Author + information
- Received June 27, 2017
- Revision received August 18, 2017
- Accepted August 29, 2017
- Published online November 27, 2017.
- Michelle M. Kittleson, MD, PhD and
- Jon A. Kobashigawa, MD∗ ()
- ↵∗Address for correspondence:
Dr. Jon A. Kobashigawa, Cedars-Sinai Heart Institute, 127 South San Vicente Boulevard, Los Angeles, California 90048.
Despite advances in pharmacologic and device treatment of chronic heart failure, long-term morbidity and mortality remain high, and many patients progress to end-stage heart failure. Over the last 5 decades, heart transplantation (HTx) has become the preferred therapy for select patients with end-stage heart disease. However, although HTx has become standard of care for the management of end-stage heart failure, challenges continue to exist. The number of patients with end-stage heart failure is increasing, whereas the number of donor organs remains constant and a limiting factor in HTx. Not only are there more potential heart transplantation candidates, but HTx candidates today are more complex: older, sensitized, and in need of mechanical circulatory support. Such candidates are at higher risk for poor outcomes including primary graft dysfunction and antibody-mediated rejection. This article focuses on current post-transplantation outcomes and recent advances in HTx that could address the current challenges. These advances include: 1) attempts to expand the donor pool; 2) proposed changes in HTx allocation policy for more equitable organ distribution; 3) a better understanding of the definition and management of primary graft dysfunction; and 4) advances in the management of sensitized HTx candidates. Developments in these areas could result in expansion and more equitable distribution of the donor pool and improved survival and quality of life for HTx recipients.
Despite advances in pharmacologic and device treatment of heart failure (HF), long-term morbidity and mortality remain high, and many patients progress to end-stage HF. Over the last 5 decades, heart transplantation (HTx) has become the preferred therapy for select patients, with a 1-year survival of almost 90% and a conditional half-life of 13 years (1), certainly far better than expected from end-stage HF.
However, challenges still exist. The number of patients with end-stage HF is increasing, whereas the number of donor organs remains a constant and limiting factor (2). Not only are there more potential HTx recipients, but they are also more complex. There are now more candidates 65 years of age and older (3), with mechanical circulatory support (3), and with antibodies to human leukocyte antigens (HLA), so-called sensitization (4).
These HTx candidates of the modern era who are older, require mechanical circulatory support, and who are sensitized are at higher risk for poor outcomes including primary graft dysfunction and antibody-mediated rejection (1,2,5). This review focuses on the current status of HTx and recent advances that could address the current challenges (Central Illustration), which include: 1) attempts to expand the donor pool; 2) changes in the allocation policy for more equitable organ distribution; 3) a better understanding of primary graft dysfunction; and 4) management of sensitized HTx candidates. These developments could result in expansion and more equitable distribution of donor hearts and improved survival and quality of life for HTx recipients.
Survival after HTx has steadily improved in the past 5 decades. In the 1980s, 1-year survival was 70%, and the conditional half-life, the time at which 50% of patients who survived the first year are still alive, was 9.4 years. In the 2016 report from the International Society of Heart and Lung Transplantation registry, 1-year survival is almost 90%, with a conditional half-life of 13.2 years (1). Notably, the mortality rate beyond 1 year after transplantation has improved only marginally for patients who received allografts after 1992. There has been no significant improvement in the past 2 decades, likely because the processes responsible for long-term mortality, including cardiac allograft vasculopathy and malignancy, remain a challenge of detection and treatment.
Advances in Immunosuppression
Most maintenance immunosuppressive protocols after HTx use a 3-drug regimen consisting of a calcineurin inhibitor (CNI) (cyclosporine or tacrolimus), an antimetabolite agent (mycophenolate mofetil [MMF] or azathioprine), and tapering doses of corticosteroids over the first year post-transplantation.
Since the introduction of cyclosporine in the early 1980s, the CNIs have remained the cornerstone of maintenance immunosuppressive therapy in patients undergoing solid organ transplantation. Tacrolimus is favored over cyclosporine based on clinical trials suggesting that tacrolimus-based immunosuppression is associated with a decrease in acute rejection (6). Mycophenolate mofetil has replaced azathioprine as the preferred antimetabolite, given reduction in mortality and the incidence of treated rejection at 1 year with MMF versus azathioprine (7).
