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

Avinash Kali, Ivan Cokic, Richard Tang, Alice Dohnalkova, Libor Kovarik, Hsin Jung Yang, Andreas Kumar, Frank S. Prato, John C. Wood, David Underhill, Eduardo Marbán, Rohan Dharmakumar

Research output: Contribution to journalArticle

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. Methods and 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.

Original languageEnglish (US)
Article numbere004996
JournalCirculation: Cardiovascular Imaging
Volume9
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

Fingerprint

Iron
Myocardial Infarction
Ventricular Remodeling
Canidae
ferric oxide
Macrophages
X-Ray Emission Spectrometry
Collagenases
Matrix Metalloproteinases
Transmission Electron Microscopy
Nanoparticles
Reperfusion
Histology
Magnetic Resonance Imaging
Hemorrhage
Cytokines

Keywords

  • Cytokines
  • hemorrhage
  • inflammation
  • iron ischemia-reperfusion injury
  • myocardial infarction

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine

Cite this

Persistent Microvascular Obstruction after Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling. / Kali, Avinash; Cokic, Ivan; Tang, Richard; Dohnalkova, Alice; Kovarik, Libor; Yang, Hsin Jung; Kumar, Andreas; Prato, Frank S.; Wood, John C.; Underhill, David; Marbán, Eduardo; Dharmakumar, Rohan.

In: Circulation: Cardiovascular Imaging, Vol. 9, No. 11, e004996, 01.11.2016.

Research output: Contribution to journalArticle

Kali, A, Cokic, I, Tang, R, Dohnalkova, A, Kovarik, L, Yang, HJ, Kumar, A, Prato, FS, Wood, JC, Underhill, D, Marbán, E & Dharmakumar, R 2016, 'Persistent Microvascular Obstruction after Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling', Circulation: Cardiovascular Imaging, vol. 9, no. 11, e004996. https://doi.org/10.1161/CIRCIMAGING.115.004996
Kali, Avinash ; Cokic, Ivan ; Tang, Richard ; Dohnalkova, Alice ; Kovarik, Libor ; Yang, Hsin Jung ; Kumar, Andreas ; Prato, Frank S. ; Wood, John C. ; Underhill, David ; Marbán, Eduardo ; Dharmakumar, Rohan. / Persistent Microvascular Obstruction after Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling. In: Circulation: Cardiovascular Imaging. 2016 ; Vol. 9, No. 11.
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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. Methods and 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.",
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AU - Cokic, Ivan

AU - Tang, Richard

AU - Dohnalkova, Alice

AU - Kovarik, Libor

AU - Yang, Hsin Jung

AU - Kumar, Andreas

AU - Prato, Frank S.

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AU - Dharmakumar, Rohan

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AB - 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. Methods and 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.

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