Low molecular weight iron and the oxygen paradox in isolated rat hearts.

Voogd, Arthur; Sluiter, Wim J.; Eijk, H.G. Van; Koster, J.F.

doi:10.1172/jci116086

Cited by 111 publications

(54 citation statements)

References 30 publications

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“…Therefore, the toxic effect of myocardial iron is dynamic and is increased in the presence of metabolic acidosis. 40 Based on the available data, it is logical to assume that peri-infarct ischemic myocardium, the target for SPIO-mediated stem cell therapy, is particularly susceptible to iron toxicity.…”

Section: Discussionmentioning

confidence: 99%

Magnetic resonance hypointensive signal primarily originates from extracellular iron particles in the long-term tracking of mesenchymal stem cells transplanted in the infarcted myocardium

Huang

Yang

et al. 2015

IJN

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Purpose The long-lasting hypointensities in cardiac magnetic resonance (CMR) were believed to originate from superparamagnetic iron oxide (SPIO)-engulfed macrophages during long-term stem cell tracking. However, the iron clearance capacity of the ischemic heart was limited. Therefore, we speculated that the extracellular SPIO particles may also be involved in the generation of false-positive signals. Methods and results Male swine mesenchymal stem cells (MSCs) were incubated with SPIO for 24 hours, and SPIO labeling had no significant effects on either cell viability or differentiation. In vitro studies showed that magnetic resonance failed to distinguish SPIO from living SPIO-MSCs or dead SPIO-MSCs. Two hours after the establishment of the female swine acute myocardial infarction model, 2×10 7 male SPIO-labeled MSCs (n=5) or unlabeled MSCs (n=5) were transextracardially injected into the infarcted myocardium at ten distinct sites. In vivo CMR with T2 star weighted imaging-flash-2D sequence revealed a signal void corresponding to the initial SPIO-MSC injection sites. At 6 months after transplantation, CMR identified 32 (64%) of the 50 injection sites, where massive Prussian blue-positive iron deposits were detected by pathological examination. However, iron particles were predominantly distributed in the extracellular space, and a minority was distributed within CD 68 -positive macrophages and other CD 68 -negative cells. No sex-determining region Y DNA of donor MSCs was detected. Conclusion CMR hypointensive signal is primarily caused by extracellular iron particles in the long-term tracking of transplanted MSCs after myocardial infarction. Consideration should be given to both the false-positive signal and the potential cardiac toxicity of long-standing iron deposits in the heart.

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Section: Discussionmentioning

confidence: 99%

Magnetic resonance hypointensive signal primarily originates from extracellular iron particles in the long-term tracking of mesenchymal stem cells transplanted in the infarcted myocardium

Huang

Yang

et al. 2015

IJN

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“…Although acute ischemia results in a spike in circulating and tissue catalytic iron, this does not appear to be solely a marker, but also a causal agent of worsened injury. Improved recovery of myocardial function after ischemia has been demonstrated with iron chelation (eg, deferoxamine) in animal models 10,16 and in one human study, providing indirect support for the toxicity of catalytic iron. Paraskevaidis et al suggested deferoxamine infusion was able to reduce myocardial stunning following elective coronary artery bypass grafting and improve long-term ejection fraction.…”

Section: Iron In Cardiovascular Diseasementioning

confidence: 98%

“…Abbreviations: CHF, congestive heart failure; CrCl, creatinine clearance; CV, cardiovascular; DM, diabetes mellitus; HR, hazard ratio; NT-pro-B-type natriuretic peptide, N terminal pro-B-type natriuretic peptide; MI, myocardial infarction. myocardium 10,16 and kidney. 17 In a rat model, Voogd et al demonstrated significant increases in the low-molecularweight-iron content of cardiac tissue after ischemia; similar results were found in a kidney model of ischemia.…”

Section: Iron In Cardiovascular Diseasementioning

confidence: 99%

Prognostic Evaluation of Catalytic Iron in Patients With Acute Coronary Syndromes

