MECHANISMS OF IMPROVED DIASTOLIC FUNCTION IN HUMAN HEART

充血性哈特衰竭是许多类型心脏病的常见终点。 心血管疾病无论是否伴有收缩功能障碍， 事实上，心力衰竭患者具有舒张功能障碍。然而，在这方面， 心肌舒张和舒张期充盈受损的细胞基础 心力衰竭患者的异常定义不明确， 存在用于舒张功能障碍的特定疗法。 这项研究的广泛工作假设是， 在细胞水平上改善心肌舒张， 循环支持提供了一个独特的机会，以确定关键 心力衰竭患者的舒张功能障碍支持机制。 我们的假设是细胞内钙离子的变化 内稳态及其决定因素代表了改善 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 多普勒衍生的体内舒张功能测量，细胞 在分离的肌细胞中的松弛和钙衰变的变化 在衰竭的人类心脏中是短暂的我们还将定义 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 援助.最后，我们将研究α 1肾上腺素能 白细胞介素1 β对正常人心肌细胞刺激作用 肌细胞可以重现舒张受损和钙离子缺乏的表型， 在心力衰竭中观察到体内平衡。 这些目标将利用肌细胞分离的最新进展来实现 多普勒超声心动图技术和建立的方法，细胞 涉及人心脏的生理学、分子生物学和细胞培养 肌细胞该项目将与其他合作伙伴密切合作。 研究人员在这项RNA应用中， 在寺评估将补充定量分析， 心肌松弛的分子决定因素。 定义心肌损伤的细胞和分子基础 人类的放松，将为人类的发展提供基础。 舒张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.