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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL055444-01A2
Application #
2029650
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1997-09-08
Project End
2001-08-31
Budget Start
1997-09-08
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Pereira, N L; Zile, M R; Harley, R A et al. (2006) Myocardial mechanisms causing heart failure early after cardiac transplantation. Transplant Proc 38:2999-3003
Baicu, Catalin F; Stroud, Jason D; Livesay, Virginia A et al. (2003) Changes in extracellular collagen matrix alter myocardial systolic performance. Am J Physiol Heart Circ Physiol 284:H122-32
Stroud, Jason D; Baicu, Catalin F; Barnes, Mary A et al. (2002) Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment. Am J Physiol Heart Circ Physiol 282:H2324-35
Harris, Todd S; Baicu, Catalin F; Conrad, Chester H et al. (2002) Constitutive properties of hypertrophied myocardium: cellular contribution to changes in myocardial stiffness. Am J Physiol Heart Circ Physiol 282:H2173-82