The evaluation of potential candidates for cardiac transplantation is performed by a multidisciplinary committee to ensure the equitable, objective, and medically justified allocation of donor organs to those patients most likely to achieve long-term benefit. It is very important to establish a mutual long-term working relationship among patient, social support system, and the entire team at the beginning of this process.
Indications and potential contraindications for cardiac transplantation are outlined in Table 64-1.1 These inclusion and exclusion criteria can vary somewhat among transplantation centers.1–4 The basic objective is to identify those relatively healthy patients with end-stage cardiac disease, refractory to other appropriate medical and surgical therapies, who possess the potential to resume a normal active life and maintain compliance with a rigorous medical regimen after cardiac transplantation.
Table 64-1 Recipient Selection for Heart Transplantation ||Download (.pdf)
Table 64-1 Recipient Selection for Heart Transplantation
|I. Systolic heart failure (as defined by ejection fraction >35%)|
|A. Inclusive etiology|
|B. Excluded etiology|
|1. Amyloid (controversial)|
|2. HIV infection|
|3. Cardiac sarcoma|
|II. Ischemic heart disease with intractable angina|
|A. Ineffective maximal tolerated medical therapy|
|B. Not a candidate for direct myocardial revascularization, percutaneous revascularization, or transmyocardial revascularization procedure|
|C. Unsuccessful myocardial revascularization|
|III. Intractable arrhythmia|
|A. Uncontrolled with pacing cardioverter defibrillator|
|1. Not amenable to electrophysiology-guided single or combination medical therapy|
|2. Not a candidate for ablative therapy|
|IV. Hypertrophic cardiomyopathy|
|A. Class IV symptoms persist despite interventional therapies|
|1. Alcohol injection of septal artery|
|2. Myotomy and myomectomy|
|3. Mitral valve replacement|
|4. Maximal medical therapy|
|5. Pacemaker therapy|
|V. Congenital heart disease in which severe fixed pulmonary hypertension is not a complication|
|VI. Cardiac tumor|
|A. Confined to the myocardium|
|B. No evidence of distant disease revealed by extensive metastatic workup|
|I. Age <70 years (may vary at different centers)|
|II. Fixed pulmonary hypertension (unresponsive to pharmacologic intervention)|
|A. Pulmonary vascular resistance <5 Wood units|
|B. Transpulmonary gradient <15 mm Hg|
|III. Systemic illness that will limit survival despite transplant|
|A. Neoplasm other than skin cancer (<5 years disease-free survival)|
|B. HIV/AIDS (CDC definition of CD4 count of <200 cells/mm3)|
|C. Systemic lupus erythematosus (SLE) or sarcoid that has multisystem involvement and is currently active|
|D. Any systemic process with a high probability of recurrence in the transplanted heart|
|E. Irreversible renal or hepatic dysfunction|
|POTENTIAL RELATIVE CONTRAINDICATIONS|
|I. Recent malignancy|
|II. Chronic obstructive pulmonary disease|
|III. Recent and unresolved pulmonary infarction and pulmonary embolism|
|IV. Diabetes mellitus with end-organ damage (neuropathy, nephropathy, and retinopathy)|
|V. Peripheral vascular or cerebrovascular disease|
|VI. Active peptic ulcer disease|
|VI. Current or recent diverticulitis|
|VIII. Other systemic illness likely to limit survival or rehabilitation|
|IX. Severe obesity or cachexia|
|X. Severe osteoporosis|
|XI. Active alcohol or drug abuse|
|XII. History of noncompliance or psychiatric illness likely to interfere with long-term compliance|
|XIII. Absence of psychosocial support|
Etiology of End-Stage Cardiac Failure
Determination of the etiology and potential reversibility of end-stage heart failure is critical for the selection of transplant candidates. Overall, from 1982 to 2008, the indications for heart transplantation in adult recipients have been overwhelmingly ischemic heart failure and nonischemic cardiomyopathy (approximately 90%); with valvular (2 to 3%), adult congenital (2%), retransplantation (2%), and miscellaneous causes comprising the remainder.5
The perception of the irreversibility of advanced cardiac failure is changing with the growing efficacy of tailored medical therapy, high-risk revascularization procedures, and newer antiarrhythmic pharmacologic agents, as well as implantable defibrillators and biventricular pacing. Additionally, other surgical modalities, such as ventricular assist devices (VADs) and surgical ventricular restoration (SVR) have found increasing application.6,7 Furthermore, it is important to consider that prognosis may differ in patients with cardiomyopathy who have neither ischemic nor valvular heart disease. Caution should be exercised when judging prognosis in these patient subgroups, and a period of observation, intense pharmacologic therapy, and/or mechanical support should be undertaken before heart transplantation is considered.4
Evaluation of the Potential Cardiac Transplant Recipient
The complexity of the recipient evaluation mandates a team approach. The initial evaluation involves a comprehensive history and physical examination because this will help to determine etiology and contraindications. Table 64-23 summarizes the cardiac transplant evaluation tests. Routine hematologic and biochemical analyses and pertinent tests as illustrated by organ system are performed.
