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Clinical Cardiology |

Current Status of Cardiac Transplantation FREE

Sharon A. Hunt, MD
[+] Author Affiliations

From the Stanford University Medical Center, Stanford, Calif.


Clinical Cardiology section editors: Bruce Brundage, MD, University of California, Los Angeles School of Medicine; Margaret A. Winker, MD, Senior Editor, JAMA.


JAMA. 1998;280(19):1692-1698. doi:10.1001/jama.280.19.1692.
Text Size: A A A
Published online

Cardiac transplantation, first introduced 30 years ago, has become a widely used and increasingly important procedure for treatment of truly end-stage heart disease. Current use is limited strictly by donor supply, making selection of appropriate recipients an important ethical and societal issue. Survival rates after transplantation rose in the 1980s with the use of cyclosporine and have remained relatively consistent since then, although recipients older than 65 years or younger than 1 year have lower survival rates than recipients of other ages. Although immunosuppressive drugs have helped establish cardiac transplantation as a successful procedure, risks of opportunistic infection and rejection, as well as coronary arteriopathy, have led to development of new immunosuppressive agents currently under study. Future alternatives to the current technology of cardiac allotransplantation may include xenotransplantation and/or nonbiological replacement of the heart with mechanical devices.

Figures in this Article

THIRTY YEARS have passed since the first human-to-human cardiac transplantation was successfully performed.1 In subsequent years, the procedure has been transformed from a radical and controversial surgical approach into a mainstream medicine approach for many patients with end-stage heart disease. Improvements that have led to widespread acceptance of the procedure have included the introduction of improved modalities for suppression of the immune system, improved techniques for both diagnosis and therapy of allograft rejection, improved surgical technique, and more general medical advances in the areas of diagnosis and treatment of infectious and malignant complications of long-term immunosuppression. In the 1990s, a number of possible breakthroughs in technology may further revolutionize the field. This review provides the reader an overview of the current status of clinical practice in the field of heart transplantation and projects the imminent advances that should have major impact on the field during its second 30 years.

Technique

The technique for performing orthotopic heart transplantation has changed little since its original description in the laboratory by Lower and Shumway2 in 1960. It involves removal of both donor and recipient hearts by transection at the midatrial level (thus preserving the multiple pulmonary venous connections to the posterior wall of the left atrium in the recipient) and transection of the great vessels just above their respective semilunar valves.

In the early years of heart transplantation, the donor cardiectomy was required to be performed in an operating room adjacent to that in which the recipient was being prepared, necessitating transport of the brain-dead donor (on life support) to the recipient hospital. In 1962 it was demonstrated in the laboratory that cold ischemic times of up to 7 hours were safe and resulted in normal cardiac allograft function.3 In the mid 1970s, what is termed distant heart procurement became the norm; the donor heart is now usually "harvested" by a surgical procurement team at a distant hospital and transported expeditiously to the transplant center in iced cardioplegic solution while the transplant surgical team prepares the recipient and explants the recipient's heart in a similar manner. The donor heart is then implanted in the orthotopic position with surgical anastomoses at the midatrial level and the aorta and pulmonary arteries. In recent years, a variation on this procedure, bicaval anastomosis, which preserves the anatomical integrity of the right atrium by using anastomoses at the level of the superior and inferior venae cavae, has gained popularity.4 Although the surgery itself takes about 15 minutes longer with this technique, the preserved right atrial anatomy may lead to more normal tricuspid valve function5 and better preservation of sinoatrial node function.6

It has not been possible to extend the safe cold ischemic time for donor hearts, a fact that clearly limits the possibility of applying the recently called-for national allocation policy for donor organs to the allocation of hearts.

Physiology

The heart reimplanted in the orthotopic position is surgically denervated and responds to physiologic stimuli with atypical adaptive mechanisms. For instance, it is unable to acutely increase heart rate in response to exercise or hypotension, but responds acutely instead with an increase in stroke volume, a reliance on the classic Frank-Starling mechanism.7,8 The transplanted heart remains sensitive to circulating catecholamines and does increase heart rate later in the course of exercise or hypotension in response to increases in levels of these hormones. Afferent denervation typically makes the patient incapable of experiencing the subjective sensation of angina pectoris in response to ischemia.9

The overall maximum exercise capacity of heart transplant recipients is subnormal, most likely due to this denervated state,1012 although most patients are capable of resuming normal lifestyles and reasonably vigorous activity levels. The issue of whether reinnervation ever occurs has been controversial.13 Although a number of studies have documented physiological evidence of reinnervation following transplantation, including release of cardiac norepinephrine in response to tyramine infusion,14 physiological functional responses to tyramine infusions,15 and the occurrence of classic angina pectoris,16 evidence of late improvement in exercise capacity has not been found.17

Indications for Heart Transplantation

The indications for heart transplantation have always generically included the presence of end-stage heart disease irremediable by any more conventional forms of therapy and the absence of contraindications such as concomitant diseases that would separately limit survival. The application or interpretations of these principles has varied among centers and, in recent years, there have been concentrated efforts to devise uniform criteria for listing patients for heart transplantation. The first such consensus conference was the American College of Cardiology Bethesda Conference in 1992.18 More recently, in 1996, the United Network for Organ Sharing (UNOS) Board of Directors approved a set of UNOS Guidelines for Cardiac Transplantation Listing that emphasizes the need for maximizing current state-of-the-art medical therapy as well as objective assessment of patients' functional capacity (mainly through peak oxygen uptake measured during maximum exercise testing) in selecting patients with the lowest probability of survival and, thus, the highest probability of benefit from transplantation (G. William Dec, MD, written communication, January 1998). The decision regarding timing of listing a patient with severe heart disease for transplantation can be difficult. Although survival rates after transplantation could be best if less-sick patients were selected, these patients' prognosis without the transplant could be just as good as their prognosis with it.19 On the other hand, truly moribund patients with severe secondary organ dysfunction despite maximum support may have such high complication rates after transplantation that the use of scarce donor organs for such patients is unethical. Determining when in the course of an individual patient's disease the individual should be listed for transplantation (that is, the point at which transplantation will improve his/her individual prognosis and lead to survival probability as good as heart transplant patients overall) is something of an art. The appropriate timing changes to later in the course of the disease as more effective measures to treat heart failure are developed.

