Chapter 64. Heart Transplantation

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 biologic 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. 64-1) 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 2200 per year) has remained relatively constant over the last decade because of limited donor-organ availability (from United Network for Organ Sharing [UNOS] data, through September 2009).

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 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.

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.

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

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.

Donor Availability

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 2007.40 Interestingly, likely owing to improved preoperative care, the death rate for patients on the waiting list for a cardiac allograft has decreased steadily.40

The 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.

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.

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 64-4), 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.41 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.42 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.41

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.41 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.43

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.44 Other high-risk donors, such as HCV-positive or HBV (core IgM-negative)–positive donors, may be appropriate in selected higher-risk recipients.41

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.45 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.46 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.41

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.47

Aggressive volume resuscitation sometimes is necessary, and the use of a Swan-Ganz catheter may be crucial to guide therapy.48 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.41 ATP is depleted rapidly by exogenous catecholamine administration, and this has an adverse effect on posttransplantation cardiac function.47 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.49 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.50 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.47

Several studies have demonstrated beneficial effects of thyroid hormones and steroids on cardiac performance in brain stem dead-organ donors.42,49,51 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 to 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 64-5 and summarized in Fig. 64-2.41

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. 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 are doubly ligated (or stapled) and divided distal to the azygous vein, leaving a long segment of superior vena cava (Fig. 64-3). The inferior vena cava 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 to 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 superior vena cava 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. It is critically important to avoid left ventricular distention and ensure thorough cooling with ice saline.

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 for transport to the recipient hospital.

Organ Preservation

Current clinical graft preservation techniques generally permit a safe ischemic period of 4 to 6 hours.52 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.52 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.53,54 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.55 A number of pharmacologic and mechanical strategies for leukocyte inhibition and depletion also have been explored.56 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.57

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 pulmonary vascular resistance in the recipient (5 to 6 Wood units), a larger donor is preferred to reduce the risk of right ventricular failure in the early postoperative period. Although practices vary by transplant program, generally if the percent of panel reactive antibody (PRA) is greater than 10%, indicating recipient presensitization to alloantigen, a prospective negative T-cell cross-match between the recipient and donor sera is mandatory before transplantation. 32,58 A cross-match is always performed retrospectively, even if the PRA is absent or low. Retrospective studies also have demonstrated that better matching at the HLA-DR locus results in fewer episodes of rejection and infection with an overall improved survival.59 Because of current allocation criteria and limits on ischemic time of the cardiac allograft, routine prospective HLA matching is not logistically possible.

Hyperacute Rejection

Hyperacute rejection results from preformed donor-specific antibodies in the recipient. ABO blood group and panel reactive antibody screening have made this condition a rare complication. The onset of hyperacute rejection occurs within minutes to several hours after transplantation, and the results are catastrophic. Gross inspection reveals a mottled or dark red, flaccid allograft, and histologic examination confirms the characteristic global interstitial hemorrhage and edema without lymphocytic infiltrate. Immunofluorescence techniques reveal deposits of immunoglobulins and complement on the vascular endothelium. Immediate plasmapheresis, intravenous immunoglobulin (IVIG), and mechanical support are immediately instituted, and retransplantation may be the only successful strategy.

Orthotopic Heart Transplantation

Operative Preparation of the Recipient

The original technique of orthotopic cardiac transplantation described by Shumway and Lower is still used commonly today. Following median sternotomy and vertical pericardiotomy, the patient is heparinized and prepared for cardiopulmonary bypass. Bicaval venous cannulation and distal ascending aortic cannulation just proximal to the origin of the innominate artery are optimal. Umbilical tape snares are passed around the superior and inferior venae cavae. Bypass is initiated, the patient is cooled to 28°C, caval snares are tightened, and the ascending aorta is cross-clamped. The great vessels are transected above the semilunar commissures, whereas the atria are incised along the atrioventricular grooves, leaving cuffs for allograft implantation. Removal of the atrial appendages reduces the risk of postoperative thrombus formation. Following cardiectomy, the proximal 1 to 2 cm of aorta and pulmonary artery are separated from one another with electrocautery, taking care to avoid injuring the right pulmonary artery. Continuous aspiration of pulmonary venous return from bronchial collaterals is achieved by insertion of a vent into the left atrial remnant either directly or via the right superior pulmonary vein.

Timing of donor and recipient cardiectomies is critical to minimize allograft ischemic time and recipient bypass time. Frequent communication between the procurement and transplant teams permits optimal coordination of the procedures. Ideally, the recipient cardiectomy is completed just before arrival of the cardiac allograft.

Implantation

The donor heart is removed from the transport cooler and placed in a basin of cold saline. If not previously performed, preparation of the donor heart is accomplished. Electrocautery and sharp dissection are used to separate the aorta and pulmonary artery. The left atrium is incised by connecting the pulmonary vein orifices, and excess atrial tissue is trimmed, forming a circular cuff tailored to the size of the recipient left atrial remnant (Fig. 64-4). Implantation begins with placement of a double-armed 3-0 Prolene suture through the recipient left atrial cuff at the level of the left superior pulmonary vein and then through the donor left atrial cuff near the base of the atrial appendage (Fig. 64-5). The allograft is lowered into the recipient mediastinum atop a cold sponge to insulate it from direct thermal transfer from adjacent thoracic structures. The suture is continued in a running fashion caudally and then medially to the inferior aspect of the interatrial septum (Fig. 64-6). The second arm of the suture is run along the roof of the left atrium and down the interatrial septum. It is important to continually assess size discrepancy between donor and recipient atria so that appropriate plication of excess tissue may be performed. The left atrium is filled with saline, and the two arms of suture are tied together on the outside of the heart. Most centers use constant insufflation of carbon dioxide into the mediastinum to reduce the amount of intracardiac air.

