Potentiation of iron accumulation in cardiac myocytes during the treatment of iron overload in gerbils with the hydroxypyridinone iron chelator CP94

Abstract

Gerbils administered iron dextran are the only animal species which have been shown to develop hemochromatosis of the liver and heart in the same manner as transfusion dependent homozygous thalassemics. The iron chelating hydroxypyridinone, CP94, has been administered prophylactically to iron overloaded gerbils in a dosing regime which favors the formation of bidentate chelated iron, to examine the possibility of additional toxicity being caused to the liver and heart by the bidentate chelated iron complex. Hepatic iron accumulation was inhibited by CP94 administration for up to 6 weeks, but not after 20 weeks. Iron accumulation in the heart was increased significantly after 6 and 20 weeks of chelator treatment. Pathological changes in both organs were markedly more severe after 20 weeks in chelator treated animals. There was a higher incidence of cardiofibrosis and more extensive liver fibrosis in iron overloaded, chelator treated animals after 20 weeks.

Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II–Infused Rats

“…Recent studies also suggested that iron and/or iron-mediated increase in the extent of oxidative stress play a role in the fibrotic changes not only in the liver 16,33 but also in other organs such as heart. 34,35 Our data may suggest the possibility that iron may also have a role in the vascular remodeling in vivo in certain diseased conditions, such as increased circulating Ang II.…”

Role of deferiprone in chelation therapy for transfusional iron overload

“…20 A letter in response to these findings noted that when the same biopsy specimens were reviewed by another hepatopathologist in a masked manner but excluding specimens with insufficient numbers of portal tracts, no progression of liver fibrosis was found in the patients treated with deferiprone. 68 The description of increased rates of iron accumulation and hepatotoxicity in iron-loaded gerbils after treatment with dimethyl-3-hydroxypyrid-4-1 (CP94), 69 a compound closely related to deferiprone, 70,71 has been identified as evidence supportive of the hepatotoxicity and fibrogenic effect of deferiprone. 20,26 However, CP94 (dimethyl-3-hydroxypyrid-4-1) and deferiprone (dimethyl-3-hydroxypyrid-4-1) are different in their biologic activity.…”

Decreased Sodium and Increased Transient Outward Potassium Currents in Iron-Loaded Cardiac Myocytes

“…The gerbils treated with repeated injections of iron dextran over a period of months developed a cardiomyopathy that mimics the cardiomyopathy that develops over a period of years in patients with chronic iron overload. 8,9 Because knowledge of cardiac electrophysiology in the gerbil is limited, we also studied the rat, a species in which knowledge of cardiac electrophysiology is extensive. 25,26 Because the rat can excrete excess iron, cardiac iron deposition could not be produced in vivo in this species.…”

“…Past efforts to examine the effects of iron on the heart have been hampered by the lack of a suitable experimental model of human iron overload; most animal species have a far greater capacity to excrete iron than humans. Recently, Carthew et al 8,9 reported that weekly subcutaneous injections of iron dextran to Mongolian gerbils reproduced critical features of the cardiomyopathy found in human iron overload, in part because the gerbil seems unable to excrete iron as effectively as other rodents. We hypothesized that abnormal excitability of iron-loaded heart cells might contribute to arrhythmias, and we examined membrane currents of single cardiomyocytes isolated from the hearts of iron-loaded gerbils.…”