A decade after Norman Shumway had accomplished the technique of a successful heart transplant in canines, Christiaan Barnard successfully performed the first human to human transplant on December 3, 1967. Now, 5 decades later, this surgery has become entrenched in the standard armamentarium for treating patients with advanced heart failure who are otherwise healthy enough to receive such a life altering treatment. Globally, >150,000 patients have undergone cardiac transplantation with a 1 year survival >80% and median survival of nearly 11 years. These gains have been ushered in due to advances in immunosuppression and identification and management of allograft rejection, as well as a comprehensive appreciation for late complications including accelerated coronary artery disease, malignancy, and renal failure.
CANDIDATES FOR CARDIAC TRANSPLANTATION
The demand for cardiac transplantation outstrips the availability of organ donors. Hence, attention to the optimal utility, equitable allocation, and patient autonomy must dominate the decisions to identify and list candidates for transplantation. Simultaneously, attempts at expanding the donor pool have surfaced. However, vigilance to evaluating candidates most likely to have a successful outcome from transplantation takes pre-eminence. In 2006, the International Society for Heart and Lung Transplantation identified a set of criteria to guide listing of patients. These criteria were updated in 2016 and include additional attention to the growing epidemiology of candidates suffering from congenital heart disease, restrictive and infiltrative cardiomyopathy (such as amyloidosis), and chronic infections in recipients (such as Chagas’ disease, tuberculosis and hepatitides). Selected general principles for listing candidates for cardiac transplantation are enumerated in Table 255-1.
TABLE 255-1Principles for Listing Candidates for Cardiac Transplantation ||Download (.pdf) TABLE 255-1 Principles for Listing Candidates for Cardiac Transplantation
|Principle ||Comment |
|Advanced Disease Severity ||Refractory heart failure with a VO2 of <14 mL/kg/min (<12, if on beta blockers) or percent predicted VO2 <50%; combination of intolerance to disease modifying therapy, cardiorenal syndrome, use of inotropic therapy to maintain stability or need for a left ventricular assist system. |
|Co-Morbidity ||Age is not an absolute contraindication, but frailty should be considered a relative contraindication; a BMI > 35 kg/m2 should require weight loss; cancer should be dealt with on an individual basis (e.g., low-grade prostate cancer may not be a contraindication); poorly controlled diabetes mellitus or end-organ damage may be a contraindication; eGFR <30 mL/min/1.73 m2 is a relative contraindication; severe cerebrovascular disease or peripheral vascular disease (which will limit rehabilitation or function) is also a relative contraindication. |
|Donor-Recipient Matching ||Sensitized individuals with circulating antibodies should have a prospective or virtual cross match; pulmonary vascular resistance with a transpulmonary gradient >15, PVR >3 Wood Units and absolute PA systolic pressure >50 mmHg provided the systolic BP is >85 mmHg is a relative contraindication unless reactive. |
|Psychosocial Issues ||Tobacco use in any form limits posttransplant survival and should be stopped for at least 6-months; substance abuse, including marijuana, should be a contraindication if the individual cannot demonstrate control and cessation; patients with severe cognitive-behavioral disabilities or dementia (inability to ever understand and cooperate with medical care) have the potential for self-harm and should not receive a transplant. |
PRINCIPLES OF DONOR RECOVERY AND ALLOCATION
Although listing criteria for candidates are typically adjudicated at a center level, organ allocation is handled by national regulatory processes in most countries. The allocation of donor hearts is based on (a) the urgency of the clinical situation, (b) the time spent on the waiting list, and (c) the distance from the recipient center. Thus, candidates who are hospitalized and require temporary mechanical cardiac support devices or daily invasive hemodynamic evaluation and intravenous inotropic therapy to maintain stability are given the highest urgency status, while those able to ambulate and live at home receive a lower urgency status. The geographical regional reach for allocation is based not only on territorial considerations but also on the time that a donor heart would be in transit and therefore in out of body “cold ischemia time,” which is typically limited to 4 h. The final key feature that is included in the allocation offer relates to the ABO blood group. Donor organs are offered based on these initial characteristics and then a more detailed donor assessment ensues, resulting in acceptance or decline for any given donor heart. It is important to note that the time constraints imposed on the retrieval process make it difficult to invoke HLA matching of the donor and recipient. In cases where there is a high likelihood of sensitization in the recipient (preformed circulating antibodies against donor antigens), a prospective or virtual cross match is entertained prior to acceptance. Other clinical criteria that are employed in the decision on accepting an offered donor include the donor-recipient size match, the age of the donor (typically restricted to under 55 years) and presence or absence of concomitant pathology such as coronary artery disease, left ventricular hypertrophy or severe injury to the allograft manifest by excess leak of injury markers (troponins) or poor contractile performance. In many cases, the prospective cardiac allograft can be reconditioned by use of hormonal therapy (including thyroid hormone supplementation) and used for transplantation even if the initial evaluation suggests poor function. In efforts to enhance the donor pool, systems that allow ex-vivo normothermic perfusion to evaluate and reanimate organs with a prolonged out of body time are being developed. The classic heart donor is derived from a donor with brain death; however, donors with circulatory death are being increasingly evaluated as candidates for cardiac reanimation using a variety of techniques including ex-vivo reanimation and subsequent transplantation.