Table 64-2 Cardiac Transplant Evaluation Tests ||Download (.pdf)
Table 64-2 Cardiac Transplant Evaluation Tests
Complete blood count with differential and platelet count, creatinine, blood urea nitrogen, electrolytes, liver panel, lipid panel, calcium, phosphorus, total protein, albumin, uric acid, thyroid panel, antinuclear antibodies, erythrocyte sedimentation rate (ESR), rapid plasma reagin (RPR), iron-binding tests, partial thromboplastin time, prothrombin time
Blood type, IgG and IgM antibodies against cytomegalovirus, herpes simplex virus, HIV, varicella-zoster virus, hepatitis B surface antigen, hepatitis C antigen, toxoplasmosis, other titers when indicated
Tuberculin skin test
Prostate-specific antigen (male >50 years)
Mammogram and Pap smear (female >40 years)
Screening against a panel of donor antigens (panel reactive antibodies) and human leukocyte antigen phenotype
24-Hour urine for creatinine clearance and total protein, urinalysis, urine culture
Baseline bacterial and fungal cultures, stool for ova and parasites if indicated
12-lead ECG, 24-hour Holter monitor
Thallium-201 imaging, positron-emission tomographic (PET) scan, or cardiac magnetic resonance imaging (MRI) to assess viability if indicated
Exercise stress test and respiratory gas analysis with oxygen uptake measurements: peak exercise oxygen consumption (V̇O2,max)
Right- and left-sided heart catheterization at the transplant center
Myocardial biopsy on selected patients in whom etiology of heart failure is in question
Peripheral vascular studies
Carotid Doppler and duplex ultrasound 55 years
|Renal||Renal ultrasound and or intravenous pyelogram if indicated|
Pulmonary function tests
Chest CT scan to evaluate abnormal chest x-ray or thoracic aorta in older patients (usually >65 years)
Upper endoscopy/colonoscopy if indicated
Upper gastrointestinal series and/or barium enema if indicated
Percutaneous liver biopsy if indicated
|Dental||Complete dental evaluation|
|Social work||Patient attitude and family support, medical insurance, and general financial resources|
For the assessment of the heart itself, in addition to routine 12-lead electrocardiogram, Holter monitor, and echocardiography, all patients should undergo cardiopulmonary exercise testing to evaluate functional capacity if disease severity allows. Peak exercise oxygen consumption measured during maximal exercise testing V̇O2,max provides a measure of functional capacity and cardiovascular reserve, and an inverse relationship between V̇O2,max and mortality in heart failure patients has been demonstrated.8 Documentation of adequate effort during exercise, as evidenced by attaining a respiratory exchange ratio greater than 1.0 or achievement of an anaerobic threshold at 50 to 60% of V̇O2,max is necessary to avoid underestimation of functional capacity.2 Right-sided heart catheterization should be performed at the transplanting center to evaluate the severity of heart failure (and hence the status level for transplant listing) and evaluate for the presence of pulmonary hypertension. Right heart catheterization also can help guide therapy while awaiting transplantation. Coronary cineangiography should be reviewed to confirm the inoperability of coronary artery lesions in cases of ischemic cardiomyopathy. As well, either a positron emission tomographic (PET) scan, a thallium-201 redistribution study, or a cardiac magnetic resonance imaging (MRI) study should assess viability in selected patients who would be candidates for revascularization if sufficient viability is present.2,3 Endomyocardial biopsy should be performed on all patients in whom the etiology of heart failure is in question, especially those with nonischemic cardiomyopathies symptomatic for fewer than 6 months.3 This can assist in therapeutic decision making and exclude diagnoses such as amyloidosis, which are considered relative contraindications to transplantation.
