Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Jana Grune; Andrew J M Lewis; Masahiro Yamazoe; Maarten Hulsmans; David Rohde; Ling Xiao; Shuang Zhang; Christiane Ott; David M Calcagno; Yirong Zhou; Kerstin Timm; Mayooran Shanmuganathan; Fadi E Pulous; Maximilian J Schloss; Brody H Foy; Diane Capen; Claudio Vinegoni; Gregory R Wojtkiewicz; Yoshiko Iwamoto; Tilman Grune; Dennis Brown; John Higgins; Vanessa M Ferreira; Neil Herring; Keith M Channon; Stefan Neubauer; Oxford Acute Myocardial Infarction (OxAMI) Study; David E Sosnovik; David J Milan; Filip K Swirski; Kevin R King; Aaron D Aguirre; Patrick T Ellinor; Matthias Nahrendorf

doi:10.1038/s44161-022-00094-w

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Nat Cardiovasc Res. 2022 Jul;1(7):649-664. doi: 10.1038/s44161-022-00094-w. Epub 2022 Jul 11.

Authors

Jana Grune^{1

2}, Andrew J M Lewis^{1

2

3}, Masahiro Yamazoe^{1

2

3}, Maarten Hulsmans^{1

2}, David Rohde^{1

2}, Ling Xiao⁴, Shuang Zhang^{1

2}, Christiane Ott^{5

6}, David M Calcagno⁷, Yirong Zhou^{1

8}, Kerstin Timm⁹, Mayooran Shanmuganathan^{10

11}, Fadi E Pulous^{1

2}, Maximilian J Schloss^{1

2}, Brody H Foy^{1

12}, Diane Capen¹³, Claudio Vinegoni^{1

2}, Gregory R Wojtkiewicz¹, Yoshiko Iwamoto¹, Tilman Grune^{5

6}, Dennis Brown¹³, John Higgins^{1

12}, Vanessa M Ferreira¹⁰, Neil Herring^{11

14}, Keith M Channon^{10

11}, Stefan Neubauer^{10

11}; Oxford Acute Myocardial Infarction (OxAMI) Study; David E Sosnovik^{4

15

16}, David J Milan¹⁷, Filip K Swirski¹⁸, Kevin R King^{7

19}, Aaron D Aguirre^{1

8

16}, Patrick T Ellinor^{4

16

20}, Matthias Nahrendorf^{1

2

21}

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 These authors contributed equally and are listed in alphabetical order: Andrew J. M. Lewis, Masahiro Yamazoe.
⁴ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
⁶ Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
⁷ Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
⁸ Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Department of Pharmacology, University of Oxford, Oxford, UK.
¹⁰ Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹¹ National Institute for Health (NIHR) Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
¹² Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
¹³ Program in Membrane Biology, Nephrology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁴ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
¹⁵ Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Leducq Foundation, Boston, MA, USA.
¹⁸ Cardiovascular Research Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Department of Medicine, Division of Cardiovascular Medicine, University of California, San Diego La Jolla, CA, USA.
²⁰ The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²¹ Department of Internal Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.

Abstract

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2 ^-/- mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36 ^-/- and Mertk ^-/- mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

Abstract

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