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Heart transplantation: Past, present, and future
Volume 50, Number 1 JUlV
The
1965
/«/./THORACIC AND
CARDIOVASCULAR SURGERY
Heart transplantation: Past, present. and future Peter Hairston, M.D., M.S., Charlottesville, Va.
Tu
.he success of renal homografts has cen tered renewed interest on the entire problem of organ replacement. A review of the sub ject of heart transplantation with the hope of altering the perspective of this hitherto impossible task therefore seems warranted. Until the twentieth century, transplanta tion of the heart was limited to the specula tive imagination of the investigative mind. The first reported performance of heart transplantation was by Alexis Carrel"· 10 who, in 1905, transplanted the heart of a dog into the neck of a larger one by anasto mosing the cut ends of the jugular vein and the carotid artery to the aorta, the pul monary artery, one of the venae cavae, and a From the University of Virginia School of Medicine, Department of Surgery, Charlottesville, Va. This paper is abstracted from a thesis entitled "Trans plantation of the Canine Heart" by Peter Hairston, M.D., in partial fulfillment for the degree of Master of Science awarded by the Graduate School of Arts and Sciences, University of Virginia, Charlottesville, Va. Received for publication Jan. 27, 1965.
pulmonary vein (Fig. 1). After re-establish ment of the circulation, the transplanted heart beat with strong contractions until intracavitary coagulation occurred some 21 hours after transplantation; sepsis was im plicated as the major factor limiting survival. No further reports appeared in the En glish literature until 1933 at which time Mann, Priestly, Markowitz, and Yater 20 de scribed a technique (Fig. 2) which utilized the principles and cervical transplantation site of Carrel. The anastomoses were per formed in a manner so as to afford perfu sion of the donor coronary circulation (viviperfusion). The longest survivor in terms of maintenance of a regular contraction was 8 days and death was attributed to rejection of the homograft by the recipient animal. Numerous investigators have subsequently utilized the Mann technique, or variations thereof, in attempting to elucidate the prob lems associated with heart transplantations. Downie,14 in 1953, reported a series of 23 homotransplantations of the dog heart with 1
Journal of
2
Hairston
Thoracic and Cardiovascular Surgery
AORTA LEFT PULMONARY VEIN
INFERIOR VENA CAVA COMMON CAROTID ARTERY
Carrel (1905) Fig. 1. Cervical transplantation method of Car rel in which the cut ends of the recipient jugular vein and carotid artery are anastomosed to the donor aorta, pulmonary artery, one of the venae cavae, and a pulmonary vein. PERIPHERAL COMMON CAROTID
PULMONARY ARTERY
Mann, Markowitz and Yater (1933) Fig. 2. Transplantation method of Mann and his associates performed in the neck, wherein the donor pulmonary artery and aorta are anasto mosed to the recipient central jugular vein and the carotid artery, thus affording perfusion (viviperfusion) of the donor coronary circulation.
an average survival of 120 hours and sug gested that the ultimate failure and destruc tion of the transplant was due to a humoral agent circulating in the recipient. His at tempts at attenuation of the antigenic reac tion by transfusing the recipient animal with donor blood were not successful. Wesolowski and Fennessey,42 in 1953, using the Mann cervical transplantation technique, enclosed a donor heart in a plas tic bag, isolating it from surrounding tissues. Their observation that the heart thus pro tected "behaved no differently" lent further support to the theory that the incompatibility to the homografted heart was blood borne. Sayegh and Creech,33 in 1957, used hearts from newborn pups and fetuses as donor organs in the Mann preparation in the hope that fetal hearts would contain less anti genic propensity, but this was not found to be the case. In an effort to attenuate the immune response, this group has treated recipient animals with a folic acid antago nist, amethopterin (methotrexate), and, in a recent report,31 stated that there was a minimal but significant prolongation in sur vival of the cervically implanted hearts of these animals. Sinitsyn3" in 1948 (Fig. 3) and Marcus, Wong, and Luisada27 in 1953 (Figs. 3 and 4) modified the Mann technique so as to impose a "work-load" on the left ventricle of the transplanted heart. With their modifi cation the coronary circulation of the trans plant was provided by the action of its own ventricle. The latter group, in spite of con stant "interim parabiotic perfusion," the use of paired mongrel dogs with compatible blood types, and elimination of reflex ir ritability of the donor heart by cervical vagotomy in the donor prior to removal of the heart, was unable to prolong survival time of the transplanted heart significantly. The Mann technique has accorded many investigators an excellent tool with which to study the metabolism of the transplanted hearts. Reemtsma, Delgado, and Creech30 analyzed the coronary arterial and venous blood which perfused the Mann transplanted heart and suggested that a metabolic de-
Volume 50
Heart transplantation
Number 1
3
July, 1965
PERIPHERAL COMMON CAROTID
Sinitsyn (1948) Marcus H ( 1953) Fig. 3. Technique similar to that of Mann and associates in which the recipient central carotid artery is anastomosed to the donor left auricular appendage. A "work-load" is thus imposed on the left ventricle.
