Pediatric Heart Transplantation

Human orthotopic heart transplantation began on December 3, 1967 when Drs. Chistiaan and Marius Barnard transplanted the heart of a 15-year-old trauma victim into a 55-year-old recipient in Capetown, South Africa. ^[4] Three days later, on December 6, 1967, Dr. Adrian Kantrowitz performed the first orthotopic heart transplantation in a neonate in New York. ^[5] The infant died of a cardiac arrest 6.5 hours after receiving the transplant.

The transplantation of infants would cease for 16 years before being attempted again. ^[6] Over those 16 years, adult heart transplantation became routine and the lower age limit of recipients declined. By 1984, the medical field was again ready for infant transplantation. For the next 10 years, orthotopic heart transplantation became an option for primary therapy in neonates with hypoplastic left heart syndrome. ^[7]  A shift toward palliation of complex congenital heart disease took place at this time, due to the limited number of infant donors.

At the same time, cardiac xenotransplantation in animal models was improving. On October 26, 1984, the first human cardiac xenotransplant took place, performed by Dr. Leonard L. Bailey at Loma Linda University in California. ^[8] A baboon heart was transplanted into a 12-day old neonate with hypoplastic left heart syndrome. She died after 20 days. Recent research has focused on the use of organs from genetically modified pigs for xenotransplantation. See Xenotransplantation.

Generally, conditions that might necessitate heart transplantation may be divided into the following 4 categories:

1. Errors in the formation of the heart (structural/anatomic defects and cardiomyopathies)
2. Cardiac tumors
3. Infections
4. Toxins (endogenous or exogenous) that damage the myocardium

Many of the congenital anomalies, including congenital cardiomyopathy, have specific associated chromosomal abnormalities. An example is the so-called Catch-22 syndrome, a 22q11 band deletion associated with DiGeorge syndrome and interrupted aortic arch.

More specifically, the indications for pediatric heart transplantation include the following:

• Cardiomyopathy (ie, dilated, hypertrophic, non-compaction, arrhythmogenic, or restrictive)

• Anatomically uncorrectable congenital heart disease (eg, hypoplastic left heart sydrome, pulmonary atresia with intact ventricular septum with right ventricular–dependent coronary circulation, transposition of the great arteries with single ventricle and heart block, and severely unbalanced atrioventricular septal defects)

• Potentially correctable congenital heart disease associated with greatly increased operative risk (eg, severe Shone complex, interrupted aortic arch and severe subaortic stenosis, critical aortic stenosis with severe endocardial fibroelastosis, and Ebstein anomaly in a symptomatic newborn)

• Refractory heart failure after previous cardiac surgery due to ventricular dysfunction or valve disease

• Complications of "failing Fontan" physiology (ie, protein-losing enteropathy, plastic bronchitis, liver cirrhosis/dysfunction, cyanosis due to pulmonary arteriovenous malformations)

• Significant cardiac allograft vasculopathy or chronic graft dysfunction of a previous heart transplant

• Unresectable symptomatic cardiac neoplasms

• Refractory ventricular arrhythmias

The pathophysiology of conditions that necessitate heart transplantation is obviously as varied as the conditions themselves. However, the basic abnormality underlying each condition is the inability of the pump to supply adequate perfusion for end-organ health and well-being.

The severity of heart failure in pediatric heart disease is divided into 4 stages, as follows:

• Stage A - At risk for developing heart failure

• Stage B - Abnormal cardiac structure or function but no symptoms of heart failure

• Stage C - Abnormal cardiac structure or function and past or present symptoms of heart failure

• Stage D - Abnormal cardiac structure or function, requiring continuous intravenous (IV) infusion of inotropes or prostaglandin E₁ (to maintain patency of the patent ductus arteriosus) or requiring mechanical ventilatory or mechanical circulatory support

The American Heart Association has published recommended indications for cardiac transplantation in children with heart disease. ^[9]

Dilated cardiomyopathy

At present, there are no specific guidelines outlining hemodynamic, echocardiographic, and clinical criteria for the advisability of cardiac transplantation in children with dilated cardiomyopathy. Because the risk of death is highest during the first 3 months after presentation, decisions regarding transplantation should be made relatively soon after diagnosis. Risk factors for poor outcome include the following:

• Age greater than 5 years at presentation
• Familial cardiomyopathy and endocardial fibroelastosis
• Severe persistent depression of left ventricular systolic function (shortening fraction < 0.12 and ejection fraction < 0.20)
• Severe mitral regurgitation
• Persistent left ventricular end-diastolic pressure higher than 20 mm Hg
• Mural thrombus on echocardiography
• Globular (rather than elliptical) left ventricular shape
• Complex atrial and ventricular arrhythmias

Any child who presents with these risk factors should be considered for early referral for transplantation.