The neuropsychiatric assessment should be performed by persons experienced in evaluating cardiac patients to determine if organic brain dysfunction or psychiatric illness is present. An experienced social worker should assess for the presence of adequate social and financial support. At the time of listing, the transplant coordinator should ensure that the patient and family understand the peculiarities of the waiting time, preoperative period, long-term maintenance medications, and the rules of living with the new heart. It is also of paramount importance that providers discuss the patient's preferences with regard to life support (duration and type), in case of a deterioration in his or her condition while awaiting transplant.
Indications for Cardiac Transplantation
Cardiac transplantation is reserved for a select group of patients with end-stage heart disease not amenable to optimal medical or surgical therapies. Prognosis for 1-year survival without transplantation should be less than 50%. Prediction of patient survival involves considerable subjective clinical judgment by the transplant committee because no reliable objective prognostic criteria are available currently. Low ejection fraction (<20%), reduced V̇O2,max (<14 mL/kg/min), arrhythmias, high pulmonary capillary wedge pressure (>25 mm Hg), elevated plasma norepinephrine concentration (>600 pg/mL), reduced serum sodium concentration (<130 mEq/dL), and more recently N-terminal probrain natriuretic peptide (>5000 pg/mL) all have been proposed as predictors of poor prognosis and potential indications for transplantation in patients receiving optimal medical therapy.8–11 Reduced left ventricular ejection fraction and low V̇O2,max are widely identified as the strongest independent predictors of survival.
The indications for cardiac transplantation listing are continuously reviewed as new breakthroughs in the medical and surgical treatment of heart disease emerge.
Contraindications for Cardiac Transplantation
Table 64-1 lists the traditional absolute and relative contraindications. It should be acknowledged that strict guidelines can be problematic; therefore, each transplant program varies regarding absolute criteria based on clinical circumstances and experience. Furthermore, traditional contraindications for transplant listing are being questioned. Age is one of the most controversial exclusionary criteria for transplantation. The upper age limit for recipients is center-specific, but emphasis should be placed on the patient's physiologic rather than chronologic age. The Official Adult Heart Transplant Report 2009 from the registry of the International Society for Heart and Lung Transplantation (ISHLT) noted that over the last 25 years, the percentage of recipients older than 60 years of age has increased steadily, approaching 25% of all heart transplants between 2002 and 2008 compared with just above 5% between 1982 and 1988.5 Although the elderly have a greater potential for occult systemic disease that may complicate their postoperative course, some recent reports have suggested that morbidity and mortality in carefully selected older patients are comparable with those of younger recipients, and they have fewer rejection episodes than younger patients.12,13
Fixed pulmonary hypertension (PH), usually manifested as elevated pulmonary vascular resistance (PVR), is one of the few absolute contraindications to orthotopic cardiac transplantation. Fixed PH increases the risk of acute right ventricular failure when the right ventricle of the allograft is unable to adapt to significant PH in the immediate postoperative period.14 Use of the transpulmonary gradient (TPG), which represents the pressure gradient across the pulmonary vascular bed independent of blood flow, may avoid erroneous estimations of PVR, such as those that may occur in patients with low cardiac output.4 Some have advocated the use of PVR index (PVRI) unit, which corrects for body size.
where MPAP is mean pulmonary arterial pressure, PCWP is pulmonary capillary wedge pressure, CO is cardiac output, CI is cardiac index, and BSA is body surface area.
