Fig. 15.1
Operative details of the first pediatric heart transplant (Reused with permission from Mendeloff [69])
Fig. 15.2
The first pediatric heart transplant: (a) the donor (b) the recipient (Reused with permission from Mendeloff [69])
Children who undergo heart transplantation show excellent outcomes. The median life expectancy is over 15 years after the first year post-transplantation [4]. Despite this, wait list mortality is higher than for any other solid organ. Infant risk of death has been reported as high as 25% [4]. This is, in part, due to the lack of available mechanical circulatory support devices for this age-group.
The Pediatric Heart Transplant Study (PHTS) was established in 1993 by six centers with the objective of advancing our understanding of the specialty by keeping an event-driven database that could be used for clinical research. The organization continues and notably produces data on outcomes and risk factors.
Indications for Heart Transplantation
Cardiomyopathies and congenital heart defects are the most common indications for pediatric heart transplantation. The proportions vary by age, with approximately half of surgeries done for congenital heart disease (CHD) and slightly less than half for cardiomyopathy in children under 11. In children 11–17 years old, two-thirds of patients have cardiomyopathy and a quarter have CHD pre-transplant. The number of pediatric heart transplants recorded by the registry of the International Society for Heart and Lung Transplantation (ISHLT) in the United States has remained relatively constant at between 400 and 600 from 1991 to 2013. The figure from 2013 represented 13% of total heart transplants, including adults, reported to the registry [4]. Donor shortages and the lack of mechanical circulatory support in the infant population are factors impeding the number of operations taking place. The Pediatric Committee of the American Society of Transplantation [5] and a consensus group of the American Heart Association (AHA) [6] broadly agree on the indications of heart transplantation in children. The procedure is considered when life expectancy is less than 2 years or when quality of life is poor. Controversy surrounds HLHS as an indication given wait list times result in high mortality [7]. Many centers advocate palliative surgical techniques such as the Norwood and Fontan procedures instead [8].
Cardiomyopathies
Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM) is the most common cardiomyopathy in children, accounting for more than half of cases. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. It can be congenital or acquired. Familial causes were previously thought to be rare but it is now known that up to 50% of cases involve patients with an underlying genetic abnormality [9]. The causative genes encode for proteins found in the cytoskeleton and sarcomere. Viruses, and in particular adenoviruses, are a significant etiology [10]. Of note is DCM secondary to Adriamycin given that malignancy can be a contraindication to transplantation. The incidence of DCM in the pediatric population is 0.57 per 100,000 per year with boys being slightly more susceptible than girls [11].
The dilated ventricle increases the stress exerted on the chamber wall. Mitral regurgitation and arrhythmias are common. Children may develop heart failure and present with anorexia and weight loss. Clinical signs include tachycardia, jugular venous distention, hepatomegaly and a systolic murmur consistent with mitral regurgitation. The echocardiograph findings include left ventricular dilation with either a low ejection fraction or fractional shortening. There may be mitral regurgitation or a pericardial effusion. The electrocardiograph (ECG) may show sinus tachycardia, pathological Q waves, bundle-branch block, heightened QRS complexes, atrial fibrillation or ventricular arrhythmias (see Fig. 15.3). The biomarker brain natriuretic peptide (BNP) can be useful when trying to distinguish lung disease from heart failure or for monitoring disease progression. An endomyocardial biopsy (EMB) is done to determine the etiology of DCM. This is necessary for identifying underlying pathologies that require different management plans such as sarcoidosis or the glycogen storage diseases. The biopsy sample can be used to detect viral genetic material with PCR (Table 15.1).
