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

• Applicant: Dr. Lars Saemann
• Subject Area: Cardiac and Vascular Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530557324

(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.

• DFG Programme: Research Grants