Cardiac Transplantation
Peter Zimbwa
I. INTRODUCTION.
Christiaan Barnard performed the first cardiac transplant in Cape Town in 1967. Since then, cardiac transplantation has become a well-established therapeutic option for a select group of patients with end-stage heart disease. It offers these patients, who have no other alternatives, a chance for extended survival and improved quality of life. Cardiac transplantation, however, should not be perceived as a curative procedure. Although the patient’s primary problem of heart failure is alleviated by a successful transplantation, a new set of potential long-term complications arises primarily owing to the secondary effects of chronic immunosuppression.
Almost 89,000 heart transplants have been reported worldwide to the International Society for Heart and Lung Transplantation (ISHLT) registry since 1983 (1). As reporting to the ISHLT is voluntary, this number underestimates the actual number of cardiac transplants. There has, however, been a reduction in the number of annual heart transplants from a peak of > 4,000 in the mid-1990s to > 3,000 now. With an estimated additional 2,000 heart transplants per year not reported to the ISHLT, the total number of cardiac transplants likely exceeds 5,000 per year worldwide.
In the United States, the United Network for Organ Sharing (UNOS) reports a 10% reduction in cardiac transplantations over the same time period. UNOS is a national organization which, along with local organ procurement agencies, maintains organ transplantation waiting lists, initiates the evaluation of potential organ donors, allocates organs when a donor is identified, and compiles statistics annually on all aspects of the transplant process, including survival. Since 1990, the number of patients listed and waiting for a cardiac transplant in the United States has more than doubled. There is a shortage of donors, and each year 1.5 to 3 times as many patients are listed for cardiac transplantation as there are donors, so this problem is only going to escalate as the population gets older unless there is a significant increase in organ donation. The annual mortality rate while on the waiting list in 2001 was 15%, which has declined continually over the last decade, probably because of improved medical therapy for end-stage congestive heart failure and increased use of implantable cardioverter—defibrillator. As the annual number of cardiac transplantations has declined, wait times have continued to lengthen. The national median waiting time by UNOS status at listing from 2003 to 2004 data is as follows: 49 days for status 1A, 77 days for status 1B, and 308 days for status 2 patients. However, this can be misleading, as patients with different blood types such as blood type O wait significantly longer than other blood types such as blood type AB on average. A blood type O, status 2 patient could easily wait for > 2 years for a cardiac transplantation.
In the last 5 years (January 2005 to June 2009), the primary indication for adult cardiac transplantation has been nonischemic cardiomyopathies (53%), followed by ischemic cardiomyopathies (38%). Valvular heart disease (3%), adult congenital disease (3%), and retransplantation (3%) and miscellaneous causes (< 1%) account for the remainder (1). The average cardiac transplant recipient is male (77.1%), with an average age of 54 years, which reflects the demographics of the patients on the waiting list. The average donor age is 33 years, and donors > 50 years of age, which were rarely reported before 1986, now account for > 12% of all donors. Outcomes of transplantation continue to improve despite transplants performed on older, sicker patients. Recent data show that 44.5% of recipients were on intravenous inotropic support compared with 34% of recipients 10 years ago. Mechanical circulatory support is also more common, with > 31% of patients on some form of mechanical circulatory support at the time of transplantation, including 20.1% with a left ventricular assist device (LVAD) compared with only 15% on mechanical circulatory support (11% with an LVAD) 10 years ago (1). Survival rates post cardiac transplantation have improved from a median of 8.3 years in the 1980s to 13 years for those surviving to 1 year (1). The risk of death is highest in the first 6 months posttransplantation. Pretransplant factors associated with higher risk of mortality in the first posttransplant year include requiring mechanical circulatory support bridging to transplantation, congenital heart disease, and ischemic cardiomyopathy. Other risk factors include hemodialysis, mechanical ventilation, prior blood transfusion, and infection (1).
Because of the scarcity of donor organs and growing transplant waiting lists, it is crucial that cardiac transplant programs adequately screen and properly select potential transplant recipients. Effective use of this limited resource is essential to avoid “wasting” organs that become available for suboptimal recipients.
II. INDICATIONS FOR CARDIAC TRANSPLANTATION
Patients should be on optimal medical therapy for congestive heart failure, as recommended by the American College of Cardiology/American Heart Association guidelines, including angiotensin-converting enzyme (ACE) inhibitor, digoxin, diuretic, β-blocker, and spironolactone. If a patient is intolerant to an ACE inhibitor, she or he should be on an angiotensin receptor blocker.
