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ABSTRACT: 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 orthotopic transplantation of hCD46-transgenic pig hearts using orthogonal polarization spectral imaging. Microvascular measurements were performed after induction of anesthesia, in the early phase of cardiopulmonary bypass (CPB), during reperfusion of the porcine heart and 1 h after the xenograft had resumed its life-supporting function. Microvascular blood flow was analyzed semiquantitatively and the number of visualized cell-to-cell interactions was counted.
The proportion of continuously perfused microvessels was 97 (96 to 97) % at baseline and 95 (94 to 97) % in the early phase of CPB. It decreased significantly (P < 0.05) during CPB to 89 (84 to 91), and alterations were still present (P < 0.05) when CPB was terminated and the xenograft had taken over systemic perfusion 83 (81 to 85) %. The microcirculatory changes correlated with the lactate levels (y = 18.1-0.18 x; r(2) = 0.55; P < 0.001), but no correlation with macrohemodynamic parameters was found.
Microvascular blood flow is altered after orthotopic pig-to-baboon heart transplantation, despite systemic hemodynamic parameters being well maintained by the porcine xenograft. These changes are moderate but persist after termination of CPB. Further studies need to elucidate whether these changes are transient or add to the mortality associated with cardiac xenotransplantation.
Xenotransplantation 07/2011; 18(4):232-8. · 2.33 Impact Factor
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ABSTRACT: 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 transplanted into baboons (Papio anubis and Papio hamadryas; body weight 9 to 26 kg) in the orthotopic life-supporting position. Animals received a propofol-based intravenous regimen or inhalation anesthesia with isoflurane. Analgesia was achieved with fentanyl in both groups. Systemic hemodynamic variables were measured before, during and after cardiopulmonary bypass (CPB) and the need for inotropic or vasoactive pharmacological support was compared before and after CPB.
Global hemodynamic variables [i.e. heart rate, mean arterial pressure (MAP) and cardiac output] were not significantly different in propofol-anesthetized baboons compared to baboons anesthetized with isoflurane. Baboons anesthetized with isoflurane showed a trend towards less pharmacological support required to achieve an adequate MAP of >60 mmHg after CPB (propofol: epinephrine 0.13 [0.05; 0.16] and norepinephrine 0.15 [0.02; 0.16] microg/kg/min vs. isoflurane: epinephrine 0.05 [0.02; 0.08] and norepinephrine 0.06 [0.02; 0.19] microg/kg/min; no significant difference).
Propofol and isoflurane appear to provide equal hemodynamic stability in orthotopic cardiac pig-to-baboon xenotransplantation prior to the start of CPB. The trend of a reduced catecholamine support needed after CPB, however, suggests that isoflurane may be the preferred drug for maintenance of anesthesia in this primate model.
Xenotransplantation 05/2007; 14(3):249-54. · 2.33 Impact Factor
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Andreas Bauer,
Florian Demetz,
Dirk Bruegger,
Martin Schmoelz,
Sebastian Schroepfer,
André Martignoni, Heiko Baschnegger,
Josef Hoelzl,
Manfred Thiel,
Alexander Choukér,
Klaus Peter,
John Gamble,
Frank Christ
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ABSTRACT: The role of microvascular fluid shifts in the adaptation to hypobaric hypoxia and its contribution to the pathophysiology of AMS (acute mountain sickness) is unresolved. In a systematic prospective study, we investigated the effects of hypobaric hypoxia and physical exercise alone, and in combination, on microvascular fluid exchange and related factors. We used computer-assisted VCP (venous congestion plethysmography) on the calves of ten altitude-acclimatized volunteers. We investigated the effects of: (i) actively climbing to an altitude of 3196 m, (ii) airlifting these subjects to the same altitude, and (iii) exercise at low altitude. CFC (capillary filtration capacity), Pvi (isovolumetric venous pressure) and Qa (calf blood flow) were assessed before and after each procedure and then repeated after an overnight rest. Measurements of CFC showed no evidence of increased microvascular permeability after any of the procedures. Pvi was significantly decreased (P<0.001) from 20.3+/-4.4 to 8.9+/-4.3 mmHg after active ascent, and was still significantly lower (P=0.009) after overnight rest at high altitude (13.6+/-5.9 mmHg). No such changes were observed after the passive ascent (16.7+/-4.0 mmHg at baseline; 17.3+/-4.5 mmHg after passive ascent; and 19.9+/-5.3 mmHg after overnight rest) or after exercise at low altitude. After the active ascent, Qa was significantly increased. We also found a significant correlation between Qa, Pvi and the number of circulating white blood cells. In conclusion, we found evidence to support the hypothesis that increased microvascular permeability associated with AMS does not occur in acclimatized subjects. We also observed that the microvascular equilibrium pressure (Pvi) fell in inverse relation to the increase in Qa, especially in hypoxic exercise. We hypothesize that this inverse relationship reflects the haemodynamic changes at the microvascular interface, possibly attributable to the flow-induced increases in endothelial surface shear forces.
