Language

English

Publication Date

5-1-2025

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI187711

PMID

40048254

PMCID

PMC12043083

PubMedCentral® Posted Date

3-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Atrial Fibrillation, Animals, Ryanodine Receptor Calcium Release Channel, Macrophages, Mice, Humans, Interleukin-6, STAT3 Transcription Factor, Mice, Knockout, Myocytes, Cardiac, Postoperative Complications, Male, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Signal Transduction, Female, Receptors, Interleukin-6, Calcium Signaling, Cardiology, Immunology, Arrhythmias, Calcium signaling, Macrophages

Published Open-Access

yes

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