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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.