Medically reversible causes of decompensated congestive heart failure should be excluded, including hypothyroidism, tachycardia-mediated cardiomyopathy, alcohol abuse, obstructive sleep apnea, hypertension, and medical noncompliance.
Surgically reversible causes of decompensated congestive heart failure should be excluded, including valvular heart disease, unrevascularized coronary artery disease with large territories of ischemia or viability, hypertrophic obstructive cardiomyopathy, and LV (left ventricular) aneurysm for which resection would improve overall cardiac hemodynamics.
Patients should be too ill or not candidates for cardiac resynchronization therapy. Alternatively, cardiac resynchronization therapy might have failed to improve symptoms or to halt progression of the underlying pathology.
If the previous criteria are met, indications for a cardiac transplant evaluation are as follows:
Cardiogenic shock requiring mechanical support (i.e., LVAD or intraaortic balloon pump counterpulsation)
Cardiogenic shock requiring continuous intravenous inotropic therapy for hemodynamic stabilization
New York Heart Association (NYHA) class III or IV congestive heart failure symptoms, particularly if progressively worsening
Recurrent life-threatening LV arrhythmias despite an implantable cardiac defibrillator, antiarrhythmic drug therapy (usually amiodarone), or attempted catheter-based ablation, if appropriate
End-stage complex congenital heart disease without pulmonary hypertension
Refractory angina without potential medical or surgical therapeutic options
III. COMPONENTS OF A CARDIAC TRANSPLANT EVALUATION AND CONTRAINDICATIONS.
The purpose of a cardiac transplant evaluation is to exclude patients with medical and psychosocial comorbidities and to quantify the severity of a patient’s cardiac functional impairment. Recommended investigations prior to a transplantation are summarized in Table 13.1 and exclusion criteria for cardiac transplantation are summarized in Table 13.2.
A. Blood work.
A standard blood work includes a complete blood cell count; a complete metabolic panel, including hepatic enzymes and thyroid function tests; and blood typing and antibody screening. A serologic assessment should also be performed to determine a potential recipient’s presensitization to cytomegalovirus (CMV), toxoplasmosis, hepatitis B and C viruses, and human immunodeficiency virus (HIV).
Patients who are anemic should have a thorough evaluation, including iron studies and a colon examination. Esophagogastroduodenoscopy and a hematologic evaluation, including a bone marrow biopsy, may also be necessary. Some patients may benefit from erythropoietin treatment to increase red blood cell counts without the need for transfusions that may expose the patient to further antigens.
Patients found to have an elevated serum creatinine level should undergo further evaluation to determine its relationship with low renal perfusion. A normal urinalysis result suggests the absence of renal parenchymal disease. This should include an assessment of cardiac hemodynamics and a renal ultrasound to assess renal parenchymal size and the presence of two kidneys without evidence of obstruction.
Patients found to have elevated hepatic enzymes should undergo further evaluation to determine the right-sided filling pressures and they should undergo a hepatic ultrasound scan. All patients should have their hepatitis B and C viral serologies assessed.
The patient’s serum should be screened for antibodies against human leukocyte antigen (HLA) of B and T lymphocytes, drawn from community volunteers representative of the major HLA allotypes. These antibodies are collectively referred to as panel reactive antibodies (PRAs) and are often elevated in multiparous women and patients with multiple transfusions (often perioperatively in the past). Elevated PRA levels (> 10%) necessitate a pretransplant donor HLA crossmatch
and increase the likelihood of it being positive, making waiting times longer and transplantation more difficult. If a patient has elevated PRA levels, an attempt to reduce them before transplantation with intravenous immunoglobulin, plasmapheresis, mycophenolate mofetil (MMF), or cyclophosphamide, alone or in combination, may be considered. Traditionally, each potential recipient would undergo a thorough HLA tissue typing analysis, including a cytotoxicity assay for assistance in matching donor hearts. In this assay, random donor lymphocytes are incubated with recipient sera. Complement-dependent antibody-mediated cytolysis identifies potential donor-specific antibodies present in that recipient. Currently, most programs use flow cytometry to assess preformed antibodies, rather than cytotoxic assays. This allows for the detection of weaker interactions and provides a wider, more efficient screening process.