Number of Transplants

The International Society for Heart and Lung Transplantation (ISHLT) has maintained a registry of heart transplantations and outcomes since 1980 and, in 1987, combined with UNOS. Reporting to the registry is mandatory in the United States and the vast majority of non-US heart transplant centers contribute their data as well. Figure 1 is a graph of the number of transplantations per calendar year reported to this registry20 and demonstrates a plateau of annual procedures worldwide at about 3500 per year since 1990. This plateau is widely agreed to be due to limitations of donor availability and there is no expectation that the numbers will increase substantially in the foreseeable future. In the United States, the number of transplantations has plateaued at an annual rate of approximately 2500 procedures.

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Figure 1.—Number of heart transplantations (gray bars) and mean donor age (black line) per calendar year. Reprinted with permission from Hosenpud et al.20
Number of Transplant Centers

According to UNOS registry data, there are currently 135 heart transplant centers in the United States, many of which perform few procedures. A recent analysis of registry data noted that 53% of US heart transplant centers (n = 80) performed fewer than 9 transplantations per year and patients at these centers had a significantly higher risk of mortality at early and intermediate points.21 The only real control of the proliferation of programs has been the setting of criteria for qualifications and training experience for cardiac transplant physicians by UNOS and the requirement that personnel meet these requirements for a program to be enrolled in the donor procurement system. In 1986, the Health Care Financing Administration (HCFA), which oversees the US Medicare program, approved coverage and payment for heart transplantation for Medicare recipients and established a transplant facility approval process that centers are required to complete to receive Medicare payment for heart transplantation.22 Most heart transplant recipients are not eligible for Medicare, but the approval program allows analysis of medical-center results according to whether programs have met the extensive HCFA criteria. A recent analysis of more than 9000 heart transplantations performed in US centers between 1986 and 1992 compared outcomes among patients having their procedures at centers with and without Medicare approval and found significantly lower mortality rates for patients from the centers that satisfied Medicare criteria, suggesting that the Medicare criteria can indeed identify "centers of excellence."23

Organ Procurement and Distribution

Since 1986, the federal government has contracted with UNOS to operate the Organ Procurement and Transplantation Network (OPTN) to develop an equitable, scientific, and medically sound organ allocation system. The policies of this organization receive broad input from numerous constituencies, including transplant recipients, patient and donor families, and the OPTN membership, as well as concerned individuals and organizations from throughout the United States. In the current heart allocation system, a central computerized registry of waiting cardiac recipients categorized according to ABO blood type and body size is maintained by UNOS. When potential organ donors are reported to the OPTN, the heart is offered to the appropriate (according to blood type and body size) recipient with the most time accrued on the waiting list in the local area. If no appropriate recipient is available locally, the donor network searches the list for the next appropriate recipient within an 800-km (500-mile) radius, then within a 1600-km (1000-mile) radius. The roughly 3-hour limit on cold ischemic preservation time generally precludes more than a 1600-km transport distance for donor hearts.

The only exception to the policy of patient priority according to time accrued on the waiting list is the listing of critically ill patients, defined as those confined to intensive care units and requiring intravenous inotropes and/or mechanical devices for circulatory support, as "status I," with priority for donor hearts over others.

As noted earlier, the procurement of the donor heart usually involves one surgical team traveling to the donor hospital to explant the donor heart and transport it back to the transplant center while another surgical team prepares to operate on the recipient. Because most donors now provide multiple organs for transplantation, which may in turn go to multiple transplant centers, coordination of multiple surgical teams converging on the donor hospital can be a complicated problem.

Survival Rates

Survival was inferior (with 1-year survival rates of 70%) prior to 1985, when cyclosporine use became widespread. However, since 1985 survival rate has not increased, with current overall 1-year survival rates of approximately 80% (Figure 2). Survival significantly declines for each increase in decade of age, with a clinically significant decrease for patients older than 65 years (Figure 3). For the pediatric age group, the older group (aged 6-15 years) has survival virtually identical to that of the adult population, whereas the youngest patients (aged <1 year) have the worst survival probability and those aged 1 to 5 years have intermediate survival rates (Figure 4).

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Figure 2.—Adult heart transplantation actuarial survival by era. Survival significantly improved after 1986. The half-life survival (when half of those who underwent transplantation have died) was 8.0 years for 1991 through 1996 vs 5.4 years for 1980 through 1985. Reprinted with permission from Hosenpud et al.20
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Figure 3.—Adult heart transplantation actuarial survival according to patient age at time of transplantation. For each age group, the younger group is significantly more likely to survive than the next older group (P<.001). Reprinted with permission from Hosenpud et al.20
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Figure 4.—Pediatric heart transplantation actuarial survival by patient age at time of transplantation. Survival is significantly different for younger than 1 year vs 6 to 15 years (P<.001) and for 1 to 5 years vs 6 to 15 years (P<.001). Reprinted with permission from Hosenpud et al.20
Recovery and Quality of Life

The majority of heart transplant recipients are able to return to New York Heart Association (NYHA) functional class I and physical and occupational activities of their choice.24 Registry data indicate that 89.9% of patients consider themselves to have no activity limitations at 1-year follow-up; however, 47.2% are not working at 1-year follow-up.20 This discrepancy may be due to the difference between capability and employability in the US job market, where health care coverage is linked to employment and can be prohibitively expensive for transplant recipients' potential employers.

Immunosuppression

Since the introduction of cyclosporine, which acts mainly by inhibiting lymphokine production and release,25 into clinical heart transplantation in the early 1980s,26 most centers have used a 3-drug regimen for long-term immunosuppression consisting of cyclosporine, azathioprine, and corticosteroids. Probably no 2 centers have identical drug protocols but all follow the principle of administering the most intense immunosuppression early after surgery and tapering the intensity later (in many cases, discontinuing maintenance corticosteroids). Many centers additionally use early postoperative lympholytic, or "induction," therapy for several days, with either polyclonal antithymocyte globulin or the monoclonal anti-CD3 preparation OKT3. The advantages of using induction therapy have been debated but probably include the ability to delay the introduction of cyclosporine in patients with initially marginal renal function and a delay of the first rejection episode,27 which occurs when the patient is in a physiologically more recovered state, with resolution of many of the changes of end-stage heart failure.

The 1990s have been an era of much activity in the field of new immunosuppressive drugs and modalities, and several have found their way into clinical practice in heart transplantation either as part of maintenance immunosuppression or as therapy for graft rejection. Tacrolimus was first shown to be an effective substitute for cyclosporine in liver transplantation28,29 (and is perhaps uniquely effective for liver grafts), but is effective30 for "rescue" therapy for intractable rejection in cardiac transplant recipients when substituted for cyclosporine in the maintenance regimen. However, in randomized trials comparing initial tacrolimus-based with cyclosporine-based immunosuppression in heart transplant recipients, there did not appear to be a major advantage to using tacrolimus.31 Both drugs are nephrotoxic and neurotoxic but have different adverse effect profiles otherwise. Cyclosporine is associated with a high incidence of arterial hypertension, hirsutism, and gingival hyperplasia, whereas tacrolimus is associated with development of glucose intolerance.

