EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: In heart failure patients, heart transplant still remains the gold standard of care. Controversy prevails whether organs from older donors or with expected prolonged ischemia times may be accepted for transplant.

Materials and Methods: Between 2010 and 2020, a total of 149 patients underwent heart transplant at our department. In a retrospective analysis, 4 different groups were defined according to donor age and total ischemia time. The younger group with short ischemia time consisted of 62 donors age < 50 years and total ischemia time < 240 minutes; the younger group with long ischemia time consisted of 32 donors age < 50 years and total ischemia time ≥ 240 minutes; the older group with short ischemia time consisted of 43 donors age ≥ 50 years and total ischemia time < 240 minutes; and the older group with long ischemia time consisted of 12 donors age ≥ 50 years and total ischemia time ≥ 240 minutes.

Results: Prolonged total ischemia time increased the risk of primary graft dysfunction (P = .02) and perioperative neurological events (P = .04). In contrast, there were no differences regarding durations of intensive care unit stay and hospital stay, perioperative bleeding, and renal failure. Although the younger donor age group showed excellent short-term survival (30-day survival rates of 97% for the younger group with short ischemia time and 91% for the younger group with long ischemia time), short-term and mid-term survival rates were impaired in patients with prolonged total ischemia time and older donor age (P = .02).

Conclusions: Our results indicate that, in younger donors, prolonged ischemia times may be acceptable. However, in donors older than 50 years, the decision for acceptance as a donor should be made with great caution if the presumed ischemia time exceeds 4 hours.

Key words : Heart failure, Marginal organ, Primary graft dysfunction

Congestive heart failure is a major cause of global morbidity and mortality.¹ As recommended by current guidelines, orthotopic heart transplant (HTx) represents the best treatment option for end-stage heart failure.^2,3 Although the outcome after HTx is still improving, with a median survival now exceeding 12 years, the overall transplant volume has stagnated.4 This is partly the result of a global shortage of donor organs.^4,5 As a consequence, the number of patients on the wait list for HTx is more than twice the number of performed transplants in the Eurotransplant area.⁶ With a median wait time of more than 6 months, about 200 patients on the Eurotransplant wait list die each year.⁶ Thus, a rising number of so-called “marginal donor organs” must be considered for acceptance.^7,8 These are organs from elderly donors or donors with a history of cardiopulmonary resuscitation, infectious diseases, or drug addiction, as well as organs with expected prolonged total ischemia times (TIT).⁹ To achieve acceptable results, a profound knowledge of these marginal organs is required to facilitate rigor in the selection of a specific donor organ for a certain patient on the wait list.⁹ Donor age and TIT of the organ are 2 potential parameters that may help to increase the donor pool.^8,10-14 Presently, there remains a lack of evidence as to whether certain age profiles or ischemia time ranges may affect outcomes after HTx.^8,10-14 Although some studies showed comparable outcomes for donors older than 50 years, others reported an increased risk for morbidity and mortality.^8,10-15

Therefore, our goal was to further strengthen the knowledge about the effects of donor age and TIT on the outcome after HTx. We compared patients who received donor organs from donors of different ages and with different ischemia times. We analyzed perioperative data as well as short-term and mid-term outcomes in a 10-year study period.

Materials and Methods

Ethical approval
This study was performed in accordance with the principles of the Declaration of Helsinki and was approved by our local university ethics committee. All patients gave their written informed consent before inclusion in the study.

Patients and study design
Between 2010 and 2020, all patients undergoing orthotopic HTx in our department (n = 149) were prospectively entered into an institutional database and continuously followed. For the purposes of this study, patient data were retrospectively reviewed and divided into 4 groups with regard to donor age (< 50 years, ≥ 50 years) and TIT (< 240 minutes, ≥ 240 minutes) of the donor heart (Figure 1).

Study objectives and follow-up period
All recipient and donor parameters were analyzed and compared among the 4 different study groups. Intraoperative data and information about early postoperative morbidity and mortality were evaluated. Follow-up examinations of the study cohort were performed on a regular basis with a mean follow-up period of 1381 days and a maximum follow-up time of 3427 days.

Statistical analyses
We used SPSS Statistics version 26 (IBM Corporation) and Prism 6 (GraphPad Software) software to perform the statistical analyses. Dichotomous variables were compared by 2-tailed Fisher-Freeman-Halton tests. Continuous results were analyzed by Kruskal-Wallis tests. Statistically significant results (P < .05) were further analyzed with post hoc pairwise comparisons by the Fisher exact test or Bonferroni correction, respectively. Survival analysis was performed by the Kaplan-Meier method and compared by the log-rank (Mantel-Cox) test. All results are presented as mean values with the standard deviation or percentage of the whole.

