Targeting inflammatory pathways in myocardial infarction

Abstract

Acute cardiomyocyte necrosis in the infarcted heart generates Damage-Associated Molecular Patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, and triggering an intense inflammatory reaction. Infiltrating leukocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels; the geometric, functional and molecular alterations associated with post-infarction remodeling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the post-infarction inflammatory reaction may be crucial to protect the myocardium from dilative remodeling and progressive dysfunction. Inhibition and resolution of post-infarction inflammation involves mobilization of inhibitory mononuclear cell subsets and requires activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the post-infarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodeling. Given the pathophysiologic complexity of post-infarction remodeling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and Monocyte Chemoattractant Protein-1) may be effective in patients with defective resolution of post-infarction inflammation who exhibit progressive dilative remodeling. In contrast, patients with predominant hypertrophic/fibrotic responses may benefit from anti-TGF strategies.

TREM-1 Mediates Inflammatory Injury and Cardiac Remodeling Following Myocardial Infarction

“…17,18,19 Here, we used several complementary animal models, as well as patients' samples, to demonstrate the role of TREM-1 in orchestrating the inflammatory response triggered by MI. Genetic invalidation or pharmacological blockade of Trem-1 inhibits the recruitment of inflammatory cells to the infarcted myocardium and their activation.…”

Cellular recruitment in myocardial ischaemia/reperfusion injury

“…These concepts suggested that subsets of leucocytes could infiltrate cardiomyocytes exerting cytotoxic effects so that ischaemic injury extended [14]. Experimental studies targeting leucocytemediated inflammation in myocardial ischaemia and reperfusion showed a marked reduction in infarct size and prevented the extension of ischaemic cardiomyocyte injury [15][16][17][18].…”

“…LFA-1 is critical in this step, given that its inhibition blocks transmigration and reduces neutrophil extravasation [38,39]. Both antibody neutralization studies [16] and genetic models [40] show the huge importance of b2-integrins for the recruitment of neutrophils in the infarcted heart [18].…”

Intracoronary Delivery of Injectable Bioabsorbable Scaffold (IK-5001) to Treat Left Ventricular Remodeling After ST-Elevation Myocardial Infarction

“…The infusion catheter was placed immediately distal to the previously deployed stent. Coronary angiography was repeated 3 minutes after IK-5001 implantation, and biomarkers (including creatine kinase and creatine kinase, muscle and brain) were obtained at 8,16, and 24 hours after device deployment.…”