Evaluation of Hypothermic Oxygenated Perfusion Ex-Vivo Heart Perfusion to Expand the Donor Pool and Improve Transplant Outcomes

心脏移植是选择性严重心力衰竭患者的最佳治疗选择。由于供体心脏的数量有限，每年在英国只有不到200名患者接受这种治疗，但我们知道大约有2000名65岁以下的患者死于心力衰竭。另一方面，许多由脑死亡捐赠者（DBD）捐赠的心脏由于担心它们在体外储存后的工作情况以及移植手术的困难而没有被移植。来自老年捐赠者和心肌增厚的人的心脏不被使用，因为它们在储存过程中变质太多。传统的心脏体外保存方法是用冰盒，这会使心脏缺氧。当血液在接受者体内恢复流向心脏时，突然向能量和营养耗尽的心脏供应氧气会导致损伤，称为缺血再灌注（IR）损伤。这会显著降低心脏的功能，是移植后最常见的死亡原因，因此我们只选择最好的心脏，并允许它们在冰盒中储存最多4小时。无心脏跳动的捐赠，或循环死亡后的捐赠（DCD），英国在这一领域处于世界领先地位，有可能增加30%的心脏移植数量。然而，由于这些DCD心脏在从供体体内取出后不久就必须提供氧气，因此它们依赖于一台机器在动脉周围泵送血液进行储存和运输。唯一可用的机器在温暖的温度（34摄氏度）下保持供体心脏处于跳动状态。然而，它的成本，每次使用£ 32 k，太贵了，无法广泛采用。低温充氧灌注是一种在低温（8 ℃）下泵送含氧血液，将心脏保存在体外的新方法。我们相信它比冰盒更好，因为里面的捐赠心脏在储存过程中获得营养和氧气。在实验室中，这给出了很好的结果，但尚未被证明用于人类心脏，特别是对于一些我们目前拒绝使用的心脏。我们想证明对心肌细胞的损伤更少，这会导致更强的心脏跳动。我们还希望展示存储时间可以延长至12小时。我们计划使用HOP储存10个DBD和10个DCD人心脏，这些人心脏被拒绝用于临床移植，但捐赠用于研究，使用HOP储存4-12小时;另一组10个DBD心脏使用冰盒储存4小时。经过这段时间的储存，他们将被放在一个测试电路，并提供血液为基础的营养丰富的解决方案，这模仿移植到一个受体，但在实验室，另外4小时。我们将采集心肌样本和回路中的溶液，并记录心脏收缩的强度。首先，我们想测试在HOP储存长达12小时后，不被接受用于临床移植的DBD和DCD心脏是否具有良好的功能。其次，将对样本进行实验，以比较有多少心肌细胞死亡或受损，以及这是否与心脏收缩的强度有关。此外，我们还将寻找可以方便快速测量并反映供体心脏质量的标记物。在临床心脏移植期间将采集类似样本。我们将测试我们发现的标记物是否也能预测患者移植后的心脏功能。随着对HOP如何保护心脏质量的更好理解，我们希望使用这种方法来增加心脏移植的数量，延长储存期，并改善心脏移植的结果。总的来说，我们想研究这种新的心脏储存方法是否会使更多等待名单上的患者从心脏移植中受益。

Heart transplantation is the best treatment option for selected patients with severe heart failure. As the number of donor hearts is limited, every year, fewer than 200 patients in the UK receive this treatment, but we know approximately 2000 patients younger than 65 years die of heart failure. On the other hand, many hearts kindly donated by the brain death donors (DBD) are not being transplanted due to the concerns about how well they may work following storage outside the body and the difficult transplant operation. Hearts from older donors and those with thickened heart muscles are not used because they deteriorate too much during storage. The traditional method to store heart outside human body, an ice box, deprives heart of oxygen. When blood flow to the heart is resumed in a recipient's body, the sudden supply of oxygen to the energy- and nutrient-depleted heart causes damage, called ischaemia reperfusion (IR) injury. This markedly reduces the function of the heart and is the commonest cause of death after transplant, so we only select the best hearts and allow them to be stored in the ice box for a maximum of 4 hours. Donation from non-heart beating, or donation after circulatory death (DCD), a field in which the UK leads the world, has the potential to increase number of heart transplants by 30%. However, as these DCD hearts have to be supplied with oxygen soon after being removed from donor bodies, they rely on a machine pumping blood around the arteries for storage and transportation. The only available machine maintains donor hearts in beating state at a warm temperature (34 degree Celsius). However, its cost, £32k per usage, is too expensive for it to be widely adopted. A new method Hypothermic Oxygenated Perfusion (HOP), which pumps blood with oxygen at low temperature (8 degree Celsius) to store heart outside human body has been developed. We believe it is better than the ice box, because donor hearts inside it receive nutrient and oxygen during storage. In the laboratory this gives good results, but has yet to be proven for the human heart, and particularly for some of the hearts we currently turn down for use. We want to show that there is less damage to the heart muscle cells, and this results in a stronger beating heart. We also want to show that the storage time can be extended for up to 12 hours. We plan to store 10 DBD and 10 DCD human hearts, that are declined for clinical transplantation but donated for research, using HOP for 4-12 hours; and another group of 10 DBD hearts using the ice box for 4 hours. After this period of storage, they will be put onto a testing circuit and provided with blood-based nutrient-rich solution, which mimics the transplant into a recipient, but in the laboratory, for another 4 hours. We will take samples of the heart muscles and solution in the circuit, and record the strength of the heart contractions. First, we would like to test whether the DBD and DCD hearts, that are not accepted for clinical transplant, have good function after being stored by HOP for up to 12 hours. Second, experiments on the samples will be performed to compare how many heart muscles cells are dead or damaged and whether this correlates with the strength of the heart contractions. In addition, we will look for markers which can be easily and quickly measured and reflect the donor heart quality. Similar samples will be taken during clinical heart transplantation. We will test whether the markers that we found also predict heart function after transplantation in patients. With a better understanding of how HOP works to protect heart quality, we hope to use this method to increase the number of hearts being transplanted, lengthen the storage period, and improve the heart transplant outcomes. Overall, we would like to study whether this new heart storage method will make more patients on the waiting list benefit from heart transplantation.