Cardiocirculatory Death Research Articles

The role of Neuregulin-1 in steatotic and non-steatotic liver transplantation from donors after cardiocirculatory death

Liver grafts from donors after cardiocirculatory death (DCDs) are sometimes not considered for liver transplantation (LT). Plasma Neuregulin-1 (NRG1) is altered in cardiac abnormalities and the liver is one of the most important targets of NRG1. We study the role of NRG1 in DCD LT. Under these conditions, NRG1 was pharmacologically modulated and their pathways were characterized. NRG1 levels were increased in steatotic and non-steatotic grafts from DCDs; NRG1 was derived from adipose tissue. When NRG1 was inhibited, injury and inflammation were exacerbated. The benefits of endogenous NRG1 in DCD grafts were associated with increased hepatic accumulation of adipocyte-derived vascular endothelial growth factor-A (VEGFA). The Id1-Wnt2 signaling pathway was involved in the action mechanisms of endogenous VEGFA. Exogenous NRG1 exacerbated damage and inflammation. Here differential role of NRG1 (endogenous versus exogenous) was demonstrated and VEGFA treatment was proposed as a highly protective strategy in steatotic and non-steatotic DCD LT.

Benefits of Living Over Deceased Donor Kidney Transplantation in Elderly Recipients. A Propensity Score Matched Analysis of a Large European Registry Cohort.

Although kidney transplantation from living donors (LD) offers better long-term results than from deceased donors (DD), elderly recipients are less likely to receive LD transplants than younger ones. We analyzed renal transplant outcomes from LD versus DD in elderly recipients with a propensity-matched score. This retrospective, observational study included the first single kidney transplants in recipients aged ≥65years from two European registry cohorts (2013-2020, n = 4,257). Recipients of LD (n = 408), brain death donors (BDD, n = 3,072), and controlled cardiocirculatory death donors (cDCD, n = 777) were matched for donor and recipient age, sex, dialysis time and recipient diabetes. Major graft and patient outcomes were investigated. Unmatched analyses showed that LD recipients were more likely to be transplanted preemptively and had shorter dialysis times than any DD type. The propensity score matched Cox's regression analysis between LD and BDD (387-pairs) and LD and cDCD (259-pairs) revealing a higher hazard ratio for graft failure with BDD (2.19 [95% CI: 1.16-4.15], p = 0.016) and cDCD (3.38 [95% CI: 1.79-6.39], p < 0.001). One-year eGFR was higher in LD transplants than in BDD and cDCD recipients. In elderly recipients, LD transplantation offers superior graft survival and renal function compared to BDD or cDCD. This strategy should be further promoted to improve transplant outcomes.

Cumulative dose of epinephrine and mode of death after non-shockable out-of-hospital cardiac arrest: a registry-based study

BackgroundEpinephrine increases the chances of return of spontaneous circulation (ROSC) in out-of-hospital cardiac arrest (OHCA), especially when the initial rhythm is non-shockable. However, this drug could also worsen the post-resuscitation syndrome (PRS). We assessed the association between epinephrine use during cardiopulmonary resuscitation (CPR) and subsequent intensive care unit (ICU) mortality in patients with ROSC after non-shockable OHCA.MethodsWe used data prospectively collected in the Sudden Death Expertise Center (SDEC) registry (capturing OHCA data located in the Greater Paris area, France) between May 2011 and December 2021. All adults with ROSC after medical, cardiac and non-cardiac causes, non-shockable OHCA admitted to an ICU were included. The mode of death in the ICU was categorized as cardiocirculatory, neurological, or other.ResultsOf the 2,792 patients analyzed, there were 242 (8.7%) survivors at hospital discharge, 1,004 (35.9%) deaths from cardiocirculatory causes, 1,233 (44.2%) deaths from neurological causes, and 313 (11.2%) deaths from other etiologies. The cardiocirculatory death group received more epinephrine (4.6 ± 3.8 mg versus 1.7 ± 2.8 mg, 3.2 ± 2.6 mg, and 3.5 ± 3.6 mg for survivors, neurological deaths, and other deaths, respectively; p < 0.001). The proportion of cardiocirculatory death increased linearly (R2 = 0.92, p < 0.001) with cumulative epinephrine doses during CPR (17.7% in subjects who did not receive epinephrine and 62.5% in those who received > 10 mg). In multivariable analysis, a cumulative dose of epinephrine was strongly associated with cardiocirculatory death (adjusted odds ratio of 3.45, 95% CI [2.01–5.92] for 1 mg of epinephrine; 12.28, 95% CI [7.52–20.06] for 2–5 mg; and 23.71, 95% CI [11.02–50.97] for > 5 mg; reference 0 mg; population reference: alive at hospital discharge), even after adjustment on duration of resuscitation. The other modes of death (neurological and other causes) were also associated with epinephrine use, but to a lesser extent.ConclusionsIn non-shockable OHCA with ROSC, the dose of epinephrine used during CPR is strongly associated with early cardiocirculatory death. Further clinical studies aimed at limiting the dose of epinephrine during CPR seem warranted. Moreover, strategies for the prevention and management of PRS should take this dose of epinephrine into consideration for future trials.

