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Bethea BT, Yuh DD, Conte JV, Baumgartner WA. Heart Transplantation.
In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:14271460.

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Chapter 60

Heart Transplantation

Brian T. Bethea/ David D. Yuh/ John V. Conte/ William A. Baumgartner

????Recipient Selection
????Management of the Potential Cardiac Recipient
????Recipient Prioritization for Transplantation
????Donor Availability
????Allocation of Donor Organs
????Brain Death
????Donor Selection
????Management of the Cardiac Donor
????Donor Heart Procurement
????Organ Preservation
????Donor-Recipient Matching
????Hyperacute Rejection
????Orthotopic Heart Transplantation
????Heterotopic Heart Transplantation
????Domino Donor Procedure
????Hemodynamic Management
????Respiratory Management
????Renal Function
????Intermediate Care Unit and Convalescent Ward
????Outpatient Follow-up
????Pharmacologic Immunosuppressive Strategies
????Individual Immunosuppressive Agents
????Nonpharmacologic Immunosuppressive Strategies
????Diagnosis of Acute Rejection
????Treatment of Acute Rejection
????Acute Vascular Rejection
????Organisms and Timing of Infections
????Preventive Measures and Prophylaxis against Infection
????Donor-Transmitted Infection
????Specific Organisms Causing Infection Following Heart Transplantation
????Allograft Coronary Artery Disease
????Renal Dysfunction
????Other Chronic Complications

Cardiac transplantation has emerged as the therapeutic procedure of choice for patients with end-stage heart failure. Tremendous advances in the fields of immunosuppression, rejection, and infection have transformed what was once considered an experimental intervention into a routine treatment readily available worldwide. Today, the success of cardiac transplantation is no longer measured by patient survival alone, but also by the quality of life attained by the transplant recipient.

The birth of cardiac transplantation can be traced back to the innovative French surgeon Alexis Carrel who performed the first heterotopic canine heart transplant with Charles Guthrie in 1905.1,2 Twenty years later, the concept of cardiac allograft rejection was proposed by Frank Mann at the Mayo Clinic to explain the eventual failure of heterotopic canine allografts.3 He described the rejection process as a biological incompatibility between donor and recipient manifested by an impressive leukocytic infiltration of the rejecting myocardium. In 1946, Vladimir Demikhov of the Soviet Union successfully implanted the first intrathoracic heterotopic heart allograft.4 He later demonstrated that heart-lung and isolated lung transplantation were also technically feasible. The use of moderate hypothermia, cardiopulmonary bypass, and an atrial cuff anastomotic technique permitted Norman Shumway and Richard Lower at Stanford University to surmount the formidable barriers of orthotopic heart transplantation using a canine model in 1960 (Fig. 60-1).5 The first human cardiac transplant was a chimpanzee xenograft performed at the University of Mississippi by James Hardy in 1964.6 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 would ever be successfully performed in humans, South African Christiaan Barnard surprised the world when he performed the first human-to-human heart transplant on December 3, 1967.7

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FIGURE 60-1 Norman Shumway.

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 his 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.8 The advent of the immunosuppressive agent cyclosporine dramatically increased patient survival and marked the beginning of the modern era of successful cardiac transplantation in 1981.9 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 because of limited donor organ availability.10

Recipient Selection

The evaluation of patients with end-stage heart disease and the selection of potential candidates for cardiac transplantation is undertaken by a multidisciplinary committee to ensure an equitable, objective, and medically justified allocation of the limited donor organs to patients with the greatest chance of postoperative survival and rehabilitation. Because of the current excellent results of transplantation and improved immunosuppression, eligibility criteria have been significantly expanded, contributing to the escalating donor shortage, complicating the selection process, and perhaps jeopardizing the results of future procedures. Indications and potential contraindications for cardiac transplantation are outlined in Table 60-1.10 These inclusion and exclusion criteria vary somewhat among transplantation centers. The basic objective of the selection process is to identify those relatively healthy patients with end-stage cardiac disease refractory to medical therapies who possess the potential to resume a normal active life and maintain compliance with a rigorous medical regimen after cardiac transplantation. Accumulating transplant experience will facilitate optimal donor organ allocation through improved risk stratification of potential recipients and prediction of successful outcomes for cardiac transplantation.

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TABLE 60-1 Recipient selection for heart transplantation


Determination of the etiology and potential reversibility of end-stage cardiac failure is critical for the selection of transplant candidates. The vast majority of patients are referred with New York Heart Association (NYHA) class III or IV symptoms caused by ischemic heart disease or idiopathic dilated cardiomyopathy.11 The spectrum of known causes of dilated cardiomyopathy include infectious (viral), inflammatory, toxic, metabolic, and familial etiologies.12 Infrequent indications for transplantation include intractable angina, refractory malignant ventricular arrhythmias, allograft occlusive coronary artery disease, and cardiac failure caused by valvular or congenital heart disease. The perception of the irreversibility of advanced cardiac failure is changing with the growing popularity of tailored medical therapy, high-risk revascularization procedures, and newer antiarrhythmic pharmacologic agents and devices.


The initial evaluation involves a comprehensive history and physical examination, chest roentgenogram, routine hematologic and biochemical laboratories, a limited panel of infectious disease serologies, and an exercise test with maximal oxygen consumption (VO2) measurements. Although the majority of referred patients have already undergone right heart cardiac catheterization and coronary angiography, the former study is repeated at the transplantation center before listing and at routine intervals thereafter to rule out irreversible pulmonary hypertension. Cine coronary angiography should be reviewed to confirm the inoperability of coronary artery lesions in ischemic cardiomyopathy. Endomyocardial biopsy should be performed on all patients with nonischemic cardiomyopathies symptomatic for less than 6 months to assist in therapeutic decision making. The complete routine preoperative evaluation in patients selected for transplantation includes thyroid function studies, fasting and postprandial blood sugar, creatinine clearance, lipoprotein electrophoresis, viral titers, fungal serologies, 12-lead electrocardiogram, Holter monitor, echocardiogram, pulmonary function tests, panel reactive antibody screen, and HLA typing. Abdominal ultrasound, carotid and lower extremity Doppler flow studies, esophagogastroduodenoscopy, and screening studies for malignancy are indicated in selected patients.


Cardiac transplantation is reserved for a select group of patients with end-stage heart disease not amenable to optimal medical therapy or other surgical procedures (such as revascularization, balloon angioplasty, or catheter ablation techniques).13 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, as no reliable objective prognostic criteria are currently available. Low ejection fraction (pulmonary capillary wedge pressure (>25 mm Hg), elevated plasma norepinephrine (>600 pg/mL), increased cardiothoracic ratio, and reduced maximal VO2 (proposed as predictors of poor prognosis and potential indications for transplantation in patients receiving optimal medical therapy.1420 A VO2 value between 10 and 15 mL/kg/min may be an indication if a steady decline has been noted. Reduced left ventricular ejection fraction and low maximal oxygen consumption are the strongest independent predictors of survival.24


Age is one of the most controversial exclusionary criteria for transplantation. The upper age limit for recipients is determined by each center, but emphasis is placed on the patient's physiologic rather than chronologic age.21 Survival and quality of life in carefully selected older patients is comparable to that of younger recipients.22 Although the elderly have a greater potential of occult systemic disease that may complicate their postoperative course, they have fewer rejection episodes than younger patients.23

Elevated pulmonary vascular resistance (PVR) is one of the few absolute contraindications for orthotopic cardiac transplantation. A fixed PVR greater than 6 Wood units or a transpulmonary gradient greater than 15 mm Hg are criteria for rejection of a candidate.2427 Preoperative assessment of these patients should include evaluation of the reversibility of the pulmonary hypertension with vasodilators (oxygen, milrinone, sodium nitroprusside, or prostaglandin E1) in the cardiac catheterization laboratory. If this hemodynamic maneuver does not reduce PVR by 50%, a trial of parenteral inotropes or vasodilators is initiated and after 48 to 72 hours repeat catheterization is performed. A fixed elevated PVR is defined as one that cannot be significantly reduced with the aforementioned interventions and predicts fatal graft right heart failure in the immediate postoperative period.2829 These patients may be candidates for heterotopic heart or heart-lung transplantation.3031 For a recipient with moderate pulmonary hypertension (36 Wood units), a larger donor heart often is selected to provide additional right ventricular reserve.

