The Role of Macrophages in Nonischemic Heart Failure

T he mammalian heart contains a population of resident macrophages that expands in response to injury through the recruitment of circulating monocytes (1).After myocardial infarction, the sudden death of a large number of cardiomyocytes releases danger signals, mobilizing monocytes in the bone marrow and possibly also in extramedullary sites, such as the spleen.Induction of CC chemokines, such as CC motif chemokine ligand 2, in the infarcted myocardium recruits abundant monocytes that express the chemokine receptor CCR2, and exhibit a proinflammatory phenotype (2,3).CCR2 þ monocytes and macrophages play an important role in the clearance of necrotic cardiomyocytes and in cardiac repair after infarction, but also contribute to the pathogenesis of adverse cardiac remodeling (2).Although macrophages have been extensively implicated in the reparative and remodeling responses to myocardial infarction, their role in chronic nonischemic heart failure remains unclear.In mouse models of heart failure associated with left ventricular pressure overload, and in heart failure with preserved ejection fraction patients, the density of myocardial macrophages is significantly increased (4,5).However, the mechanisms of recruitment and activation of cardiac macrophages in response to chronic pressure overload and their functional role in the development of heart failure are poorly understood.In this issue of JACC: Basic to Translational Science, Patel et al. (6) demonstrate an important role for CCR2 þ macrophages in the pathogenesis of fibrosis, hypertrophy, and cardiac dysfunction in the pressure-overloaded heart.In a mouse model of transverse aortic constriction, a significant increase in circulating Ly6C hi CCR2 þ monocytes was associated with a marked expansion of myocardial CCR2 þ macrophages, driven by cardiac induction of CC chemokines.Blocking CCR2 through early administration of the small molecule CCR2 antagonist RS-504393, or through treatment with the anti-CCR2 monoclonal antibody MC21, inhibited myocardial infiltration with CCR2 þ macrophages, abrogated the expansion of T cells in heart-draining mediastinal lymph nodes, and reduced left ventricular hypertrophy after 1 week of pressure overload.Moreover, 4 weeks after transverse aortic constriction, MC21-treated mice exhibited significantly attenuated systolic dysfunction and profoundly reduced cardiac interstitial fibrosis, in comparison to immunoglobulin G-treated animals.The study adds to a growing body of evidence suggesting that chemokine-driven, macrophagemediated inflammation plays a critical role in the pathogenesis of pressure overload-induced heart failure.The findings not only support the significance of CCR2 þ macrophages as cellular effectors of myocardial fibrosis, hypertrophy, and dysfunction in nonischemic heart failure, but also open new research directions by raising several important questions.