The oblique spirals of myocardial fibers in the heart wall form a remarkable mechanical system, designed to amplify small amounts of myocardial shortening into extensive thickening, then to recoil briskly, allowing sudden, rapid filling. With this proposal we continue our studies of LV wall deformation using MRI tissue tagging. This powerful new imaging technique, developed in our laboratory and now widely used, permits the non-invasive tracking of tissue through the cardiac cycle, and measurement of deformation. Previous work with tagging has shown the importance of the heart's wringing motion, or torsion , for systolic and diastolic function. Normal aging in humans is accompanied by a sharp and progressive decline in the rate of LV early diastolic filling. This predisposes the elderly to congestive heart failure, presenting a large burden to the aging population in terms of morbidity and mortality, and enormous medical costs to society. The objective of this project is to explore the mechanisms of diastolic dysfunction of aging, and ways to slow its progression. Four projects are proposed. First, the rate of recoil of torsion seems to be a valuable new non-invasive marker of the process of LV relaxation. As opposed to the standard non-invasive parameter, isovolumic relaxation time, recoil rate is independent of aortic and left atrial pressures, and may therefore be a superior index. This hypothesis will be rested in an experimental model. Second, it is thought that relaxation contributes to filling by generating suction, which augments inflow from the left atrium. New evidence suggests that in the young, relaxation and filling are, in fact, tightly coupled. However, in the elderly, filling seems to become uncoupled from relaxation, perhaps due to increased stiffness. That is, the aging heart may not generate suction, leaving filling dependent upon the LA driving pressure. The relation between relaxation and filling will be tested using MRI in normal humans over a wide range of ages. Third, systolic fiber shortening will be measured in the same population. And finally, since angiotensin converting enzymes inhibitors and angiotensin receptor blockers inhibit fibrosis, which contributes to heart stiffness, their effect on the diastolic dysfunction of aging will be studied in a rat model. The results will help clarify the mechanisms of age-induced diastolic dysfunction, and will improve our understanding of how aging interacts with disease to influence the course of heart failure in the elderly. This may lead to the development of rational new therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046223-10
Application #
6389165
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Dunn, Rosalie
Project Start
1992-02-27
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2003-06-30
Support Year
10
Fiscal Year
2001
Total Cost
$283,230
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Hees, Paul S; Fleg, Jerome L; Dong, Sheng-Jing et al. (2004) MRI and echocardiographic assessment of the diastolic dysfunction of normal aging: altered LV pressure decline or load? Am J Physiol Heart Circ Physiol 286:H782-8
Hees, Paul S; Fleg, Jerome L; Lakatta, Edward G et al. (2002) Left ventricular remodeling with age in normal men versus women: novel insights using three-dimensional magnetic resonance imaging. Am J Cardiol 90:1231-6
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Azhari, H; Denisova, O E; Montag, A et al. (1996) Circular sampling: perspective of a time-saving scanning procedure. Magn Reson Imaging 14:625-31
Azhari, H; Weiss, J L; Rogers, W J et al. (1995) A noninvasive comparative study of myocardial strains in ischemic canine hearts using tagged MRI in 3-D. Am J Physiol 268:H1918-26

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