Recruited macrophages elicit atrial fibrillation

Maarten Hulsmans; Maximilian J Schloss; I-Hsiu Lee; Aneesh Bapat; Yoshiko Iwamoto; Claudio Vinegoni; Alexandre Paccalet; Masahiro Yamazoe; Jana Grune; Steffen Pabel; Noor Momin; Hana Seung; Nina Kumowski; Fadi E Pulous; Daniel Keller; Constanze Bening; Ursula Green; Jochen K Lennerz; Richard N Mitchell; Andrew Lewis; Barbara Casadei; Oriol Iborra-Egea; Antoni Bayes-Genis; Samuel Sossalla; Chin Siang Ong; Richard N Pierson; Jon C Aster; David Rohde; Gregory R Wojtkiewicz; Ralph Weissleder; Filip K Swirski; George Tellides; George Tolis Jr; Serguei Melnitchouk; David J Milan; Patrick T Ellinor; Kamila Naxerova; Matthias Nahrendorf

doi:10.1126/science.abq3061

Recruited macrophages elicit atrial fibrillation

Science. 2023 Jul 14;381(6654):231-239. doi: 10.1126/science.abq3061. Epub 2023 Jul 13.

Authors

Maarten Hulsmans^#^{1

2}, Maximilian J Schloss^#^{1

2}, I-Hsiu Lee^#^{1

2}, Aneesh Bapat³, Yoshiko Iwamoto^{1

2}, Claudio Vinegoni^{1

2}, Alexandre Paccalet^{1

2}, Masahiro Yamazoe^{1

2}, Jana Grune^{1

2}, Steffen Pabel^{1

2

4}, Noor Momin^{1

2}, Hana Seung^{1

2}, Nina Kumowski^{1

2}, Fadi E Pulous^{1

2}, Daniel Keller⁵, Constanze Bening⁵, Ursula Green⁶, Jochen K Lennerz⁶, Richard N Mitchell⁷, Andrew Lewis^{8

9}, Barbara Casadei^{8

9}, Oriol Iborra-Egea¹⁰, Antoni Bayes-Genis¹⁰, Samuel Sossalla^{4

11}, Chin Siang Ong^{12

13}, Richard N Pierson¹², Jon C Aster⁷, David Rohde^{1

2}, Gregory R Wojtkiewicz^{1

2}, Ralph Weissleder^{1

2}, Filip K Swirski^{14

15}, George Tellides¹³, George Tolis Jr¹⁶, Serguei Melnitchouk¹², David J Milan¹⁷, Patrick T Ellinor^{3

18}, Kamila Naxerova^#^{1

2}, Matthias Nahrendorf^#^{1

2

3

19}

Affiliations

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.

^# Contributed equally.

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.

MeSH terms

Animals
Atrial Fibrillation* / genetics
Atrial Fibrillation* / immunology
Cell Movement
Gene Deletion
Heart Atria
Humans
Macrophages* / immunology
Mice
Mitral Valve Insufficiency / genetics
Osteopontin* / genetics
Single-Cell Gene Expression Analysis

Substances

Spp1 protein, mouse
Osteopontin
SPP1 protein, human

Abstract

MeSH terms

Substances

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