Cardiac transplantation

Transplantation as the primary therapy for hypoplastic left heart syndrome emerged in the late eighties, primarily due to the work of Leonard Bailey at Loma Linda Medical Center.^{2, 3} Overcoming a myriad of medical, ethical, and political problems, Dr Bailey developed the concept of neonatal transplantation to produce unprecedented survival of children with hypoplastic left heart syndrome. His team reported survival of 85% at 5 years, associated with near normal growth and development, and these results were subsequently reproduced by others. Transplantation as a neonate seems to provide a survival advantage over those undergoing transplantation at older ages. Unfortunately, lack of donor organs, for a variety of reasons, was and continues to be the major limitation in the use of this option as primary therapy. Furthermore, the initially held concept of freedom from graft arteriopathy is no longer tenable, since up to one-sixth of patients are showing signs of significant coronary arterial lesions. Transplantation, nevertheless, continues to play a valuable role in the overall care of these critically ill patients with hypoplasia of the left heart.

Staged reconstruction

This approach has a long and colorful history. The pioneering work of Bill Norwood and others^4–6 in the early 1980s, utilizing a variety of technical modifications, set the stage for further refinements.^{7, 8} The current results for selected patients at experienced centers continue to demonstrate improved survival in the short and intermediate term. Conventional neonatal surgical techniques can be applied to a wide variety of patients creating the functionally univentricular physiology. The refinements in surgical technique continue.^{9, 10} Determination of the optimal shunt, as well as trials with newer materials for reconstruction of the aortic arch with less reactivity, is the current area of greatest interest. Perhaps the most profound reason for improved survival in recent years has been the understanding and application of the management of patients with functionally univentricular hearts in the perioperative period, as discussed elsewhere in this Supplement (see pp 52–60). Nevertheless, significant problematic issues, including deteriorating ventricular and valvar function, difficult arrhythmias, and morbidities such as protein losing enteropathy, continue to plague our patients. Many of these late problems associated with staged palliation will require treatment, with the need for further surgical interventions, including cardiac transplantation. Thus, for some patients, staged palliation may not simply be the initial three stages leading to establishment of the Fontan circulation, but a potential fourth stage involving cardiac transplantation.

Realizing there is no Holy Grail, all things considered, staged reconstruction is still felt by many to be the best primary treatment for the majority of patients with hypoplastic left heart syndrome. Large centers, previously committed to primary replacement therapy, now transplant only approximately one-tenth of their patients. It is likely, however, as further experience is gained, and learning curves mature, that critical analysis of outcomes will identify problematic subgroups, and hopefully dictate the optimal strategies for treating the specific subgroups. For example, the patient with a poorly functioning ventricle, and valvar insufficiency, may well be better served with primary transplantation.

Previous studies have suggested that the best surgical results are obtained in centers committed either to cardiac transplantation, or to staged palliation.¹ We would now disagree with this generalization. We feel that it is possible to offer both options for treatment in a single mature programme and obtain excellent results. Once a programme has progressed through its learning curve, excellent results may be achieved simultaneously with selective utilization of both strategies. Although the time needed to progress through the programmatic learning curve may be shortened by committing to one strategy, in our opinion a programme with suitable maturity can achieve excellent outcomes by employing both strategies.

The experience of the Congenital Heart Institute of Florida

At the Congenital Heart Institute of Florida, the largest programme dealing with surgical treatment of congenital cardiac malformations in Florida, we selectively offer three options for treatment of patients with hypoplastic left heart syndrome. The majority of our patients undergo staged palliation along the Norwood sequence, or cardiac transplantation, with most patients undergoing staged palliation and a minority being offered cardiac transplantation. In a much smaller group of patients, including those with the so-called “hypoplastic left heart complex”, critical aortic stenosis with left ventricular hypoplasia, and aortic atresia with ventricular septal defect, we opt for biventricular repair.

In 2002, our team performed 811 surgical operations for children and young adults with congenital cardiac disease, including 404 open heart procedures, with an overall operative mortality of 3.08%. Our volumes for 2003 are on pace to be higher. The majority of our neonates with hypoplastic left heart syndrome are now treated with staged palliation. Our operative strategy for the first stage has evolved over the last several years. Circulatory arrest is avoided, and typically used only during the atrial septectomy. The majority of our cases are performed with continuous antegrade cerebral perfusion, either through the aortopulmonary shunt in neonates with a small aorta, or through direct aortic cannulation, with the arterial cannula advanced into the brachiocephalic artery, in those with a larger ascending aorta, as described elsewhere in this Supplement (see pp 70–74). Flow of blood to the lungs is most commonly through a systemic-to-pulmonary arterial shunt, but we selectively use a conduit placed from the right ventricle to the pulmonary arteries in smaller neonates weighing less than 2500 g at the time of the first stage. We have performed 129 first stage palliations, with a 30 day survival of 82%. Since January 1, 2001, we have performed 53 first stage procedures, with 30 day survival of 89%.