rangement of the lactate utilization mecha nism existed. Bing1' r> has reported similar findings and attributes the disturbance to an increase in the permeability of the myocar dium which leads to a loss of certain en zymes and coenzymes. This altered perme ability is in turn thought to be due to path ologic changes resulting from the immune rejection mechanism. Similarly, the Mann technique has been utilized in studying methods by which the heart might be preserved in an extracorporeal phase prior to its transplantation into a recipient animal. Super-cooling (-8° C.) of the excised canine heart has been attempt ed by Barsamian2 and associates and Connaughton and Lewis,12 but without success. Webb and HowardfT' 3!) reported in 1957 the use of the Marcus II or Sinitsyn tech nique to investigate other factors that might contribute to the maintenance of a viable and functional excised heart. They demon
strated that the excised canine heart could be returned to a functional state after re frigeration at 0° to 4° C. in a nutrient medium for periods up to 8 hours, if intracoronary coagulation of blood was prevented either by perfusion with Ringer's solution or by massive heparinization of the donor animal. Lee and Webb, 20 · 21 in a similar experiment with the Sinitsyn technique, found "an alteration in the carbohydrate metabolism" of the heart implanted after refrigeration for 6 to 8 hours. They also found that this alteration responded favor ably to the enzyme precursors, thiamine or nicotinamide (an observation recently veri fied by Bing 5 ). A gradual evolution from the concept of the transplanted heart as a physiologic tool has occurred in the past decade. Marcus and associates27 in 1953 demonstrated that the transplanted heart was capable of func tioning in accessory support of the recipient animal. One of the techniques devised by
DISTAL CAROTID ARTERY
Marcus, Wong and Luisada I (1953) Fig. 4. This cervical transplantation technique of Marcus and associates is devised so as to bypass the left heart chambers but furnishes the coro nary circulation with oxygenated blood from the recipient proximal carotid artery.
Journal of
4
Hairston
Thoracic and Cardiovascular Surgery
Marcus,Wong and Luisada I I I (1953)
Fig. 5. The donor heart and lungs are interposed in the abdomen of the recipient in a manner that allows the donor organs to function in accessory support of the host animal.
the group (Fig. 5, Method III) was the transportation of the donor heart and lungs into the abdomen of the recipient animal, and the preparation thus functioned as an accessory heart. The suggestion was made that this would possibly be the manner in which cardiac transplantation might even tually be employed clinically. A more recent application of this prin ciple was reported in 1959 by Demichov13 of the Sklifosovsky Institute in Moscow. He presented a very ingenious method (Fig. 6) of intrathoracic transplantation of the canine heart in which the "body-own" heart supplied the upper half, and the donor heart
the lower half of the body of the recipient animal. The many vascular anastomoses were facilitated by the use of a suture ap paratus described by Androsov.1 A 32 day survival was reported which remained for some time the longest reported survival after cardiac transplantation. With the advent of supportive techniques, cardiac transplantation entered the phase of total heart replacement. Neptune, Cookson, and Bailey-8 in 1953 employed hypothermia (21° to 24° C.) of both the donor and the recipient animal to afford protection during the period of circulatory arrest. The donor heart and lungs were removed and sub stituted into the natural position of the re cipient organs in the mediastinum (Fig. 7 ) . A total heart-lung replacement thus was achieved. One animal survived 6 hours with the donor heart maintaining the circulation, and during this period the recipient animal resumed reflex activity and regained a nor mal body temperature before death ensued. Webb and Howard,38 in 1957, performed cardiopulmonary replacement with the ani mal maintained on mechanical pump-oxygenerator support. The method previously described by this group 37 · 39 of interim pres-
Demichov
Fig. 6. Demichov's method of intrathoracic im plantation of the heart and lungs in which the "body own" organs supply the upper half, and the donor organs the lower half of the body of the recipient animal.
Volume 50 Number 1
Heart transplantation
July, 1965
5
Neptune, Cookson and Bailey (1953) Fig. 7. Earliest attempt at cardiac replacement involved transplantation of the heart and lungs with the recipient animal protected by profoi hypothermia.
ervation of the donor heart in a chilled physiologic medium was employed. Survival periods up to 22 hours were achieved, but these investigators were not able to confirm the findings of Neptune-8 that the denervated lung is capable of adequate prolonged spontaneous respiration. In their experi ments in which the heart and one lung was transplanted,41 the longer-term survivors as sumed spontaneous respiration. The final step in heart transplantation, that of mediastinal replacement of the heart in which the heart occupies the same locus in the host that it does in the donor, now occupies the interest of many investigators. Goldberg, Berman, and Akman, 15 in 1958, reported their attempts with the use of mon grel dogs supported on the pump oxygenator, two operating teams, and an atrial suture technique (Fig. 8). Survivors of 21 and 117 minutes were obtained but in neither case was the heart able to function adequately in support of the recipient ani mal. Webb, Howard, and Neely40 were able to achieve more satisfying results with their methods of mediastinal replacement of the heart (Fig. 9) and functioning survivors for periods of IVi hours were obtained. They emphasized the use of interim refrigeration of the excised heart in a nutrient medium
to obviate the need for two operating teams. The donor heart was thus preserved while the recipient animal was prepared. Vascular couples expedited the actual transplant and lessened the time for mechanical pump sup port, the latter having been implicated as a factor contributing to the limited transplant survival in other studies. Similar techniques were employed by Blanco and co-workers,7 Cass and Brock,11 and Hairston and Mül ler10· 17 but no long-term survival was achieved. The latter investigators were able to utilize the limited survival time to study metabolism of the transplanted canine hearts which were in this case functioning in sup port of the recipient animals.17 They found that the metabolism in the transplanted heart proceeded normally, but utilization of the carbohydrates substrates was impaired in a manner analogous to the human failing heart.3·6·2S> This was attributed to damage of the contractile proteins during the trans plantation procedure, probably due to faulty surgical technique. In 1960, Lower and Shumway22 reported the first really significant breakthrough in the technical aspects of cardiac homotransplantation. Isotopic or orthotopic homotransplantation of the heart by means of the Goldberg technique was performed in dogs, and survivals of 6 and 21 days were
Journal of
6
Hairston
Thoracic and Cardiovascular Surgery
Goldberg, Berman, and Akman (1958) Fig. 8. The Goldberg technique of mediastinal replacement of the heart while the recipient animal is maintained on cardiopulmonary bypass is illustrated here. The donor heart is seen from a posterior view to depict the left atrial cuff that is left in order to facilitate the anasto mosis with the recipient.