Once the left atrial anastomosis is complete, a curvilinear incision is made from the inferior vena caval orifice toward the right atrial appendage of the allograft. This modification in the right atriotomy initially introduced by Barnard reduces the risk of injury to the sinoatrial node and accounts for the preservation of sinus rhythm observed in most recipients. The tricuspid apparatus and interatrial septum are inspected. Recipients are predisposed to increased right-sided heart pressures in the early postoperative period owing to preexisting pulmonary hypertension and volume overload. Both conditions are poorly tolerated by the recovering right ventricle. To avoid refractory arterial desaturation associated with shunting, patent foramen ovale are closed. The right atrial anastomosis is performed in a running fashion similar to the left, with the initial anchor suture placed either at the most superior or inferior aspect of the interatrial septum so that the ends of the suture meet in the middle of the anterolateral wall (Fig. 64-7A,B).

The end-to-end pulmonary artery anastomosis is next performed using a 4-0 Prolene suture beginning with the posterior wall from inside of the vessel and then completing the anterior wall from the outside (Fig. 64-8). It is crucial that the pulmonary artery ends be trimmed to eliminate any redundancy in the vessel that might cause kinking.60 Finally, the aortic anastomosis is performed using a technique similar to that for the pulmonary artery, except that some redundancy is desirable in the aorta because it facilitates visualization of the posterior suture line (Fig. 64-9). Rewarming usually is begun before the aortic anastomosis, which is performed in a standard end-to-end fashion. Routine deairing techniques are then employed. Lidocaine (100 to 200 mg intravenously) and methylprednisone (500 to 1000 mg) is administered, and the aortic cross-clamp is removed. Half of patients require electrical defibrillation. A needle vent is inserted in the ascending aorta for final deairing, with the patient in steep Trendelenburg position. Suture lines are inspected carefully for hemostasis. Inotrope infusion is initiated, and temporary pacing may be required. The patient is weaned from cardiopulmonary bypass, and the cannulae are removed. Temporary epicardial pacing wires are placed in the donor right atrium and ventricle. Following insertion of mediastinal and pleural tubes, the median sternotomy is closed in the standard fashion.

Cold-blood cardioplegia is used in many centers. An initial dose often is given following removal from the cold storage solution before implantation. A second dose, or the initial dose as given by some centers, is administered after the right atrial anastomosis or inferior vena cava (IVC) anastomosis, when a bicaval technique is used.

Alternative Techniques for Orthotopic Heart Transplantation

The most commonly employed technique today is a bicaval anastomotic method. With this technique, the recipient right atrium is excised completely, leaving a left atrial cuff and a generous cuff of the IVC and superior vena cava (SVC), respectively. The left atrial cuff of the donor is anastomosed to the left atrial cuff of the recipient using the standard Shumway technique. Individual end-to-end anastomoses of the IVC and SVC are performed. The IVC anastomosis usually is performed following the left atrial anastomosis and the SVC anastomosis after the cross-clamp is removed. Total heart transplantation involves complete excision of the recipient heart with bicaval end-to-end anastomoses and bilateral pulmonary venous cuff anastomoses. The Wythenshawe bicaval technique is performed in a similar fashion except that the recipient left atrium is prepared as a single cuff with all four pulmonary vein orifices (Fig. 64-10). Although these procedures are more technically difficult than standard orthotopic transplantation, published series using these techniques have reported shorter hospital stays, reduced postoperative dependence on diuretics, and lower incidences of atrial dysrhythmias, conduction disturbances, mitral and tricuspid valve incompetence, and right ventricular failure.61 A single-center study comparing biatrial versus bicaval transplant showed an improved 12-month survival in the bicaval group.62 However, a recent analysis of the UNOS database, including more than 11,000 patients, did not demonstrate a survival difference between patients in whom biatrial versus bicaval anastomotic techniques were used; although the bicaval technique was associated with decreased duration of hospital stay and postoperative pacemaker placement.63 Long-term outcomes and prospective, randomized studies evaluating these alternative techniques are still needed.

Heterotopic Heart Transplantation

Pulmonary hypertension and right-sided heart failure have remained the leading causes of early mortality in cardiac transplantation. This has led to an interest in heterotopic heart transplantation. Currently, heterotopic heart transplants are performed rarely but may be indicated in patients with irreversible pulmonary hypertension or significant donor–recipient size mismatch.22

Heart Transplantation after VAD

Cardiac transplantation after VAD poses unique challenges. All patients should have a recent contrasted chest CT to identify location and course of outflow grafts. The femoral artery and vein should be exposed for cannulation before redo sternotomy. Sternal reentry should carefully dissect the heart from pleura to pleura to safely place a retractor. The initial focus is on dissection of the IVC, SVC, and aorta. Further dissection is ideal, but may require cardiopulmonary bypass. The apex and left atrium should not be manipulated before bypass as there is a risk of entraining air, particularly with axial-flow devices. Finally, before initiating bypass, the outflow graft should be clamped to prevent regurgitation through the device. The sternotomy and adhesiolysis can be difficult and time consuming. Patience is critical.

Hemodynamic Management

Heart Allograft Physiology

The intact heart is innervated by antagonistic sympathetic and parasympathetic fibers of the autonomic nervous system. Transplantation necessitates transection of these fibers, yielding a denervated heart with altered physiology. Devoid of autonomic input, the sinoatrial (SA) node of the transplanted allograft fires at its increased intrinsic resting rate of 90 to 110 beats per minute.64 The allograft relies on distant noncardiac sites as its source for catecholamines; thus its response to stress (eg, hypovolemia, hypoxia, and anemia) is somewhat delayed until circulating catecholamines can exert their positive chronotropic effect on the heart. The absence of a normal reflex tachycardia in response to venous pooling accounts for the frequency of orthostatic hypotension in transplant patients.

