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Introduction: After orthotopic cardiac xenotransplantation, the combination of both the inflammatory responses to the exposure of a recipient to the xenogeneic organ and the use of cardiopulmonary bypass has been assumed to cause detrimental side effects. These have been described not only to affect the transplanted organ (heart) itself, but also the recipient's lungs. In this article, we summarize how these possible detrimental processes can be minimized or even avoided. Methods: Data from eight pig‐to‐baboon orthotopic cardiac xenotransplantation experiments were analyzed with a special focus on early (within the first week) postoperative organ dysfunction and systemic inflammatory responses. Non‐ischemic heart preservation and the careful management of the heart‐lung machine were deemed essential to guarantee not only the immediate function of the transplanted xenogeneic organ but also the prompt recovery of the recipient. Results: After weaning from cardiopulmonary bypass, very low catecholamine amounts were needed to ensure an adequate pump function and cardiac output. Central venous oxygen saturation and serum lactate levels remained within normal ranges. All animals were successfully weaned from ventilation within the first postoperative hours. Serum parameters of the transplants and native kidneys and livers were initially slightly elevated or always normal, as were hemoglobin, LDH, and platelet measurements. Markers of systemic inflammation, C‐reactive protein, and IL‐6 were slightly elevated, but the reactions caused no lasting damage. Conclusion: Consistent short‐term and long‐term results were achieved after orthotopic cardiac pig‐to‐baboon transplantation without detrimental inflammatory responses or signs of multiorgan failure. In comparison to allogeneic procedures, non‐ischemic heart preservation was important for successful immediate organ function, as was the management of the heart‐lung machine. Thus, we believe that genetically modified porcine hearts are ready for use in the clinical setting. [ABSTRACT FROM AUTHOR]

Summary: The future clinical application of animal‐to‐human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen‐free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first‐in‐human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first‐in‐human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders. [ABSTRACT FROM AUTHOR]

Background Gender differences between donor and recipient might have an impact on the outcome after heart transplantation (HT). Data of more than 67,000 patients registered at the International Society of Heart Lung Transplantation (ISHLT) were reviewed focusing on the influence of gender differences on short- and long-term outcome after HT. Methods We performed a retrospective analysis of 67,855 cardiac allograft recipients. They received orthotopic HT between January 1, 1980 and June 30, 2009. In contrast to other studies the data for gender differences (donor gender and recipient gender) were calculated with respect to actuarial and conditional survival (without 30-day mortality). Results One-year survival was highest in male recipients of male donor hearts (mR/ mD: 83.74%). The lowest 1-year outcome showed male recipients of female donor organs (mR/fD: 78.95%). Best 5-year survival rates were shown by male recipients with male donor organs (70.75%, p < 0.0001). These differences disappeared in survival conditional to 1 year, indicating that gender predominantly influences short-term outcome. Conclusions The combination male recipient/female donor carries a higher risk for early mortality, whereas female recipients/male donor reveals favorable short-term results. Gender-matched HT would be ideal, but not suitable in practice because of the shortage of organs. [ABSTRACT FROM AUTHOR]

Deutsch M-André, Kauke T, Sadoni S, Kofler S, Schmauss D, Bigdeli AK, Weiss M, Reichart B, Kaczmarek I. Luminex-based virtual crossmatching facilitates combined third-time cardiac and de novo renal transplantation in a sensitized patient with sustained antibody-mediated cardiac allograft rejection. Pediatr Transplantation 2010: 14:E96-E100. © 2009 John Wiley & Sons A/S. Allosensitization represents a major obstacle to successful re-transplantation since circulating antibodies can elicit antibody-mediated rejection episodes with subsequent graft failure. Since sensitization is primarily considered a contraindication to transplantation the duration for patients waiting for a suitable donor organ to become available is considerably prolonged. Herein, we report on the successful application of a Luminex-based virtual crossmatch approach to facilitate combined third-time cardiac and de novo renal transplantation in a sensitized patient with sustained antibody-mediated cardiac allograft rejection. [ABSTRACT FROM AUTHOR]

The optimal maintenance therapy after lung transplantation remains to be established. The aim of this study was to analyse the impact of tacrolimus and mycophenolate mofetil (MMF) as first line immunosuppression on long-term survival and Bronchiolitis Obliterans Syndrome (BOS). From January 1996 through December 2006, all 155 recipients receiving tacrolimus and MMF as maintenance immunosuppression were included in this study. Tacrolimus and MMF was discontinued in 36 patients (23.2%). The overall survival rates were 91.6% at 6 months, 86.4% at 1 year, 74.9% at 3 years, 60.3% at 5 years and 32.4% at 10 years. The overall freedom from acute rejection was 74.6%, 63.2% and 59.4% at 1, 3, and 5 years respectively. The overall BOS-free survival was 95.6% at 1 year, 88.4% at 3 years, 69.5% at 5 years and 30.5% at 10 years. The development of BOS ≥ 1 was associated with a significantly increased risk of death and reduced long-term survival. The combination of tacrolimus and MMF offers safe and reliable maintenance immunosuppression after lung transplantation. However, substantial improvements of long-term survival and freedom from BOS might only be achieved by a change in organ allocation policies and patient management beyond differential immunosuppressive protocols. [ABSTRACT FROM AUTHOR]

