VENTRICULAR MECHANO-ENERGETICS AND MYOCARDIAL REMODELING

现已认识到，心肌结构和生化特征 心肌细胞和间质是心脏疾病的主要决定因素 肌肉力学和能量学。然而，心肌之间的联系 心室力学和能量学的组成和指标是 不确定。本文提出的研究的长期目标是 解开将全球心功能与各种 细胞事件和心肌结构。这样的努力将有助于 得出关于心肌重塑的有意义的结论 评估整体心功能。据建议，这一点 从多个角度探讨脑室检查问题 要点，包括本研究中使用的三组分析：(I) 压力-体积-流出与应力-应变-应变率的关系 定量测定室腔和心肌收缩弹性 阻力；(Ii)心肌耗氧量(MVO2) 和收缩压-容积面积(PVA)来评估能量学；和(Iii) 机械回复曲线用于检测兴奋-收缩耦合和 细胞内钙离子处理。具体目标包括：(1)发展一种 使左室收缩弹性和阻力正常化的程序 代表“单位”心肌的力学性质。法律程序的有效性 建议的理论程序将使用收集的数据进行检验 同时取自离体心和原位乳头肌 制备；(2)量化LV的机械和能量特性 压力超负荷性肥厚同时控制异肌球蛋白 使用甲状腺激素操作的成分；(3)相关归一化 心肌结构和/或的机械和能量特性 生化成分；(4)研究变化的时间模式 在机械和能量性质上，并将这些变化与 可逆性心肌梗死后心肌结构和成分的变化 心肌病模型。将进行原位和离体心实验 为实现具体目标而执行(2)-(4)。形态计量分析 将对组织进行灌流固定以确定纤维角度。 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 形态将通过光学和电子显微镜进行检查。生化 新鲜组织的分析将包括异肌球蛋白的测定 天然凝胶电泳法组成、钙激活的ATPase活性 纯化的肌球蛋白和羟脯氨酸浓度。这些信息 从拟议的研究中获得的信息将有助于绘制有意义的图画 基于整体功能的心肌重构推论 测量与合理设计药理校正形式 克服心肌重塑不良后果的治疗 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.