Abstract 16193: Crystallized Iron Deposits From Hemorrhagic Myocardial Infarctions Promote Macrophage Polarization Preferentially to a Pro-Inflammatory, M1, Phenotype within Chronic Myocardial Infarcts
Introduction: Reperfusion hemorrhage in acute myocardial infarction (AMI) has been identified as a major contributor to adverse ventricular remodeling. Recent evidence points to hemorrhagic AMI (h-AMI) evolving into regions of persistent iron deposits (PID) and that these iron deposits are associated with prolonged recruitment of macrophages throughout the chronic phase of MI. However, the physicochemical characteristics of PID and the phenotype of these macrophages have not been characterized.
Hypothesis: In the present study, we hypothesized that h-AMI leads to crystallized iron deposits, which in turn drive macrophages in the chronic MI (CMI) to a preferentially pro-inflammatory (M1) phenotype.
Methods: Ten canines were subjected to 3 hours of LAD occlusion followed by reperfusion. AMIs were confirmed as hemorrhagic on T2* MRI on day 5 post-MI. Hearts were explanted 8 weeks post-MI and underwent Transmission Electron Microscopy (TEM) to determine iron crystallinity. Energy-dispersive X-ray spectroscopy was used to identify the chemical composition of the iron crystals. Iron-driven macrophage polarization was determined histologically.
Results: Iron deposits within CMI were found within macrophages as aggregates of nanocrystals (~2.5 nm diameter) in the ferric state (Figure 1a). Histological evaluation of CMI revealed extensive co-localization of PID (Perls’ stain) with newly recruited macrophages (MAC387 marker), CD163 (marker of iron-specific macrophage activation), as well as the proinflammatory cytokines (TNF-α, IL-1β) within the scar territory (Figure 1b).
Conclusions: Reperfusion hemorrhage evolves into crystallized iron deposition in CMI and promotes macrophage polarization preferentially to a M1 phenotype. Since M1 macrophages are known to impart deleterious effects on the heart, therapeutic strategies to combat post h-AMI adverse remodeling should take into account the chronic iron-driven inflammatory process.
Author Disclosures: I. Cokic: None. A. Kali: None. R. Tang: None. A. Dohnalkova: None. L. Kovarik: None. H. Yang: None. A. Kumar: None. F.S. Prato: None. J.C. Wood: None. J. Francis: None. D. Underhill: None. E. Marbán: None. R. Dharmakumar: None.
- © 2016 by American Heart Association, Inc.