STIFFNESS IN HYPERTROPHY-ROLE OF CARDIOCYTE CYTOSKELETON

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DESCRIPTION (adapted from the applicant's abstract): The applicant hypothesizes that changes in both the myocardial extracellular matrix (ECM) and the cardiac muscle cell (cardiocyte) are responsible for the changes in diastolic function which occur during diastolic congestive heart failure (CHF). Changes in the ECM which occur in some forms of cardiac hypertrophy can cause significant changes in diastolic function, but abnormalities in diastolic function cannot be explained on the basis of changes in the ECM alone. The applicant states that studies by the principal investigator suggest that changes in the cardiocyte itself make a major, independent contribution to the development of myocardial diastolic dysfunction and diastolic CHF. However, neither the absolute nor relative contribution that primary changes in cardiocyte constitutive properties make to these abnormalities in diastolic function have been clearly defined. The applicant indicates that questions about the role of the cardiocyte in the development of diastolic CHF have not been fully answered: 1) Is cardiocyte relaxation rate, stiffness, or viscosity changed by disease processes which cause diastolic CHF? 2) What cellular structures or processes cause these change in cardiocyte function? And 3) Do these changes at the cellular, cardiocyte level contribute causally to the changes which occur at the myocardial, cardiac tissue level? Studies will be performed in cardiocytes and papillary muscles isolated from normal cats, cats with right ventricular pressure-overload hypertrophy and cats with right ventricular volume-overload hypertrophy. Relaxation, stiffness, and viscosity will be examined in the baseline state and then after an acute change in microtubule polymerization. The applicant believes preliminary data suggest that: 1) pressure overload hypertrophy causes a decrease in cardiocyte relaxation rate, an increase in passive stiffness, and an increase in viscous damping; 2) these changes are caused, at least in part, by an increase in the microtubule portion of the cytoskeleton; and 3) these abnormalities in cardiocyte function contribute to the decrease in myocardial relaxation rate, increase in myocardial stiffness, and increase in myocardial viscosity which occur during pressure overload hypertrophy.