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已得到推广，特别是在欧洲的老年捐赠者和世界各地的循环系统决定的死亡捐赠者(DCD)。尽管如此，在DCD中使用老捐赠者几乎是未被探索的，但可能会大大促进捐赠者数量的进一步增加。陈旧供心更易受缺血和缺血/再灌注(I/R)损伤。过度的I/R损伤增加了发生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。促炎细胞因子参与了青年和老年心肌和冠脉内皮细胞的I/R损伤。衰老的细胞随着年龄的增长而积累。这些衰老的、老的细胞，独立于I/R，已经分泌了一系列被称为衰老相关分泌表型(SASP)的分子，由广泛的促炎细胞因子和降低非衰老邻近细胞活力的基质降解因子组成。SASP可导致细胞因子诱导的I/R损伤的累积效应。DCD心脏主要通过体外血液灌流(EVBP)维持。虽然EVBP限制了总的缺血时间，但DCD心脏暴露在多种I/R情况下。Senalics描述了一组通过靶向与SASP表达相关的途径来阻断SASP的药物。EVBP允许在移植前对同种异体心脏移植物进行治疗。这项工作将集中在老年和年轻供者的DCD HTX中使用同种异构体，特别是Ruxolitinib，以改善移植后的收缩、舒缩功能和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.