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

评估低温氧合灌注离体心脏灌注以扩大供体库并改善移植结果

基本信息

批准号：
MR/V002074/1
负责人：
Lu Wang
金额：
$ 21.8万
依托单位：
Newcastle University
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FV002074%2F1
关键词：
Evaluation Hypothermic Oxygenated Perfusion Ex

项目摘要

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.

心脏移植是某些严重心力衰竭患者的最佳治疗选择，由于捐赠心脏的数量有限，每年英国只有不到200名患者接受这种治疗，但我们知道大约有2000名65岁以下的患者死于这种治疗。另一方面，许多由脑死亡捐献者（DBD）捐献的心脏没有被移植，因为担心它们在体外储存后的工作情况以及老年捐献者的心脏移植手术的难度。那些有增厚的心肌不被使用，因为它们在储存过程中过度恶化。在体外储存心脏的传统方法（冰盒）会剥夺心脏的氧气，当接受者体内恢复心脏的血液流动时，会突然供应氧气。氧气输送到能量和营养耗尽的心脏会造成损害，称为缺血再灌注（IR）损伤，这会显着降低心脏功能，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让它们进行移植。被存储在冰盒中保存最长 4 小时的无心跳捐赠或循环死亡后捐赠 (DCD) 是英国领先世界的领域，有可能使心脏移植数量增加 30%。然而，由于这些 DCD 心脏在从捐献者体内取出后必须立即供氧，因此它们依靠一台机器将血液泵送到动脉周围进行储存和运输，唯一可用的机器使捐献者心脏在温暖的温度下保持跳动状态。 34度然而，其每次使用的成本为 32,000 英镑，无法广泛采用。一种新方法低温氧合灌注 (HOP)，可在低温（8 摄氏度）下泵入氧气以将心脏储存在体外。我们相信它比冰盒更好，因为供体心脏在储存过程中会在其中接收营养和氧气，这在实验室中给出了良好的结果，但对于人类心脏，特别是对于心脏来说，还没有得到证实。一些我们希望证明，我们目前拒绝使用的心脏对心肌细胞的损害较小，并且这会导致心脏跳动更强。我们还想证明，存储时间可以延长长达 12 小时。我们计划将 10 颗 DBD 和 10 颗 DCD 人类心脏（拒绝用于临床移植但捐赠用于研究）使用 HOP 保存 4-12 小时，另一组 10 颗 DBD 心脏在这段时间后使用冰盒保存 4 小时。储存后，它们将被放入测试回路中，并提供基于血液的营养丰富的溶液，模拟移植到接受者体内，但在实验室中，我们将在另外 4 小时内采集心肌和溶液样本。首先，我们要测试不接受临床移植的DBD和DCD心脏在HOP保存长达12小时后是否具有良好的功能。将进行样品实验以进行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相关。此外，我们将寻找可以轻松快速测量并反映供体心脏质量的标记物。我们将测试我们发现的标记物是否也可以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了解，我们希望使用这种方法来增加移植的心脏数量，延长心脏的寿命。保存期，提高心脏移植效果。总的来说，我们想研究这种新的心脏储存方法是否会让更多等待名单上的患者受益于心脏移植。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pharmacological testing of therapeutics using normothermic machine perfusion: A pilot study of 2,4-dinitrophenol delivery to steatotic human livers.

使用常温机器灌注进行治疗的药理学测试：2,4-二硝基苯酚递送至脂肪变性人类肝脏的初步研究。

DOI：
10.1111/aor.14309
发表时间：
2022
期刊：
Artificial organs
影响因子：
2.4
作者：
Tingle SJ
通讯作者：
Tingle SJ

LVAD decommissioning for myocardial recovery: Long-term ventricular remodeling and adverse events.

DOI：
10.1016/j.healun.2021.08.001
发表时间：
2021-12
期刊：
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
影响因子：
0
作者：
Gerhard EF;Wang L;Singh R;Schueler S;Genovese LD;Woods A;Tang D;Smith NR;Psotka MA;Tovey S;Desai SS;Jakovljevic DG;MacGowan GA;Shah P
通讯作者：
Shah P

(189) Non-Ischaemic Heart Preservation to Improve Donor Heart Quality

(189) 非缺血性心脏保存，提高供体心脏质量