Theodore Billroth could never have imagined that one day cardiac transplantation would be a viable clinical entity. First, surgical techniques needed to be developed. The operation had to be reproducible. Myocardial protection was crucial. The heart was not so important to the organism that the organism would not reject it.¹ Over the course of the 20th century cardiac transplantation evolved from an experimental heterotopic model, where a puppy heart was placed in the neck of an adult mongrel dog, to an orthotopic operation where over 4400 heart transplants were performed in 1994.² Unfortunately, the number of donor hearts are not such that everyone with end-stage heart failure can be treated with transplantation. This has given rise to the evolution of mechanical circulatory assist devices that can be placed in patients to at least postpone cardiac transplantation.

Since cardiac transplantation became a clinical entity on December 3, 1967, well over 89,000 heart transplants have been performed.³ Records have been collected by the International Society for Heart and Lung Transplantation in the form of a Scientific Registry since 1983. It has been interesting to watch the field evolve over the past 46 years. Over that course of time, decreased lengths of stay and increased ages of the donor and recipient have been realized.⁴ Recipient waiting list times have increased dramatically, as have times before first rejection episodes.

Alexis Carrel and Charles Guthrie performed the first documented cardiac transplant in 1905 at the University of Chicago. The heart of a small dog was transplanted into the neck of an adult mongrel dog. Mann performed a heterotopic cardiac transplant in 1933.⁵ A canine heart was sewn into the carotid-jugular circulation. The explanted heart revealed dense infiltration of the heart by lymphocytes, large mononuclear cells, and polymorphonuclear cells. It was cellular rejection.

By the late 1950s, experimental cardiac transplantation, both autografts and homografts, were being performed in the laboratory at Stanford. Using local hypothermia, orthotopic transplantation in dogs was successfully performed in 1959. Richard Lower reported successful experiments in cardiac transplantation at the 1960 Surgical Forum of the American College of Surgeons.⁶ By 1965, long-term survival of orthotopic cardiac transplantation was achievable in dogs. Electrocardiography was used to guide treatment of rejection. In the laboratory, using local and systemic hypothermia for myocardial protection, successful transplantation of the canine heart was achievable after 7 h of ischemia.

James Hardy transplanted a chimpanzee heart into a human as a desperate measure in 1964. Christiaan Barnard performed the first human-to-human heart transplant in Cape Town, South Africa, on December 3, 1967. The first cardiac transplant at Stanford University was performed on January 6, 1968. A number of programs throughout the world subsequently performed cardiac transplants between 1967 and the early 1970s with relatively poor outcomes; 5-year survival rates hovered around 40 percent. By the early 1970s Stanford and the Medical College of Virginia were the only two programs still actively conducting clinical cardiac transplant programs, with Stanford taking the lead in conducting basic and clinical transplant research. In 1971 Philip Caves, a British American research fellow, along with Margaret E. Billingham, developed a technique for the interpretation of percutaneous transvenous endomyocardial biopsies.⁷ This important advance provided clinicians with the ability to better identify and treat cardiac allograft rejection.

By December 1980, the immunosuppressant cyclosporine was introduced into clinical use. By 1984, cyclosporine, corticosteroids, and azathioprine were combined as “triple drug therapy.” This proved to be an effective immunosuppression regimen that was adopted widely.⁸ Cardiac transplantation in children began in 1984.⁹ By the 1990s, it was clear that induction therapy could be added to triple drug therapy in order to delay early acute rejection.¹⁰ Chronic allograft rejection, manifested primarily as graft atherosclerosis, became the bête-noire of clinical cardiac transplantation.

The mid 1990s also saw the evolution of medical devices directed toward the treatment of heart failure, specifically ventricular assist devices and more reliable pacemakers and automatic implantable defibrillators. Over the past 20 years, ventricular assist devices have developed into effective bridges to transplantation or so-called “destination therapy” for end-stage heart failure.

The potential cardiac transplant recipient must undergo a battery of tests to determine whether or not he or she is an appropriate transplant candidate. Initially, a thorough history and physical examination, standard laboratory tests, plain chest radiography, and pulmonary function tests are obtained. Cardiac function is evaluated by electrocardiography, echocardiography, right and left heart catheterization, endomyocardial biopsy, and peak exercise oxygen consumption measurements.

Screening tests include: stool guaiac, mammography for women, prostate-specific antigen screening for men, Papanicolaou smear for women, bone densitometry, and a carotid duplex study. Occult infectious diseases are ruled out with serologies for hepatitis B and C, HIV, HTLV1, and HTLV2, cytomegalovirus, Toxoplasma, Epstein–Barr virus, syphilis, and tuberculosis. Pretransplant data also includes blood type and antibody screening, HLA–DR typing, panel reactive antibody (PRA) screening, and a 12-h urine collection to measure creatinine clearance and total protein.¹¹

Idiopathic and ischemic cardiomyopathies each comprise about 45 percent of the diagnoses among adult cardiac transplant recipients. The remaining diagnoses consist of valvular and congenital disease. Most recipients present in New York Heart Association class III or class IV heart failure refractory to medical therapy. Some patients suffer from intractable ischemia that is not amenable to catheter intervention or surgical revascularization. Still other patients present with intractable ventricular arrhythmias refractory to conventional therapies.

