Abstract
Improvements in early interventions after acute myocardial infarction (AMI), notably, the increased use of timely reperfusion therapy, have increased survival dramatically in recent decades. Despite this, maladaptive ventricular remodelling and subsequent heart failure (HF) following AMI remain a significant clinical challenge, particularly because several pre-clinical strategies to attenuate remodelling have failed to translate into clinical practice. Monocytes and macrophages, pleiotropic cells of the innate immune system, are integral in both the initial inflammatory response to injury and subsequent wound healing in many tissues, including the heart. However, maladaptive immune cell behaviour contributes to ventricular remodelling in mouse models, prompting experimental efforts to modulate the immune response to prevent the development of HF. Seminal work in macrophage biology defined macrophages as monocyte-derived cells that are comprised of two populations, pro-inflammatory M1 macrophages and reparative M2 macrophages, and initial investigations into cardiac macrophage populations following AMI suggested they aligned well to this model. However, more recent data, in the heart and other tissues, demonstrate remarkable heterogeneity and plasticity in macrophage development, phenotype, and function. These recent insights into macrophage biology may explain the failure of non-specific immunosuppressive strategies and offer novel opportunities for therapeutic targeting to prevent HF following AMI. Here, we summarize the traditional monocyte-macrophage paradigm, experimental evidence for the significance of these cells in HF after AMI, and the potential relevance of emerging evidence that refutes canonical models of monocyte and macrophage biology.
Highlights
The spleen contains myeloid precursors that expand rapidly after acute myocardial infarction (AMI); on adoptive transfer of splenic granulocyte-macrophage progenitors after AMI, these cells differentiate into splenic macrophages that mobilize to the healing myocardium.[38]
These findings have been corroborated when classical monocytes are defined as CD14þCD62Lþ cells, with high levels associated with greater infarct size and regional systolic LV dysfunction at 4-month follow-up after segment elevation MI (STEMI), which remained significant even after stratification according to the extent of transmural infarction.[44]
Pericardial macrophages were enriched for genes associated with homoeostasis and metabolism, whilst cardiac Tissue resident macrophages (TRM) were relatively enriched for genes involves in inflammation and, whilst this study did not take into account the newly recognized heterogeneity of cardiac TRM, it does illustrate the existence of a distinct populations of macrophages, whose contributions to cardiac homoeostasis and following injury has hitherto not been appreciated
Summary
Emergency management of acute myocardial infarction (AMI) has been revolutionized by timely reperfusion therapy and, in particular, increasing access to primary percutaneous coronary intervention, leading to dramatic improvements in early survival.[1,2,3] Despite this, AMI remains the commonest cause of heart failure (HF) and HF-related morbidity and mortality following AMI remain high.[4,5,6,7] In view of the burden of HF following AMI, there is an unmet need for better understanding of the pathogenesis of ventricular remodelling and development of novel therapeutic targets. In AMI, reduced blood flow to a region of myocardium results in infarction, mediated mainly through oncosis and necrosis.[8] This necrotic myocardium becomes a region of mechanical weakness that requires scar deposition to prevent myocardial rupture and limit functional deterioration This adaptive remodelling is necessary to prevent early mortality following AMI. Recognition of DAMPs by pattern recognition receptors on resident innate immune cells prompts a cascade of chemokine and pro-inflammatory cytokine release, recruiting and activating neutrophils, monocytes, and macrophages Together, these cells degrade the extracellular matrix and phagocytose necrotic cells. The final, maturation phase occurs over subsequent months and is characterized by remodelling of the extracellular matrix, with few immune cells present at the site of injury During this period following AMI, there are significant changes to ventricular size, shape, and function, with maladaptive remodelling leading to the development of HF.[11]. We discuss how recognition of macrophage heterogeneity and plasticity may benefit ongoing investigation and the development of new treatments in this important clinical area
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