Claudio Vinegoni, Ph.D. | Recruited macrophages elicit atrial fibrillation

Sci.
Recruited macrophages elicit atrial fibrillation

Hulsmans, M., Schloss, M.J., Lee, I.H., Bapat, A., Iwamoto, Y., Vinegoni, C., Paccalet, A., M., Yamazoe, Grune, J., Pabel, S., Momin, N., Seung, H., Kumowski, N., Pulous, F.E., Keller, D., C., Bening, Green, U., Lennerz, J.K., Mitchell, R.N., Lewis, A., Casadei, B., Iborra-Egea, O., Bayes-Genis, A., Sossalla, S., Ong, C.S., Pierson, R.N., Aster, J.C., Rohde, D., Wojtkiewicz, G.R., Weissleder, R., Swirski, F.K., Tellides, G., Tolis, G., Melnitchouk, S., Milan, D.J., Ellinor, P.T., Naxerova, K., and Nahrendorf^#, M.

Science 2023

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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{2023-SCIENCE, author= {Hulsmans, M. and Schloss, M.J. and Lee, I.H. and Bapat, A. and Iwamoto, Y. and Vinegoni, C. and Paccalet, A. and Yamazoe M. and Grune, J. and Pabel, S. and Momin, N. and Seung, H. and Kumowski, N. and Pulous, F.E. and Keller, D. and Bening C. and Green, U. and Lennerz, J.K. and Mitchell, R.N. and Lewis, A. and Casadei, B. and Iborra-Egea, O. and Bayes-Genis, A. and Sossalla, S. and Ong, C.S. and Pierson, R.N. and Aster, J.C. and Rohde, D. and Wojtkiewicz, G.R. and Weissleder, R. and Swirski, F.K. and Tellides, G. and Tolis, G. and Melnitchouk, S. and Milan, D.J. and Ellinor, P.T. and Naxerova, K. and Nahrendorf, M.}, title = {Recruited macrophages elicit atrial fibrillation}, journal = {Science}, alternatejournal = {Sci.}, year = {2023}, volume = {381}, number = {6654}, pages = {231–239}, doi = {10.1126/science.abq3061}, }
37440641

10.1126/science.abq3061

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:

Hulsmans, M., Schloss, M. J., Lee, I. H., Bapat, A., Iwamoto, Y., Vinegoni, C., Paccalet, A., M., Y., Grune, J., Pabel, S., Momin, N., Seung, H., Kumowski, N., Pulous, F. E., Keller, D., C., B., Green, U., Lennerz, J. K., Mitchell, R. N., … Nahrendorf^#, M. (2023). Recruited macrophages elicit atrial fibrillation. Science, 381(6654), 231–239. https://doi.org/10.1126/science.abq3061