INTRODUCTION
This year we celebrate 50 years of the first interhuman heart transplantation. So,
I
believe that it is interesting to review the most important steps of this glorious
journey.
Heart transplantation first performed in the course of experiments of other nature
in
the beginning of 20th century, seen as a speculation for the future in
the middle of the same century, is now widely accepted by medical and lay
communities as a valuable therapeutic procedure.
This history can be divided into an experimental and a clinical heart transplantation
periods, with the first one in heterotopic non-auxiliary, heterotopic auxiliary and
orthotopic transplantations.
Heterotopic Non-Auxiliary Heart Transplantation
The first heart transplant was performed by Alexis Carrel and Charles Guthrie in 1905
at the University of Chicago[1]. In
the course of experiments to develop the technique of vascular anastomoses, they
have done limb reimplantation, thyroid gland as well kidney and heart
transplantation. The description of their heterotopic heart transplantation is as
follows: "The heart of a small dog was extirpated and transplanted into the neck of
a larger one by anastomosing the cut ends of the jugular vein and the carotid artery
to the aorta, the pulmonary artery, one of the venae cavae and a pulmonary vein. The
circulation was reestablished through the heart, about an hour and 15 minutes after
the cessation of the beat; 20 minutes after the reestablishment of the circulation,
the blood was actively circulating through the coronary system. A small opening
being made through the wall of a small branch of the coronary vein, an abundant dark
hemorrhage was produced. Then strong fibrillar contractions were seen. Afterward
contractions appeared and about an hour after the operation, effective contractions
of the ventricles began. The transplanted heart beat at the rate of 88 per minute,
while the rate of the normal heart was 100 per minute. A little later tracing was
taken. Owing to the fact that the operation was made without aseptic technique,
coagulation occurred in the cavities of the heart after about two hours, and the
experiment was interrupted".
Although the exact details of experiments were not known the most probable
arrangement of anastomosis are shown in Figure
1 adaptation in a book by Najarian and Simmons[2]. The problem with this model is
that arterial
inflow is in the atrium and aortic outflow is under venous pressure, in other words,
totally not physiological. Despite these problems, the experiment demonstrated that
heart transplantation was possible, that the heart separated of its blood supply
could be sutured to the circulation of other animal and recover normal function.
Fig. 1
On the left, the elegant Alexis Carrel. On the right, the probable
anastomotic arrangement: a= distal carotid artery; a'= proximal carotid;
b= distal jugular vein and b'= proximal jugular vein.
The next reference to transplantation of heart in dogs was made by Mann et
al.[3] in 1933. The
objective of the experiments was to obtain a totally denervated heart. In one of
their models, the heart transplanted in the neck had pulmonary artery anastomosed
to
proximal jugular vein and aorta to distal carotid artery with a more adequate
coronary perfusion. They obtained a longest survival of eight days and mean survival
of four days. They made observations of recipient donor heart different response of
rate and furthermore studied the histology of rejection, and as Carrel stating that
surgical technique is not the cause of failure of the grafted heart.
More than two decades later, Marcus et al.[4] working at the Chicago Medical School,
using a modified
Mann technique, studied complicated methods of cardiac preservation with poor
survival. In 1953, Marcus et al.[5]
again modified the Mann preparation, so that the donor left ventricle would act as
a
pump. The proximal end of the divided recipient common carotid artery was
anastomosed to the donor left atrium and the recipient distal common carotid to the
donor innominate artery, so that the donor left ventricle supplied blood to its own
coronary arteries and to the recipient cerebral circulation. Maximum survival with
this technique was 48 hours. Longer survival were obtained later on with
heterotopic, non-functioning heart transplant.
The heterotopic abdominal and neck technique is a valuable tool for studies of
immunosuppressors or other studies on the graft[6]. In 1962, Demikhov[7] published
an extensive work he developed in Russia. Among
his achievements, there are reports of heterotopic heart transplantation in the
inguinal region in 1940, heterotopic intrathoracic heart transplants in 1946.
Twenty-four variants were described and he mentions a 32 days survival of the
graft.
Another technical amazing achievement by Demikhov was the transplantation of an
additional head in a dog and the intrathoracic heart - lung transplantation before
the availability of cardiopulmonary bypass (Figure
2). Differently than previous authors, Demikhov considered that the
failure of grafts was due to surgical technical factors.
Fig. 2
On the left, Vladimir Demikhov and a dog with two heads. On the right, an
intrathoracic heart-lung transplant.
Heterotopic Auxiliary Heart Transplantation
In this field, Demikhov[7] performed
22 canine intrathoracic auxiliary heart transplants between 1951 and 1955. After
grafting, he excluded the recipient heart from circulation by ligating the great
vessels and mitral annulus. One such animal awoke from anesthesia stood up, drank
but died 15 hours later.
This experiment was the first one to demonstrate that transplanted heart could assume
total circulation and the death of the dog was attributed to superior vena cava
thrombosis.
