Paolo Brenner

Ludwig-Maximilians-University of Munich | LMU · Clinic of Cardiac Surgery

Purpose Major hurdles in oXHTx are the delayed xenograft rejection, the early perioperative cardiac xenograft dysfunction (PCXD) and the pig heart overgrowth, which were solved in this study with a costimulation blockade, a new non-ischemic cold preservation and a growth inhibition by anti-proliferative drugs. Aim was to achieve a 90-days-survival...

Introduction: Due to an increasing waiting time for available donor organs in pediatric heart transplantation (pHTx) ABO-incompatible HTx (HTxi) may be a satisfying option and probably an unpreventable one. There is an immunological window of tolerance during the human embryonic development which persists into the time of infancy. It has the potent...

Background: The perioperative phase of preclinical cardiac xenotransplantations significantly affects the experimental outcome. Moderate or even severe hemodynamic and respiratory impairment occurs frequently in baboons after receiving a cardiac transplant. The perioperative management of such postoperative instability is very demanding, especiall...

Objectives: Renal neoplasms frequently expand into renal veins and inferior vena cava from the early stages of the disease. In this study, we set out to define the long-term outcomes of patients with Stage IV tumorous cavoatrial extension, undergoing radical nephrectomy with excision of cavoatrial extension in deep hypothermic circulatory arrest (...

Aim: To verify and reproduce the excellent > 2 years long-term survival of the heterotopic, nonlife-supporting abdominal heart xenotransplantation (AHHXTx) model of Mohiuddin's group with a recombinant mouse-rhesus chimeric CD40 antibody (clone 2C10R4) this costimulation blockade was used in the life-supporting thoracic heterotopic (THHXTx) and ort...

Human allotransplantation has been very successful over the past six decades. Heart and kidney transplantations remain the therapy of choice for end-stage organ failure. Although surgical competence is available in many medical centres around the world, the demand for organs far exceeds the supply from human donors. The consequences for patients wa...

Background: As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then tre...

Human organ transplantation is the therapy of choice for end-stage organ failure. However, the demand for organs far exceeds the donation rate, and many patients die while waiting for a donor. Clinical xenotransplantation using discordant species, particularly pigs, offers a possible solution to this critical shortfall. Xenotransplantation can also...

Objectives: New immunologic approaches are needed to overcome xenogeneic rejection to make clinical cardiac xenotransplantation possible. Anti-CD40-antibody reduces the adaptive immune response by inhibiting costimulation between T-cells and antigen presenting cells respectively B-cells. We investigated the effect on different peripheral cell lines...

Objectives: Proteasome inhibition by bortezomib, a constitutive proteasome inhibitor (PI) approved for the treatment of multiple myeloma, was reported in the field of organ transplantation; despite known role in antigen presentation, the positive effect on graft rejection has not been verified. Since bortezomib is associated with many side effects...

The heterotopic thoracic pig-to-baboon heart transplantation has been established by our group as a safe preclinical model. Since the recipient's own heart remains in place, it is possible to evaluate immunological reactions of various types and the symptoms of the thrombotic microangiopathy under working heart conditions. However, these experiment...

Background Cell injury, particularly as consequence of ischemia/reperfusion or acute rejection after (xeno)transplantation, leads to release of intracellular components like RNA. Extracellular RNA, (i) causes edema as a result of increasing permeability of blood vessels [1], (ii) is described as a procoagulation factor by activation of the contact...

Background: The aim of this study was to establish a new experimental model to directly analyse the coronary microcirculation in cardiac xenografts. Methods: Intravital fluorescence microscopy (IVM) of the subepicardial microcirculation in heterotopically transplanted hamster-to-rat cardiac xenografts was performed at 30 and 90 min of reperfusio...

Xenotransplantation is a potential solution for the worldwide persisting donor organ shortage. However, immunological and physiological barriers need to be overcome before the first clinical trials can be started. Nonhuman primates are considered the most suitable recipients in preclinical xenotransplantation models. Heterotopic abdominal cardiac x...

