The number of patients with heart failure is growing. End-stage heart failure is associated with significant morbidity, need for recurrent hospitalizations, decrease in quality of life, and increased mortality. Cardiac transplantation has evolved as an effective therapy for many of these patients. Tremendous advancements in the fields of immunosuppression, rejection, and infection have transformed what was once considered an experimental intervention into a routine treatment available worldwide.

The innovative French surgeon Alexis Carrel performed the first heterotopic canine heart transplant with Charles Guthrie in 1905. Frank Mann at the Mayo Clinic further explored the idea of heterotopic heart transplantation in the 1930s. The neck became the preferred site of implantation in early experimental animal models because of the ease of monitoring the organ, the simplicity of access to major vessels, and because the recipient’s native heart could serve as a built-in cardiac assist device for the transplanted organ. Mann also proposed the concept of cardiac allograft rejection, in which biological incompatibility between donor and recipient was manifested as a leukocytic infiltration of the rejecting myocardium. In 1946, after unsuccessful attempts in the inguinal region, Vladimir Demikhov of the Soviet Union successfully implanted the first intrathoracic heterotopic heart allograft. He later demonstrated that heart-lung and isolated lung transplantation also were technically feasible.

The use of moderate hypothermia, cardiopulmonary bypass, and an atrial cuff anastomotic technique permitted Norman Shumway (Fig. 60-1) and Richard Lower at Stanford University to further explore orthotopic heart transplantation using a canine model in 1960.

The first human cardiac transplant was a chimpanzee xenograft performed at the University of Mississippi by James Hardy in 1964. Although the procedure using Shumway’s technique was technically satisfactory, the primate heart was unable to maintain the recipient’s circulatory load and the patient succumbed several hours postoperatively.

Despite great skepticism that cardiac transplantation ever would be performed successfully in humans, South African Christiaan Barnard surprised the world when he performed the first human-to-human heart transplant on December 3, 1967. Over the next several years, poor early clinical results led to a moratorium on heart transplantation, with only the most dedicated centers continuing experimental and clinical work in the field. The pioneering efforts of Shumway and colleagues at Stanford eventually paved the way for the reemergence of cardiac transplantation in the late 1970s.

The introduction of transvenous endomyocardial biopsy by Philip Caves in 1973 finally provided a reliable means for monitoring allograft rejection. Ultimately, however, it was the advent of the immunosuppressive agent cyclosporine that dramatically increased patient survival and marked the beginning of the modern era of successful cardiac transplantation in 1981.

Heart transplantation is now a widely accepted therapeutic option for end-stage cardiac failure; however, the annual number of transplants in the United States (approximately 2400 per year) has slowly increased since 2002, however, limited donor-organ availability remains a major limitation (from United Network for Organ Sharing [UNOS] data, through September 2012).

Recipient Selection

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 60-1.¹ 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.

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 2012, the indications for heart transplantation in adult recipients have been overwhelmingly ischemic heart failure and nonischemic cardiomyopathy (approximately 90%); with valvular (2-3%), 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 60-2 summarizes the cardiac transplant evaluation tests.³ Routine hematologic and biochemical analyses and pertinent tests as illustrated by organ system are performed.³

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 V̇O_2,max provides a measure of functional capacity and cardiovascular reserve, and an inverse relationship between V̇O_2,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 V̇O_2,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 (PH). 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 V̇O_2,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 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 V̇O_2,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 60-1 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 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 PH 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 (PGE₁), 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 PH.²⁰ Recently, 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. 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.²³ Most programs will consider patients who are free of disease for at least 5 years. A recent multicenter study investigated the influence of pretransplant malignancy on posttransplant recurrence and long-term survival in heart and lung transplant recipients. In this cohort, 111 recipients (lung: 37; heart: 74) with 113 pretransplant malignancies were identified. The cohort was divided into 3 groups by pretransplant cancer-free interval of <12 months, ≥12 to 60 months, and ≥60 months. Pretransplant cancer-free survival of ≥5 years was associated with the lowest recurrence at a mean follow-up of 70 ± 63 months (6% at ≥60 months vs 26% at 12 to 60 months vs 63% at <12 months). Survival was significantly poorer in those cancer-free for <12 months, whereas there was no survival difference in the other 2 groups. Further study is warranted to determine the optimal malignancy-free period.²⁴ 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,²⁵ survival beyond 1 year tends to be reduced.²³

