Claudio Vinegoni, Ph.D. | Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Nat. Card. Res.
Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Grune, J., Lewis, A.J.M., Yamazoe, M., Hulsmans, M., Rohde, D., Xiao, L., Zhang, S., Ott, C., Calcagno, D.M., Zhou, Y., Timm, K., Shanmuganathan, M., Pulous, F.E., Schloss, M.J., Foy, B.H., Capen, D., Vinegoni, C., Wojtkiewicz, G.R., Iwamoto, I., Grune, T., Brown, D., Higgins, J., Ferreira, V.M., Herring, N., Channon, K.M., Neubauer, S., Study, Oxford Acute Myocardial Infarction (OxAMI), Sosnovik, D.E., Milan, D.J., Swirski, F.K., King, K.R., Aguirre, A.D., Ellinor, P.T., and Nahrendorf^#, M.

Nature Cardiovascular Research 2022

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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.
@article{2022-NCR-2, author= {Grune, J. and Lewis, A.J.M. and Yamazoe, M. and Hulsmans, M. and Rohde, D. and Xiao, L. and Zhang, S. and Ott, C. and Calcagno, D.M. and Zhou, Y. and Timm, K. and Shanmuganathan, M. and Pulous, F.E. and Schloss, M.J. and Foy, B.H. and Capen, D. and Vinegoni, C. and Wojtkiewicz, G.R. and Iwamoto, I. and Grune, T. and Brown, D. and Higgins, J. and Ferreira, V.M. and Herring, N. and Channon, K.M. and Neubauer, S. and Oxford Acute Myocardial Infarction (OxAMI) Study and Sosnovik, D.E. and Milan, D.J. and Swirski, F.K. and King, K.R. and Aguirre, A.D. and Ellinor, P.T. and Nahrendorf, M.}, title = {Neutrophils incite and macrophages avert electrical storm after myocardial infarction}, journal = {Nature Cardiovascular Research}, alternatejournal = {Nat. Card. Res.}, year = {2022}, volume = {1}, number = {1}, pages = {649–664}, doi = {10.1038/s44161-022-00094-w}, }
36034743

PMC9410341

10.1038/s44161-022-00094-w

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."

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For attribution in academic contexts, please cite this work as:

Grune, J., Lewis, A. J. M., Yamazoe, M., Hulsmans, M., Rohde, D., Xiao, L., Zhang, S., Ott, C., Calcagno, D. M., Zhou, Y., Timm, K., Shanmuganathan, M., Pulous, F. E., Schloss, M. J., Foy, B. H., Capen, D., Vinegoni, C., Wojtkiewicz, G. R., Iwamoto, I., … Nahrendorf^#, M. (2022). Neutrophils incite and macrophages avert electrical storm after myocardial infarction. Nature Cardiovascular Research, 1(1), 649–664. https://doi.org/10.1038/s44161-022-00094-w