MECHANISMS OF IMPROVED DIASTOLIC FUNCTION IN HUMAN HEART

改善人类心脏舒张功能的机制

• 批准号: 6372367
• 负责人: Kenneth Ber Margulies
• 金额: $ 30万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 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 2003-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372367
• 关键词: action potentials; alpha adrenergic agent; calcium flux; calcium transporting ATPase; cardiac myocytes; circulatory assist; congestive heart failure; dobutamine; echocardiography; enzyme activity; heart contraction; heart failure; heart function; heart pharmacology; human tissue; interleukin 1; muscle contraction; muscle pharmacology; sarcoplasmic reticulum

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.

充血性心力衰竭是许多类型的常见终点 心血管疾病。有或没有相关的收缩功能障碍， 事实上，心力衰竭患者存在舒张功能障碍。然而， 心肌舒张和舒张压受损的细胞基础 心力衰竭患者的异常情况尚不明确，目前尚无 针对舒张功能障碍存在特定疗法。 这项研究的广泛工作假设是最近观察到 心肌松弛在细胞水平上的改善 循环支持提供了一个独特的机会来识别关键的 舒张功能障碍支持心力衰竭患者的机制。 我们的具体假设是细胞内钙的变化 体内平衡及其决定因素代表了改善的主要机制 循环支持后心脏和细胞松弛。 这项研究的一个主要目标是建立之间的关系 体内、细胞舒张功能的多普勒测量 离体肌细胞的松弛和钙衰变的变化 在失败的人心中转瞬即逝。我们还将定义 肌浆网钙 ATP 酶和 Na/Ca 交换的变化 活动导致晚期心脏钙稳态异常 循环后细胞松弛的失败和改善 协助。最后，我们将检查α1肾上腺素能是否 白细胞介素1β对正常人心脏的刺激 肌细胞可以重现松弛和钙受损的表型 在心力衰竭中观察到稳态。 这些目标将利用肌细胞分离的最新进展来实现 多普勒超声心动图、细胞技术和既定方法 涉及人类心脏的生理学、分子生物学和细胞培养 肌细胞。该项目将涉及与其他机构的密切合作 研究人员将 RNA 应用纳入该功能中 天普大学的评估将得到定量分析的补充 加州大学旧金山分校的合作者研究了心肌舒张的分子决定因素。 定义心肌受损的细胞和分子基础 人类的放松，将为人类的发展提供基础 针对舒张功能障碍患者的特定疗法。