Denervation alters the heart's response to therapeutic interventions that act directly through the cardiac autonomic nervous system.64 Carotid sinus massage, Valsalva maneuver, and atropine have no effect on SA node firing or atrioventricular conduction. Because of depletion of myocardial catecholamine stores associated with prolonged inotropic support of the donor, the allograft often requires high doses of catecholamines.

Routine Hemodynamic Management

Donor myocardial performance is transiently depressed in the immediate postoperative period. Allograft injury associated with donor hemodynamic instability and the hypothermic, ischemic insult of preservation contribute to reduced ventricular compliance and contractility characteristics of the newly transplanted heart.65 Abnormal atrial dynamics owing to the midatrial anastomosis exacerbate the reduction in ventricular diastolic loading. An infusion of epinephrine or dobutamine is initiated routinely in the operating room to provide temporary inotropic support. Cardiac denervation brings in several consequences, which may include a chronotropic and inotropic supersensitivity to exogenous catecholamines.66 Restoration of normal myocardial function usually permits the cautious weaning of inotropic support within 2 to 4 days.

Early Allograft Failure

Early cardiac failure still accounts for up to 20% of perioperative deaths of heart transplant recipients.67 The cause may be multifactorial, but the most important etiologies are myocardial dysfunction owing to donor instability, pulmonary hypertension, ischemic injury during preservation, and occasionally acute rejection. Mechanical support with an intra-aortic balloon pump, ventricular assist device, or ECMO can be used in patients refractory to pharmacologic interventions, although this measure, as well as retransplantation, has historically been associated with increased mortality.68,69

Chronic left ventricular failure frequently is associated with elevated pulmonary vascular resistance, and the unprepared donor right ventricle may be unable to overcome this increased afterload. Although recipients are screened to ensure that those with irreversible pulmonary hypertension are not considered for transplantation, right-sided heart failure remains a leading cause of early mortality. Initial management involves employing pulmonary vasodilators such as inhaled nitric oxide, nitroglycerin, or sodium nitroprusside. Pulmonary hypertension that is refractory to these vasodilators sometimes responds to prostaglandin E1 (PGE1) or prostacyclin.14,70 Intra-aortic balloon counterpulsation and right ventricular assist devices also can be used in patients unresponsive to medical therapy.71

Arrhythmias

Denervation of the transplanted heart leads to loss of autonomic nervous system modulation of the heart's electrophysiologic properties. Parasympathetic denervation causes loss of basal suppression of SA node automaticity, leading to a persistent increase in resting heart rate and a loss of normal, rapid heart rate modulation. This parasympathetic loss also causes elimination of the chronotropic effects of digoxin and atropine after heart transplantation. At the same time, sympathetic denervation causes a decrease and delay in exercise- or stress-induced augmentation of SA node automaticity, resulting in a decreased maximum heart rate with exercise.72

Sinus or junctional bradycardia occurs in up to half of transplant recipients. Risk factors for sinus node dysfunction include prolonged organ ischemia, angiographic nodal artery abnormalities, biatrial versus bicaval anastomosis, preoperative amiodarone use, and rejection.73 Adequate heart rate is achieved with inotropic drug infusions and/or temporary epicardial pacing. Most bradyarrhythmias resolve over 1 to 2 weeks. Theophylline has been effective in patients with bradyarrhythmias and has decreased the need for permanent pacemakers in this patient population.74

Atrial fibrillation, atrial flutter, and other supraventricular arrhythmias have been reported in 5 to 30% of patients after heart transplantation.72 Individual assessment of the risk:benefit ratio for anticoagulation therapy is necessary. Supraventricular tachycardia (SVT) in transplant patients should be treated in the same manner as in nontransplant patients but with lower doses. Recurrent arrhythmias from reentry circuits or defined ectopic foci often can be cured by radiofrequency ablation.

Premature ventricular complexes (PVCs) are generally not considered ominous. Because of their rapidly terminal nature, sustained ventricular tachycardia (VT) and ventricular fibrillation presumably are responsible for a significant portion of the 10% of sudden and unexplained deaths in heart transplant patients.75

Unique aspects of common antiarrhythmic drugs reflecting the differences in their therapeutic effects in heart transplant recipients compared with nontransplant patients are shown in Table 64-6.72 Persistence of any form of arrhythmia should warrant further investigative efforts and an aggressive search for the presence of indicators of cardiac ischemia, rejection, pulmonary pathology, or infection. If arrhythmic episodes are frequent or underlying cardiac pathology is severe, retransplantation may be considered.

Systemic Hypertension

Systemic hypertension should be treated to prevent unnecessary afterload stress on the allograft. In the early postoperative period, intravenous sodium nitroprusside or nitroglycerin usually is administered. Nitroglycerin is associated with less pulmonary shunting because of a relative preservation of the pulmonary hypoxic vasoconstrictor reflex. Nicardipine infusion has been reported to control postoperative hypertension more rapidly and was superior to sodium nitroprusside in maintaining left ventricular performance immediately after drug infusion.76 If hypertension persists, an oral antihypertensive can be added, if possible, to permit weaning of the parenteral agents.

Respiratory Management

The respiratory management of the cardiac transplant recipient uses the same protocols employed following routine cardiac surgery.