TABLE 13.1 Recommended Evaluation prior to Transplantation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 13.2 Exclusion Criteria for Cardiac Transplantation | ||||||||||||||
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B. Imaging
All patients should undergo coronary angiography or a functional assessment for ischemia and viability. If ischemia or viability can be demonstrated, consideration should be given to percutaneous or surgical revascularization.
Bilateral carotid ultrasound scans should be performed in patients with risk factors for atherosclerosis. Select patients with carotid stenoses, who would otherwise be cardiac transplant candidates, may undergo pretransplantation percutaneous or surgical intervention, thereby eliminating this contraindication.
Occasionally, an abdominal aortic ultrasound is obtained to rule out an aneurysm, particularly in patients being considered for mechanical support.
C. Functional assessment
Metabolic stress testing is performed to assess the severity of cardiac functional impairment. Patients with compensated congestive heart failure and a peak oxygen consumption of < 14 mL/kg/min or < 50% predicted are considered sufficiently impaired for transplantation (2). Adequate patient effort during the stress test can be assessed by the respiratory exchange ratio, which should be > 1.1, indicating the onset of anaerobic metabolism.
Generally, a right heart catheterization is performed to assess cardiac hemodynamics and to optimize a patient’s medical therapy. Fixed, severe pulmonary hypertension, defined as a pulmonary vascular resistance (PVR) > 4 Wood units, is a contraindication to cardiac transplantation. In this setting, the donor right ventricle will likely immediately fail after implantation because it is not accustomed to high pulmonary pressures. An attempt should be made to medically decrease the pulmonary hypertension with inotropic agents, nitrates, or nitroprusside. Sometimes an LVAD is required to sufficiently decompress the left ventricle to reverse the pulmonary hypertension. Rarely, endomyocardial biopsy (EMB) is performed, except when an infiltrative cardiomyopathy is suspected.
Pulmonary function tests are performed to exclude patients with significant chronic obstructive or restrictive pulmonary disease.
Peripheral vascular studies may be obtained to exclude patients with significant peripheral arteriosclerosis obliterans.
D. Comorbidities and implications of heart transplant listing.
Advanced age, cancer, and obesity are the three common comorbidities that remain somewhat controversial with respect to their impact on whether an individual program will list a patient for heart transplantation.
Age criteria for eligibility were initially quite rigorous; however, it has become apparent that chronologic and physiologic age are often discrepant. Most centers do not have a fixed upper age limit, but generally patients > 65 years of age are very carefully screened to rule out comorbidities. ISHLT recommends considering patients for cardiac transplantation if they are ≤70 years of age (3). Patients > 70 years of age may be considered for cardiac transplantation at the discretion of the transplant program and should theoretically be in excellent health except for heart disease. An alternate type of program has been proposed for these patients, whereby older donor hearts would be utilized in this population (3).
Active malignancy other than skin cancer is an absolute contraindication to cardiac transplantation due to limited survival rates. Chronic immunosuppression is associated with a higher than average incidence of malignancy and is associated with increased recurrence of prior malignancy. Patients with cancers that have been in remission for ≥5 years and patients with low-grade cancers such as prostate cancer are generally accepted for transplant evaluation. Preexisting malignancies are heterogeneous in nature and some are readily treatable with chemotherapy. Thus an individualized approach to these patients is required, and consultation with an oncologist regarding prognosis is often very helpful.
Traditionally, centers have been cautious when considering obese patients for transplantation. Most currently available data indicate that patients with a pretransplant body mass index (BMI) > 30 kg/m2 have poor outcomes following cardiac transplantation, with increased rates of infection and higher mortality rates. However, this area remains controversial and some recent data presented in abstract form only demonstrate no significant mortality differences between obese (BMI, 30 to 34.99) transplant recipients and overweight (BMI, 25 to 29.99) transplant recipients. Despite this controversy, the current ISHLT recommendations are that patients achieve a BMI < 30 kg/m2 or a percent ideal body weight < 140% prior to being listed for cardiac transplantation (3). This cutoff will vary from center to center, but generally a BMI > 35 kg/m2 will preclude listing for cardiac transplantation.