Mycophenolate mofetil is the second new immunosuppressive agent to be approved by the US Food and Drug Administration (FDA) in the 1990s and is widely accepted and used as a substitute for azathioprine in renal transplant regimens.3234 A preliminary report of its superiority to azathioprine in cardiac transplant recipients is encouraging (Jon Kobashigawa, MD, oral communication, 1998), but longer-term follow-up will be required to know whether the drug fulfills the laboratory model promise of decreased incidence of graft coronary artery disease35 and makes the high cost of the drug a worthwhile investment.

A number of other drugs (rapamycin, deoxyspergualin, leflunomide) are currently in preclinical and clinical trials, and the options for designing individual immunosuppressive regimens will multiply greatly in the coming years. It seems doubtful that we will ever again see a time when all patients are given basically the same drug regimen.

Augmented corticosteroid doses remain the basic form of therapy for cardiac graft rejection, but a number of other drugs and modalities have been investigated and are used for steroid-resistant rejection. They include the use of a course of daily lympholytic therapy with antithymocyte globulin or OKT3,36 the adjunctive use of methotrexate in doses similar to those used for rheumatologic diseases,37,38 the administration of total lymphoid irradiation,39,40 and the use of photopheresis.41,42

Early Limitations: Infection and Rejection

Given the current nonspecific means available to suppress the immune system, all organ allograft recipients can be viewed as existing on a fairly fine line between overimmunosuppression and underimmunosuppression. Underimmunosuppression can lead to graft rejection and even graft loss, whereas overimmunosuppression leaves a functioning graft but high susceptibility to opportunistic infections. With all organ allografts, the tendency toward rejection is most active early after transplantation and diminishes over time. The intensity of immunosuppression is usually adjusted accordingly.

Rejection of the cardiac allograft generally is not accompanied by clinical signs or symptoms in its early stages and may prove irreversible in the later stages, when clinical signs do supervene. Although a wide variety of electrocardiographic, echocardiographic, immunologic, and other modalities have been investigated as means to screen for early cardiac allograft rejection, none have been agreed on to have the high degree of sensitivity and specificity required to guide life-and-death decisions regarding immunosuppression. The endomyocardial biopsy was introduced at Stanford University, Stanford, Calif, in 1974 as means to diagnose rejection and assess the adequacy of rejection therapy,43 and it remains the "gold standard" of rejection diagnosis in 1998. The biopsy specimen is obtained by a transvascular approach with standard bioptome forceps, usually from a percutaneous right internal jugular approach, and processed for light microscopy. It is performed as an outpatient procedure and takes approximately 20 minutes to accomplish. An internationally accepted grading scale for reporting cardiac allograft rejection was adopted by the ISHLT in 199044 and consists of grades 0 to 4, with 4 being the most severe rejection. The recommended frequency for performing surveillance right ventricular biopsies varies from program to program, but most perform weekly biopsies for the first 4 postoperative weeks, then every other week for another month, monthly until 6 months following surgery, and every 3 months until the end of the first postoperative year. After the first year biopsy surveillance is highly individualized. Therapy for rejection generically consists of increasing immunosuppression; the intensity of the increase is determined by the histological and, occasionally, clinical severity of the rejection episode.

The most common, basic way to augment immunosuppression is by increasing corticosteroid dose, either as a "pulse" with intravenous methylprednisolone or with an increase in and subsequent taper of the oral maintenance dose. More intensive therapy, necessitated by the development of hemodynamic compromise or histologically high grades of rejection, usually includes lympholytic therapy (with polyclonal antithymocyte globulin or monoclonal anti-CD3 globulin) added to the augmented corticosteroid dose.

Infectious complications after heart transplantation, often associated with a necessarily high level of immunosuppression, run the gamut of opportunistic viral, protozoal, fungal, and bacterial organisms. The lung is the most frequent site of infection but clinical infections can occur in virtually any organ. A high level of surveillance is most important to detect such infections early in their course, especially with screening chest x-rays, and an aggressive approach to prompt specific diagnosis and therapy of the infection is essential for patient survival.

Only a few regimens for infection prophylaxis have been shown to be effective in transplant recipients, but these are important to pursue. They include prophylaxis against Pneumocystis carinii with sulfamethoxazole and trimethoprim45 and prophylaxis against cytomegalovirus with ganciclovir46 and probably with cytomegalovirus hyperimmune globulin in cytomegalovirus-seronegative recipients of a seropositive donor's organ.47

Late Limitations: Graft Coronary Artery Disease and Malignancy

A diffuse obliterative form of coronary arteriopathy affects increasing numbers of cardiac transplant recipients over time and its ischemic sequelae are currently the main complications limiting truly long-term survival in cardiac transplant recipients. The disease is angiographically apparent in up to 10% of patients by 1 year after transplantation48 and affects approximately 50% by 5 years following the procedure.49,50 The vascular disease is limited to the allograft, a fact that intuitively attests to its immunologic origins, but nonimmunologic features are widely thought to be associated with acceleration of the process; these include the traditional risk factors, such as dyslipidemia,51 obesity,52 glucose intolerance,53 and probably cigarette smoking, as well as the occurrence of postoperative cytomegalovirus infection.54,55 Early onset of disease is associated with a worse clinical outcome.56 The process is not unique to the cardiac allograft57 and is thought to be analogous to chronic immunologically mediated changes seen in all other organ allografts. The process is called chronic rejection in the kidney,58vanishing bile duct syndrome in liver allografts,59 and obliterative bronchiolitis in lungs.60

Morphologically, cardiac allograft arteriopathy is a concentric, longitudinal, and diffuse process generally affecting all of the epicardial coronary arteries and their branches. Occasional focal proximal lesions occur but these are unusual, and collateral vessel formation is correspondingly unusual.61 This diffuse nature of the disease tends to make angiography, which only outlines the lumen of the vessel, a gross underestimate of the severity of the disease. A graphic but, unfortunately, not uncommon example of such underestimation is shown in Figure 5. In this figure, an apparently normal frame of a left coronary injection done at 14 postoperative months in a young patient is contrasted with the histological cross-section of the patient's left main coronary artery obtained at autopsy after he died suddenly 2 months after the arteriogram. The histological section demonstrates a striking amount of concentric intimal proliferation that was not at all apparent on the arteriogram. Figure 6 shows a typical elastic stain of a cross-section of a cardiac allograft coronary artery with graft vasculopathy and demonstrates the typical concentric intimal proliferation with an intact internal elastic lamina.

