DIASTOLIC HEART FAILURE: DEFINING CARDIOCYTE MECHANISMS

舒张性充血性心力衰竭（CHF）的诊断可在患者出现液体超负荷、射血分数正常和舒张功能明显异常的症状和体征时作出。在CHF患者的一般人群中，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，舒张期CHF的患病率增加至50%，5年死亡率接近50%。因此，舒张期CHF是一个主要的卫生保健问题，特别是在我们的老龄化人口中。尽管其重要性，但引起舒张性CHF的基本潜在机制以及衰老对这些机制的影响尚未完全了解。由于这些原因，我的研究的主要重点是确定导致舒张功能异常的机制。当心肌组织的被动材料性质发生根本改变时（即，舒张期心肌硬度增加）。可能导致心肌硬度增加的三种可能机制包括心肌细胞（心肌细胞）的变化、细胞外基质（ECM）的变化和神经体液激活的变化。我相信这三种机制的变化，单独或联合，导致舒张功能异常 导致舒张期CHF检查ECM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补助金的主题。研究检查心肌细胞内的机制将是本计划项目提案的重点。项目6的目的是证明基本的心肌细胞机制在舒张期CHF的发展中发挥重要的因果作用的假设。将使用三个具体目标来检验这一假设：1）确定心脏细胞的粘弹性性质的变化是否发生在由压力超负荷肥大（POH）和高龄产生的增加的心肌硬度中，以及在何种程度上与由压力超负荷肥大（POH）和高龄产生的增加的心肌硬度有因果关系，2）定义引起增加的心脏细胞粘弹性硬度的基本细胞机制，和3）确定这些基本细胞机制的转基因调节是否将预防或纠正由POH和高龄引起的舒张僵硬度的增加。

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.