Webb and Howard (I960) Fig. 9. Transplantation technique of Webb and Howard in which the donor's left atrium is left intact and the pulmonary veins are separately anastomosed. Cardiopulmonary bypass supports the recipient animal.
achieved. The mode of death was obscure, but electrocardiographic studies suggested that it was not related to a disturbance in cardiac rhythm or conduction. The differ ences in survival, it was assumed, were at tributed to varying immunologie responses. This assumption was verified by the finding of pathologic changes in the myocardium which were characteristic of the varying stages of the homograft rejection mecha
nism. Subsequent reports by these investiga tors 18 ' 2 3 ' 2 4 · 2 5 in which additional long-term survivors have been obtained confirm their original studies. A review of this subject is not complete without mention of autotransplantation. The importance of such a biological preparation has been recognized for some time because, among other reasons, it furnishes a means by which the characteristics of a totally de-
Volume 50
Heart transplantation
Number 1
7
July, 1965
nervated heart might be observed. Actual performance of this procedure had to await the development of the previously mentioned supportive techniques, primarly cardiopulmonary bypass. Webb and Howard39 in 1957 attempted heart, as well as heart-lung, autotransplantation, utilizing, in the latter, principles established by the work of Sen, Shah, and Satoskar.34 More recent attempts were reported by Cass and Brock11 and Hairston and Müller,16· " but are of his torical interest only since neither group was able to obtain long-term survivors. It re mained for Willman and co-workers43 to achieve survivors of a significant period, up to 9 months, after excision and reimplanta tion of the canine heart. In spite of their good results, this group expressed the belief that complete interruption of neural and lymphatic pathways to the heart is not com patible with prolonged existence. Hurley and his group 18 ' 1U currently dispute this view on the basis of canine autotransplant survivors in excess of 18 months. They have found that the hearts respond in an "altered fash ion," but produce a normal hemodynamic pattern compatible with life. Summary
It is obvious from this review that prodi gious efforts of numerous investigators have been invested toward the establishment of heart transplantation in its current status. At present the stage differs little from that through which renal homografts passed in 1959. The major barriers to successful car diac transplantation have in large measure been surmounted. Preservation of the ex cised (extracorporeal) donor heart is af forded by immersion of the heart in a physi ologic solution at 0° to 4° C.32· 27· 29 Support of the homograft recipient during the interim of donor heart implantation can be main tained on cardiopulmonary bypass. 11 · 15 ' 19 · 22-25,35,40 j n e d en ervated heart's capability to function in a manner compatible with long-term existence has been demonstrated by survival of the canine for periods up to 18 months after cardiac autotransplantation. 19 · 43 · 44 The single remaining obstacle
and greatest deterrent to heart transplanta tion is the problem of tissue incompatibility or the homograft rejection mechanism. It seems not unreasonable to anticipate that the present inroads into an understanding of the basic immunologie processes will, in the foreseeable future, afford investigators a solution to this problem. The ultimate in organ transplantation, when the heart of one individual sustains the life of another, is perhaps no longer a visionary concept. REFERENCES 1 Androsov, P. I.: New Method of Surgical Treatment of Blood Vessel Lesions, Arch. Surg. 73: 902-910, 1956. 2 Barsamian, E. M., Jacob, S. W., Collins, S. C , and Owen, O. E.: Preliminary Studies on the Transplantation of Supercooled Hearts, Plast. & Reconstruct. Surg. 25: 405-408, 1960. 3 Bing, R. J.: The Metabolism of the Heart. Harvey Lecture Series. L. 27. New York, 1956, Academic Press, Inc. 4 Bing, R. J., Chiba, C , Chrysohon, A., Wolf, P. L., and Gudbjarnason, S.: Transplantation of the Heart, Circulation 25: 273-276, 1962. 5 Bing, R. J., Chiba, C , Chrysohon, S., Gud bjarnason, S., and Wolf, P. L.: Metabolic His tologie and Histochemical Aspects of the Homografted Heart, Tr. A. Am. Physicians 74: 318-332, 1961. 6 Bing, R. J., Siegel, A., Vitale, A. Balboni, F., Sparks, E., Saeschler, M., Klapper, M., and Edwards, S.: Metabolic Studies on the Human Heart In Vivo. 1. Studies on Carbohydrate Metabolism of the Human Heart and Lungs, Am. J. Med. 15: 284-296, 1953. 7 Blanco, G., Adam, A., Rodrigues-Perez, D. and Fernandez, A.: Complete Homotransplan tation of the Canine Heart, Arch. Surg. 76: 20-23, 1958. 8 Carrel, A.: La technique opératoire des anas tomoses vasculaires et la transplantation des viscères, Lyon méd. 98: 859-864, 1902. 9 Carrel, A., and Guthrie, C. C : The Trans plantation of Veins and Organs, Am. Med. 10: 1101-1102, 1905. 10 Carrel, A.: The Surgery of Blood Vessels, Johns Hopkins Hosp. Bull. 18: 18-28, 1907. 11 Cass, M. N., and Brock, R.: Heart Excision and Replacement, Guy's Hosp. Rep. 108: 285-290, 1959. 12 Connaughton, P. J., and Lewis, F. J.: Use of Glycerol and Chloroform in Heart Preserva tion by Freezing, S. Forum 12: 177-179, 1961. 13 Demichov, V. P.: Transplantation of the Heart and Lungs Experimentally, Tr. Acad. M. Se. USSR 12: 18-22. 1959.