Objectives: Organ shortages and increased numbers of nontransplant older patients have necessitated a search for alternatives to heart transplants. The Jarvik 2000 assist device (Jarvik Heart, Inc., Manhattan, NY, USA), as a small long-term axial flow pump, offers many advantages, such as retroauricular power supply, which minimizes driveline infe...

Aims: For ventricular and pulmonary support the extracorporeal membrane oxygenation (ECMO) system using the Bio-Medicus centrifugal pump (Medtronic®, Minneapolis, MN, USA) was applied in 231 patients with low cardiac output for a prolonged period of several days. Methods: From December 1996 to May 2011 the ECMO was implanted in 231 patients (180 ad...

In this investigation, we hypothesize that quality of oral anticoagulation (OA) and long-term outcome after mechanical heart valve (MHV) replacement with self-management (Self-M) of OA is superior to conventional anticoagulation treatment (Conv-T), even in outside trial conditions. One hundred sixty patients (78.8% aortic valve replacements) were t...

Whilst macrohemodynamic function of porcine xenografts transplanted into baboons has been assessed perioperatively, the ability of the xenograft to maintain systemic microcirculatory perfusion has not been investigated after pig-to-baboon xenotransplantation so far. We investigated the sublingual microcirculation of six baboons undergoing orthotopi...

For short-term ventricular and pulmonary support the extracorporeal membrane oxygenation (ECMO) system using the Bio-Medicus centrifugal pump (Medtronic®, Minneapolis, MN, USA) was applied in 108 patients with cardiac low-output. From December 1996 to July 2006 the ECMO was implanted in 108 patients (73 adult, mean age: 49.3±18.0 yrs and 35 childre...

Hyperacute xenograft rejection (HXR) is characterized by complement activation and intravascular thrombosis. The pathogenesis of HXR is attributed to antibodies binding to α-Gal-epitopes on the endothelial cells (EC) of the xenograft, activating complement and thrombin-mediated coagulation mechanisms. Our aim was to evaluate the influence of thromb...

The Galalpha1-3Galbeta1-4GlcNAc-R is the major antigen on pig tissue bound by human xenoreactive natural antibodies in xenotransplant. We have investigated in vitro the influence of hypothermic storage with cardioplegic solutions on expression of Galalpha1-3Galbeta1-4GlcNAc-Rs and hyperacute xenograft rejection. To analyze effects of hypothermia on...

Heterotopic thoracic heart transplantation may be an alternative to the established heterotopic abdominal or orthotopic cardiac xenotransplantation model as it combines the safety of heterotopic transplantation with the benefit of a working heart model. In a first series of two animals, we tested the surgical feasibility of this procedure with non-...

In this report we describe a 42-year-old man with idiopathic pulmonary fibrosis with a progressive course who underwent right single-lung transplantation in November 2007. The post-operative course showed a decline of gas exchange, and chest X-ray revealed pneumonic infiltrates. Computerized tomography (CT) scans showed high-grade stenosis of the r...

In an orthotopic xenogenic heart transplant study with baboons (weight 10-25 kg) it was necessary to create a low-prime heart-lung machine setup. As a first step we modified our standard Lilliput 2 [D902] set (Dideco). Facing the facts of using too much priming solution we changed from a half closed system to a totally closed system (no softbag res...

Solid organ xenograft rejection is associated with vascular injury resulting at least in part in platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis and interstitial hemorrhage. Complement activation plays a prominent role in platelet-endothelial interaction. We tested the effects of platelet GPIIb/IIIa inhi...

Cytotoxic anti-Galalpha(1,3)Gal antibodies play a key role in the rejection of pig organs transplanted into primates. Regimens reducing anti-Galalpha(1,3)Gal antibodies were associated with severe side effects unable to prevent antibody rebound until soluble synthetic oligosaccharides with terminal Galalpha(1,3)Gal inhibiting antigen binding became...

Acute massive or submassive pulmonary embolism is a life-threatening condition with a poor prognosis. It causes sudden hemodynamic deterioration and warrants immediate surgery. We report the case of a 41-year-old male heart transplant recipient who had not been treated prophylactically for thrombosis, who was referred to our center because of exert...

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. Thi...

