The Evolution of Infant Heart Transplantation

Human heart transplantation! Incredible idea! The sort of moonshot that inhabited the dreams of 1950s- and 1960s-era cardiac surgeons worldwide. Perhaps as many as two dozen or more centers were actually experimenting with the concept, and the science was becoming irrepressible. By the 1960s, heart transplantation (HTx) had become a virtual obsession in the cardiac surgical laboratory at Stanford University.1Lower R.R. Stoffer R.C. Shumway N.E. Homovital transplantation of the heart.J Thorac Cardiovasc Surg. 1961; 41: 196PubMed Google Scholar There, under the direction of Norman Shumway and Richard Lower, the operative procedure in experimental animals had become second nature. The great utility of hypothermia for graft preservation was emphasized. Indeed, the technical components of HTx were ready for prime-time. The Stanford investigators knew, however, that it was not just about the drama of lacing in a heart graft. Heart transplantation was about keeping the recipient alive, and well. It was about understanding and controlling the host immune response. It was about avoiding lethal recipient infection. Indeed, Stanford's laboratory animal studies were leading them in the direction of intelligent control of the recipient immune response. Then, suddenly, and quite unexpectedly, mega-news circled the globe that, on December 3, 1967, the first clinical heart allotransplant had occurred. Where? In Capetown, South Africa!2Barnard C.N. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Capetown.S Afr Med J. 1967; 41: 1271PubMed Google Scholar The surgical team was led by a gregarious and charismatic 44-year-old named Christiaan Barnard.3Cant G. The ultimate operation.Time. December 15, 1967Google Scholar He was assisted by his younger brother, Marius. They had orthotopically transplanted the heart of 15-year-old trauma victim, Denise Darvall, into the chest of 55-year-old Louis “Washy” Washkansky (Figure 1). The recipient was a wholesale grocer and an insulin-dependent diabetic. He had developed end-stage ischemic cardiomyopathy. Both donor and recipient were managed “on-pump.” Despite the fact that Washkansky died of pneumonia only 18 days later, the transplant was hailed a success. Success or not, the adult HTx genie was out of the bottle. But what about infants and children? That genie was somewhat reluctantly pulled from the bottle just 3 days later on December 6, 1967, in Brooklyn, New York.4Kantrowitz A. Haller J.D. Joos H. et al.Transplantation of the heart in an infant and an adult.Am J Cardiol. 1968; 22: 782-790Abstract Full Text PDF PubMed Scopus (175) Google Scholar A 19-day-old boy with severely symptomatic Ebstein's anomaly had progressed poorly following creation of an aortopulmonary shunt on his second day of life. He was transplanted orthotopically with the heart of a newborn anencephalic boy. The donor had been transferred from Philadelphia to New York after his parents had consented for organ donation. Forty-nine-year-old Adrian Kantrowitz, who had performed more than 150 experimental HTxs in puppies,5Kondo Y. Grädel F. Kantrowitz A. Homotransplantations of the heart in puppies under profound hypothermia: long survival without immunosuppressive treatment.Ann Surg. 1965; 162: 837Crossref PubMed Google Scholar led the operative team. Kantrowitz understood, better than most transplant investigators, the privileged nature of the neonatal immune response. The well-rehearsed, 4:25 a.m. transplant was accomplished “off-pump,” utilizing surface-induced hypothermia for both donor heart recovery, and for the 30 minutes of recipient circulatory arrest required for the transplant procedure. The infant graft and its recipient initially appeared to respond well. Sadly, however, the donor heart abruptly arrested 6.5 hours later, and the recipient died. A clear explanation for the sudden death was never identified. Although it would be 16 years before neonatal heart transplantation was again attempted, the dream persisted. A Columbia University team, headed by Eric Rose and Linda Addonizio, pushed the recipient age down to include James P. Lovette.6Addonizio L.J. Rose E.A. Cardiac transplantation in children and adolescents.J Pediatr. 