Renal Function

Preoperative renal insufficiency owing to chronic heart failure and the nephrotoxic effects of calcineurin inhibitors such as FK506 and cyclosporine place the recipient at increased risk of renal insufficiency. Acute calcineurin inhibitor–induced renal insufficiency usually will resolve with a reduction in dose. Continuous intravenous infusion to eliminate the wide fluctuations in levels associated with oral dosing can be attempted. Furthermore, concurrent administration of mannitol with calcineurin inhibitors may reduce their nephrotoxicity. Most centers administer a cytolytic agent in the immediate postoperative period and delay the initiation of calcineurin inhibitor therapy.

Outpatient Follow-Up

Before discharge, patients should receive comprehensive education about their medications, diet, exercise, and infection recognition. Close follow-up by an experienced transplant team is the cornerstone for successful long-term survival after cardiac transplantation. This comprehensive team facilitates the early detection of rejection, opportunistic infections, patient noncompliance, and adverse sequelae of immunosuppression. Clinic visits routinely are scheduled concurrently with endomyocardial biopsies and include physical examination, a variety of laboratory studies, chest roentgenogram, and electrocardiogram.

Cardiac allograft rejection is the normal host response to cells recognized as nonself. The vast majority of cases are mediated by the cellular limb of the immune response through an elegant cascade of events involving macrophages, cytokines, and T lymphocytes. Humoral-mediated rejection (also called vascular rejection) is less common. The highest risk factors are allografts from younger and female donors (irrespective of recipient sex). Although about 85% of episodes can be reversed with corticosteroid therapy alone,77 rejection is still a major cause of morbidity in cardiac transplant recipients.5,78

Diagnosis of Acute Rejection

In the precyclosporine era, the classic clinical manifestations of acute rejection included low-grade fever, malaise, leukocytosis, pericardial friction rub, supraventricular arrhythmias, decreased voltage on ECG, low cardiac output, reduced exercise tolerance, and signs of congestive heart failure. In the cyclosporine era, however, most episodes of rejection characteristically are insidious, and patients can remain asymptomatic even with late stages of rejection. Thus routine surveillance studies for early detection are crucial to minimize cumulative injury to the allograft. Right ventricular endomyocardial biopsy remains the gold standard for the diagnosis of acute rejection. The most frequently used technique for orthotopic allografts is a percutaneous approach through the right internal jugular vein. Interventricular septal specimens are fixed in formalin for permanent section, although frozen sections are performed occasionally if urgent diagnosis is necessary. Hemodynamic parameters may also be obtained with a pulmonary artery catheter. Complications are infrequent (1 to 2%) but include venous hematoma, carotid puncture, pneumothorax, arrhythmias, heart block, and right ventricular perforation and injury to the tricuspid valve. The exact schedule for endomyocardial biopsies varies among institutions but usually reflects the associated risk of increased rejection during the first 6 months after transplantation. Biopsies are performed initially every 7 to 10 days in the early postoperative period and eventually tapered to 3- to 6-month intervals after the first year. Suspicion of rejection warrants additional biopsies.

Evaluation of sample adequacy for the ISHLT grading scheme requires a minimum of four good endomyocardial tissue fragments, with less than 50% of each fragment being fibrous tissue, thrombus, or other noninterpretable tissues (eg, crush artifact or poorly processed fragments).79 The pattern and density of lymphocyte infiltration, in addition to the presence or absence of myocyte necrosis in the endomyocardial biopsy, determine the severity grade of cellular rejection.80 Further elaboration of the pathologic features and identification of antibody-mediated rejection were addressed more recently.81 In 2004, the ISHLT Pathology Council proposed simplification of the 1990 diagnostic categories for cellular rejection to mild, moderate, and severe and identification of the histologic characteristics of antibody-mediated rejection.82 The new grading scale was developed to better address the challenges and inconsistencies in use of the old grading system. Tables 64-7 and 64-8 show the new 2004 ISHLT grading scale.82

Noninvasive studies for the diagnosis of acute rejection have been unreliable. Electrocardiographic voltage summation and E-rosette assay techniques were useful adjuncts in the early cardiac transplant experience83; however, they currently are of no value in patients receiving cyclosporine.84 Attempts with signal-averaged electrocardiography,85 echocardiography,86 or in combination,87 magnetic resonance imaging,88 technetium ventriculography,89 and a variety of immunologic markers90 have not provided sufficient sensitivity and specificity to warrant widespread use.91 Peripheral blood gene expression profiling is an exciting new field that may provide the answer to noninvasive discrimination of rejection in cardiac allograft recipients.92

Treatment of Acute Rejection

Corticosteroids are the cornerstone for antirejection therapy. The treatment of choice for any rejection episode occurring during the first 1 to 3 postoperative months or for an episode considered to be severe is a short course (3 days) of intravenous methylprednisolone (1000 mg/d). Virtually all other episodes are treated initially with increased doses of oral prednisone (100 mg/d) followed by a taper to baseline over several weeks.93 Although not yet universally accepted, many centers have reduced the doses of these corticosteroids successfully with reversal rates of rejection similar to traditional dosing.

Repeat endomyocardial biopsy should be performed 7 to 10 days after the cessation of antirejection therapy to assess adequacy of treatment. If the biopsy does not show significant improvement, a second trial of pulse-steroid therapy is recommended; if rejection has progressed (or if the patient becomes hemodynamically unstable), rescue therapy is indicated.