SURGERY FOR CARDIAC TRANSPLANTATION
The most common contemporary operation is referred to as a “bicaval” orthotopic cardiac transplant that mimics the natural anatomic position. In this operation, the donor and recipient superior and inferior vena cava are connected as are the aortic and pulmonary great vessels. The left atrium of the recipient retains its roof including the draining pulmonary veins and the donor left atrium is then sutured to the retained atrial tissue. This technique maintains function of the donor right atrium, important for governing early postoperative right heart output, and may prevent atrial arrhythmias. The recipient is left with a surgical denervation and the allograft is not responsive to any direct sympathetic or parasympathetic stimuli. Therefore, early in the adaptive postoperative phase, high-dose catecholamines are required to maintain adequate function. Due to denervation, bradycardia in a cardiac allograft cannot be treated with atropine and the drug of choice is isoproterenol. Once the cardiac allograft adapts to its host circulation, the function is usually adequate at rest and with exercise to provide normal physical activity.
CARDIAC ALLOGRAFT REJECTION AND IMMUNOSUPPRESSION
The ability to perform endomyocardial biopsies, evaluate rejection pathologically and the introduction of the immunosuppression agent cyclosporine heralded cardiac transplantation as a viable clinical therapy. Triple drug immunosuppression, which includes a calcineurin inhibitor (cyclosporine or tacrolimus), corticosteroids and anti-proliferative immunosuppression (azathioprine, mycophenolate mofetil, sirolimus or everolimus) is now the standard cocktail used. The combination that is most commonly used and achieves the best standard outcomes includes the combination of tacrolimus, mycophenolate mofetil, and prednisone. In those at high risk for rejection (multiparous women, sensitized individuals) or in situations where use of calcineurin inhibitors is delayed (renal dysfunction), induction therapy using monoclonal (basiliximab) or polyclonal antibodies (anti-thymocyte globulin) to provide augmented immunosuppression is used. The typical management strategy includes gradual weaning of steroids over time as surveillance endomyocardial biopsies are performed and clinical as well as sub-clinical pathological quiescence is established. Table 255-2 describes the immunosuppression drugs in common use.
TABLE 255-2Immunoprophylaxis Drugs in Cardiac Transplantation ||Download (.pdf) TABLE 255-2 Immunoprophylaxis Drugs in Cardiac Transplantation
|Drug Class ||Generic Drug ||Cellular Target ||Major Side Effects |
|Calcineurin Inhibitors ||Cyclosporine ||Binds to cyclophilin which then inhibits calcineurin ||Hypertension, dyslipidemia, gum hypertrophy, hypertrichosis |
|Tacrolimus ||Binds to immunophilin FK506 binding protein which inhibits calcineurin ||Hypertension, dyslipidemia, alopecia, diabetes mellitus |
|Anti-Thymocyte Globulin (ATG) ||Rabbit ATG ||T-cell depletion in blood and peripheral lymphoid tissues through complement-dependent lysis and T-cell activation and apoptosis ||Cytokine release syndrome, leukopenia, thrombocytopenia, serum sickness |
|Horse ATG ||Same as above ||Same as above |
|Interleukin-2 receptor antagonists ||Basiliximab ||Inhibition of CD-25 of IL-2 receptor ||Well tolerated; rare hypersensitivity; increased infection risk |
|Anti-metabolites ||Azathioprine ||Imidazolyl derivative and prodrug of 6-mercaptopurine (cell cycle inhibitor) ||Bone marrow suppression, pancreatitis, hepatitis |
|Mycophenolate Mofetil ||Inhibits inosine monophosphate dehydrogenase, which controls guanine monophosphate in the de novo pathway of purine synthesis (inhibits T and B cell proliferation) ||Leukopenia, gastrointestinal toxicity |
|Proliferation-Signal Inhibitors ||Sirolimus ||Binds with FKBP12 and complex inhibits the mechanistic Target of Rapamycin (mTOR) ||Delayed wound healing, non-specific pneumonia, pericardial effusion, hyperlipidemia (hypertriglyceridemia) |
|Everolimus ||Binds to FKBP12, which inhibits mTORC1 (and not mTORC2) ||Dyslipidemia, stomatitis, pericardial effusions and pancytopenia |