Donor parameters
A total of 149 patients who underwent transplant between 2010 and 2020 were enrolled in the study (62 younger donors with short ischemia time [YS group]; 32 younger donors with long ischemia time [YL group]; 43 older donors with short ischemia time [OS group]; and 12 older donors with long ischemia time [OL group]). No patient was listed for retransplant to mitigate a previous graft failure. Patients were distributed equally to the different groups within the 10-year period regarding the inclusion time to the study. Characteristics of the donors are shown in Table 1. Donor age of the YS group versus the YL group and the OS group versus the OL group did not differ significantly. Because of the study design, there was a significant difference in donor age (P < .01). The younger donors were more likely to be drug addicted. In addition, body mass index (calculated as weight in kilograms divided by height in meters squared) of YL donors and YS donors was significantly lower compared with respective values of the OL group. In contrast, there was no difference between the OL group and the OS group with regard to body mass index. All other donor parameters were comparable among the 4 different groups.

Recipient preoperative characteristics
Most baseline parameters of HTx recipients were comparable among the 4 groups (Table 2). Nonetheless, a few parameters differed. First, there were significantly more patients with high-urgency status in the YL group than in the OS group (P < .01). Furthermore, there was a difference regarding the incidence of preoperative cardioverter-defibrillator implants. Finally, there was also a significantly increased incidence of diabetes in the YL group compared with the YS group (P < .01). The remaining parameters, especially the incidence of implanted preoperative ventricular assist devices, cardiopulmonary resuscitation, extracorporeal life support, mechanical ventilation, and hemodialysis and diabetes, did not show any significant intergroup differences.

Ischemia and operation time
Average TIT was significantly longer in the YL group and the OL group compared with the YS and OS groups (P < .01) (Table 3). There was no difference between the YS and OS groups (P = .28) and the YL and OL groups (P = .99). According to our protocol, organs with prolonged TIT underwent longer reperfusion times, and therefore patients in the YL and OL groups had longer cardiopulmonary bypass times compared with the other groups (Table 3).

Early perioperative morbidity and mortality
Data on perioperative morbidity and mortality are shown in Table 4. The duration of postoperative mechanical ventilation and duration of intensive and intermediate care unit stay, as well as duration of overall postoperative hospital stay, did not differ among the 4 different groups, although there was a trend toward longer ventilation times in the YL group (P = .07). However, there was a significant difference regarding the incidence of primary graft dysfunction requiring temporary mechanical circulatory support (P = .02). Although only 26% of the recipients with TIT of less than 240 minutes needed postoperative extracorporeal life support (ie, venoarterial extracorporeal membrane oxygenation [va-ECMO]), a high incidence of need for va-ECMO was observed in 44% (YL group) and 67% (OL group) of patients with TIT of at least 240 minutes. Post hoc pairwise analyses showed significantly increased incidence in the OL group compared with both the YS group and the OS group (P < .01 each). These findings were also observed regarding the incidence of perioperative neurological events. Patients in the OL group had the highest incidence of transient ischemia attack and stroke (42%), which was significantly increased compared with the YS group (13%, P = .03) or the OS group (12%, P = .03) but not significantly increased compared with the YL group (28%, P = .48). In contrast to that, there were no differences in incidences of delayed chest closure, reexploration for bleeding, renal failure, primary allograft rejection, and severe infections.

Early survival rate was highest in patients in the YS group (97% at 30 days and 92% at 1 year), which was significantly higher than for the other groups (Table 4).

Survival analyses
All patients received regular follow-up examinations (every 3-6 months) during the entire study period, with mean follow-up time of 1381 days and maximum follow-up time of 3427 days. Patients were censored at the end of the study period. Figure 2 shows the Kaplan-Meier survival curves of the 4 different study groups. The log-rank test showed significant differences concerning survival after HTx among the different study groups (P = .02). Patients with young donors and short TIT (YS group) presented the best survival rates followed by patients with young donors and long TIT (YL group). In contrast, recipients of donor hearts from donors of 50 years and older experienced an impaired long-term survival. Especially in patients in the OL group, survival rates after transplant were substantially impaired. Pairwise post hoc log-rank analysis revealed a significantly decreased survival rate in the OS group (P = .01) and the OL group (P = .04) compared with the YS group, but no significant differences were shown between the YS group and the YL group (P = .10). Interestingly, in a direct comparison of survival rates, patients in the YL group showed no significant benefit compared with recipients in the YS group (P = .22) or the OL group (P = .47). Moreover, there was no difference in survival rates between the OS group and the OL group (P = .96) (Figure 2).

This study was designed to shed a light on the effects of donor age and ischemia time on outcomes after HTx. The motivation for this study is the increased clinical demand for expanding the donor organ pool in times of organ shortages, which is particularly urgent in some European countries, such as Germany. We analyzed data from our center comprising 149 transplant patients over a 10-year period. Patient outcome measures were subjected to statistical analyses that compared 4 different subcohorts defined by either young or old donor age, as well as short or long TIT. We found a significant impairment of outcomes for older donors compared with younger donors, especially for donors ≥ 50 years old in combination with TIT > 240 minutes.

Other than age, there were few differences in donor features among the 4 different study groups. In particular, parameters like previous cardiopulmonary resuscitation of the donor, left ventricular ejection fraction, comorbidities, and laboratory values did not differ. In addition, preoperative data of the recipients were also comparable.

