IRON INDUCED CONGESTIVE HEART FAILURE

描述 （摘自申请人摘要）这项多学科研究 该项目旨在描述铁诱导的 充血性心力衰竭使用系统的一系列研究， 心肌病的铁超载在一个新的动物模型，蒙古沙鼠。 铁诱导的心肌疾病是最常见的死亡原因， 地中海贫血是一种严重的生命限制并发症， 输血依赖性难治性贫血、遗传性血色病和 其他形式的铁超载。 研究人员假设（I） 体内铁负荷是心脏铁含量的主要决定因素 重型地中海贫血患者的沉积，（ii）不均匀的模式 铁沉积在心脏中导致铁的变异性 心肌细胞内的浓度，和（iii）增加的细胞内 铁选择性地影响心肌细胞中的特定离子通道， 产生钠和钾电流的异常，并损害其他 细胞成分，产生心肌细胞功能障碍和心力衰竭。 本研究有三个具体目的：（1）确定 慢性铁超载对心脏功能的影响， 沙土鼠铁致心力衰竭的研究进展 超负荷，使用体内心脏生理学的小型化评估， 完整的动物，离体心脏的生理学研究，以及细胞 新鲜分离的心肌细胞的研究;（2）确定 铁螯合疗法和其他药物干预 沙土鼠铁性心力衰竭模型的进展和消退 铁超载，使用类似的方法;和（3），以确定分子 心脏Na+电流降低和Ca 2+非依赖性的机制 在铁诱导的心脏中，瞬时外向心脏K+电流增加 失败，使用来自沙鼠模型的新鲜分离的心肌细胞， 铁诱导的心肌病和培养的大鼠新生心肌细胞。 这项研究将提供第一个电生理和功能 数据来自一个新的心力衰竭实验模型。 结果将 提供有关影响的分子基础的基本信息， 铁对心力衰竭心肌离子通道和心肌细胞功能的影响 铁超负荷 (End摘要）

DESCRIPTION (Adapted from the applicant's abstract) 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. (End of Abstract)