Lower and Shumway at Stanford University performed the first successful orthotopic heart transplantation in a dog in 1960. Barnard in South Africa unexpectedly performed the first successful human heart transplantation in 1966. This was followed by an explosive interest in heart transplantation but almost uniformly poor results because of organ rejection. Introduction of cyclosporine in 1980 markedly improved the results of adult heart transplantation. This success has extended to pediatric patients, and the first infant cardiac transplantation was carried out by Bailey at Loma Linda University in 1985. Although some ethical and medical issues exist, cardiac transplantation will continue to contribute to the treatment of children with some heart diseases.
Physicians may have a chance to participate in the care of cardiac transplant recipients. Therefore, practitioners should have some basic knowledge on the topic, and that is the aim of this chapter. This chapter is not intended to review up-to-date advances or to provide management guidelines on transplant patients. Cardiac transplantation is done by transplantation centers with multidisciplinary teams of professionals and supporting staff who are primarily responsible for follow-up of their posttransplant patients according to the management protocol established by the center.
Pediatric heart transplantation is a treatment option for children with intractable heart failure or congenital heart defects (CHDs) not amenable to surgical palliation. Several decades ago, when the surgical mortality rate was very high, hypoplastic left heart syndrome (HLHS) was a major indication for heart transplantation. With improved surgical outcome, HLHS is no longer considered a major indication for heart transplantation.
The majority of pediatric transplant patients are those with pre- and postoperative complex CHDs and those with cardiomyopathies. In infants younger than 12 months of age, who account for about 23% of pediatric cardiac transplantation, HLHS is still the most common indication followed by dilated cardiomyopathy. In children, cardiomyopathies (dilated, hypertrophic, and restrictive) account for about 60% of the cases. Most of the other indications for the transplant are patients who had surgical repairs for complex CHDs (e.g., single ventricle, atrioventricular canal defect, truncus arteriosus, L-transposition of the great arteries). Rarely, patients with unresectable cardiac tumor are candidates for transplantation. Significant cardiac allograft vasculopathy and chronic graft dysfunction of a previous heart transplant are rare indications for heart transplantation.
Selection of the Recipient
Careful selection of appropriate recipients remains the most important determinant of a favorable outcome. Multidisciplinary evaluation of the recipient includes assessment of cardiopulmonary, renal, hepatic, neurologic, and infectious disease status and socioeconomic assessment. In general, the recipient should satisfy the following selection criteria:
1. Terminal heart disease with death expected within 6 to 12 months
2. The presence of adequate dimension of hilar pulmonary arteries. If the pulmonary vascular resistance (PVR) is high or if severe hypoplasia or stenosis of the pulmonary arteries is present, the patient may be a candidate for heart and lung transplantation.
3. Other general requirements:
a. Normal function or reversible dysfunction of the kidneys and liver
b. Lack of systemic infection
c. Malignancy under complete remission for longer than 1 year
d. Lack of systemic disease (e.g., diabetes and degenerative neuromuscular disease) that would limit recovery or survival
e. Lack of drug addiction
f. Lack of mental deficiency
4. Equally important for successful pediatric heart transplantation are a family history of stability, past history of compliance, and evidence of strong motivation for the transplant as assessed by physicians and social workers. The child and parents should demonstrate sufficient responsibility, resources, and psychological strength to cope with multiple outpatient clinic visits, routine endomyocardial biopsy, and a lifetime of vigilance of the immunosuppressed state.
5. Unique to pediatric transplantation is the requirement of a reliable caregiver for the recipient child. The caregiver identified need not be a parent but must have legal responsibility for total care and be prepared to deal with the strict medical regimen required.
Cardiac transplantation is contraindicated:
1. If PVR is 6 Wood units/m2 or greater or
2. Transpulmonary gradient (TPG = Pulmonary artery [PA] pressure – PA wedge pressure) is 15 mm Hg or greater, which does not respond to vasodilators.
After the decision has been made for heart transplantation and after complete multidisciplinary evaluation, the patient is placed on the cardiac transplantation waiting list (to the United Network of Organ Sharing [UNOS] and the Regional Organ Bank). Each listing is specific for ABO blood type and the recipient’s weight.
Evaluation and Management of the Cardiac Donor
1. The cardiac donor must meet the legal definition of brain death. Most neonatal donors are victims of sudden infant death syndrome or birth asphyxia. Most older children donors are victims of car accidents or violence.