Bioethical aspects of organ transplantation. A comparative study between Spain and Mexico

Loss of life, whether with signs of cardiocirculatory death or brain death, are relevant aspects for the decision on organ transplants, since in many cases it is preferable to obtain them from cadaveric patients, although there is always the option that the recipient is alive. . The article proposes a comparative study between Spanish and Mexican legislation, in relation to some aspects of a bioethical nature, considering organ procurement, informed consent, cadaveric or intervivos donation, cross donation, confidentiality and issues on criminal types.

Donation after Cardiocirculatory Death: A program that we must implement. Experts Argentinean meeting report

The global organ transplant activity remains satisfying less than 10% of the total number of patients in the waiting list. Brain dead donors and living donors have been the most common source of organs used worldwide. Nevertheless, as part of the different measures and policies implemented to increase donation, the use of donors after cardio-circulatory death (DCD), has been propitiated and expanded in the last couple of years. In Europe and North America, DCD programs had increased the number of available donors in up to 30%; but in many countries, the absence of DCD is mainly due to the lack of laws to legislate the process. We aim to report here the result of legal, ethical, procurement and specific organ working groups which met to assess the current regulatory framework, to evaluate the preliminary local experiences; and to produce a document to inform physicians and the community the current status of this program in our country.Argentina, a pioneer country in procurement and donation has the regulatory and ethical frameworks to enable the transparent use and access to DCDs’, as well as its implantation for organs and tissues in the whole country. In spite of a very preliminary experience, we are proud to present that the process for using DCD has already started. But this novel process requires to be well understood and perceived by the general public and medical community. Education becomes essential.

(905) Can We Safely Use Donors after Cardiocirculatory Death for Lung Transplantation

(905) Can We Safely Use Donors after Cardiocirculatory Death for Lung Transplantation

Tackling regulated cell death yields enhanced protection in lung grafts.

Background: Effective preservation strategies to ameliorate lung graft ischaemia injury are needed to rescue 'extended criteria' or 'marginal' lung grafts, and to improve recipient outcomes after transplantation. Methods: Lung grafts from male Lewis rats were extracted after 40 min of cardiocirculatory death, and healthy human lung tissues were collected from patients undergoing a lobectomy. Lung samples were then preserved in a 4°C preservation solution supplemented with 0.1 nM Dexmedetomidine (Dex, α2-adrenoceptor agonist) for 16 h. In vitro, human lung epithelial A549 cells were preserved in the 4°C preservation solution with 0.1 nM Dex for 24 h, then re-cultured in the cell culture medium at 37°C to mimic the clinical scenario of cold ischaemia and warm reperfusion. Lung tissues and cells were then analysed with various techniques including western blot, immunostaining and electron microscope, to determine injuries and the protection of Dex. Results: Prolonged warm ischaemia after cardiocirculatory death initiated Rip kinase-mediated necroptosis, which was exacerbated by cold storage insult and enhanced lung graft injury. Dex supplementation significantly reduced necroptosis through upregulating Nrf2 activation and reducing oxidative stress, thereby significantly improving lung graft morphology. Dex treatment also attenuated endoplasmic reticulum stress, stabilised lysosomes and promoted cell membrane resealing function, consequently reducing cell death and inflammatory activation after hypothermic hypoxia-reoxygenation in A549 cells. Conclusions: Inhibition of regulated cell death through Dex supplementation to the graft preservation solution improves allograft quality which may aid to expand the donor lung pool and enhance lung transplant outcomes per se.