Substitution of tacrolimus for cyclosporine may obviate the need for admission in patients with steroid-refractory persistent rejection.94 Alternatively, sirolimus may be substituted for mycophenolate or azathioprine.95 The use of OKT3, antithymocyte globulin, and thymoglobulin generally is reserved for severe rejection with hemodynamic compromise.96 Methotrexate has been particularly successful in eradicating chronic low-grade rejection. Total lymphoid irradiation and photopheresis also have demonstrated success in some cases of refractory rejection.97 Cardiac retransplantation is the ultimate therapeutic option for patients who do not respond to the aforementioned interventions. However, the results of retransplantation for rejection are dismal, and in most centers, it is no longer performed for this indication.

Asymptomatic mild rejection (grade 1) usually is not treated but is monitored with repeat endomyocardial biopsies because only 20 to 40% of mild cases progress to moderate rejection.98 On the other hand, the presence of myocyte necrosis (grades 3b and 4) represents a definite threat to allograft viability and is a universally accepted indication for therapy. Management of moderate rejection (grade 3a) is controversial and requires consideration of multiple variables.99 Notably, Stoica and colleagues recently demonstrated that acute moderate to severe cellular rejection has a cumulative impact on cardiac allograft vasculopathy (CAV) onset.100 Regardless of the biopsy results, allograft dysfunction is an indication for hospitalization, antirejection therapy, and if severe, invasive hemodynamic monitoring and inotropic support.

Acute Vascular Rejection

Vascular rejection is mediated by the humoral limb of the immune response. Unlike cellular rejection, hemodynamic instability requiring inotropic support is common in patients with vascular rejection.101 Diagnosis requires evidence of endothelial cell swelling on light microscopy and immunoglobulin-complement deposition by immunofluorescence techniques.102 Aggressive treatment of patients with allograft dysfunction consists of plasmapheresis, high-dose corticosteroids, heparin, IgG, and cyclophosphamide.103 Despite these interventions, symptomatic acute vascular rejection is associated with a high mortality.101,103 Repeated episodes of acute vascular rejection or chronic low-grade vascular rejection are believed to play a dominant role in the development of allograft coronary artery disease.104

Organisms and Timing of Infections

Infection is a leading cause of morbidity and mortality in the cardiac transplant population.5,105 The introduction of new chemoprophylactic regimens with the resultant prevention of serious disease caused by CMV has resulted in significant reductions in the number of infectious episodes and a delay in presentation after heart transplantation.105 Patients are at greatest risk of life-threatening infections in the first 3 months after transplantation and following increases in immunosuppression for acute rejection episodes or retransplantation.105Table 64-9 illustrates the most common organisms causing infections in the cardiac recipient.

Preventive Measures and Prophylaxis Against Infection

Transmission of infections such as CMV, Toxoplasma gondii, HBV, HCV, and HIV after organ transplantation is well documented.106 Prevention of postoperative infection begins with pretransplant screening of the donor and recipient.107 Current suggested guidelines are outlined in Table 64-10. Perioperative and postoperative antimicrobial prophylaxes, as well as immunizations, are also outlined.

Specific Organisms Causing Infection Following Heart Transplantation

Bacteria

Gram-negative bacilli are the most common cause of bacterial infectious complications following heart transplantation. Furthermore, Escherichia coli and Pseudomonas aeruginosa are the most prevalent organisms and usually cause urinary tract infections and pneumonias, respectively.105Staphylococcus species have been shown to cause the majority of gram-positive–related infections.

Viruses

CMV remains the single most important cause of infectious disease morbidity and mortality in the heart transplant patient.108 CMV not only results in infectious disease syndromes but also is indirectly associated with acute rejection episodes, acceleration of CAV, and posttransplant lymphoproliferative disease.108 Furthermore, the reduction in leukocytes associated with CMV infection predisposes the patient to superinfection with other pathogens (eg, Pneumocystis carinii pneumonia). Infections develop secondary to donor transmission, reactivation of latent recipient infection, or reinfection of a CMV-seropositive patient with a different viral strain.108 Variable regimens for CMV prophylaxis with ganciclovir are being used by different centers.109 The standard of care for symptomatic CMV disease is 2 to 3 weeks of intravenous ganciclovir (at a dose of 5 mg/kg twice daily, with dosage adjustment for renal dysfunction). For tissue-invasive disease, particularly pneumonia, many centers add anti-CMV hyperimmune globulin to this regimen.110 Preemptive treatment strategies employ periodic surveillance using techniques such as plasma polymerase chain reaction (PCR) and CMV antigenemia, a rapid diagnostic test that detects viral protein in peripheral blood leukocytes at a significant interval before clinical disease.111 Valganciclovir (Valcyte) is an oral prodrug of ganciclovir with a 10-fold greater bioavailability than oral ganciclovir. It has been shown to be effective for prophylaxis and preemptive treatment of CMV and allows for more convenient use.112,113

Although not a cure for herpes simplex or zoster viruses, acyclovir can reduce recurrences and the discomfort associated with the vesicular lesions. Epstein-Barr virus infection may be associated with posttransplant lymphoproliferative disorders in immunocompromised hosts.114

Fungi

Mucocutaneous candidiasis is common and usually can be treated with topical antifungal agents (nystatin or clotrimazole). Fluconazole is indicated for candidiasis refractory to this therapy or involving the esophagus. It is also useful for therapy of candidemia. One important caveat in the treatment of Candida infection with fluconazole is that certain species such as C. krusei and C. glabrata have a low susceptibility in vitro.105

Among patients undergoing heart transplantation, Aspergillus is the opportunistic pathogen with the highest attributable mortality.115 It causes a serious pneumonia in 5 to 10% of recipients during the first 3 months after transplantation. Dissemination of Aspergillus to the central nervous system is almost uniformly fatal.116 Because aspergillosis is highly lethal in the immunocompromised host, even in the face of therapy, workup must be prompt and aggressive, and therapy may need to be initiated on suspicion of the diagnosis without definitive proof. Amphotericin B, itraconazole, and recently voriconazole are acceptable therapy.