Fig. 15.3
ECG of a patient with DCM and decompensated heart failure (Reused with permission from Jefferies and Towbin [70])
Table 15.1
Genetic causes of dilated cardiomyopathy by chromosome locus
Locus | Gene | Protein | Protein location |
|---|---|---|---|
Xp21.2 | DMD | Dystrophin | Cytoskeleton/SL |
Xq28 | G4.5 | Tafazzin | Phospholipid |
1q12 | TNNI1 | Cardiac troponin I | Sarcomere |
1q32 | TNNT2 | Cardiac troponin type 2 | Sarcomere |
2q31 | TTN | Titin | Sarcomere |
2q35 | DES | Desmin | Cytoskeleton |
5q34 | SGCD | δ-sarcoglycan | Cytoskeleton/SL |
6q12–q16 | CMD1K | Unknown | Unknown |
6q22.1 | PLN | Phospholamban | Calcium |
9q13-q22 | CMD1B | Unknown | Unknown |
9q22-q31 | SEMA4D | Unknown | Unknown |
10q22.1 | MYPN | Myopalladin | Sarcomere |
10q22.3–23.2 | ZASP/Cypher (LDB3) | LIM domain binding protein 3 | Sarcomere |
1q42–q43 | α2-actinin | ACTN | Sarcomere |
10q22.1–q23 | VCL | Metavinculin | Cytoskeleton |
10q23.22 | ANKRD1 | CARP | Sarcomere |
10q25.3 | RBM20 | RNA binding motif protein 20 | Unknown |
11p11.2 | MYBPC3 | Myosin binding protein C | Sarcomere |
11p15.1 | CSRP3 | Muscle-LIM protein | Sarcomere |
14q11.2–q13 | MYH7 | β-myosin heavy chain | Sarcomere |
15q11–q14 | ACTC1 | Cardiac actin | Sarcomere |
15q22.1 | TPM1 | α-tropomyosin | Sarcomere |
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the second most common cardiomyopathy seen in children. It is the most common form of Mendelian inherited heart disease, and it is often found to be the underlying pathology in young people who suffer from sudden cardiac death [12]. Several gene mutations have been described, with most encoding for proteins found in the sarcomere. Unlike DCM and restrictive cardiomyopathy there are no acquired forms of the disease. HCM less often leads to transplantation, with only 5% of patients carrying the diagnosis pre-operatively [6].
HCM is characterized by asymmetric, concentric rings of hypertrophy. There is gross hypertrophying of the heart, predominantly occurring at the inter-ventricular septum. On a microscopic level, cardiac myocytes are in disarray. The anatomical changes may result in left ventricular outflow obstruction, termed hypertrophic obstructive cardiomyopathy.
The clinical presentation of HCM is highly variable. Most patients are asymptomatic with some experiencing chest pain and dyspnea. Palpitations and pre-syncopal episodes can occur. Syncope is rare but is a risk factor for sudden cardiac death (SCD) [13]. Children under the age of 1 often present with congestive heart failure. HCM is infamous for its insidiousness and its tendency to present with SCD in young athletes. The ECG may show atrial fibrillation or a supraventricular arrhythmia. HCM is benign relative to other indications for transplantation with only a 1% annual mortality rate [14]. Holter monitoring is useful for identifying arrhythmias which carry an increased risk of SCD. Genetic testing for inborn errors of metabolism may be warranted to exclude them as a cause of cardiac hypertrophy. Given the autosomal dominance of HCM, screening of siblings is advisable.
Treatment depends on the severity of symptoms and the presence of risk factors for SCD. Patients with chest pain and dyspnea are treated medically with beta-blockers and calcium channel antagonists. The detection of ventricular arrhythmias warrants the placement of an implantable cardioverter defibrillator (ICD). Patients with severe left ventricular outflow obstruction may undergo myomectomy, although this is only for symptom relief and does not slow disease progression, nor does it prevent potentially fatal arrhythmias. Heart transplantation is not a first-line therapy for HCM and is only considered when there are ventricular arrhythmias refractory to treatment or when features of DCM or restrictive cardiomyopathy develop.
Restrictive Cardiomyopathy
Restrictive cardiomyopathy (RCM) is the least common cardiomyopathy seen in children and represents only 3% of pediatric cases [15]. It is characterized by diastolic dysfunction due to restrictive filling with a normal ventricle wall thickness and a normal-sized chamber. RCM often lacks symptoms early on and can present with a decreased exercise tolerance, exertional chest pain and syncope. Physical findings include jugular venous distension (possibly with Kussmaul sign), hepatomegaly, a prominent S2 heart sound, a gallop rhythm, peripheral edema and ascites. Echocardiography generally shows dilated atria and normal ventricles. With disease progression, the estimated pulmonary artery pressure will be elevated. The electrocardiograph shows low voltage QRS complexes, non-specific ST-T segment changes and sometimes atrial arrhythmias or AV block. Cardiac catheterization is useful for confirming elevated pulmonary pressures seen on the echo. An endomyocardial biopsy (EMB) is only done to exclude etiologies such as amyloidosis or sarcoidosis which more commonly cause RCM in adults. Once the diagnosis is established, first-degree relatives should be screened.
Pharmacological treatments for RCM are principally for palliative symptom relief. Diuretics are used to reduce venous congestion. Caution should be exercised, however, to ensure cardiac output is not compromised. Beta-blockers provide relief to patients by prolonging the diastolic interval, allowing for better filling. Anticoagulants are sometimes used prophylactically to prevent mural thrombi from forming. Given that RCM is refractory to other therapies, patients are more likely to be considered for transplantation. Despite being the rarest cardiomyopathy in children, 12% of cardiomyopathy transplant recipients have RCM [16]. In the Unites States many centers advocate immediate listing for transplantation because of the rapid development of pulmonary hypertension, the high risk of thromboembolisms and a mean survival of approximately 2 years [17].