Feasibility and performance of a combined extracorporeal assisted cardiac resuscitation and an organ donation program after uncontrolled cardiocirculatory death (Maastricht II).

Approximately 500.000 people in Europe sustain cardiac arrest (CA) every year, being myocardial infarction the main etiology. Interest has been raised in a new approach to refractory cardiac arrest (rCA) using extra-corporeal oxygenation (ECMO). In settings where it can be rapidly implemented, ECMO assisted resuscitation (ECPR) may be considered. Additionally, donation after circulatory death, which seeks to obtain solid organs donation from patients suffering rCA, has increased its role effectively increasing the pool of donors. Combined programs with integration of ECPR and uncontrolled donation after circulatory determination of death (uDCDD) are worldwide limited and experience integrating these two techniques is lacking. We report a 24months experience of ECPR and uDCDD kidney transplantation based on a management protocol in a university teaching hospital in the urban area of Lisbon. Over a period of 24months, 58 patients were admitted to our ICU with rCA, 6 (10%) in the ECPR program and 52 (90%) in the uDCDD. Seventy-eight percent of patients were male, with an average age of 49year-old. CA was witnessed in 83% of cases and initial rhythm was ventricular fibrillation in 20 cases (35%). 13 (25%) patients were effective organ donors. Refusal for effective donation was mainly due to prior comorbidities. The development of an integrated program for ECPR and uDCDD is feasible and requires a well-established and efficient activation program. In an era of significant organ shortage, it provides a viable option for increasing the organ donation pool, with promising results.

Normothermic regional perfusion in liver transplantation from donation after cardiocirculatory death: Technical, biochemical, and regulatory aspects and review of literature.

Organs from donation after circulatory death (DCD) are increasingly used for liver transplantation, due to the persisting organ shortage and waiting list mortality. However, the use of DCD grafts is still limited by the inferior graft survival rate and the increased risk of primary non-function and biliary complications when compared to brain death donors' grafts. Abdominal normothermic regional perfusion with extracorporeal membrane oxygenation (ECMO) is an in situ preservation strategy. which may mitigate ischemia-reperfusion injuries. and has been proposed to restore blood perfusion after the determination of death thus optimizing liver function before implantation. In this systematic review, we highlighted the clinical evidence supporting the use of normothermic regional perfusion in DCD liver underlying the pathophysiological mechanisms, and technical, logistic, and regulatory aspects. Despite the lack of properly designed, prospective, randomized trials, the current available data suggest beneficial effects of normothermic regional perfusion on clinical outcomes after liver transplantation.

Lung transplant outcome following donation after euthanasia.

Organ transplantation is hampered by shortage of suitable organs. In countries with a legal framework, organ donation following euthanasia is an option labeled "donation after cardio-circulatory death category V" (DCD-V). We describe our experience with lung transplantation (LTx) after euthanasia and evaluate post-transplant outcome using a matched comparison to DCD-III (withdrawal from life-sustaining therapy) and donation after brain death (DBD). All bilateral LTx between 2007 and 2020 were retrospectively analyzed. Matching was performed for recipient age and gender, indication for LTx, mean pulmonary artery pressure, extracorporeal life support, and donor age, which resulted in 1:2 DCD-III and 1:3 DBD matching. Primary graft dysfunction (PGD), chronic lung allograft dysfunction (CLAD), and patient survival were analyzed. A total of 769 LTx were performed of which 22 from DCD-V donors (2.9%). Thirteen women and 9 men expressed their wish to become organ donor after euthanasia. Euthanasia request was granted for irremediable neuromuscular (N=9) or psychiatric (N=8) disorder or unbearable and unrecoverable pain (N=5). PGD (grade 3, within 72 hours post-transplant) was 23.8% in the DCD-V cohort, which is comparable to DCD-III (27.9%; p=1.00) and DBD (32.3%; p=.59). CLAD-free 3- and 5-year survival were 86.4% and 62.8%, respectively, and comparable to DCD-III (74.4% and 60.0%; p=.62) and DBD (72.6% and 55.5%; p=.32). Five-year patient survival was 90.9%, not significantly different from both DCD-III (86.0%; p=1.00) and DBD (78.1%; p=.36). We observed that LTx with DCD-V allografts is feasible and safe, yielding no evidence for differences in short- and long-term outcome compared to matched cohorts of DCD-III and DBD.