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Figure 5.—Left, Frame from left coronary injection (right anterior oblique projection) from coronary arteriography performed 14 months after transplantation in a 22-year-old patient. Right, Histological cross-section of left main coronary artery (corresponding to area noted by black arrow on arteriogram) of same patient. Specimen obtained at autopsy after sudden death 2 months after arteriogram.
Graphic Jump Location
Figure 6.—Cross-section of circumflex coronary artery and branch obtained at autopsy in a 33-year-old patient who died suddenly 5 years after heart transplantation (elastic von Gieson stain, magnification ×30).

In recent years, intravascular ultrasonography has been shown to be a more sensitive modality for detecting and following the progression of cardiac allograft vasculopathy.62,63 Intravascular ultrasound measurements of intimal thickness are currently used as surrogate end points in several clinical trials of new immunosuppressive agents that have shown promise of decreasing the incidence of cardiac allograft vasculopathy in animal models.

The clinical presentation of the sequelae of this obliterative disease generally involves the results of the attendant ischemia, such as left ventricular dysfunction, ventricular arrhythmias, and sudden death.64 Occasionally, long-term patients with cardiac allografts do seem able to experience the subjective sensation of angina pectoris,16 but a lack of chest pain is more characteristic of the process. The prognosis for transplant recipients with angiographically established disease, especially after the occurrence of an ischemic event, is poor. In 1 study,65 the 1-year survival rate after the demonstration of any 40% lesion was only 63%, and the 1-year survival rate after the onset of congestive heart failure was 23%.

The standard and widely used methods for catheter-based and surgical revascularization of coronary arteries are infrequently applicable to patients with cardiac transplant vasculopathy because of the diffuse nature of their disease. One report of pooled data on coronary interventional procedures in cardiac transplant recipients in major US centers did show that catheter-based interventions appeared safe with a good procedural success rate, but patient follow-up showed progression of diffuse disease and its consequences and emphasized the essentially short-term palliative role of such intervention.66

Any medical regimen involving long-term immunosuppression is associated with an increased risk of subsequent malignancy, most often lymphoproliferative disease and cutaneous cancers. Organ transplantation has proved to be no exception, and a registry based at the University of Cincinnati, Cincinnati, Ohio, has documented the incidence of posttransplantation malignancies since 1968. According to the most recent ISHLT registry report, malignancy accounts for 11.8% of deaths after heart transplantation.20 Most of these have been posttransplantation lymphoproliferative disease.

There is convincing evidence that most posttransplantation lymphoproliferative disease is related to infection (either primary or reactivation) with the Epstein-Barr virus.6769 The tumors frequently occur in unusual extranodal locations and may respond to reduction in immunosuppression,70 although such reduction is clearly a "double-edged sword" in the field of heart transplantation because it may result in graft rejection.

Improved Immunosuppression

Newer drugs that are moving into clinical trials so far seem to have fewer toxic effects than those they may replace, and, in animal models, several have shown promise of being associated with a lesser incidence of cardiac allograft vasculopathy. Even if this were the only advantage of a new drug it would be a major advance in the field. Ultimately, it is hoped that advances in immunology will lead to the ability to induce a state of specific donor tolerance in which long-term or maintenance immunosuppression is unnecessary. Recent reports of the use of CTLA4-Ig and anti-CD40 ligand in animal models have been encouraging in this regard.71

Permanent Mechanical Support

Even the development of the most optimum ways of suppressing the immune system will not address the disparity of the increasing demand for donor hearts and the plateau of supply at a level that provides perhaps 1 in 10 potential recipients18 with a needed donor heart. For this reason, alternatives to cardiac allografting continue to be actively pursued, and none is more vigorous than the work on nonbiological or mechanical heart replacement. First introduced as temporary support devices or bridges to transplantation in the 1980s, both the total artificial heart72,73 and the left ventricular assist device were intended ultimately to provide alternatives to biological replacement of the heart. The left ventricular assist device has proved quite effective as a bridge to transplantation, extending life and restoring moribund patients to a much more normal physiological state and much better candidacy for transplantation.74,75 A first clinical trial of a left ventricular assist device as an alternative to medical therapy for patients who are not transplant candidates (for reasons of age or comorbid conditions) is currently under way (Eric A. Rose, MD, written communication, January 1998) and will likely be followed by other clinical trials directly comparing left ventricular assist device support with transplantation. The advantages of a mechanical device for cardiac replacement include the lack of need to suppress the immune system and all of the consequences attendant on such suppression, as well as potentially unlimited supply of devices, in contrast with the limited supply of donor hearts. The disadvantages of mechanical devices (at least of the current generation of them) include a variable tendency for thromboembolic complications necessitating systemic anticoagulation (and its attendant problems) for some devices, an incidence of device-related infections because of the need for transcutaneous connections, and a variable incidence of device malfunction. Technical limitations such as the need for the patient to be "tethered" to a power source will likely be solved, but the expense of such devices may deter their widespread use initially.

Xenotransplantation

Competing with the advancing technology for mechanical replacement of the heart is the alternative of biological replacement with nonhuman hearts, the field known as xenotransplantation.76 The use of nonhuman hearts is currently limited by strong immunologic barriers to acceptance of such grafts. However, advances in genetic technology are producing transgenic animals with important epitopes incorporated into their genetic materials. When these epitopes are expressed, they ameliorate or abrogate the intensity of the phenomenon of hyperacute rejection, which is otherwise a virtually uniform and immunologically violent reaction to the presence of a discordant xenograft. Because the development of hyperacute xenograft rejection depends absolutely on the activation of complement, one current line of work is focused on inserting human complement regulatory proteins into the porcine genome and producing lines of pigs that will not be able to activate complement and generate hyperacute rejection.77 Once this immunologic hurdle is cleared, the potential for a cellular immune response as well as the later development of graft vasculopathy will remain potential problems, and the extent to which they may be controlled by conventional immunosuppression is uncertain. It is also uncertain whether any fundamental physiological incompatibilities will preclude adequate function of a cardiac xenograft, although recent results from the Cambridge group78 did document xenograft survival in a porcine to nonhuman primate model for several-month periods.