In 1989, at the International Society for Heart-Lung Transplantation Annual Meeting,
in Munich, the Organizing Committee could find Dr. Demikhov in the country of Russia
and payed a tribute to him at Gala Dinner. Apparently, he was bright and could not
understand or speak a word in English, nevertheless, we could shake his hands.
Reemtsma group, in 1964 and later in 1966[8], studied also intrathoracic auxiliary
transplanted canine
hearts with immunosuppression with a 4-hour survival with the recipient heart
fibrillated. Another group, Johansson, Soderlund and William-Olsson[9] working at
the Karolinska Institute
in Sweden performed intrathoracic auxiliary heart transplantation for assistance of
the recipient left heart maintaining cardiac output for one hour.
Orthotopic Heart Transplantation
By the beginning of 1950, there was evidence of the feasibility of heart
transplantation and recovery of adequate function of grafted heart. The step forward
was the experimental orthotopic heart transplantation. In this phase, the major
concern was the maintenance of the recipient animal, the preservation of the graft
and the development of a surgical technique to minimize ischemia. In 1953, Neptune
et al.[10] faced all these
problems in their experiments. Their option was to use topical hypothermia for both
donor and recipient and to avoid multiple venous anastomoses they performed
heart-lung transplants. Three dogs survived six hours.
In 1957, Webb and Howard[11]
reported preservation of the heart in dogs by flushing the organ with cold potassium
citrate and successfully transplant heterotopically. So, these authors in a certain
way, opened the pathway for long distance procurement.
In 1959, Goldberg et al.[12] at the
University of Maryland performed the first orthotopic heart transplantation in dog.
They created the technique of left atrial anastomosis with a cuff of the orifices
of
the four pulmonary veins the conventional technique of cardiac transplantation that
was used routinely for decades. The anastomosis of great vessels was performed by
sutures and both vena cava were connected with methacrylate tubes. Recipient was
maintained with cardiopulmonary bypass, but surprisingly the donor heart was
arrested with potassium citrate in normothermia. The longest survival was 20
minutes.
Webb et al. in 1959[13] performed
orthotopic heart transplantation in dogs with hypothermic preservation but
individual pulmonary veins connection. Ten dogs survived from 30 to 450 minutes.
Subsequently, in the same year, Cass and Brock[14] working at the Guy's Hospital in
London, performed
autotransplantation and homologous transplantation using the left atrial cuff
technique described by Goldberg and introducing the right atrial anastomosis instead
of caval anastomosis. In other words, they established the standard technique of
orthotopic heart transplantation used clinically until introduction of bicaval
technique. In this scenario, late 1950, Dr. Shumway group, at Stanford, started to
perform orthotopic heart transplantation in dogs with cardiopulmonary bypass,
preservation of the donor heart by immersion for 5 minutes in a in 4°C saline. They
standardized surgical technique incorporating the previous concepts of left and
right atrial cuffs. Lower and Shumway[15] published their experience in 1960 reporting
that five of
eight animals survived for 6-21 days without immunosuppression. In sequence, Lower
et al.[16] made an important
contribution in 1965, showing a decrease of electrocardiography voltage in rejection
and the reversal of process with a combination of azathioprine and
methylprednisolone achieving a survival of 250 days (Figure 3).
Fig. 3
On left, Dr. Shumway and I. On the right, Stanford University
experimental laboratory. Standing, Dr. Schumway and Richard Lower, Dr.
Stofer, a veterinarian that was also chief of clinical cardiopulmonary
bypass with a transplanted dog.
Clinical Heart Transplantation
By the mid - 1960 solutions for the key problems were reasonably addressed in the
experimental laboratory. Recipient support, myocardial protection, function of the
transplanted organ, diagnosis and treatment of rejection seem to be solved remaining
the ethical and legal aspects. In 1964, Hardy et al.[17] working at the University
hospital in Jackson,
Mississippi felt justified to move to human heart transplantation. As the concept
of
brain death was not stablished, this group discussed all the legal ethical issues
considering that they have to wait for cardiorespiratory arrest and not interrupting
mechanical ventilation of the donor, thus, the possibility that the donor would have
cardiac arrest and recipient would be in serious decompensation would be slim. A
second potential recipient was admitted, actually, he was an extremely bad case, in
cardiogenic shock, leg amputation, tracheostomy and finally put on cardiopulmonary
bypass. It was decided to use a large chimpanzee as the donor. On January,
23rd, 1964 Dr. Hardy[17] performed the first human transplantation, actually, a
xenotransplant. The transplant was unable to maintain the circulatory load and the
patient died one hour later (Figure 4). On
December, 3rd, 1967, the medical and lay people were amazed by the news
of first interhuman heart transplantation. At the Groote Schuur Hospital, in Cape
Town, South Africa. Dr. Christiaan Nethling Barnard performed this heart
transplant[18]. The
recipient Louis Washkansky, a 54-year-old man in end stage ischemic cardiomyopathy
received the heart of a girl, Denise Darvall hit by a drunk driver, became the first
human heart donor. They stopped ventilation, waited for cardiac arrest and then
cardiopulmonary bypass was initiated to resuscitate the heart. After an initial
excellent recovery, the patient died on the 18th postoperative day (Figures 5 and
6). Three days later, Adrian Kantrowitz performed the 2nd
transplant, a pediatric one[19].
