Sex differences in cardiac recovery and corresponding gene expression in a rat model of donation after circulatory death

Recovery of left ventricular function was significantly better in females than in males, with OVX resembling the males. Reperfusion induces inflammatory and hypoxia-responsive gene programs in all sexes. Overall, 136 genes correlated with recovery, many of which were more abundant in females, consistent with a role in improved post-ischemic function.

Among these genes, Igfbp3, Fam78b, and Galnt10 were enriched in females compared to males and OVX, supporting a role for female sex hormones. Compared to male hearts, cardiac recovery is significantly higher in female hearts after exposure to DCD conditions and is accompanied by an increased expression of genes related to core homeostatic programs that have been connected to increased recovery. A significantly higher expression of genes related to energy metabolism, including fatty acid metabolism and inflammatory pathways, were more highly expressed in males compared to females and are associated with decreased recovery.

This study identifies potential therapeutic targets underlying sex-specific differences in DCD heart recovery and highlights the importance of treating DCD hearts in a sexually dimorphic manner, considering differences in inflammatory pathways and metabolic adaptations, to improve cardiac graft quality in both sexes.