The potential use of xenotransplantation to benefit some patients has, however, raised some serious ethical issues because of the attendant risk for transmission of infectious illnesses into humans along with the xenogeneic tissue, illnesses that would be termed xenoses. Because the pathogenic potential of a given microbe may change when it is transmitted to a new species, it is possible that organisms that are not particularly pathogenic in their host species will cause serious and transmittable disease when transplanted along with a donor organ. Many examples of such a change in pathogenicity with transmission to a different species exist and likely include the human immunodeficiency virus 1 and 2 epidemics resulting from simian retroviruses introduced across species lines into humans.79 There is a general presumption that the greater phylogenetic distance between humans and swine makes swine safer donors, but no data exist to substantiate this assumption. This potential risk to public health has led some prominent leaders in the field to call for a moratorium on human xenotransplantation until the risks are better defined and national and international policy addresses the issue at a societal level.80 Thus, whether xenotransplantation will become a common part of clinical practice remains unclear, but if and when it does, the field of organ replacement will have taken its most major step forward.

Conclusion

Thus, cardiac transplantation has become a mature field during the past 30 years. Slow progress is being made in conquering the complications that limit truly long-term survival, but the limited donor supply will always mean that transplantation can only save a fraction of those who could benefit from it. How to distribute these scarce organs is a difficult societal and ethical issue and one that is currently being addressed at the highest levels. In the larger picture, alternatives to allotransplantation for cardiac replacement are the most pressing need.

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Kahan BD. Cyclosporine.  N Engl J Med.1989;321:1725-1737.
Oyer PE, Stinson EB, Jamieson SW.  et al.  Cyclosporine A in cardiac allografting: a preliminary experience.  Transplant Proc.1983;15:1247-1252.
Starnes VA, Oyer PE, Stinson EB, Dein JR, Shumway NE. Prophylactic OKT3 used as induction therapy for heart transplantation.  Circulation.1989;80(suppl 3):79-83.
The US Multicenter FK506 Liver Study Group.  A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation.  N Engl J Med.1994;331:1110-1115.
European FK506 Multicentre Liver Study Group.  Randomized trial comparing tacrolimus (FK506) and cyclosporine in prevention of liver allograft rejection.  Lancet.1994;344:423-428.
Armitage JM, Kormos RL, Griffith BP.  et al.  A clinical trial of FK506 as primary and rescue immunosuppression in cardiac transplantation.  Transplant Proc.1991;23:1149-1152.
Pham SM, Kormos RL, Hattler BG.  et al.  A prospective trial of tacrolimus (FK506) in clinical heart transplantation: intermediate-term results.  J Thorac Cardiovasc Surg.1996;111:1-9.
European Mycophenolate Mofetil Cooperative Study Group.  Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection.  Lancet.1995;345:1321-1325.
Sollinger HW.for the US Renal Transplant Mycophenolate Mofetil Study Group.  Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients.  Transplantation.1995;60:225-232.
The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group.  A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation.  Transplantation.1996;61:1029-1037.
Gregory CR, Pratt RE, Huie P.  et al.  Effects of treatment with cyclosporine, FK506, rapamycin, mycophenolic acid, or deoxyspergualin on vascular smooth muscle proliferation in vitro and in vivo.  Transplant Proc.1993;25:770-771.
Gilbert EM, DeWitt CW, Eiswirth CC.  et al.  Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody.  Am J Med.1987;82:202-206.
Costanzo-Nordin MR, Grusk BB, Silver MA.  et al.  Reversal of recalcitrant cardiac allograft rejection with methotrexate.  Circulation.1988;78(suppl 3):III47-III57.
Bouchart F, Gundry SR, Van Schaak-Gonzales J.  et al.  Methotrexate as rescue/adjunctive immunotherapy in infant and adult heart transplantation.  J Heart Lung Transplant.1993;12:427-433.
Levin B, Bohannon V, Warvariv V, Bry W, Collins G. Total lymphoid irradiation (TLI) in the cyclosporine era: use of TL1 in resistant cardiac allograft rejection.  Transplant Proc.1989;21:1793-1795.
Keogh A, Morgan G, Macdonald P, Spratt P, Mundy J, McCosker C. Total lymphoid irradiation for resistant rejection after heart transplantation: only moderate success medium-term.  J Heart Lung Transplant.1996;15:231-233.
Costanzo-Nordin MR, Hubbell EA, O'Sullivan EJ.  et al.  Successful treatment of heart transplant rejection with photophoresis.  Transplantation.1992;53:808-815.
Meiser BM, Kur F, Reichenspurner H.  et al.  Reduction of the incidence of rejection by adjunct immunosuppression with photochemotherapy after heart transplantation.  Transplantation.1994;57:563-568.
Caves PK, Stinson EB, Billingham ME, Shumway NE. Serial transvenous biopsy of the transplanted human heart: improved management of acute rejection episodes.  Lancet.1974;1:822-826.
Billingham ME, Cary NRB, Hammond ME.  et al.  A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group.  J Heart Transplant.1990;9:587-592.
Olsen SL, Eastburn TE, Renlund DG.  et al.  Trimethoprim sulfamethoxazole prevents Pneumocystis carinii pneumonia in cardiac transplant recipients.  J Heart Transplant.1990;9:20A.
Merigan TC, Renlund DG, Keay S.  et al.  A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation.  N Engl J Med.1992;326:1182-1186.
Valantine HA. Prevention and treatment of cytomegalovirus disease in thoracic organ transplant patients: evidence for a beneficial effect of hyperimmune globulin.  Transplant Proc.1995;27(suppl 1):49-57.
Gao SZ, Schroeder JS, Alderman EL.  et al.  Prevalence of accelerated coronary artery disease in heart transplant survivors: comparison of cyclosporine and azathioprine regimens.  Circulation.1989;80(suppl 3):III100-III105.
Olivari MT, Homans DC, Wilson RF, Kubo SH, Ring WS. Coronary artery disease in cardiac transplant patients receiving triple-drug immunosuppressive therapy.  Circulation.1989;80(suppl 3):III111-III115.
Uretsky BF, Murali S, Reddy PS.  et al.  Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone.  Circulation.1987;76:827-834.
Park JW, Merz M, Braun P, Vermeltfoort M. Lipid disorder and transplant coronary artery disease in long-term survivors of heart transplantation.  J Heart Lung Transplant.1996;15:572-579.
Rickenbacker PR, Kemna MS, Pinto FJ.  et al.  Coronary artery intimal thickening in the transplanted heart.  Transplantation.1996;61:46-53.
Valantine H, Rickenbacker P, Kemna MS.  et al.  Metabolic abnormalities characteristic of syndrome X predict long-term outcome in heart transplant patients.  J Heart Lung Transplant.1995;14(pt 2):S58.
Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis.  JAMA.1989;261:3561-3566.
McDonald K, Rector TS, Braunlin EA, Kubo SH, Olivari MT. Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection.  Am J Cardiol.1989;64:359-362.
Gao SZ, Hunt SA, Schroeder JS, Alderman EL, Hill IR, Stinson EB. Early development of accelerated graft coronary artery disease: risk factors and course.  J Am Coll Cardiol.1996;28:673-679.
Tilney NL, Whitley WD, Diamond JR, Kupiec-Weglinski JW, Adams JH. Cardiac rejection: an undefined conundrum.  Transplantation.1991;52:389-398.
Callard P, Bedrossian J, Idatte JM.  et al.  The arterial lesions in the cause of renal allograft rejection.  Adv Nephrol.1975;5:333-353.
Ludwig J, Wiesner RH, Batts KP, Perkins JD, Krom RAF. The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation.  Hepatology.1987;7:476-483.
Griffith BP, Paradis IL, Zeevi A.  et al.  Immunologically mediated disease of the airways after pulmonary transplantation.  Ann Surg.1988;208:371-378.
Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary angiographic findings.  J Am Coll Cardiol.1988;12:340-344.
St Goar FG, Pinto FJ, Alderman EL.  et al.  Intracoronary ultrasound in cardiac transplant recipients: in vivo evidence of "angiographically silent" intimal thickening.  Circulation.1992;85:979-987.
Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TC, Ramee SR. Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy.  J Heart Lung Transplant.1995;14:632-639.
Gao SZ, Schroeder JS, Hunt SA, Billingham ME, Valantine HA, Stinson EB. Acute myocardial infarction in cardiac transplant recipients.  Am J Cardiol.1989;64:1093-1097.
Keogh AM, Valantine HA, Hunt SA.  et al.  Impact of proximal or midvessel discrete coronary artery stenoses on survival after heart transplantation.  J Heart Lung Transplant.1992;11:892-901.
Halle AA, DiSciascio G, Massin EK.  et al.  Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients.  J Am Coll Cardiol.1995;26:120-128.
Young L, Alfieri C, Hennessy K.  et al.  Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative diseases.  N Engl J Med.1989;321:1080-1085.
Hanto DW, Frizzera G, Gail-Peczalska KJ.  et al.  The Epstein-Barr virus (EBV) in the pathogenesis of posttransplant lymphoma.  Transplant Proc.1981;13:756-760.
Hanto DW. Classification of Epstein-Barr virus-associated post-transplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies.  Annu Rev Med.1995;46:381-394.
Starzl TE, Porter FA, Iwatsuki S.  et al.  Reversibility of lymphoma and lymphoproliferative lesions developing under cyclosporine-steroid therapy.  Lancet.1984;1:583-587.
Kirk AD, Harlan DM, Armstrong NN.  et al.  CTDLA4-Ig and anti-CD40 prevent renal allograft rejection in primates.  Proc Natl Acad Sci U S A.1997;94:8789-8794.
DeVries WC, Anderson JL, Joyce LD.  et al.  Clinical use of the total artificial heart.  N Engl J Med.1984;310:273-278.
Griffith BP, Hardesty RL, Kormos RL.  et al.  Temporary use of the Jarvik-7 total artificial heart before transplantation.  N Engl J Med.1987;316:130-134.
Portner PM, Oyer PE, Pennington DG.  et al.  Implantable left ventricular assist system: bridge to transplant and the future.  Ann Thorac Surg.1989;47:142-150.
Kormos RL, Murali S, Dew MA.  et al.  Chronic mechanical circulatory support: rehabilitation, low morbidity, and superior survival.  Ann Thorac Surg.1994;57:51-58.
Platt JL. Approaching the clinical application of xenotransplantation.  Am J Med Sci.1997;313:315-321.
McCurry KR, Kooyman DL, Alvarado CG. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury.  Nat Med.1995;1:423-427.
Thompson C. Humanized pigs' hearts boost xenotransplantation.  Lancet.1995;346:766.
Chapman LE, Folks TM, Salomon D, Patterson AP, Eggerman TE, Noguchi PD. Xenotransplantation and xenogeneic infections.  N Engl J Med.1995;333:1498-1501.
Bach FH, Fishman JA, Daniels N.  et al.  Uncertainty in xenotransplantation: individual benefit vs collective risk.  Nat Med.1998;4:141-144.

