Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction

Abstract

Myocardial infarction (MI) leads to rapid necrosis of cardiac myocytes. To achieve tissue integrity and function, inflammatory cells are activated, including monocytes/macrophages. However, the effect of monocyte/macrophage recruitment after MI remains poorly defined. After experimental MI, monocytes and macrophages were depleted through serial injections of clodronate-containing liposomes. Monocyte/macrophage infiltration was reduced in the myocardium after MI by active treatment. Mortality was increased due to thromboembolic events in monocyte- and macrophage-depleted animals (92 vs. 33%; P<0.01). Left ventricular thrombi were detectable as early as 24 h after MI; this was reproduced in a genetic model of monocyte/macrophage ablation. A general prothrombotic state, increased infarct expansion, and deficient neovascularization were not observed. Severely compromised extracellular matrix remodeling (collagen I, placebo liposome vs. clodronate liposome, 2.4 ± 0.2 vs. 0.8 ± 0.2 arbitrary units; P<0.001) and locally lost integrity of the endocardium after MI are potential mechanisms. Patients with a left ventricular thrombus had a relative decrease of CD14CD16 monocyte/macrophage subsets in the peripheral blood after MI (no thrombus vs. thrombus, 14.2 ± 0.9 vs. 7.80 ± 0.4%; P<0.05). In summary, monocytes/macrophages are of central importance for healing after MI. Impaired monocyte/macrophage function appears to be an unrecognized new pathophysiological mechanism for left ventricular thrombus development after MI.

Emerging roles for macrophages in cardiac injury: cytoprotection, repair, and regeneration

“…Experimental evidence also suggests that macrophage subsets play a crucial role in regulating all aspects of the reparative response following infarction (20,21). During the inflammatory phase of infarct healing, macrophages with potent phagocytotic properties clear the infarct of dead cells and matrix debris, and distinct macrophage subsets may contribute to suppression and resolution of inflammation after infarction.…”

Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction

“…Between days 4 and 7 after MI, a late Ly6C lo population, associated with the M2 "healing" phenotype, infiltrates the myocardium (18). Interestingly, targeted depletion of either population with clodronate liposomes leads to impaired infarct healing (14,19,20). Characterization of M1 and M2 subpopulations has been well-established (21)(22)(23), and macrophages can assume a multitude of activated states in response to microenvironmental cues (6,24).…”

Role of Lymphocytes in Myocardial Injury, Healing, and Remodeling After Myocardial Infarction

“…[5][6][7] Besides their pivotal function in modulating wound healing, monocytes also protect against ventricular thrombi formation early after MI. 8 Broadly speaking, we now have a firm understand of innate leukocyte, especially monocyte-derived cells, activity after MI.…”