Journal of
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14 Downie, H . G.: Homotransplantation of the Dog Heart, Arch. Surg. 66: 624-636, 1953. 15 Goldberg, M., Berman, E. F . , and Akman, L. C : Homologous Transplantation of the Canine Heart, J. Internat. Coll. Surgeons 30: 575-586, 1958. 16 Hairston, P.: Transplantation of the Canine Heart. Thesis, University of Virginia Gradu ate School, Charlottesville, Virginia, 1960. 17 Hairston, P., and Müller, W . H., Jr.: Metab olism of the Homotransplanted Canine Heart, S. Forum 12: 206-207, 1961. 18 Hurley, E . J., Dong, E., Jr., Lower, R. R., Hancock, E. W., Stofer, R. C , and Shumway, N . E.: An Approach to Extracorporeal Surgery of the Heart, J. THORACIC & CARDIOVAS. SURG.
44: 776-784, 1962. 19 Hurley, E. J., Dong, E., Jr., Stofer, R. C , and Shumway, N . E.: Isotopic Replacement of the Totally Excised Canine Heart, J. S. Res. 2: 90-93, 1962. 20 Lee, S. S., and Webb, W. R.: Cardiac Metabo lism as Influenced by Ischemia, Refrigeration and Enzyme Precursors, A m . Surgeon 2 5 : 776-781, 1959. 21 Lee, S. S., and Webb, W. R.: Metabolism of the Isolated Normothermic and Rewarmed Heart, S. Forum 9: 284-286, 1958. 22 Lower, R. R., and Shumway, N . E.: Studies on Orthotopic Transplantation of the Canine Heart, S. Forum 11: 18-19, 1960. 23 Lower, R. R., Stofer, P. C , and Shumway, N . E.: Homovital Transplantation of the Heart,
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25
26
27
28
29
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SURG. 41:
196-204, 1961. Lower, R. R., Stofer, R. C , Hurley, E. J., and Shumway, N . E.: Complete Homograft Replacement of the Heart and Both Lungs, Surgery 50: 842-845, 1961. Lower, R. R., Stofer, R. C , Hurley, E. J., Dong, E., Jr., Cohn, R. B., and Shumway, N . E.: Successful Homotransplantation of the Canine Heart After Anoxic Preservation for Seven Hours, Am. J. Surg. 104: 302-306, 1962. Mann, F . C , Priestly, J. R., Markowitz, J., and Yater, W. M.: Transplantation of the Intact Mammalian Heart, Arch Surg. 26: 219-224, 1933. Marcus, E., Wong, S. N . I., and Luisada, A. A.: Homologous Heart Grafts. I. Technique of Interim Parabiotic Perfusion. IL Trans plantation in Dogs, Arch. Surg. 66: 179-191, 1953. Neptune, W. B., Cookson, B. A., and Bailey, C. P.: Complete Homologous Heart Trans plantation, Arch. Surg. 66: 174-178, 1953. Olson, R. E., and Schwartz, W. B.: Myocardial Metabolism in Congestive Failure, Medicine 30: 21-41, 1951.
30 Reemtsma, K., Delgado, J. P., and Creech, O.: Transplantation of the Homologous C a nine Heart: Serial Studies of Myocardial Blood Flow, Oxygen Consumption and Carbohydrate Metabolism, Surgery 47: 292-300, 1960. 31 Reemtsma, K., Williamson, W. E., Jr., Iglesias, F., Pena, E., Sagegh, S. F . , and Creech, O., Jr.: Studies in Homologous Canine Heart Transplantation: Prolongation of Survival With a F o l k Acid Antagonist, Surgery 52: 127-133, 1962. 32 Robicsek, F . , Sanger, P . W., and Taylor, F . H.: Simple Method of Keeping the Heart "Alive" and Functioning Outside of the Body for Prolonged Periods, Surgery 5 3 : 525-530, 1963. 33 Sayegh, S. F . , and Creech, O.: Transplantation of the Homologous Canine Heart, J. THORACIC SURG. 34: 692-706, 1957.
34 Sen, O. K „ Shah, C. B., and Satoskar, R. S.: Studies on Isolated Heart-Lung Preparations in the Hypothermie Animal. A Preliminary Exercise for Homologous Heart-Lung Trans plants, J. Internat. Coll. Surgeons 26: 32-37, 1956. 35 Shumway, N . E . : Cardiac Transplantations, Heart Bull. 12: 57-60, 1963. 36 Sinitsyn, H . : Transplantation as New Method in Experimental Biology and Medicine, 1948, Moscow; Photostat of Dispatch No. 763 from Army Medical Library, Washington, D . C. 37 Webb, W . R., and Howard, H. S.: Extension of the Limits of Cardiac Viability With Total Coronary Occlusion, Surgery 42: 92-100, 1957. 38 Webb, W. R., and Howard, H. S.: Cardiopulmonary Transplantation, S. Forum 8: 313317, 1957. 39 Webb, W . R., and Howard, H . S.: Restoration of Function of the Refrigerated Heart, S. Forum 8: 303-306, 1957. 40 Webb, W . R., Howard, H . S., and Neely, W. N.: Practical Method of Homologous Cardiac Transplantation, J. THORACIC SURG. 37: 361-
366, 1959. 41 Webb, W . R., deGuzman, V., and Hoopes, J. E.: Cardiopulmonary Transplantation: Ex perimental Study of Current Problems, A m . Surgeon 27: 236-241, 1961. 42 Wesolowski, S. A., and Fennessey, J. F . : Pat tern of Failure of the Homografted Heart, Circulation 8: 750-755, 1953. 43 Willman, V. L., Cooper, T., Cian, L. G., and Hanlon, C. R.: Autotransplantation of the Canine Heart, Surg., Gynec. & Obst. 115: 299-302, 1962. 44 Willman, V. L., Cooper, T., Cian, L. G., and Hanlon, C . R.: Mechanisms of Cardiac Fail ure After Excision and Reimplantation of the Canine Heart, S. Forum 13: 93-95, 1962.
