Mitochondrial DNA-Mediated Immune Activation After Resuscitation From Cardiac Arrest.

BACKGROUND

Postcardiac arrest syndrome is characterized by systemic inflammation that contributes to poor outcomes after resuscitation from sudden cardiac arrest. Mitochondrial DNA (mtDNA) has been implicated as a proinflammatory stimulus in other contexts, but its role in postcardiac arrest syndrome is unclear. We determined if postcardiac arrest syndrome is characterized by a rise in circulating mtDNA, how mtDNA activates immune cells, and if targeting mtDNA-sensing pathways attenuates leukocyte activation.

METHODS

Plasma mtDNA and nuclear DNA levels were measured ~4-hours after return of spontaneous circulation following sudden cardiac arrest in swine (n=8) and humans (n=57). Additionally, porcine peripheral blood mononuclear cells were treated with mtDNA or extracellular vesicles (EVs) isolated from porcine plasma collected after return of spontaneous circulation. Pharmacological agents were used to inhibit TLR9 (toll-like receptor 9)- and cGAS (cyclic GMP-AMP synthase)-mediated mtDNA sensing.

RESULTS

A ~250-fold elevation in circulating mtDNA was observed after return of spontaneous circulation in swine despite negligible changes in circulating nuclear DNA, a finding that was corroborated in humans. Circulating mtDNA was largely encapsulated within EVs in both species, suggesting a conserved mechanism of release. In vitro studies demonstrated that peripheral blood mononuclear cell internalization of mtDNA-containing-EVs was required for leukocyte activation. This response was attenuated by EV disruption, DNA degradation, and blockade of TLR9 or cGAS pathways, identifying novel targets to modulate inflammation in postcardiac arrest syndrome.

CONCLUSIONS

Brief whole-body ischemia and reperfusion in the context of resuscitation from sudden cardiac arrest elicits mtDNA release, primarily within EVs, that triggers leukocyte activation. Targeting mtDNA release or its downstream sensors may offer a new therapeutic strategy to improve outcomes after sudden cardiac arrest.