Doxorubicin-Induced Cardiomyopathy
The chemotherapy agent doxorubicin (Adriamycin) has long been used in the treatment of neoplasms such as Hodgkin’s and non-Hodgkin’s lymphomas and sarcomas. One of the most detrimental side-effects of the drug is the development of cardiomyopathy [19]. The mechanism of action is thought to be free radical-induced oxidative damage to cardiac myocytes [20]. There is a dose-dependent relationship between doxorubicin use and cardiotoxicity. At very high doses, cardiomyopathy develops in 36% of patients [19]. This number is negligible at the lowest doses. There can be a delay of up to 20 years after the completion of chemotherapy before cardiomyopathy becomes clinically apparent [21].
Endomyocardial biopsy is the best diagnostic tool available for its detection [22]. The best non-invasive tests are an echo or radionuclide imaging showing a decrease in left-ventricular ejection fraction and should be done in the primary follow-up after doxorubicin therapy. ECG changes are non-specific and include sinus tachycardia, a flattened T wave or a prolonged QT interval. Treatment options are limited. Doxorubicin-induced cardiomyopathy is refractory to usual regimens. Symptom relief can be provided by beta blockers but there is no improvement in mortality. Heart transplantation remains the only therapeutic option.
Congenital Heart Disease
Congenital heart disease remains the most common pre-operative diagnosis in the pediatric heart transplant population in the United States, although it is in decline due to advances in palliative surgery and a lack of available donors [4]. During the advent of pediatric heart transplantation in the 1980s, the overwhelming majority of recipients had hypoplastic left heart syndrome (HLHS). At the time, the palliative Norwood procedure had much worse outcomes than cardiac transplantation. Improvements in the management of patients undergoing palliative procedures saw post-operative survival rise to more than 80% while waiting-list mortality rose to 25% because of donor shortages [7]. Now, therefore, heart transplantation is rarely performed as a first-line treatment for HLHS. Instead, children are being listed once refractory heart failure develops after previous palliative procedures.
The most common forms of congenital heart disease listed for transplantation are non-HLHS single-ventricle abnormalities (36%) followed by conditions in which the right ventricle functions as the systemic pump (20%) [18].
Candidate Evaluation
Evaluating pediatric candidates for heart transplantation is similar to the process used for adults (see Chap. 4). This chapter will examine considerations unique to children. Generally, potential recipients are evaluated for life expectancy, morbidity and weighing the relative advantages and disadvantages of alternative treatments. Due to the diverse pathologies leading to transplantation, special consideration must be given to the anatomy and hemodynamics. An assessment looking for chronic disease and the involvement of other organ systems is of particular importance in the pediatric population given that heart failure etiologies such as inborn errors of metabolism will often have widespread effects. The issue of compatibility is somewhat different in children as sensitization is not always preclusive.
Anatomy
The most important anatomical considerations relate to the systemic and pulmonary vasculature. Adequately developed, appropriately sized and confluent pulmonary arteries are essential for successful transplantation. Any anomalies of the venous return to the heart will also require special attention. If transplantation is being performed after previous palliative surgery, then caution is required in dealing with adhesions and anatomical distortions such as enlarged atria resulting from the Fontan procedure. The visceral anatomy of the heart is of minimal significance given that it will be almost entirely removed. Magnetic resonance imagining and computer tomography can delineate the anatomy as part of the pre-operative assessment. Further surgical considerations are discussed later.
Pulmonary Vascular Resistance
An increase in pulmonary vascular resistance features in many forms of pediatric heart disease. Congenital heart disease is more strongly associated with pulmonary hypertension, particularly fixed forms. As mentioned previously, in the adult population, when the pulmonary vascular resistance index (PVRI) exceeds 6 Wood units/m2 or when the transpulmonary gradient exceeds 15 mmHg, heart transplantation is contraindicated. This is due to concerns over acute right-sided failure of the donor heart. The adult guideline is overly restrictive in the pediatric population and patients with a PVRI of up to 9 Wood units/m2 can safely undergo heart transplantation [24] (see Fig. 15.4). In patients with a high PVRI, inotropes and vasodilators can be used intensively to reduce the PVRI pre-operatively. Inhaled nitric oxide, milrinone and vasodilators may also be considered intra-operatively. A period of prolonged sedation and intubation may be warranted immediately following surgery. Patients can be weaned onto oral agents—such as nifedipine, digoxin and sildenafil [24]—to maintain a lower PVRI. Ventricular assist devices (VADs) are increasingly being used in the pediatric population as a bridge-to-transplant after their successful use in adults. Adults with previously “fixed” pulmonary hypertension have seen a reduction in PVRI after being on a VAD, allowing for successful orthotopic heart transplantation [25]. A number of case reports show similar findings in children. More extensive evaluation is required.
