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