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Pediatric Heart Transplantation

  • Author: Richard E Chinnock, MD; more...
 
Updated: Nov 13, 2014
 

Background

Heart transplantation in infants and children is now accepted therapy. According to the registry of the International Society for Heart and Lung Transplantation, approximately 350-500 pediatric heart transplantation procedures are performed worldwide each year, representing about 12% of the total number of heart transplants performed. In 2012, 512 heart transplants were performed in children worldwide. The proportion of pediatric transplant patients by recipient age has remained relatively stable for over last decade.[1]

Congenital malformations are still the most common indication for infant heart transplantation. Congenital cardiomyopathy occurs in approximately one in 10,000 live births. The most common indication for heart transplantation in older children is cardiomyopathy. The number of children who have failing cardiac function late after palliative surgery for congenital heart disease is increasing. An important example is so-called failed Fontan.

An estimated 10% of congenital heart disease cases have been deemed uncorrectable. One of the most common indications for infant heart transplantation had been hypoplastic left heart syndrome (HLHS), which occurs in about one in 6000 live births. HLHS has diminished as an indication for heart transplantation because of the limited donor supply and the improvements that have been achieved in the surgical palliative approach (ie, the Norwood procedure, with or without the Sano modification).

Infants with serious congenital heart disease generally present in the newborn period with varying degrees of cyanosis, tachypnea, tachycardia, dysrhythmias, poor perfusion, feeding intolerance, and other symptoms of heart failure. Symptoms of heart failure, either rapid or slow onset, are associated with the cardiomyopathies. Children with tumors may present with congestive heart failure (CHF) or with syncope or cardiac arrest due to arrhythmias. An increasing number of congenital lesions are diagnosable by means of fetal ultrasonography.

Survival in excess of 20 years after pediatric heart transplantation has been achieved. Most programs now report that more than 70% of their recipients survive at least 5 years. However, although an additional 5 years of life is important for all, the goal of pediatric heart transplantation is to provide as much of a normal life span for these children as possible.

The donor supply remains inadequate. Improved public and physician awareness of donor issues is the most important factor in increasing donor supply because many potential donors are not identified as such. Other more innovative and controversial sources of donors include resuscitation of asystolic donors and the use of xenografts.

For patient education resources, see the Heart Center, as well as Heart and Lung Transplant.

Disease processes necessitating heart transplantation

Generally, conditions that might necessitate heart transplantation may be divided into 4 categories: (1) errors in the formation of the heart, (2) cardiac tumors, (3) infections, and (4) toxins (either endogenous or exogenous) that damage the myocardium. Many of the congenital anomalies, including congenital cardiomyopathy, are now known to 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, these conditions include the following:

  • Cardiomyopathy (ie, dilated, hypertrophic, or restrictive)
  • Anatomically uncorrectable congenital heart disease (eg, HLHS, pulmonary atresia with intact ventricular septum plus sinusoids, congenitally corrected 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
  • Significant cardiac allograft vasculopathy or chronic graft dysfunction of a previous heart transplant
  • Unresectable symptomatic cardiac neoplasms

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 E 1 (to maintain patency of the patent ductus arteriosus) or requiring mechanical ventilatory or mechanical circulatory support
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Indications

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
  • The presence of 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. A tendency for a progressive increase in pulmonary vascular resistance also exists. Early referral for cardiac transplantation is indicated.[2]

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 subsets with poor short-term or intermediate survival rates.

A special case is the infant with HLHS.[3] 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 all patients considered for the Fontan pathway, 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 significant systemic atrioventricular (AV) valve insufficiency, moderate (but not severe) elevation of pulmonary vascular resistance, and depressed systemic ventricular function.

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 complex truncus arteriosus (with severe truncal valve insufficiency, interrupted aortic arch, or coronary artery anomalies), some severe forms of Shone complex, and 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.

The American Heart Association has published recommended indications for cardiac transplantation in children with heart disease.[4]

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Contraindications

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 renal or hepatic dysfunction
  • Multiorgan system failure
  • Major central nervous system (CNS) abnormality
  • Severe dysmorphism
  • Marked prematurity (< 36 wk)
  • Small size (< 1800 g)
  • Positive finding on drug screen
  • Lack of family support systems
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Outcomes

In the current era, 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. 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.

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.[5]

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 survival in the infant and older child has been achieved. Longer-term prognosis is unknown. Significant numbers of children are now entering the second decade after their transplantation and are generally in good health.

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.[6] 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 in the long term is preventing or treating 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 the primary transplant.

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

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Contributor Information and Disclosures
Author

Richard E Chinnock, MD Medical Director of Pediatric Heart Transplant Program, Professor and Chair, Department of Pediatrics, Loma Linda University School of Medicine and Children's Hospital

Richard E Chinnock, MD is a member of the following medical societies: American Academy of Pediatrics, American Heart Association, American Medical Association, American Society of Transplantation, California Medical Association, Western Society for Pediatric Research, Transplantation Society, International Society for Heart and Lung Transplantation, Society for Pediatric Research

Disclosure: Received grant/research funds from Roche Pharmaceuticals for other.

Acknowledgements

Richard G Ohye, MD Head, Division of Pediatric Cardiovascular Surgery; Program Director, Pediatric Cardiac Surgery Fellowship, University of Michigan Medical Center

Richard G Ohye, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Thoracic Surgery, American College of Cardiology, American College of Chest Physicians, American College of Surgeons, Association for Academic Surgery, Congenital Heart Surgeons Society, International Society for Heart and Lung Transplantation, Society of Thoracic Surgeons, and Society of University Surgeons

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
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  2. Fenton MJ, Chubb H, McMahon AM, et al. Heart and heart-lung transplantation for idiopathic restrictive cardiomyopathy in children. Heart. 2006 Jan. 92(1):85-9. [Medline].

  3. Chrisant MR, Naftel DC, Drummond-Webb J, et al. Fate of infants with hypoplastic left heart syndrome listed for cardiac transplantation: a multicenter study. J Heart Lung Transplant. 2005 May. 24(5):576-82. [Medline].

  4. Canter CE, Shaddy RE, Bernstein D, et al. Indications for heart transplantation in pediatric heart disease: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology, Cardiovascular Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007 Feb 6. 115(5):658-76. [Medline]. [Full Text].

  5. Godown J, Donohue JE, Yu S, Friedland-Little JM, Gajarski RJ, Schumacher KR. Differential effect of body mass index on pediatric heart transplant outcomes based on diagnosis. Pediatr Transplant. 2014 Nov. 18(7):771-6. [Medline].

  6. Cohen A, Addonizio LJ, Softness B, et al. Growth and skeletal maturation after pediatric cardiac transplantation. Pediatr Transplant. 2004 Apr. 8(2):126-35. [Medline].

  7. Moll S, Pascual M. Humoral rejection of organ allografts. Am J Transplant. 2005 Nov. 5(11):2611-8. [Medline].

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  13. Behera SK, Trang J, Feeley BT, Levi DS, Alejos JC, Drant S. The use of Doppler tissue imaging to predict cellular and antibody-mediated rejection in pediatric heart transplant recipients. Pediatr Transplant. 2008 Mar. 12(2):207-14. [Medline].

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  20. Dipchand AI, Edwards LB, Kucheryavaya AY, Benden C, Dobbels F, Levvey BJ, et al. The registry of the international society for heart and lung transplantation: seventeenth official pediatric heart transplantation report-2014; focus theme: retransplantation. J Heart Lung Transplant. 2014 Oct. 33(10):985-95. [Medline].

 
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View of the recipient's chest after the heart is removed, with the patient on cardiopulmonary bypass.
 
 
 
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