Orthotopic pig-to-baboon xenogeneic heart transplantation (oXHTx) is the only accepted preclinical animal model for cardiac xenotransplantation. We compared the hemodynamic stability of a propofol- and isoflurane-based anesthetic regimen during oXHTx. Hearts from 12 hDAF or hCD46 transgenic pigs (Sus scrofa; body weight 7 to 32 kg) were transplante...

Pig organs are at risk for hyperacute and acute vascular rejection mediated by anti-pig antibodies, mainly binding to the Galalpha(1,3)Gal epitope. Acute cellular rejection is characterized by progressive infiltration of mononuclear cells. There is an ongoing search for immunosuppressive regimens that provide adequate protection against all pattern...

Classic features of hyperacute rejection show differential severity in the inner compared to the outer myocardium. In the present study, regional blood flow (RBF) measured by fluorescent microspheres served as a marker of the extent of hyperacute rejection. Using a working heart model, hearts of nontransgenic and hDAF transgenic pigs were perfused...

Only limited data are available on the physiological functional compatibility of cardiac xenografts after orthotopic pig to baboon transplantation (oXHTx). Thus we investigated hemodynamic parameters including cardiac output (CO) before and after oXHTx. Orthotopic xenogeneic heart transplantation from nine hDAF transgeneic piglets to baboons was pe...

Long-term survival of transgenic cardiac xenografts is currently limited by a form of humoral rejection named acute vascular rejection. Preformed and elicited cytotoxic antibodies against Galalpha(1,3)Gal terminating carbohydrate chains, known as the primary cause of hyperacute rejection, are crucial for this process. We investigated whether GAS914...

Hyperacute xenograft rejection (HXR) and acute vascular rejection (AVR) after xenotransplantation are triggered by xenoreactive antibodies (XAb) and an activated complement cascade. In a heterotopic (abdominal) xenotransplantation model we combined immunoadsorption (IA, Ig-Therasorb column) and a quadruple immunosuppressive drug therapy in recipien...

Xenograft rejection is associated with vascular injury resulting at least in part from platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis. Assuming that complement activation is a major determinant of humoral immune reactions bringing about platelet-endothelial cell interactions, we tested the effects of th...

Objectives: On the 20th anniversary of the worldwide first Novacor LVAS implantation, this system holds the record with over six years of long-term support. In our single-center in 1993 the first wearable Novacor N100P system was implanted. Worldwide more than 1500 Novacor devices were implanted with nearly 600 cumulative patient-years of supportin...

Objectives: Hyperacute rejection (HAR) shows different features in the inner compared to the outer myocardium according to the pathologic effects of the obstructed venous drainage. Assuming a close relation to the extent of hyperacute rejection, regional blood flow (RBF) was measured by fluorescent microspheres. Material and Methods: In a working...

In a discordant orthotopic xenotransplantation model (pig-to-baboon) donor pigs expressing human decay accelerating factor (hDAF) as a regulator of complement activity were used to prevent hyperacute xenograft rejection (HXR). We investigated a modified immunosuppressive therapy consisting of ERL080 (Novartis Pharma AG, Base, Switzerland), cyclospo...

Cardiopulmonary bypass (CPB) and operative trauma are associated with increased expression of proinflammatory mediators. We determined the relative contribution of CPB on activation of cytokines and adhesion molecules in patients undergoing coronary revascularization by comparing them with patients receiving off-pump coronary artery bypass grafting...

In xenotransplantation long ischemic time of grafts is supposed to have a marked influence on hyperacute rejection (HXR). We investigated the influence of different cold ischemic times on HXR of ex vivo "working pig hearts" perfused with human blood. Xenoreactive natural antibodies (XNAb) as a trigger of HXR were eliminated by Ig-Therasorb immunoad...

To prevent hyperacute xenograft rejection (HXR) caused by preformed natural antibodies (XNAb) after orthotopic heart xenotransplantation (oXHTx) of landrace pig hearts into baboons, we used immunoadsorption of immunoglobulins IgG, IgM and IgA and complement with the reusable Ig-Therasorb column. In addition to functional data, tissue was sampled fo...