A fixed PVR greater than 5 to 6 Wood units and a TPG greater than 15 mm Hg generally are accepted as absolute criteria for rejection of a candidate.1–4,11 Over the years, several studies have found PH to have a significant effect on posttransplant mortality using various parameters, threshold values, and follow-up periods.15,16 However, a lack of mortality difference after heart transplantation between patients with and without preoperative PH has also been reported.17 Perhaps more significantly, measurable parameters of pulmonary hypertension have been shown to improve following heart transplantation. A study of 172 patients followed for up to 15.1 years, published in 2005 from the Johns Hopkins Hospital, showed that mild to moderate pretransplantation PH (PVR = 2.5 to 5.0 Wood units) was not associated with higher mortality rate, although there was increased risk of posttransplantation PH within the first 6 months.18 However, when the continuous variable PVR was examined, each 1 Wood unit increase in preoperative PVR demonstrated a 15% or more increase in mortality, especially within the first year, but these associations did not reach statistical significance. Severe preoperative PH (PVR ≥ 5 Wood units) was associated with death within the first year after adjusting for potential cofounders but not with overall mortality or mortality beyond the first year.
In the preoperative evaluation of the transplant recipient, if PH is discovered, an assessment of its reversibility should be performed in the cardiac catheterization laboratory.16 Sodium nitroprusside traditionally has been used at a starting dose of 0.5 μg/kg per minute and titrated by 0.5 μg/kg per minute until there is an acceptable decline in PVR, ideally 2.5 Wood units or at least by 50%, with maintenance of adequate systemic systolic blood pressure. If sodium nitroprusside fails to produce an adequate response, other vasodilators such as adenosine, prostaglandin E1, milrinone, or inhaled nitric oxide or prostacyclin (eg, aerosolized Iloprost) may be used.2,19 Some patients who do not respond acutely may respond to continuous intravenous inotropic therapy, and repeat catheterization can be performed after 48 to 72 hours. Intravenous B-type natriuretic peptide, eg, nesiritide (Natrecor), has shown some efficacy in refractory pulmonary hypertension.20 Recently, ventricular assist devices (VADs) are playing an important role in heart transplantation candidates with PH.21 A period of left ventricular assist device (LVAD) support may allow for a decrease of pulmonary artery pressure secondary to unloading of the left ventricle. Patients with irreversible PH may be candidates for heterotopic heart transplantation, heart-lung transplantation, or LVAD destination therapy.22 Use of modestly larger donor hearts for recipients with severe pretransplantation PH can provide additional right ventricular reserve.
Systemic diseases with poor prognosis and potential to recur in the transplanted heart or the potential to undergo exacerbation with immunosuppressive therapy are considered absolute contraindications for heart transplantation. Heart transplantation for amyloid remains controversial because amyloid deposits recur in the transplanted heart. Although case reports of long-term survival can be found in the literature,23 survival beyond 1 year tends to be reduced.24 Human immunodeficiency virus (HIV)–infected patients generally are excluded. Previously, any occurrence of neoplasm was a reason to exclude patients from transplantation. Currently available data do not appear to justify excluding some of these patients.25 Most programs will consider patients who are free of disease for at least 5 years.
