Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling

Abstract

Background Emerging evidence indicates that persistent microvascular obstruction (PMO) is more predictive of major adverse cardiovascular events than myocardial infarct (MI) size. But, it remains unclear how PMO, a phenomenon limited to the acute/sub-acute period of MI, drives adverse remodeling in chronic MI setting. We hypothesized that PMO resolves into chronic iron crystals within MI territories, which in turn are proinflammatory and favor adverse remodeling post-MI. Methods and Results Canines (n=40) were studied with cardiac MRI to characterize the spatiotemporal relationships among PMO, iron deposition, infarct resorption, and LV remodeling between day 7 (acute) and week 8 (chronic) post-MI. Histology was used to assess iron deposition, and to examine relationships between iron content with macrophage infiltration, pro-inflammatory cytokine synthesis, and matrix metalloproteinase activation. Atomic-resolution TEM was used to determine iron crystallinity and energy-dispersive X-ray spectroscopy was used to identify the chemical composition of the iron composite. PMO with or without reperfusion hemorrhage led to chronic iron deposition and the extent of this deposition was strongly related to PMO volume (r>0.8). Iron deposits were found within macrophages as aggregates of nanocrystals (~2.5 nm diameter) in the ferric state. Extent of iron deposits was strongly correlated with proinflammatory burden, collagen degrading enzyme activity, infarct resorption, and adverse structural remodeling (r>0.5). Conclusions Crystalized iron deposition from PMO is directly related to proinflammatory burden, infarct resorption, and adverse LV remodeling in the chronic phase of MI in canines. Therapeutic strategies to combat adverse remodeling could potentially benefit from taking into account the chronic iron-driven inflammatory process.

Persistent Iron Within the Infarct Core After ST-Segment Elevation Myocardial Infarction

“…This theory is further supported by a recent canine study by Kali et al. (10) , which demonstrated the presence of proinflammatory cells in areas of iron deposition post-myocardial infarction.…”

“…Myocardial hemorrhage is a result of severe microvascular injury, with extravasation of erythrocytes secondary to loss of endothelial integrity 1 , 5 , 6 , 7 , 8 . Hemoglobin degradation products are toxic 9 , 10 , 11 , and their persistence is evidenced by immunohistochemical staining of iron within macrophages reflecting sustained inflammation within the infarct zone (10) . Information relating to the clinical significance of persistent iron within the infarct core in patients with acute STEMI complicated by myocardial hemorrhage has been limited (e.g., sample size of n ≤ 40 11 , 12 , 13 ), and prognostic data on health outcomes are lacking.…”

Cardiovascular Magnetic Resonance in Acute ST-Segment–Elevation Myocardial Infarction

“…These findings were recently confirmed in a canine model of MI, and the extent of residual iron was strongly correlated with markers of inflammation and adverse LV remodeling. 55 Roghi and colleagues 56 found higher levels of non-transferrin bound iron in 7 out of 15 STEMI patients with microvascular obstruction and postulated that intramyocardial hemorrhage could be a source of cardiotoxicity in these patients.…”

Efferocytosis and Outside-In Signaling by Cardiac Phagocytes. Links to Repair, Cellular Programming, and Intercellular Crosstalk in Heart

“…STEMI patients with intramyocardial hemorrhage also frequently present with residual myocardial iron that is associated with adverse left ventricular remodeling and suggestive of ongoing inflammation ( 83 ). In canines, myocardial iron deposits were directly related to proinflammatory burden with iron deposits found directly in cardiac macrophages ( 84 ). The accumulation of iron in macrophages is likely a direct consequence of excessive erythrophagocytosis in the hemorrhage.…”