VENTRICULAR MECHANO-ENERGETICS AND MYOCARDIAL REMODELING

人们认识到心肌的结构和生化特性

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.