Human immunodeficiency virus (HIV)-infected patients generally were excluded until a recent case series by the Columbia University Heart Transplant Group. With the newer antiretroviral drugs, the estimated 10-year survival after seroconversion exceeds 90%. In a retrospective single-center analysis of 1679 cardiac transplant patients, seven HIV-positive patients underwent heart transplantation. Five (4 men) were diagnosed with HIV before transplantation and 2 patients seroconverted after transplantation. Dilated cardiomyopathy was the indication for transplant in all patients. The 5 HIV recipients were aged 42 ± 8 years, and time after HIV seroconversion averaged 9.5 years. All underwent cardiac transplantation as high-risk candidates. The CD4 count was 554 ± 169 cells/microl, and viral load was undetectable in all patients at the time of transplantation. Two patients seroconverted to HIV-positive status at 1 and 7 years after transplant. No AIDS-defining illness was observed in any patient before or after transplant. Six patients received highly active antiretroviral therapy. Viral load remained low in the presence of immunosuppression. All patients were alive with a follow-up from transplant of 57 ± 78.9 months.^26,27

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.^4,28 The effect of chronic kidney dysfunction (CKD) on post-HTx outcomes was recently examined in 1732 recipients. In this population, 3% were CKD stage 4 and 5 at the time of transplant, increasing to 11% at 1 year and more than 15% at 6 years after transplantation. The risk of death was significantly higher in patients with CKD 4 and 5 (hazard CKD4:1.66; CKD5:8.54; dialysis:4.07). Multiorgan transplantation was not assessed in this cohort.²⁹ 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.³⁰ The use of MELD and MELD-XI (excluding international normalized ratio) were shown to be predictive of survival after heart transplantation and VAD. Moreover, if the MELD-XI normalized during VAD support, posttransplant survival was similar to those without prior liver dysfunction. In VAD patients with an elevated MELD-XI score, a decrease in score <17 may help identify optimal transplant candidates.^31,32

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.³³

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.³⁴

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.³⁵ Poor nutritional status also may limit early postoperative rehabilitation. The effect of metabolic risk factors (hypertension, diabetes, obesity) was assessed in 15,960 recipients using an analysis of the UNOS Registry (1998-2008). Individually, these risk factors increased the risk of death posttransplant, with a hazard ratio of 1.10 for hypertension, 1.22 for diabetes, and 1.17 for obesity. Moreover, there was an exponential trend of increasing mortality with the addition of each risk factor, such that recipients with all 3 risk factors had a 63% increased mortality compared with recipients with none.³⁶

The ultimate success of transplantation depends on the psychosocial stability and compliance of the recipient.³⁷ 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.³⁸ Consequently, before proceeding with transplantation, many medical centers do prospective cross-matching, ie, either by flow cytometry or enzyme-linked immunosorbent assay (ELISA), to determine whether 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.³⁹Furthermore, not all antibodies are complement fixing or dangerous. Performing a prospective cross-match can be time-consuming and often it 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 (IVIGs), cyclophosphamide, mycophenolate mofetil (MMF), 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.⁴⁰ 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 intraaortic 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.⁴¹

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).^6,42 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.⁴³

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.⁴⁴

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 (VT) 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.⁴⁵ Biventricular VADS and the TAH can be considered in this subgroup.

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 60-3. 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).⁴⁶

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 PH. Presently, there is no established method to delist patients who have stabilized on medical therapy without loss of their previously accrued waiting time.

