CONTRACTILITY OF FAILING AND RECOVERING HUMAN MYOCYTES

人类心肌细胞衰竭和恢复的收缩性

• 批准号: 6788808
• 负责人: Steven R Houser
• 金额: $ 37.63万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788808
• 关键词: action potentials; calcium channel; calcium flux; calcium transporting ATPase; cardiac myocytes; clinical research; dobutamine; heart contraction; heart electrical activity; heart failure; heart rate; heart ventricle; human subject; molecular pathology; pathologic process; phospholamban; phosphorylation; sarcoplasmic reticulum

DESCRIPTION (provided by applicant): Congestive heart failure continues to be a leading health concern in Western society. This syndrome is caused by a variety of different diseases with ischemic heart disease being the most common. The prognosis for heart failure patients remains very poor even though some beneficial treatments have recently been developed. The purpose of this research is to identify defective processes that contribute to the initiation and progression of human heart failure in the hope that they can be targeted for improved heart failure therapies The specific aims are to: 1) Determine the in-vivo "contractility reserve" of nonfailing, failing and LVAD-supported human hearts by measuring the changes in cardiac performance caused by increases in heart rate (pacing stress) and adrenergic agonists (dobutamine stress). The most important aspect of these descriptive studies is that we will also obtain tissue samples before and during pacing and during adrenergic stress (and subsequently obtain tissues and myocytes from these hearts when they are explanted) to define the cellular and molecular bases of defective rate and adrenergic responses (Aims 2 and 3). These studies will allow us to translate biochemical, molecular and biophysical abnormalities within single myocytes to impaired function of the intact heart. 2): Determine why SR Ca load does not increase normally (negative versus positive force frequency relationship) when the pacing rate is increased in failing human myocytes (depressed "rate reserve"). The respective roles of the SR (uptake, release and leak), the NCX, the action potential duration and the L-type Ca channel will be studied. 3): Determine why adrenergic agonists do not produce the normal increase in SR Ca loading in failing human myocytes. The respective roles of the SERCA, PLB, RYR and the L-type Ca channel in the inability of adrenergic agonists to increase SR Ca loading and release ("adrenergic reserve") will be studied. These experiments will be performed in nonfailing and failing human hearts to more clearly define the mechanism responsible for abnormal "contractility reserve."

描述（由申请人提供）：充血性心力衰竭仍然是西方社会主要的健康问题。这种综合征是由多种不同的疾病引起的，其中以缺血性心脏病最为常见。尽管最近已经开发出一些有益的治疗方法，但心力衰竭患者的预后仍然很差。本研究的目的是确定导致人类心力衰竭发生和发展的缺陷过程，希望它们能够成为改进心力衰竭治疗的目标。具体目的是：1)通过测量心率增加（起搏应激）和肾上腺素能激动剂（多巴酚丁胺应激）引起的心脏性能变化，确定非衰竭、衰竭和lvad支持的人类心脏的体内“收缩性储备”。这些描述性研究最重要的方面是，我们还将在起搏前、起搏期间和肾上腺素能应激期间获得组织样本（随后从这些心脏中获得组织和肌细胞，当它们被移植时），以确定缺缺率和肾上腺素能反应的细胞和分子基础（目的2和3）。这些研究将使我们能够将单个心肌细胞内的生化、分子和生物物理异常转化为完整心脏功能受损。2)：确定为什么当衰竭的人肌细胞的起搏速率增加时，SR - Ca负荷没有正常增加（负与正的力频率关系）（“速率储备”下降）。研究SR（吸收、释放和泄漏）、NCX、动作电位持续时间和l型钙通道各自的作用。确定为什么肾上腺素能激动剂不能在衰竭的人肌细胞中产生正常的SR - Ca负荷增加。将研究SERCA、PLB、RYR和l型Ca通道在肾上腺素能激动剂无法增加SR Ca装载和释放（“肾上腺素能储备”）中的各自作用。这些实验将在正常和衰竭的人类心脏中进行，以更清楚地定义异常“收缩性储备”的机制。