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.

心脏移植是患有严重心力衰竭患者的最佳治疗选择。由于捐助者心脏的数量有限，每年，英国少于200名患者接受这种治疗，但我们知道大约有2000名年龄在65岁以下的患者死于心力衰竭。另一方面，由于人们担心在身体外部存储和困难的移植操作之后，许多由脑死亡供体（DBD）捐赠的心脏（DBD）没有被移植。不使用年龄较大的捐助者和心脏增厚的心脏，因为它们在存储过程中检测到过多。将心脏在人体外部储存的传统方法，一个冰盒剥夺了心脏的氧气。当血液流向心脏的血液在接受者的体内恢复时，氧气突然供应能量和营养缺乏的心脏会造成损害，称为缺血再灌注（IR）损伤。这显着降低了心脏的功能，并且是移植后最常见的死亡原因，因此我们只选择最佳的心脏，并允许将它们存储在冰箱中最多4小时。英国领导世界的领域，从非心跳或循环死亡后的捐赠（DCD）捐赠，有可能将心脏移植数量增加30％。但是，由于这些DCD心脏必须在从捐助体中取出后不久就可以提供氧气，因此它们依靠机器在动脉周围抽血进行存储和运输。唯一可用的机器将供体的心保持在温暖温度（34度摄氏度）下击败状态。但是，它的成本（每用物32K英镑）太昂贵了，无法广泛采用。一种新方法的低温氧化灌注（HOP），它在低温下（8度摄氏）将血液泵入人体外部的心脏。我们认为它比冰箱更好，因为它内部的供体心脏在存储期间会收到营养和氧气。在实验室中，这给出了良好的效果，但尚未得到人类心脏的证明，尤其是对于我们目前拒绝使用的某些心脏。我们想表明，心肌细胞的损害较小，这导致心脏跳动更强。我们还想表明，存储时间最多可以延长12个小时。我们计划存储10个DBD和10个DCD人心的心脏，这些心脏被拒绝进行临床移植，但捐赠了4-12个小时；另一组10 dbd心脏使用冰盒4个小时。在此期间存储后，它们将被放到测试电路上，并提供富含血液的营养溶液，该解决方案将移植物模拟到接受者中，但在实验室中又持续了4个小时。我们将在电路中采集心脏肌肉和溶液的样本，并记录心脏收缩的强度。首先，我们想测试未接受临床移植的DBD和DCD心脏是否在HOP储存长达12小时后具有良好的功能。其次，将对样品进行实验，以比较多少心肌细胞死亡或损坏，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，快速测量的标记并反映供体心脏质量。在临床心脏移植期间将采集类似的样本。我们将测试我们发现的标记是否还可以预测患者移植后的心脏功能。为了更好地了解Hop如何保护心脏质量，我们希望使用这种方法来增加移植的心脏数量，延长存储期并改善心脏移植的结果。总体而言，我们想研究这种新的心脏存储方法是否会使等待名单上的更多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