Macrophage-mediated IL-6 signaling drives ryanodine receptor-2 calcium leak in postoperative atrial fibrillation.

Summary

Using single-cell transcriptomics and multi-level functional studies, the authors identify infiltrating CCR2+ macrophages that drive IL-6–STAT3–CaMKII signaling to phosphorylate RyR2-S2814, promoting atrial Ca2+ leak and postoperative AF. Genetic (Il6ra and Stat3 cKOs; RyR2-S2814A) and pharmacologic (STAT3 inhibitor TTI-101; CaMKII inhibition) interventions prevented poAF in mice with corroborative human pericardial fluid data.

Key Findings

• CCR2+ macrophages were the most altered atrial nonmyocytes in poAF by single-cell RNA-seq.
• Macrophage-specific Il6ra knockout or macrophage depletion prevented poAF in mice.
• STAT3 inhibition (TTI-101) or cardiomyocyte Stat3 knockout rescued poAF.
• A novel mechanistic link: STAT3 → CaMKII-mediated RyR2-S2814 phosphorylation; RyR2-S2814A mice were protected and CaMKII inhibition normalized Ca2+ handling.
• Human pericardial fluid after cardiac surgery confirmed IL-6 involvement.

Clinical Implications

Targeting IL-6/STAT3/CaMKII signaling (e.g., perioperative use of STAT3 or CaMKII inhibitors, or IL-6 pathway modulation) may offer prophylaxis for poAF. Pericardial inflammatory profiling could refine risk stratification.

Limitations

• Predominantly preclinical; causality in humans not yet established via trials.
• Potential off-target or safety concerns with systemic STAT3/CaMKII inhibition in perioperative settings.

Future Directions

Pilot perioperative trials testing IL-6/STAT3/CaMKII pathway modulators for poAF prevention; development of localized delivery strategies; biomarkers for patient selection.