Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review

Josef Stehlik, MD, MPH; Jon Kobashigawa, MD; Sharon A. Hunt, MD; Hermann Reichenspurner, MD, PhD; James K. Kirklin, MD


Circulation. 2018;137(1):71-87. 

In This Article


Although the surgical challenges of heart transplantation were overcome in the 1960s, interest in the procedure quickly waned because recipients had a high rate of early rejection and mortality. By the 1970s, most major centers abandoned heart transplantation, and it was not until the discovery of cyclosporine that heart transplantation re-emerged to become an accepted treatment for end-stage heart disease. Advances in immunosuppression and perioperative care have dramatically improved survival, with 1-year post-transplant survival of 90% and a median post-transplant survival of >12 years in the modern era (Figure 4).[36]

Figure 4.

Median survival after heart transplantation and approximate time of introduction of key immunosuppressive agents and standardized clinical care approaches in heart transplantation based on data submitted to the International Society for Heart and Lung Transplantation International Thoracic Transplant Registry.
Median survival between 1968 and 1980 is a best estimate because complete survival information for the early transplantation era is not available. Median survival after 2005 has not been reached, and displayed data represent an estimate based on survival through August 2017. Analysis courtesy of Wida Cherikh, PhD, and Anna Kucheryavaya, MS.

The host immune response against the allograft necessitates lifelong immunosuppression (Figure 5), striking a delicate balance between modulating the immune system enough to prevent rejection while avoiding the adverse effects of immunodeficiency (infection, malignancy) and drug toxicities (nephrotoxicity, hypertension, hyperglycemia, hyperlipidemia).

Figure 5.

List of immunosuppressive drugs commonly used in heart transplantation and their site of action in the T cell.
CDK indicates cyclin-dependent kinase complex; IL-2R Ab, interleukin-2 receptor antibody; MHC, major histocompatibility complex; MMF, mycophenolate mofetil/mycophenolic acid; NFAT, nuclear factor of activated T cells; and TOR, target of rapamycin.

The immune system has innate and adaptive mechanisms capable of both recognizing antigens on the allograft and mounting a response. The innate response is the first line of defense and requires no prior sensitization. Cells of the innate immune system can activate the adaptive immune response through cytokine release and antigen presentation. The adaptive immune system consists of thymus-derived lymphocytes (T cells) and bursa-derived lymphocytes (B cells). T cells can recognize only antigens that have been processed and bound to major histocompatibility molecules on other cells, including antigen-presenting cells of the adaptive immune system and B cells. Bound antigens stimulate the T-cell receptor, which activates downstream pathways, including the calcineurin pathway, leading to proliferation and production of cytokines such as interleukin-2, which promotes clonal expansion of T cells. Helper T cells activate the effector cells of the immune system: natural killer cells, B cells, and cytotoxic T cells.

Immunosuppression strategies have been designed to mitigate the immune response of the recipient against the donor allograft while limiting the toxicity of the individual agents (Figure 5). Immunosuppressive regimens fall into 3 categories: induction, maintenance, and rejection treatment. Induction therapy is an intensive course of immunosuppression given perioperatively that aims to aggressively modulate immunity during this high-risk period. This is particularly useful for the allosensitized patient who carries preformed antibodies against HLA antigens[37] and for the patient with renal impairment where it allows for delayed start of nephrotoxic immunosuppressive drugs. Approximately 50% of heart transplant recipients receive induction therapy, and the most commonly used agents are T cell–depleting agents (anti-thymocyte globulin, alemtuzumab) and interleukin-2 receptor antagonists (basiliximab).[36] Induction therapy may reduce the incidence of cellular rejection and possibly slow the progression of CAV[38] but increases the risk of infection and malignancy.[39,40] The comparative efficacy of induction therapy agents has not been examined in a randomized trial, and no survival benefit has been demonstrated compared with no induction.