Proliferation signal inhibitors (PSIs) or mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are relatively recent advances in standard immunosuppression. Both sirolimus and everolimus reduce the incidence of acute rejection and prevent development of cardiac allograft vasculopathy (CAV) (8). When sirolimus is used in HTx recipients with significant renal impairment, it permits minimization or complete withdrawal of the CNIs, resulting in improvements in renal function without an increased risk of rejection (9,10).
Steroid withdrawal protocols may be used early (3 to 6 months) or late (6 to 12 months) after transplantation. Individual trials include small numbers of patients, but overall, the results indicate that the use of corticosteroids for more than 1 year after transplantation does not appear to confer benefit with regards to allograft function or rejection (11,12). In low-risk patients without a history of rejection or donor-specific antibodies, weaning corticosteroids by 1 year is reasonable.
Advances in Allograft Vasculopathy
The incidence of CAV varies widely due to differences in definition of disease and patient populations but, by various estimates, ranges from 42% at 5 years to 50% at 10 years (13,14). Given the denervation of the transplanted heart, patients do not experience typical angina (15). Thus, routine surveillance angiography is performed in cardiac transplant recipients, usually at 1-year intervals (Figure 1). The use of mTOR inhibitors, statins, and vitamins C and E have been demonstrated to slow the progression of CAV, but to date, there is no therapy to completely prevent or reverse this significant complication (16–18).
Intravascular ultrasonography (IVUS) is currently the only technique which offers cross-sectional images of the coronary vessel wall comparable to histological sections to detect even early plaque burden. IVUS is more sensitive than angiography in detecting CAV (Figure 2) (19) and has prognostic value: progression of intimal thickening >0.5 mm in the first year after transplantation is associated with an increased risk of death and development of angiographic CAV up to 5 years later (20). Information gleaned from IVUS may trigger a switch from MMF to a proliferation signal inhibitor therapy (8,21,22).
Expanding the Donor Pool
Extended criteria donors
Currently, fewer than 50% of potential organ donors in the United States become actual donors (23). Initiatives have been taken to increase the usage rate (24). Transplantation centers now use extended criteria donor (ECD) hearts with acceptable outcomes, which matches higher risk recipients with higher risk donors. Higher risk recipient criteria include: age >65 years old, renal insufficiency, peripheral arterial disease, or poorly controlled diabetes. Considerable evidence shows that ECD hearts that may result in favorable post-HTx survival continue to be discarded. A retrospective review of 1,872 potential organ donors in California from 2001 to 2008 showed predictors of nonusage to be >50 years of age, female, death attributable to cerebrovascular accident, hypertension, diabetes mellitus, a positive troponin assay result, left ventricle (LV) dysfunction (LV ejection fraction of <50%), regional wall motion abnormalities, and LV hypertrophy. These characteristics of ECD hearts, however, seemed to have little effect on recipient outcomes when some of these hearts were transplanted (25).
Other ongoing efforts to expand the donor pool include an increase in identification of donors, increase in the consent rate, expansion of donor selection criteria, maximization of donor organ function, and use of mechanical support devices as an adjunctive approach to organ donation.
Ex vivo heart perfusion
Another way to expand the donor pool would be to remove the geographic constraints of ischemic time with an ex vivo heart perfusion platform that maintains the donor heart in a warm, beating state for transplantation. A number of small registries have demonstrated safety of an ex vivo perfusion platform (26). In the largest randomized trial to assess the safety of an ex vivo platform, 130 patients were randomized to receive donor hearts preserved by using either the Organ Care System or standard cold storage. There were no differences in 30-day patient and graft survival rates or serious adverse events (27).
The ex vivo perfusion platform offers great potential for extended criteria donor hearts, where cold storage would conventionally be associated with poorer outcomes, and donor hearts that are currently not even considered for HTx, such as donors that are older, have left ventricular hypertrophy, or moderately impaired left ventricular function.
