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Background <p>Heart donation after circulatory death (DCD) is a promising strategy to increase graft supply. However, in contrast to conventional heart transplantation, in which organs are retrieved from heart-beating donors, DCD hearts are subjected to damaging conditions before and during functional, warm <i>in-situ</i> ischemia in the donor, leading to ischemia-reperfusion injury (IRI). Although sex differences have been identified in other contexts of cardiac IRI, such as myocardial infarction, they remain underexplored in DCD. Therefore, we aimed to investigate whether sex differences induce changes in the expression of genes in response to cardiac DCD conditions, including IRI, which may contribute to sexual dimorphism in graft quality.</p> Methods <p>102 animals were included in this study. Male, female, and ovariectomized (OVX) Wistar rats underwent simulated DCD with no or 22&#xa0;min of functional, warm <i>in-situ</i> ischemia, followed by oxygenated reperfusion with left-ventricular loading. Functional recovery was assessed and left-ventricular tissue was used for RNA-sequencing.</p> Results <p>Recovery of left ventricular function was decreased by functional, warm <i>in-situ</i> ischemia, but significantly better in females than in males, with OVX resembling the males. Reperfusion induced inflammatory, stress-response and metabolic-related pathways in all groups. Expression of 110 genes correlated with cardiac recovery, many of which were more abundant in females compared to males, consistent with a role in improved post-ischemic ventricular function. Among these genes, Igfbp3, Fam78b, and Galnt10 were differentially expressed in females compared to males and OVX, suggesting an influence of female sex hormones.</p> Conclusions <p>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 quality control programs that positively correlate with ventricular function. Significantly higher expression of genes related to energy metabolism, including fatty acid metabolism, and inflammatory pathways was revealed in males compared to females and is associated with decreased recovery. This study suggests potential new therapeutic targets for optimizing cardiac DCD graft quality, and highlights the importance of underlying sex and sex-hormone differences, e.g. in inflammatory pathways and metabolic adaptations, that should be taken into consideration for the implementation of sex-specific precision therapies.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Anja Helmer,
  • Alexia Clavier,
  • Maria Arnold,
  • Adrian Segiser,
  • Heidi E. L. Lischer,
  • Selianne Graf,
  • Mojgan Masoodi,
  • Georgia Beer,
  • Rahel Ottersberg,
  • Manuel Egle,
  • Matthias Siepe,
  • Sarah Longnus

摘要

Background

Heart donation after circulatory death (DCD) is a promising strategy to increase graft supply. However, in contrast to conventional heart transplantation, in which organs are retrieved from heart-beating donors, DCD hearts are subjected to damaging conditions before and during functional, warm in-situ ischemia in the donor, leading to ischemia-reperfusion injury (IRI). Although sex differences have been identified in other contexts of cardiac IRI, such as myocardial infarction, they remain underexplored in DCD. Therefore, we aimed to investigate whether sex differences induce changes in the expression of genes in response to cardiac DCD conditions, including IRI, which may contribute to sexual dimorphism in graft quality.

Methods

102 animals were included in this study. Male, female, and ovariectomized (OVX) Wistar rats underwent simulated DCD with no or 22 min of functional, warm in-situ ischemia, followed by oxygenated reperfusion with left-ventricular loading. Functional recovery was assessed and left-ventricular tissue was used for RNA-sequencing.

Results

Recovery of left ventricular function was decreased by functional, warm in-situ ischemia, but significantly better in females than in males, with OVX resembling the males. Reperfusion induced inflammatory, stress-response and metabolic-related pathways in all groups. Expression of 110 genes correlated with cardiac recovery, many of which were more abundant in females compared to males, consistent with a role in improved post-ischemic ventricular function. Among these genes, Igfbp3, Fam78b, and Galnt10 were differentially expressed in females compared to males and OVX, suggesting an influence of female sex hormones.

Conclusions

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 quality control programs that positively correlate with ventricular function. Significantly higher expression of genes related to energy metabolism, including fatty acid metabolism, and inflammatory pathways was revealed in males compared to females and is associated with decreased recovery. This study suggests potential new therapeutic targets for optimizing cardiac DCD graft quality, and highlights the importance of underlying sex and sex-hormone differences, e.g. in inflammatory pathways and metabolic adaptations, that should be taken into consideration for the implementation of sex-specific precision therapies.