Donor Availability

The US Uniform Anatomic Gift Act of 1968 states that all competent individuals over the age of 18 may donate all or part of their bodies and established the current voluntary basis of organ donation practiced in the United States. To accommodate the increasing demand for organs, the original stringent criteria for donor eligibility have been relaxed, and educational campaigns have increased awareness of the need for a larger donor pool. In 1986, the Required Request Law, which required hospitals to request permission from next of kin to recover organs, was passed to encourage physician compliance in the donor request process. Future reforms will be molded by the evolving public attitude to transplantation and likely will focus on continued public and physician education.

The availability of donor organs remains the major limiting factor to heart transplantation. In the early years of heart transplantation, the number of heart transplants performed in the United States increased steadily to a peak in 1995 of 2363 and then reached a plateau in 1998. After 1998, there was a gradual decline in heart transplants per year to a nadir of 2015 in 2004, after which the number has steadily increased to 2207 in 2007.⁴⁶ A more risk-averse approach to donor use has been discussed as contributing factor for decreased organ use.⁴⁷ Conversely, successful use of hearts with donor cardiac arrest history < 8 minutes⁴⁸ and donor cardiopulmonary resuscitation⁴⁹ has recently been reported.

Interestingly, likely owing to improved preoperative care, the death rate for patients on the waiting list for a cardiac allograft has decreased steadily.⁴⁶

Allocation of Donor Organs

In an effort to increase organ donation and to coordinate an equitable allocation of allografts, Congress passed the National Organ Transplant Act in 1984. This act resulted in the drafting of the aforementioned Required Request Law, as well as the awarding of a federal contract to the UNOS for the development of a national organ procurement and allocation network. To facilitate transplantation, the United States is divided into 11 geographic regions.

Organs are offered to sick patients within the region in which they were donated before being offered to other parts of the country. This helps to reduce organ preservation time, improve organ quality and survival outcomes, reduce the costs incurred by the transplant patient, and increase access to transplantation.

The effect of the new UNOS broader regional algorithm for donor organ sharing that prioritizes donor heart allocation to higher-risk (status 1A and 1B) wait-listed patients was a significant reduction in waiting list mortality in status 1A and 1B patients, with no change in the waiting list mortality for lower-priority patients (status 2). Importantly posttransplant outcomes were sustained despite the higher-risk nature of the recipients.⁵⁰

Donor Selection

Once a brain-dead individual has been identified as a potential cardiac donor, the patient undergoes a rigorous three-phase screening regimen. The primary screening is undertaken by the organ procurement agency. Information regarding the patient’s age, height and weight, gender, ABO blood type, hospital course, cause of death, and routine laboratory data including cytomegalovirus (CMV), HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) serologies are collected. Cardiac surgeons and/or cardiologists perform the secondary screening, which involves further investigation in search of potential contraindications (Table 60-4), determination of the hemodynamic support necessary to sustain the donor, and review of the electrocardiogram, chest roentgenogram, arterial blood gas determination, and echocardiogram. Even when adverse donor criteria are reported, a team often is dispatched to the hospital to evaluate the donor on-site.

Although echocardiography is effective in screening for anatomical abnormalities of the heart, the use of a single echocardiogram to determine the physiologic suitability of a donor is not supported by evidence.⁵¹ The Papworth Hospital transplant program in Great Britain increased its donor yield substantially by using a pulmonary artery catheter to guide the physiologic assessment and management of ventricular dysfunction.⁵² Coronary angiography is indicated in the presence of advanced donor age (traditionally for male donors >45 years of age and female donors >50 years of age). Angiography also should be performed if there is a history of cocaine use or the donor has three risk factors for coronary artery disease (CAD), such as hypertension, diabetes, smoking history, dyslipidemia, or family history of premature CAD.⁵¹

The final and often most important screening of the donor occurs intraoperatively at the time of organ procurement by the cardiac surgical team. Direct visualization of the heart is performed for evidence of right ventricular or valvular dysfunction, previous infarction, or myocardial contusion secondary to closed-chest compressions or blunt chest trauma. The coronary arterial tree is palpated for gross calcifications indicative of atheromatous disease. If direct examination of the heart is unremarkable, the recipient hospital is notified, and the procurement surgeons proceed with donor cardiectomy, usually in conjunction with multiorgan procurement.

