The applicant's objective is to understand the molecular basis of altered contraction of failing human ventricular muscle. In this study the applicant will examine, in terms of the elementary biochemical and mechanical steps of the actomyosin crossbridge cycle, the differences between non-failing and failing myocardial performance in patients with dilated cardiomyopathy or mitral regurgitation. The differences in crossbridge function are most likely caused by alterations in the thin filament proteins, of which troponin subunit T is a prime candidate. The applicant plans to examine this possibility directly by determining to what extent changes in troponin subunit T isoform stoichiometry contribute to depressed myofibrillar function via alterations in the elementary steps of the crossbridge cycle.
The specific aims are to: 1) measure the chemomechanical function of Ca-activated skinned ventricular strips from a control group of patients exhibiting normal ventricular function and from two other groups exhibiting ventricular dysfunction associated with dilated cardiomyopathy or mitral regurgitation; 2) establish the extent to which TnT isoform alterations change the kinetic constant(s) in myocardium from non-failing and failing hearts, demonstrating causality of correlations by isoform substitutions; 3) establish the extent to which selected indices of skinned fiber performance, excitable strip performance, and left ventricular performance correlate.
| Maughan, David W (2005) Kinetics and energetics of the crossbridge cycle. Heart Fail Rev 10:175-85 |
| Mulieri, L A; Barnes, W; Leavitt, B J et al. (2002) Alterations of myocardial dynamic stiffness implicating abnormal crossbridge function in human mitral regurgitation heart failure. Circ Res 90:66-72 |
| Maughan, D; Moore, J; Vigoreaux, J et al. (1998) Work production and work absorption in muscle strips from vertebrate cardiac and insect flight muscle fibers. Adv Exp Med Biol 453:471-80 |
