title: Iron and oxidative stress in cardiomyopathy in thalassemia.
abstract: With repeated blood transfusions, patients with thalassemia major rapidly become loaded with iron, often surpassing hepatic metal accumulation capacity within ferritin shells and infiltrating heart and endocrine organs. That pathological scenario contrasts with the physiological one, which is characterized by an efficient maintenance of all plasma iron bound to circulating transferrin, due to a tight control of iron ingress into plasma by the hormone hepcidin. Within cells, most of the acquired iron becomes protein-associated, as once released from endocytosed transferrin, it is used within mitochondria for the synthesis of protein prosthetic groups or it is incorporated into enzyme active centers or alternatively sequestered within ferritin shells. A few cell types also express the iron extrusion transporter ferroportin, which is under the negative control of circulating hepcidin. However, that system only backs up the major cell regulated iron uptake/storage machinery that is poised to maintain a basal level of labile cellular iron for metabolic purposes without incurring potentially toxic scenarios. In thalassemia and other transfusion iron-loading conditions, once transferrin saturation exceeds about 70%, labile forms of iron enter the circulation and can gain access to various types of cells via resident transporters or channels. Within cells, they can attain levels that exceed their ability to chemically cope with labile iron, which has a propensity for generating reactive oxygen species (ROS), thereby inducing oxidative damage. This scenario occurs in the heart of hypertransfused thalassemia major patients who do not receive adequate iron-chelation therapy. Iron that accumulates in cardiomyocytes forms agglomerates that are detected by T2* MRI. The labile forms of iron infiltrate the mitochondria and damage cells by inducing noxious ROS formation, resulting in heart failure. The very rapid relief of cardiac dysfunction seen after intensive iron-chelation therapy in some patients with thalassemia major is thought to be due to the relief of the cardiac mitochondrial dysfunction caused by oxidative stress or to the removal of labile iron interference with calcium fluxes through cardiac calcium channels. In fact, improvement occurs well before there is any significant improvement in the total level of cardiac iron loading. The oral iron chelator deferiprone, because of its small size and neutral charge, demonstrably enters cells and chelates labile iron, thereby rapidly reducing ROS formation, allowing better mitochondrial activity and improved cardiac function. Deferiprone may also rapidly improve arrhythmias in patients who do not have excessive cardiac iron. It maintains the flux of iron in the direction hemosiderin to ferritin to free iron, and it allows clearance of cardiac iron in the presence of other iron chelators or when used alone. To date, the most commonly used chelator combination therapy is deferoxamine plus deferiprone, whereas other combinations are in the process of assessment. In summary, it is imperative that patients with thalassemia major have iron chelators continuously present in their circulation to prevent exposure of the heart to labile iron, reduce cardiac toxicity, and improve cardiac function.
authors.affiliation: Section of Hematology, Division of Hematology, Oncology, and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA. Electronic address: vberdoukas@yahoo.com.au.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Berdoukas
authors.affiliation: Section of Hematology, Division of Hematology, Oncology, and Blood & Marrow Transplantation, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA 90027, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Coates
authors.affiliation: Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, E Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors.forename: Zvi Ioav
authors.initials: ZI
authors.lastname: Cabantchik
mesh_terms: D009202:Cardiomyopathies / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D019190:Iron Overload / Q000150:complications / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects*; D013789:Thalassemia / Q000150:complications* / Q000503:physiopathology; D014168:Transferrin
chemical_list: D007502:Iron Chelating Agents; D014168:Transferrin
keywords: Free radicals; Iron cardiomyopathy; Iron chelation therapy; Iron overload; Labile cellular iron; Labile plasma iron; Reactive oxygen species; Thalassemia major; Transfusion