Myocardial Stiffness in Aging Associated Diastolic Heart Failure

描述（由申请人提供）：舒张功能障碍是老年人群中充血性心力衰竭的最常见原因。年龄在70岁或以上的患病个体的一年死亡率约为50%。治疗方案仍然是经验性的。尽管对舒张性心力衰竭（DHF）的病因知之甚少，但大多数研究认为受累患者表现出心室僵硬度增加（心室顺应性降低）。这项工作的假设是，DHF在老年人群中反映了跨桥活动，持续不适当的心脏舒张（或“放松”）阶段的心动周期。这些交叉桥产生心肌硬度的“主动”成分，其通过增加对流入血液的阻力来增强心脏的基础（被动）硬度并损害心室充盈。拟议的研究将使用Fischer 344大鼠，这些大鼠在25个月大时表现出与衰老相关的DHF。具体目标1将确定老化对大鼠心肌硬度的影响。实验将检验这一假设，即由于不适当的约束横桥的主动刚度增加到更大程度上与老化比刚度，由于结构组件。将从幼龄（5个月）和老龄（25个月）大鼠中分离完整的小梁，并在存在和不存在BDM（一种跨桥抑制剂）的情况下拉伸，以确定主动和被动刚度的年龄依赖性变化程度。具体目标2将评价代谢物浓度改变对年轻和老年心脏活动刚度的影响。实验将使用从5个月和25个月大鼠心脏分离的化学透化制剂，并通过测量在肌节长度控制下施加的小拉伸的张力反应来评估主动刚度。假设当氢离子、磷酸根离子和ADP的浓度升高到模拟缺血心肌的水平时，由于持续的跨桥活动而导致的主动刚度在老年心脏中将比在年轻心脏中更大程度地增强。这项研究与公共卫生有关，因为它调查了一个新的假设，即衰老相关的DHF反映了心动周期放松期的不适当收缩活动。实验结果将提供有关DHF潜在原因的新信息，并应帮助科学家开发更好的老年人群舒张功能障碍治疗方法。

DESCRIPTION (provided by applicant): Diastolic dysfunction is the most common cause of congestive heart failure in elderly populations. One year mortality rates for afflicted individuals aged 70 years or older approximate 50%. Therapy options remain empirical. Although very little is known about the etiology of Diastolic Heart Failure (DHF) most studies agree that affected patients exhibit increased ventricular stiffness (reduced chamber compliance). The hypothesis underlying this work is that DHF in elderly populations reflects cross-bridge activity that persists inappropriately during the diastolic (or 'relaxed') phase of the cardiac cycle. These cross-bridges produce an 'active' component of myocardial stiffness that augments the heart's basal (passive) stiffness and impairs ventricular filling by increasing the resistance to inflowing blood. The proposed research will utilize Fischer 344 rats that exhibit aging-associated DHF at 25 months of age. Specific Aim 1 will establish the effects of aging on rat myocardial stiffness. Experiments will test the hypothesis that active stiffness due to inappropriately bound cross-bridges increases to a greater extent with aging than stiffness due to structural components. Intact trabeculae will be isolated from young (5 month) and old (25 month) rats and stretched in the presence and absence of BDM, a cross-bridge inhibitor, to establish the extent of age-dependent changes in active and passive stiffness. Specific Aim 2 will evaluate the effects of altered metabolite concentrations on active stiffness in young and old hearts. Experiments will utilize chemically permeabilized preparations isolated from 5 month and 25 month rat hearts and active stiffness will be assessed by measuring the tension responses to small stretches imposed under sarcomere length control. It is hypothesized that active stiffness due to persistent cross-bridge activity will be enhanced to a greater extent in the old hearts than in the young hearts when the concentrations of hydrogen ions, phosphate ions and ADP are raised to levels mimicking ischemic myocardium. This research is relevant to public health because it investigates the novel hypothesis that aging-related DHF reflects inappropriate contractile activity during the relaxed phase of the cardiac cycle. The experimental results will provide new information about the underlying causes of DHF and should help scientists develop better treatments for diastolic dysfunction in elderly populations.