Clinical Science 02/2006; 110(2):207-15. · 4.61 Impact Factor
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Andreas Bauer, Heiko Baschnegger,
Jan M Abicht,
Ulrike Brandl,
Paolo Brenner,
Eckart Thein,
Claus Hammer,
Bruno Reichart,
Klaus Peter,
Michael Schmoeckel,
Frank Christ
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ABSTRACT: 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 performed. We used femoral arterial thermodilution for the invasive assessment of CO and stroke volume.
Baseline CO of the baboons after induction of anesthesia was 1.36 (1.0-1.9) l/min. 30 to 60 min after termination of the cardiopulmonary bypass, CO of the cardiac xenograft was significantly increased to 1.72 (1.3-2.1) l/min (P < 0.01). The stroke volumes of the baboon heart before transplantation and the cardiac xenograft was comparable [14.9 (11-26) vs. 11.8 (10-23) ml]. Thus the higher CO was achieved by an increase in heart rate after oXHTx [75.0 (69-110) vs. 140.0 (77-180)/min; P < 0.01]. Despite the increased CO, oxygen delivery was reduced [256 (251-354) vs. 227 (172-477) ml/min; P < 0.01] due to the inevitable hemodilution during the cardiopulmonary bypass and the blood loss caused by the surgical procedures.
Our results demonstrate that in the early phase after orthotopic transplantation of hDAF pig hearts to baboons, cardiac function of the donor heart is maintained and exceeds baseline CO. However, in the early intraoperative phase this was only possible by using inotropic substances and vasopressors due to the inevitable blood loss and dilution by the priming of the bypass circuit.
Xenotransplantation 11/2005; 12(6):444-9. · 2.33 Impact Factor
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Ulrike Brandl,
Sebastian Michel,
Matthias Erhardt,
Paolo Brenner,
Iris Bittmann,
Matthias Rössle, Heiko Baschnegger,
Andreas Bauer,
Claus Hammer,
Michael Schmoeckel,
Bruno Reichart
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ABSTRACT: 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, a soluble, polymeric form of a Galalpha(1,3)Gal trisaccharide would sufficiently minimize xenograft rejection of hDAF-transgenic pig hearts orthotopically transplanted into baboons.
Orthotopic heart transplantations were performed using hDAF transgenic piglets as donors and four non-splenectomized baboons as recipients. Baseline immunosuppression consisted of tacrolimus, sirolimus, ATG, steroids. In addition two animals received low-dose GAS914, and two animals high-dose GAS914. One of these baboons received high dose GAS914 and cyclophosphamide induction therapy. Serum levels of anti-Galalpha(1,3)Gal IgM and IgG antibodies, and anti-pig antibodies were controlled daily by anti-Galalpha(1,3)Gal enzyme-linked immunosorbant assay and anti-pig hemolytic assays. Histomorphological (hematoxylin and eosin, elastic van Gieson) and immunohistochemical (IgM, IgG) evaluations were performed on tissue specimens.
Following low-dose GAS914 therapy survival time was 1 and 9 days, respectively. In baboons treated with high dosages of GAS914 a survival of 30 h and 25 days could be obtained. GAS914 caused an immediate and significant reduction of both anti-Galalpha(1,3)Gal IgM and IgG antibodies. However, sufficient antibody reduction was independent of dosage and form of application of GAS914. A pre-transplant GAS914 treatment was not necessary to effectively reduce antibody levels and prevent hyperacute rejection. In the early postoperative period preformed anti-pig antibodies corresponded predominantly to anti-Galalpha(1,3)Gal antibodies making them susceptible to GAS914. Subsequently, while anti-Galalpha(1,3)Gal antibodies remained low, anti-pig antibodies increased despite of GAS914 application. Corresponding to increased anti-pig antibody titers depositions of IgM and IgG immunoglobulins were detected, which were possibly non-Galalpha(1,3)Gal-specific.
Following orthotopic transplantation of hDAF-transgenic pig hearts into baboons, GAS914 is able to maintain a sufficient reduction of Galalpha(1,3)Gal-specific cytotoxicity to the graft. GAS914 therefore is able to prevent not only hyperacute rejection, but also acute vascular rejection at its beginning, when serum cytotoxicity to the pig heart appears to be predominantly Galalpha(1,3)Gal-specific. A sustained prevention of acute vascular rejection, however, still requires the identification of antibody specificities other than to Galalpha(1,3)Gal.
Xenotransplantation 04/2005; 12(2):134-41. · 2.33 Impact Factor