Transplantation in patients with diabetes mellitus is contraindicated only in the presence of significant end-organ damage (diabetic nephropathy, retinopathy, or neuropathy).3233 Control of blood sugar is possible with the reduction (or elimination) of corticosteriods in the cyclosporine era.3436 Active infection (including human immunodeficiency virus), irreversible renal or hepatic dysfunction, significant chronic lung disease, severe noncardiac arteriosclerotic vascular disease, and malignancy are generally considered contraindications for transplantation. Poor nutritional status as manifested by cachexia increases risk of infection and may limit early postoperative rehabilitation.

The ultimate success of transplantation is intimately dependent on the psychosocial stability and compliance of the recipient.36 The rigorous postoperative regimen of multidrug therapy, frequent clinic visits, and routine endomyocardial biopsies demands 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.3739 Lack of supportive family members or companions is an additional relative contraindication.

Management of the Potential Cardiac Recipient


Pharmacologic advances in the treatment of heart failure have clearly led to improvements in both quality of life and long-term outcomes. Conventional outpatient management of congestive heart failure includes angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and diuretics (especially spironolactone).4047 Patients with moderate to severe congestive heart failure have shown improved survival with drug therapy.4143


Critically compromised patients require admission to the intensive care unit for intravenous inotropic therapy. Milrinone, dobutamine, and dopamine are the agents of choice.4445 Placement of an intra-aortic balloon pump (IABP) also may be necessary in heart failure refractory to initial pharmacologic measures. Patients with continued pulmonary congestion or global hypoperfusion despite maximal pharmacologic and IABP therapies have been shown to improve with placement of mechanical devices as bridges to transplantation.4649


The increased success of cardiac transplantation in conjunction with the static number of available organs has created a need for mechanical assist devices as a bridge to transplantation.50 Ventricular assist devices (VAD) or total artificial hearts (TAH) may be indicated in potential cardiac recipients who remain unstable after 24 to 48 hours of maximal pharmacologic support (Table 60-2).5157 Since these devices are rarely weaned, however, it is imperative that the patient's candidacy for transplantation be scrutinized prior to placement of a VAD or TAH. Patient selection for a mechanical device is a complex, evolving field closely followed by the U.S. Food and Drug Administration.58 Recent data shows that approximately 70% of patients are successfully bridged to transplantation and the actuarial survival is 80% at one year.59 Most large series suggest an improvement in survival because the devices allow patients to be rehabilitated while on the device.47,60 Initial results from the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study indicate that patients with devices have improved survival and quality of life at 1 year compared to medical therapy and may prove to be an acceptable long term option in those patients who are not candidates for cardiac transplantation.61

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TABLE 60-2 Recipient selection criteria for ventricular assist device


Symptomatic ventricular tachycardia or fibrillation and a history of sudden cardiac death (SCD) are indications for placement of an automatic implantable cardioverter-defibrillator (AICD), long-term amiodarone therapy, or occasionally radiofrequency catheter ablation.6263 SCD is the most common cause of death in patients awaiting heart transplantation and is most common within the first 3 months after referral for transplantation.6465 Several studies have shown that implantation of a defibrillator improved survival in patients with either a history of or inducible ventricular tachycardia or fibrillation.6667

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 to maximal medical and surgical alternatives.68 Organ allocation is based on recipient priority status (IA, IB, or II), duration on the waiting list, and geographic distance between donor and potential recipient. Highest priority is given to local status IA patients possessing the earliest listing dates. The recipient status criteria established by the United Network for Organ Sharing (UNOS) in 1999 are outlined in Table 60-3. In 1999, of the patients who received cardiac transplants, 34% of recipients were in status IA, 37% were in status IB, and only 26% were in status II.69 Furthermore, the cardiac transplant waiting list has more than doubled over the last 10 years and, in 1999, more than 39% of the waiting list was comprised of patients who have been listed for more than 2 years.69 Patients considered for transplantation should be examined at least every 3 months for reevaluation of recipient status. Yearly right 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 de-list patients who have stabilized on medical therapy without loss of their previously accrued waiting time.

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TABLE 60-3 Current recipient status criteria of the United Network for Organ Sharing (UNOS)*


Donor Availability

The availability of donor organs remains the major limiting factor to heart transplantation. The number of heart transplants performed in the United States has declined over the past 10 years but appears to have leveled at approximately 2200 per year. Interestingly, likely due to improved preoperative care, the death rate for patients on the waiting list for a cardiac allograft declined to an all time low of 172.4 per 1000 patients in 1999.69 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.70 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. Interestingly, several reports indicate that the most important reason for the organ shortage is not the indifference of the public, but rather a failure of health care providers to discuss the option of organ donation with families of dying patients.71 In 1986, the Required Request Law, which required hospitals to request permission from next of kin to harvest organs, was passed to encourage physician compliance in the donor request process.72 Several European countries have implemented controversial "presumed consent" legislation whereby organ procurement may automatically proceed in brain-dead individuals if wishes to the contrary are not expressed by the patient prior to death.73 Even in the presence of documentation of the patient's wishes to donate, consent for organ donation in the United States usually is verified with the family. The adoption of presumed consent legislation, the use of anencephalic newborns as donors, and financial incentives for the donor family have all stimulated considerable controversy.7475 Future reforms will be molded by the evolving public attitude towards transplantation and will likely focus on continued public and physician education as well as enforcement and expansion of required request legislation.76

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 1984.77 This act resulted in the drafting of the aforementioned Required Request Law as well as the awarding of a federal contract to the United Network of Organ Sharing (UNOS) for the development of a national organ procurement and allocation network.78 Eleven regions were created that are locally managed by transplant coordinators of individual organ procurement organizations (OPOs).

Brain Death

Establishment of criteria for brain death was imperative with the advent of heart transplantation so that the organ could be procured while still functioning to minimize ischemic injury. After early attempts to define brain death by the Harvard Committee, the University of Minnesota, and the National Institutes of Health, the Uniform Brain Death Act (1978) and later the Uniform Determination of Death Act (1980) were passed to provide national guidelines for state legislators to adopt.7982 The basic criteria used for the diagnosis of brain death include loss of cortical function, apnea, absence of brain stem reflexes, and irreversibility over a 12 to 24 hour observation period. Furthermore, any potentially reversible cause for the patient's neurologic status, including metabolic disturbances, pharmacologic agents, and hypothermia must be ruled out.8384 The vast majority of donors are victims of blunt head trauma (motor vehicle accident), penetrating head trauma (gunshot wound), or cerebrovascular accident. The diagnosis of brain death can be made by clinically established criteria by the patient's physician. However, if uncertainty exists or the observation period must be abbreviated because of patient instability, ancillary confirmatory tests should be performed for uncertainty or declining clinical status of the donor and include electroencephalogram, cerebral angiography, or radionuclide cortical blood flow studies.85 Declaration of brain death and confirmation of written informed consent must be documented in the patient's chart.