Protozoa

In heart transplant recipients, the reported incidence of P. carinii pneumonia ranges from less than 1 to 10%.117 Because the organism resides in the alveoli, bronchoalveolar lavage usually is necessary for diagnosis.118 In the case of lung biopsy specimens, histopathologic examination is also helpful. P. carinii pneumonia is treated with high-dose trimethoprim-sulfamethoxazole or intravenous pentamidine.105

Toxoplasmosis following heart transplantation usually is the result of reactivation of latent disease in the seropositive donor heart because of the predilection of the parasite to invade muscle tissue.119T. gondii infection may be acquired from undercooked meat and cat feces. The diagnosis is made with certainty only by histologic demonstration of trophozoites with surrounding inflammation in biopsy tissue; PCR also has been used.120T. gondii usually causes central nervous system infections and is treated with pyrimethamine with sulfadiazine or clindamycin.105

Cardiac Allograft Vasculopathy

CAV is a unique, rapidly progressive form of atherosclerosis in transplant recipients that is characterized in its early stages by intimal proliferation and in its later stages by luminal stenosis of epicardial branches, occlusion of smaller arteries, and myocardial infarction. Long-term survival of cardiac transplant recipients is limited primarily by the development of CAV, the leading cause of death after the first posttransplant year.5 Angiographically detectable CAV is reported in approximately 40 to 50% of patients by 5 years after transplantation.121 Although CAV resembles atherosclerosis, there are some important differences that are illustrated in Fig. 64-11.122 In particular, intimal proliferation is concentric rather than eccentric, and the lesions are diffuse, involving both distal and proximal portions of the coronary tree. Calcification is uncommon, and the elastic lamina remains intact.

The detailed pathogenesis of CAV is unknown, but there are strong indications that immunologic mechanisms that are regulated by nonimmunologic risk factors are the major causes of this phenomenon.123 The immunologic mechanisms include acute rejection and anti-HLA antibodies, and some of the implicated risk factors relating to the transplant itself or the recipient are donor age, hypertension, hyperlipidemia, and preexisting diabetes. The side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids, eg, CMV infection, nephrotoxicity, and new-onset diabetes, after transplantation also play significant roles.124–126

It is generally believed that the initiating event of CAV is subclinical endothelial cell injury in the coronary artery of the allograft, which leads to a cascade of immunologic processes involving cytokines, inflammatory mediators, complement activation, and leukocyte adhesion molecules. These changes produce inflammation and, ultimately, thrombosis, smooth muscle cell proliferation, and vessel constriction. The initial endothelial injury may be the result of ischemia-reperfusion damage or the host-versus-graft immune response.125,126

CAV may begin within several weeks posttransplantation and progress insidiously at an accelerated rate to complete obliteration of the coronary lumen with allograft failure secondary to ischemia. The clinical diagnosis of CAV is difficult and complicated by allograft denervation, resulting in silent myocardial ischemia. Ventricular arrhythmias, congestive heart failure, and sudden death are commonly the initial presentation of significant CAV.127 An annual coronary angiogram usually is performed for CAV surveillance. Intravascular ultrasound (IVUS) is better equipped to provide important quantitative information regarding vessel wall morphology and the degree of intimal thickening.128

Because angiography and IVUS are invasive tests, they pose increased risks for patients. Noninvasive tests (eg, thallium scintigraphy and dobutamine stress echocardiography), however, have not been sensitive or specific enough to be a reliable screen for CAV.129 Other possible modalities include pulse-wave tissue Doppler imaging, electron beam computed tomography (CT), fast CT scanning, and MRI. These modalities may replace invasive procedures in the future.

Currently, the only definitive treatment for advanced CAV is retransplantation, which has risks for the patient and poses problems associated with scarcity of donor organs.127 Owing to the diffuse and distal nature of the disease, procedures such as stenting and angioplasty are inherently less effective than in nontransplant patients and result in a higher need for repeated procedures.130 Therefore, prophylactic management is of paramount importance. Before transplantation, the focus should be on preventing endothelial injury at brain death, reducing cold ischemia time and improving myocardial preservation during storage and transportation.127 Postransplantation care focuses on empiric risk factor modification (eg, dietary and pharmacologic reduction in serum cholesterol, cessation of smoking, hypertension control, etc). Several studies have demonstrated a decrease in CAV in patients treated with a calcium channel blocker and angiotensin-converting enzyme (ACE) and HMG-CoA reductase inhibitors.131,132

Newer immunosuppressive drugs, specifically the proliferation signal inhibitors (eg, everolimus and sirolimus), may be useful in reducing the incidence and severity of CAV and slowing disease progression.133–137

Renal Dysfunction

The 2009 ISHLT registry reported a significant improvement in long-term renal dysfunction in the most recent cohort of heart transplant recipients (2001 to 2007) as compared to the previous cohort (1994 to 2000). Whereas only 60% of heart transplant recipients from 1994 to 2000 were free of severe renal dysfunction (defined as a creatinine concentration of more than 2.5 mg/dL and the need for dialysis or renal transplantation) by Kaplan-Meier estimates at 10 years, recipients transplanted from 2001 to 2007 had an 11% absolute decrease in severe renal dysfunction at 5 years compared with the previous cohort.5 Notably, the risk of death after heart transplantation is markedly increased by the development of end-stage renal failure.138

