TRANSPLANT MEDICINE FACES NEW CHALLENGES
The profiles of donors and recipients have changed fundamentally in recent years: The increasing numbers of patients with MCS prior to a heart transplant put extreme demands on the surgical site in terms of preparation and postoperative management.
Changes in the donor’s cause of death reflect a shift from traumas to ischaemic brain injuries due to safety improvements, triggering a rise in donor age at the time of donation [55].
The rising donor age in recent decades—especially in Europe—is associated with more comorbidities and less-than-ideal graft quality (Fig. 6) [8]
Figure 6:  Adult and paediatric heart transplants according to median donor age by location and year. Reprinted with permission from Ref. [8].

Current developments in transplants: cardiac allocation score
Creating a more just system for and clarifying the risks of a patient’s prospects for success in heart allocation (with the lung-allocation score being a good example of a suitable system [56]) has long been discussed. Sufficient long-term experience with MCS is still lacking, and satisfactory data from databases are only just beginning to be available. There are no substantiated scoring systems available that are capable of estimating device-related complications. Because of this gap in knowledge, it is impossible to balance the risk-benefit ratio of patients with MCS awaiting a heart transplant against those without MCS. So, use of a VAD might currently be deemed to be responsible for a lower status on the waiting list and therefore worse organ allocation. These problems need to be solved by creating a suitable scoring system for the allocation of hearts.

Current developments in transplants: expanding the donor pool by early donor management
Expansion of the existing donor pool is crucial and includes early donor identification and comprehensive care and diagnostics prior to selecting hearts acceptable for transplant. Early donor management by scouting teams can contribute to higher organ utilization rates with comparable transplant results. In existing programmes, allocated implant centres send specialized medical staff to the possible donor and guide further diagnosis and treatment until a final decision is made about the suitability of the organ donation [57].

Current developments in transplants: ex vivo graft perfusion
Facing increasing donor ages, all means must be undertaken to assess donated hearts as thoroughly as possible. New preservation technology [Organ Care System® (OCS), TransMedics, Andover, MA, USA] has been introduced to reduce ischaemic damage to the graft and enable further examination. This commercially available device preserves the heart in an ex vivo beating, perfused, normothermic and oxygenated state (Video 1). Although longer ischaemia times worsen prognosis [8], this device can contribute to consistent outcomes or to an expanded donor pool. The PROCEED-II trial (Randomized Study of Organ Care System Cardiac for Preservation of Donated Hearts for Eventual Transplantation), a randomized study, demonstrated non-inferiority in the OCS intention-to-treat group compared to standard cold-ischaemic preservation [58]. After receiving clinical approval due to the PROCEED-II trial’s findings, other investigators confirmed a favourable outcome in conjunction with OCS use in unfavourable donor–recipient constellations [59, 60]. Ex vivo preservation is also a significant chance in marginal organ selection to enable a post-mortem examination (e.g. using coronary angiography) and to evaluate metabolism, oxygen saturation, aortic pressure and coronary blood flow as surrogate parameters for good graft status. Furthermore, the application delivers valuable time for the transplant team to expand transport distances or use time for difficult situs preparation (e.g. explantation or preparation of MCS after several previous operations in adult patients with congenital heart defects). In addition, an economic benefit became apparent with a shorter period of ischaemia [61].
Video 1:  During a training session, a porcine heart after harvesting and preparation is connected via the aorta to the ex-vivo perfusion device (Organ Care System®, TransMedics, Andover, MA, USA) and perfused with autologous blood. After 20 seconds of reperfusion, the heart starts beating and will be secured for clinical and biochemistry assessment.

Current developments in transplants: donation after circulatory death
Since the first human heart transplant [42], declaring death prior to organ procurement had historically been based on the cessation of circulation. However, following the subsequent increase in the discussions about death criteria, later heart transplants were not carried out until the death of the donor’s brain had been verified using a previously accepted definition of brain death [62]. The current shortage of organs forced the revitalization of the method of donation after circulatory death (DCD) because some dying patients will never meet formal brain death criteria. The Maastricht agreement defined 5 categories based on the circumstances of the cardiac arrest, of which only selected cohorts can lead to DCD donations [63]. Once cardiac function has ceased and death has been declared, the heart must be retrieved as soon as possible. Unlike procurement after brain death, there is perforce a period of cardiac ischaemia and ventricular distention that can compromise the vitality of the organ after removal and that was the source of initial concern regarding the vitality of DCD hearts after retrieval [64]. Ex vivo perfusion and/or normothermic regional perfusion may guarantee graft metabolism and function and ensure post-transplant function [65, 66]. Early outcome of a DCD heart transplant is apparently comparable with outcomes with a transplant from a donation after brain death [67], and thus DCD programmes have contributed to greater transplant activity in some regions [68, 69]. Whether the DCD programme can be successfully implemented worldwide remains to be seen: although some countries successfully perform transplants in compliance with the DCD, the German Medical Association declared in 1998 that organ procurement and transplants in Germany may not follow the DCD criteria because they do not fulfil the strict German ethical end-of-life guidelines.

Current developments in organ transplants: transplants incompatible with the ABO blood group
The ABO blood group-antigen system is based on carbohydrate epitopes present on different core saccharide chains that are bound to lipids (glycolipids) or to proteins (glycoproteins) and that form in early childhood. Because the ABO-antigen system is always present on the cell surface, it plays a central role in solid organ transplants due to its capacity to induce rejection [70]. Compatibility between the donor’s and the recipient’s ABO alloantigens has long been required, and an ABO-incompatible heart transplant was absolutely contradicted in adults. However, acceptable ABO-incompatible abdominal transplant outcomes—especially renal transplants [71]—in adult patients and advances in ABO-incompatible heart transplants in paediatric patients [72, 73] have led to discussions about the potential for adult ABO-incompatible heart transplants to expand the donor pool. In a recent registry study, Bergenfeldt et al. [74] demonstrated no difference in the incidence of deaths or retransplants between ABO-compatible and ABO-incompatible heart transplants in a transplant collective after 2005. However, ABO-incompatible transplants remain exceptional and are severely restricted to individual decisions due to non-standardized immunosuppression protocols, a high-risk rejection constellation and the unknown long-term prognosis.

Current developments in transplants: xenotransplants
Due to the scarcity of cardiac donors and the long waiting lists for heart transplants in many countries, the alternative of using xenografts has been explored for several years. The obviously most difficult limitation of using xenografts is the accelerated rate of rejection. Few, but very active, research groups focus on strategies to overcome the cross-species-derived rejection. Thus, genetically modified pig hearts were successfully transplanted into baboons using a modified preservation and immunosuppression protocol with an excellent 90-day survival rate with no signs of rejection [75]. This promising approach with xenotransplants must acquire further basic knowledge and long-term data before it can be tested further via large clinical examinations and human trials [76]. Comparing the major treatment options for end-stage heart failure from a future perspective, we believe that in the coming 10 years MCS will further improve and precise risk prediction can discriminate better candidates for heart transplants or MCS, hopefully. It is likely that treatment with an allograft heart transplant will be reserved for those patients who would profit the most from the donor heart in terms of the likelihood for long-term survival, such as young and otherwise healthy recipients. It is possible that a xenotransplant will be a clinical option in 10 years and that the indications for heart transplant and MCS might be discussed differently at that point.