Iron-Overload Cardiomyopathy: Evidence for a Free Radical– Mediated Mechanism of Injury and Dysfunction in a Murine Model

Abstract

Iron-overload cardiomyopathy is a restrictive cardiomyopathy that manifests itself as systolic or diastolic dysfunction secondary to increased deposition of iron in the heart and occurs with common genetic disorders such as primary hemochromatosis and beta-thalassemia major. Although the exact mechanism of iron-induced heart failure remains to be elucidated, the toxicity of iron in biological systems is believed to be attributed to its ability to catalyze the generation of oxygen-free radicals. In the current investigation, the dose-dependent effects of chronic iron-loading on heart tissue concentrations of iron, glutathione peroxidase (GPx) activity, free-radical production, and cardiac dysfunction were investigated in a murine model of iron-overload cardiomyopathy. It was shown that chronic iron-overload results in dose-dependent (a) increases in myocardial iron burden, (b) decreases in the protective antioxidant enzyme GPx activity, (c) increased free-radical production, and (d) increased mortality. These findings show that the mechanism of iron-induced heart dysfunction involves in part free radical-mediated processes.

Iron overload thalassemic cardiomyopathy: Iron status assessment and mechanisms of mechanical and electrical disturbance due to iron toxicity

“…This reaction is not only restricted to cell membrane phospholipids, but also to other membrane-bound cellular organelles. By studying iron overload in cultured NRVMs, Link et al (54) demonstrated evidence of lipid peroxidation, reduction in polyunsaturated fatty acids (PUFAs) and increased products from cellular lipid peroxidation, particularly toxic aldehydes (47,53,55,56). The aldehyde products such as malondialdehyde and 4-hydroxynonenal can form a covalent link to proteins (aldehyde-protein adducts), rendering the loss of cellular protein function (57).…”

Dual T‐type and L‐type calcium channel blocker exerts beneficial effects in attenuating cardiovascular dysfunction in iron‐overloaded thalassaemic mice

“…However, excess iron levels can lead to increased reactive oxygen species (ROS) production via the Haber-Weiss and Fenton reactions (Bartfay & Bartfay, 2000;Lekawanvijit & Chattipakorn, 2009). High ROS production can damage cellular lipids, proteins, DNA and mitochondria (Bartfay & Bartfay, 2000;Lekawanvijit & Chattipakorn, 2009). Previous studies suggested that mitochondrial dysfunction could be responsible for cardiac failure resulting from chronic iron overload (Gao et al 2009(Gao et al , 2010.…”

Baroreflex function in conscious rats submitted to iron overload

“…Before DFO After DFO Chronic iron overload produces heart dysfunction in a dose-dependent manner (8), probably resulting from the time lag necessary to deposit iron in tissues. In the heart, iron, initially deposited in the epicardium, has a long term-effect on transmural wall thickness (23,24).…”

“…Nevertheless, iron overload has undeniably been associated with cardiac and vascular dysfunctions in experimental conditions (5)(6)(7). Experiments conducted ex vivo have shown that iron overload induces a condition of heart failure (8) in Langendorff preparations of isolated hearts. In fact, deposition of iron into the heart is emerging as an important cause of heart failure (6).…”