Heart transplant is the gold standard therapy for patients with end-stage heart failure, with more than 5,000 transplants performed worldwide annually. Primary graft dysfunction (PGD) represents the most common cause of early mortality after cardiac transplantation, accounting for up to 40% of deaths occurring in the first thirty postoperative days. It represents a significant barrier to expansion of cardiac transplantation as definitive therapy for patients with end-stage heart failure. Despite its clinical impact, significnt gaps remain in our understanding of PGD. Factors related to the donor, the transplant procedure itself, and systemic recipient factors potentially contribute to the pathogenesis of PGD. However, PGD is not adequately predicted by donor factors, pre-transplant organ function, or compatibility. Importantly, cardiac allografts objectively considered to be of margina status by these metrics do not demonstrate an increased rate of PGD. Emerging evidence suggests a fundamental role for mitochondrial dysfunction in PGD, specifically as a result of oxidative stress. Furthermore, oxidative stress-induced mitochondrial injury likely further stimulates pro-inflammatory signaling, thus contributing to dysfunction in aggregate with an augmented alloimmune response. Our central hypothesis is that mitochondrial injury and subsequent immune consequences of mitochondrial dysfunction are critical in development of the PGD phenotype. The proposed studies will investigate the fundamental injury processes underlying PGD following cardiac transplantation and subsequent immune consequences that may contribute to graft dysfunction. The goal of these studies is to interrogate the fundamental injury processes and subsequent immune consequences that contribute to graft dysfunction. These studies will inform the design of new strategies to facilitate improved prediction, prevention, and management of PGD.
Primary graft dysfunction (PGD) represents the most common cause of early mortality after cardiac transplantation, accounting for up to 40% of deaths occurring in the first thirty postoperative days. It represents a significant barrier to expansion f cardiac transplantation as definitive therapy for patients with end-stage heart failure. The goal o these studies is to interrogate the fundamental injury processes and subsequent immune consequences that contribute to graft dysfunction. These studies will inform the design of new strategies to facilitate improved prediction, prevention, and management of PGD.
| Ganapathi, Asvin M; Mulvihill, Michael S; Englum, Brian R et al. (2017) Transplant size mismatch in restrictive lung disease. Transpl Int 30:378-387 |