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, weight, gender, ABO blood type, hospital course, cause of death, and routine laboratory data including CMV, HIV, HBV, and HCV serologies are collected. Cardiac surgeons or cardiologists perform the secondary screening, which involves further investigation in search of potential contraindications (Table 60-4), determination of the hemodynamic support necessary to sustain the donor, and review of the electrocardiogram, chest roentgenogram, arterial blood gas, and echocardiogram. Although adverse donor criteria may be reported, a team is often dispatched to the hospital to evaluate the donor on-site. Echocardiography is performed in the United States but not in Europe. While echocardiography has been extremely useful for detection of wall motion abnormalities and unsuspected congenital heart lesions, pulmonary catheters are used to determine cardiac output because of inaccuracies of echocardiography.80 Coronary angiography is indicated in the presence of advanced donor age (male donors >45 years of age, female donors >50 years of age) or risk factors for atherosclerotic coronary artery disease (tobacco abuse, diabetes, significant family history). 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 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.

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TABLE 60-4 Donor selection for heart transplantation

In light of continued attempts to liberalize the criteria for donor eligibility,86 the screening process continues to evolve and intensify to predict early allograft failure because of latent cardiac disease. Currently, several studies have been evaluating the routine use of angiography in potential cardiac donors in an effort to increase the number of available organs.87 Considerable experimental work is still necessary for the development of a simple, reproducible test for detecting cardiac allograft injury prior to explantation.

Management of the Cardiac Donor

Medical management of cardiac donors, an integral part of organ preservation, is complicated by the complex physiological phenomenon of brain death and the need to coordinate procurement with other organ donor teams. Optimal care requires that the donor be treated as any other intensive care unit patient with invasive hemodynamic monitoring, ventilatory support, and meticulous attention to intravascular volume status and electrolytes (Table 60-5).88 Continuous monitoring of arterial pressure, central venous pressure, and urinary output is mandatory. As the number of marginal donors increases with the acceptance of more lenient eligibility criteria, some transplant centers have established mobile intensive care teams that are dispatched to ensure appropriate management of these highly labile patients.89 Hemodynamic instability in the donor may result from vasomotor dysfunction, hypovolemia, hypothermia, and dysrhythmias. Increased intracranial pressure may lead to massive sympathetic discharge with elevated levels of circulating endogenous catecholamines. The resultant episodes of systemic hypertension and coronary vasospasm place the allograft at significant risk of ischemic injury.90 Rapid afterload reduction may be achieved with sodium nitroprusside, whereas volatile anesthetics assist in reducing the intensity of sympathetic bursts. To minimize cerebral edema prior to the declaration of brain death, potential donors have been intravascularly volume depleted via strict fluid restriction and osmotic diuresis. Aggressive volume resuscitation is sometimes necessary and may require use of a Swan-Ganz catheter.91 Fluid overload, however, should be avoided to prevent postoperative allograft dysfunction caused by chamber distention and myocardial edema. Blood transfusions are indicated to optimize oxygen delivery if the hemoglobin falls below 10 g/dL. Mean arterial pressure should be maintained between 80 and 90 mm Hg. If fluid resuscitation is inadequate to restore blood pressure in the hypotensive donor, a dopamine infusion is initiated for inotropic support.9293 Vasopressors are occasionally indicated for hypotension caused by loss of systemic vasomotor tone. Prolonged administration of high-dose catecholamine therapy (dopamine >1015 ?g/ kg/min) has been associated with poor cardiac function in the posttransplant period because of depletion of myocardial norepinephrine stores.9495 Traditionally, these patients were rejected for use as cardiac donors, but high-dose inotropic support is no longer an absolute contraindication for donation.96 Maintenance of normal temperatures, electrolyte levels, osmolarity, acid-base balance, and oxygenation is critical for optimal donor management. Common electrolyte disturbances include hypernatremia, hypokalemia, hypomagnesemia, and hypophosphatemia.97 Central diabetes insipidus develops in more than 50% of donors because of pituitary dysfunction, and massive diuresis complicates fluid and electrolyte management.98 A low-dose aqueous vasopressin (Pitressin) infusion is initiated at 0.8 to 1.0 U/h and titrated to keep urinary output at approximately 100 to 200 mL/h.99 Alternatively, vasopressin may be administered periodically subcutaneously or intramuscularly (10 U every 4 hours). Standard ventilator management with diligent endotracheal suctioning is essential in these vulnerable patients.100

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TABLE 60-5 Management of the cardiac donor

Broad-spectrum antibiotic therapy with a cephalosporin is initiated following collection of blood, urine, and tracheal aspirate for culture. Brain death is associated with the depletion of a variety of hormones, including free triiodothyronine (T3), cortisol, and insulin.101102 Donor pretreatment with hormone replacement therapy has proven to be beneficial.103105

Donor Heart Procurement

A median sternotomy is performed and the pericardium incised longitudinally. The heart is inspected and palpated for evidence of cardiac disease or injury. The superior and inferior vena cava and azygous vein are circumferentially mobilized 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 U 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. 60-2). The inferior vena cava is clamped at the level of the diaphragm (if the abdominal IVC is vented) and then divided proximal to the clamp to permit efflux of the cardioplegia. Additional venting is achieved with transection of the right superior pulmonary vein. The aortic cross-clamp is applied at the takeoff of the innominate artery and the heart is arrested with a single flush (500 mL) of cardioplegic solution infused through a 14-gauge needle inserted 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. Following 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 appropriately modified 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 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.

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FIGURE 60-2 Donor cardiectomy.

Once the explantation is complete, the allograft is examined for evidence of a patent foramen ovale, which should be closed at that time, or any valvular anomalies. The allograft is then placed in a sterile container for transport back to the recipient hospital.

Organ Preservation

Current clinical graft preservation techniques generally permit a safe ischemic period of 4 to 6 hours. The donor heart is vulnerable to injury at all stages of the transplantation procedure. 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 is the preferred preservation method by most transplant centers.130 Despite two decades of investigation, no single preservation regimen has demonstrated consistent, clinically significant superior myocardial protection when used within the current safe limits of ischemia.106 Controversy abounds in the literature regarding optimal storage temperature, composition of cardioplegic and storage solutions, techniques of solution delivery, additives, and reperfusion modification. Hypothermia remains the cornerstone of organ preservation. The ideal storage temperature is unknown, but most institutions aim for temperatures between 4?C and 10?C.107 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.108110 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) 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. Stanford, Hopkins, and St. Thomas Hospital solutions are representative extracellular cardioplegic solutions. Although a plethora of pharmacologic additives have been included in cardioplegic storage solutions, the greatest potential for future routine use may lie with impermeants, substrates, and antioxidants. Currently used impermeants (mannitol, lactobionate, raffinose, and histidine) counteract intracellular osmotic pressure to reduce hypothermia-induced cellular edema in the allograft. The preservation of myocardial high-energy phosphates during ischemia (to prevent contracture bands) and their rapid regeneration at reperfusion (to fuel the newly contracting heart) are the primary objectives for the use of substrate-enhanced media. Adenosine, L-pyruvate, and L-glutamate have been studied most intensely.111 Recognizing that oxygen-derived free radicals and neutrophils likely are critical mediators of myocardial reperfusion injury, considerable investigative effort has been undertaken to modify the untoward effects of ischemia-reperfusion with antioxidant additives including allopurinol, glutathione, superoxide dismutase, catalase, mannitol, and histidine. A variety of pharmacologic and mechanical strategies for leukocyte inhibition and depletion are also being explored.112113 Potential benefits of continuous perfusion preservation techniques are currently overshadowed by exacerbation of extracellular cardiac edema and logistical problems inherent to a complex perfusion apparatus.114 Experimental low-pressure (microperfusion) and intermittent flush techniques theoretically provide sufficient oxygen and substrates for basal metabolic demands without causing significant edema.115 Continued research will be necessary to resolve these ongoing debates over the various aspects of cardiac allograft preservation, since the heart transplant registry continues to report that 20% of perioperative deaths are caused by cardiac dysfunction.

