CLINICAL RESEARCH: CARDIAC TRANSPLANT AND ASSIST DEVICES: EDITORIAL COMMENT
Adverse outcomes from the use of older donor hearts in cardiac transplant recipients
The pros and cons of expanded donor criteria*
Howard J. Eisen, MD, FACC ,*
Advanced Heart Failure and Transplant Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
* Reprint requests and correspondence: Dr. Howard J. Eisen, Advanced Heart Failure and Transplant Center, Temple University School of Medicine, 9 Parkinson Pavilion, 3401 North Broad Street, Philadelphia, Pennsylvania 19140, USA.
eisenh{at}tuhs.temple.edu
Cardiac transplantation provides definitive therapy for selected patients with end-stage congestive heart failure and has resulted in improved survival for these patients. Cardiac transplantation has also been associated with improving survival during the past two decades since it re-emerged as an important option after the introduction of cyclosporine in 1983 (1). In particular, the improvements in survival that have been noted both in a multi-institutional study and in the study by Lietz et al. (2) in this issue of the Journal appear to be the result of several innovations in therapy for cardiac transplant recipients (1,2). These include improvements in immunosuppressive therapies over the last 15 years, refinements in surgical techniques, and improvement in therapies to treat or prevent post-transplant infectious diseases (3,4). These improvements in survival have occurred despite the increasing use of expanded donor criteria and what have been termed "marginal donors." As the donor shortage has worsened and the number of patients waiting for transplants has increased, efforts have been made to expand what is considered acceptable in a wide variety of categories related to the donor (5). Expanded donor criteria include the use of donors substantially smaller than the recipients, donors with but sometimes-obstructive coronary artery disease, left ventricular dysfunction, or donors from older age groups (5). Undersized hearts have been used successfully with excellent long-term outcomes (6). Traditionally, cardiac transplants were obtained from donors <35 years in age (7). Perhaps the greatest area of expansion of the donor population has been because of the increasing use of hearts from older donors, including donors older than 40 years of age or even older than 50 years of age. Several small single-center studies have shown that the use of these donors does not impart diminished survival to the recipients (8,9). In contrast, a multi-institutional study from the Cardiac Transplant Research Database indicates that the use of donors older than 40 years or age is associated with diminished survival after cardiac transplantation (2).
To more definitely answer this question, Lietz et al. (2) retrospectively studied the outcomes of their population of cardiac transplant recipients at Columbia-Presbyterian Medical Center from 1992 to 1999. Numerous factors related to the recipient and donor were studied, including the etiology of brain death in the donor, the era in which the transplant was performed, the United Network for Organ Sharing priority status, the use of left ventricular assist devices before transplant, recipient gender, and the age of the recipient and donor. Post-transplant outcomes studied included survival, acute allograft rejection, and the development of cardiac allograft vasculopathy defined by the presence of a new discrete angiographic lesion >50%, in the proximal or midportions of the major graft vessels or the presence of diffuse concentric narrowing of the whole vessels, including the branches. Alternatively, intravascular ultrasound was also used to determine the presence of increased intimal thickness. The analysis of the data showed that there was, in fact, a significant increase in mortality in cardiac allograft recipients receiving hearts from donors >40 years of age, with the most significant reduction in survival due to increased one-month mortality. If one eliminated the patients who died within the first month, however, there was no difference in long-term survival among the recipients of older hearts compared with those who received hearts from younger donors. However, there were more patients who developed cardiac allograft vasculopathy among the patients who received hearts from older donors compared with those who received hearts from younger donors.
The authors also identified additional risk factors for poor outcome in the first month after survival, including ischemic times >4 h. However, they also concluded that if one looked at the survival of recipients who received hearts from older donors and compared this with the survival of patients who never received transplants, that the mortality was much higher among those who did not receive a transplant than for those who received hearts from older donors in the Status 1 group, although the same could not be said for the Status 2 group. The implication of this finding is that despite the increased risk of using allografts from older donors, especially during the first month after transplant, that it is still appropriate in selected patients, particularly those who are Status 1 before transplant, to use hearts from older donors and that this strategy imparted a survival benefit.
This work has important implications for both the selection of the patients awaiting cardiac transplantation, as well as, the post-transplant management strategies for these patients. In particular, it is apparent that the greatest risk for using hearts from older donors is within the first month after transplant. Therefore, efforts should be made to reduce coincident risks. Thus, recipients receiving who are candidates for receiving hearts from older donors should only receive these allografts if the ischemic time can be kept to <4 h as a longer ischemic time resulted in an increased risk for poor outcome.
Unfortunately, the present study provided no clearly defined predominant etiology for death within the first month for those receiving hearts from older donors. The causes of death, including sepsis, heart failure, hemorrhage, and acute rejection, and distribution of causes of death were similar between heart recipients of hearts from older donors and those of hearts from younger donors. Therefore, approaches to try to further minimize poor outcomes in recipients of hearts from older donors may be hampered by a lack of knowledge at the present time regarding the relationships of the use of older allografts to the specific causes of the poor outcomes within the first 30 days after transplant. Nonetheless, careful selection of recipients and donors, including donors at hospitals relatively close to the recipient site, may be in order. Older donors at hospitals close to the recipient hospital, as well as recipients with less comorbidity, ideally should be considered to optimize survival in the recipients of hearts from older donors. More aggressive efforts to prevent infections in the post-transplant period may also be beneficial to recipients of older-donor hearts. Cardiac allograft rejection by itself was not increased in recipients of hearts from older donors, and one would not expect this to be the case because rejection is determined by the response of the immune system of the recipient to the alloantigens of the donor. There is no evidence that hearts from older donors are less likely to express alloantigens.
