normally in the post operative period. This then became the first descriptions of a simple, routinely used successful technique for orthotopic cardiac transplantation whereby the recipient returned to normal activity, circulation supported by the transplanted heart. Despite the obviously successful technique, all these dogs eventually died and autopsy showed massive mononuclear cells infiltration and haemorrhage which immediately pointed to the presence of immunologic mechanisms of the host resulting in destruction of the heart. Thus it became clear that if the immunologic mechanism of the host were preserved from destroying the graft, the transplanted heart would function adequately for the normal life span of the animal. This led to the search for good immune suppressive drugs. wrote that he had transplanted a dog's heart into an inguinal region of the second animal even in 1940 and that 6 years later, performed an intra thoracic heterotopic cardiac transplant and recorded that one of the hearts continued to beat for 32 days. This experiment raised the possibility that cardiac allograft might assume some or all of the circulatory load and showed that with the donors heart fully resuscitated, the recipients heart was excluded from the circulation by ligating the great vessels and the mitral annulus. Later in 1967 Johansson, Soderlund and William Olsson from Stockholm reported the technique of intrathoracic heterotopic transplantation in which the graft functioned as an auxillary left heart bypass pump. Here the donors vena cavae was ligated and coronary venous return was vented via a tube connecting the donor pulmonary artery and the recipients right atrium. Parallel systematic circulation was established via, tubes connecting the recipients and donors left atria and aortae. This model demonstrated total heart bypass by clamping the recipient's aorta. Now the stage was set verily for the natural event to take place and the very first human to human transplant was carried out at Cape Town in 1967 by Christian Barnard with excellent success. Meanwhile, Lower and Shumway had set up in the late 1950's a series of experimental studies in dogs which culminated in 1968 with the inception of standard clinical cardiac transfer programme at Stanford. Thus during the next decade this one center performed more than half of the total number of cardiac transplants world wide and it was during this period that several important principles were established under the control of graft rejection. These include: 1.The use of rabbit antithymocyte globuling (Bieber et al 1977) 2.The development and introduction of endomyocardial biospy for the diagnosis of rejection (Caves et al 1973) 3.The introduction of laboratory methods for monitoring the immune status of the recipient (Bieber et al 1976) 4.The introduction of cyclosporin into clinical cardiac transplant practice (Oyer et al 1982) During the following year 101 transplants were performed by 64 teams and 22 countries around the world. However, the rate of survival was poor and the one most important reason being non standardised immune suppression - the risk of loosing the patient from infection or avoidance over immuno suppression with a risk of losing a patient from graft rejection. As White notes " So difficult was the balancing act between those two fatal options, that almost all those transplant centers which had entered the field with such enthusiasm withdrew from the unequal contest". Though the immune nature of tissue rejection was firmly established in 1943 by Gibbson and Medawar, further work had to be undertaken before routine immunologic suppression could be used as a form of therapy. The introduction of cyclosporine into heart transplant immunosuppresion (Oyer 1982a,b) caused a major reevaluation of the techniques used for monitoring the patients. Newer protocols were established only to be rescheduled when some disadvantages were noted such as an inability to appreciate clinically early rejection. This led logically to histological examination of the allograft tissue requiring the introduction of endomyocardial biopsy. This latter plays a major role in the management of the cyclosporine, immunosuppressed heart transplant recipient. Newer monoclonal antibodies, refinements in technique in myocardial preservation and various other parameters are now taking place steadily thoughout the world and the second millenium will no doubt usher in valuable information making heart and other organ transplant a routine and established procedure to make life on earth more meaningful. Towards this end then, more organs for transplant are needed here and Heaven knows, they don't need them there.