Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation
Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation
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DOI：
10.1111/xen.12636
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发表时间：
2020-08-25
影响因子：
3.9
通讯作者：
Brenner, Paolo
中科院分区：
文献类型：
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作者：
Laengin, Matthias;Reichart, Bruno;Brenner, Paolo
背景在开始临床试验之前，需要成功地将猪心移植到狒狒受体中。尽管多年的研究，超过一半的原位心脏异种移植物在移植后的前48小时内丢失，主要是由围手术期心脏异种移植物功能障碍（PCXD）引起的。为了降低PCXD的发生率，我们在猪-狒狒异种心脏移植中采用了冷非缺血灌注的保存技术。方法以转基因幼年猪（GGTA 1- KO/hCD 46/hTBM）为供体，圈养狒狒为受体，进行14次异种原位心脏移植实验。根据应用的两种技术比较器官保存：冷静态缺血性心脏停搏液（IC; n = 5）和冷非缺血性连续灌注（CP; n = 9），含氧白蛋白的高钾心脏停搏液含有营养物质，红细胞和激素。在手术前，我们测量了预先形成的抗-非-Gal-抗体的血清水平。手术期间，采用经肺热稀释法监测血流动力学参数。定期进行中心静脉血气分析，以估计氧提取以及乳酸产生。术后测定肌钙蛋白T及受者肾、肝、凝血功能的血清学参数。结果在用IC保存的猪移植物中，我们发现移植后心脏收缩功能明显降低，尽管增加了正性肌力支持，但仍未恢复。术后氧摄取和乳酸产生显著增加。肌钙蛋白T、肌酐、天冬氨酸转氨酶水平病理性升高，而凝血酶原比值异常低。在五个IC实验中的三个中，PCXD在24小时内发展。相比之下，所有9个心脏保存与CP保留完全保留收缩功能，没有显示任何PCXD的迹象。氧摄取量在正常范围内;血清乳酸以及器官功能参数仅轻度升高。在接受IC或CP保存移植物的受体中，预先形成的抗非Gal抗体相似。结论：虽然标准的缺血性心脏停搏液已在人类同种异体移植中取得了巨大成功，但我们的数据表明，它们不足以保存移植到狒狒体内的猪心：缺血性储存导致心脏功能严重受损，组织氧供应减少，导致超过一半的异种移植实验中多器官衰竭。相比之下，冷非缺血心脏保存与连续灌注可靠地防止早期移植失败。在围手术期一致的生存率是异种心脏移植后临床前长期结果的先决条件。
Background Successful preclinical transplantations of porcine hearts into baboon recipients are required before commencing clinical trials. Despite years of research, over half of the orthotopic cardiac xenografts were lost during the first 48 hours after transplantation, primarily caused by perioperative cardiac xenograft dysfunction (PCXD). To decrease the rate of PCXD, we adopted a preservation technique of cold non-ischemic perfusion for our ongoing pig-to-baboon cardiac xenotransplantation project. Methods Fourteen orthotopic cardiac xenotransplantation experiments were carried out with genetically modified juvenile pigs (GGTA1- KO/hCD46/hTBM) as donors and captive-bred baboons as recipients. Organ preservation was compared according to the two techniques applied: cold static ischemic cardioplegia (IC; n = 5) and cold non-ischemic continuous perfusion (CP; n = 9) with an oxygenated albumin-containing hyperoncotic cardioplegic solution containing nutrients, erythrocytes and hormones. Prior to surgery, we measured serum levels of preformed anti-non-Gal-antibodies. During surgery, hemodynamic parameters were monitored with transpulmonary thermodilution. Central venous blood gas analyses were taken at regular intervals to estimate oxygen extraction, as well as lactate production. After surgery, we measured troponine T and serum parameters of the recipient's kidney, liver and coagulation functions. Results In porcine grafts preserved with IC, we found significantly depressed systolic cardiac function after transplantation which did not recover despite increasing inotropic support. Postoperative oxygen extraction and lactate production were significantly increased. Troponin T, creatinine, aspartate aminotransferase levels were pathologically high, whereas prothrombin ratios were abnormally low. In three of five IC experiments, PCXD developed within 24 hours. By contrast, all nine hearts preserved with CP retained fully preserved systolic function, none showed any signs of PCXD. Oxygen extraction was within normal ranges; serum lactate as well as parameters of organ functions were only mildly elevated. Preformed anti-non-Gal-antibodies were similar in recipients receiving grafts from either IC or CP preservation. Conclusions While standard ischemic cardioplegia solutions have been used with great success in human allotransplantation over many years, our data indicate that they are insufficient for preservation of porcine hearts transplanted into baboons: Ischemic storage caused severe impairment of cardiac function and decreased tissue oxygen supply, leading to multi-organ failure in more than half of the xenotransplantation experiments. In contrast, cold non-ischemic heart preservation with continuous perfusion reliably prevented early graft failure. Consistent survival in the perioperative phase is a prerequisite for preclinical long-term results after cardiac xenotransplantation.