Two Decades of Experimental and Clinical Orthotopic Homotransplantation of the Heart

TWO DECADES OF EXPERIMENTAL AND CLINICAL ORTHOTOPIC HOMOTRANSPLANTATION OF THE HEART NORMAN E. SHUMWAY and EDWARD B. STlNSON* The subject matter ofthis paper is especially appropriate on diis occasion since experiments in organ transplantation by Alexis Carrel and Charles Guthrie were conducted at the University of Chicago shortly after the turn ofdie century. Heterotopic cardiac transplants in animals were inaugurated by Gudirie and Carrel with contractions of die donor heart noted up to a few hours [I]. The carotid artery of the larger host animal was anastomosed to the aorta of die donor puppy heart. Little, if any, further progress was reported until 1933 when Frank Mann and his associates at die Mayo Clinic [2] showed survival of the heterotopic homograft as long as 8 days. Mann separated out transplant failures based on problems in surgical techniques from those effected by some kind of biological incompatibility (rejection) when he concluded that "me general behavior ofsuch a transplant organ (heart) as regards function , period of survival and cytolytic changes is similar to diat of other homotransplanted organs." Ofcourse there was no immune suppression at diat time, and die field of experimental heart transplantation came to a halt for anodier 20 years. Marcus, Wong, and Luisada [3] in 1951 suggested diat heart transplantation might be used for replacement ofa diseased organ but called it "a fantastic dream." Webb, Howard, and Neely [4] described experiments in orthotopic heart and right lung homotransplants. Twelve such transplants were termed successful and 10 showed maintenance of normal blood pressures from 30 minutes to 7î4 hours. The year of that publication was 1959, and in December of the same year experimental orthotopic transplantation ofthe heart in dogs became a reality through the simple technical maneuver of leaving behind segments of bodi atria so that multiple, time-consuming venous anastomoses were converted»Department of Cardiovascular Surgery, Stanford University Medical Center, Stanford, California 94305.© 1979 by The University of Chicago. 0031-5982/79/2222-0005$01.00 Perspectives m Biofogy and Medicine ¦ Winter 1979 ¦ Part 2 | S81 into radier long, easy to accomplish atrial suture lines [5]. The pump oxygenator maintained die recipient during its acardiac phase, and the donor heart was preserved by local cooling in a saline badi at 2°-4° C. It was shown for the first time that the denervated, homotransplanted heart could sustain the total circulatory burden. Performance of the Transpfanted Heart The physiological responses and capabilities of the transplanted heart were extensively investigated in the laboratory before consideration of human application was possible. It is ofinterest that this represented the first successful function of any striated muscle separated from die central nervous system. Soon after successful experimental homotransplantation of die heart was reported, a series of animals was developed for die primary purpose ofstudying die physiology ofthe denervated heart [6]. Since long-term survival after homotransplantation of the heart was such a difficult and fragile attainment, a series of animals was prepared with autotransplantation of the heart. This experimental model mimicked the homotransplant in every regard except for the immune reaction. Accordingly, long-term survival was easy to obtain, and various physiological parameters could be explored by invasive techniques. Repetitive cardiac cadieterization studies showed normal or near normal function of the transplanted heart under bodi resting and stressful conditions. Subsequent and extensive studies performed in patients after cardiac transplantation have totally confirmed die early experimental data. Utilizing chemical immune suppression derived from die original discovery by Schwartz, Stack, and Dameshek in 1958 [7], long-term survival oforthotopic canine heart homograft was achieved in 1965 [8]. Periodic or pulsatile use of azathioprine and methylprednisolone minimized the toxic effects of die drugs, and one dog lived a full year suffering only slightly from drug toxicity. At this point renal and, to a much lesser extent, hepatic transplantation had reached clinical threshold, and in December 1967 the first human cardiac homograft was performed in Cape Town, South Africa. The following mondi the Stanford clinical program was inaugurated, and its results constitute the material for die balance of this communication. Clinical Results As ofJanuary 1, 1978, 55 of 136 patients are alive from 1 month to 8 years after orthotopic homotransplantation of the heart at Stanford...