Recruited macrophages elicit atrial fibrillation

Author:

Hulsmans Maarten12ORCID,Schloss Maximilian J.12ORCID,Lee I-Hsiu12ORCID,Bapat Aneesh3ORCID,Iwamoto Yoshiko12,Vinegoni Claudio12ORCID,Paccalet Alexandre12ORCID,Yamazoe Masahiro12,Grune Jana12ORCID,Pabel Steffen124,Momin Noor12ORCID,Seung Hana12ORCID,Kumowski Nina12ORCID,Pulous Fadi E.12ORCID,Keller Daniel5ORCID,Bening Constanze5,Green Ursula6ORCID,Lennerz Jochen K.6ORCID,Mitchell Richard N.7ORCID,Lewis Andrew89ORCID,Casadei Barbara89ORCID,Iborra-Egea Oriol10ORCID,Bayes-Genis Antoni10ORCID,Sossalla Samuel411,Ong Chin Siang1213ORCID,Pierson Richard N.12ORCID,Aster Jon C.7,Rohde David12ORCID,Wojtkiewicz Gregory R.12ORCID,Weissleder Ralph12ORCID,Swirski Filip K.1415ORCID,Tellides George13ORCID,Tolis George16,Melnitchouk Serguei12ORCID,Milan David J.17,Ellinor Patrick T.318ORCID,Naxerova Kamila12ORCID,Nahrendorf Matthias12319ORCID

Affiliation:

1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

2. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

3. Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

4. Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.

5. Department of Thoracic and Cardiovascular Surgery, University Hospital Wuerzburg, Wuerzburg, Germany.

6. Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

7. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

8. Radcliffe Department of Medicine, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.

9. British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, UK.

10. Institut del Cor Germans Trias i Pujol, CIBERCV, Badalona, Barcelona, Spain.

11. Department of Cardiology and Angiology, University of Giessen/DZHK, Partner Site Rhein-Main, Germany.

12. Division of Cardiac Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

13. Department of Surgery, Yale School of Medicine, New Haven, CT, USA.

14. Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

15. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

16. Department of Cardiac Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

17. Leducq Foundation, Boston, MA, USA.

18. Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard University, Cambridge, MA, USA.

19. Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany.

Abstract

Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1 + macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2 −∕− HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1 + macrophages as targets for immunotherapy in atrial fibrillation.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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