DIASTOLIC HEART FAILURE: DEFINING CARDIOCYTE MECHANISMS

舒张性心力衰竭：定义心肌细胞机制

• 批准号: 6808271
• 负责人: Michael R Zile
• 金额: $ 16.15万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6808271
• 关键词: Adenoviridae; adenosinetriphosphatase; aging; calcium flux; cellular pathology; cytoskeleton; disease /disorder model; echocardiography; genetically modified animals; heart catheterization; heart cell; heart enlargement; heart failure; heart metabolism; intracardiac pressure; laboratory mouse; microtubule associated protein; model design /development; myocardium; pathologic process; phospholamban; sarcoplasmic reticulum; transfection; tubulin

The diagnosis of diastolic congestive heart failure (CHF) can be made when patients have symptoms and signs of fluid overload, a normal ejection fraction, and pronounced abnormalities in diastolic function. In a general population of patients with CHF, the prevalence of diastolic CHF is 30-35% and the 5 year mortality rate is 25%. In patients over 70 years old, the prevalence of diastolic CHF increases to 50% and the 5 year mortality rate approaches 50%. Therefore, diastolic CHF is a major health care problem, especially in our aging population. Despite its importance, the basic underlying mechanisms that cause diastolic CHF and the impact that aging makes on these mechanisms are not completely understood. For these reasons, the primary focus of my research has been to define the mechanisms, which cause abnormal diastolic function. Diastolic CHF develops when there has been a fundamental alteration in the passive material properties of the cardiac muscle tissue (i.e., increased diastolic myocardial stiffness). Three of the possible mechanisms which may cause this increase in myocardial stiffness include changes in the cardiac muscle cell (cardiocyte), changes in the extracellular matrix (ECM), and changes in neurohumoral activation. I believe that changes in each of these three mechanisms, individually and in combination, cause the abnormalities in diastolic function that lead to diastolic CHF. Studies examining the ECM and neurohumoral activation are the subject of my ongoing Department of Veterans Affairs Merit Review grant. Studies examining mechanisms within the cardiocyte will be the focus of this Program Project Proposal. The purpose of Project 6 is to prove the hypothesis that basic cardiocyte mechanisms play a significant cause and effect role in the development of the diastolic CHF. This hypothesis will be tested using three specific aims: 1) Determine whether, and to what degree, changes in the viscoelastic properties of the cardiocyte occur in, and are causally related to the increased myocardial stiffness produced by pressure-overload hypertrophy (POH) and advanced age, 2) Define the basic cellular mechanisms which cause increased cardiocyte viscoelastic stiffness, and 3) Determine whether transgenic modulation of these basic cellular mechanisms will prevent or correct the increases in diastolic stiffness produced by POH and advanced age.

当患者有液体超负荷的症状和体征，射血分数正常，舒张期功能明显异常时，可诊断舒张性充血性心力衰竭(CHF)。在普通CHF患者中，舒张期CHF的患病率为30-35%，5年死亡率为25%。在70岁以上的患者中，舒张性心力衰竭的患病率增加到50%，5年死亡率接近50%。因此，舒张期充血性心力衰竭是一个主要的医疗保健问题，特别是在我们老龄化的人口中。尽管它很重要，但导致舒张期充血性心力衰竭的基本潜在机制以及衰老对这些机制的影响尚不完全清楚。出于这些原因，我的研究的主要焦点一直是确定导致舒张期功能异常的机制。当心肌组织的被动物质特性发生根本改变(即舒张期心肌硬度增加)时，舒张性充血性心力衰竭就会发生。可能导致心肌僵硬增加的三种可能机制包括心肌细胞(心肌细胞)变化、细胞外基质(ECM)变化和神经体液激活变化。我认为，这三种机制中的每一种变化，无论是单独的还是联合的，都会导致舒张期功能的异常。 导致舒张性心力衰竭。检查细胞外基质和神经体液激活的研究是我正在进行的退伍军人事务部功绩审查拨款的主题。检测心肌细胞内机制的研究将是本计划项目提案的重点。项目6的目的是证明这一假设，即基本的心脏机制在舒张性充血性心力衰竭的发展中起着重要的因果作用。这一假说将通过三个具体的目标进行验证：1)确定压力超负荷肥厚(POH)和高龄引起的心肌僵硬增加是否发生以及在多大程度上与心肌细胞粘弹性特性的变化有关，2)确定导致心肌细胞粘弹性增加的基本细胞机制，以及3)确定这些基本细胞机制的转基因调节是否将防止或纠正由POH和高龄引起的舒张期僵硬增加。