The
1965
/«/./THORACIC AND
CARDIOVASCULAR SURGERY
Heart transplantation: Past, present. and future Peter Hairston, M.D., M.S., Charlottesville, Va.
Tu
.he success of renal homografts has cen tered renewed interest on the entire problem of organ replacement. A review of the sub ject of heart transplantation with the hope of altering the perspective of this hitherto impossible task therefore seems warranted. Until the twentieth century, transplanta tion of the heart was limited to the specula tive imagination of the investigative mind. The first reported performance of heart transplantation was by Alexis Carrel"· 10 who, in 1905, transplanted the heart of a dog into the neck of a larger one by anasto mosing the cut ends of the jugular vein and the carotid artery to the aorta, the pul monary artery, one of the venae cavae, and a From the University of Virginia School of Medicine, Department of Surgery, Charlottesville, Va. This paper is abstracted from a thesis entitled "Trans plantation of the Canine Heart" by Peter Hairston, M.D., in partial fulfillment for the degree of Master of Science awarded by the Graduate School of Arts and Sciences, University of Virginia, Charlottesville, Va. Received for publication Jan. 27, 1965.
pulmonary vein (Fig. 1). After re-establish ment of the circulation, the transplanted heart beat with strong contractions until intracavitary coagulation occurred some 21 hours after transplantation; sepsis was im plicated as the major factor limiting survival. No further reports appeared in the En glish literature until 1933 at which time Mann, Priestly, Markowitz, and Yater 20 de scribed a technique (Fig. 2) which utilized the principles and cervical transplantation site of Carrel. The anastomoses were per formed in a manner so as to afford perfu sion of the donor coronary circulation (viviperfusion). The longest survivor in terms of maintenance of a regular contraction was 8 days and death was attributed to rejection of the homograft by the recipient animal. Numerous investigators have subsequently utilized the Mann technique, or variations thereof, in attempting to elucidate the prob lems associated with heart transplantations. Downie,14 in 1953, reported a series of 23 homotransplantations of the dog heart with 1
Journal of
2
Hairston
Thoracic and Cardiovascular Surgery
AORTA LEFT PULMONARY VEIN
INFERIOR VENA CAVA COMMON CAROTID ARTERY
Carrel (1905) Fig. 1. Cervical transplantation method of Car rel in which the cut ends of the recipient jugular vein and carotid artery are anastomosed to the donor aorta, pulmonary artery, one of the venae cavae, and a pulmonary vein. PERIPHERAL COMMON CAROTID
PULMONARY ARTERY
Mann, Markowitz and Yater (1933) Fig. 2. Transplantation method of Mann and his associates performed in the neck, wherein the donor pulmonary artery and aorta are anasto mosed to the recipient central jugular vein and the carotid artery, thus affording perfusion (viviperfusion) of the donor coronary circulation.
an average survival of 120 hours and sug gested that the ultimate failure and destruc tion of the transplant was due to a humoral agent circulating in the recipient. His at tempts at attenuation of the antigenic reac tion by transfusing the recipient animal with donor blood were not successful. Wesolowski and Fennessey,42 in 1953, using the Mann cervical transplantation technique, enclosed a donor heart in a plas tic bag, isolating it from surrounding tissues. Their observation that the heart thus pro tected "behaved no differently" lent further support to the theory that the incompatibility to the homografted heart was blood borne. Sayegh and Creech,33 in 1957, used hearts from newborn pups and fetuses as donor organs in the Mann preparation in the hope that fetal hearts would contain less anti genic propensity, but this was not found to be the case. In an effort to attenuate the immune response, this group has treated recipient animals with a folic acid antago nist, amethopterin (methotrexate), and, in a recent report,31 stated that there was a minimal but significant prolongation in sur vival of the cervically implanted hearts of these animals. Sinitsyn3" in 1948 (Fig. 3) and Marcus, Wong, and Luisada27 in 1953 (Figs. 3 and 4) modified the Mann technique so as to impose a "work-load" on the left ventricle of the transplanted heart. With their modifi cation the coronary circulation of the trans plant was provided by the action of its own ventricle. The latter group, in spite of con stant "interim parabiotic perfusion," the use of paired mongrel dogs with compatible blood types, and elimination of reflex ir ritability of the donor heart by cervical vagotomy in the donor prior to removal of the heart, was unable to prolong survival time of the transplanted heart significantly. The Mann technique has accorded many investigators an excellent tool with which to study the metabolism of the transplanted hearts. Reemtsma, Delgado, and Creech30 analyzed the coronary arterial and venous blood which perfused the Mann transplanted heart and suggested that a metabolic de-
Volume 50
Heart transplantation
Number 1
3
July, 1965
PERIPHERAL COMMON CAROTID
Sinitsyn (1948) Marcus H ( 1953) Fig. 3. Technique similar to that of Mann and associates in which the recipient central carotid artery is anastomosed to the donor left auricular appendage. A "work-load" is thus imposed on the left ventricle.