Irreversible renal dysfunction is a contraindication to heart transplantation. A creatinine clearance of less than 50 mL/min and a serum creatinine concentration of greater than 2 mg/dL are associated with increased risk of postoperative dialysis and decreased survival following heart transplantion.4,26 However, patients may be considered for combined heart and kidney transplantation. Irreversible hepatic dysfunction has implications similar to renal dysfunction.4 If transaminase levels are more than twice their normal value and associated with coagulation abnormalities, percutaneous liver biopsy should be performed to exclude primary liver disease. This should not be confused with chronic cardiac hepatopathy, which is characterized by elevated cholestatic parameters along with little or no changes in transaminases and is potentially reversible after heart transplantation.27
Severe chronic bronchitis or obstructive pulmonary disease may predispose patients to pulmonary infections and may result in prolonged ventilatory support after heart transplantation. Patients who have a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of less than 40 to 50% of predicted or an FEV1 of less than 50% of predicted despite optimal medical therapy are considered poor candidates for transplantation.2,4 Transplantation in patients with diabetes mellitus is only contraindicated in the presence of significant end-organ damage (eg, diabetic nephropathy, retinopathy, or neuropathy).2,4 Some centers have expanded their criteria successfully to include patients with mild to moderate end-organ damage.28 Active infection was a sound reason to delay transplantation before assist devices became more commonplace. Up to 48% of patients with implanted LVADs reportedly have evidence of infection. Interestingly, treatment for LVAD infection in these patients is to proceed with urgent transplantation.29
Other relative contraindications include severe noncardiac atherosclerotic disease, severe osteoporosis, and active peptic ulcer disease or diverticulitis, all of which may lead to increased morbidity.2,4 Cachexia, defined as a body mass index (BMI) of less than 20 or less than 80% ideal body weight (IBW), and obesity, defined as BMI greater than 35 or greater than 140% of IBW, are associated with increased mortality after transplantation.30 Poor nutritional status also may limit early postoperative rehabilitation.
The ultimate success of transplantation depends on the psychosocial stability and compliance of the recipient.31 The rigorous postoperative regimen of multidrug therapy, frequent clinic visits, and routine endomyocardial biopsies demand commitment on the part of the patient. A history of psychiatric illness, substance abuse, or previous noncompliance (particularly with medical therapy for end-stage heart failure) may be sufficient cause to reject the candidacy of a patient. Lack of a supportive social system is an additional relative contraindication.
Management of the Potential Cardiac Recipient
Preformed Anti-HLA Antibodies
Patients with elevated levels of preformed panel reactive antibodies (PRAs) to human leukocyte antigens (HLAs) have higher rates of organ rejection and decreased survival than do patients without such antibodies.32 Consequently, before proceeding with transplantation, many medical centers do prospective cross-matching, ie, either by flow cytometry or ELISA, to determine whether a donor-specific antibodies that threaten the allograft are present. The problem has been compounded by the increased frequency of preformed reactive antibodies in patients with VADs who are awaiting cardiac transplantation.33 Furthermore, not all antibodies are complement fixing or dangerous. Performing a prospective cross-match can be time consuming and often is impossible because of the unstable condition of the organ donor or travel logistics, leading to increased costs for transplantation and longer waiting times for recipients. Recently, virtual cross-matching has been used to eliminate the need for prospective tissue cross-matching. Modern laboratory techniques allow for identification and titer of antibodies. Because all donor antigens are known at the time of allocation, an assessment can be made without an actual tissue/sera assay. However, a particular patient's antibody population is dynamic and may change from the time of the antibody screen. As a result, care must be taken in patients with particularly diverse and high antibody titers. Plasmapheresis, intravenous immunoglobulins, cyclophosphamide, mycophenolate mofetil, and rituximab all have been used to lower the PRA levels with variable results.2
Pharmacologic Bridge to Transplantation
Critically compromised patients require admission to the intensive care unit for intravenous inotropic therapy. Dobutamine, a synthetic catecholamine, remains the prototype of this drug group. However, the phosphodiesterase III inhibitor milrinone is similarly effective.34 The catecholamine dopamine is used often as a parenteral positive inotrope, but at moderate to high dose it evokes considerable systemic vasoconstriction. In candidates in whom an inotropic infusion has progressed to higher doses, combinations of dobutamine with milrinone are used. For transplant candidates dependent on inotropic infusions, eosinophilic myocarditis may develop as an allergic response to the dobutamine and may result in accelerated decline. VADs are being considered earlier, particularly as indices of nutrition decline.