1987; 111: 1034-1038Abstract Full Text PDF PubMed Scopus (32) Google Scholar The boy, who was from Denver, Colorado, was just 4.5 years old on June 9, 1984, the day he was transplanted. Lovette required retransplantation in 1989, and then went on to live a colorful and productive life until his untimely death (in his sleep) on June 29, 2005. He died just a couple of months before he was scheduled to begin his freshman year at the University of Buffalo Medical School. Soon after Lovette's transplant, a team headed by Douglas Behrendt at the University of Michigan7Boy 7, gets new liver; girl has heart surgery.New York Times. July 29, 1984Google Scholar moved the recipient age even further down when, on June 20, 1984, they performed HTx on Jonita Greer, a 2-year-old African-American girl from Detroit. The child initially did well, but suffered severe graft rejection about 6 months later. She required extracorporeal membrane oxygenation for circulatory support, and rabbit anti-thymocyte globulin (supplied by the Stanford group) for reversal of her intense immune response. She survived that event,8Behrendt D. Personal communication, June 25, 2009.Google Scholar but died on November 9, 1985. Going back to 1968, I had engaged in the HTx dream when, as a third-year medical student at Loma Linda University (LLU), I was invited to visit the Stanford University cardiac surgical research laboratory. I watched as the gifted young surgeon, Ed Stinson, performed HTx in one of their study animals. I was hooked, as during that year, worldwide enthusiasm for clinical HTx roared to life. But then, enthusiasm perished just as dramatically, as recipient after recipient died of graft rejection or sepsis, or both. Still, the Stanford team (to its credit) and a couple of allied centers in Virginia and Paris, France, pressed on. They were targeting young adult recipients. In 1975, I was finishing a pediatric cardiac surgical fellowship at The Hospital for Sick Children, Toronto. There, I had been introduced again and again to the devastating constellation of left heart anomalies, which had come to be labeled hypoplastic left heart syndrome (HLHS). It became clear to me that these neonates, with their naive immune systems and uniformly lethal heart disease, were custom-made for HTx. I became intensely focused on the idea of neonatal HTx. I returned to LLU to join the surgical faculty and to spearhead cardiovascular surgical research. By 1978, my LLU laboratory crew and I had begun orthotopically transplanting neonatal goat recipients with both allo (goat) and xeno (lamb and piglet) heart grafts. We corroborated Kantrowitz's finding of prolonged allograft survival without host immunosuppression. In 1981, we began using the new immunoregulatory agent called cyclosporine A. The substance was graciously supplied to us as a powder in large brown jars by Jean Borel of Sandoz Pharmaceuticals in Basel, Switzerland. Using cyclosporine A monotherapy, we witnessed normal host maturation, reproduction (Figure 2), and active survival into late adult years following neonatal orthotopic HTx.9Bailey L.L. Ze-Jian L. Roost H. et al.Host maturation after orthotopic cardiac transplantation during neonatal life.Heart Transplant. 1984; 3: 265-267Google Scholar In all, we gained laboratory experience with more than 200 neonatal recipients of HTx. We were poised to begin clinical trials, but understood that human infant allografts would be few and far between, if there would be any at all. Hence, we began studying infant baboons as a potential donor resource. Our immunology team, headed by Sandra Nehlsen-Cannarella, performed bench assays to identify homologies (between human neonates and infant baboons) that might aid us in the selection of a specific donor. We studied ex vivo perfusion of isolated baboon hearts using Type O human whole blood. We developed a donor panel (of infant female baboons) that was screened for a wide array of both simian and human infectious diseases. It was the summer of 1984. I had spent nearly a year in a variety of discussions with the LLU institutional review board (IRB). The IRB was evaluating our protocol for experimental clinical neonatal xenotransplantation using baboon donors. Multiple internal and external reviews had been accomplished, and I felt IRB approval would eventually be forthcoming. Then, news spread to America that, in London, on July 30, 1984, Magdi Yacoub had performed HTx on a 10-day-old baby named Hollie Roffey.10Youngest transplant patient dies in Britain after 28 days.New York Times. August 18, 1984Google Scholar Hollie had been born with HLHS, the same disease that I had targeted. Baby Hollie experienced a post-operative period complicated by necrotizing enterocolitis with perforation and hemorrhage following endomyocardial biopsy, which led to acute renal failure and, finally, respiratory insufficiency and death at 