Myosin is a major contractile protein involved in the generation of mechanical force and shortening of cardiac muscle fibers. Multiple isomeric forms of cardiac myosin exist, each exhibiting characteristic biochemical and mechanical properties. The isomyosin composition is responsive to a number of physiologic and pathologic factors including developmental stage, thyroid hormone, and ventricular loading. However, this relationship between the isomyosin composition and the intrinsic mechanical and metabolic properties of the intact left ventricle is unknown. Additionally, it is not known whether the changes in isomyosin composition represent a process of physiologic adaptation at the intact organ level and whether this adaptation becomes inadequate for a certain combination of cardio-circulatory conditions (i.e., end-diastolic volume, arterial load, and heart rate), leading to functional failure of the left ventricle. Accordingly, the two major goals of this proposal are: i) to examine the relationship between changes in isomyosin composition and the intrinsic mechanical and metabolic properties of the left ventricle; and ii) to assess the effects of changing isomyosin composition on the overall performance of the left ventricle. In order to establish whether there exists a 'unique' relationship (i.e., independent of the inciting stimulus) between changes in isomyosin composition and the mechanical and metabolic properties of the left ventricle, several animal models will be examined; hypo- and hyper-thyroidism (rats and rabbits); and pressure-overload (aortic banding in rabbits and spontaneous hypertension in rats). Furthermore, in order to dissect the effects of hypertrophy alone from those due to the variations in isomyosin composition, the pressure-overload models will be further studied with isomyosin composition held constant by concomitant manipulation of thyroid hormone status. The mechanical properties (systolic elastance and resistance) will be assessed both in-situ and in an isolated heart preparation. The metabolic properties will be quantified in isolated heart studies by relating myocardial oxygen consumption to external mechanical work and to systolic pressure-volume area. Isomyosin composition will be analysed both in terms of relative amounts (native-gel, radioimmunoassay with monoclonal antibodies, and ATPase activity), and anatomical distribution (immunofluorescence with monoclonal antibodies).
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