Figures

Graphic Jump Location
Figure 1.—Number of heart transplantations (gray bars) and mean donor age (black line) per calendar year. Reprinted with permission from Hosenpud et al.20
Graphic Jump Location
Figure 2.—Adult heart transplantation actuarial survival by era. Survival significantly improved after 1986. The half-life survival (when half of those who underwent transplantation have died) was 8.0 years for 1991 through 1996 vs 5.4 years for 1980 through 1985. Reprinted with permission from Hosenpud et al.20
Graphic Jump Location
Figure 3.—Adult heart transplantation actuarial survival according to patient age at time of transplantation. For each age group, the younger group is significantly more likely to survive than the next older group (P<.001). Reprinted with permission from Hosenpud et al.20
Graphic Jump Location
Figure 4.—Pediatric heart transplantation actuarial survival by patient age at time of transplantation. Survival is significantly different for younger than 1 year vs 6 to 15 years (P<.001) and for 1 to 5 years vs 6 to 15 years (P<.001). Reprinted with permission from Hosenpud et al.20
Graphic Jump Location
Figure 5.—Left, Frame from left coronary injection (right anterior oblique projection) from coronary arteriography performed 14 months after transplantation in a 22-year-old patient. Right, Histological cross-section of left main coronary artery (corresponding to area noted by black arrow on arteriogram) of same patient. Specimen obtained at autopsy after sudden death 2 months after arteriogram.
Graphic Jump Location
Figure 6.—Cross-section of circumflex coronary artery and branch obtained at autopsy in a 33-year-old patient who died suddenly 5 years after heart transplantation (elastic von Gieson stain, magnification ×30).

