title: 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/subacute 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.
  
  
  RESULTS
  Canines (n=40) were studied with cardiac magnetic resonance imaging to characterize the spatiotemporal relationships among PMO, iron deposition, infarct resorption, and left ventricular 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, proinflammatory cytokine synthesis, and matrix metalloproteinase activation. Atomic resolution transmission electron microscopy 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
  Crystallized iron deposition from PMO is directly related to proinflammatory burden, infarct resorption, and adverse left ventricular 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.
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Avinash
authors.initials: A
authors.lastname: Kali
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Ivan
authors.initials: I
authors.lastname: Cokic
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Richard
authors.initials: R
authors.lastname: Tang
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Alice
authors.initials: A
authors.lastname: Dohnalkova
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Libor
authors.initials: L
authors.lastname: Kovarik
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Hsin-Jung
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Kumar
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Frank S
authors.initials: FS
authors.lastname: Prato
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: John C
authors.initials: JC
authors.lastname: Wood
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: David
authors.initials: D
authors.lastname: Underhill
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.).
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
authors.affiliation: From the Cedars-Sinai Medical Center, Los Angeles, CA (A.K., I.C., R.T., H.-J.Y., A.K., D.U., E.M., R.D.); University of California, Los Angeles (A.K., H.-J.Y., D.U., E.M., R.D.); Pacific Northwest National Laboratory, Environmental Molecular Sciences Laboratory, Richland, WA (A.D., L.K.); Lawson Health Research Institute, University of Western Ontario, London, Canada (F.S.P.); and Children's Hospital Los Angeles, CA (J.C.W.). rohandkumar@csmc.edu.
authors.forename: Rohan
authors.initials: R
authors.lastname: Dharmakumar
mesh_terms: D000818:Animals; D003326:Coronary Circulation; D003460:Crystallization; D004195:Disease Models, Animal; D004285:Dogs; D005290:Ferric Compounds / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008833:Microcirculation; D046529:Microscopy, Electron, Transmission; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D013052:Spectrometry, X-Ray Emission; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D005290:Ferric Compounds; D018836:Inflammation Mediators; C000499:ferric oxide
keywords: cytokines; hemorrhage; inflammation; iron ischemia-reperfusion injury; myocardial infarction