Grants and Contracts Details
Description
Diastolic dysfunction afflicts 1.9 million Americans and is a major cause of morbidity and mortality. The
condition forms the primary diagnosis for at least one-third of all heart failure patients and is characterized by
diminished cardiac output in the absence of impaired systolic performance. It is particularly prevalent in elderly
populations. The proposed experiments examine the general hypothesis that diastolic dysfunction reflects low
levels of contractile activity that persist inappropriately throughout the filling phase of the cardiac cycle.
Specific Aim 1: Compare the active and passive components of myocardial stiffness in pigs, dogs,
rats and mice.
Experiments will test the hypotheses that (1) cycling cross-bridges augment the basal passive
stiffness of myocardial samples isolated from both large mammals (pigs and dogs) and small
rodents (rats and mice) and that (2) the relative size of the cross-bridge stiffness component
increases with the N2BAlN2B titin isoform expression ratio and is greatest in large mammals.
Specific Aim 2: Identify the molecular mechanisms underpinning age-related changes in myocardial stiffness.
Approach: Age-dependent effects on myocardial stiffness will be assessed by stretching intact trabeculae
isolated from young, middle-aged and senescent Fischer 344 x Brown Norway F1 rats in the
presence and absence of the cross-bridge inhibitor BDM. Potential changes in intracellular
free calcium transients will be evaluated using indo-1 fluorescence measurements.
Specific Aim 3: Determine how altered cross-bridge kinetics affect dynamic myocardial mechanical properties.
Approach: Myocardial stiffness will be measured under conditions where the rates of different acto-myosin
state transitions have been altered by changing the concentrations of hydrogen ions, phosphate
ions and ADP in the bathing solution. Experiments will utilize (1) porcine preparations as a
useful model of human myocardium and (2) enzymatically digested single rat myocytes
which exhibit minimal extracellular structural stiffness.
Status | Finished |
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Effective start/end date | 1/1/06 → 12/31/08 |
Funding
- American Heart Association: $79,450.00
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