2. The screening of donor is accomplished in three phases.
a. Primary screening is done by organ procurement specialists to obtain information on body size, ABO blood type, serologic data on hepatitis B and human immunodeficiency virus (HIV), cause of death, clinical course, and routine laboratory data.
b. Secondary screening is performed by cardiac surgeons or cardiologists, who pay attention to the extent of other (especially thoracic) injuries, the extent of treatment required to sustain acceptable hemodynamic status, electrocardiogram (ECG), chest radiographs, arterial blood gas analysis, and echocardiogram.
c. Tertiary screening is inspection of the heart by a “harvesting” surgeon to ensure that there is no evidence of a palpable thrill over the heart and great arteries, obvious arteriosclerotic heart disease, or myocardial contusion.
3. Donor heart should have:
a. No evidence of cardiac abnormalities by echocardiography, ECG, or myocardial enzyme tests
b. Left ventricular fractional shortening greater than 28%, regardless of inotropic support
4. Specific compatibility should exist between the donor and recipient in three aspects
a. ABO blood group compatibility
b. The donor’s body weight should be within 20% of the recipient’s weight; a larger donor heart is better tolerated than a smaller one.
c. The donor should be within close geographic range so that the donor heart can be harvested, transported, and implanted within 4 hours (up to 9 hours for infants).
5. Medical management of donor heart before transplantation: The donor should be managed in the intensive care unit with routine monitoring. The systolic blood pressure should be maintained in the normal range (>100 mg Hg for adults). Inotropic support and fluid resuscitation may be necessary. Normal serum electrolyte levels, acid–base balance, and oxygenation should be maintained. The hematocrit should be above 30%.
FIGURE 35-1 “Right atrial” technique of cardiac transplantation. A, The recipient cardiectomy has been completed, leaving the anastomosis to be performed in the following sequence: (1) left atrium (LA), (2) aorta (Ao), (3) right atrium (RA), and (4) pulmonary artery (PA). B, The completed transplant. From Backer CL, Mavroudis C: Pediatric transplantation, Part A: Heart transplantation. In Stuart FP, Abecassis MM, Kaufman DB (eds): Organ transplantation, Georgetown, TX, Landes Bioscience, 2000.
Informed Consent from the Family and Recipient
The public often misunderstands what transplantation can accomplish. The recipient and parents must fully understand the short- and long-term implications of transplantation by knowing the following facts, which are not well publicized:
1. Unlike most cardiac surgeries, cardiac transplantation is not a cure for the condition for which it is being considered. It can be viewed as another medical problem that will require lifelong medical attention, including frequent hospital visits or admissions for noninvasive and invasive procedures, frequent adjustments of immunosuppressive and antibiotic medications, varying degrees of limitations in activity, and adjustments in lifestyle.
2. There is always a threat of rejection and infection throughout the patient’s life. Even with full compliance, rejection can occur, resulting in death or a need for retransplantation.
3. The heart received will not last for an indefinite period; it will eventually develop allograft coronary artery disease (CAD), requiring consideration of retransplantation.
4. Immunosuppressive therapy may cause malignancies (especially lymphoma in children) and an increased risk of infection.
5. Lifelong medical attention will place a tremendous financial, emotional, and social burden on the family. A dysfunctional family could result.
There are currently two surgical techniques used in cardiac transplantation: the right atrial (RA) technique and the bicaval technique. The latter is a more recent technique and has become more popular than the former.
In the RA cardiac transplantation, when the native heart is explanted, the posterior walls of both atria of the recipient heart are left in place and are anastomosed to the donor heart. End-to-end anastomoses are also made between the donor and recipient aortas and pulmonary arteries (Fig. 35-1). This technique is similar to those described by Lower and Shumway in 1960. The hospital mortality rate is 10% to 15%.
A modification of the above, called “bicaval” cardiac transplantation, has become popular in some institutions (Fig. 35-2). In this technique, the RA is also explanted from the recipient, leaving only the posterior wall of the left atrium (LA) with four pulmonary veins attached. Anastomoses are made between the venae cavae, the aorta, the PA, and the LA.
FIGURE 35-2 “Bicaval” technique of cardiac transplantation. A, The recipient cardiectomy has been completed. Note that the entire right atrium has been removed. The sequence of the anastomosis is (1) left atrium (LA), (2) aortic (Ao), (3) inferior vena cava, (4) pulmonary artery (PA), and (5) superior vena cava. B, The completed transplant. From Backer CL, Mavroudis C: Pediatric transplantation, Part A: Heart transplantation. In Stuart FP, Abecassis MM, Kaufman DB (eds): Organ transplantation, Georgetown, TX, Landes Bioscience, 2000.
