Abstract Body: BACKGROUND
Heart transplantation is the gold standard treatment for end-stage heart failure patients. However, only about half of patients will receive a transplant, and hearts from donors >55 years of age are often not transplanted due to concerns about primary graft dysfunction (PGD). The molecular mechanisms behind the increased risk of PGD in old donor age are not well-known.
METHODS
We examine the chromatin architecture changes in old and young human donor hearts via HiC. We determine the effects of Brd4 inhibition on the on old mouse donor heart cold preservation quality via ex vivo perfusion.
RESULTS
we found that older human donor hearts are associated with upregulated BRD4 expression and increased chromatin accessibility. We also identified that human cardiac aging is associated with altered 3D chromatin architecture at BRD4 sites at baseline. Unexpectedly, the cold preservation process in older donor hearts further intensifies chromatin looping at BRD4 sites. Functionally, we showed that old murine donor hearts are more susceptible to cold preservation-reperfusion injury. Importantly, Brd4 inhibition with JQ1 improved the function of ex vivo cold-preserved old donor hearts, restoring them to levels comparable to young donor hearts. Moreover, AAV9-mediated Brd4 knockdown in cardiomyocytes similarly improved ex vivo old donor heart function after cold preservation.
CONCLUSIONS
Brd4-associated 3D chromatin reorganization plays a critical role in the vulnerability of old donor hearts to cold preservation injury. Therefore, Brd4 could be a potential target for aging-associated PGD.