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 heart transplantation, as incompatibility frequently results in fatal hyperacute rejection. Donor weight should be within 30% of recipient weight except in pediatric patients, where closer size matching is required. In cases of elevated pulmonary vascular resistance in the recipient (>6 Wood units), a larger donor is preferred to reduce the risk of right ventricular failure in the early postoperative period. A random panel of pooled lymphocytes representing the major histocompatibility antigens in the community is used to screen the recipient for antihuman lymphocyte antigen (HLA) antibodies that may also mediate hyperacute rejection. If the percentage (or panel) of reactive antibody (PRA) is greater than 10% to 15%, indicating recipient presensitization to alloantigen, a prospective negative T-cell crossmatch between the recipient and donor sera is mandatory prior to transplantation.116117 A positive crossmatch is an absolute contraindication to transplantation. A crossmatch is always performed retrospectively, even if the PRA is absent or low. Retrospective studies have also demonstrated that better matching at the HLA-DR locus results in fewer episodes of rejection and infection with an overall improved survival.118 Because of current allocation criteria and limits on ischemic time of the cardiac allograft, prospective HLA matching is not possible logistically.

Hyperacute Rejection

Hyperacute rejection results from preformed, donor-specific antibodies in the recipient.119 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,120 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.121 No treatment is effective except retransplantation, and even this aggressive strategy frequently is unsuccessful.

Orthotopic cardiac transplantation, the surgical technique of choice, involves the replacement of part (or occasionally all) of the recipient's heart with a healthy donor allograft. Heterotopic cardiac transplantation, the piggy-backing of an allograft onto the patient's heart, is rarely performed today. It may be indicated if orthotopic transplantation is not possible because of elevated pulmonary vascular resistance or when a donor heart is too small to sustain the recipient.122123 Even in these selected cases, results are not equivalent to orthotopic transplant.124

Orthotopic Heart Transplantation


Once the organ procurement team has confirmed the acceptability of the donor allograft at time of operation, recipient induction may commence. High-dose narcotics (e.g., fentanyl) usually are employed for induction and maintenance anesthesia.125126 In light of the poor ventricular function of the recipient, all anesthetic agents should be titrated carefully with inotropic and vasoactive agents readily accessible for the rapid management of induction-induced hypotension. Inhaled agents may be added if necessary, but their potential myocardial depressant effects limit widespread use in this patient population. Prior to skin incision, some centers initiate aprotinin or aminocaproic acid therapy to minimize perioperative blood loss.127


The surgical technique of orthotopic cardiac transplantation has changed little from the original description reported by Shumway and Lower.5 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 is optimal. Umbilical tape snares are passed around the superior and inferior vena cava. 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.128 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 prior to the arrival of the cardiac allograft.129


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. 60-3). Implantation begins with placement of a double-armed 3-0 Prolene 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. 60-4). 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. 60-5). Upon completion of the posterior left atrial suture line, continuous topical cold saline irrigation of the pericardial well is initiated, and the patient is oriented in a left side downhead up position to allow drainage of the saline away from the operative field and maximal cold saline exposure of the left and right ventricles. 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. Some centers introduce a line into the left atrial appendage for continuous endocardial cooling of the allograft (5075 mL/min) and evacuation of intracardiac air.

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FIGURE 60-3 Donor allograft preparation for orthotopic heart transplantation. Pulmonary vein orifices joined to form left atrial cuff.


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FIGURE 60-4 Implantation of allograft. First suture is placed at the level of the left superior pulmonary vein.


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FIGURE 60-5 Implantation of allograft (continued). Left atrial anastomosis.

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.130 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 right-to-left shunting, patent foramen ovale are oversewn.131 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. 60-6).

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FIGURE 60-6 Implantation of allograft (continued). Right atrial anastomosis.

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. It is crucial that the pulmonary artery ends be trimmed to eliminate any redundancy in the vessel that might cause kinking.132 Rewarming is initiated at this time. Finally, the aortic anastomosis is performed using a technique similar to the pulmonary artery except that some redundancy is desirable in the aorta as it facilitates visualization of the posterior suture line (Fig. 60-7). Rewarming is usually begun prior to the aortic anastomosis, which is performed in a standard end-to-end fashion. Routine de-airing techniques are then employed.133 Cold saline lavage is discontinued, lidocaine (100200 mg IV) 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 de-airing with the patient in steep Trendelenburg. Suture lines are carefully inspected for hemostasis. Inotrope infusion is initiated and titrated to achieve a heart rate between 90 and 110 bpm.134 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 standard fashion.

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FIGURE 60-7 Implantation of allograft (continued). Aortic anastomosis.


Two alternative techniques for orthotopic heart transplantation have been gaining popularity over the past several years. Total heart transplantation involves complete excision of the recipient heart with bicaval end-to-end anastomoses and bilateral pulmonary venous anastomoses.135137 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. 60-8).138 Although these procedures are more technically difficult than standard orthotopic transplantation, series using these techniques have reported shorter hospital stays and reduced postoperative dependence on diuretics, in addition to lower incidences of atrial dysrhythmias, conduction disturbances, mitral and tricuspid valve incompetence, and right ventricular failure.138140 Furthermore, a recently completed randomized study comparing bi-atrial versus bicaval transplant showed an improved twelve month survival in the bicaval group.141 Long term outcomes and additional randomized studies evaluating these alternative techniques are still needed.

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FIGURE 60-8 Bicaval heart transplantation.


Unlike children and infants, transplantation in adults with previous palliative procedures for congenital anomalies is uncommon. It is critical that a generous donor cardiectomy be performed so that sufficient tissue is available for optimal reconstruction. There are a variety of anomaly-specific implantation techniques.142144

Heterotopic Heart Transplantation

Pulmonary hypertension and right heart failure has remained one of the leading causes of death in cardiac transplantation. This has led to an interest in heterotopic heart tranplantation. Currently, heterotopic heart transplants are indicated in patients with irreversible pulmonary hypertension or significant donor-recipient size mismatch.


Like the cardiectomy for patients with congenital disease, the maximal length of aorta, superior vena cava, and pulmonary arteries is procured. The inferior vena cava and the right pulmonary veins are oversewn, and a common left pulmonary vein orifice is created (Fig. 60-9). A linear incision is made along the long axis of the posterior right atrium extending 3 to 4 cm into the superior vena cava.

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FIGURE 60-9 Donor allograft preparation for heterotopic heart transplantation.


The details of the technique are well described in the literature145147 and are beyond the scope of this chapter. Briefly, the sequence of anastomoses is as follows: donor left pulmonary vein orifice to recipient left atrium, donor superior vena cava-right atrial orifice to recipient right atrium, end-to-side aortic-aortic anastomosis, and finally an end-to-side anastomosis joining the pulmonary arteries of donor and recipient (Fig. 60-10). By employing this technique, the strengths of both the native and transplanted heart are utilized. The conserved recipient's right ventricle provides the necessary assistance to the transplanted heart to overcome significant pulmonary hypertension.

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FIGURE 60-10 Heterotopic heart transplantation.