After transplantation, most patients are prescribed a 3-drug maintenance immunosuppression regimen consisting of a calcineurin inhibitor (CNI), an antimetabolite, and a tapering dose of corticosteroids. Calcineurin is a calcium-dependent serine/threonine phosphatase that activates nuclear factor of activated T cells, a transcription factor that upregulates the expression of interleukin-2. The CNIs cyclosporine and tacrolimus work by dampening the T-cell response to alloantigens. The efficacy profile of cyclosporine allowed the return of heart transplantation into the clinical mainstream in the 1980s (Figure 4). Tacrolimus has since become the preferred CNI because of lower rates of rejection and a more favorable side-effect profile.[41] The key adverse effects of CNIs are nephrotoxicity, hypertension, dyslipidemia, and hyperglycemia. CNIs are metabolized by the cytochrome p450 system, which is a degradation pathway for numerous drugs, thereby setting the stage for multiple drug-drug interactions.

The antimetabolites azathioprine and mycophenolate mofetil/mycophenolic acid (MMF) interfere with cell growth and division. Azathioprine, a prodrug metabolized into a purine analog, inhibits DNA synthesis in T and B lymphocytes. Adverse effects include leukopenia, thrombocytopenia, and anemia. MMF reversibly inhibits inosine monophosphate dehydrogenase, the rate-limiting enzyme of the de novo guanine synthesis pathway. MMF selectively targets proliferating lymphocytes because they are entirely dependent on the de novo pathway, whereas other cell types can use the salvage pathway. A large clinical trial comparing MMF with azathioprine in heart transplantation showed improved survival and lower rates of rejection for patients treated with MMF.[42] As a result, MMF has almost entirely replaced azathioprine as the preferred antimetabolite.

Corticosteroids were among the first immunosuppressive agents used in transplantation and remain an important component of maintenance regimens because of their potent and diverse anti-inflammatory and immunosuppressive effects. Corticosteroids prevent the production of cytokines, growth factors, vasoactive substances, and adhesion molecules by inhibiting transcription factors such as activator protein-1 and nuclear factor-κB. Long-term corticosteroid use is associated with many adverse effects, including Cushing syndrome, glucose intolerance, infection, and osteoporosis. Patients at low risk for rejection are typically tapered to a low dose or entirely weaned off steroids by 12 months after transplantation.

The proliferation signal inhibitors sirolimus and everolimus inhibit the mammalian target of rapamycin, an important kinase regulating the cell cycle, and thus inhibit proliferation of T and B cells and vascular smooth muscle cells. Sirolimus or everolimus when substituted for azathioprine and used in combination with cyclosporine produce lower rates of rejection and CAV.[43,44] Sirolimus in combination with tacrolimus decreases the rates of treated rejection, cytomegalovirus infection, and malignancy.[45] However, sirolimus worsens the nephrotoxicity of CNIs and delays sternal wound healing and thus should not be initiated immediately after transplantation.[43] Sirolimus used in place of CNI (CNI-free regimen) late after transplantation may improve kidney function in patients with renal impairment.[46] Proliferation signal inhibitors used in place of MMF may reduce progression of CAV, viral infections, and malignancy.[43,44,47]

Although triple-drug regimens are the most common for maintenance immunosuppression, CNI avoidance and CNI monotherapy have been trialed. A small study showed that sirolimus used in place of a CNI is noninferior for rates of rejection and mortality, but further validation is needed.[48] Single-drug immunosuppression with tacrolimus after early withdrawal of MMF and steroids is effective but requires a higher dose and may promote nephrotoxicity.[49]

The treatment of AMR focuses on removing and neutralizing antibodies, inhibiting B cells and plasma cells, and dampening the inflammatory and coagulation pathways.[27] Immunosuppressive agents used for the treatment of AMR include rituximab, bortezomib, and eculizumab. Rituximab is a monoclonal antibody against CD20 antigen present on B cells, which induces prolonged B-cell depletion. Bortezomib inhibits 26S proteasome, which interferes with protein synthesis in plasma cells and eventually leads to plasma cell apoptosis. Eculizumab is a humanized monoclonal antibody that inhibits the C5 component of the complement, preventing formation of the complement membrane attack complex.

Many drug-drug interactions need to be taken into consideration in patients on long-term immunosuppressive therapy. Among the most common are interactions between CNIs and other drugs metabolized by the cytochrome P450 system such as certain antifungal agents, antibiotics, and statins.[50] Other less frequent (and less commonly known) interactions can also take place, and it is therefore a good practice to exclude possible interactions every time a new medication is prescribed in a transplant recipient.