Hypertrophic cardiomyopathy

The clinical presentation of hypertrophic cardiomyopathy varies widely, as does the natural history. Risk factors for poor prognosis include the following:

• Presentation in infancy
• Syncopal symptoms
• Family history of progressive hypertrophic cardiomyopathy
• Sustained ventricular tachycardia
• Mitral regurgitation
• Development of atrial fibrillation

Heart transplantation is generally reserved for patients who are symptomatic and who have either multiple risk factors for poor survival or impaired systolic function marking the onset of advanced stages of disease.

Restrictive cardiomyopathy

In children with restrictive cardiomyopathy, survival rates are generally poor, with a median time from diagnosis to death of about 1 year. ^[10] A tendency for a progressive increase in pulmonary vascular resistance also exists. Early referral for cardiac transplantation is indicated. ^[11]

Arrhythmogenic cardiomyopathy (arrhythmogenic right ventricular dysplasia)

Progressive biventricular dysfunction can occur, leading to end-stage heart failure and refractory arrhythmia, and may require cardiac transplantation.

Left ventricular non-compaction cardiomyopathy

 Progressive left ventricular dysfunction and dilation occur, leading to end-stage heart failure, and may require cardiac transplantation.

Anatomically uncorrectable congenital heart disease

Anatomically uncorrectable congenital heart disease is understood to include any cardiac malformation for which a 2-ventricle repair is not possible or advisable. Cardiac transplantation is recommended for certain patient subsets with poor short-term or intermediate survival rates.

A special case is the infant with HLHS. ^[12] There are 2 currently recommended options:

• A series of palliative operations that lead to a later Fontan procedure (also known as the Norwood operation)
• Cardiac transplantation

Each option has pros and cons. The staged surgical repair requires multiple operative procedures and ends with single-ventricle physiology; transplantation requires lifelong immunosuppression. Both options are palliative. With both options, the child is likely to require transplantation or retransplantation at some point in the future.

For infants with HLHS, cardiac transplantation should be considered more appropriate if the mortality with the Fontan procedure is expected to be 20% or higher. Factors that increase the Fontan mortality include the following:

• Significant systemic atrioventricular (AV) valve insufficiency
• Moderate (but not severe) elevation of pulmonary vascular resistance
• Depressed systemic ventricular function

Complications of "failing Fontan" physiology

Several complications of single ventricular Fontan physiology may occur, necessitating cardiac transplantation

• End-stage heart failure due to ventricular dysfunction and/or AV valve regurgitation
• Protein-losing enteropathy
• Plastic bronchitis
• Liver cirrhosis/dysfunction
• Cyanosis due to pulmonary arteriovenous malformations

Correctable conditions associated with high operative risk

Patients with potentially correctable congenital heart disease who are at greatly increased operative risk should also be considered for transplantation. This decision depends to some extent on the surgical results at specific institutions. Lesions that may fall into this category include the following:

• Complex truncus arteriosus (with severe truncal valve insufficiency, interrupted aortic arch, or coronary artery anomalies)
• Some severe forms of Shone complex
• Complex interrupted aortic arch

Cardiac tumors

Because primary cardiac tumors rarely metastasize, they do not constitute a contraindication for transplantation. Transplantation is indicated if the tumor is unresectable and is confined to the portion of the heart removed at transplantation; major associated congenital anomalies must not be present. In children with tumors associated with tuberous sclerosis, spontaneous regression is common. Transplantation should be considered if severe left ventricular outflow obstruction, hemodynamic compromise, or life-threatening arrhythmias are present.

Intractable arrhythmia

Intractable arrhythmia, typically ventricular, can lead to ventricular dysfunction and end-stage heart failure necessitating transplantation.

The major anatomic contraindication for heart transplantation in pediatric patients is the presence of small pulmonary arteries that cannot be satisfactorily surgically enlarged. Other features that could preclude safe heart transplantation include subsets of anomalous pulmonary venous connection without a suitable pulmonary venous confluence for direct anastomosis to the donor left atrium.

