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ResearchIn-Press PreviewCardiologyImmunology Open Access | 10.1172/JCI187711

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

Joshua A. Keefe,1 Yuriana Aguilar-Sanchez,2 Jose Alberto Navarro-Garcia,1 Isabelle Ong,1 Luge Li,3 Amelie Paasche,1 Issam Abu-Taha,5 Marcel A. Tekook,6 Florian Bruns,7 Shuai Zhao,1 Markus Kamler,8 Ying H. Shen,9 Mihail G. Chelu,1 Li Na,1 Dobromir Dobrev,10 and Xander H. T. Wehrens1

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Keefe, J. in: JCI | PubMed | Google Scholar |

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Aguilar-Sanchez, Y. in: JCI | PubMed | Google Scholar |

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Navarro-Garcia, J. in: JCI | PubMed | Google Scholar |

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Ong, I. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Li, L. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Paasche, A. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Abu-Taha, I. in: JCI | PubMed | Google Scholar |

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Tekook, M. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Bruns, F. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Zhao, S. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Kamler, M. in: JCI | PubMed | Google Scholar |

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Shen, Y. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Chelu, M. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Na, L. in: JCI | PubMed | Google Scholar

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Dobrev, D. in: JCI | PubMed | Google Scholar |

1Cardiovascular Research Institute, Baylor College of Medicine, Houston, United States of America

2Cardiovascular Research Institute, Baylor colelge of Medicine, Houston, United States of America

3Department of Medicine, Baylor College of Medicine, Houston, United States of America

4Cardiovascular Research Institute, Baylor College of Medicine, Houston, Germany

5Institute of Pharmacology, University Duisburg-Essen, Essen, Germany

6Department of Cardiology, Angiology and Pneumology, University of Duisburg-Essen, Essen, Germany

7Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany

8Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, Essen, Germany

9Department of Surgery, Baylor College of Medicine, Houston, United States of America

10Department of Integrative Physiology, Baylor College of Medicine, Houston, Germany

Find articles by Wehrens, X. in: JCI | PubMed | Google Scholar |

Published March 6, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI187711.
Copyright © 2025, Keefe et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 6, 2025 - Version history
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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 sequencing comparing atrial non-myocytes from mice with versus without poAF, which revealed infiltrating CCR2+ macrophages to be the most altered cell type. Pseudotime trajectory analyses identified Il-6 as a top gene 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 pro-arrhythmogenic role of STAT3 in poAF development. Confocal imaging in isolated atrial cardiomyocytes (ACMs) uncovered a novel link between STAT3 and CaMKII-mediated ryanodine receptor-2 (RyR2)-Ser(S)2814 phosphorylation. Indeed, non-phosphorylatable 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 that portends therapeutic utility for poAF prevention.

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