Background: Cytotoxic anti-Galα(1,3)Gal antibodies play a key role in the rejection of pig organs transplanted into primates. Regimens reducing anti-Galα(1,3)Gal antibodies were associated with severe side effects unable to prevent antibody rebound until soluble synthetic oligosaccharides with terminal Galα(1,3)Gal inhibiting antigen binding became available. We displayed kinetics of anti-pig and anti-Galα(1,3)Gal IgM and IgG antibody levels using GAS914, a Galα(1,3)Gal trisaccharide conjugated to poly-l-lysine, and investigated corresponding changes of parameters of heart function. Methods: Using a working heart model, hDAF pig hearts were perfused with human blood containing GAS914 (group 1). As controls hDAF pig hearts (group 2) and landrace pig hearts (group 3) were perfused with human blood only. Levels of anti-Galα(1,3)Gal (IgM, IgG) and anti-pig antibodies were assessed to prove the effectiveness of GAS914. As parameters of heart function, cardiac output (CO), stroke work index (SWI), coronary blood flow (CBF) and coronary resistance were measured. Creatine phosphokinases, lactate dehydrogenase and aspartate aminotransferase were evaluated as markers of myocardial damage. Histological and immunohistochemical investigations were performed at the end of perfusion. Results: In group 1 an immediate and extensive reduction in both IgM and IgG anti-Galα(1,3)Gal was found. Anti-pig antibodies were eliminated accordingly. Antibody binding to GAS914 was complete before the start of organ perfusion. Corresponding to rapid antibody elimination in group 1 GAS914 not only was able to significantly prolong the beating time of the heart in hDAF pigs, but also to clearly improve functional parameters. When switching to the working heart mode hDAF pig hearts perfused with human blood containing GAS914 (group 1) revealed a CO starting at a significantly higher level than hDAF (group 2) and non-transgenic pig hearts (group 3) perfused with human blood only. Similarly, in group 1 SWI was significantly increased at the beginning of perfusion compared to that of group 2 and group 3. The increase in CBF during perfusion and the corresponding fall of coronary resistance occurred without significant differences between the groups revealing the independence of hDAF and GAS914. Conclusions: Due to an immediate and profound reduction in Galα(1,3)Gal-specific antibodies, soluble Galα(1,3)Gal conjugates not only prolong survival, but also improve the hemodynamic performance of the heart in DAF pigs. [ABSTRACT FROM AUTHOR]

The article presents the program and abstracts featured at the 9th Minisymposium on Xenotransplantation of the German working Group on Xenotransplantation held at Robert Kock Institute in Berlin, Germany on June 8-9, 2006. They include generation and characteristics of multi-transgenic pigs, immunologic aspects, virological aspects, islet cell and hepatocyte xenotransplantation and stem cell research.

The appearance of re-stenosis after repair of an interrupted aortic arch may be a surgical challenge due to adhesions. Here, we describe an approach using off-pump coronary artery bypass grafting techniques to reach the descending aorta through a median sternotomy in a patient with aortic arch stenosis after conduit repair. The 17-year-old patient with diagnoses of interrupted aortic arch and ventricular septal defect presented after two previous operations (one left lateral thoracotomy and one median sternotomy) with a stenosed vascular graft between ascending and descending aorta. Surgery was done via re-sternotomy without cardio-pulmonary bypass. An extraanatomic graft was used to connect ascending and descending aorta. When performing the distal anastomosis, the heart was exposed using a standard suction device. This case demonstrates that the use of modern techniques may facilitate surgical approaches dramatically. In our opinion the above-described technique is the first choice for all patients requiring arch repair following multiple previous operations, performed via sternotomy and thoracotomy. [ABSTRACT FROM AUTHOR]

An abstract of the article "Aims and status of the DFG-transregio research unit xenotransplantation," by Bruno Reichart is presented.