Domino Donor Procedure

Of historical interest, the Domino donor procedure was used to avoid wasting relatively healthy hearts from selected heart-lung transplant recipients. These organs were transplanted into a different recipient using standard orthotopic or heterotopic techniques.148149

Hemodynamic Management


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 heart fires at its increased intrinsic resting rate of 90 to 110 bpm.150151 The allograft relies on distant noncardiac sites as its source for catecholamines; thus, its response to stress (e.g., hypovolemia, hypoxia, anemia) is somewhat delayed until circulating catecholamines can exert their positive chronotropic effect on the heart.152154 Careful examination of the electrocardiogram occasionally may reveal a distinct P wave originating from the innervated atrial remnant of the recipient, and an increase in its rate may be used as an early indicator of stress. 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. Carotid sinus massage, Valsalva maneuver, and atropine have no effect on sinoatrial node firing or atrioventricular conduction.150 Because of depletion of myocardial catecholamine stores associated with prolonged inotropic support of the donor, the allograft often requires high doses of catecholamines.


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 the reduced ventricular compliance and contractility characteristics of the newly transplanted heart.155157 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.157159 Restoration of normal myocardial function usually permits the cautious weaning of inotropic support within 2 to 4 days.160


Early cardiac failure accounts for up to 25% of perioperative deaths of transplant recipients.160162 The cause may be multifactorial, but the most important etiologies are pulmonary hypertension, ischemic injury during preservation, and acute rejection. Mechanical support with an intra-aortic balloon pump or ventricular assist device is indicated in cases refractory to pharmacologic interventions.163 Retransplantation in this setting is associated with very high mortality.164165

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 heart failure remains a leading cause of early mortality.166168 Initial management involves employing pulmonary vasodilators such as inhaled nitric oxide, nitroglycerin, or sodium nitroprusside. Pulmonary hypertension refractory to these vasodilators will often respond to prostaglandin E1 (PGE1).169171 Inhalation nitric oxide is considered the standard at several institutions. Intra-aortic or pulmonary artery balloon counterpulsation and right ventricular assist devices have been utilized in patients unresponsive to medical therapy.172


Sinus or junctional bradycardia occurs in more than half of transplant recipients.173 The primary risk factor for sinus node dysfunction is prolonged organ ischemia. Adequate heart rate is achieved with inotropic drug infusions and/or temporary epicardial pacing. Most bradyarrhythmias resolve over 1 to 2 weeks, although recovery may be further delayed in patients who received preoperative amiodarone therapy.174 Theophylline has been effective in patients with bradyarrhythmias and has decreased the need for permanent pacemakers in this patient population.175176 Ventricular arrhythmias, primarily premature ventricular beats (PVCs) and nonsustained ventricular tachycardia, have been reported in up to 60% of recipients when monitored continuously.177179 Atrial fibrillation-flutter is treated with digoxin, but at a higher dose than used in the setting of an innervated heart.180 Arrhythmias occasionally are markers for acute rejection.


Mean arterial pressures greater than 80 mm Hg should be treated to prevent unnecessary afterload stress on the allograft. In the early postoperative period, intravenous sodium nitroprusside or nitroglycerin is administered.181182 Nitroglycerin is associated with less pulmonary shunting because of a relative preservation of the pulmonary hypoxic vasoconstrictor reflex.183 If hypertension persists, an oral antihypertensive can be added to permit weaning of the parenteral agents.

Respiratory Management

The respiratory management of the cardiac transplant recipient utilizes the same protocols used following routine cardiac surgery.

Renal Function

Preoperative renal insufficiency owing to chronic heart failure and the nephrotoxic effects of cyclosporine places the recipient at increased risk of renal insufficiency. Acute cyclosporine-induced renal insufficiency usually will resolve with the reduction in cyclosporine dose. Patients at risk for renal failure initially may receive cyclosporine as a continuous intravenous infusion to eliminate the wide fluctuations in levels associated with oral dosing. Furthermore, concurrent administration of mannitol with cyclosporine may reduce its nephrotoxicity. Alternatively, some centers administer a cytolytic agent in the immediate postoperative period and delay the initiation of cyclosporine therapy.

Intermediate Care Unit and Convalescent Ward

The increasing risk of nosocomial infections with resistant organisms has led to shorter hospital stays for cardiac transplant recipients. Most patients are discharged 7 to 14 days following transplantation.184 Patient education is performed by the cardiac nursing staff. Topics include medications (regimens and potential side effects), diet, exercise (routines and restrictions), and infection recognition.

Outpatient Follow-up

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.

An organism's ability to distinguish self from nonself is critical for its survival in a hostile environment. In transplantation, the recipient's host defense mechanisms recognize the human leukocyte antigens (HLA) on allograft cells as being nonself and, if permitted, will respond to eradicate the foreign cells.185 The ultimate goal of immunosuppressive therapy is the selective modulation of the recipient's immune response to prevent rejection, while concurrently sparing immune defenses against infections or neoplasia and minimizing the toxicity associated with immunosuppressive agents (Table 60-6).

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TABLE 60-6 Complications associated with immunosuppressive agents

Pharmacologic Immunosuppressive Strategies

Immunosuppression following transplantation consists of an early induction phase followed by a long-term maintenance phase. This basic strategy essentially is universal, although the choice of immunosuppressive agents, dosages, and combination protocols vary among transplantation centers.186 Since the tendency for allograft rejection is greatest in the early postoperative period, the most intense immunosuppression is administered during this induction phase. Most programs employ a triple immunosuppressive regimen while some centers also provide additional induction prophylaxis with potent polyclonal antibodies, and OKT3 or IL-2 blockers. After several months, immunosuppression and rejection surveillance are gradually reduced to chronic maintenance phase levels and frequencies.

Currently, most centers use triple drug therapy consisting of cyclosporine, steroids, and mycophenolate mofentil or azathioprine.187 The use of a multidrug regimen permits adequate immunosuppression with reduced doses of individual agents to minimize their toxicity. The immunosuppressive regimen currently used at the Johns Hopkins Hospital is outlined in Table 60-7.

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TABLE 60-7 Immunosuppressive regimen for heart transplantation at the Johns Hopkins Hospital

The use of cyclosporine has allowed for steroid-free maintenance immunosuppression, thus avoiding the multiple untoward sequelae associated with chronic corticosteroid therapy immunosuppression.188189 The timing of steroid withdrawal varies as some clinicians discontinue prednisone within several weeks of transplantation,188,190191 whereas others delay the taper until 6 to 12 months posttransplantation.189,192193 Recently, it has been suggested that the majority of patients can be completely tapered off steroids without an increased incidence of rejection.194 Attempts at corticosteroid withdrawal in patients with history of rejection, however, have usually been unsuccessful.195

Individual Immunosuppressive Agents


Corticosteroids have played an integral role in immunosuppression since the beginning of cardiac transplantation. These nonselective agents influence essentially all limbs of the immune response.196198 Currently, methylprednisolone is used during induction, and prednisone is usually part of maintenance immunosuppressive regimens. Corticosteroids are also the first-line therapy for acute rejection in most centers. The numerous untoward sequelae associated with long-term corticosteroid therapy have driven clinicians to significantly reduce doses of or even eliminate these drugs from maintenance regimens.199


