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Conditions to which the cardiac graft is exposed during transplantation with donation after circulatory death (DCD) can trigger the recruitment of macrophages that are either unpolarized (M0) or pro‐inflammatory (M1) as well as the release of extracellular vesicles (EV). We aimed to characterize the effects of M0 and M1 macrophage‐derived EV administration on post‐ischaemic functional recovery and glucose metabolism using an isolated rat heart model of DCD. Isolated rat hearts were subjected to 20 min aerobic perfusion, followed by 27 min global, warm ischaemia or continued aerobic perfusion and 60 min reperfusion with or without intravascular administration of EV. Four experimental groups were compared: (1) no ischaemia, no EV; (2) ischaemia, no EV; (3) ischaemia with M0‐macrophage‐dervied EV; (4) ischaemia with M1‐macrophage‐derived EV. Post‐ischaemic ventricular and metabolic recovery were evaluated. During reperfusion, ventricular function was decreased in untreated ischaemic and M1‐EV hearts, but not in M0‐EV hearts, compared to non‐ischaemic hearts (p < 0.05). In parallel with the reduced functional recovery in M1‐EV versus M0‐EV ischaemic hearts, rates of glycolysis from exogenous glucose and oxidative metabolism tended to be lower, while rates of glycogenolysis and lactate release tended to be higher. EV from M0‐ and M1‐macrophages differentially affect post‐ischaemic cardiac recovery, potentially by altering glucose metabolism in a rat model of DCD. Targeted EV therapy may be a useful approach for modulating cardiac energy metabolism and optimizing graft quality in the setting of DCD.

Biological sex affects cardiac tolerance to ischemia and reperfusion, but little is known about sex differences in heart transplantation with donation after circulatory death (DCD). Using a rat model, we characterized differences between sexes both in the donor, during simulated DCD, and in the procured heart, to evaluate recovery upon reperfusion. Adult male, female and ovariectomized Wistar rats underwent simulated DCD with 22 min of warm, in-situ ischemia. Hearts were then explanted and maintained in cold static storage for 30 min. Isolated hearts then underwent normothermic, oxygenated reperfusion for 60 min with left ventricular loading. In-situ characteristics, as well as ventricular function, coronary flows and metabolic post-ischemic recovery were assessed. Post-ischemic ventricular recovery was significantly higher in female compared to male and ovariectomized hearts. Furthermore, several in-situ circulating factors, including free fatty acids and potassium, were significantly lower in females compared with males. Greater post-ischemic ventricular function in female vs. male and ovariectomized hearts following DCD indicates that sex affects tolerance to DCD conditions and that female sex hormones contribute to cardioprotection. Greater understanding of sex-specific tolerance to DCD conditions may serve as a basis to better define precise mechanisms of cardiac injury and thereby contribute to optimizing clinical protocols.

Heart transplantation with donation after circulatory death (DCD) provides excellent patient outcomes and increases donor heart availability. However, unlike conventional grafts obtained through donation after brain death, DCD cardiac grafts are not only exposed to warm, unprotected ischemia, but also to a potentially damaging pre-ischemic phase after withdrawal of life-sustaining therapy (WLST). In this review, we aim to bring together knowledge about changes in cardiac energy metabolism and its regulation that occur in DCD donors during WLST, circulatory arrest, and following the onset of warm ischemia. Acute metabolic, hemodynamic, and biochemical changes in the DCD donor expose hearts to high circulating catecholamines, hypoxia, and warm ischemia, all of which can negatively impact the heart. Further metabolic changes and cellular damage occur with reperfusion. The altered energy substrate availability prior to organ procurement likely plays an important role in graft quality and post-ischemic cardiac recovery. These aspects should, therefore, be considered in clinical protocols, as well as in pre-clinical DCD models. Notably, interventions prior to graft procurement are limited for ethical reasons in DCD donors; thus, it is important to understand these mechanisms to optimize conditions during initial reperfusion in concert with graft evaluation and re-evaluation for the purpose of tailoring and adjusting therapies and ensuring optimal graft quality for transplantation.

The machine perfusion (MP) of transplantable grafts has emerged as an upcoming field in Cardiothoracic (CT) transplantation during the last decade. This technology carries the potential to assess, preserve, and even recondition thoracic grafts before transplantation, so it is a possible game-changer in the field. This technology field has reached a critical turning point, with a growing number of publications coming predominantly from a few leading institutions, but still need solid scientific evidence. Due to the increasing need to expand the donor pool, especially in Europe, where the donor age is steeply increased, a consensus has been established to address the growing need and knowledge of machine perfusion in cardiothoracic transplantation, targeting the unmet scientific need in this growing field but also, priorities for development, and regional differences in utilization rates and organizational issues. To address MP in CT, the European Society of Organ Transplantation (ESOT) convened a dedicated Working group comprised of experts in CT to review literature about MP to develop guidelines that were subsequently discussed and voted on during the Consensus Conference that took place in person in Prague during the TLJ 3.0 in November 2022. The findings and recommendations of the Cardiothoracic Working Group on MP are presented in this article.