Steen

Cannon

Lele³

et al. 2013

Clinical Cardiology

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Background: The potential of iron to generate reactive oxygen species has motivated a long-standing interest in whether excess iron is causally linked to atherosclerotic heart disease. Circulating catalytic iron (''free'' iron) is that which is not bound to transferrin or ferritin and is available to generate reactive oxygen species that may have deleterious vascular effects. Hypothesis: We hypothesized that increased levels of catalytic iron would be associated with increased cardiovascular events. Methods: We investigated the association of catalytic iron with clinical outcomes in 1701 patients with unstable angina, non-ST-segment elevation myocardial infarction (MI), or ST-segment elevation MI who were followed for a median of 10 months. All endpoints were adjudicated by a blinded Clinical End Points Committee. Results: The median catalytic iron level was significantly higher in those who died, 0.45 μmol/L (0.37, 0.57), compared with survivors, 0.37μmol/L (0.31, 0.46; P = 0.016). Catalytic iron was associated with a stepwise increased risk of death, with the highest quartile at an almost 4-fold risk compared with baseline (hazard ratio: 3.94, P = 0.035), which persisted after adjustment for age, diabetes, prior MI, prior congestive heart failure, ST-segment deviation, creatinine clearance, B-type natriuretic peptide, smoking, and Killip class (adjusted hazard ratio: 3.97, P = 0.036). There was no association between catalytic iron and risk of MI, recurrent ischemia, heart failure, or bleeding. Conclusions: Increasing catalytic iron levels were associated with increased all-cause mortality. Although our findings suggest that catalytic iron is not likely to add to available tools as a routine biomarker for risk stratification of recurrent ischemic events, its association with mortality is intriguing and leaves open the question of whether cardiovascular therapeutics aimed at catalytic iron may be useful.

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“…Iron within the liver is found in several biochemical forms such as ferritin, hemosiderin, heme, and also in the putative intracellular low molecular weight form chelated to nucleotides, amino acids and other low molecular weight compounds (8)(9)(10). Various theories of cellular toxicity resulting from excess iron deposition emphasize specific cytopathologic mechanisms whereby chronic iron overload causes organelle damage and altered cell function (4,11).…”

Section: Introductionmentioning

confidence: 99%

Iron supplementation generates hydroxyl radical in vivo. An ESR spin-trapping investigation.

Kadiiska¹,

Burkitt²,

Xiang³

et al. 1995

J. Clin. Invest.

130

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Electron spin resonance (ESR) spectroscopy has been used to investigate hydroxyl radical generation in rats with chronic dietary iron loading. A secondary radical spin-trapping technique was used where hydroxyl radical forms methyl radical upon reaction with DMSO. The methyl radical was then detected by ESR spectroscopy as its adduct with the spin trap a-phenyl-N-t-butylnitrone (PBN). This adduct was detected in the bile of rats 10 wk after being fed an iron-loading diet and 40 min after the i.p. injection of the spin trap PBN dissolved in DMSO. Bile samples were collected into a solution of the ferrous stabilizing chelator 2,2 '-dipyridyl in order to prevent the generation of radical adducts ex vivo during bile collection. Identification of the ESR spectrum of the major radical adduct as that of PBN/ 'CH3 provides evidence for the generation of the hydroxyl radical during iron supplementation. Desferal completely inhibited in vivo hydroxyl radical generation stimulated by high dietary iron intake. No radical adducts were detected in rats which were fed the control diet for the same period of time. This is the first evidence of hydroxyl radical generation in chronic iron-loaded rats. (J. Clin. Invest. 1995.

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Low molecular weight iron and the oxygen paradox in isolated rat hearts.

Cited by 111 publications

References 30 publications

Magnetic resonance hypointensive signal primarily originates from extracellular iron particles in the long-term tracking of mesenchymal stem cells transplanted in the infarcted myocardium

Magnetic resonance hypointensive signal primarily originates from extracellular iron particles in the long-term tracking of mesenchymal stem cells transplanted in the infarcted myocardium

Prognostic Evaluation of Catalytic Iron in Patients With Acute Coronary Syndromes

Iron supplementation generates hydroxyl radical in vivo. An ESR spin-trapping investigation.

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