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