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Leading the world in infant heart transplantation
A strong interdisciplinary team approach

Dr. Bailey in surgery

Paul HolcHeart transplantation in newborn infants at Loma Linda University Medical Center (LLUMC) had its beginning in the research laboratory in 1978. This research involved transplantation between newborn animal models, most often cross-species heart transplantation between sheep and goats.1 World focus on the potential benefits of transplantation in this age group came to LLUMC in October 1984 when an infant, born with a lethal heart disease and known to the world as "Baby Fae," received the heart of a baboon when a human donor was not available.2 She lived only 20 days, but her legacy goes on, encouraging attempts at extending the life of these otherwise normal babies who would die for lack of functional heart muscle.

From that beginning, Loma Linda has become a world leader in infant heart transplantation. Long-term survival results are encouraging.3 Approximately 80 percent of these infants have survived surgery and are going on to experience childhood. Because of these results, LLUMC has developed a broad regional, national, and international patient referral base. However, the spectrum of patients undergoing heart transplantation at Loma Linda includes not only these young infants, but also many older children and adults.

A strong interdisciplinary team
A strong interdisciplinary team has emerged, actively dedicated to the success of heart transplantation. It was Leonard Bailey, MD, professor of surgery, who first chose to invest his energy in efforts to offer doomed children a second chance at life. The pediatric heart transplant team has since grown to include four cardiac surgeons, three general pediatricians, four pediatric cardiologists, a group of neonatologists, an immunologist, two infectious disease specialists, four nurse coordinators, two clinic nurses, and a host of other support personnel.

Eddie AnguianoLLUMC regularly serves as host to numerous transplant physicians and nurses who study this program as a model for their own institutions. Loma Linda plays a prominent role in national and international professional meetings and is an integral part of an international network of transplant professionals. The imagination of researchers and clinicians at LLUMC has been stimulated by this diverse group of individuals who are committed to improving the quality of life for these children and adults. LLUMC researchers have contributed heavily to both the scientific and lay literature in the field of heart transplantation. A number of patients have garnered extensive media interest.

LLUMC clinicians recognize and accept the responsibility for world leadership in this field. This sense of responsibility has spurred diverse research endeavors here. One important research frontier deals with the need to increase the donor pool. Growth of transplantation is limited by the paucity of human donors.

Addressing this problem has led researchers to look at the use of hearts from different species (xenografts) to serve as a bridge to transplantation (to span the time until a human heart would become available).

Other investigators have attempted to "reanimate" hearts (hearts that have already stopped beating). Organs used for transplantation come from brain dead individuals who have maintained their cardiac function. The concept of revitalizing hearts that have sustained a cardiac death would greatly enhance donor resources.

Prolongation of ischemic times in children
Experience at LLUMC has also led to a prolongation of ischemic times in children (the time outside the chest when the heart is not beating or being supplied with oxygen). Once the heart has been removed from a donor's chest, the heart muscle begins to die. In an adult, the maximum ischemic time before serious damage is sustained is thought to be about four hours. The time limit for an infant's myocardium was not known. The limited donor supply pushed LLUMC surgeons to extend the limits set for infants; ischemic times in excess of nine hours have been well tolerated in some infants. Thus another barrier to donor supply has been diminished. The LLUMC team has recovered pediatric hearts from all over the continental United States and Canada and as far away as Alaska and Puerto Rico. This long-distance procurement procedure sets LLUMC apart from other transplant centers. Studies are ongoing to assess the effects of prolonged ischemic times on function of these grafts in the recipients.4

Older heart transplant candidateThe severely limited supply of donors has led to the acceptance of greater size disparity between donor and recipient.5, 6 Newborn infants have received the hearts of babies up to three times their size by weight. Individuals are placed on heart transplant lists according to their blood type, weight, and medical urgency.

Another unique concern about heart transplantation in infants has been the question of graft growth. Will these hearts continue to grow? Dr. Bailey's research in animal models demonstrated that the heart would grow along with the recipient. That model has held true, as has been reported in the scientific literature by LLUMC's pediatric cardiologists.

A serious area of concern in the pre-transplant period involves being able to "buy" time for infants while they await an appropriate donor heart. Despite the best efforts to extend this waiting period, approximately 20 percent of all babies registered for transplantation have died before a suitable donor has been identified. This fact has become a stimulus to optimize and extend the waiting period. Because transplantation has now become a reasonable option for the treatment of otherwise uncorrectable heart disease, more infants are being referred for this therapy. Efforts must now be directed towards maintaining these infants while awaiting donor hearts. "Buying time" presents a great challenge to the caregivers. Most of these babies require that a remnant of their fetal circulation (ductus arteriosus) be kept open to provide circulation to both the lungs and the body.

girl/cupcake batterLLUMC clinicians are looking at ways to noninvasively monitor rejection of the heart grafts. In adults, endomyocardial biopsies are the gold standard for determination of rejection. This involves inserting a scissor-like device into the right heart and taking little "snippets" for evaluation under a microscope. Because infants have tiny hearts and because venous access is limited, LLUMC physicians deemed it impractical and potentially hazardous to rely on biopsy to reveal rejection. So a variety of non-invasive parameters have been developed and these are constantly being assessed.7, 8, 9 , 10

Efforts to develop other indicators are ongoing. A digitized echocardiogram has proven a reliable tool in monitoring for rejection in addition to EKG parameters.

