MECHANISMS OF IMPROVED DIASTOLIC FUNCTION IN HUMAN HEART

充血性HART衰竭是许多类型HART的常见终点 心血管疾病。不管有没有相关的收缩功能障碍， 事实上，心力衰竭患者有舒张期功能障碍。然而， 心肌松弛和舒张期修整受损的细胞学基础 心力衰竭患者的异常是不明确的，没有 对舒张期功能障碍有特殊的治疗方法。 这项研究的广泛工作假设是最近观察到的 术后心肌松弛功能在细胞水平的改善 循环支持提供了一个独特的机会来确定枢纽 心力衰竭患者的舒张期功能障碍支持机制。 我们的具体假设是细胞内钙离子的变化 动态平衡及其决定因素代表了改善的主要机制 循环支持后的心脏和细胞松弛。 这项研究的一个主要目标是建立 体内细胞舒张期功能的多谱勒测量 离体肌细胞的松弛与钙离子衰变的变化 在衰竭的人的心脏中短暂的。我们还将定义以下范围 肌浆网钙ATPase和Na/Ca交换的变化 活动在晚期心脏钙稳态异常中的作用 循环后细胞松弛功能的衰竭和改善 援助。最后，我们将检查阿尔法1肾上腺素能 白细胞介素1β对正常人心脏的刺激作用 心肌细胞可以重现松弛和钙离子受损的表型 在心力衰竭中观察到的动态平衡。 这些目标将利用心肌细胞分离的最新进展来实现 多普勒超声心动图的技术和已建立的方法 人体心脏生理学、分子生物学和细胞培养 肌细胞。该项目将涉及与其他公司的密切合作 研究人员包括在该RNA应用中功能 坦普尔的评估将得到以下量化分析的补充 加州大学旧金山分校合作者的心肌松弛分子决定因素。 明确心肌损害的细胞和分子基础 在人类的放松，将提供一个基础的发展 对舒张期功能障碍患者的特殊治疗。

Congestive hart failure is a common endpoint for many types of cardiovascular disease. With or without associated systolic dysfunction, virtually patients with heart failure have diastolic dysfunction. However, the cellular basis of impaired myocardial relaxation and diastolic filing abnormalities in patients with heart failure is poorly defined, and no specific therapies exist for diastolic dysfunction. The broad working hypothesis of this research is that recently observed improvements in myocardial relaxation at the cellular level following circulatory support provides a unique opportunity to identify pivotal mechanisms of diastolic dysfunction support in humans with heart failure. Our specific hypothesis is that changes in intracellular calcium homeostasis and its determinants represent primary mechanisms of improved cardiac and cellular relaxation following circulatory support. A major goal of this research is to establish relationships between Doppler-derived measures of diastolic function in vivo, cellular relaxation in isolated myocytes and changes in the decay of the calcium transient in failing human hearts. We will also define the extent to which changes in sarcoplasmic reticulum calcium ATPase and Na/Ca exchanges activity contribute to abnormal calcium homeostasis in advanced heart failure and improvements in cellular relaxation following circulatory assistance. Finally, we will examine whether alpha 1 adrenergic stimulation of interleukin 1beta stimulation in normal human cardiac myocytes can recapitulate the phenotype of impaired relaxation and calcium homeostasis observed in heart failure. These aims will be accomplished using recent advances in myocyte isolation techniques and established methods of Doppler echo-cardiography, cell physiology, molecular biology and cell culture involving human cardiac myocytes. This project will involve close collaboration with other investigators include in this RNA application in that functional assessments at Temple will be complemented by quantitative analyses of the molecular determinants of myocardial relaxation by collaborators at UCSF. Defining the cellular and molecular basis for impaired myocardial relaxation in humans, will provide a foundation for the development of specific therapies for patients with diastolic dysfunction.