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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
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
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
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

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

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

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.