Fig. 15.4
Kaplan-Meier curves showing survival of pediatric heart transplant recipients with a PVRI of less than 6 WU versus greater than 6 WU (a) unmatched (b) propensity matched (Reused with permission from Chiu et al. [23])
A recent retrospective study of the UNOS database by Chiu et al. [23] demonstrated that pulmonary vascular resistance was not an independent predictor of post-operative mortality in the pediatric population. Further work is needed, but patients previously excluded on the basis of irreversible elevated PVRI are now being considered for single orthotopic heart transplantation. With improvements in perioperative management, an elevated PVRI may be removed as an absolute contraindication in the future.
Compatibility
Heart transplantation usually mandates that the recipient and donor are ABO-compatible because there is a high probability that preformed anti-A or anti-B antibodies (isohemagglutinins) will precipitate hyperacute rejection. The shortage of donors in the infant population led to ABO-incompatible (ABOi) transplantation on the basis that the immune system is underdeveloped in this age-group. Infants with isohemagglutinin titers that show absent or low levels of antibodies can receive a heart from an ABOi donor with results comparable to ABO-compatible heart transplantation [26]. Most recipients do not go on to form antibodies later in life despite no enhancements to their immunosuppressive therapy [27]. Even recipients who do form antibodies still have good outcomes [27]. More recently, older children have been successfully ABOi transplanted [28]. The lack of B-cells with receptors for donor blood groups and antibody titers of less than 1:4 allow for safe ABOi transplantation [27]. Survival in this patient group is reported at 100% 1-year, 96% 5-years and 69% 10-years post-transplant with the oldest child being 7.5 years old at the time of surgery [27]. An important perioperative consideration for patients where ABOi is likely is the avoidance of blood products that contain isohemagglutinins. ABOi heart transplantation in the pediatric population has had positive effects by reducing wait list mortality and wait list times [27].
Sensitivity to human leukocyte antigen (HLA) and non-HLA donor antigens remain a significant factor in the already high wait list mortality for children awaiting heart transplantation. The presence of donor-specific antibodies (DSAs) carries the risk of allograft rejection and/or cardiac allograft vasculopathy (CAV) [29]. Sensitization can occur from blood products (especially platelets), palliative procedures for congenital heart disease, and the use of mechanical circulatory support devices (MCSDs). The latter has increased in recent times and is the reason for more children being sensitized prior to transplantation.
Potential recipients are tested for panel reactive antibodies (PRA). Testing demonstrates preformed anti-HLA antibodies. Historically this was done using a complement dependent cytotoxicity (CDC) assay on T-lymphocytes from individuals in the donor area. Most centers now use Luminex® solid-phase flow cytometry to detect alloantibodies. The newer test is able to distinguish IgG specificities whereas older tests would indiscriminately test for any antibodies [31]. The result is expressed as a percentage. Patients with a PRA > 10% are considered sensitized and are at increased risk of graft loss [30]. Not all antibodies are of clinical significance. Antibodies that bind C1q complement result in worse outcomes than antibodies that do not [32]. Many centers perform HLA typing so that “virtual” cross-matching can be done once a potential donor is found.
Infection
All potential recipients require serological evaluation for Epstein-Barr virus (EBV), cytomegalovirus (CMV), Toxoplasma gondii, HIV, varicella zoster virus (VZV), measles, hepatitis and HIV. Positive results are now rarely an absolute contraindication for heart transplantation but help determine necessary prophylactic treatments and perioperative management plans. HIV was once considered an absolute contraindication owing to concerns that organs were “wasted” on those with a terminal illness, and concerns that immunosuppression would result in further deterioration of CD4 T-lymphocytes. With newer anti-retroviral therapies, survival is now over 90% at 10-years [33]. Good outcomes have been realized for HIV-positive adults who are compliant and have low or undetectable viral loads at the time of transplantation [34]. Outcomes in the pediatric HIV-positive population have yet to be evaluated. Heart transplant recipients who are seropositive for hepatitis B show similar survival rates to those who are seronegative, however, the majority of deaths in seropositive patients are due to hepatitis [35]. Reactivation of hepatitis B after transplantation is controlled with lamivudine [36]. EBV infection either preoperatively or postoperatively (usually from donor tissue) puts the patient at risk for post-transplant lymphoproliferative disease (PTLD). Patients must be vaccinated against measles, mumps, rubella, Hemophilus influenzae, VZV, pneumococcus and hepatitis A and B prior to transplantation.
