Circulating ATP from hepatic ischemia-reperfusion drives remote cardiac injury via macrophage inflammasome activation.

Summary

HIRI releases ATP that activates P2X7 on cardiac macrophages, triggering NLRP3–GSDMD pyroptosis in cardiomyocytes and remote cardiac dysfunction; this mechanism is supported by human association data (MINS rising with liver injury severity) and mouse causal experiments. Pharmacologic P2X7 antagonism or A2A receptor activation confers cardioprotection within a defined post-reperfusion window.

Key Findings

• MINS incidence increased from 20.5% to 50% with greater postoperative liver damage severity in 382 hepatectomy patients (P < 0.0001).
• Reperfusion surged circulating ATP within 1 hour; ATP was necessary and sufficient to induce remote cardiac injury in mice.
• Cardiac macrophage P2X7 activation triggered NLRP3 inflammasome and GSDMD-mediated cardiomyocyte pyroptosis; macrophage depletion preserved cardiac function.
• JNJ-47965567 (P2X7 antagonist) and adenosine A2A receptor activation reduced injury when given up to ~3 hours after reperfusion, defining a pharmacologic window.

Clinical Implications

Suggests monitoring and mitigating purinergic signaling after hepatic surgery; supports testing P2X7 antagonists or A2A agonists for perioperative cardioprotection in high-risk hepatectomy patients.

Limitations

• Human data are observational and may be confounded; interventional efficacy not yet demonstrated in patients.
• Translational dosing, safety, and timing of P2X7/A2A agents in surgical patients require clinical trials.

Future Directions

Prospective trials of P2X7 antagonism or A2A agonism in hepatectomy; biomarker-guided strategies (ATP, inflammasome signatures) to select high-risk patients and optimize timing.