rangement of the lactate utilization mecha nism existed. Bing1' r> has reported similar findings and attributes the disturbance to an increase in the permeability of the myocar dium which leads to a loss of certain en zymes and coenzymes. This altered perme ability is in turn thought to be due to path ologic changes resulting from the immune rejection mechanism. Similarly, the Mann technique has been utilized in studying methods by which the heart might be preserved in an extracorporeal phase prior to its transplantation into a recipient animal. Super-cooling (-8° C.) of the excised canine heart has been attempt ed by Barsamian2 and associates and Connaughton and Lewis,12 but without success. Webb and HowardfT' 3!) reported in 1957 the use of the Marcus II or Sinitsyn tech nique to investigate other factors that might contribute to the maintenance of a viable and functional excised heart. They demon
strated that the excised canine heart could be returned to a functional state after re frigeration at 0° to 4° C. in a nutrient medium for periods up to 8 hours, if intracoronary coagulation of blood was prevented either by perfusion with Ringer's solution or by massive heparinization of the donor animal. Lee and Webb, 20 · 21 in a similar experiment with the Sinitsyn technique, found "an alteration in the carbohydrate metabolism" of the heart implanted after refrigeration for 6 to 8 hours. They also found that this alteration responded favor ably to the enzyme precursors, thiamine or nicotinamide (an observation recently veri fied by Bing 5 ). A gradual evolution from the concept of the transplanted heart as a physiologic tool has occurred in the past decade. Marcus and associates27 in 1953 demonstrated that the transplanted heart was capable of func tioning in accessory support of the recipient animal. One of the techniques devised by
DISTAL CAROTID ARTERY
Marcus, Wong and Luisada I (1953) Fig. 4. This cervical transplantation technique of Marcus and associates is devised so as to bypass the left heart chambers but furnishes the coro nary circulation with oxygenated blood from the recipient proximal carotid artery.
Journal of
4
Hairston
Thoracic and Cardiovascular Surgery
Marcus,Wong and Luisada I I I (1953)
Fig. 5. The donor heart and lungs are interposed in the abdomen of the recipient in a manner that allows the donor organs to function in accessory support of the host animal.
the group (Fig. 5, Method III) was the transportation of the donor heart and lungs into the abdomen of the recipient animal, and the preparation thus functioned as an accessory heart. The suggestion was made that this would possibly be the manner in which cardiac transplantation might even tually be employed clinically. A more recent application of this prin ciple was reported in 1959 by Demichov13 of the Sklifosovsky Institute in Moscow. He presented a very ingenious method (Fig. 6) of intrathoracic transplantation of the canine heart in which the "body-own" heart supplied the upper half, and the donor heart
the lower half of the body of the recipient animal. The many vascular anastomoses were facilitated by the use of a suture ap paratus described by Androsov.1 A 32 day survival was reported which remained for some time the longest reported survival after cardiac transplantation. With the advent of supportive techniques, cardiac transplantation entered the phase of total heart replacement. Neptune, Cookson, and Bailey-8 in 1953 employed hypothermia (21° to 24° C.) of both the donor and the recipient animal to afford protection during the period of circulatory arrest. The donor heart and lungs were removed and sub stituted into the natural position of the re cipient organs in the mediastinum (Fig. 7 ) . A total heart-lung replacement thus was achieved. One animal survived 6 hours with the donor heart maintaining the circulation, and during this period the recipient animal resumed reflex activity and regained a nor mal body temperature before death ensued. Webb and Howard,38 in 1957, performed cardiopulmonary replacement with the ani mal maintained on mechanical pump-oxygenerator support. The method previously described by this group 37 · 39 of interim pres-
Demichov
Fig. 6. Demichov's method of intrathoracic im plantation of the heart and lungs in which the "body own" organs supply the upper half, and the donor organs the lower half of the body of the recipient animal.
Volume 50 Number 1
Heart transplantation
July, 1965
5
Neptune, Cookson and Bailey (1953) Fig. 7. Earliest attempt at cardiac replacement involved transplantation of the heart and lungs with the recipient animal protected by profoi hypothermia.
ervation of the donor heart in a chilled physiologic medium was employed. Survival periods up to 22 hours were achieved, but these investigators were not able to confirm the findings of Neptune-8 that the denervated lung is capable of adequate prolonged spontaneous respiration. In their experi ments in which the heart and one lung was transplanted,41 the longer-term survivors as sumed spontaneous respiration. The final step in heart transplantation, that of mediastinal replacement of the heart in which the heart occupies the same locus in the host that it does in the donor, now occupies the interest of many investigators. Goldberg, Berman, and Akman, 15 in 1958, reported their attempts with the use of mon grel dogs supported on the pump oxygenator, two operating teams, and an atrial suture technique (Fig. 8). Survivors of 21 and 117 minutes were obtained but in neither case was the heart able to function adequately in support of the recipient ani mal. Webb, Howard, and Neely40 were able to achieve more satisfying results with their methods of mediastinal replacement of the heart (Fig. 9) and functioning survivors for periods of IVi hours were obtained. They emphasized the use of interim refrigeration of the excised heart in a nutrient medium
to obviate the need for two operating teams. The donor heart was thus preserved while the recipient animal was prepared. Vascular couples expedited the actual transplant and lessened the time for mechanical pump sup port, the latter having been implicated as a factor contributing to the limited transplant survival in other studies. Similar techniques were employed by Blanco and co-workers,7 Cass and Brock,11 and Hairston and Mül ler10· 17 but no long-term survival was achieved. The latter investigators were able to utilize the limited survival time to study metabolism of the transplanted canine hearts which were in this case functioning in sup port of the recipient animals.17 They found that the metabolism in the transplanted heart proceeded normally, but utilization of the carbohydrates substrates was impaired in a manner analogous to the human failing heart.3·6·2S> This was attributed to damage of the contractile proteins during the trans plantation procedure, probably due to faulty surgical technique. In 1960, Lower and Shumway22 reported the first really significant breakthrough in the technical aspects of cardiac homotransplantation. Isotopic or orthotopic homotransplantation of the heart by means of the Goldberg technique was performed in dogs, and survivals of 6 and 21 days were
Journal of
6
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Thoracic and Cardiovascular Surgery
Goldberg, Berman, and Akman (1958) Fig. 8. The Goldberg technique of mediastinal replacement of the heart while the recipient animal is maintained on cardiopulmonary bypass is illustrated here. The donor heart is seen from a posterior view to depict the left atrial cuff that is left in order to facilitate the anasto mosis with the recipient.