Expanded Donor Criteria and Alternate Listing

As the donor shortage has worsened and the number of patients waiting for transplants has increased, one of the areas of increasing interest is the use of marginal donors for marginal recipients. For this purpose, an alternate recipient list is being used by some centers to match certain recipients who might be excluded from a standard list with marginal donor hearts that otherwise would go unused. Expanded donor criteria include the use of donors substantially smaller than the recipients, donors with coronary artery disease that may require coronary artery bypass grafting (CABG), left ventricular dysfunction, or donors from older age groups.⁵¹ Acceptable operative mortality has been reported, and the University of California, Los Angeles (UCLA) heart transplant group has shown that alternate listing did not independently predict early or late mortality.⁵³

It also appears more beneficial in terms of patient survival to receive an allograft from a donor older than 40 years of age compared to remaining on the waiting list.⁵⁴ Other high-risk donors, such as HCV-positive or HBV (core IgM-negative)-positive donors, may be appropriate in selected higher-risk recipients.⁵¹

Also of special interest is the effect of donor alcohol and cocaine abuse on heart transplantation. A small single-center study showed unfavorable early outcome of patients receiving hearts from alcoholic donors (>2 oz of pure alcohol daily for 3 or more months), suggesting the presence of a subclinical preoperative alcoholic cardiomyopathy and poor tolerance of rejection episodes after transplantation.⁵⁵ Because of widespread cocaine abuse, donor guidelines have declared intravenous drug abuse a “relative” contraindication for donor selection. However, the dilemma of selecting donor hearts from nonintravenous drug abusers remains an open issue. A favorable outcome for patients who received transplanted hearts obtained from nonintravenous cocaine users has been reported.⁵⁶ However, judicious use of organs from donors with a history of cocaine use is strongly advised. Specific recommendations were made in a consensus report to improve the yield of donor hearts.⁵¹

Management of the Cardiac Donor

Medical management of cardiac donors, an integral part of organ preservation, is complicated by the complex physiologic phenomenon of brain death and the need to coordinate procurement with other organ donor teams. Brain death is associated with an “autonomic and cytokine storm.” The release of noradrenaline (norepinephrine) leads to subendocardial ischemia. Subsequent cytokine release results in further myocardial depression. This is accompanied by pronounced vasodilatation and loss of temperature control.³ Rapid afterload reduction may be achieved with sodium nitroprusside, whereas volatile anesthetics reduce the intensity of sympathetic bursts. The initial period of intense autonomic activity is followed by loss of sympathetic tone and a massive reduction in systemic vascular resistance. Overall, brain stem death results in severe hemodynamic instability, the degree of which appears to be directly related to the severity of the brain injury and may result from vasomotor autonomic dysfunction, hypovolemia, hypothermia, and dysrhythmias.⁵⁷

Aggressive volume resuscitation sometimes is necessary, and the use of a Swan-Ganz catheter may be crucial to guide therapy.⁵⁸ Fluid overload should be avoided to prevent postoperative allograft dysfunction caused by chamber distention and myocardial edema. Inotropic support (eg, dopamine or dobutamine, epinephrine, or norepinephrine) to maintain a mean arterial blood pressure (MAP) of 60 mm Hg or more in the presence of a central venous pressure (CVP) of 6 to 10 mm Hg is recommended.⁵¹ ATP is depleted rapidly by exogenous catecholamine administration, and this has an adverse effect on posttransplantation cardiac function.⁵⁷ Low-dose vasopressin is being used increasingly as first-line support because, in addition to treating diabetes insipidus, it independently improves arterial blood pressure and reduces exogenous inotrope requirements in brain stem dead donors.⁵⁹ Maintenance of normal temperature, electrolyte levels, osmolarity, acid-base balance, and oxygenation is critical for optimal donor management. Central diabetes insipidus develops in more than 50% of donors because of pituitary dysfunction, and massive diuresis complicates fluid and electrolyte management.⁶⁰ The initial treatment of diabetes insipidus is aimed at correcting hypovolemia and returning the plasma sodium concentration to normal levels by fluid replacement with 5% dextrose or nasogastric water. In severe cases, intermittent treatment with the synthetic analogue 1-D-amino-8-D-arginine vasopressin (DDAVP) also may be required in addition to vasopressin infusion.⁵⁷

