Differential transcriptomic and metabolomic landscape between human hearts donated after cardiac vs brain death

With rapid advances in donor heart preservation technology, insights into related molecular responses are needed.

We performed single-nuclei RNA sequencing and metabolomics on the human left ventricle to elucidate differences between donation after brain (DBD) vs cardiac death (DCD).

Our study revealed fundamentally different human cardiac biology at the transcriptomic and metabolomic levels between DBD vs DCD. DCD hearts are marked by ischemic metabolic responses and generation of oxidative substrates. DCD cardiomyocytes and fibroblasts also display robust proinflammatory and profibrotic responses, while endothelial cells are already primed for leukocyte recruitment at the time of procurement. Interestingly, resident cardiac macrophages also shifted towards a proinflammatory phenotype with an increase in human leukocyte antigen expression in DCD hearts. DBD hearts have a more favorable transcriptional profile for oxidative phosphorylation processes but also harbor a proinflammatory endothelium, possibly related to brain death.

These insights offer an understanding of biological processes underlying these donation protocols which may impact early donor heart function as well as graft longevity after transplantation. Our study also describes potential molecular targets for developing future therapies to mitigate preservation-induced cardiac injury and immune-mediated rejection.