FIGURE 35-3 Modification of heart transplantation surgery for hypoplastic left heart syndrome. AO, aorta; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle.
For patients with HLHS who are placed on a transplantation algorithm, it is necessary to keep the ductus arteriosus open and to increase the size of the interatrial communication. A hybrid procedure as described under HLHS (in Chapter 14) may be used as a bridge to cardiac transplantation, in which an endovascular stent is placed in the closing ductus to keep the ductus open and PA branches are banded to control pulmonary blood flow (see Fig. 14-49). Blade atrial septostomy followed by balloon dilatation is performed to increase the size of the interatrial communication.
For most babies with HLHS, the donor cardiectomy is modified in that the entire aortic arch is harvested well beyond the insertion of the ligamentum arteriosus to augment the ascending aorta and aortic arch, such as those shown in Figure 35-3.
This section is not meant to describe how to take care of patients after heart transplantation. Medical professionals and support staff of the transplantation center are the providers of appropriate care for these children. This section is intended to show what is involved in the proper care of posttransplant patients for physicians who may become involved in their care. Very close follow-ups are required by frequent clinic visits and a number of investigations to detect possible rejection or infection.
Frequency of Clinic Visits and Investigations
The early postoperative period is the period of highest risk and requires a very close follow-up with frequent clinic visits and laboratory tests and other investigations. In general, the frequency of clinic visits and investigation is most intense in the first year after the transplant, and it decreases gradually thereafter. The following is an excerpt of the posttransplant follow-up plans at the Loma Linda University Children’s Hospital (Chinnock, 2012). It should be pointed out, however, that each institution has a detailed management plan established by the transplantation team, which may be somewhat different from the Loma Linda’s.
1. Office visit twice weekly for 6 weeks; then monthly visit for the first year. It is then reduced to every 3 months thereafter.
2. Echocardiography study is done twice weekly for 4 weeks; then reduced to monthly to coincide with the clinic visit.
3. ECG is done monthly for 3 months, then every 3 months for the first year, and then every 6 months thereafter.
4. Chest radiography is performed monthly for 3 months, at 12 months, and then annually.
5. Blood levels of immunosuppressive agents are obtained twice weekly for 2 weeks, weekly for 4 weeks, monthly for the first year, and then every 3 months thereafter. See a later section for target trough levels of each immunosuppressive agent.
6. Complete blood count and platelets are obtained every 2 weeks, then monthly for the first year, and then every 3 months thereafter.
7. Cytomegalovirus (CMV) immunoglobulin titer is assessed at 6 and 12 months and then annually until conversion. Epstein-Barr virus (EBV) polymerase chain reaction is assessed every 3 months. HIV and the surface antigen of the hepatitis B virus (HBsAg) tests are obtained at 6 months.
8. Isotopic glomerular filtration rate is assessed at 3 and 12 months and every year thereafter for patients who received transplant during infancy. For those who received transplant after infancy, it is assessed every 2 years.
9. Renal ultrasonography is performed at 3 and 12 months and every other year thereafter.
10. Endomyocardial biopsy is obtained annually for newborns and children 2 years or younger. For children 2 to 8 years of age, it is obtained at 1, 3, and 12 months and annually thereafter. For children 9 years of age and older, it is obtained at 1, 2, 3, 6, and 12 months and annually thereafter.
11. Coronary angiography is performed annually starting at the first anniversary of transplantation.
12. Intravascular echocardiography is performed at age 6 years and every other year thereafter.
13. All routine vaccinations, except for live virus vaccines (e.g., oral polio, varicella, and measles–mumps–rubella vaccines) should be administered, starting as early as 6 weeks after transplantation.
Overview of Immunosuppressive Therapy
Successful immunosuppression depends on a delicate balance between suppression of the host mechanisms that would reject the foreign graft and preservation of the mechanisms of the immune response that protect against bacterial, fungal, and viral invasion.
The so-called triple-drug therapy consists of three classes of medications.
1. Calcineurin inhibitors (e.g., cyclosporine [Neoral], tacrolimus [Prograf, FK506]) block T-cell cytokine gene expression.