10:15 a.m. on August 18, 1984. She had lived 18 days with the heart of a 3-day-old Dutch baby. Although Hollie's death was enormously disappointing, neonatal HTx had, once again, become a clinical reality. In the fall of 1984, our team at LLU obtained IRB and university board approval to perform experimental neonatal HTx using immunologically selected infant baboons as donors. That approval coincided with the presence of a newly diagnosed, 2.3-kg infant with HLHS, named Stephanie Fae Beauclair. With the consent of both her parents, Baby Fae (as she became known) had orthotopic cardiac xenotransplantation on October 26, 1984, her 12th day of life.11Bailey L.L. Nehlsen-Cannarella S.L. Concepcion W. et al.Baboon-to-human cardiac xenotransplantation in a neonate.JAMA. 1985; 254: 3321-3329Crossref PubMed Scopus (286) Google Scholar Her immune response to the selected xenograft was managed, as in our laboratory animals, with cyclosporine monotherapy. Her initial recovery was uncomplicated (Figure 3, Figure 4), but alas, she died during the late evening of November 15, 1984, her 20th post-operative day. The exact causes of her death remain incompletely understood, although they included an unexpected widespread systemic vascular hemagglutination. Importantly, after 3 weeks, the xenograft contained scant cellular immune response, and deposition of complement and immunoglobulins that involved <15% of the examined myocardial sections. The total Baby Fae experience, however, was chronicled around the world and raised both heated debate and widespread awareness of the need for human infant donors. Indeed, within a week of Baby Fae's procedure, a 2-year-old donor became available for 8-month-old Sara Remington, a Houston baby with end-stage restrictive cardiomyopathy. Denton Cooley, who, on September 15, 1968 had attempted heart–lung transplantation in a 2-month-old,12Cooley D.A. Bloodwell R.D. Hallman G.L. et al.Organ transplantation for advanced cardiopulmonary disease.Ann Thorac Surg. 1969; 8: 30-46Abstract Full Text PDF PubMed Scopus (86) Google Scholar led the operative team that performed Sara Remington's November 1, 1984 HTx.13Cooley D.A. Frazier O.H. Van Buren C.T. et al.Cardiac transplantation in an 8-month-old female infant with subendocardial fibroelastosis.JAMA. 1986; 256: 1326-1329Crossref PubMed Scopus (21) Google Scholar Sara lived and developed well for 13 years, until her death in 1997.Figure 4Baby Fae, the neonate who was transplanted with the heart of a baboon, is seen recovering from her procedure. She lived 20 days with her xenograft.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Just over a year after the Baby Fae experimental xenotransplant, a potential neonatal donor, who was a victim of birth asphyxia, was identified in northern California. This discovery occurred only 3 days after the birth of a baby boy at LLU on November 16, 1985. The LLU baby weighed 2.8 kg, and had been diagnosed with HLHS. His first 3 days of life were spent in so-called “comfort care.” He had become acidotic and had not produced urine for 36 hours, yet he was still clinging to life. Consenting parents of both donor and recipient babies permitted transport of the intact donor to LLU for brain-death confirmation, organ recovery, and for transplantation of the recipient on November 20, 1985.14Bailey L.L. Nehlsen-Cannarella S.L. Doroshow R.W. et al.Cardiac allotransplantation in newborns as therapy for hypoplastic left heart syndrome.N Engl J Med. 1986; 315: 949-951Crossref PubMed Scopus (204) Google Scholar That recipient, Eddie Anguiano (Figure 5, Figure 6) presently lives with his family in Las Vegas, Nevada, where he works in one of the hotels. Eddie's HTx also generated considerable media attention, which, combined with the Baby Fae and Sara Remington experiences, led procurement agencies throughout North America to vigorously pursue neonatal and infant organ donors.Figure 6Eddie Anguiano, the first recipient of a successful neonatal heart transplant, pictured here in July 2009, with his original heart graft functioning well. His current immunoregulatory medications include tacrolimus and sirolimus.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In the decade that followed, HTx among young infants became the major area of growth with regard to the number of heart transplant procedures performed across North America. Complex univentricular heart disease became the key indication for HTx among neonates and young infants, whereas end-stage cardiomyopathy was the major indication for HTx among older children and teenagers.15Boucek M.M. Novick R.J. Bennett L.E. et al.The registry of the International Society of Heart and Lung Transplantation: second official pediatric report—1998.J Heart Lung Transplant. 