Cyclosporine (cyclosporin A), a cyclic undecapeptide fungal metabolite,200 inhibits the production of the lymphokine interleukin-2 (IL-2) by helper T-lymphocytes, attenuating cytotoxic T-lymphocyte proliferation.201 By sparing macrophages, neutrophils, suppressor T lymphocytes, and some B lymphocytes, cyclosporine provides more selective immunosuppression compared to azathioprine and corticosteroids.202,203 It has also permitted the reduction in corticosteroid doses in maintenance immunosuppression.204,205 Indeed, the improved survival of cardiac recipients in the cyclosporine era is primarily secondary to a reduction in infection-related mortality likely associated with a relative preservation of host defense against microbials. Although the introduction of cyclosporine has not altered the incidence of acute rejection, it has dramatically attenuated the severity and associated morbidity of rejection episodes.206 Doses of cyclosporine are adjusted to achieve trough serum levels between 150 and 300 ng/mL.207208 The low therapeutic index of cyclosporine and the wide variation in individual pharmacokinetics mandate close monitoring of levels to maximize immunosuppression while minimizing nephrotoxicity.209211 In light of the frequency of cyclosporine drug interactions, the initiation or discontinuation of drugs should prompt frequent measurements of levels. For patients who develop renal insufficiency, cyclosporine may be administered temporarily as a continuous infusion to reduce wide fluctuations in serum levels. Neoral, the preferred formulation, has been shown to have more predictable intestinal absorption and improved pharmacokinetics compared with the original formulation.212213 Nephrotoxicity and hypertension are the primary complications associated with cyclosporine.214


Tacrolimus or FK506 is derived from the fungus Streptomyces and is an alternative to cyclosporine. Like cyclosporine, FK506 ihibits calcineurin and thus decreases the formation of IL-2.215 Similarly, the side effect profile of FK106 also resembles cyclosporine. Furthermore, several recent studies have compared FK506 to cyclosporine and report similar survival and rejection rates and a possible improvement in the side effect profile.216 Furthermore, recent studies have found FK506 to be most effective in reversing recalcitrant rejection.217 This has prompted some institutions that use cyclosporine to employ FK506 as a "rescue" agent.


The mechanism of action of mycophenolate mofetil (MMF, or CellCept) involves lymphocyte-specific inhibition of de novo purine synthesis and has largely replaced azathioprine.218 In randomized trials comparing MMF to azathioprine, the MMF groups had decreased mortality, while maintaining similar rejection rates.218 MMF currently provides the most promise for the induction of allograft-specific unresponsiveness.219


An imidazole derivative from 6-mercaptopurine, azathioprine inhibits antigen-stimulated proliferation of lymphocytes.220 Dosage adjustments are made to maintain the leukocyte count between 4000 and 5000/mm3. Azathioprine causes a dose-related bone marrow suppression that can be profound if administered concurrently with allopurinol.221


Sirolimus, or rapamycin, is another antibiotic derived from Streptomyces. Rapamycin, however, inhibits the action (not the transcription) of IL-2 (and IL-4)-driven proliferation of T-lymphocytes instead of blocking IL-2 production.222 Clinical trials are ongoing to evaluate the efficacy and toxicity of rapamycin.223 Several studies have indicated that rapamycin is effective in cases of refractory rejection.224225


Polyclonal antibodies (antithymocyte, antilymphocyte) are produced by animals following immunization with human lymphocytes. By attaching to circulating lymphocytes and thus promoting cytolysis or opsonization by the reticuloendothelial system, these antibodies can decrease the level of circulating T cells to less than 10% of normal. The precise mechanism by which polyclonal antibodies provide their immunosuppressive effect is still under investigation. Antithymocyte globulin (ATG) and sera (ATS) have been used as part of induction therapy protocols and for rescue therapy for acute rejection refractory to corticosteroids.226227 Use in the immediate postoperative period permits a reduction in early corticosteroid doses and a delay in initiating cyclosporine therapy in the patient at risk of perioperative renal failure.228229


OKT3 is a murine monoclonal antibody that binds and modulates the CD3 receptor site on cytotoxic T lymphocytes interfering with antigen recognition and preventing cellular proliferation.230231 Like polyclonal preparations, administration of OKT3 can also eliminate almost all circulating T lymphocytes, though its monoclonal specificity prevents it from having a cytolytic effect on other circulating cells.232 Monitoring of T3 subpopulation cell counts can be used to determine adequacy of therapy. While it has been used for induction therapy, OKT3 has demonstrated its greatest benefit on rescue therapy.233236 Thirty percent of patients develop antibodies against OKT3, but few patients develop high enough titers to preclude reuse of the drug in the future.237238 Studies comparing efficacy of OKT3 and ATG have yielded conflicting results.239240 Controversy exists concerning the long-term side effects of both monoclonal and polyclonal antibody therapy (i.e., increased risk of viral infections and malignancy).

Nonpharmacologic Immunosuppressive Strategies


Fractionated delivery of radiation to lymphatic tissues using an inverted Y-mantle field provides several weeks of generalized, nonspecific immunosuppression. Experimental indications for TLI include recurrent rejection unresponsive to pharmacologic intervention and treatment-limiting toxicity associated with standard immunosuppressive agents.241243 Because of the potential for life-threatening bone marrow suppression, azathioprine is discontinued during TLI therapy.


Peripheral mononuclear blood cells are obtained via leukopheresis from recipients who have received a photoactivatable agent (e.g., 8-methoxypsoralen). Following ex vivo activation with ultraviolet A light, the mononuclear cells are reinfused into the recipient where they have a suppressor effect on T lymphocytes (mechanism unclear). Preliminary studies have demonstrated that this nontoxic immunomodulating technique can reverse acute rejection (including recalcitrant cases).244245


Apheresis procedures (e.g., therapeutic plasma exchange) permit the removal of circulating antibodies and cytokines. In the future, selective immunoabsorption filtration techniques may allow the reduction of antibodies and HLA antigens in sensitized patients as well as the removal of specific cellular subsets. Controversy exists regarding current indications for the use of apheresis.

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. More than 80% of episodes of acute rejection occur in the first 3 months after transplantation, and most recipients will have at least one episode of rejection during this period.246247 The highest risk factors are female gender, human leukocyte antigen (HLA) mismatches, and allografts from younger or female donors.248 Although 80% to 96% of episodes can be reversed with corticosteroid therapy alone,249251 rejection is still a major cause of morbidity in cardiac recipients.252253

Diagnosis of Acute Rejection

In the era before cyclosporine, the classic clinical manifestations of acute rejection included low-grade fever, malaise, leukocytosis, pericardial friction rub, supraventricular arrhythmias, low cardiac output, reduced exercise tolerance, and signs of congestive heart failure. In the cyclosporine era, however, most episodes of rejection are characteristically 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.254255 The most frequently utilized technique for orthotopic allografts is a percutaneous approach through the right internal jugular vein.256257 Interventricular septal specimens are fixed in formalin for permanent section although frozen sections occasionally are performed if urgent diagnosis is necessary. Hemodynamic parameters may also be obtained with a pulmonary artery catheter. Complications are infrequent (1%2%), but include venous hematoma, carotid puncture, pneumothorax, arrhythmias, heart block, and right ventricular perforation. The exact schedule for endomyocardial biopsies varies among institutions but reflects the greater risk of rejection during the first 6 months following transplantation. Biopsies are initially performed 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.

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 (Table 60-8). 258 Interpretation of histology may be complicated by the lymphocyte infiltration and perimyocytic fibrosis associated with cyclosporine therapy.259260 Inflammatory infiltrates associated with organ preservation injury or infection may also mimic rejection.261 Etiologies of biopsy-negative allograft dysfunction include focal rejection, accelerated coronary artery disease, and occasionally, vascular (humoral-mediated) rejection.