2. Corticosteroids (methylprednisolone or prednisone) suppress cell-mediated immunity as well as the humoral immunity.
3. Antiproliferative agents (e.g., azathioprine [Imuran], mycophenolate mofetil [CellCept]) prevent rejection by interfering with purine synthesis, resulting in antiproliferative effects on T and B cells.
Cyclosporine. Cyclosporine is the most commonly used agent for maintenance therapy. The first dose of cyclosporine (10 mg/kg) is administered before surgery because it may be most effective when given before the antigenic challenge (Table 35-1). Target trough levels of cyclosporine are as follows; 250 to 300 ng/mL for 6 months, 200 to 250 ng/mL for 6 to 12 months, and 125 to 150 ng/mL thereafter. Cyclosporine is continued for as long as the patient lives.
The drug’s primary toxic effects are hypertension and associated renal insufficiency. Other side effects of the drug include hyperlipidemia, hirsutism, gingival hyperplasia, and facial dysmorphism (with widening of the nose, thickening of the nares and lips, and prominence of the supraorbital ridge and eyebrows).
Tacrolimus (Prograf), a newer agent in the same class as cyclosporine, is being used increasingly by some centers as a primary calcineurin agent. It has remarkably lower rates of hypertension and hyperlipidemia and does not cause hirsutism, gingival hyperplasia, or the facial dysmorphism associated with cyclosporine.
Methylprednisolone (10 mg/kg for children) is administered intravenously (IV) as the sternotomy is made. After cardiopulmonary bypass has been discontinued, a 2-mg/kg IV dose is given every 8 hours, totaling three doses. After 24 hours, prednisone is administered in high doses (1 mg/kg per day by mouth). After about 3 weeks, the dose is tapered to 0.2 mg/kg per day by 3 months after surgery (see Table 35-1). Further tapering or discontinuation depends on the institution’s protocol and the presence or absence of rejection. Some centers discontinue it after 6 months, particularly in neonates and infants. Most centers aim to establish a steroid-free regimen in selected patients by 1 year after the transplantation to minimize the risk of steroid-associated morbidity.
Azathioprine. It is given immediately after the transplantation surgery. The starting dose is 1 to 2 mg/kg per day to produce a peripheral white blood cell count around 5000/mm3. If the count falls below 4000/mm3, the drug is reduced, or it is stopped if the reduction is severe (see Table 35-1). The major toxicity of azathioprine is bone marrow depression and less frequently hepatotoxicity. The drug is generally continued indefinitely.
Mycophenate mofetil (CellCept) is a new agent in the antiproliferative agent group. A clinical study has demonstrated a lower rate of rejection rates than azathioprine when used with cyclosporine and corticosteroids. This agent also allowed reduction of the dosage of cyclosporine and tacrolimus, which may potentially reduce the side effects of these drugs. The dose is 600 mg/m2/dose orally twice a day. Its side effects include gastrointestinal (GI) symptoms (in 30%), bone marrow suppression (anemia), hypertension, headache, fever, and increased risk of developing lymphomas or other malignancies.
DOSAGES OF IMMUNOSUPPRESSIVE AGENTS
IV, Intravenous; PO, oral; q, every
0–3 mo postoperatively 300 ng/mL
3–12 mo postoperatively 200–250 ng/mL
>12 mo postoperatively 150–200 ng/mL
∗ Adjust cyclosporine dosage by PO twice-a-day dosing (or q8h dosing for infants younger than 6 mo of age) to maintain target trough level as follows:
Adapted from Canter CE: Pediatric cardiac transplantation. In Moller JH, Hoffman JIE (eds): Pediatric Cardiovascular Medicine. New York, Churchill Livingstone, 2000, pp 942-952.
Early Posttransplantation Follow-Up
The highest risk of dying is in the first 6 months after transplantation. In the early postoperative period, acute graft dysfunction and technical issues account for more than 50% of the deaths. The two most common causes of death in the early posttransplant period are acute rejection (26%) and infection (16%).
1. Subtle symptoms may be the only indication of the beginning of a rejection episode. These symptoms include unexplained fever, tachycardia, fatigue, shortness of breath, joint pain, and personality changes.
2. Echocardiographic techniques rely on a physiologic abnormality of the rejecting heart (myocardial edema or decreased left ventricular contractility) (see a later section for further discussion).