Webb and Howard (I960) Fig. 9. Transplantation technique of Webb and Howard in which the donor's left atrium is left intact and the pulmonary veins are separately anastomosed. Cardiopulmonary bypass supports the recipient animal.
achieved. The mode of death was obscure, but electrocardiographic studies suggested that it was not related to a disturbance in cardiac rhythm or conduction. The differ ences in survival, it was assumed, were at tributed to varying immunologie responses. This assumption was verified by the finding of pathologic changes in the myocardium which were characteristic of the varying stages of the homograft rejection mecha
nism. Subsequent reports by these investiga tors 18 ' 2 3 ' 2 4 · 2 5 in which additional long-term survivors have been obtained confirm their original studies. A review of this subject is not complete without mention of autotransplantation. The importance of such a biological preparation has been recognized for some time because, among other reasons, it furnishes a means by which the characteristics of a totally de-
Volume 50
Heart transplantation
Number 1
7
July, 1965
nervated heart might be observed. Actual performance of this procedure had to await the development of the previously mentioned supportive techniques, primarly cardiopulmonary bypass. Webb and Howard39 in 1957 attempted heart, as well as heart-lung, autotransplantation, utilizing, in the latter, principles established by the work of Sen, Shah, and Satoskar.34 More recent attempts were reported by Cass and Brock11 and Hairston and Müller,16· " but are of his torical interest only since neither group was able to obtain long-term survivors. It re mained for Willman and co-workers43 to achieve survivors of a significant period, up to 9 months, after excision and reimplanta tion of the canine heart. In spite of their good results, this group expressed the belief that complete interruption of neural and lymphatic pathways to the heart is not com patible with prolonged existence. Hurley and his group 18 ' 1U currently dispute this view on the basis of canine autotransplant survivors in excess of 18 months. They have found that the hearts respond in an "altered fash ion," but produce a normal hemodynamic pattern compatible with life. Summary
It is obvious from this review that prodi gious efforts of numerous investigators have been invested toward the establishment of heart transplantation in its current status. At present the stage differs little from that through which renal homografts passed in 1959. The major barriers to successful car diac transplantation have in large measure been surmounted. Preservation of the ex cised (extracorporeal) donor heart is af forded by immersion of the heart in a physi ologic solution at 0° to 4° C.32· 27· 29 Support of the homograft recipient during the interim of donor heart implantation can be main tained on cardiopulmonary bypass. 11 · 15 ' 19 · 22-25,35,40 j n e d en ervated heart's capability to function in a manner compatible with long-term existence has been demonstrated by survival of the canine for periods up to 18 months after cardiac autotransplantation. 19 · 43 · 44 The single remaining obstacle
and greatest deterrent to heart transplanta tion is the problem of tissue incompatibility or the homograft rejection mechanism. It seems not unreasonable to anticipate that the present inroads into an understanding of the basic immunologie processes will, in the foreseeable future, afford investigators a solution to this problem. The ultimate in organ transplantation, when the heart of one individual sustains the life of another, is perhaps no longer a visionary concept. REFERENCES 1 Androsov, P. I.: New Method of Surgical Treatment of Blood Vessel Lesions, Arch. Surg. 73: 902-910, 1956. 2 Barsamian, E. M., Jacob, S. W., Collins, S. C , and Owen, O. E.: Preliminary Studies on the Transplantation of Supercooled Hearts, Plast. & Reconstruct. Surg. 25: 405-408, 1960. 3 Bing, R. J.: The Metabolism of the Heart. Harvey Lecture Series. L. 27. New York, 1956, Academic Press, Inc. 4 Bing, R. J., Chiba, C , Chrysohon, A., Wolf, P. L., and Gudbjarnason, S.: Transplantation of the Heart, Circulation 25: 273-276, 1962. 5 Bing, R. J., Chiba, C , Chrysohon, S., Gud bjarnason, S., and Wolf, P. L.: Metabolic His tologie and Histochemical Aspects of the Homografted Heart, Tr. A. Am. Physicians 74: 318-332, 1961. 6 Bing, R. J., Siegel, A., Vitale, A. Balboni, F., Sparks, E., Saeschler, M., Klapper, M., and Edwards, S.: Metabolic Studies on the Human Heart In Vivo. 1. Studies on Carbohydrate Metabolism of the Human Heart and Lungs, Am. J. Med. 15: 284-296, 1953. 7 Blanco, G., Adam, A., Rodrigues-Perez, D. and Fernandez, A.: Complete Homotransplan tation of the Canine Heart, Arch. Surg. 76: 20-23, 1958. 8 Carrel, A.: La technique opératoire des anas tomoses vasculaires et la transplantation des viscères, Lyon méd. 98: 859-864, 1902. 9 Carrel, A., and Guthrie, C. C : The Trans plantation of Veins and Organs, Am. Med. 10: 1101-1102, 1905. 10 Carrel, A.: The Surgery of Blood Vessels, Johns Hopkins Hosp. Bull. 18: 18-28, 1907. 11 Cass, M. N., and Brock, R.: Heart Excision and Replacement, Guy's Hosp. Rep. 108: 285-290, 1959. 12 Connaughton, P. J., and Lewis, F. J.: Use of Glycerol and Chloroform in Heart Preserva tion by Freezing, S. Forum 12: 177-179, 1961. 13 Demichov, V. P.: Transplantation of the Heart and Lungs Experimentally, Tr. Acad. M. Se. USSR 12: 18-22. 1959.
