IRON INDUCED CONGESTIVE HEART FAILURE

铁引起的充血性心力衰竭

• 批准号: 6142588
• 负责人: ARTHUR M BROWN
• 金额: $ 28.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6142588
• 关键词: cardiac myocytes; chelation therapy; congestive heart failure; gerbil /jird; heart electrical activity; heart function; iatrogenic disease; iron poisoning; laboratory rat; membrane channels; nonhuman therapy evaluation; tissue /cell culture

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)

描述 （改编自申请人的摘要）这项多学科研究 该项目旨在表征铁诱导的病理生理学 充血性心力衰竭通过一系列系统研究 一种新的动物模型——蒙古沙鼠——铁超负荷心肌病。 铁诱发的心肌病是最常见的死亡原因 重型地中海贫血是其他疾病的主要限制生命的并发症 输血依赖性难治性贫血、遗传性血色素沉着症和 其他形式的铁过载。 研究人员假设 (I) 身体铁负荷是​​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) 不均匀模式 心脏中铁沉积的变化导致铁的变化 心肌细胞内的浓度，以及（iii）细胞内浓度增加 铁选择性地影响心肌细胞中的特定离子通道， 产生钠和钾电流异常，并损害其他 细胞成分，导致心肌细胞功能障碍和心力衰竭。 拟议的研究有三个具体目标：（1）确定效果 慢性铁超负荷对心脏功能的影响 铁沙鼠模型中铁诱导的心力衰竭的进展 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和细胞 对新鲜分离的心肌细胞的研究； (2) 确定效果 铁螯合疗法和其他药物干预 沙鼠模型中铁诱导的心力衰竭的进展和消退 铁过载，使用类似的方法； (3) 确定分子 心脏 Na+ 电流减少且不依赖 Ca2+ 的机制 铁诱导心脏中瞬时外向心脏 K+ 电流增加 失败，使用从沙鼠模型中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学和功能学研究 来自新的心力衰竭实验模型的数据。 结果将 提供有关影响的分子基础的基本信息 铁对心脏离子通道和心力衰竭心肌细胞功能的影响 铁过载。 （摘要完）