Molecular biology and mechanics of the cardiac interstitium

描述(申请人提供)：我们的主要目标是证明以早期缩短/晚期延长为特征的心壁运动异常会触发心外膜局部炎症、活性氧生成、基质金属蛋白酶(MMP)激活和纤维状胶原降解，从而导致不利的室壁重构。心力衰竭时继发于左心室(LV)不同步收缩的室壁运动异常可降低射血分数并促进重塑。在左前壁心外膜起搏的动物模型中也有类似的变化，其特征是起搏部位变薄和后壁肥厚。局部应变模式显示早期激活区(前壁)早期缩短和收缩晚期延长，以及后壁早期延长和随后缩短。初步数据表明，前壁起搏提供了心外膜白细胞(可能是中性粒细胞)介导的炎症、MMPs激活、活性氧生成(ROS)和胶原降解的局部证据。我们认为炎症/损伤的机制是冠状静脉血流模式改变继发于微血管内黏附分子的局部表达。提出了四个目标。目的1验证起搏诱导的早期收缩导致冠状动脉微静脉局部黏附分子表达、白细胞滞留、心外膜ROS生成、基质金属蛋白酶原激活和胶原纤维降解的假说。目的2验证LV早期缩短区表现为心外膜收缩组织体积异常改变和心外膜静脉血流模式改变的假说。目的3将在体外和体内验证白细胞产生的ROS从结构上修饰PRO-MMP9的假说。目的4将验证这一假说，即长期的室壁运动异常导致以心外膜室壁变薄为特征的与早期缩短区相关的不良房室重构。将使用多种心脏力学、活体显微镜、蛋白质组学、生化和组织学方法。这些研究的结果将有助于我们理解心力衰竭和左束支传导阻滞患者的心室不同步是如何导致不利的心腔重构和收缩功能丧失的。拟议研究的预期结果也可能有助于临床医生优化心脏再同步化治疗。 公共卫生相关性拟议的研究解决了一个重要的临床问题，该问题涉及当心脏不一致收缩时，如何出现结构和功能异常，这些异常本质上是有害的。这些异常经常见于心力衰竭患者，我们的观察表明，潜在的炎症过程可能解释了这些不利的变化。

DESCRIPTION (provided by applicant): Our major objective is to demonstrate that heart wall motion abnormalities characterized by early shortening/late lengthening trigger in the epicardium, local inflammation, reactive oxygen species generation, matrix metalloproteinase (MMP) activation and fibrillar collagen degradation leading to adverse chamber remodeling. Wall motion abnormalities secondary to dysynchronous contraction of the left ventricle (LV) as seen in heart failure reduce ejection fraction and promote remodeling. Similar changes occur in animal models of anterior LV wall epicardial pacing whereby adverse remodeling is characterized by thinning at the pacing site and hypertrophy of the posterior wall. Local strain patterns demonstrate early shortening and late systolic lengthening in the early activated areas (anterior wall) and early lengthening and subsequent shortening of the posterior wall. Preliminary data indicates that anterior wall pacing yields localized evidence for epicardial leucocyte (likely neutrophil) mediated inflammation, activation of MMPs, reactive oxygen species generation (ROS) and collagen degradation. We propose that the mechanism responsible for inflammation/injury is the local expression of adhesion molecules in the microvasculature secondary to alterations in coronary venule blood flow patterns. Four aims are proposed. Aim 1 will test the hypothesis that pacing induced early shortening leads to the local expression of adhesion molecules in coronary venules, trapping of leucocytes, generation of ROS, pro-MMP activation and fibrillar collagen degradation in the epicardium. Aim 2 will test the hypothesis that early shortening regions of the LV demonstrate abnormal epicardial systolic tissue volume changes and modified patterns of epicardial venular blood flow. Aim 3 will test the hypothesis that leucocyte generated ROS structurally modifies pro-MMP-9 in vitro and in vivo. Aim 4 will test the hypothesis that long- term LV wall motion abnormalities induce adverse chamber remodeling characterized by epicardial wall thinning in areas associated with early shortening. A variety of cardiac mechanics, intravital microscopy, proteomics, biochemical and histological methods are to be used. Results from the proposed studies should aid in our understanding of how ventricular dysynchrony as seen in patients with heart failure and left bundle branch block leads to the development of adverse chamber remodeling and loss of contractile function. Anticipated outcome from the proposed studies may also aid clinicians in optimizing cardiac resynchronization therapy. PUBLIC HEALTH RELEVANCE The proposed research addresses an important clinical problem related to how, when the heart does not contract in unison it develops structural and functional abnormalities that are detrimental in nature. These abnormalities are frequently seen in patients with heart failure and our observations indicate that an underlying inflammatory process may explain these adverse changes.