Tables

References

Barnard CN. The operation.  S Afr Med J.1967;30:1271-1274.
Lower RR, Shumway NE. Studies of orthotopic homotransplantation of the canine heart.  Surg Forum.1960;11:18-19.
Lower RR, Stofer RC, Hurley EJ, Dong E, Cohn RB, Shumway NE. Successful homotransplantation of the canine heart after anoxic preservation for seven hours.  Am J Surg.1962;104:302-306.
Dreyfus G, Jebara V, Mihaileanu MD, Carpentier A. Total orthotopic heart transplantation: an alternative to the standard technique.  Ann Thorac Surg.1991;52:1181-1184.
Deleuze PH, Benvenuti C, Mazzucotelli MD.  et al.  Orthotopic cardiac transplants with direct caval anastomosis: is it the optimal procedure?  J Thorac Cardiovasc Surg.1995;109:731-737.
Trento A, Czer LSC, Blanche C. Surgical techniques for cardiac transplantation.  Semin Thorac Cardiovasc Surg.1996;8:126-132.
Pope SE, Stinson EB, Daughters GT, Schroeder JS, Ingels NV, Alderman EL. Exercise response of the denervated heart in long-term cardiac transplant recipients.  Am J Cardiol.1980;46:213-218.
Pflugfelder PW, Purves PD, McKenzie FN, Kostuk WJ. Cardiac dynamics during supine exercise in cyclosporine-treated orthotopic heart transplant recipients: assessment by radionuclide angiography.  J Am Coll Cardiol.1987;10:336-341.
Gao SZ, Schroeder JS, Hunt SA, Billingham ME, Valantine HA, Stinson EB. Acute myocardial infarction in cardiac transplant recipients.  Am J Cardiol.1989;64:1093-1097.
Savin W, Schroeder J, Haskell W. Response of cardiac transplant recipients to static and dynamic exercise: a review.  Heart Transplant.1982;1:72-79.
Ehrman J, Keteyian S, Fedel F, Rhoads K, Levine T, Shepard R. Cardiovascular responses of heart transplant recipients to graded exercise testing.  J Appl Physiol.1992;73:260-264.
Stevenson L, Sietsema K, Tillisch J.  et al.  Exercise capacity for survivors of cardiac transplantation or sustained medical therapy for stable heart failure.  Circulation.1990;81:78-85.
Mancini D. Surgically denervated cardiac transplant: rewired or permanently unplugged?  Circulation.1997;96:6-8.
Wilson RF, Christensen BV, Oliari MT, Simon A, White CW, Laxson MD. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans.  Circulation.1991;83:1210-1220.
Burke MN, McGinn AL, Homans DC, Christensen BV, Kubo SH, Wilson RF. Evidence for functional sympathetic reinnervation of left ventricle and coronary arteries after orthotopic cardiac transplantation in humans.  Circulation.1995;91:72-78.
Stark RP, McGinn AL, Wilson RF. Chest pain in cardiac transplant recipients: evidence of sensory reinnervation after cardiac transplantation.  N Engl J Med.1991;324:1791-1794.
Givertz MM, Harley H, Colucci WS. Long-term sequential changes in exercise capacity and chronotropic responsiveness after cardiac transplantation.  Circulation.1997;96:232-237.
Hunt SA. 24th Bethesda Conference: Cardiac Transplantation.  J Am Coll Cardiol.1993;22:1-64.
Stevenson WG, Stevenson LW, Middlekauf HR.  et al.  Improving survival for patients with advanced heart failure: a study of 737 consecutive patients.  J Am Coll Cardiol.1995;26:1417-1423.
Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. The registry of the International Society for Heart and Lung Transplantation: 15th official report—1998.  J Heart Lung Transplant.1998;17:656-668.
Hosenpud JD, Breen TJ, Edwards EB, Daily OP, Hunsicker LG. The effect of transplant center volume on cardiac transplant outcome.  JAMA.1994;271:1844-1849.
 Medicare programs: criteria for Medicare coverage of heart transplants. 52 Federal Register 10935-10951 (1987).
Krakuer H, Shakar SS, Kaye MP. The relationship of clinical outcomes to status as a Medicare-approved heart transplant center.  Transplantation.1995;59:840-846.
Grady KL, Jalowiec A, White-Williams C. Improvement in quality of life in patients with heart failure who undergo transplantation.  J Heart Lung Transplant.1996;15:749-757.
Kahan BD. Cyclosporine.  N Engl J Med.1989;321:1725-1737.
Oyer PE, Stinson EB, Jamieson SW.  et al.  Cyclosporine A in cardiac allografting: a preliminary experience.  Transplant Proc.1983;15:1247-1252.
Starnes VA, Oyer PE, Stinson EB, Dein JR, Shumway NE. Prophylactic OKT3 used as induction therapy for heart transplantation.  Circulation.1989;80(suppl 3):79-83.
The US Multicenter FK506 Liver Study Group.  A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation.  N Engl J Med.1994;331:1110-1115.
European FK506 Multicentre Liver Study Group.  Randomized trial comparing tacrolimus (FK506) and cyclosporine in prevention of liver allograft rejection.  Lancet.1994;344:423-428.
Armitage JM, Kormos RL, Griffith BP.  et al.  A clinical trial of FK506 as primary and rescue immunosuppression in cardiac transplantation.  Transplant Proc.1991;23:1149-1152.
Pham SM, Kormos RL, Hattler BG.  et al.  A prospective trial of tacrolimus (FK506) in clinical heart transplantation: intermediate-term results.  J Thorac Cardiovasc Surg.1996;111:1-9.
European Mycophenolate Mofetil Cooperative Study Group.  Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection.  Lancet.1995;345:1321-1325.
Sollinger HW.for the US Renal Transplant Mycophenolate Mofetil Study Group.  Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients.  Transplantation.1995;60:225-232.
The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group.  A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation.  Transplantation.1996;61:1029-1037.
Gregory CR, Pratt RE, Huie P.  et al.  Effects of treatment with cyclosporine, FK506, rapamycin, mycophenolic acid, or deoxyspergualin on vascular smooth muscle proliferation in vitro and in vivo.  Transplant Proc.1993;25:770-771.
Gilbert EM, DeWitt CW, Eiswirth CC.  et al.  Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody.  Am J Med.1987;82:202-206.
Costanzo-Nordin MR, Grusk BB, Silver MA.  et al.  Reversal of recalcitrant cardiac allograft rejection with methotrexate.  Circulation.1988;78(suppl 3):III47-III57.
Bouchart F, Gundry SR, Van Schaak-Gonzales J.  et al.  Methotrexate as rescue/adjunctive immunotherapy in infant and adult heart transplantation.  J Heart Lung Transplant.1993;12:427-433.
Levin B, Bohannon V, Warvariv V, Bry W, Collins G. Total lymphoid irradiation (TLI) in the cyclosporine era: use of TL1 in resistant cardiac allograft rejection.  Transplant Proc.1989;21:1793-1795.