Donation after circulatory death
In an effort to expand the donor pool, donation after circulatory death (DCD) has been explored for HTx. In DCD, retrieval of organs for the purpose of transplantation occurs from patients (those with severe and irreparable brain injury but who do not meet brain dead criteria) whose death is declared and confirmed using cardiorespiratory criteria as life support is withdrawn. Asystole must be confirmed for at least 5 min for declaration of death. The heart is then removed and resuscitated through the use of ex vivo heart perfusion as described above.
A major challenge with DCD heart donation, which has prevented more widespread uptake, has been assessment of myocardial viability after death. With the DCD pathway, the heart is exposed to an unavoidable period of severe, warm ischemia. In addition, the donor hemodynamic trajectory is highly variable after withdrawal of life support. The challenge for HTx using DCD donors is the minimization of ischemic injury of the donor organs.
Despite these challenges, post-HTx survival and graft function in almost 50 DCD HTx performed to date are comparable to those observed in contemporary HTx performed with hearts from donors who have undergone neurological determination of death (28–30).
Heart Transplantation Allocation Policy
Need for a new approach
The allocation of thoracic organs in the United States is seemingly equitable in that the sickest patients who have been waiting the longest are considered first when a donor heart becomes available (Table 1). However, changes in the HTx landscape have motivated efforts to improve the current system (32,33): there is an increase in candidates awaiting transplantation without a corresponding increase in donors, the highest acuity (status 1A) patients have undesirably high mortality, and advances in mechanical circulatory support have improved waitlist mortality in this subset.
These changes have exposed 2 major problems with the current status criteria. First, the system offers inadequate resolution. Status 1A includes patients supported with extracorporeal membrane oxygenation (ECMO) and inotropic support and continuous hemodynamic monitoring with equal urgency. However, HTx candidates receiving ECMO support are more tenuous and have lower projected survival than candidates receiving support from 2 inotropic agents with continuous hemodynamic monitoring; such patients should not receive the same priority as they do under the current 3-tiered system. Second, the current system ignores candidates with poor prognosis who would not qualify for traditional status 1A listing, such as those with complex congenital heart disease, restrictive or infiltrative cardiomyopathies, or refractory ventricular tachycardia (32,33).
Changing the heart allocation policy
The new allocation system consists of 7 status levels (Table 2) (34). Proposed status 1 to 3 levels are generally defined by current status 1A criteria; proposed status 4 is generally defined by current status 1B; and proposed status 5 and 6 are defined by current status 2 criteria. The major change is the stratification of patients within the current 1A status into 3 groups of decreasing acuity. The proposed system also addresses potentially underserved populations, such as adults with congenital heart disease, re-transplantation, restrictive cardiomyopathy, and hypertrophic cardiomyopathy in a separate tier above current status 2 patients.
The new system addresses the current geographical disparity in organ allocation (Figure 3) by broader sharing for the highest tier patients. In the new approach, the 2 sickest patient groups will draw organs from a 500-mile radius (donor service area “Zone A”) in the first round of organ allocation as opposed to a stepped approach.
The new allocation system was approved by the Organ Procurement and Transplant Network and United Network of Organ Sharing board in December 2016 and is expected to go into effect by mid-2018. Although no system can be perfect, these efforts should allow for more equitable distribution of the scarce resource of donor organs such that the most critically ill patients are most likely to receive transplantation before the window of viability closes. Simulations using this new donor heart allocation system have predicted reduction in waitlist mortality while not compromising post-transplantation outcome.
Primary Graft Dysfunction
Defining primary graft dysfunction
In 2013, a consensus conference convened to formulate guidelines regarding primary graft dysfunction (PGD) highlighted the significant burden of this problem (35). In an international survey of 47 centers treating almost 10,000 patients, a PGD rate of 7.4% was reported with a 30-day mortality of 30%. A strict definition of PGD was established at this conference (Table 3). The advantages of a strict definition include, first, the ability to create future registries to follow the care and outcomes of patients with PGD; and, second, an assurance that future studies undertaken to determine risk factors or effect of therapies will include that patients of comparable degree of PGD.