The data presented here demonstrate that prolonged TIT in the YL group and the OL group was caused by longer cold ischemia time as well as warm ischemia times, but differences in cold ischemia time were predominant and the duration of the warm ischemia time was comparable to data reported previously.^16,17 Extended cold ischemia time has been shown to decrease the early ventricular function and is associated with primary graft dysfunction, contributing to increased mortality after HTx.^17-19 Warm ischemia time has an even higher negative effect on graft function and further increases the risk of early mortality.^16,17As a consequence, in our cohort, reperfusion time and overall cardiopulmonary bypass time were increased in the YL and OL groups compared with the YS and OS groups. The duration of cardiopulmonary bypass has also been identified to be associated with impaired outcomes after HTx.²⁰ Similar to this, the incidence of primary graft dysfunction requiring mechanical circulatory support was increased in the YL group and the OL group, with significantly higher incidence of postoperative va-ECMO in the OL group compared with the YS and OS groups. These data support previous findings that TIT is associated with primary cardiac graft dysfunction and that donor age may further aggravate primary organ dysfunction. Nicoara and colleagues²¹ described identical effects for ischemia time on the incidence of primary graft dysfunction but did not find any correlation with donor age. In contrast to that, Avtaar Singh and colleagues²² suggested that the risk of primary graft dysfunction may be multifactorial, with both donor age and ischemia time representing contributing factors, which agrees with our results presented here. To address primary graft dysfunction, we promote a liberal protocol in our center with early implantation of va-ECMO to support the patient.²³ Therefore, the rate of va-ECMO implantation may appear large compared with other centers, although its use can achieve low mortality and good results.^24,25

Perioperative complications such as renal failure, allograft rejection, or infection were not related with donor age and ischemia time, which is in agreement with contemporary reports.^11,12 However, in our cohort, the incidence of perioperative neurological events was increased in the OL group compared with the YS and OS groups, respectively. We speculate that this finding may be related to the significantly higher incidence of extracorporeal life support in this group,26 although current evidence to prove this remains scarce.

The 30-day survival rate was significantly increased in patients with grafts from younger donors in combination with short TIT compared with the outcome shown in subgroups with donors of 50 years or older, regardless of TIT. At 1-year follow-up, there was also a significant disadvantage for recipients of younger donors with prolonged TIT compared with those with short ischemia time. These results support the assumption that both donor age and TIT have important effects on early mortality and late survival after HTx.^15,27

Survival analyses with the log-rank Mantel-Cox test and Kaplan-Meier method revealed 3 important results: First, outcomes in patients with grafts from older donors was significantly impaired compared with outcomes in younger donors. Simultaneously, prolonged graft ischemia can further contribute to mortality and worsen the outcome after HTx. Additionally, grafts from younger donors seemed capable to sustain longer TIT with good results. As a consequence, to achieve and maintain good results after HTx, it appears advisable to tolerate either older donor age or a prolonged TIT but inadvisable to tolerate the combination of both factors.^10,12,27 Nonetheless, considering the high mortality of patients on the wait list, the acceptance of heart offers from older donors or donors with expected prolonged TIT may still improve the prognosis in selected patients with a particular instability while awaiting HTx. Consequently, such donor organ acceptance should always be considered but performed in a patient-specific manner.²⁸

In our center, we do not use normothermic or hypothermic machine perfusion of the donor heart during retrieval and transport. There remains a lack of evidence with regard to the potential benefits of machine perfusion for the long-term outcome after HTx, especially for brain-death-determined donors, as organ recovery is not allowed after circulatory-determined death in Germany.^29,30 In addition, lack of reimbursement is another reason why machine perfusion systems are currently not widely established in Germany. Nonetheless, machine perfusion to reduce graft ischemia may play an important role in the future.³¹

Limitations
The present study is limited by its single-center design and the limited number of enrolled patients. Because of the relatively short-to-medium follow-up period of the patients, the disproportional high 1-year mortality after HTx is overrepresented in the survival analysis, which limits the statistical power of the Kaplan-Meier curves. In addition, the small size of the different subgroups further increases this statistical problem. As we continuously follow our patients, data from longer observation periods will become accessible in the future, possibly providing novel insight into long-term outcomes of the patients studied herein. Nevertheless, the presented data clearly demonstrate significant donor-organ-related differences in the perioperative morbidity and the mid-term survival of the recipients.

Heart transplant offers the best treatment option for end-stage heart failure patients. Unfortunately, severe organ shortages threaten the lives of patients on the wait list. To extend the organ pool, an increasing number of marginal organs are accepted. Our findings indicate that organs from younger donors will tolerate prolonged ischemia times with good operative outcomes. Furthermore, organs of donors exceeding 50 years of age may still achieve acceptable results. However, it is important to reduce the TIT of these organs to a minimum. Organs of older donors with prolonged ischemia times are correlated to a higher risk for perioperative morbidity and cause significantly impaired postoperative survival rates. Therefore, these organs should be selected wisely and allocated carefully to preserve good postoperative outcomes.

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