Mechanical Bridge to Transplantation
Placement of an intra-aortic balloon pump (IABP) may be necessary in patients with heart failure who are refractory to initial pharmacologic measures. Ambulatory IABP through the axillary artery has been reported in few patients as a bridge to cardiac transplantation but is not commonly used today.35
The landmark Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure (REMATCH) trial provided evidence that LVAD support provided a statistically significant reduction in the risk of death from any cause when compared with optimal medical management. The survival rates for patients receiving LVADs (n = 68) versus patients receiving optimal medical management (n = 61) were 52% versus 28% at 1 year and 29% versus 13% at 2 years (p = .008, log-rank test).6,36 The extended follow-up confirmed the initial observation that LVAD therapy renders significant survival and quality-of-life benefits compared with optimal medical management for patients with end-stage heart failure. A recent systematic review of the published literature supported these findings. In the studies reviewed, implantation of an LVAD provided support for up to 390 days, with as many as 70% of patients surviving to transplantation.37
The total artificial heart (TAH) positioned orthotopically replaces both native cardiac ventricles and all cardiac valves. Potential advantages of this device include eliminating problems commonly seen in the bridge to transplantation with left ventricular and biventricular assist devices, such as right-sided heart failure, valvular regurgitation, cardiac arrhythmias, ventricular clots, intraventricular communications, and low blood flows. Copeland and colleagues reported that the TAH allowed for bridge to transplantation in 79% of their patients with 1- and 5-year survival rates after transplantation of 86 and 64%, respectively.38
Because these devices cannot be weaned, it is imperative that the patient's candidacy for transplantation be scrutinized before placement of the device. Trends toward better device durability and reduced complication rates likely will continue to improve through the development of newer, more innovative VADs, allowing destination therapy to be considered more frequently.
Life-Threatening Ventricular Arrhythmias
Symptomatic ventricular tachycardia and a history of sudden cardiac death are indications for placement of an automatic implantable cardioverter-defibrillator (AICD), long-term antiarrhythmic therapy with amiodarone, or occasionally, radiofrequency catheter ablation, which have been shown to improve survival.39
Recipient Prioritization for Transplantation
The prioritization of appropriate recipients for transplantation is based on survival and quality of life expected to be gained in comparison with maximal medical and surgical alternatives.3 The United Network for Organ Sharing (UNOS) is a national organization that maintains organ transplantation waiting lists and allocates identified donor organs on the basis of recipients' priority status. This priority status is based on a recipient's status level (eg, IA, IB, or II), blood type, body size, and duration of time at a particular status level.2 Geographic distance between donor and potential recipient is also taken into consideration. Highest priority is given to local status IA patients possessing the earliest listing dates. The recipient status criteria established by UNOS in 1999 are outlined in Table 64-3. In 1994, the percentage of patients awaiting transplantation for more than 2 years was 23%; this increased to 49% by 2003. From 1998 (with the institution of a new status system) to 2007, the distribution of patient status at transplant changed dramatically. In 1999, the distribution was 34% (1A), 36% (1B), and 26% (2). This shifted in 2007 to 50% (1A), 36% (1B), and 14% (2).40
Table 64-3 Current Recipient Status Criteria of the United Network for Organ Sharing (UNOS)* ||Download (.pdf)
Table 64-3 Current Recipient Status Criteria of the United Network for Organ Sharing (UNOS)*
|A. Patients who require mechanical circulatory assistance with one or more of the following devices:|
|1. Total artificial heart|
|2. Left and/or right ventricular assist device implanted for 30 days or less|
|3. Intra-aortic balloon pump|
|4. Extracorporeal membrane oxygenator (ECMO)|
|B. Mechanical circulatory support for more than 30 days with significant device-related complications|
|C. Mechanical ventilation|
|D. Continuous infusion of high-dose inotrope(s) in addition to continuous hemodynamic monitoring of left ventricular filling pressures|
|E. Life expectancy without transplant <7 days|
|A. A patient who has at least one of the following devices or therapies in place:|
|1. Left and/or right ventricular assist device implanted for >30 days|
|2. Continuous infusion of intravenous inotropes|
|All other waiting patients who do not meet status Ia or Ib criteria|
Patients considered for transplantation should be examined at least every 3 months for reevaluation of recipient status. Yearly right-sided heart catheterization is indicated for all candidates on the waiting list and in selected cases for patients rejected because of pulmonary hypertension. Presently, there is no established method to delist patients who have stabilized on medical therapy without loss of their previously accrued waiting time.