It is more than 1 year since our Consortium commenced. The following abstracts provide an account of what has been achieved so far and document our understanding of xenotransplantation and some of our future strategies: Since (microencapsulated) islets are the first in the clinic, our basic research focuses on immediate (innate) rejection reactions and means of counteracting them. Once transplanted and working, porcine and primate islets may respond differently, for example to glucose challenges., We will gain preclinical experience regarding the safety of genetically modified islets as quickly as possible., We are currently in dialogue with German authorities (Paul-Ehrlich-Institution as representative of the European Medicines Agency) to decide how best to formulate a successful clinical application within European standards., Are there any ethical objections from within German society? A recent 3-day meeting, held at the Munich Catholic Academy explored the issues, including opinions from the Jewish and Islamic communities. In brief, the outcome revealed no major objections as long as xenogeneic procedures are safe and effective. All talks will be published in German, with abstracts in English. There will also be an English review of the meeting possibly published in the journal Xenotransplantation., Successful preclinical organ (heart, kidney) xenotransplantation is still difficult to achieve. Heterotopic thoracic (working) heart transplantation has been established with consistent results. It seems that hyperacute and delayed humoral rejection reactions are manageable; but thrombotic microangiopathy currently presents the main obstacle. Porcine hearts that express human thrombomodulin will be used next, together with complement antibodies and/or co-stimulation blockade. Human thrombomodulin has provided promising results in the laboratory (cell based)., Porcine heart valves will be tested using single and multiple antigen knock out., In conclusion, the German Xenotransplantation Consortium supported by the German Research Foundation (DFG) is on track for a successful (first?) period. There seems to be broad support from a majority of German cardiovascular surgeons, and this is spreading to those in other parts of Europe [1]. Reference [1] Reichart B., Guethoff S., Mayr T. et al. Discordant cardiac xenotransplantation - broadening the horizons. Eur J Cardiothorac Surg 2013; Epub ahead of print. [ABSTRACT FROM AUTHOR]

Chronic rejection is still the major limitation of long-term outcome of heart transplant recipients. Several recent studies demonstrated that a not negligible proportion of chronic allograft rejection episodes are not only mediated by T-cell response but also triggered by pre-transplant and de novo post-transplant donor-specific alloantibodies. This points at a fundamental role of humoral immune response mechanisms that contribute to early and late graft failure. This type of rejection is an unsolved problem solid organ transplantation because current immunosuppressive regimens are generally intended to interfere in T-cell signalling pathways. Various options for the removal of circulating alloantibodies and the prevention of alloantibody formation by B-cell depletion have been described. Nevertheless, effective standardized schemes for the treatment of antibody-mediated graft rejection have to be defined. We present a heart transplant recipient with sustained antibody-mediated graft rejection who was successfully managed with a combination treatment consisting of 3 cycles of immunoadsorption and a single-dose administration of the anti-CD20 monoclonal antibody rituximab. [Copyright &y& Elsevier]

Abstract: Objective: Donor organ shortage in pediatric heart transplantation (HTx) is causing mortality rates of 30–50% on the waiting list. Due to immaturity of the immune system of newborns and infants, ABO-incompatible HTx may be an option to increase donor availability. We present our experience with ABO-incompatible HTx. Methods: Three infants were transplanted ABO-incompatible since 12/2004: (1) hypoplastic left heart complex, (2) restrictive hypertrophic cardiomyopathy, (3) dilative cardiomyopathy. Age at HTx was 7, 5, and 3.5 months. All recipients had blood type O, donors were A, A, and B. Informed consent was given by parents, the ethics committee, and Eurotransplant. Results: Preoperative isohemagglutinin titers were low (Patient 1: 1:4 for anti-A1, A2, B, Patient 2: 1:4, 1:1, 1:4 for anti-A1, A2, B, respectively, and Patient 3: 0 for all, but quick spin 1+ for all). Intraoperatively, plasma was separated from red blood cells and discarded up to six times until antibodies were eliminated. Immunosuppressive induction with ATG was started for 5 days. Basic immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisone. Extubation was performed on days 15, 2, and 1, respectively. After a follow-up of 17, 16, and 12 months all patients are well, ventricular function is excellent without any acute rejection periods; Patient 1 is still on dialysis. Isohemagglutinin titers against donor blood type have disappeared in follow-up. Conclusions: ABO-incompatible cardiac transplantation shows good short-term results in young infants and seems to be a safe procedure to lower the mortality on the waiting list. [Copyright &y& Elsevier]

Background: Late after cardiac transplantation, limited reinnervation of the transplanted heart may occur, but little is known about the effect of reinnervation on cardiac function and exercise performance. Methods: We quantified the extent of myocardial reinnervation noninvasively in 29 cardiac-transplant recipients, using positron-emission tomography and the catecholamine analogue [11C]hydroxyephedrine. Global and regional ventricular function at rest and during standardized exercise testing was measured with the use of radionuclide angiography, and the results were compared with those in 10 healthy controls. Results: Sympathetic reinnervation, mainly in the anteroseptal wall, was present in 16 of the 29 transplant recipients. At rest, hemodynamic differences were not observed between the patients with reinnervation and those with denervation. However, the latter group had a shorter mean (±SD) exercise time (6.1±1.5 minutes, vs. 8.2±1.2 in the group with reinnervation; P<0.01) and a lower peak heart rate (121±13 vs. 143±15 beats per minute, P<0.01). The contractile response to exercise was significantly enhanced in transplant recipients with reinnervation and similar to that of normal controls. In a multivariate analysis, hydroxyephedrine retention was the only independent determinant of the exercise-induced increase in the ejection fraction. Conclusions: In heart-transplant recipients, the restoration of sympathetic innervation is associated with improved responses of the heart rate and contractile function to exercise. These results support the functional importance of reinnervation in transplanted hearts. (N Engl J Med 2001;345:731-8.) [ABSTRACT FROM AUTHOR]