Lung Biomolecular Profile and Function of Grafts from Donors after Cardiocirculatory Death with Prolonged Donor Warm Ischemia Time.

The acceptable duration of donor warm ischemia time (DWIT) after cardiocirculatory death (DCD) is still debated. We analyzed the biomolecular profile and function during ex vivo lung perfusion (EVLP) of DCD lungs and their correlation with lung transplantation (LuTx) outcomes. Donor data, procurement times, recipient outcomes, and graft function up to 1 year after LuTx were collected. During EVLP, the parameters of graft function and metabolism, perfusate samples to quantify inflammation, glycocalyx breakdown products, coagulation, and endothelial activation markers were obtained. Data were compared to a cohort of extended-criteria donors after brain death (EC-DBD). Eight DBD and seven DCD grafts transplanted after EVLP were analyzed. DCD’s DWIT was 201 [188;247] minutes. Donors differed only regarding the duration of mechanical ventilation that was longer in the EC-DBD group. No difference was observed in lung graft function during EVLP. At reperfusion, “wash-out” of inflammatory cells and microthrombi was predominant in DCD grafts. Perfusate biomolecular profile demonstrated marked endothelial activation, characterized by the presence of inflammatory mediators and glycocalyx breakdown products both in DCD and EC-DBD grafts. Early graft function after LuTx was similar between DCD and EC-DBD. DCD lungs exposed to prolonged DWIT represent a potential resource for donation if properly preserved and evaluated.

The Gift of Life: Interprofessional Organ Donation Curriculum in Pediatric Critical Care.

BackgroundThe number of patients awaiting organ transplantation is high, particularly in Pediatrics, in which available organs are scarce. To maximize organ donation opportunities and to provide quality end-of-life care, clinicians from all professions must be familiar with the process. There continues to be important gaps in core competencies regarding organ donation, including donor criteria and eligibility, timing of referral to organ procurement organizations, neurological determination of death, donation after cardiocirculatory death, and donor management. These gaps affect healthcare providers across multiple professions and are significant barriers to donation.ObjectiveWe describe an interprofessional curriculum that is designed to teach Pediatric Critical Care Medicine (PCCM) clinicians about the process of organ donation and supporting the families through that process. The approach of families is the purview of organ procurement organization, and the support of the families through the process remains with PCCM clinicians.MethodsKern’s six-step approach to curriculum development was used to develop, implement, and evaluate an interprofessional curriculum on organ donation in PCCM for physicians, nurses, and respiratory therapists.ResultsProblem formulation and both general and targeted needs assessments were performed through a comprehensive literature review, including review of national guidelines and Royal College of Physicians and Surgeons of Canada training objectives. Learning objectives and educational strategies were then outlined using two educational frameworks. After implementation, the curriculum was evaluated using learner self-assessments with a retrospective pre–post design.ConclusionAfter identifying educational gaps contributing to barriers to organ donation, an interprofessional curriculum was developed to increase competency in multiple aspects of organ donation, including team communication and collaboration, with the ultimate goal of promoting a culture of donation while ensuring it is part of quality end-of-life care.

P0334 - Kidney transplantation from Donation after Cardiocirculatory Death (DCD) after Extracorporeal Membrane Oxygenation (ECMO) – What can we say after 5 years of experience?

P0334 - Kidney transplantation from Donation after Cardiocirculatory Death (DCD) after Extracorporeal Membrane Oxygenation (ECMO) – What can we say after 5 years of experience?

