Minimally invasive extracorporeal circulation protects against postoperative pulmonary endothelial injury in elderly cardiac surgery via suppressing the C5a-mtDNA-cGAS-STING axis: a mechanistic randomized controlled trial.

BACKGROUND

Elderly patients undergoing cardiac surgery are highly susceptible to postoperative pulmonary complications triggered by conventional extracorporeal circulation (CECC)-driven systemic inflammation and subsequent pulmonary endothelial injury. Minimally invasive extracorporeal circulation (MiECC) lowers perioperative hemodilution and systemic inflammatory load, yet the underlying intracellular protective mechanisms in aged populations remain incompletely understood. This study therefore aimed to delineate the C5a-mtDNA-cGAS-STING signaling cascade as the central pathway mediating MiECC's pulmonary protective effect.

METHODS

This prospective randomized controlled trial enrolled 94 patients ≥70 years undergoing elective valve or coronary bypass surgery, randomly allocated to MiECC (n = 46) or CECC (n = 48). Perioperative hemoglobin trajectories and 7-day postoperative adverse events were compared using appropriate statistical tests. For mechanistic validation, serum from 5 propensity-matched patient pairs (matched by age, surgery type, and CPB duration) was used to stimulate human pulmonary microvascular endothelial cells (HPMECs). Quantitative phenotypic assays, including fluorometric quantification coupled with high-content screening, were employed to evaluate endothelial barrier integrity, apoptosis, mitochondrial dysfunction, and activation of the cGAS-STING signaling axis. Two targeted pharmacological rescue experiments were conducted using C5a receptor antagonist PMX53 and STING selective inhibitor C-176, to establish the hierarchical causality of this proposed signaling axis.

RESULTS

No perioperative mortality was recorded in either cohort. The MiECC group exhibited markedly higher intraoperative hemoglobin levels and a 52.6% relative risk reduction in postoperative pulmonary exudative complications, with no extension of postoperative recovery timelines. Postoperative serum levels of complement C5a, pro-inflammatory cytokines, and endothelial injury biomarkers were significantly lower in the MiECC cohort. Quantitative analyses demonstrated that MiECC serum significantly attenuated endothelial hyperpermeability and reduced apoptosis rates. At the mechanistic level, MiECC serum suppressed mitochondrial superoxide accumulation (38.2% reduction) and preserved mitochondrial membrane potential, resulting in a 46.5% reduction in cytosolic mtDNA leakage. Consequently, MiECC serum downregulated cGAS and STING protein expression and suppressed nuclear translocation of phosphorylated IRF3 (p-IRF3). The dual inhibitor rescue demonstrated that pretreatment with PMX53 fully reversed all CECC serum-induced pathological phenotypes, whereas the STING inhibitor C-176 selectively ameliorated downstream endothelial injury without rescuing upstream mitochondrial dysfunction or cytosolic mtDNA leakage. Dual inhibitor rescue demonstrated that PMX53 completely reversed all pathological phenotypes, whereas C-176 only rescued downstream endothelial injury without correcting upstream mitochondrial damage or mtDNA release.

CONCLUSIONS

MiECC is a safe, effective perfusion strategy that mitigates postoperative pulmonary exudation in elderly cardiac surgical recipients. At the mechanistic level, MiECC restricts CPB-induced C5a overproduction, thereby preventing C5a-driven mitochondrial impairment and mtDNA release, which initiates the cGAS-STING inflammatory cascade. Selective C5aR blockade fully interrupts this pathological axis, providing robust translational evidence to support broader adoption of MiECC in high-risk elderly patients and identifying C5aR as a tractable therapeutic target for CPB-associated lung injury.