There have been recent advances in medical therapies for heart failure. In 2001, the COPERICUS trial found that patients with severe heart failure treated with Carvedilol had a reduced 1-year mortality of 11 percent compared with the placebo group who had a 1-year mortality of 19 percent. Waiting list mortality has decreased from about 32 to 17 percent due to the expanded use of ventricular assist devices and earlier consideration for cardiac transplantation.

There are relative, temporary, and absolute contraindications to cardiac transplantation (Tables 50-1–50-3). Severe pulmonary hypertension with pulmonary vascular resistances in excess of 4 Wood units or transpulmonary gradients greater than 15 mm Hg can lead to acute right ventricular failure of the newly implanted donor heart. Irreversible renal or hepatic dysfunction represent absolute contraindications to cardiac transplantation, although multiorgan transplants (e.g., heart–kidney, heart–liver) have been performed with some success.^12,13

All potential recipients are screened for occult malignancy. Severe peripheral vascular disease and diabetes resulting in end-stage organ damage are also contraindications. Primary diseases of the heart such as amyloidosis or sarcoidosis and giant cell myocarditis can be contraindications. Relative contraindications to transplantation include age greater than 70 years, obesity greater than 140 percent ideal body weight, severe osteoporosis, a history of substance abuse, and psychiatric disorder. A history of medical noncompliance and lack of social support are other potential contraindications.

Once a patient has been listed for transplantation, he or she should be followed by a cardiologist at the transplant center, usually every 3 months. Cardiac rehabilitation is also an important tool during this waiting time. Patients suffering from severe heart failure may require intravenous inotropic support (e.g., dobutamine). Milrinone, a phosphodiesterase inhibitor with inotropic and vasodilatory affects, is also an effective inotrope, especially for right heart failure.

A number of devices have been used as adjuncts to medical therapy. Intra-aortic balloon pumps have provided circulatory support for as long as 2 to 3 weeks prior to heart transplantation. This appears to be most effective in patients with ischemic cardiomyopathies. For patients with severe refractory ventricular failure, a left ventricular assist device (LVAD) or right ventricular assist device may be necessary. INTERMACS is a database recently developed to track all patients requiring ventricular assist devices.¹⁴

The REMATCH trial, published in 2001, compared 1- and 2-year survival rates of heart failure patients who were not candidates for cardiac transplantation and were treated with either medical therapy or LVAD implantation.¹⁵ The investigators reported a 25-percent 1-year survival rate and 8-percent 2-year survival rates in the medical therapy group compared with a 52-percent 1-year survival rate and a 23-percent 2-year survival rate in the LVAD group. The use of ventricular assist devices for bridging to transplantation is increasing.

As with any organ donor assessment, the two most important goals are to prevent disease transmission from the donor to the recipient and to obtain a graft that will function appropriately. Donor heart exclusion criteria include (1) malignancy with extracranial metastatic potential, (2) systemic sepsis or endocarditis, (3) significant coronary artery disease, (4) anatomic heart disease that will shorten the recipient’s expected life span, and (5) poor ventricular function.

Ideally, the cardiac donor is less than 55 years of age with no history of chest trauma or cardiac disease. There should be no prolonged hypotension or hypoxemia. Hemodynamically, the mean arterial blood pressure should be maintained above 60 mm Hg and the CVP between 8 and 12 mm Hg. Inotropic support requirements should be less than 10 mg/kg/min of dopamine or dobutamine. Normal electrocardiograms and echocardiograms should be verified. Risk factors for coronary artery disease mandate normal coronary angiography. All pertinent serologies should be negative.

Due to the relative donor organ shortage, there has been a trend toward liberalizing certain donor selection criteria. Expanded organ criteria include the use of older donors and allowing for longer ischemic times. Donors with mild left ventricular hypertrophy, mild valvular abnormalities, or mild coronary artery disease have been used with success.¹⁶ Hearts that have experienced cardiac arrest have also been used.

Most organ donors who have suffered acute brain injury will display some hemodynamic instability. Neurogenic shock can cause excessive fluid losses and bradycardia. Careful fluid management is necessary. It is also important to wean inotropic support as much as possible. Blood transfusion is also used sparingly to maintain a hematocrit of at least 30 percent. If possible, cytomegalovirus negative and leukocyte-filtered blood should be used. Donors may require intravenous vasopressin to keep up with the excessive urine losses caused by diabetes insipidus.

A single echocardiogram may show decreased ventricular function related to brain death, so serial echocardiograms may show functional recovery. The Papworth group has instituted a very aggressive protocol for donor management.¹⁷ Using pulmonary arterial catheter monitoring, donors are managed by a cardiac trained anesthetist. Hormonal therapy includes the use of thyroxine, cortisol, antidiuretic hormone, and insulin. If a left ventricular ejection fraction of greater than 45 percent is attained, the organ should be usable.