Keogh A, Morgan G, Macdonald P, Spratt P, Mundy J, McCosker C. Total lymphoid irradiation for resistant rejection after heart transplantation: only moderate success medium-term.  J Heart Lung Transplant.1996;15:231-233.
Costanzo-Nordin MR, Hubbell EA, O'Sullivan EJ.  et al.  Successful treatment of heart transplant rejection with photophoresis.  Transplantation.1992;53:808-815.
Meiser BM, Kur F, Reichenspurner H.  et al.  Reduction of the incidence of rejection by adjunct immunosuppression with photochemotherapy after heart transplantation.  Transplantation.1994;57:563-568.
Caves PK, Stinson EB, Billingham ME, Shumway NE. Serial transvenous biopsy of the transplanted human heart: improved management of acute rejection episodes.  Lancet.1974;1:822-826.
Billingham ME, Cary NRB, Hammond ME.  et al.  A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group.  J Heart Transplant.1990;9:587-592.
Olsen SL, Eastburn TE, Renlund DG.  et al.  Trimethoprim sulfamethoxazole prevents Pneumocystis carinii pneumonia in cardiac transplant recipients.  J Heart Transplant.1990;9:20A.
Merigan TC, Renlund DG, Keay S.  et al.  A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation.  N Engl J Med.1992;326:1182-1186.
Valantine HA. Prevention and treatment of cytomegalovirus disease in thoracic organ transplant patients: evidence for a beneficial effect of hyperimmune globulin.  Transplant Proc.1995;27(suppl 1):49-57.
Gao SZ, Schroeder JS, Alderman EL.  et al.  Prevalence of accelerated coronary artery disease in heart transplant survivors: comparison of cyclosporine and azathioprine regimens.  Circulation.1989;80(suppl 3):III100-III105.
Olivari MT, Homans DC, Wilson RF, Kubo SH, Ring WS. Coronary artery disease in cardiac transplant patients receiving triple-drug immunosuppressive therapy.  Circulation.1989;80(suppl 3):III111-III115.
Uretsky BF, Murali S, Reddy PS.  et al.  Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone.  Circulation.1987;76:827-834.
Park JW, Merz M, Braun P, Vermeltfoort M. Lipid disorder and transplant coronary artery disease in long-term survivors of heart transplantation.  J Heart Lung Transplant.1996;15:572-579.
Rickenbacker PR, Kemna MS, Pinto FJ.  et al.  Coronary artery intimal thickening in the transplanted heart.  Transplantation.1996;61:46-53.
Valantine H, Rickenbacker P, Kemna MS.  et al.  Metabolic abnormalities characteristic of syndrome X predict long-term outcome in heart transplant patients.  J Heart Lung Transplant.1995;14(pt 2):S58.
Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis.  JAMA.1989;261:3561-3566.
McDonald K, Rector TS, Braunlin EA, Kubo SH, Olivari MT. Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection.  Am J Cardiol.1989;64:359-362.
Gao SZ, Hunt SA, Schroeder JS, Alderman EL, Hill IR, Stinson EB. Early development of accelerated graft coronary artery disease: risk factors and course.  J Am Coll Cardiol.1996;28:673-679.
Tilney NL, Whitley WD, Diamond JR, Kupiec-Weglinski JW, Adams JH. Cardiac rejection: an undefined conundrum.  Transplantation.1991;52:389-398.
Callard P, Bedrossian J, Idatte JM.  et al.  The arterial lesions in the cause of renal allograft rejection.  Adv Nephrol.1975;5:333-353.
Ludwig J, Wiesner RH, Batts KP, Perkins JD, Krom RAF. The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation.  Hepatology.1987;7:476-483.
Griffith BP, Paradis IL, Zeevi A.  et al.  Immunologically mediated disease of the airways after pulmonary transplantation.  Ann Surg.1988;208:371-378.
Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary angiographic findings.  J Am Coll Cardiol.1988;12:340-344.
St Goar FG, Pinto FJ, Alderman EL.  et al.  Intracoronary ultrasound in cardiac transplant recipients: in vivo evidence of "angiographically silent" intimal thickening.  Circulation.1992;85:979-987.
Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TC, Ramee SR. Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy.  J Heart Lung Transplant.1995;14:632-639.
Gao SZ, Schroeder JS, Hunt SA, Billingham ME, Valantine HA, Stinson EB. Acute myocardial infarction in cardiac transplant recipients.  Am J Cardiol.1989;64:1093-1097.
Keogh AM, Valantine HA, Hunt SA.  et al.  Impact of proximal or midvessel discrete coronary artery stenoses on survival after heart transplantation.  J Heart Lung Transplant.1992;11:892-901.
Halle AA, DiSciascio G, Massin EK.  et al.  Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients.  J Am Coll Cardiol.1995;26:120-128.
Young L, Alfieri C, Hennessy K.  et al.  Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative diseases.  N Engl J Med.1989;321:1080-1085.
Hanto DW, Frizzera G, Gail-Peczalska KJ.  et al.  The Epstein-Barr virus (EBV) in the pathogenesis of posttransplant lymphoma.  Transplant Proc.1981;13:756-760.
Hanto DW. Classification of Epstein-Barr virus-associated post-transplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies.  Annu Rev Med.1995;46:381-394.
Starzl TE, Porter FA, Iwatsuki S.  et al.  Reversibility of lymphoma and lymphoproliferative lesions developing under cyclosporine-steroid therapy.  Lancet.1984;1:583-587.
Kirk AD, Harlan DM, Armstrong NN.  et al.  CTDLA4-Ig and anti-CD40 prevent renal allograft rejection in primates.  Proc Natl Acad Sci U S A.1997;94:8789-8794.
DeVries WC, Anderson JL, Joyce LD.  et al.  Clinical use of the total artificial heart.  N Engl J Med.1984;310:273-278.
Griffith BP, Hardesty RL, Kormos RL.  et al.  Temporary use of the Jarvik-7 total artificial heart before transplantation.  N Engl J Med.1987;316:130-134.
Portner PM, Oyer PE, Pennington DG.  et al.  Implantable left ventricular assist system: bridge to transplant and the future.  Ann Thorac Surg.1989;47:142-150.
Kormos RL, Murali S, Dew MA.  et al.  Chronic mechanical circulatory support: rehabilitation, low morbidity, and superior survival.  Ann Thorac Surg.1994;57:51-58.
Platt JL. Approaching the clinical application of xenotransplantation.  Am J Med Sci.1997;313:315-321.
McCurry KR, Kooyman DL, Alvarado CG. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury.  Nat Med.1995;1:423-427.
Thompson C. Humanized pigs' hearts boost xenotransplantation.  Lancet.1995;346:766.
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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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