Intriguingly, the development of cardiac allograft vasculopathy, generally defined angiographically, was greater in the recipients of hearts from older donors than in the recipients of hearts from younger donors. The relationship of donor age to the development of cardiac allograft vasculopathy has not been clearly defined. There are single-center studies that indicate that the risk of this disease is not increased using hearts from older donors, but multi-institutional studies, such as from the Cardiac Transplant Research Database (CTRD), have suggested that the risk is greater for the development of cardiac allograft vasculopathy in recipients of hearts from older donors (1,8,9). This, in fact, may be a reflection of age-related endothelial dysfunction, which has been observed in nontransplant recipients. Although the present study is also from a single center, given the very large size of the patient cohort studied, as well as the careful statistical analysis, it does appear that this work confirms that in the multi-institutional study that donor age does increase the risk for cardiac allograft vasculopathy. Tuzcu et al. (10) have defined the normal intimal thickness using a surrogate marker of adverse vascular remodeling and endothelial damage in newly transplanted patients. They found that maximal intimal thickness does increase with increasing age of donors as defined by intravascular ultrasound.
Another potential explanation for the increased likelihood of development of cardiac allograft vasculopathy is the etiology of brain death in the donor. Mehra et al. (11) have shown that more explosive causes of brain death may result in significant damage to the heart while in the donor and that this may result in endothelial damage and subsequently in cardiac allograft vasculopathy. If one looks at the etiology of brain death in the donors, in fact, head trauma, which would be a more abrupt cause of brain death, was less likely to occur in donors older than 40 years of age. This indicates that this potential mechanism would not be operative as a cause for the increases in cardiac allograft vasculopathy in those receiving donor hearts from older patients. The fact that cardiac allograft vasculopathy did not increase past the first year after transplant is not entirely surprising because several investigators have shown that most of the development of allograft vasculopathy is within the first years after transplant (12).
It is clear that these potential risks in older donors should not in any way dissuade transplant cardiologists and surgeons from using these hearts in sick Status 1 patients because the survival using these hearts is still significantly better than if these patients are allowed to wait longer on the transplant list or, in fact, if they make it to transplant. There is a potential problem with this analysis in that there may be additional reasons that would prevent patients from undergoing cardiac transplantation, such as intermittent episodes of infections or other comorbidities, and that the population that was not transplanted may, in fact, have contributors to their poor mortality that transplantation alone may not have alleviated. Nonetheless, the use of these hearts in appropriately selected patients who are critically ill and are Status 1 would certainly be indicated. In contrast, the use of hearts from older donors does not appear to be improve survival in the less sick patients, such as the Status 2 patients, and therefore cannot really be justified. In fact, one can argue that using these hearts should be reserved for the sicker populations, such as the Status 1 patients, who are at higher risk of poor outcomes.
Furthermore, efforts should be made to minimize additional risks, such as reducing donor ischemic time, by using more local donors in these selected patients and aiming for elimination of other comorbidities. It is possible that even longer follow-up on the order of a decade or more might have revealed increased major adverse cardiac events and diminished survival as the result of this increase in cardiac transplant vasculopathy. The fact that angiography was used to define the disease does raise some questions as to whether, in fact, the extent of disease both in the patients receiving the older donor hearts and those who received younger donor hearts may in fact have underestimated the disease. If intravascular ultrasound was used routinely, this might have either shown a greater difference between the recipients of older-donor hearts and those of younger-donor hearts. This would appear to be likely in light of the results regarding the presence of increased maximal intimal thickness in older-donor hearts just after transplant.
The newer therapies available to prevent rejection are proliferation or mammalian target of rapamycin (mTOR) inhibitors, which have been associated with reduction in both incidence and severity of cardiac allograft vasculopathy as determined intravascular ultrasound one year after transplant (13). This may offer the opportunity to potentially reduce the extent of cardiac allograft vasculopathy and would particularly beneficial to patient populations at higher risk for the development of cardiac allograft vasculopathy, such as those who receive hearts from older donors. This would be a patient population that should be started early on with mTOR inhibitors, such as sirolimus or everolimus.
There are several unanswered questions that remain regarding the outcomes of using hearts from older donors. In particular, the exact relationship of using older-donor hearts to the poor survival observed within the first month after transplant is still not clearly defined. Furthermore, the exact extent of the cardiac allograft vasculopathy is not known because intravascular ultrasound was not used to define the presence of cardiac allograft vasculopathy. In addition, the fact that cardiac allograft vasculopathy was not associated with an increase in mortality beyond the first 30 days after transplant raises the question as to whether the extent of cardiac allograft vasculopathy has any relationship as defined in the study to major adverse cardiac events or is a purely an epiphenomenon. These answers will have to wait further studies using intravascular ultrasound as well as the newer immunosuppressive agents and efforts to minimize potential comorbidities that can diminish survival in the early post-transplant period.
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Footnotes
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Supported by a grant from the American Heart Association National Center.
* editorials published in the journal of the american college of cardiology reflect the views of the authors and do not necessarily represent the views of jacc or the american college of cardiology. 
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References
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