Cyclosporine nephrotoxicity after heart transplantation is well recognized and well documented. The improved bioavailability of cyclosporine microemulsion (Neoral) compared with the conventional formulation has led to investigations into monitoring of cyclosporine levels 2 hours after dosing (C2).139 Neoral C2 monitoring may be a better indicator of immunosuppression efficacy than trough levels and a better measure to avoid nephrotoxicity and other cyclosporine-associated side effects.140 Lowering cyclosporine dose may be helpful in slowing the progression of renal disease, especially with concomitant use of newer immunosuppressive regimens such as mycophenolate mofetil and sirolimus (rapamycin).141,142 Calcineurin-free immunosuppression is also being implemented by some centers.143

Hypertension

Moderate to severe systemic hypertension afflicts 50 to 90% of cardiac transplant recipients.5 Peripheral vasoconstriction in combination with fluid retention seems to play the greatest role. Although the exact mechanisms are unclear, it likely involves a combination of cyclosporine-induced tubular nephrotoxicity and vasoconstriction of renal and systemic arterioles mediated by sympathetic neural activation.144 Tacrolimus is associated with a lower incidence of hypertension than is cyclosporine.145 No single class of antihypertensive agents has proven uniformly effective, and treatment of this refractory hypertension remains empirical and difficult. In a prospective, randomized trial, titrated monotherapy with either diltiazem or lisinopril controlled the condition in fewer than 50% of patients.146 Diuretics should be used cautiously because the balance between edema/hypertension and volume depletion/hypotension can be tenuous in a subset of these patients. Overzealous diuresis can potentiate the apparent nephrotoxicity of cyclosporine by further reducing renal blood flow and altering cyclosporine pharmacokinetics.147 Beta-blockers also should be used with caution because they may further blunt the heart rate response to exercise.

Malignancy

Chronic immunosuppression is associated with an increased incidence of malignancy ranging from about 4 to 18%, which is 100-fold greater than in the general population.148 Improved graft and patient survival, owing to pharmacologic advances in the area of immunosuppressive therapy, has led to an increase in the incidence of neoplasms.148 Malignant neoplasias have become, along with graft vasculopathy, a significant limiting factor for the long-term survival of heart transplant recipients.5 Lymphoproliferative disorders and carcinoma of the skin are the most common malignancies found in heart transplant recipients.148 Loss of T-lymphocyte control over Epstein-Barr virus (EBV)–stimulated B-lymphocyte proliferation appears to be the primary mechanism for the development of lymphoproliferative disorders.149 The risk of these malignancies is increased further following monoclonal and polyclonal antibody therapy.150,151 Treatment options in transplantation include a reduction in immunosuppression and initiation of high-dose acyclovir (to attenuate EBV replication), in addition to conventional therapies for carcinoma (eg, chemotherapy, radiation therapy, and surgical resection), which are associated with very high risk and limited success.

Other Chronic Complications

Hyperlipidemia eventually develops in the majority of recipients and is managed with dietary restrictions, exercise, and lipid-lowering agents.152 Other complications that commonly contribute to posttransplant morbidity include osteoporosis, obesity, cachexia, and gastrointestinal complications, notably cholelithiasis.153,154

Retransplantation accounts for fewer than 3% of the cardiac transplants currently performed.5 Primary indications for retransplantation are early graft failure, allograft coronary artery disease, and refractory acute rejection.155,156 The operative technique and immunosuppressive regimen are similar to those employed for the initial transplantation. Despite reduced mortality in the cyclosporine era, actuarial survival remains markedly reduced. Analysis of the ISHLT registry for retransplantations performed between 1987 and 1998 reveals survival to be 65, 59, and 55% for 1, 2, and 3 years, respectively. Intertransplant interval of 6 months or less was associated with a dismal 1-year survival of 50% in this analysis. Conversely, when the interval between primary and retransplantation was more than 2 years, 1-year survival after retransplantation approached that of primary transplantation.156 The 2009 ISHLT registry report indicates that the 5-year survival of retransplanted patients has increased by 15 to 17% with each successive decade (1982 to 1991, 1992 to 2001, 2002 to 2007). As well, in the most recent cohort (2002 to 2008), patients undergoing retransplantation at greater than 5 years from initial transplant had the same 1-year survival rate as primary transplants from the same era (86%).5 Advanced donor age also was a predictor of increased mortality among these recipients.156 These data suggest that although cardiac retransplantation is associated with significant morbidity and mortality, careful selection of patients, especially those who are younger and with longer intertransplant intervals, may be associated with more favorable outcome. Nonetheless, the disparity between the demand and supply for donor hearts continues to make cardiac retransplantation an ethical dilemma.157

Although no direct comparative trials have been or are likely to be performed, survival following heart transplantation remains favorable if compared with both the medical and device arms of the REMATCH trial.2,6 The superiority of heart transplantation is more clearly evident in medium- and high-risk patients with end-stage heart failure.158 The overall results actually are improving despite increasing risk profiles.5,67 The reported operative (ie, 30-day) mortality for cardiac transplantation ranges from 5 to 10%.159 Overall 1-year survival is up to 86%.5,67 After the steep fall in survival during the first 6 months, survival decreases at a linear rate (approximately 3.5% per year), even well beyond 15 years posttransplantation.5 Graft failure (primary and nonspecific), multisystem organ failure, and infection account for most deaths within the first 30 days. Infection, graft failure, and acute rejection are the leading causes of death during the first year; thereafter, cardiac allograft vasculopathy and malignancy are the major causes of death.5,67 Studies examining the health-related quality of life (HRQOL) in patients after cardiac transplantation demonstrate marked improvement, particularly in the absence of complications, and approaches the general population by 10 years after transplantation.160

Insights from the United Network for Organ Sharing Database

The recent literature on heart transplantation has seen a notable increase in clinical studies analyzing the multi-institutional UNOS open transplant cohort. This database is publically accessible and includes all heart transplants performed in the United States from October 1987 onward. The database also includes patients on the waitlist, donor information, and outcomes. As with all large administrative datasets, it is limited by potential errors in coding as well as incompletely populated variables. However, questions that had previously only been addressed using single or limited multi-institutional data can now be investigated using this cohort of over 20,000 patients.