Pediatric heart transplantation has few absolute contraindications. Many children who are quite ill can make a remarkable recovery once a new heart restores adequate perfusion. However, the following are considered incompatible with successful transplantation:

• Irreversible elevated pulmonary vascular resistance (> 6 Wood units/m ² or a transpulmonary gradient > 15 mm Hg)
• Diffuse hypoplasia of the central branch pulmonary arteries
• Total anomalous pulmonary venous connection without pulmonary venous confluence
• Ectopia cordis
• Active systemic infection
• Infection with HIV or chronic active hepatitis B or C
• Malignancy that is not cured or is of recent onset
• Severe primary kidney or liver dysfunction
• Multiorgan system failure
• Major central nervous system (CNS) abnormality
• Severe dysmorphisMarked prematurity (< 36 wk)
• Small size (< 1800 g)
• Positive finding on drug screen
• Lack of family support systems

In the current era of heart transplantation, the expected 1-year survival rate is 80-90%, the 2-year survival rate is 80-85%, and the 5-year survival rate is approximately 70-80% in experienced centers. ^[13] Beyond 10 years, a slow attrition rate continues, and a number of children require an additional transplant procedure, usually because of graft vasculopathy. Mortality while waiting for a donor organ is additive to these survival figures.

Overall 15-year survival of 41% after initial heart transplantation was reported in a single-institution analysis of outcomes in children with congenital heart disease. ^[14]  

Godown and colleagues examined the effects of body mass index (BMI) on waitlist mortality in a study of 2,712 children waitlisted for heart transplantation between 1997 and 2011. BMI percentile > 95% or < 1% was an independent risk factor for waitlist mortality in children with cardiomyopathy, but not in those with congenital heart disease. BMI did not affect post-transplant outcomes, regardless of the indication for transplantation. ^[15]

Infants who undergo transplantation in the first month of life appear to have a survival advantage over infants who undergo transplantation during the remainder of the first year of life. This is likely related to immunologic and nonimmunologic factors.

Twenty-year median survival in the infant and older child has been achieved, with some children surviving greater than 30 years with their first graft. Longer-term prognosis is unknown. Significant numbers of children are now entering the second decade after their transplantation and are generally in good health.

Historically, patients with a prior Fontan procedure for complex congenital heart disease have been considered at higher risk for death after heart transplant. However, more recently, Fontan patient survival has significantly improved, with 1-year survival comparable to non-Fontan  patients with congenital heart disease (89% vs 92%, respectively). ^[16]

Two thirds of infant recipients older than 10 years are described as developmentally normal by their parents. More formal psychometric testing shows that infant heart transplant recipients score lower on intelligence quotient (IQ) testing than healthy controls do, with about a 10-point decrement in standardized testing scores. These results are similar to those seen in infants undergoing comparable procedures for congenital heart disease.

In the absence of long-term higher-dose steroid therapy, children grow appropriately after heart transplantation. ^[17] Data indicate that they progress through puberty in a normal fashion. In the absence of repeated graft rejection or graft vasculopathy, cardiac function and exercise tolerance are normal.

The biggest challenge is the long-term prevention or treatment of graft vasculopathy. Retransplantation at some later date is probably inevitable for most, if not all, children who have undergone heart transplantation. If the vasculopathy is diagnosed in a timely manner, these children tolerate the second transplant well, with better survival rates than for their primary transplant.  However, retransplantation in general, especially when required early after primary transplantation, leads to inferior survival with the second graft and earlier development of post-transplant co-morbidities (eg, cardiac allograft vasculopathy, rejection, renal dysfunction). ^[18]

The role of calcium channel blockers, statins, anti-platelet agents, and newer immunosuppressive agents (eg, mycophenolate mofetil, sirolimus, everolimus) in the prevention or treatment of vasculopathy remains to be determined.

In children with cardiomyopathy who have structurally normal extracardiac circulatory systems, the transplantation procedure is similar to adult heart transplantation. In children with structural congenital heart disease, the arterial and venous malformations can pose a challenge to the success of the transplant procedure itself. Additional donor structures, such as the aortic arch and branch pulmonary arteries, may be needed to enable transplantation in a child with hypoplasia of the aortic arch or branch pulmonary arteries. Venous anomalies, such as a left-sided superior or inferior vena cava, may necesitate routing of venous blood to the appropriate location in the chest to complete the required anastamoses.