VENTRICULAR MECHANO-ENERGETICS AND MYOCARDIAL REMODELING

人们认识到，心肌结构和生化特征 心肌细胞和心肌细胞的增殖是心肌细胞增殖的主要决定因素， 肌肉力学和能量学 然而，心肌细胞与 心室力学和能量学的组成和指标， 不确定 本研究的长期目标是 解开将整体心室功能与各种 细胞事件和心肌结构。 这样的奋进将有助于 从心肌重塑中得出有意义的结论， 评估整体心室功能。 拟将这一 这个问题可以通过从几个Vantage检查心室来解决 点，包括本研究中使用的3组分析：（一） 压力-体积-流出量和应力-应变-应变率之间的关系， 量化心室腔和心肌收缩弹性， 阻力;（ii）心肌耗氧量（MVO 2） 和收缩压-容积面积（PVA），以评估能量学;以及（iii） 机械恢复曲线，以检查兴奋-收缩耦合， 细胞钙处理。 具体目标包括：（1）制定 使LV收缩弹性和阻力正常化的程序， 表示“单位”心肌的机械特性。 的有效性 建议的理论程序将使用收集的数据进行检查 同时从离体心脏和原位乳头肌 制备;（2）量化LV的机械和能量特性 在同时控制异肌球蛋白的压力超负荷性肥大中 使用甲状腺激素操作的组合物;（3）将标准化的 机械和能量特性对心肌结构和/或 生化组成;（4）检查变化的时间模式 在机械和能量特性方面，并将这些变化与 心肌结构和组成的变化，在一个可逆的 心肌病模型。 原位和离体心脏实验将 为实现具体目标而开展的活动（2）-（4）。 的形态测定分析 将进行灌注固定的组织以确定纤维角度 分布、平均肌细胞直径、单位肌细胞数密度 长度和面积，以及肌细胞总数，而胶原基质 通过光学和电子显微镜检查形态。 生化 新鲜组织的分析将包括异肌球蛋白的测定 天然凝胶电泳，Ca++激活的ATP酶活性 纯化肌球蛋白和羟脯氨酸浓度。 的信息 从拟议的研究中获得的将允许绘制有意义的 基于整体功能的心肌重塑推断 测量和合理设计药物的纠正形式 治疗，克服心肌重塑的不利后果， 各种疾病状态。

It is recognized that myocardial structure and biochemical characteristics of cardiac myocytes and interstitium are major determinants of cardiac muscle mechanics and energetics. However, the link between myocardial composition and indices of ventricular mechanics and energetics is uncertain. The long-term objective of the research proposed herein is to unravel the puzzle that links global ventricular function to various cellular events and myocardial structure. Such an endeavor will facilitate drawing meaningful conclusions regarding myocardial remodeling from the assessment of global ventricular function. It is proposed that this problem be approached by examining the ventricle from several vantage points, including 3 sets of analyses used in this research: (i) the relation between pressure-volume-outflow and stress-strain-strain rate to quantify ventricular chamber and myocardial systolic elastance and resistance; (ii) the relation between myocardial oxygen consumption (MVO2) and systolic pressure-volume area (PVA) to assess energetics; and (iii) the mechanical restitution curve to examine excitation-contraction coupling and cellular calcium handling. Specific aims include: (1) to develop a procedure to normalize LV systolic elastance and resistance so that they represent mechanical properties of "unit" myocardium. The validity of the proposed theoretical procedure will be examined using data collected simultaneously from isolated heart and in-situ papillary muscle preparations; (2) to quantify mechanical and energetic properties of the LV in pressure-overload hypertrophy with simultaneous control of isomyosin composition using thyroid hormone manipulation; (3) to correlate normalized mechanical and energetic properties to myocardial structural and/or biochemical composition; and (4) to examine the temporal pattern of changes in mechanical and energetic properties and to relate these changes to variations in myocardial structure and composition seen in a reversible model of cardiomyopathy. In-situ and isolated heart experiments will be performed to address specific aims (2)-(4). Morphometric analysis of perfusion-fixed tissue will be undertaken to determine fiber angle distribution, average myocyte diameter, myocyte numerical density per unit length and area, and the total number of myocytes, while collagen matrix morphology will be examined by light and electron microscopy. Biochemical analysis of fresh tissue will include determination of isomyosin composition by native gel-electrophoresis, Ca++-activated ATPase activity of purified myosin, and hydroxyproline concentration. The information gained from the proposed research will allow for drawing meaningful inferences regarding myocardial remodeling based on global functional measurements and to rationally design corrective forms of pharmacologic therapy that overcome the adverse consequence of myocardial remodeling in various disease states.