3. Endomyocardial biopsy remains the most important method for identifying acute rejection. The endomyocardial biopsy is graded according to the International Society of Heart and Lung Transplantation (ISHLT) scale (2005) (Table 35-2).
Treatment. Rejection treatment depends on the grade of rejection. Generally, specific antirejection therapy is initiated only for moderate or severe rejection (grade 2R or greater).
1. Methylprednisolone (1000 mg for adults; 15 mg/kg for children weighing <50 kg) given IV or prednisone (100 mg for adults) given orally for 3 days is followed by tapering to the baseline dose over the next 2 weeks.
2. If rejection does not respond to steroids or if hemodynamic compromise occurs, antithymocyte sera such as antithymocyte globulin (ATG) or the monoclonal antibody to T3 lymphocytes (OKT3) are used for 5 or 10 days, respectively.
3. If all measures prove ineffective, retransplantation is considered.
Immunosuppressive medications used to prevent allograft rejection increase the risk of infection. There are two peak incidences for infection after transplantation.
1. An “early” infection, occurring within the first month of transplantation, is dominated by nosocomial, often catheter-related, infection caused by Staphylococcus spp. and gram-negative organisms.
2. A “late” infection, occurring within 2 to 5 months, is caused by opportunistic infections from organisms such as CMV, Pneumocystis spp., and fungal pathogens (see later section). The lung is the most common site of infection in heart transplant recipients followed by the blood, urine, GI tract, and sternal wound.
INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION CARDIAC BIOPSY GRADING SCHEME FOR THE DIAGNOSIS OF ACUTE CELLULAR REJECTION
Interstitial or perivascular infiltrate with up to one focus of myocyte damage
Two or more foci of infiltrate-associated myocyte damage
Diffuse infiltrate with multifocal myocyte damage ± edema ± hemorrhage ± vasculitis
From Stewart S, Winters GL, Fishbein MC, et al: Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 24:1710-1720, 2005.
Late Posttransplantation Follow-Up
Late follow-up examinations are intended to detect rejection, infection, and the side effects of immunosuppression. Infection and rejection remain the most common causes of death after heart transplantation. For those who survive beyond 1 year after transplantation, acute rejection (30%), allograft vasculopathy (24%), and infection (12%) account for most of the deaths. Graft failure, lymphoma, and CAD are responsible for the remaining deaths.
Although the risk of rejection is greatest in the first 3 months after transplantation, continued surveillance for rejection is necessary. A high index of suspicion is necessary to detect rejection because many rejections occur without symptoms. Endomyocardial biopsy at regular intervals is required to detect rejection.
1. Clinically evident cardiac dysfunction or congestive heart failure (CHF) is usually absent. Nonspecific clinical signs and symptoms (e.g., fever, tachycardia, malaise, personality changes, gallop rhythm, arrhythmias, hypotension) may be the only indications of rejection. These symptoms are often caused by infection rather than rejection. Decreased ECG voltages and decreased ventricular function (by echocardiography) are late signs of acute rejection.
2. Some centers have used serial echocardiography to assess rejection, but this method has not been universally accepted.
3. Endomyocardial biopsies are the criterion standard and are graded according to the criteria of the ISHLT, with treatment generally occurring only for biopsy samples that demonstrate a 2R or greater histology. Patients with no or mild rejection (grade 0R or 1R) on the biopsy receive no change in drug dosage.
Infection is a common cause of death and is probably related to the immunosuppressive therapy. Infection after the immediate posttransplantation period is caused by opportunistic infective agents such as CMV, Pneumocystis organisms, and fungi. The average mortality rate from infection is about 12%; that of fungal infection is about 36%. The lung is the most commonly infected organ; the mortality rate of patients with infected lungs is 22%. CMV remains the most common single infection, but the specific antiviral agent for CMV, ganciclovir, does not appear to reduce the incidence of primary CMV infection. The efficacy of pyrimethamine and trimethoprim–sulfamethoxazole has been proved for the prophylaxis of toxoplasmosis and Pneumocystis infection, respectively. The risk-to-benefit ratio of using influenza vaccines after transplantation remains controversial.
Most researchers agree that children receiving immunosuppressive therapy, as well as their siblings, should not receive all live vaccines, including varicella, measles, mumps, rubella, and oral polio. Because of their immunosuppressed status, there is an increased risk that these patients will develop active disease from the vaccine strains.