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14 Downie, H . G.: Homotransplantation of the Dog Heart, Arch. Surg. 66: 624-636, 1953. 15 Goldberg, M., Berman, E. F . , and Akman, L. C : Homologous Transplantation of the Canine Heart, J. Internat. Coll. Surgeons 30: 575-586, 1958. 16 Hairston, P.: Transplantation of the Canine Heart. Thesis, University of Virginia Gradu ate School, Charlottesville, Virginia, 1960. 17 Hairston, P., and Müller, W . H., Jr.: Metab olism of the Homotransplanted Canine Heart, S. Forum 12: 206-207, 1961. 18 Hurley, E . J., Dong, E., Jr., Lower, R. R., Hancock, E. W., Stofer, R. C , and Shumway, N . E.: An Approach to Extracorporeal Surgery of the Heart, J. THORACIC & CARDIOVAS. SURG.
44: 776-784, 1962. 19 Hurley, E. J., Dong, E., Jr., Stofer, R. C , and Shumway, N . E.: Isotopic Replacement of the Totally Excised Canine Heart, J. S. Res. 2: 90-93, 1962. 20 Lee, S. S., and Webb, W. R.: Cardiac Metabo lism as Influenced by Ischemia, Refrigeration and Enzyme Precursors, A m . Surgeon 2 5 : 776-781, 1959. 21 Lee, S. S., and Webb, W. R.: Metabolism of the Isolated Normothermic and Rewarmed Heart, S. Forum 9: 284-286, 1958. 22 Lower, R. R., and Shumway, N . E.: Studies on Orthotopic Transplantation of the Canine Heart, S. Forum 11: 18-19, 1960. 23 Lower, R. R., Stofer, P. C , and Shumway, N . E.: Homovital Transplantation of the Heart,
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26
27
28
29
J.
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SURG. 41:
196-204, 1961. Lower, R. R., Stofer, R. C , Hurley, E. J., and Shumway, N . E.: Complete Homograft Replacement of the Heart and Both Lungs, Surgery 50: 842-845, 1961. Lower, R. R., Stofer, R. C , Hurley, E. J., Dong, E., Jr., Cohn, R. B., and Shumway, N . E.: Successful Homotransplantation of the Canine Heart After Anoxic Preservation for Seven Hours, Am. J. Surg. 104: 302-306, 1962. Mann, F . C , Priestly, J. R., Markowitz, J., and Yater, W. M.: Transplantation of the Intact Mammalian Heart, Arch Surg. 26: 219-224, 1933. Marcus, E., Wong, S. N . I., and Luisada, A. A.: Homologous Heart Grafts. I. Technique of Interim Parabiotic Perfusion. IL Trans plantation in Dogs, Arch. Surg. 66: 179-191, 1953. Neptune, W. B., Cookson, B. A., and Bailey, C. P.: Complete Homologous Heart Trans plantation, Arch. Surg. 66: 174-178, 1953. Olson, R. E., and Schwartz, W. B.: Myocardial Metabolism in Congestive Failure, Medicine 30: 21-41, 1951.
30 Reemtsma, K., Delgado, J. P., and Creech, O.: Transplantation of the Homologous C a nine Heart: Serial Studies of Myocardial Blood Flow, Oxygen Consumption and Carbohydrate Metabolism, Surgery 47: 292-300, 1960. 31 Reemtsma, K., Williamson, W. E., Jr., Iglesias, F., Pena, E., Sagegh, S. F . , and Creech, O., Jr.: Studies in Homologous Canine Heart Transplantation: Prolongation of Survival With a F o l k Acid Antagonist, Surgery 52: 127-133, 1962. 32 Robicsek, F . , Sanger, P . W., and Taylor, F . H.: Simple Method of Keeping the Heart "Alive" and Functioning Outside of the Body for Prolonged Periods, Surgery 5 3 : 525-530, 1963. 33 Sayegh, S. F . , and Creech, O.: Transplantation of the Homologous Canine Heart, J. THORACIC SURG. 34: 692-706, 1957.
34 Sen, O. K „ Shah, C. B., and Satoskar, R. S.: Studies on Isolated Heart-Lung Preparations in the Hypothermie Animal. A Preliminary Exercise for Homologous Heart-Lung Trans plants, J. Internat. Coll. Surgeons 26: 32-37, 1956. 35 Shumway, N . E . : Cardiac Transplantations, Heart Bull. 12: 57-60, 1963. 36 Sinitsyn, H . : Transplantation as New Method in Experimental Biology and Medicine, 1948, Moscow; Photostat of Dispatch No. 763 from Army Medical Library, Washington, D . C. 37 Webb, W . R., and Howard, H. S.: Extension of the Limits of Cardiac Viability With Total Coronary Occlusion, Surgery 42: 92-100, 1957. 38 Webb, W. R., and Howard, H. S.: Cardiopulmonary Transplantation, S. Forum 8: 313317, 1957. 39 Webb, W . R., and Howard, H . S.: Restoration of Function of the Refrigerated Heart, S. Forum 8: 303-306, 1957. 40 Webb, W . R., Howard, H . S., and Neely, W. N.: Practical Method of Homologous Cardiac Transplantation, J. THORACIC SURG. 37: 361-
366, 1959. 41 Webb, W . R., deGuzman, V., and Hoopes, J. E.: Cardiopulmonary Transplantation: Ex perimental Study of Current Problems, A m . Surgeon 27: 236-241, 1961. 42 Wesolowski, S. A., and Fennessey, J. F . : Pat tern of Failure of the Homografted Heart, Circulation 8: 750-755, 1953. 43 Willman, V. L., Cooper, T., Cian, L. G., and Hanlon, C. R.: Autotransplantation of the Canine Heart, Surg., Gynec. & Obst. 115: 299-302, 1962. 44 Willman, V. L., Cooper, T., Cian, L. G., and Hanlon, C . R.: Mechanisms of Cardiac Fail ure After Excision and Reimplantation of the Canine Heart, S. Forum 13: 93-95, 1962.