Cause and risk factors
The donor heart is subject to a series of insults during the transplantation process, including brain death and its sequelae in the donor, hypothermic ischemia during transport, warm ischemia during implantation, and reperfusion injury after release of the aortic cross-clamp in the recipient. In addition, systemic factors in the recipient may create a “hostile” environment that further compromises donor heart function after reperfusion (35,36).
Management and potential prevention
There are no biomarkers for PGD, and treatment is supportive (Figure 4). Many of the risk factors for PGD are not modifiable, such as age, diabetes, and need for inotropic support. However, the length of cold ischemic time could be improved with an ex vivo heart perfusion platform as outlined above.
Advances in the Diagnosis of Rejection
Allomap: peripheral blood gene expression
Although performing an endomyocardial biopsy is straightforward, the morbidity associated with this invasive procedure motivated development of other means of diagnosing rejection. The gene expression profile (GEP) test (AlloMap, CareDx Inc., San Francisco, California), an 11-gene expression signature derived from peripheral blood mononuclear cells, is a noninvasive test with a high negative predictive value for acute cellular rejection (ACR) (37). In randomized trials, GEP was noninferior to biopsy results in the diagnosis of ACR (38) and also useful in early post-transplantation (39). One role of the GEP is to screen low-risk patients at pre-determined intervals, using biopsies performed only if the GEP score is abnormal. However, patients at risk for antibody-mediated rejection (AMR) are not candidates for GEP screening as the test has only been validated for ACR.
Another emerging technology in the noninvasive diagnosis of rejection involves cell-free DNA. Cell-free donor-derived DNA is detectable in both the urine and blood of transplant recipients (40,41). This cell-free DNA may be a candidate marker for noninvasive diagnosis of graft injury, as increased levels of donor-derived DNA appear to correlate with acute cellular and antibody-mediated rejection events (42).
Tissue-level gene expression
As noted above, the Allomap relies on peripheral blood GEP to refine diagnostic accuracy and does not aid in the diagnosis of AMR. However, a recent study examined mRNA extracted from biopsy samples and hybridized to a microarray system. From this analysis, variations in AMR-selective gene expression could accurately classify AMR and was correlated to disease activity and International Society of Heart and Lung Transplantation AMR grade (43). This advance may refine diagnostic accuracy and provide insight into the treatment of AMR (44).
Detection of anti-HLA antibodies
Identification and quantification of anti-HLA antibodies is most commonly performed using solid-phase assays (Figure 5). Quantification is important because antibodies of greater intensity in vitro are considered potentially more cytotoxic in vivo. The presence of high levels of anti-HLA antibodies (usually above 3,000 to 5,000 median fluorescent intensity) is considered potentially cytotoxic (44).
However, intensity of antibodies may not be the best test of potential cytotoxicity because not all antibodies at high intensity may be detrimental to graft function. The ability of donor-specific antibodies to fix complement may be a better marker of their cytotoxicity (45,46). Activation of the classical complement pathway by antibodies begins with their binding of C1q, the first component of the pathway. Once activated by C1q, the classic pathway leads to the formation of the membrane attack complex and ultimately results in cell lysis and death. Thus, one would expect that antibodies with the ability to bind C1q would be more likely to be cytotoxic, and this has been borne out in renal transplant recipients (45,47). For centers where the C1q assay is not currently available, considering only antibodies that are strongly binding by median fluorescent intensity after a 1:8 or 1:16 dilution may offer comparable information (46).
Figure 6 outlines one approach to the detection of anti-HLA antibodies in HTx candidates and how the presence of such antibodies would change management for patients awaiting transplantation.
Approach to the crossmatch
Detection of anti-HLA antibodies prior to transplantation is important as one would avoid donors who have HLA corresponding to high-level anti-HLA antibodies in the potential recipient, as this would be a risk for hyperacute rejection. In the past, the only way to assess this was with a prospective crossmatch, in which the potential recipient’s serum was mixed with donor cells to assess for complement-dependent cytotoxicity. However, this presented a severe geographic restriction to the donor pool, to hospitals near where the candidate’s serum was stored, thus reducing the number of potential donors.