Treatment modalities
Danica ReynoldsTreatment modalities against rejection have been under constant evaluation. A current research protocol utilizes anti-thymocyte globulin for prophylaxis against rejection and for use as a rescue agent in severe rejection. There is ongoing research on the use of cyclosporine and other new immunosuppressive agents. An increased incidence of coronary artery disease has plagued adult recipients of heart transplants. Analysis of the degree of coronary artery disease in infant recipients is ongoing.11 The mechanism for the development of coronary artery disease is unknown, but is thought to be immune mediated. All pediatric recipients are also evaluated at regular intervals for growth and development.

Questions for the future
The future seems bright for transplant recipients but questions remain. Will there be sufficient improvement in immunoregulation to arrive at a point of immune tolerance where heart transplant recipients would be free from chronic drugs and would not be susceptible to infection? Will donor resources be so enhanced that few patients will die waiting for a replacement heart? Will more specific and sensitive markers for rejection be developed? Can there be greater sensitivity in the measurement of coronary artery changes?

These and dozens of other questions--some not yet asked--will continue to challenge the scientists and clinicians who labor at the frontier of heart transplantation, offering the only hope we see today for hundreds of otherwise healthy infants, children, and adults.

1Bailey LL, Lacour-Gayet F, Perier P, et al: Orthotopic Cardiac Transplantation in the Neonate: Survival Studies in a Goat Model. In Proceedings of Beijing Symposium on Cardiothoracic Surgery, Lyman A. Brewer III International Surgical Society, (Beijing and New York: China Academic Publishers, John Wiley & Sons), PP 342-350, 1982.
2Bailey LL, Gundry SR, Razzouk AJ, et al: Bless the babies: One hundred fifteen late survivors of heart transplantation during the first year of life. The Journal of Thoracic and Cardiovascular Surgery 105: 805-815, 1993.
3Bailey LL: Another Look at Cardiac Xenotransplantation, Journal of Cardiac Surgery Vol. 5: No 3, Dec 1990.
4Kawauchi M, Gundry SR, Alonso de Begona J, Fullerton DA, Razzouk AJ, Boucek M, Kanakriyeh M, and Bailey LL: Prolonged Preservation of Human Pediatric Hearts: Correlation of Ischemic Time and Subsequent Function. Surg Forum 76: 211-212, 1990.
5Boucek MM, Kanakriyeh MS, Mathis SM, et al: Cardiac Transplantation in infancy: An Evaluation of Donors and Recipients, J Peds 116:171-176, 1990.
6Kanakriyeh MS, Mathis CM, Boucek MM, McCormack J, Gundry SR, and Bailey LL: Effect of Donor Size on Graft Function Post Infant Heart Transplantation. J of Heart Transplantation 9(1): 77 (92), Jan/Feb 1990.
7Kanakriyeh MS, Mullins CE, Parisi F, Bailey LL: Late Hemodynamic Results after Orthotopic Heart Transplantation for Hypoplastic Left-heart Syndrome. Cathet Cardiovasc Diagn 18(4): 232-236, 1989.
8Johnston JK, Sakala EP, and the Loma Linda University Heart Transplant Group: Neonatal Cardiac Allotransplantation Facilitated by In-Utero Diagnosis of Hypoplastic Left-Sided Heart Syndrome. West J Med 152(1): 70-72, 1990.
9Johnston JK, Mathis CM: Determination of Rejection using Non-Invasive Parameters Following Cardiac Transplantation in Very Early Infancy - The Loma Linda Experience. Prog Cardiovasc Nurs 3(1): 13-18, 1988.
10Chandrasekaran K, Bansal R, Greenleaf J, et al: Early Recognition of Heart Transplant Rejection by Backscatter Analysis from Serial 2D ECHOS in a Heterotopic Transplant Model. J Heart Transplant 6: 1-7, 1987.
11Bailey LL, Bui RB, Nehlsen-Cannarella SL, et al: Surveillance Techniques in Infant Heart Transplantation. Heart and Heart-Lung Transplantation Update Italy. Proceedings of the First International Course on Heart, Heart-Lung, Liver and Pancreas Transplantation, USES Edisioni Scientifiche Firense: 89-94, 1988.
12Kanakriyeh MS, Boucek MM, Thompson R, Petry EL, McCormack J, Zuppan GW, Hauck AJ, Mathis C, Gundry SR and Bailey LL: The Incidence of Coronary Artery Disease after Pediatric Heart Transplantation, JACC 15(2): 174A, February 1990.


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