The donor was an anencephalic baby and the recipient was 18-day-old child with
Ebstein anomaly. The operation was performed at the Maimonides Hospital, Brooklyn,
New York and the patient survived six hours[19]. The fourth heart transplant was performed
at Stanford,
January, 6th, 1968 in an adult patient.
Fig. 4
On the left, Dr. James Hardy and, on the right, a photograph of the
operating room of the first human xenotransplantation.
Fig. 5
On the left, Dr. Barnard and, on the right, Louis Washkansky, the first
recipient.
Fig. 6
Denise Darvall, the first donor for a heart transplant
The great interest of cardiovascular surgeons for this challenging surgical procedure
is testified by the fact that at the end of 1968, 102 transplants were made in 17
countries and 52 centers. In Brazil, heart transplant has been performed in dogs by
Marques and others. The enthusiasm of this group led to Marques and Stolf (then a
medical student) to propose to Prof. Zerbini the performance of human transplant in
1964. It was considered a premature indication (Figure
7). After Barnard's successful procedure, Prof. Zerbini decided to
prepare the group to perform clinical heart transplantation. Preparation included
cardiologists, surgeons and a hematologist serving also as an immunologist. On May,
26th, 1968 the transplant took place, the recipient was a patient
with dilated cardiomyopathy and the donor, a patient with severe cerebral trauma.
The donor was in an adjacent room to the recipient, had electrocardiography and
electroencephalography monitoring. The brachiocephalic trunk was cumulated,
ventilation turned off. When heart stopped, perfusion of the heart was started
through the cannula, the heart was harvest and transferred to the recipient room .
Transplantation was performed with continuous normothermic perfusion of the heart
(Figure 8 and 9). The patient had an excellent recovery and died on the
28th postoperative day from rejection. The second patient with
ischemic cardiomyopathy had a little more than one-year survival in excellent
clinical condition. The third patient, also with ischemic cardiomyopathy and
diabetes, died on the 60th day from infection starting in the femoral
artery cannulation site.
Fig. 7
In A, an electrocardiography and, in B, angiography of an intrathoracic
heterotopic heart transplant. In C, an abstract of a paper presented by
our team.
Fig. 8
Photograph of preparation of the donor for the first Brazilian heart
transplant with continuous normothermic blood perfusion.
Fig. 9
Final aspect of first Brazilian heart transplant.
On July, 13-16th, 1968 Dr. Barnard organized a meeting called "Experience
with human heart transplantation", in Cape Town, South Africa. Sixteen guest
speakers were invited; three from South Africa; four from USA; two from England; one
from India; one from Argentina; 1 from Chile and Dr. Zerbini. Brazil was included
among the pioneer countries (Figure 10).
Fig. 10
In 1969, photograph of the visit of Christiaan Barnard to University of
São Paulo Medical Center. Sitting on the left, Dr. Zerbini and,
on the right, Dr. Barnard observing an electrocardiogram tracing of a
transplanted patient.
This meeting resulted in a very interesting publication: "The Proceedings of this
Symposium". It is extremely interesting to read this book. All participants
commented on the subjects. These comments go from silly to wise observations.
Worldwide in 1969, 50 patients were transplanted; in 1970, less than 20 and in 1971,
10 patients.
On April, 4th, 1969, Denton Cooley implanted the first total artificial
heart. It was a device that was being tested by Dr. Domingo Liotta, from Argentina,
in Dr. DeBakey laboratory across the street. The patient was kept in mechanical
circulatory assistance for three days and then transplanted. It was the first bridge
to transplantation, but the patient died two days later. The 1970 decade is what I
call the disenchantment period. Virtually, only four centers kept their heart
transplantation programs: the Groote Schuur in Cape Town under the leadership of
Marius Barnard (Christian brother); Stanford-Shumway group; Richard
Lower-Richmond-Virginia (after leaving Stanford) and Christian Cabrol-La
Pitié Salpetrieri in Paris. Nevertheless, in this period, we had several
important achievements mostly at Stanford. The introduction of immunological
monitoring, important in azathioprine/steroids era and the development of
endomyocardial biopsy by Phillip Caves, both at Stanford. The bioptome was developed
based on the Sakakibara clamp and made by Schultz. Schultz was a little old nice
man. In 1977, when I spent three months and a half at Stanford following the
transplantation program, I went to Schultz home and bought a bioptome manufactured
in his garage. With this bioptome, I performed almost 400 biopsies in several
cardiomyopathies and transplanted patients.
In 1978, cyclosporine was introduced in kidney transplantation and, in 1980, in
cardiac transplantation at Stanford. In 1980, the modern era of heart
transplantation started with rapid increase of annual number of transplant centers
and number of transplanted patients. It is amazing to look back and see such
progress in an 80-year period.