Acute cellular rejection (ACR) and antibody-mediated rejection (AMR) are two separate forms of cardiac allograft rejection that are recognized and can sometimes coexist. ACR occurs early after transplantation and then declines in incidence after 6 months. This occurs due to a T cell–mediated assault on the donor allograft tissue and histologically is characterized by lymphocytic infiltrates. In mild cases these infiltrates are localized to the peri-venular regions, and in severe cases progresses diffusely into the cardiac interstitium. In late stages of severe ACR, most often associated with hemodynamic compromise, multi-clonal cells such as macrophages, neutrophils, and eosinophils are observed with intramyocardial hemorrhage, myocyte injury and myocyte necrosis. Subclinical ACR is typically treated with high doses of corticosteroid pulses although some centers choose to simply observe mild forms of infiltration since it is known that these recover longitudinally. If hemodynamic compromise occurs, rescue polyclonal antibodies are used in tandem with corticosteroids. Conversely, AMR is immunologically described as a non-cellular antibody-driven phenomenon associated with a pattern of immunopathologic findings of immunoglobulin deposition and complement fixation on immunofluorescence, along with histopathologic findings of endothelial swelling and interstitial edema and cardiac allograft arteriolar vasculitis. AMR is characterized by the emergence of circulating donor-specific antibodies that are thought to fix, complement, and bind to the allograft. Commonly, AMR leads to acute allograft dysfunction and increases the risk for cardiac allograft vasculopathy, and results in worsened cardiac allograft survival compared with ACR. In this form of rejection, therapy is directed towards suppression and removal of circulating antibodies using plasmapheresis and drugs such as rituximab (chimeric monoclonal antibody directed against the CD20 antigen) or in refractory cases, bortezomib (a proteasome inhibitor) or eculizumab (a terminal complement inhibitor). The treatment with immunosuppression requires prophylaxis for opportunistic infections and ongoing surveillance and expertise in recognizing the more common clinical presentations of infections caused by cytomegalovirus (CMV), aspergillus, and other opportunistic agents such as nocardia and toxoplasmosis.
LATE COMPLICATIONS AFTER CARDIAC TRANSPLANTATION
The long-term consequences of exposure to chronic immunosuppression result in a variety of non-immunological cardio-metabolic effects such as hypertension and hyperlipidemia as well as systemic disorders of bone loss and renal dysfunction. One aggressive complication that limits late survival of cardiac allografts includes the development of an accelerated form of coronary artery disease, referred to as cardiac allograft vasculopathy (CAV). This is characterized by a proliferative thickening of the vascular intima of the vasculature that is initiated as a diffuse endothelialitis in the setting of the confluence of the consequences of brain death, ischemia reperfusion injury during the transplant process and early immunological insults. Chronically, the metabolic consequences of hypertension, hyperlipidemia, and disordered glucose regulation result in a further worsening of vascular lesions that are diffuse and noted throughout the coronary tree. Early diagnosis and preventative therapy are critical since it is commonly silent in genesis. Statins, antihypertensive agents, and anti-CMV agents all have demonstrated benefits in reducing CAV. Anti-proliferative immunosuppressive therapy such as mycophenolate mofetil and sirolimus or everolimus prevent vascular intimal thickening compared with azathioprine-based regimens. However, retransplantation is the only definitive form of therapy for advanced allograft CAV (Fig. 255-1).
Cardiac allograft vasculopathy is initiated and propagated by the combined influence of immunological and non-immunological insults on the allograft vasculature. An inflammatory milieu determines the development of diffuse, aggressive luminal blockages that in early forms exhibit intimal thickening and fibrosis. IVUS, Intravascular Ultrasound (can be used to diagnose early forms of intimal thickening).
Another consternation in cardiac transplantation is the development of malignancy with a greater frequency than in the normal population, suggesting that immunosuppression plays a sentinel role in its generation. Posttransplant lymphoproliferative disorders, typically driven by Epstein-Barr virus, occur most frequently and require a reduction in immunosuppression, administration of antiviral agents, and traditional chemo- and radiotherapy. Specific antilymphocyte (targeted against CD20) therapy has also shown promise. Solid cancers most often manifest as skin malignancies (both basal cell and squamous cell carcinomas), and use of sun-screens is advised. Future research is required to define strategies for immune modulation, immune suppression, and malignancy prevention, however the impact of decreasing immunosuppression in the treatment of these cancers is unclear.