Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure

Abstract

Rationale Macrophages reside in the healthy myocardium, participate in ischemic heart disease and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of non-ischemic remote myocardium, however, remain unclear. Objective This study investigated the number, origin, phenotype and function of remote cardiac macrophages residing in the non-ischemic myocardium in mice with chronic heart failure after coronary ligation. Methods and Results Eight weeks post-MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6Chigh monocytes rose from 64±5 to 108±9 /μl blood (p<0.05). Cardiac monocyte recruitment declined in Ccr2−/− mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the MAPK pathway, while specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (p<0.05). Steady-state cardiac macrophages, monocyte-derived and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 vs.19.1±2%, p<0.05). Conclusions Myocardial failure is influenced by an altered myeloid cell repertoire.

Monocytes and macrophages in cardiac injury and repair

“…Accordingly, elevated blood monocyte counts in patients after MI negatively correlate with ejection fraction (39). Along these lines, humans and mice with heart failure also display a blood leukocytosis (3,40,41). In general, elevated white blood cell numbers are an independent risk factor for CAD (42)(43)(44) and more specifically, higher monocyte counts independently predict risk for atherosclerosis after adjustment for conventional risk factors (45)(46)(47)(48)(49).…”

“…Apart from these chemokines, cell adhesion molecules expressed on both, blood monocytes and cardiac endothelial cells, also contribute to enhanced leukocyte recruitment. It was reported that intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion protein 1 (VCAM1), E-and P-selectin are upregulated in the remote myocardium (the non-ischemic part) in mice with heart failure with reduced ejection fraction (HFrEF) (3) and that simultaneous blocking of endothelial ICAM1, ICAM2, VCAM1, E-and P-selectin reduced monocyte recruitment in the setting of acute MI (13 (19).…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…It should be emphasized that in the presence of a large infarction with significant hemodynamic consequences, viable noninfarcted myocardium also exhibits slowly progressive interstitial fibrosis related to the pathophysiologic effects of pressure and volume loads. Inflammation and fibrosis are suppressed in the healing infarct, leading to formation of a mature collagen-based scar, but in the viable noninfarcted zone, increased wall stress may locally activate macrophages and fibroblasts, triggering chronic progressive expansion of the cardiac interstitial matrix (97,98).…”

A Guardian of the Heartbeat

“…Although changes in macrophage type and number had been documented in various forms of heart disease, 3 it was assumed that cardiac macrophages played a canonical role in immune surveillance, protecting against pathogens and maintaining tissue integrity. The current story starts with a serendipitous observation: mice without properly functioning macrophages had sluggish, irregular heartbeats, which led Hulsmans et al to look more carefully at clusters of these cells around the atrioventricular node.…”