Neutrophils incite and macrophages avert electrical storm after myocardial infarction

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.

Comparative single-cell profiling reveals distinct cardiac resident macrophages essential for zebrafish heart regeneration

“…Lastly, among genes of the “NO and ROS production in Macrophages” pathway, we found continuous activation of DAMP/PAMP receptor tlr2 , neutrophil cytosolic factors ( ncf1, ncf2 , and ncf4 ), myeloid cell-lineage committed gene spi1 and its downstream target ptpn6 , in addition to the macrophage differentiation marker irf8 in CL-treated hearts at 21 dpci (Figure 1-figure supplement 2D). ROS play dual roles in tissue repair and are largely produced by macrophages (58). On one hand, ROS attract leukocytes recruitment to the wound (59) and promote CM proliferation post cardiac injury (60).…”

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

“…Despite multiple obstacles to unequivocal detection of myocardial inflammation, it has been long known that myocardial inflammation [3][4][5][6][7][8][9][10][11][12] occurs in association with multiple types of 'genetic' [13][14][15][16][17][18] and 'non-genetic' [19,20] cardiomyopathies. The possible therapeutic potential of immunomodulation has been addressed in this context [21][22][23], but this issue remains unsolved so far.…”

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

“…Despite multiple obstacles to unequivocal detection of myocardial inflammation, it has been long known that myocardial inflammation [3][4][5][6][7][8][9][10][11][12] occurs in association with multiple types of 'genetic' [13][14][15][16][17] and 'non-genetic' [18,19] cardiomyopathies. Fig.…”