MO420ROLE OF IL-6 ON ACUTE KIDNEY INJURY (AKI) DEVELOPMENT AFTER LIVER TRANSPLANTATION

Abstract Background and Aims Acute kidney injury (AKI) post-liver transplantation is a frequent complication with an incidence up to 70%, requiring renal replacement therapy in about 25% of transplant patients. AKI in patients with normal renal function is a recognized risk factor (FR) of chronic renal failure (CKD) de novo, associated with a 4.5 times greater mortality at 5 years post-transplant. Pathogenesis of AKI is multifactorial. Beyond the classical pre-transplant risk factors, the hypoxia of the graft and the ischemia-reperfusion injury (IRI) have recently been recognized to exert a pathogenetic role with specific mechanisms. It has been recently demonstrated in experimental setting that ischemic tissues put in place protective mechanisms in response to hypoxia aimed at increasing the release of oxygen with the activation of angiogenesis mediated by the expression of factors induced by hypoxia (HIF)-1-alpha. HIF1-alfa has been shown to promote cell survival under hypoxic conditions by switching metabolism from oxidative to glycolytic, by affecting the production of ATP to prevent excessive mitochondrial generation of reactive oxygen species, by promoting secondary release of vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGF-ß1), with following activation of inflammatory cytokines responsible for systemic inflammatory response syndrome (SIRS). Tumor necrosis factor-α, IL-1 and IL-6 are the most important cytokines released in IRI and seem to play a pivotal role in the onset of AKI in SIRS and sepsis. The development of AKI after hypoxia/ischemia of the graft, as observed more frequently in the population of recipients from donors after cardiocirculatory death (DCD) compared to donation after brain death (DBD), confirms this pathogenetic mechanism. Aim of the study is to evaluate AKI occurrence among liver transplanted patients and its relationship with IRI and cytokines systemic release. Method Data of 78 patients (62 males, 79.5%) undergone liver transplantation (2007-2011) were retrieved. Results The following clinical investigations were performed: AKI patients demonstrated a progressive increasing of IL-6 after liver transplantation (AKI 34.4-37.8-88.2 ng/ml vs no AKI 30.5-21.6-23.3 ng/ml). Conclusion Patients who experienced greater ischaemia-reperfusion injury of the liver graft developed more frequently AKI. Patients with AKI experienced an increased release and circulation of IL-6, that probably is involved in AKI development with interesting implications in future therapy.

Impact of cardiopulmonary resuscitation on organ donation in Switzerland.

The lack of suitable donor organs limits the number of solid organ transplants. Patients who underwent cardiopulmonary resuscitation (CPR) after cardiac arrest may represent a sizeable subgroup of deceased organ donors, as they often progress to brain death or have life-sustaining therapy withdrawn. We aimed to quantify deceased organ donation after CPR in Switzerland for the first time by analysing the characteristics of potential and utilised organ donors after CPR. Data on deceased adult and paediatric patients who were reported to and approved by Swisstransplant for organ donation were analysed, including both donation after brain death (DBD) and donation after controlled cardiocirculatory death (cDCD) from 2016 to 2018. We analysed baseline characteristics of potential donors who underwent CPR in the context of their hospitalisation, as compared with donors without prior CPR. Considering the varying characteristics between these two donor groups, we assessed the effect of CPR on different allocation outcomes (donor and organ utilisation, organ yield per utilised donor) using multivariable regression. Additionally, we present selected CPR circumstances and compared different subgroups of CPR donors according to duration of CPR and duration of no-flow time. Of the 461 deceased potential organ donors included in the analysis, 173 (37.5%) underwent CPR. CPR donors were, on average, younger (median age 53 vs 62, p &lt;0.001), had different causes of death (p &lt;0.001), and were more often of the cDCD type (30.1% vs 18.4%, p = 0.004) as compared with non-CPR donors. Of the 173 CPR donors, 152 (87.9%) could be utilised (minimum one organ transplanted), and in the multivariable analysis, utilisation rate was higher in the CPR donor group than in the non-CPR donor group (odds ratio 3.3, 95% confidence interval 1.1&ndash;11.5; p = 0.046). Organ specific utilisation of heart, liver, and kidney, and total organ yield per donor, did not differ significantly between CPR and non-CPR donors. Our study reveals that a substantial proprotion of deceased organ donors in Switzerland underwent CPR in context of their hospitalisation. CPR donors are different from non-CPR donors with respect to age, cause of death and donation type. However, when carefully selected according to their haemodynamic condition, CPR donors are comparable to non-CPR donors in terms of donor and organ utilisation, as well as the average organ yield. Thus, all patients who are resuscitated from cardiac arrest but who subsequently progress to death should be evaluated for organ donation. How CPR donors compare with non-CPR donors regarding transplant outcomes should be studied further.