Other Organ Systems
Severe and irreversible end-organ damage, including kidney and liver failure, are usually considered contraindications to single orthotopic heart transplantation. Multisystem organ failure carries a 1-year post-transplant mortality of 16.6% [4] in children. Requiring dialysis prior to transplantation is the second worst risk factor for 1-year mortality [4]. Given that immunosuppressive agents are highly nephrotoxic, children with moderate to severe renal impairment should be considered for combined heart-kidney transplantation [40].
Diabetes mellitus is rarer in the pediatric population and is not considered an absolute contraindication. Due to the scarcity of donors and the desire to allocate organs to those with the best chances of survival, patients with diabetes are less often listed for transplantation. In the adult population patients with diabetes have significantly worse survival overall, but when stratified according to those with or without diabetic complications, those without complications have survival rates that are similar to non-diabetic patients [41].
Obesity is a relative contraindication in adults owing to concerns over poor wound healing, an increased risk of infection and an increased risk of deep vein thrombosis and pulmonary emboli [42]. Similar concerns translate over to the pediatric population, although little data exists. A review of the PHTS database showed few children were listed for transplantation when their BMI was more than 2 standard deviations above normal [43].
Psychosocial Factors
Family support is paramount to successful transplantation and long-term survival. A full assessment of the psychosocial state of the family should be made. This includes access to transportation, compliance and whether the family is able to make informed decisions. These factors should not exclude a child from being listed but instead act as a guide for providing adequate support from allied medical professionals. Developmental delay is a feature of some diseases and syndromes associated with congenital heart disease. Children should be assessed on a case-by-case basis for suitability. A common example is Down’s syndrome (trisomy 21). Down’s syndrome is associated with congenital heart defects and developmental delay. There is a broad spectrum, with patients having varying degrees of both developmental delay and other comorbidities. Although rarely listed for heart transplantation, Down’s syndrome patients have shown reasonable outcomes after both renal and bone marrow transplantation [37, 38] highlighting the need to comprehensively assess each case.
Donor Selection
The number and quality of donor hearts remain significant limiting factors in pediatric heart transplantation. A study of the UNOS database from July 2000 to December 2008 found that only 65.7% of potential pediatric donor hearts were transplanted [39]. Common reasons for declining an organ included the prolonged use of cardiopulmonary resuscitation (CPR), the use of high-dose inotropes, blunt trauma to the chest wall and prolonged ischemia time [39]. The lack of studies means clinicians rely on experience or data from the adult population. The donor pool may be unnecessarily narrow as a result.
As with adults, vital organ donation from children can only occur after a diagnosis of brain death has been established. The criteria for diagnosing brain death are the same as in adults. There are also additional criteria that vary according to age [45]. In addition, an interval of between 12 and 48 h between two evaluations is required [45].
Donor evaluation should include gender, age, weight, height, the cause of death, a review of any chest trauma, inotrope use and hemodynamic status. Donor hearts have been declined in the past because of CPR use but it has been shown to have no impact on outcomes [44]. Allograft ischemic time is a risk factor for survival in older children, particularly those 11–17 years old, and has almost no impact on the survival of infants < 1 year old [4].
An echocardiogram should be done to exclude structural and functional abnormalities. A reduction in ejection fraction to below 50% after inotrope use will normally preclude a heart’s use. Some regurgitation of the mitral and tricuspid valves is normal after brain death. Prior chest trauma may result in a pericardial effusion being visualized. The ECG normally shows non-specific changes that are due to hemostatic disturbances resulting from brain death. Donor troponin I levels were thought to be predictive of outcomes but recent analysis shows no difference in children who received a heart from a donor with elevated troponin I levels [46].
The donor-to-recipient weight ratio is used for size matching. An undersized donor with a ratio below 0.6 is associated with worse outcomes and most centers avoid going below 0.75 [47]. This is especially the case if the recipient suffers from pulmonary hypertension. Oversizing the donor can be done safely up to a weight ratio of 3 [48]. This is helpful for dealing with shortages particularly in the infant population. In older children, 25% of recipients received adult hearts [4]. Patients with cardiomyopathy often have significant cardiomegaly that creates a cavity amenable to oversizing the donor.
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