Among those issues addressed have been the impact of various recipient factors, on short- and long-term survival after heart transplantation. Russo and coworkers reported that uncomplicated diabetes mellitus should not preclude listing for heart transplantation due to equivalent survival with nondiabetics.161 However, severe diabetics did have poorer survival and should be considered for destination LVAD therapy or high-risk listing. Zaidi and coworkers reported better short and intermediate survival after heart transplantation in patients with sarcoidosis compared to recipients with other diagnoses, and concluded that a diagnosis of sarcoidosis should not preclude heart transplantation.162 Kpodonu and coworkers demonstrated that 1-year survival after heart transplant for amyloid cardiomyopathy was significantly decreased in female recipients, whereas it was comparable with other diagnoses for male recipients.163 Nwakanma and coworkers confirmed increasing risk of rejection in the year after transplantation and decreased survival with increasing panel reactive antibody levels.164 Weiss and coworkers reported that advanced age (>60 years) was associated with acceptable long-term outcomes (>70% 5-year survival).165 Although elderly recipients did have slightly higher rates of infection and acute renal failure, as well as a 2-day longer hospital length of stay, the survival benefit of transplantation in elderly CHF patients was compelling. Another study by Weiss and coworkers identified a potential provider bias in the listing of obese patients as potential heart transplant recipients.166 Specifically, that obese individuals wait longer and have a lower likelihood of receiving a donor heart after listing, despite similar short-term survival.

Insights into the impact of operative technique and the use of LVADs on posttransplant survival have also been gained from the UNOS database. As noted, Weiss and coworkers reported equivalent survival after heart transplantation using biatrial versus bicaval anastomotic techniques.63 However, they did identify that the bicaval technique was associated with a shorted hospital length of stay and decreased rates of permanent pacemaker placement. Pal and coworkers investigated status 1 patients bridged to transplant using LVADs and IV inotropes, and found that patients bridged to transplant using LVADs were, by in large, those who failed bridging with IV inotropes.167 In contrast with International Society of Heart and Lung Transplantation data, no increase in posttransplant morbidity or mortality was found in LVAD-bridged patients compared with nonbridged status 1 patients. Shuhaiber and coworkers compared patients bridged with transplant with Novacor versus HeartMate LVADs and found no difference in 1-year survival, rates of rejection, or rates of infection.168 However, patients bridged with Novacor LVADs demonstrated lower 5-year survival posttransplant.

Weiss and coworkers also investigated the effect of transplant center volume on long-term outcomes after heart transplantation, and reported that annual center volume is an independent predictor of short-term mortality in OHT.169 Although the current Centers for Medicare and Medicaid Services mandate is that heart transplant centers perform 10 per year to qualify for funding, this study found that a higher cutoff resulted in better outcomes; centers performing greater than 40 per year have a 30-day mortality less than 5%.

As a result of a series of unprecedented advances over the past decade, the clinical outcome of heart transplantation has improved dramatically. Although cardiac replacement remains the best therapeutic option for patients with end-stage heart failure, a number of challenges await future investigators to further improve survival and reduce transplant-related morbidity. A major factor limiting long-term survival of recipients is allograft rejection and the untoward effects of immunosuppression. Development of reliable, noninvasive diagnostic studies will permit more frequent evaluations for the early detection of rejection and for monitoring the effectiveness of therapy. Ultimately, this will allow more precise control of immunosuppression and, in turn, a reduction in cumulative allograft injury and infectious complications. Molecular tests and gene expression profiling could be available soon and may provide the best noninvasive option.91

Immunosuppressive strategists will continue their efforts to establish specific unresponsiveness to antigens of transplanted organs in hopes of preserving much of the recipient's immune responses. Proliferative signal inhibitors such as sirolimus and everolimus are showing promising results. Alternatively, donor organs may be made less susceptible to immunologic attack through genetic engineering techniques by altering the expression of cell membrane–bound molecules. This approach is being used currently in the pursuit of clinically applicable xenotransplant sources. Xenografts eventually may be an additional source of donor organs, although extended xenograft survival remains an elusive goal. Complicating this alternative are unresolved ethical issues concerning transgenic experimentation and the potential for transmission of veterinary pathogens to an immunosuppressed recipient.

Future improvements in organ preservation permitting extension of the storage interval will have several benefits. In addition to a modest increase in the donor pool, extension of storage times would permit better allocation of organs with respect to donor-recipient immunologic matching. Assist devices are being used currently both as a bridge to transplantation and as a destination therapy. It appears that as the technology of assist devices continues to improve, it is only a matter of time before they become a long-term solution for patients with severe congestive heart failure.

The concept of regenerating the failing heart using cardiomyocytes of different sources, autologous smooth muscle cells, and dermal fibroblasts is in the experimental stage. Lineage-negative bone marrow cells or bone marrow–derived endothelial precursor cells are also being studied to induce new blood vessel formation after experimental myocardial infarction.170 Cardiac transplantation remains a remarkable achievement of the twentieth century and has revolutionized therapy for end-stage heart failure. Further investigations are needed to overcome the current obstacles to long-term graft function and patient survival.