Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans

Abstract

The immune system plays critical roles in myocardial injury and repair following acute myocardial infarction (AMI). Evidence from experimental models strongly implicates monocytes as critical to these processes and their specific targeting results in a significant reduction in infarct size and improved healing. It is currently unclear if monocytes play a similarly important role in humans. Examining changes in the patterns of gene expression can address this question. Here, we show that the peripheral blood monocyte response following AMI is conserved between species and that monocytes appear to be ‘programmed’ prior to their arrival at sites of myocardial injury. This investigation may translate to the future development of therapeutics to treat patients presenting with AMI that importantly would be effective in the hours after the onset of ischaemia.

Inflammatory processes in cardiovascular disease: a route to targeted therapies

“…Conversely, TLR2 deficiency is associated with reduced myocardial fibrosis after AMI and improved left ventricular remodelling 29 . TLR4, therefore, seems to be an important component in the initial inflammatory response, and TLR2 central to repair and left ventricular remodelling 30 .…”

“…To this end, transcriptomic analysis of circulating monocytes after AMI has identified patterns of gene expression that are conserved between mice and humans 30 . Although not yet formally tested, defined patterns of gene expression in downstream effector cells might plausibly give a more-precise insight into the activity of relevant pathways than measuring soluble biomarkers of uncertain origin and or site of action.…”

“…In AMI, circulating monocytes display patterns of gene expression in common with ‘inflammation’ and ‘mitosis’, with CD14, IL-1, and TLR2 identified as highly relevant components of the response using gene-set-enrichment techniques 30,74 . Analogous approaches have been used to validate preclinical models of disease, identify new therapeutic targets 30 and, clinically, gene sets in circulating leukocytes have been used to diagnose cardiac transplantation rejection 75 .…”

“…Analogous approaches have been used to validate preclinical models of disease, identify new therapeutic targets 30 and, clinically, gene sets in circulating leukocytes have been used to diagnose cardiac transplantation rejection 75 . Such approaches also borrow from the field of oncology, where they have enabled the reclassification of many malignancies on the basis of molecular signatures that have different prognostic and therapeutic responses 76 .…”

Ischaemia alters the effects of cardiomyocyte‐derived extracellular vesicles on macrophage activation

“…Acute myocardial infarction (AMI), due to a blockage of blood supply to the heart, restricts the availability to oxygen and nutrients, ultimately leading to cell death . Although a fine‐tuned inflammatory response is essential for an efficient cardiac repair following injury, its abnormal intensification can be detrimental and it has been implicated in the pathological remodelling of the heart, namely in AMI and heart failure …”