In the second half of the 1990s, our programme used primary cardiac transplantation and staged palliation on an equal basis. We have now evolved to the more selective use of cardiac transplantation. Although the majority of our patients are now treated primarily through staged palliation, we offer transplantation in the setting of family preference, significant ventricular dysfunction, severe atrioventricular or ventriculo-arterial valvar regurgitation, and in patients suffering failure at any point in the process of staged palliation. We performed our first cardiac transplantation on May 21, 1995. We have now transplanted 64 children. Of these, 31 had hypoplastic left heart syndrome, 21 had cardiomyopathy, and the other 12 had various forms of postoperative complex congenital cardiac disease. We transplanted 8 as neonates, and 40 as infants. The overall 30-day survival after cardiac transplantation is 91%.

Biventricular repair for hypoplastic left heart syndrome has been performed in a much smaller group of patients. We remain very selective in choosing patients with hypoplastic left heart syndrome to undergo biventricular repair. Thus, only 7 children with hypoplastic left heart syndrome have undergone biventricular repair, with a survival of 71%, or five of seven. Of these, 3 deemed to have the hypoplastic left heart complex had reconstruction of the aortic arch and closure of septal defects. All three of these patients had small non-apex forming left ventricles, ductal-dependent flow to the descending thoracic aorta, and hypoplastic aortic and mitral valves. Of these 3 patients, 2 are currently alive and well with 2 ventricles. Unfortunately, 1 of these 3 neonates was found at surgery to have intrinsic stenosis of the mitral valve, and died after attempted biventricular repair. Of the remaining 3 surviving patients who underwent biventricular repair, 2 have had the first stage of the Norwood sequence along with a simultaneous Rastelli procedure, while the other underwent the first stage of the Norwood protocol and later had a Rastelli procedure. One patient died after insertion of an aortic homograft and a Konno procedure during the neonatal period, followed by replacement of the leaking aortic homograft and then cardiac transplantation.

Potential future advances in the treatment of hypoplastic left heart syndrome

A variety of future advances may further improve outcomes for children with hypoplastic left heart syndrome. These advances will likely affect both staged palliation and transplantation.

With regard to staged palliation, during our symposium we heard Mark Boucek suggest an interventional approach to initial palliation, with placement of a stent to maintain ductal patency, along with placement bilaterally of bands on the pulmonary arteries. Using this initial strategy, it may one day be feasible to achieve the Fontan circulation with resort to only one surgical procedure, namely a hemi-Fontan procedure with reconstruction of the aortic arch, with the completion again being achieved using a transcatheter approach.¹¹

As strategies for immunosuppression of children following transplantation evolve, more aggressive strategies may expand the donor pool and increase the use of donor organs. These intensive immunosuppressive protocols can facilitate both transplantation in children with elevated panel reactive antibody, and possibly infants receiving ABO incompatible transplants. Children with previous exposure to allograft material and blood transfusions are at high risk for sensitization and elevation of the panel reactive antibody. The Congenital Heart Institute of Florida recently reported that, with aggressive immunosuppression, children with elevated panel reactive antibodies are reasonable candidates for cardiac transplantation.^{12, 13} We have also begun to list infants for ABO incompatible donor hearts following the protocol developed at the Hospital for Sick Children, Toronto.¹⁴ We recently successfully performed our first and only ABO incompatible transplant to date in a recipient of blood type O, the universal donor with limited conventional options, into whom we intentionally transplanted a heart from a donor with blood type AB, the universal recipient within the conventional scheme. The protocol used for immunosuppression in this patient is similar to that used for our patients with increased levels of the panel reactive antibody. Both of these strategies of aggressive immunosuppression may help combat some problems associated with the shortage of donor organs.

Summary

In the modern era, it is possible to achieve programmatic balance in the approach to the treatment of hypoplastic left heart syndrome by offering staged palliation, transplantation, and in suitable cases, biventricular repair. Strategies for optimal selection should continue to improve and evolve.¹⁵ Overall, the current hope for survival, and excellent quality of life, for patients with hypoplastic left heart syndrome and other forms of functionally univentricular heart is better than ever before. Pioneering efforts allowed what we achieve today. Our challenge is to continue to improve the surgical and medical care of these patients towards normalization of survival and quality of life for future generations. These goals will be achieved by capitalizing on current advances in the field, and continuing to “push the envelope”, with research into new advances.