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TABLE 60-8 ISHLT standard cardiac biopsy grading system*

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 experience262; however, they currently are of no value in patients receiving cyclosporine.263 More recent attempts with signal-averaged electrocardiography,264265 echocardiography,266267 magnetic resonance imaging,268 technetium ventriculography,269 and a variety of immunologic markers270271 have not provided sufficient sensitivity to warrant widespread use.272

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 initially treated with increased doses of oral prednisone (100 mg/d) followed by a taper to baseline over several weeks.273 Although not yet universally accepted, many centers successfully reduce the doses of these corticosteroids with reversal rates of rejection similar to traditional dosing.274

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.

Rescue protocols for recurring or refractory rejection include methylprednisolone plus OKT3 polyclonal antibody therapy (ATS, ATG, ALG), or methotrexate.275277 Methotrexate has been particularly successful in eradicating chronic low-grade rejection. Clinical studies using FK-506, rapamycin, and mycophenolate mofetil have also shown to be effective and further trials are ongoing. Total lymphoid irradiation and photopheresis also demonstrate success in some cases of refractory rejection. 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.

Except in the occasional case of rejection associated with significant symptoms or hemodynamic instability, the decision to treat acute rejection is complex. The risk of infection associated with increased immunosuppression must be carefully weighed against the potential sequelae of untreated rejection. Asymptomatic mild rejection (grade 1) is usually not treated but is monitored with repeat endomyocardial biopsies, because only 20% to 40% of mild cases progress to moderate rejection.278279 On the other hand, 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.280281 Regardless of the biopsy results, allograft dysfunction is an indication for hospitalization, antirejection therapy, and, if severe, invasive hemodynamic monitoring and inotropic support. Interestingly, biopsy results of up to 60% of patients presenting with hemodynamically significant rejection reveal only mild or moderate rejection.282

Acute Vascular Rejection

Vascular rejection is mediated by the humoral limb of the immune response.283285 There is growing interest in antibody-mediated mechanisms of acute rejection particularly in patients with a history of treatment with cytolytic agents, an elevated panel of reactive antibodies, or multiparity.286287 Unlike cellular rejection, hemodynamic instability often necessitating inotropic support is common in cases of vascular rejection.288 Diagnosis requires evidence of endothelial cell swelling on light microscopy and immunoglobulin-complement deposition by immunofluorescence techniques.289290 Aggressive treatment of patients with allograft dysfunction consists of plasmapheresis, high-dose corticosteroids, heparin, IgG and cyclophosphamide.291293 Despite these interventions, symptomatic acute vascular rejection is associated with a high mortality.294 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.295297

Infection is a leading cause of morbidity and mortality in the cardiac transplant population.298299 Impaired host defense secondary to chronic immunosuppression is the primary predisposing factor for the increased susceptibility to microbial pathogens. The introduction of cyclosporine (CsA), coincident with a more aggressive approach to diagnosis and treatment, has resulted in a dramatic reduction in the frequency and severity of transplant-related infections over the past decade.300302 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.298,303

Organisms and Timing of Infections

The source of posttransplant infection may be exogenous (nosocomial, latent infection in the donor organ, and community-acquired) or endogenous (reactivation of a latent recipient infection). Table 60-9 illustrates the most common organisms causing infections in the cardiac recipient. The types of infections often follow a predictable temporal sequence following transplantation.304305 During the first postoperative month, nosocomial bacterial pathogens common to any patient undergoing surgery and requiring intensive care unit admission account for the majority of early infections.306 Opportunistic pathogens (e.g., microorganisms that almost never cause severe illness in healthy individuals with normal cellular immunity) are responsible for the majority of infections between 1 and 6 months.307 Thereafter, infections in the immunosuppressed recipient are caused by a mixture of community-acquired bacterial and opportunistic organisms.308309 Major infections are rare after the first year in the absence of recurrent acute rejection episodes.

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TABLE 60-9 Infections in cardiac transplant recipients

Preventive Measures and Prophylaxis against Infection


Prevention of postoperative infection begins with pretransplant screening of the donor and recipient.310 Current suggested guidelines are outlined in Table 60-10. Potential donors or recipients with active systemic infection or positive serologies for human immunodeficiency virus (HIV) or hepatitis B virus (HBV) are not candidates for transplantation.311 Controversy exists regarding cardiac transplantation in patients seropositive for hepatitis C virus (HCV).312313 Recipient prophylaxis is indicated for donors seropositive for cytomegalovirus (CMV) or Toxoplasma gondii if the recipient is seronegative.314315

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TABLE 60-10 Guidelines for routine screening and prophylaxis of infections in heart transplantation


A first-generation cephalosporin, or vancomycin for patients with beta-lactam allergy, should be initiated prior to induction of anesthesia and continued for 48 hours following transplantation.316 Although transplant recipients are still admitted to a private room, elaborate protective isolation procedures are no longer used.317 Meticulous handwashing and a concerted effort to decrease the risk of infection have been shown to be effective prophylaxis.318 Patients requiring prolonged intubation for ventilatory support may benefit from selective oropharyngeal and bowel decontamination.319


Trimethoprim-sulfamethoxazole (TMP/SMX) or aerosolized pentamidine (if TMP/SMX not tolerated) provide effective prophylaxis against Pneumocystis carinii pneumonia.320321 TMP/SMX also reduces the incidence of Toxoplasma gondii, Listeria, Legionella, and possibly Nocardia infections. Nystatin or clotrimazole is routinely given to prevent mucocutaneous candidiasis.322 The frequency and severity of recurrences of herpes simplex and varicella-zoster infections can be reduced with low-dose oral acyclovir although routine prophylaxis is not universally accepted.323 Standard endocarditis antibiotic prophylaxis is indicated prior to bacteremia-producing procedures. Recipients with a positive PPD skin test should be considered for prophylactic isoniazid (rifampin) therapy.324


Recommended postoperative vaccinations are listed in Table 60-10.325326 Live, attenuated virus vaccines should be avoided in the immunocompromised transplant patient. Immunization for influenza A virus is controversial as this pathogen is not responsible for significant morbidity in cardiac transplantation.327 Exposure to measles, varicella, tetanus, or hepatitis B by a nonimmunized recipient often warrants specific immunoglobulin therapy (e.g., varicella-zoster immune globulin, VZIG).328

Donor-Transmitted Infection

CMV, Toxoplasma gondii, HBV, HCV, and HIV may be transmitted to the recipient via the donor allograft.329330 Ideally, recipients seronegative (SN) for CMV or Toxoplasma would receive appropriately SN organs to prevent the development of a life-threatening primary infection postoperatively.331 However, due to the improvement in CMV prophylaxis and treatment, CMV serologic matching is no longer performed. Currently, the most effective prophylaxis for CMV is intravenous ganciclovir for 1 to 2 weeks followed by oral dosing for 3 months.332

Specific Organisms Causing Infection Following Heart Transplantation


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.333 Staphylococcus species have been shown to cause the majority of gram-positive related infections.


