SenoHTX to extend DCD - Treatment of old donor hearts with senomorphics during ex-vivo machine perfusion to extend the boundaries in heart transplantation with donation after circulatory death

(HTX)特别是在欧洲的老年供体和全世界的循环确定的死亡供体（DCD）。尽管如此，在DCD中使用旧供体几乎未被探索，但可能显著有助于供体数量的进一步增加。老年供体心脏更容易受到缺血和缺血/再灌注（I/R）损伤。过度I/R损伤增加了原发性移植物功能障碍（PGD）和冠状动脉微血管功能障碍（CMVD）的风险。促炎细胞因子参与驱动年轻和老年心肌和冠状动脉内皮的I/R损伤。衰老细胞随着年龄的增长而积累。这些衰老的老细胞，独立于I/R，已经分泌一种称为衰老相关分泌表型（SASP）的分子谱，由广泛的促炎细胞因子和基质降解因子组成，降低非衰老邻近细胞的活力。SASP可导致脑缺血再灌注损伤的累积效应。DCD心脏主要通过离体血液灌注（EVBP）维持。尽管EVBP限制了总缺血时间，但DCD心脏暴露于多种I/R情况。Senomorphics描述了一组通过靶向与SASP表达相关的途径来阻断SASP的药理学试剂。EVBP允许在移植前治疗心脏移植物。这项工作将集中在使用senomorphics，特别是ruxolitinib，在DCD HTX从老年人相比，年轻的捐助者，以改善移植后收缩，舒张功能，冠状动脉微血管功能。

(HTX) has been extended, especially in Europe by older donors and all over the world by circulatory-determined death donors (DCD). Nevertheless, the use of old donors in DCD is almost unexplored but could significantly contribute to a further increase in donor numbers. Old donor hearts are more vulnerable to ischemia and ischemia/reperfusion (I/R) injury. Excessive I/R injury increases the risk for primary graft dysfunction (PGD) and coronary microvascular dysfunction (CMVD). Proinflammatory cytokines are involved in driving I/R injury of the myocardium and the coronary endothelium at young and old age. Senescent cells accumulate with age. These senescent, old cells, independently of I/R, already secrete a profile of molecules known as the senescence-associated secretory phenotype (SASP), consisting of a wide range of proinflammatory cytokines and matrix-degrading factors reducing the viability of non-senescent neighboring cells. The SASP could lead to accumulating effects of cytokine-induced injury in the context of I/R. DCD hearts are predominantly maintained by ex-vivo blood perfusion (EVBP). Although EVBP limits total ischemic time, DCD hearts are exposed to multiple I/R situations. Senomorphics describe a group of pharmacological agents which block the SASP by targeting pathways related to the SASP expression. EVBP allows treatment of the cardiac allograft before transplantation. This work will focus on the use of senomorphics, particularly ruxolitinib, in DCD HTX from old compared to young donors to improve post-transplant contractility, diastolic function, and coronary microvascular function.