High Incidence of Cardiomyopathy in Beta-Thalassaemia Patients Receiving Regular Transfusion and Iron Chelation: Reversal by Intensified Chelation

Aldouri, M A; Wonke, B; Hoffbrand, A. V.; Flynn, D.M.; Ward, Susan E.; Agnew, J. E.; Hilson, AJ

doi:10.1159/000205046

Cited by 160 publications

(83 citation statements)

References 10 publications

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“…Especially in patients with secondary (transfusion-mediated) iron overload, heart failure is a prominent cause of death (25,26). In this case, clinically important cardiac dysfunction often requires years to appear following the establishment of an iron overload state.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Damage in Iron Overload

Gao

Campian

Qian

et al. 2009

Journal of Biological Chemistry

102

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Chronic iron overload has slow and insidious effects on heart, liver, and other organs. Because iron-driven oxidation of most biologic materials (such as lipids and proteins) is readily repaired, this slow progression of organ damage implies some kind of biological "memory." We hypothesized that cumulative iron-catalyzed oxidant damage to mtDNA might occur in iron overload, perhaps explaining the often lethal cardiac dysfunction. Real time PCR was used to examine the "intactness" of mttDNA in cultured H9c2 rat cardiac myocytes. After 3-5 days exposure to high iron, these cells exhibited damage to mtDNA reflected by diminished amounts of near full-length 15.9-kb PCR product with no change in the amounts of a 16.1-kb product from a nuclear gene. With the loss of intact mtDNA, cellular respiration declined and mRNAs for three electron transport chain subunits and 16 S rRNA encoded by mtDNA decreased, whereas no decrements were found in four subunits encoded by nuclear DNA. To examine the importance of the interactions of iron with metabolically generated reactive oxygen species, we compared the toxic effects of iron in wild-type and rho o cells. In wild-type cells, elevated iron caused increased production of reactive oxygen species, cytostasis, and cell death, whereas the rho o cells were unaffected. We conclude that long-term damage to cells and organs in iron-overload disorders involves interactions between iron and mitochondrial reactive oxygen species resulting in cumulative damage to mtDNA, impaired synthesis of respiratory chain subunits, and respiratory dysfunction.Patients with primary or secondary iron overload are liable to cardiac and hepatic failure, and type II diabetes. Iron is required for the activity of numerous iron-and heme-containing proteins, but "free" (i.e. redox active) iron catalyzes the formation of highly toxic reactive oxygen species (ROS) 2 that damage lipids, proteins, and DNA (1). This damage is assumed to arise from iron-catalyzed hydroxyl radical formation or, perhaps more likely, iron-centered radicals such as ferryl and perferryl (2, 3). Iron-driven oxidation events require that the metal interact with cellular oxidizing and reducing equivalents such as superoxide and hydrogen peroxide, a major source of which is "leak" of electrons from the mitochondrial electron transport chain (4 -6).The present investigations were focused on the etiology of iron-mediated cardiac damage and specifically on the question of why, in patients with chronic iron overload, damage to organs such as the heart develops over a period of years, whereas most types of iron-mediated oxidation events can be repaired within minutes or hours. We have investigated the hypothesis that cumulative damage to DNA, specifically mtDNA, is critical to the slow development of cardiac dysfunction in chronic iron overload. In partial support of this idea, earlier studies clearly show that iron does promote DNA base oxidation as well as single and double strand DNA breaks. Mitochondrial DNA may be particularly vulnerable ...

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA Damage in Iron Overload

Gao

Campian

Qian

et al. 2009

Journal of Biological Chemistry

102

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“…Although the survival of patients with beta thalassemia is good and has been improving in recent years, the prevalence of severe complications is still high and the main cause of morbidity and mortality remains heart failure secondary to iron overload (2). The iron-induced cardiomyopathy is treatable and reversible if intensive chelation treatment is instituted in time (3)(4)(5). Then, direct measurement of myocardial iron may allow earlier diagnosis and treatment and help to reduce the mortality due to iron-induced cardiomyopathy.…”

mentioning

confidence: 99%

Influence of myocardial fibrosis and blood oxygenation on heart T2* values in thalassemia patients

Meloni

Pepe

Positano

et al. 2009

Magnetic Resonance Imaging

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Purpose:To determine whether T2* measurements quantifying myocardial iron overload in thalassemia patients are influenced by myocardial fibrosis and blood oxygenation. Materials and Methods:Multislice multiecho T2* was performed in 94 thalassemia patients in order to quantify myocardial iron overload. The left ventricle was automatically segmented into a 16-segment standardized heart model, and the T2* value on each segment as well as the global T2* were calculated. Delayed enhanced cardiovascular magnetic resonance (DE-CMR) images were obtained to detect myocardial fibrosis. The blood oxygenation was assessed by the noninvasive measurement of partial pressure of oxygen (pO2).

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“…Iron deposition in the heart cells is of outstanding interest [66][67][68]. Heart failure is the leading cause of death among hemosiderotic -thalassemia patients [69][70][71]. In pathological examinations, iron loading for 6 months did not show any morphological changes of the liver, spleen and heart in all groups.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice

Srichairatanakool¹,

Pangjit²,

Phisalaphong³

et al. 2013

ABB

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Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising effective iron chelatorsfor the treatment of iron overload in -thalassemia patients; nonetheless, their side effects have also been reported. 3-Hydroxypyridinone derivatives are being developed as a safer new chelator and in combined chelation therapy. We evaluated the iron-chelating activity of 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) in iron-loaded C57BL6 mice. The feeding of a ferrocene-supplemented diet (Fe diet) to mice resulted in iron overload, detectable plasma nontransferrin-bound iron (NTBI) and labile plasma iron (LPI), and increases of red cell membrane iron, plasma malondialdehyde (MDA) and excessive tissue iron deposits. Like DFP, the CM1 lowered the levels of the membrane non-heme iron, the NTBI and LPI (p < 0.05) and the MDA after 3 months of treatment. Administration of the Fe diet and the Fe diet along with the chelators did not change the morphology of the liver and heart. Numerous iron accumulations were observed in the liver and spleen tissues of the Fe dietfed mice, whereas the CM1 reduced such iron deposition. Thus, 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) can be considered a candidate bidentate oral iron chelator and is effective in the removal of toxic irons in blood compartment and tissues. The effectiveness and toxicity of the CM1 need to be investigated extensively in thalassemia mice and patients with iron overload.

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High Incidence of Cardiomyopathy in Beta-Thalassaemia Patients Receiving Regular Transfusion and Iron Chelation: Reversal by Intensified Chelation

Cited by 160 publications

References 10 publications

Mitochondrial DNA Damage in Iron Overload

Mitochondrial DNA Damage in Iron Overload

Influence of myocardial fibrosis and blood oxygenation on heart T2* values in thalassemia patients

Evaluation of a novel oral iron chelator 1-(N-acetyl-6-aminohexyl)-3-hydroxypyridin-4-one (CM1) for treatment of iron overload in mice

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