CMV remains the most common causative pathogen in patients following cardiac transplantation.334 Infections develop secondary to donor transmission, reactivation of latent recipient infection, or reinfection of a CMV-seropositive patient with a different viral strain.335 Mortality from serious CMV infections has been dramatically reduced with ganciclovir. The reduction in leukocytes associated with CMV infection predisposes the patient to superinfection with other pathogens (e.g., CMV, Pneumocystis carinii pneumonia).336 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.337


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.338 Aspergillus causes a serious pneumonia in 5% to 10% of recipients during the first 3 months after transplantation and requires intravenous amphotericin B (or oral itraconazole).339 Dissemination of Aspergillus to the central nervous system is almost uniformly fatal.340


Pneumocystis carinii is the most common cause of late pneumonia.341 Since the organism resides in the alveoli, bronchoalveolar lavage usually is necessary for diagnosis. TMP/SMX or pentamidine are the agents of choice for treatment of this protozoa.316317 In addition to donor transmission, Toxoplasma gondii infection may be acquired from undercooked meat and cat feces. It usually causes CNS infections and is effectively treated with pyrimethamine and sulfonamides for 6 months.342

Allograft Coronary Artery Disease

Long-term survival of cardiac transplant recipients is primarily limited by the development of allograft coronary artery disease (ACAD), the leading cause of death after the first posttransplantation year.343345 Angiographically detectable ACAD is reported in approximately 50% of patients by 5 years after transplantation. The etiology of this allograft vasculopathy is multifactorial and involves both immunologic and nonimmunologic components. Recently, it has been shown that immune-related risk factors appear to be more significant in the development of ACAD.346348 Likewise, many nonimmune-associated related risks have been implicated in ACAD including increased donor age, hyperlipidemia, and CMV infection.349352 These immune and nonimmune risk factors lead to unique coronary pathology characterized by diffuse, concentric intimal proliferation with infiltration by smooth muscle cells and macrophages leading to narrowing along the entire length of the vessel.353354 Furthermore, collateral vessels are notably absent. ACAD may begin within several weeks posttransplantation and insidiously progress at an accelerated rate to complete obliteration of the coronary lumen with allograft failure secondary to ischemia.355

The clinical diagnosis of ACAD 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 ACAD. Noninvasive screening tests (e.g., thallium scintigraphy) are unreliable in transplant recipients.356 Annual coronary angiogram is the current gold standard for ACAD surveillance. However, due to the previously mentioned pathological changes, it underestimates the extent of disease and is insensitive to early atherosclerotic lesions.357 This has led to growing interest in intravascular ultrasound (IVUS) devices.

IVUS is better equipped to provide important quantitative information regarding vessel wall morphology and the degree of intimal thickening.358359 Some centers have begun to use IVUS for the early detection of ACAD; however, concerns have been raised concerning its ability to assess more long-term lesions.360 Currently, the only definitive treatment for advanced ACAD is retransplantation due to the diffuse and distal nature of ACAD. Based on this lack of effective treatment options, an emphasis has been placed on prevention of ACAD. Currently, prophylactic management focuses on empiric risk factor modification (dietary and pharmacologic reduction of serum cholesterol, cessation of smoking, hypertension control, etc.). Several studies have demonstrated a decrease in ACAD in patients treated with a calcium channel blocker or HMG-CoA reductase inhibitors.348,361

Renal Dysfunction

Irreversible interstitial fibrosis caused by cyclosporine nephrotoxicity is chiefly responsible for the chronic renal dysfunction observed in cardiac transplant recipients.362363 Its pathogenesis is unclear but is believed to be secondary to afferent arteriolar vasoconstriction with secondary ischemia.364365 Direct tubular toxicity also may play a contributory role.366 Most renal injury occurs during the first 6 months following transplantation concurrent with the highest levels of cyclosporine. Little additional decline in renal function occurs after 1 year.367 Frequent monitoring of cyclosporine levels and avoidance of intravascular volume depletion are important preventive measures.368 Approximately 3% to10% of patients develop end-stage renal failure requiring dialysis or renal transplantation.369


Moderate to severe systemic hypertension afflicts 50% to 90% of cardiac transplant recipients and is a difficult problem to manage.370 Peripheral vasoconstriction in combination with fluid retention seem 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.371373 No single class of antihypertensive agents has proven uniformly effective, and treatment of this refractory hypertension remains empiric and difficult.


Chronic immunosuppression is associated with an increased incidence of malignancy.374375 The estimated risk of carcinoma in transplant recipients is almost 100-fold greater than in the general population.376 Lymphoproliferative disorders377378 and carcinoma of the skin379 are the most common malignancies found in heart transplant recipients. Attenuation 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.380382 The risk of these malignancies is increased further following monoclonal and polyclonal antibody therapy.383 Unlike lymphomas in nontransplant patients, these lymphoproliferative disorders demonstrate a predilection for unusual extranodal locations (e.g., lung, bowel, and brain).384 Treatment options in transplantation include a reduction in immunosuppression and high-dose acyclovir (to attenuate EBV replication) in addition to conventional therapies for carcinoma (chemotherapy, radiation therapy, and surgical resection).385387 Despite these efforts, mortality remains high.

Other Chronic Complications

Hyperlipidemia eventually develops in the majority of recipients and is managed with dietary restrictions, exercise, and lipid-lowering agents.388 Other complications that commonly contribute to posttransplant morbidity include osteoporosis,389 avascular necrosis of weight-bearing joints,390 obesity,391 and cholelithiasis.392393

Retransplantation accounts for fewer than 3% of the cardiac transplants currently performed.10 Primary indications for retransplantation are allograft coronary artery disease and refractory acute rejection.394395 The operative technique and immunosuppressive regimen are similar to those employed for the initial transplantation.396 Despite reduced mortality in the cyclosporine era, actuarial survival remains markedly reduced following retransplantation if performed within 6 months of the initial procedure or in the setting of acute rejection.395,397 A recently completed study showed that the survival rate for cardiac retransplantation at 1 year was 55%.396

Interestingly, however, recent data from the International Society for Heart and Lung Transplantation (ISHLT) shows that if retransplantation occurs 2 years after the initial transplant procedure, the 1-year survival rate markedly improves but remains approximately 4% to 6% below that of primary cardiac transplantation.10

Operative (i.e., 30-day) mortality for cardiac transplantation ranges from 5% to 10%.398 Primary graft failure is the most frequent cause of early death. Overall 1-year survival is approximately 80% with a 4% mortality per year for subsequent years.10 Infection and rejection account for the majority of deaths in the first 6 months; thereafter, accelerated coronary artery disease eventually claims the lives of most recipients. Risk factors associated with increased mortality include ventilator dependence, previous cardiac transplantation, preoperative ventricular assist device or balloon pump, recipient age greater than 65 years, female gender (donor or recipient), and donor age greater than 50 years.10

Studies examining the health-related quality of life (HRQOL) in patients following cardiac transplantation demonstrate that most experience a HRQOL that approaches that of the normal population.399400 Although cardiac reserve is reduced, exercise tolerance is improved dramatically compared to preoperative level, and recipients usually can enjoy an active lifestyle.401 Nevertheless, because of concerns about future disability, recipients often encounter significant problems with postoperative employment and health insurance coverage particularly if over 50 years of age.402

As a result of a series of unprecedented advances over the past decade, the clinical outcome of heart transplantation has dramatically improved. 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.

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. Novel immunosuppressive agents and techniques are under continuous investigation for this purpose. 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 currently utilized 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. There is growing evidence that human lymphocyte antigen (HLA) matching may be important for long-term graft function through attenuation of chronic rejection. Reducing the ischemic injury may also result in an attenuation of transplant coronary artery disease.

Finally, mechanical assist devices are being used more frequently in patients with end-stage heart failure and may prove to be the best solution for the current organ shortage. Assist devices are being currently used both as a bridge to transplantation and a destination therapy. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study demonstrated a survival benefit in heart failure patients in which assist devices were utilized versus all other forms of treatment for heart failure.61 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.

Clearly, in light of the advancements witnessed over recent years, solutions to many of the aforementioned obstacles in cardiac transplantation are within reach in the foreseeable future. Further research into these solutions will require dedicated resources and financial investments from government agencies, foundations, and interested organizations.

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