The virtual crossmatch has replaced the prospective crossmatch at most centers. With the virtual crossmatch, HLA corresponding to high-level anti-HLA antibodies in the transplantation candidate are listed as “avoids” in the United Network of Organ Sharing database, and thus, potential donors with such HLA are not considered. This method has proven safe and successful in HTx (48).
The identity and intensity of anti-HLA antibodies is useful not only in safely finding a donor organ for a sensitized recipient but also in deciding on which sensitized patients require desensitization (44,49). Centers often use a threshold of the calculated PRA (cPRA) to decide on treatment of the sensitized patient. The cPRA is the frequency of unacceptable HLA in the donor population. For example, if a HTx candidate had high-level antibodies relative to that of common HLA, the cPRA may be 90%, and thus, only 10% of all potential donors would be compatible. cPRA highlights the fact that some high-level anti-HLA antibodies will impact the ability to find a suitable donor heart more than others (50). If the cPRA is above 50% to 70%, therapies to reduce antibody levels prior to transplantation may be used.
Approach to desensitization
Management of the sensitized patient involves protocols to target antibodies by inactivation (intravenous [IV] injection of immune globulin [Ig]) (51), removal (plasmapheresis), and decreased production (rituximab  and bortezomib ). At our center, the first step in desensitization is often a modified protocol based on that established for desensitization of kidney transplantation recipients (Figure 7) (51).
If the protocol of IV Ig and rituximab is ineffective in reducing the cPRA below 50%, or if a patient requires rapid desensitization (i.e., they are listed as status 1A), then bortezomib, a proteasome inhibitor against plasma cells, may be used (52). To increase effectiveness, bortezomib can be combined with plasmapheresis (Figure 8).
There are no randomized, placebo-controlled trials of desensitization in solid-organ transplantation. In comparison to nonsensitized controls (n = 428), desensitized patients treated with IV Ig and rituximab had significantly lower 1-year freedom from acute rejection (57% vs. 87%, respectively) and AMR (67% vs. 97%, respectively), but comparable 5-year survival (71% vs. 76%, respectively), freedom from CAV (74% vs. 76%, respectively), nonfatal major adverse events (95% vs. 91%, respectively), and treated infection (71% vs. 72%, respectively) (53). Bortezomib and plasmapheresis regimen was studied in 30 broadly sensitized (cPRA >50%) heart transplantation candidates. Approximately one-half of the patients had a reduction in cPRA (mean 18 ± 19%), and 22 patients were able to achieve a negative crossmatch to proceed to transplantation. At 12 months, there was 100% survival and 74% freedom from any treated rejection (54). Adverse effects include non-life-threatening infections, but desensitization therapies are generally well tolerated.
As we continue to expand the boundaries of HTx to higher risk patients who are older and who require mechanical circulatory support and antibody sensitization, the goal must be to maintain superior outcomes with this scarce resource. Challenges remain in the management of HTx recipients, including the scarce supply and equitable distribution of donor hearts, prevention of primary graft dysfunction, diagnosis of rejection, and management of sensitization. The advances outlined here, including efforts to expand the donor pool, revise the HTx allocation policy, increase understanding of primary graft dysfunction, develop newer ways to diagnose rejection, and make advances in the identification and treatment of sensitized HTx candidates will serve to improve the survival and quality of life of end-stage patients who undergo HTx.
Dr. Kobashigawa has received research support from Novartis, CareDx, and TransMedics. Dr. Kittleson has reported she has no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute cellular rejection
- antibody-mediated rejection
- biventricular assist device
- calcineurin inhibitor
- calculated panel reactive antibodies
- donation after circulatory death
- deoxyribonucleic acid
- extracorporeal membrane oxygenation
- Food and Drug Administration
- gene expression profile
- heart failure
- human leukocyte antigen
- heart transplantation
- intra-aortic balloon pump
- mechanical circulatory support
- organ care system
- primary graft dysfunction
- ventricular assist device
- Received June 27, 2017.
- Revision received August 18, 2017.
- Accepted August 29, 2017.
- 2017 American College of Cardiology Foundation
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