This multidisciplinary research project is designed to characterize the pathophysiology of iron-induced congestive heart failure using a systematic series of studies of the cardiomyopathy of iron overload in a new animal model, the Mongolian gerbil. Iron-induced myocardial disease is the most frequent cause of death in thalassemia major and is a major life-limiting complication of other transfusion-dependent refractory anemias, hereditary hemochromatosis and other forms of iron overload. The investigators hypothesize that (I) the body iron burden is a principal determinant of the magnitude of cardiac iron deposition in patients with thalassemia major, (ii) the nonuniform pattern of iron deposition in the heart results in variability in iron concentrations within cardiac myocytes, and (iii) increased intracellular iron selectively affects specific ion channels in cardiac myocytes, producing abnormalities in sodium and potassium currents, and damages other cellular components, producing cardiomyocyte dysfunction and heart failure. The proposed research has three specific aims: (1) to determine the effects of chronic iron overload on cardiac function during the development and progression of iron-induced heart failure in the gerbil model of iron overload, using miniaturized assessment of cardiac physiology in vivo in the intact animal, physiological studies of the isolated heart, and cellular studies of freshly isolated cardiomyocytes; (2) to determine the effects of iron-chelating therapy and other pharmacological interventions on the progression and regression of iron-induced heart failure in the gerbil model of iron overload, using similar methods; and (3) to determine the molecular mechanisms by which cardiac Na+ currents are decreased and Ca2+-independent transient outward cardiac K+ currents are increased in iron-induced heart failure, using both freshly isolated cardiomyocytes from the gerbil model of iron-induced cardiomyopathy and rat neonatal cardiomyocytes in culture. This research will furnish the first electrophysiological and functional data from a new experimental model of heart failure. The results will provide fundamental information about the molecular basis for the effects of iron on cardiac ion channels and cardiomyocyte function in the heart failure of iron overload.
Showing the most recent 10 out of 13 publications