965 - Kidney transplantation from donation after cardiocirculatory death (DCD) after extracorporeal membrane oxygenation (ECMO) – outcomes from a longitudinal assessment with three years of experience

965 - Kidney transplantation from donation after cardiocirculatory death (DCD) after extracorporeal membrane oxygenation (ECMO) – outcomes from a longitudinal assessment with three years of experience

P1601COMPLEMENT MEMBRANE ATTACK COMPLEX DURING THE FIRST WEEK AFTER KIDNEY TRANSPLANTATION AS SEVERITY BIOMARKER TO DELAYED GRAFT FUNCTION

Abstract Background and Aims Ischemia-reperfusion (I/R) damage is a relevant cause of delayed graft function (DGF). Complement activation is involved in experimental I/R injury, but few data are available about the expression of the complement cascade final component -membrane attack complex (MAC)- and I/R injury in KT patients. We studied the dynamics of membrane attack complex (MAC) as plasma fraction (pMAC) and the histological deposit pattern of C3b, complement factor H (FH) and MAC in DGF patients. Method We evaluated pMAC levels in 59 recipients, 38 with immediate graft function and 21 without serum creatinine decreased at day 7 (DGF). pMAC was measured at admission for KT (day 0) and 7 days after KT (day 7). Sandwich ELISAs were used to measure MAC. Additionally, we performed imunohistoquimical stained for MAC, C3b and kidney biopsies (KB) with DGF (n=12) and a control group of one-year protocol biopsies without damage (n=4) Results Patients in the DGF group were older, more frequently diabetics and received kidneys from older donors and more frequently controlled cardio-circulatory death type. Day0 and day7 post-KT pMAC levels were similar in non-DGF patients 5902±3049 mAu/L vs 6178±2882 mAu/L; p=0.686). However, patients with DGF showed a significant increase of pMAC levels between day0 and day7 (6621±2202 mAu/L vs 9625±4142 mAu/L; p=0.006. Figure 1 Percentage pMAC levels increase (Δ0-7 pMAC%) discriminative assessment analyzed by ROC curve showed a good discriminative value for DGF with an AUC of 0.78; p&amp;lt;0.001 (sensitivity 81%, specificity 66% by cut-off point of 5%). In patients with DGF longer than ten days, we found more frequently patients with a Δ0-7 pMAC &amp;gt;5% (83% vs 17% Δ0-7 pMAC &amp;lt;5% ; p=0.003).Patients with DGF showed renal function at 3 and 6 months, but worse renal function 1 year after KT (serum creatinine 1.78±0.61 vs 1.35±0.30 mg/dl in non-DGF patients). DGF patients with Δ0-7 pMAC &amp;gt;5% displayed worse renal function 1 and 2 year after KT compared to DGF patients with Δ0-7 pMAC &amp;lt;5%. MAC, C3b and FH stains were observed in tubular epithelial cells basal membrane. DGF-kidney biopsies showed more frequently high-intensity stain for MAC and FH than controls, without differences to C3b stain. DGF-kidney biopsies also showed a higher number of tubules with positive stain and larger perimeter of tubules with positive stains for MAC, C3b and FH than the controls. Figure 2. Among the 12 patients with DGF-biopsies, three (25%) never recovered renal function, all of them presented Δ0-7 pMAC &amp;gt;5% and intense, diffuse and positive staining in more than 50% of tubular perimeter for MAC, FH and C3b Conclusion Complement activation during peritrasplant period could be related with the severity of graft injury and the presence of DGF. Therefore, the determination of MAC levels could be useful to identify patients with possible complement dependent graft injury that might benefit from complement inhibitor therapies

Mitochondrial Transplantation for Myocardial Protection in Ex-Situ Perfused Hearts Donated after Cardio-Circulatory Death