E. Consultations
A psychosocial assessment is a crucial component of every cardiac transplant evaluation. Accepted psychosocial contraindications for cardiac transplantations include active smoking; active substance abuse, including alcohol; medical noncompliance; and significant untreated psychologic or psychiatric diagnoses.
Relative psychosocial contraindications to cardiac transplantation include posttraumatic stress disorder and lack of an adequate support structure.
For diabetic patients, an ophthalmology consultation is obtained for an assessment of retinal end-organ damage related to the diabetes.
IV. UNOS AND THE RECIPIENT LIST.
After a patient is accepted as a potential cardiac transplant recipient by a UNOS-certified transplant program, the patient’s name is entered on a national list compiled by UNOS. The patient is given a status level based on predefined clinical criteria (Table 13.3), which can be adjusted as the patient’s clinical situation evolves. A patient’s priority on the UNOS list depends on his or her status level and the duration of time on the list. Highest priority is given to patients with status 1A and those who have been waiting the longest. A critical patient initially listed as status 1A immediately has a higher priority than a patient with a status 1B, regardless of the duration of time spent as status 1B. Whether a patient is hospitalized or not does not affect priority on the list, other than the fact that hospitalized patients are more likely to be receiving hemodynamic support (mechanical or inotropic) and are
at a higher status level. A hospitalized patient on continuous inotropic therapy has the same status as a similar patient on home continuous inotropic therapy. Patients on home continuous inotropic therapy awaiting cardiac transplantation are generally thought to have an increased mortality related to the proarrhythmic effect of inotropic therapy, and most programs require implantation of an intracardiac defibrillator as a prerequisite for discharge.
at a higher status level. A hospitalized patient on continuous inotropic therapy has the same status as a similar patient on home continuous inotropic therapy. Patients on home continuous inotropic therapy awaiting cardiac transplantation are generally thought to have an increased mortality related to the proarrhythmic effect of inotropic therapy, and most programs require implantation of an intracardiac defibrillator as a prerequisite for discharge.
TABLE 13.3 Description of Status Levels in the United Network of Organ Sharing List | ||||||||||||||||||||||||||||||||||||||||||||
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V. WORKUP OF A POTENTIAL CARDIAC DONOR.
Potential cardiac donors are patients who are declared brain dead but otherwise have viable internal organs. Generally, these are patients with lethal head injuries or catastrophic central nervous system events (i.e., intracranial hemorrhage, stroke, or cerebral anoxia).
A. Declaration of brain death.
A neurologist or a neurosurgeon usually declares the brain death of a potential organ donor. Usually, this declaration is made after a period of observation (about 12 hours) during which no neurologic improvement is seen. Physicians involved in the care of potential transplant recipients are not involved in this decision to avoid conflicts of interest. Criteria for the determination of brain death are very specific. Absence of any one of the following criteria makes the patient ineligible for organ donation.
A known cause of death
Absence of hypotension, hypothermia, hypoxemia, and metabolic perturbations
Absence of medical or recreational drugs known to depress the central nervous system
Absence of cerebral cortical function
No response to painful stimuli
Absence of brainstem reflexes
Pupillary constriction to light
Corneal reflex
Vestibular ocular reflexes (i.e., doll’s eyes or cold caloric testing)
Gag reflex
Cough reflex
Positive apnea test: no spontaneous respiration despite arterial Pco2 > 60 mm Hg for at least 10 minutes after disconnection from the ventilator
An electroencephalogram (EEG) is not required but may be performed at the discretion of the examining physician. The EEG should demonstrate electrical silence.
B. Potential donor screening.
After a patient is declared brain dead, a local organ procurement organization (OPO), under the auspices of UNOS, performs the initial evaluation of a potential donor. This evaluation includes a thorough patient and family history, focusing specifically on cardiac risk factors and potentially transmittable diseases (i.e., malignancy and infection). Preliminary blood tests are done, including determinations of cardiac enzymes; serologies for hepatitis B and C viruses, HIV, toxoplasmosis, and CMV; ABO blood group typing; and HLA antigen typing. An echocardiogram is routinely performed to assess the cardiac function and to rule out congenital anomalies and valvular disease. At the request of the potential recipient’s physician, a coronary angiogram may be obtained if a donor has significant cardiac risk factors, has positive cardiac enzymes, or is relatively advanced in age. Cardiac donor selection criteria are summarized in Table 13.4.