1998; 17: 1141-1160PubMed Google Scholar William Norwood, then at the Children's Hospital, Boston, had also targeted HLHS in the late 1970s as an indication for palliative reconstruction, a 2-stage process ending in Fontan's physiology. In 1983, he reported the first successful outcome of an infant with HLHS who was managed with staged reconstruction.16Norwood W.I. Lang P. Hansen D.D. Physiologic repair of aortic atresia-hypoplastic left heart syndrome.N Engl J Med. 1983; 308: 23-26Crossref PubMed Scopus (576) Google Scholar Norwood (who had been supportive of our effort during the Baby Fae trial in 1984; Figure 7) and I were soon joined by numerous surgeons in America and around the world. Some of these surgeons helped to develop the HTx strategy for infants with HLHS and its equivalent, and some, indeed the majority, helped to develop Norwood's staged reconstruction for the same kind of univentricular heart disease. The tide began to shift in favor of Norwood's procedure in the mid-1990s. It had become apparent by then that the donor supply for newborns would be limited to fewer than 100 annually in North America. Also, outcomes of reconstruction, accomplished by that time in three stages, had become very competitive in experienced centers such as those in Michigan, Boston and Philadelphia, among others. Heart transplantation was then reserved for infants who were unsuitable for, or who had failed, reconstructive palliation at one stage or another, and for the occasional young infant with severe cardiomyopathy or cardiac neoplasm. The present decade has witnessed a gradual, if inevitable, transition in pediatric HTx toward infants and youngsters who have experienced one or more previous conventional heart operations.17del Nido P. Bailey L.L. Kirklin J.K. Surgical techniques in pediatric heart transplantation.in: Canter C.E. Kirklin J.K. ISHLT monograph series 2 Pediatric heart transplantation. Elsevier, Philadelphia2007: 83-102Google Scholar Included among current recipients are those who have had one or more stages of Norwood's procedure, but who are unsuitable (on the basis of inadequate physiology) for additional palliation, or those who have experienced all stages of palliative reconstruction and are failing Fontan's physiology. Today's recipients include those with primary end-stage cardiomyopathy, those who have developed cardiomyopathy superimposed on congenital heart disease, and those who require retransplantation. In addition, today's pediatric HTx candidates often require mechanical circulatory support (Figure 8) as a bridge to HTx.18Kirklin J.K. Mechanical circulatory support as a bridge to pediatric cardiac transplantation.Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2008; 11: 80-85Abstract Full Text Full Text PDF Scopus (17) Google Scholar Many of these transplant procedures (and the selection of appropriate potential recipients) have become technically challenging when compared with primary neonatal HTx. In today's world, infant pediatric recipients are coupled with fewer than two thirds of the donors made available by the nation's organ recovery agencies.19Bailey L.L. Razzouk A.J. Hasaniya N.W. et al.Pediatric transplantation using hearts refused on the basis of donor quality.Ann Thorac Surg. 2009; 87: 1902-1909Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar Should the utilization of available donors, or the absolute number of donors, increase, primary HTx for a variety of complex congenital heart anomalies would likely increase among neonates and young infants. Strategies to increase infant organ donation might include ABO-mismatched donor–recipient pairs,20West L.J. Pollock-Barziv S.M. Dipchand A.I. et al.ABO-incompatible heart transplantation in infants.N Engl J Med. 2001; 344: 793-800Crossref PubMed Scopus (340) Google Scholar the use of anencephalic organs, and perhaps again one day the use of animal organs. Until then, neonatal HTxs will occur infrequently. Secondary or salvage transplant procedures will continue to occupy a major role in HTx among infants and children. A number of patient names have been included in this article. All names have been in the public domain and, as such, individual releases were not obtained. I have no financial interest with any commercial entities represented in this manuscript.

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