In the United States, organ allocation is governed by the United Network for Organ Sharing (UNOS). Heart allocation takes into consideration medical urgency, time on the waiting list, and blood type. The medical urgency categories include status 1A, 1B, 2 and 7 (Table 50-4). The allocation algorithm is also modified by age so that adolescent donor hearts are preferentially used by pediatric recipients. Organs are initially allocated locally, then regionally.

Prospective recipients and donors must be ABO blood type compatible, except in infants. As far as size is concerned, typical acceptable donor weight ranges are between 70 and 130 percent of the recipient weight.¹⁸ For recipients with moderately elevated pulmonary vascular resistance, it is often prudent to use a larger donor. Using smaller hearts in a heterotopic position for larger recipients has fallen out of favor. The donor team should have a checklist to ensure completeness of the donor organ assessment (Table 50-5).

There are certain strategies that have been used to improve preservation of the heart during organ retrieval. This has included the use of hypothermia, cardioplegia, and various preservation solutions. The heart is maintained in a hypothermic environment between 4°C and 8°C to reduce the rate of myocardial metabolism. Cardioplegia is used to arrest the heart. Adequate decompression of the ventricles during the organ retrieval limits injury to the heart during the actual procurement. The heart is stored in either cold saline or a variety of preservation solutions. Most preservation solutions were designed for perfusion or storage of abdominal organs.¹⁹ Many also contain antioxidant additives to help prevent reperfusion injury. Cardiac preservation is usually limited to 4 to 6 h of cold ischemia time. Longer ischemia times have affected recipient survival. This is an area of active research.

Cardiac Allograft Procurement

Donor cardiac procurement is performed through a complete median sternotomy. The pericardium is opened widely and the edges are suspended. Care is taken not to enter either pleural space should the lungs be infected. The heart is inspected for any signs of trauma, infection, or congenital anomalies. Overall contractility of both the right and left ventricles is appreciated. The coronary arteries are palpated to rule out any evidence of coronary artery disease. The ascending aorta is separated from the pulmonary artery. The superior vena cava (SVC) is mobilized circumferentially up to and beyond the level of the azygos vein, and encircled with two heavy ties of 0 silk sutures. The inferior vena cava likewise is mobilized circumferentially and surrounded with a vessel loop.

At least 300 units of heparin/kg of donor weight are administered intravenously to the donor. A cardioplegia needle is inserted into the ascending aorta. Venous return to the heart is interrupted by dividing the SVC between two secured ties. The IVC is divided flush with the diaphragm. The tip of the left atrial appendage is amputated. The ascending aorta is cross-clamped and approximately 2 L of cold cardioplegia is administered into the ascending aorta. In children, 50 mL/kg of cardioplegia is appropriate. Ice slush is immediately poured into the pericardial space and onto the heart to provide rapid topical cooling. Once a complete cardiac arrest is achieved and all of the cardioplegia has been administered, the topical ice slush is removed from the pericardial space and the heart is excised in a expedient fashion. First, the pulmonary veins are divided flush with the pericardium. The aorta is divided as distally as possible, usually at the take off of the innominate artery, and the main pulmonary artery is divided at its bifurcation. The heart is then placed in a secure Teflon container filled with cold saline or other preservation solution and then placed in a cooler filled with ice.

Ideally, the donor cardiac graft should be reperfused in the recipient within 4 to 6 h of its excision from the donor.²⁰ Ischemic times greater than 4 h have resulted in decreased recipient survival. If the recipient requires reconstruction of both pulmonary arteries, then the branch pulmonary arteries are divided at the level of the pulmonary hilum. Additional length of the ascending aorta may be required for recipients with hypoplastic left heart syndrome or with L-transposition of the great vessels.²¹

Recipient Cardiectomy

If the recipient has undergone previous cardiac surgery, it is helpful to obtain a CT scan of the chest to demonstrate the proximity of the heart or other critical structures (e.g., LVAD outflow graft) to the undersurface of the sternum. All recipients are fully heparinized. Bicaval cannulation with caval snares and a standard aortic cannula are used. The SVC is cannulated high enough to facilitate the SVC anastomosis. The recipient is then placed on total cardiopulmonary bypass and an aortic cross-clamp is placed across the ascending aorta. When bicaval anastomoses are being performed, the recipient cuffs are fashioned at the level of the superior and inferior vena cava after the interatrial groove is developed in order to facilitate excision of the right atrium. Generally, the native right atrium is open anteriorly and the right atriotomy is extended superiorly, trimming off the right atrial appendage (see Fig. 50-1). The right atriotomy is then extended inferiorly into the coronary sinus. Each great vessel is divided above its semilunar valves. The cardiectomy continues by opening the roof of the left atrium. The left pulmonary veins are identified and the left atriotomy continues along the atrioventricular groove. The pericardial sac is irrigated with cold saline solution to remove debris. The left atrial cuff is further trimmed as needed. In patients with ischemic cardiomyopathy, the epicardial portion of the left atrial cuff may require cauterization.