Journal Article

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

Zhao, Shuai, Aguilar-Sanchez, Yuriana, Shen, Ying H., Keefe, Joshua A., Tekook, Marcel A., Li, Na, Paasche, Amelie, Dobrev, Dobromir, Chelu, Mihail G., Wehrens, Xander H.T., Ong, Isabelle, Navarro-Garcia, J. Alberto, Li, Luge, Abu-Taha, Issam, Bruns, Florian, Kamler, Markus

2025

Overview

Postoperative atrial fibrillation (poAF) is AF occurring days after surgery, with a prevalence of 33% among patients undergoing open-heart surgery. The degree of postoperative inflammation correlates with poAF risk, but less is known about the cellular and molecular mechanisms driving postoperative atrial arrhythmogenesis. We performed single-cell RNA-seq comparing atrial nonmyocytes from mice with and without poAF, which revealed infiltrating CCR2+ macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a gene of interest driving in macrophages, which we confirmed in pericardial fluid collected from human patients after cardiac surgery. Indeed, macrophage depletion and macrophage-specific Il6ra conditional knockout (cKO) prevented poAF in mice. Downstream STAT3 inhibition with TTI-101 and cardiomyocyte-specific Stat3 cKO rescued poAF, indicating a proarrhythmogenic role of STAT3 in poAF development. Confocal imaging in isolated atrial cardiomyocytes (ACMs) uncovered what we believe to be a novel link between STAT3 and CaMKII-mediated ryanodine receptor-2 (RyR2)-Ser(S)2814 phosphorylation. Indeed, nonphosphorylatable RyR2S2814A mice were protected from poAF, and CaMKII inhibition prevented arrhythmogenic Ca2+ mishandling in ACMs from mice with poAF. Altogether, we provide multiomic, biochemical, and functional evidence from mice and humans that IL-6-STAT3-CaMKII signaling driven by infiltrating atrial macrophages is a pivotal driver of poAF, which portends therapeutic utility for poAF prevention.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Atrial fibrillation / Atrial Fibrillation - etiology / Atrial Fibrillation - genetics / Atrial Fibrillation - metabolism / Atrial Fibrillation - pathology / Ca2+/calmodulin-dependent protein kinase II / Calcium - metabolism / Calcium channels / Calcium Signaling / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism / Cardiac arrhythmia / Cardiology / Cardiomyocytes / Complications / Cytokines / Development and progression / Female / Fibrillation / Flow cytometry / Health aspects / Heart muscle / Heart surgery / Humans / Immunology / Inflammation / Interleukin 6 / Interleukin-6 - genetics / Interleukin-6 - metabolism / Leak channels / Leukocytes / Macrophages / Macrophages - metabolism / Macrophages - pathology / Male / Mice / Mice, Knockout / Molecular modelling / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / Ostomy / Pathogenesis / Phosphorylation / Physiological aspects / Postoperative Complications - genetics / Postoperative Complications - metabolism / Postoperative Complications - pathology / Receptors, Interleukin-6 - genetics / Receptors, Interleukin-6 - metabolism / Ryanodine Receptor Calcium Release Channel - genetics / Ryanodine Receptor Calcium Release Channel - metabolism / Ryanodine receptors / Signal Transduction / Sinuses / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Surgery