If the potential recipient also has elevated PRA levels, a prospective complement-dependent antibody-mediated lymphocytotoxic crossmatch is usually performed, in which the recipient’s serum is incubated with donor lymphocytes to identify potential donor—recipient HLA incompatibility. Many centers today perform a “virtual crossmatch” for patients with elevated PRA levels to improve donor availability. With the HLA technologies available today, the exact antigen specificity of the recipients’ anti-HLA antibodies is known. If the HLA tissue typing of the potential donor
does not include the antigens against which the recipient is sensitized, it is assumed that the actual crossmatch will be negative (i.e., a “virtual” negative crossmatch). If a prospective crossmatch is not performed, a retrospective crossmatch (by lymphocy-totoxic assay or by flow cytometry) is performed using donor lymphocytes obtained from donor aortic lymph nodes retrieved at the time of harvest.
does not include the antigens against which the recipient is sensitized, it is assumed that the actual crossmatch will be negative (i.e., a “virtual” negative crossmatch). If a prospective crossmatch is not performed, a retrospective crossmatch (by lymphocy-totoxic assay or by flow cytometry) is performed using donor lymphocytes obtained from donor aortic lymph nodes retrieved at the time of harvest.
TABLE 13.4 Cardiac Donor Selection Criteria | |||||||||||
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C. Donor—recipient matching.
UNOS maintains a computerized list of all patients listed and waiting for cardiac transplantation. A list of potential recipients with compatible blood types is generated for each potential donor organ and is made available to the OPO. In this list, priority is given to local patients (defined as within the OPO’s territory) with the highest status level who have been waiting the longest. Recent changes to the UNOS donor net criteria mean that a local status 2 patient is no longer higher on the list than a status 1A patient from outside the OPO’s territory.
Transplant physicians of the potential recipient may also reject a potential organ because of a positive prospective crossmatch, donor—recipient size mismatch, or a prolonged projected ischemic time (usually related to long-distance travel). Matching donor and recipient size is important, because an oversized donor organ may not allow closure of the chest without compression of the organ and an undersized donor organ may not be able to pump a sufficient quantity of blood. Current guidelines suggest that the recipient’s weight should range between 70% and 130% of a potential donor’s weight (4).
VI. SURGICAL ISSUES RELATED TO CARDIAC TRANSPLANTATION.
Most surgical issues related to cardiac transplantation are beyond the scope of this chapter and are mainly of interest to the cardiac surgeon. The main surgical issue of interest to the transplant cardiologist is related to the anastomosis of the right atrium. The surgeon may suture the donor atrium to the recipient atrium (i.e., biatrial anastomosis) or suture the donor superior vena cava to the recipient superior vena cava and the donor inferior vena cava to the recipient inferior vena cava (i.e., bicaval anastomosis). The bicaval anastomosis approach is more time consuming but reduces the incidence of atrial arrhythmias (including sinus
node dysfunction), reduces the incidence of posttransplant tricuspid regurgitation, and improves right atrial hemodynamics. The bicaval anastomosis approach does, however, provide some potential difficulties to the cardiologist trying to perform surveillance EMBs, because these anastomoses have a tendency to scar and narrow the central lumen over time. Currently, most centers employ the bicaval anastomosis approach, although no survival advantage has been conclusively demonstrated with this approach.
node dysfunction), reduces the incidence of posttransplant tricuspid regurgitation, and improves right atrial hemodynamics. The bicaval anastomosis approach does, however, provide some potential difficulties to the cardiologist trying to perform surveillance EMBs, because these anastomoses have a tendency to scar and narrow the central lumen over time. Currently, most centers employ the bicaval anastomosis approach, although no survival advantage has been conclusively demonstrated with this approach.
VII. POSTOPERATIVE COMPLICATIONS AFTER CARDIAC TRANSPLANTATION
A. Surgical complications.
The most common surgical complication is the development of a pericardial effusion with or without tamponade. Pericardial effusions are very common because of the large potential space left behind as the dilated and dysfunctional recipient left ventricle is replaced with a more appropriately sized donor left ventricle. Rarely, pericardial tamponade develops, necessitating percutaneous or surgical evacuation of the pericardium. Other surgical complications are much less common but can be catastrophic and usually result from a problem either at a site of anastomosis or at a site of cannulation.
B. Early graft dysfunction
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