Ex situ heart perfusion (ESHP) was developed to preserve and evaluate donated hearts in a perfused beating state. However, myocardial function declines during ESHP, which limits the duration of perfusion and the potential to expand the donor pool. In this research, we combine a novel, minimally-invasive sampling approach with comparative global metabolite profiling to evaluate changes in the metabolomic patterns associated with declines in myocardial function during ESHP. Biocompatible solid-phase microextraction (SPME) microprobes serving as chemical biopsy were used to sample heart tissue and perfusate in a translational porcine ESHP model and a small cohort of clinical cases. In addition, six core-needle biopsies of the left ventricular wall were collected to compare the performance of our SPME sampling method against that of traditional tissue-collection. Our state-of-the-art metabolomics platform allowed us to identify a large number of significantly altered metabolites and lipid species that presented comparable profile of alterations to conventional biopsies. However, significant discrepancies in the pool of identified analytes using two sampling methods (SPME vs. biopsy) were also identified concerning mainly compounds susceptible to dynamic biotransformation and most likely being a result of low-invasive nature of SPME. Overall, our results revealed striking metabolic alterations during prolonged 8h-ESHP associated with uncontrolled inflammation not counterbalanced by resolution, endothelial injury, accelerated mitochondrial oxidative stress, the disruption of mitochondrial bioenergetics, and the accumulation of harmful lipid species. In conclusion, the combination of perfusion parameters and metabolomics can uncover various mechanisms of organ injury and recovery, which can help differentiate between donor hearts that are transplantable from those that should be discarded.

Heart transplantation remains the ultimate treatment strategy for neonates and children with medically refractory end-stage heart failure and utilization of donors after circulatory death (DCD) can expand th donor pool. We have previously shown that mitochondrial transplantation preserves myocardial function and viability in neonatal swine DCD hearts to levels similar to that observed in donation after brain death (DBD). Herein, we sought to investigate the transcriptomic and proteomic pathways implicated in these phenotypic changes using ex situ perfused swine hearts. Pathway analysis showed that ATP binding, voltage-gated K channel activity involved in cardiac cell muscle contraction and ribosomal RNA biogenesis were upregulated in the mitochondrial transplantation group, while mitochondria were the predicted source. Promotion of ribosome biogenesis and downregulation of apoptosis were the overlapping mechanisms between transcriptomic and proteomic alterations. Moreover, we showed that mitochondrial transplantation modulates ischemic transcriptomic and proteomic profiles to that of non-ischemia through the mitochondria. Replication of these findings in human in vivo experiments is warranted.

Heart transplant for adults following Donation after Circulatory Death (DCD) is well established in many parts of the world, including the United Kingdom (UK). Small child DCD hearts have now been recovered in the UK and internationally utilising novel technologies. Despite these recent advances, extension of this practice to pediatric cardiac transplantation has been slow and difficult despite the severe shortage of donors for children leading to a high number of deaths annually of children waiting for heart transplant. This is in direct contrast with the thriving UK programme of adult DCD heart transplant and pediatric DCD donation for non-cardiac organs. There has been insufficient action in addressing this inequality thus far. Barriers to development of a pediatric cardiac DCD programme are multifaceted: ethical concerns, technological paucity, financial and logistical hurdles. We describe the background, live issues, current developments and how we are driving resources toward a sustainable DCD programme for small children in the UK to provide valuable insights to other countries of the elements and principles at play. This is a call to responsible bodies to take urgent and achievable actions to establish an equitable paediatric DCD cardiac programme for donors, recipients and their families.

Normothermic ex-situ heart perfusion (ESHP) enables assessment of hearts donated after circulatory death (DCD) prior to transplantation. However, sensitive parameters of cardiac function of DCD hearts on ESHP are needed. This study proposes a novel approach using electrophysiological (EP) parameters derived from electrical mapping as biomarkers of post-ischemic cardiac performance. Porcine slaughterhouse hearts (PSH) were divided in two groups based on the type of warm ischemia (Group 1: 10 ± 1 min with animal depilation vs. Group 2: ≤5 min without depilation). Electrical mapping of the right (RV) and left ventricle (LV) was performed on ESHP. Potential voltages, slopes and conduction velocities were computed from unipolar electrograms and compared between groups. Voltages were lower in Group 1 compared to Group 2 (RV: 3.6 vs. 15.3 mV, p = 0.057; LV: 10.8 vs. 23.6 mV, p = 0.029). In addition, the percentage of low-voltage potentials was higher and potential slopes were flatter in Group 1. Voltages and slopes strongly correlated with the visual contractile performance of PSH, but showed weaker correlation with lactate profiles. In conclusion, unipolar potential voltages and potential slopes were decreased in hearts with severe warm ischemia. As such, EP parameters could aid transplantation teams in decision-making on transplantability of DCD hearts.

Orthotopic heart transplantation is the gold standard treatment for end-stage heart failure. However, the persistent shortage of available donor organs has resulted in an ever-increasing waitlist and longer waiting periods for transplantation. On the contrary, increasing the number of heart transplants by preserving extended criteria donors and donation after circulatory death hearts with the Organ Care System™ (OCS) Heart System has the potential to provide the gold standard, life-saving treatment to patients with end-stage heart failure. The objective of the Donation After Circulatory Death Heart Trial is to evaluate the effectiveness of the OCS Heart System to preserve and assess hearts donated after circulatory death for transplantation to increase the pool of donor hearts available for transplantation, which can potentially provide patients with end-stage heart failure with the life-saving treatment. Clinical Trial Registration: NCT03831048 ( )

Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.