Donation after circulatory death (DCD) offers an additional source of cardiac allografts, potentially allowing expansion of the donor pool. In this study, we investigated the efficacy of mitochondrial transplantation to improve myocardial function in DCD hearts. Cardiocirculatory death was induced in Yorkshire pigs (40-50 kg, n=22) by cessation of mechanical ventilation. After 20 minutes of warm ischemia, cardioplegia was administered. The hearts were then reperfused on an ex-situ blood perfusion system for 240 minutes. Following 15 minutes of ex-situ perfusion, mitochondria (5 × 109 in respiration buffer, Mitochondria, n=8) or respiration buffer alone (Vehicle, n=8) were delivered as a single bolus to the coronary arteries. A control group (Sham, n=6) was not subjected to warm ischemia. Hearts were perfused in a resting mode for 120 minutes before converting the system to a continuous isovolumic loading mode. Left ventricular (LV) global function, myocardial oxygen consumption, and arterial lactates were compared by two-way repeated-measures analysis of variance (ANOVA) with Bonferroni adjustment. At the end of 240 minutes of reperfusion, LV peak developed pressure (LVdevP) and dP/dt max were significantly higher in the Sham group than in Vehicle (p<0.001 both) and Mitochondria (p=0.002 and p=0.022, respectively). Hearts treated with mitochondria showed a significantly greater LVdevP (p=0.002), dP/dt max (p<0.001) and myocardial oxygen consumption (p=0.004) compared to Vehicle (Figure A-C). There was no significant difference in myocardial oxygen consumption between Sham and Mitochondria (p>0.05), which was significantly lower in Vehicle (p=0.004). No differences were found in arterial lactate levels (Figure D) (p> 0.05). Mitochondrial transplantation significantly preserves myocardial function and oxygen consumption in DCD hearts, thus providing an additional possible benefit for expanding heart donor pool.

The Effect of Fibroblast Growth Factor 15 Signaling in Non-Steatotic and Steatotic Liver Transplantation from Cardiocirculatory Death.

We elucidate the relevance of fibroblast growth factor 15 (FGF15) in liver transplantation (LT) using rats with both steatotic and non-steatotic organs from donors after cardiocirculatory death (DCD). Compared to LT from non-DCDs, the induction of cardiocirculatory death (CD) increases hepatic damage, proliferation, and intestinal and circulatory FGF15. This is associated with high levels of FGF15, bilirubin and bile acids (BAs), and overexpression of the enzyme involved in the alternative BA synthesis pathway, CYP27A1, in non-steatotic livers. Furthermore, CD activates the proliferative pathway, Hippo/YAP, in these types of liver. Blocking FGF15 action in LT from DCDs does not affect CYP27A1 but causes an overexpression of CYP7A, an enzyme from the classic BA synthesis pathway, and this is related to further accumulation of BAs and exacerbated damage. FGF15 inhibition also impairs proliferation without changing Hippo/YAP. In spite of worse damage, steatosis prevents a proliferative response in livers from DCDs. In steatotic grafts, CD does not modify CYP7A1, CYP27A1, BA, or the Hippo/YAP pathway, and FGF15 is not involved in damage or proliferation. Thus, endogenous FGF15 protects against BA accumulation and damage and promotes regeneration independently of the Hippo/YAP pathway, in non-steatotic LT from DCDs. Herein we show a minor role of FGF15 in steatotic LT from DCDs.

The Role of GLP1 in Rat Steatotic and Non-Steatotic Liver Transplantation from Cardiocirculatory Death Donors.

In liver transplantation (LT), organ shortage has led to the use of steatotic and non-steatotic grafts from donors after cardiocirculatory death (DCD). However, these grafts, especially those with steatosis, exhibit poor post-operative outcomes. To address this problem, we investigated the roles of gut-derived glucagon-like peptide 1 (GLP1) and dipeptidyl peptidase 4 (DPP4), the serine protease that cleaves it, in steatotic and non-steatotic LT from DCDs. Using Zucker rats, liver grafts from DCDs were cold stored and transplanted to recipients. GLP1 was administered to donors. The levels of GLP1 in intestine and of both GLP1 and DDP4 in circulation were unaltered following cardiocirculatory death (CD). In steatotic livers from DCD, increased GLP1 and decreased DPP4 were recorded, and administration of GLP1 caused a rise in hepatic GLP1 and a reduction in DDP4. This protected against inflammation, damage, and proliferation failure. Conversely, low GLP1 and high DDP4 were observed in non-steatotic livers from DCD. The exogenous GLP1 did not modify hepatic DDP4, and the accumulated GLP1 exerted harmful effects, increasing damage, inflammation, and regeneration failure. Herein, we show that there are differences in GLP1/DDP4 regulation depending on the type of liver implanted, suggesting that GLP1 can be used as a novel and effective therapy in steatotic grafts from DCDs but that it is not appropriate for non-steatotic DCDs.