Several studies have demonstrated beneficial effects of thyroid hormones and steroids on cardiac performance in brain stem dead-organ donors.^52,59,61 Recent guidelines advocate the addition of a standardized hormonal resuscitation package consisting of methylprednisolone (15 mg/kg bolus), triiodothyronine (4-μg bolus followed by infusion of 3 μg/h), and arginine vasopressin (1-unit bolus followed by 0.5-4 units/h) to the standard donor management protocol.⁴¹ Donors also receive insulin, titrated to keep blood glucose at 120 to 180 mg/dL. Other pertinent strategies include standard ventilator management with diligent endotracheal suctioning and a thermoregulation goal of 34 to 36°C using warming blankets and lights, warm intravenous fluids, and warm inspired air. Broad-spectrum antibiotic therapy with a cephalosporin is initiated following collection of blood, urine, and tracheal aspirate for culture. The approach for management of the cardiac donor recommended at the conference entitled, Maximizing Use of Organs Recovered from the Cadaver Donor: Cardiac Recommendations, is shown in Table 60-5 and summarized in Fig. 60-2.⁵¹

Donor Heart Procurement

A median sternotomy is performed, and the pericardium is incised longitudinally. The heart is inspected and palpated for evidence of cardiac disease or injury. This visualization is communicated to the transplant team so the operation on the recipient can proceed timed with the expected arrival of the donor organ.

The superior and inferior venae cavae and the azygous vein are mobilized circumferentially and encircled with ties. The aorta is dissected from the pulmonary artery and isolated with umbilical tape. To facilitate access to the epigastrium by the liver procurement team, the cardiac team often then temporarily retires from the operating room table or assists with retraction. Once preparation for liver, pancreas, lung, and kidney explantation is completed, the patient is administered 30,000 units of heparin intravenously.

The azygous vein and superior vena cava (SVC) are doubly ligated (or stapled) and divided distal to the azygous vein, leaving a long segment of SVC (Fig. 60-3). The inferior vena cava (IVC) is incised and the left atrium vented either at the left atrial appendage or via a transected pulmonary vein. The aortic cross-clamp is applied at the takeoff of the innominate artery, and the heart is arrested with a single flush (1000 mL or 10-20 mL/kg) of cardioplegia solution infused proximal to the cross-clamp. Rapid cooling of the heart is achieved with copious amounts of cold saline and cold saline slush poured into the pericardial well.

After the delivery of cardioplegia, cardiectomy proceeds as the apex of the heart is elevated cephalad and any remaining intact pulmonary veins are divided.

This maneuver is modified appropriately to retain adequate left atrial cuffs for both lungs and the heart if the lungs also are being procured. While applying caudal traction to the heart with the nondominant hand, the ascending aorta is transected proximal to the innominate artery, and the pulmonary arteries are divided distal to the bifurcation (again, modification is necessary if the lungs are being procured).

More generous segments of the great vessels and SVC may be required for recipients with congenital heart disease. Alternatively, the SVC and IVC are transected, followed by the aorta and pulmonary artery. The left atrium is then divided as the last step. This allows for optimal division of the left atrium, particularly when lungs are recovered.

Once the explantation is complete, the allograft is examined for evidence of a patent foramen ovale, which should be closed at that time. Any valvular anomalies are identified. The allograft then is placed in a sterile container and kept cold for transport to the recipient hospital.

