ArticlemedRxiv : the preprint server for health sciences2025
Mitochondrial DNA-Mediated Immune Activation After Resuscitation from Cardiac Arrest.
Article in medRxiv : the preprint server for health sciences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Post-cardiac arrest syndrome (PCAS) is characterized by a robust inflammatory response that contributes to significant morbidity and mortality among patients resuscitated from sudden cardiac arrest (SCA). Mitochondrial DNA (mtDNA), with its bacterial-like genomic motifs, has been implicated as a damage-associated molecular pattern in other inflammatory contexts, but its role as a pro-inflammatory stimulus in PCAS has not been studied. Accordingly, the present study was designed to determine if PCAS is characterized by a rise in circulating mtDNA and, if so, whether mtDNA is selectively released, how it activates immune cells, and if targeting mtDNA-sensing pathways attenuates leukocyte activation. Methods: Plasma mtDNA and nuclear DNA (nucDNA) levels were measured in peripheral blood samples collected ∼4-hours post-ROSC from swine with PCAS (n=8) and patients hospitalized after resuscitation from out-of-hospital cardiac arrest (OHCA; n= 57). Additionally, Results: A significant ∼250-fold elevation in circulating mtDNA was observed shortly after ROSC in swine despite negligible changes in circulating nucDNA, suggesting selective release of mtDNA in PCAS. This finding was corroborated in human OHCA survivors, in which circulating mtDNA was similarly elevated during the early post-ROSC period. Circulating mtDNA was largely encapsulated within EVs in swine and humans, suggesting a conserved mechanism of release across species. Conclusions: These novel findings demonstrate that brief whole-body ischemia and reperfusion in the context of resuscitation from SCA triggers selective mtDNA release, primarily within EVs, that acts as a potent driver of immune activation in PCAS. By linking EV-encapsulated mtDNA to TLR9 and cGAS activation, this study provides a foundation for the development of novel therapeutic interventions aimed at limiting mtDNA release or disrupting its downstream sensing pathways to enhance survival and improve outcomes after SCA. Clinical Perspective:
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