Allograft Coronary Artery Disease
An unusual, accelerated form of CAD, probably an immune-mediated disease, is the third most common cause of death after infection and rejection. CAD is the major determinant of long-term survival. Virtually all adult patients have some histopathologic evidence of CAD by 1 year after transplantation. It may occur in up to 40% of transplanted hearts in 3 years and in more than 50% in 5 years. This disease also occurs in pediatric patients, perhaps to a lesser degree, but 28% of pediatric patients surviving 6 months to 6 years after transplantation develop CAD.
Most patients with transplanted, denervated hearts fail to experience typical chest pain. Life-threatening ventricular arrhythmias, CHF, silent myocardial infarction, and sudden death may result. Coronary angiography (or computed tomography [CT] coronary angiography) is necessary to diagnose the disease. The unique angiographic hallmark of this disease is diffuse, concentric, longitudinal, and rapid pruning and obliteration of distal branch vessels. Many centers recommend performing the first coronary angiography (or CT coronary angiography) within 2 to 4 weeks of transplantation to obtain a baseline; some centers also recommend performing an exercise stress test, if appropriate for the patient’s age, and coronary angiography (or CT coronary angiography) 1 year after transplantation to evaluate graft function and to detect premature and aggressive coronary atherosclerosis. The only effective treatment of allograft CAD is retransplantation.
Side Effects of Immunosuppression
1. Cyclosporine. Hypertension and renal toxicity are common side effects, and malignancies are rare side effects of cyclosporine therapy. Less severe adverse side effects of the drug include reversible hepatotoxicity, fluid retention, hirsutism, gum hypertrophy, and GI symptoms. Rarely (10% of patients), lymphoma develops with a larger dose of the drug.
Hypertension occurs in 50% to 90% of heart transplant recipients who take cyclosporine. The mechanisms of cyclosporine-associated hypertension include nephrotoxicity, increased sympathetic tone, volume expansion, increased endothelin levels, and stimulation of the renin–angiotensin system. Calcium channel blockers, angiotensin-converting enzyme inhibitors, and beta- and alpha-blockers have been used with varying degrees of success.
Another side effect of chronic immunosuppressive treatment is the development of malignant neoplasms, occurring in 1% to 2% of patients each year, or 12.5% during a mean follow-up period of 50 months. A unique form of lymphoma, posttransplant lymphoproliferative disease, is the most common tumor reported (80%) with cyclosporine-based immunosuppression; it occurs more frequently in young patients. Most of these tumors are thought to be the result of EBV infection. The use of OKT3 and ATG, as well as higher initial doses of cyclosporine and prednisone, appears to increase the risk of posttransplant lymphoproliferative disease. About 40% of patients respond to a reduction in immunotherapy, but chemotherapy and radiation therapy may be needed.
2. Corticosteroids. Growth retardation may occur with large doses of steroids. The dosage of steroids is kept at a minimum, or steroids are not given at all.
3. Azathioprine may produce bone marrow depression (e.g., thrombocytopenia, leukocytopenia, anemia), alopecia, and GI symptoms. Cutaneous malignancy (squamous cell and basal cell carcinoma) is the most common tumor associated with the use of azathioprine, perhaps related to the drug’s enhanced photosensitivity. The mortality rate from posttransplant tumors is high (38%).
Physiology of the Transplanted Heart
In following posttransplantation patients, physicians should first be aware of the unique physiology of the transplanted heart, which responds differently to exercise and to certain medications. The transplanted heart remains largely, but not entirely, denervated throughout the life of the recipient.
1. The response of the transplanted heart to exercise or stress is less than normal but adequate for most activities. With exercise, the heart rate accelerates slowly, and it parallels the rise in circulating catecholamine levels.
2. Most patients with denervated hearts experience no chest pain even with significant CAD.
3. Transplant recipients are supersensitive to catecholamines, in part because of the upregulation of β-adrenergic receptors and in part because of a loss of norepinephrine uptake in sympathetic neurons.
4. Coronary vasodilator response may be abnormal if allograft CAD has developed.
Recent data from the ISHLT Registry (2009) revealed that the overall 20-year survival rate for all pediatric heart transplant recipients is 40%. The 1-, 5-, and 10-year survival rates are 80%, 68%, and 58%, respectively. Another recent study (Zuppen et al, 2009) reported similar overall survivals of 85% at 1 year, 75% at 5 years, and 65% at 10 years. Newborns and infants appear to have better survival rates after transplantation; the 5-year actuarial survival rate is 80%.