Organ Preservation

Current clinical graft preservation techniques generally permit a safe ischemic period of 4 to 6 hours.⁶² Factors contributing to the severity of postoperative myocardial dysfunction include insults associated with suboptimal donor management, hypothermia, ischemia-reperfusion injury, and depletion of energy stores.

A single flush of a cardioplegic or preservative solution followed by static hypothermic storage at 4 to 10°C is the preferred preservation method by most transplant centers. Crystalloid solutions of widely different compositions are available, and the debate over them speaks for the fact that no ideal solution currently exists. Depending on their ionic composition, solutions are classified as intracellular or extracellular.⁶²

Intracellular solutions, characterized by moderate-to-high concentrations of potassium and low concentrations of sodium, purportedly reduce hypothermia-induced cellular edema by mimicking the intracellular milieu. Commonly used examples of these solutions include University of Wisconsin, Euro-Collins, and in Europe, Bretschneider (HTK) and intracellular Stanford solutions.

Extracellular solutions, characterized by low-to-moderate potassium and high sodium concentrations, avoid the theoretical potential for cellular damage and increased vascular resistance associated with hyperkalemic solutions. Hopkins, Celsior, Krebs, and St. Thomas Hospital solutions are representative extracellular cardioplegic solutions. Several comparisons of the different types of intracellular and extracellular solutions have shown variable results.^63,64 Although a plethora of pharmacologic additives has been included in cardioplegic-storage solutions, the greatest potential for future routine use may lie with impermeants, substrates, and antioxidants.⁶⁵ A number of pharmacologic and mechanical strategies for leukocyte inhibition and depletion also have been explored.⁶⁶ Potential benefits of continuous hypothermic perfusion (CHP) preservation such as uniform myocardial cooling, continuous substrate supplementation, and metabolic by-product washout are currently overshadowed by exacerbation of extracellular cardiac edema and logistical problems inherent to a complex perfusion apparatus. Newer portable perfusion circuits are being developed, and recent studies showed reduction in oxidative stress and attenuation of DNA damage in canine heart transplant models preserved by 24-hour CHP compared with 4 hours of static preservation.⁶⁷

In a prospective, randomized, multi-center, international, non-inferiority trial led by the University of California, Los Angeles (UCLA), the investigators hypothesized that the clinical outcomes of patients undergoing heart transplantation with donor hearts preserved on Organ Care System (OCS) versus standard cold storage are similar. This study was designed to provide data that would allow in a follow-up study to test if OCS can expand the donor heart pool (by testing/improving “non-standard/marginal” donor hearts).The OC is the only clinical platform (2014) for exvivo human donor heart perfusion. It preserves the donor heart in a warm beating state during transport from the donor hospital to the recipient hospital. This study was conducted at 10 heart transplant centers in the United States and Europe. One hundred and twenty-eight patients were transplanted in the PROCEED II trial: 65 in the OCS group and 63 in the control group. With respect to the primary endpoint of 30-day patient and graft survival, the OCS group was found to be noninferior to the control group (OCS group: 94% [61/65] vs control group: 97% [61/63]). The results of secondary endpoints were similar for the two groups. Total preservation time was significantly longer in the OCS group versus control group, with a shorter cold ischemia time. Five donor hearts in the OCS group developed abnormal metabolic profile and were rejected for transplantation.⁶⁸ The clinical role of this system is yet to be determined. However, extended preservation times and better scheduling of a heart transplant are the real potential benefit of OCS preservation.

Donor-Recipient Matching

Criteria for matching potential recipients with the appropriate donor are based primarily on ABO blood group compatibility and patient size. ABO barriers should not be crossed in adult heart transplantation because incompatibility may result in fatal hyperacute rejection. Donor weight should be within 30% of recipient weight except in pediatric patients, in whom closer size matching is required. In cases of elevated PVR in the recipient (5-6 Wood units), a larger donor is preferred to reduce the risk of right ventricular failure in the early postoperative period. At UCLA we prefer a male donor for a male recipient when size and PH are an issue.