Exercise intolerance due to diastolic heart failure (DHF) is a major cause of disability among older Americans. However, relatively little is known regarding the pathophysiology and potential treatment of this )ivotal outcome. Several lines of evidence suggest that aldosterone antagonism may improve exercise ntolerance in DHF. Our preliminary data show that serum aldosterone is increased in elderly patients with DHF. Aldosterone shifts the critical balance in collagen turnover within the myocardium in favor of deposition causing an increase in left ventricular (LV) diastolic stiffness. This is notable because we have previously shown that exercise intolerance in DHF is related to increased diastolic LV stiffness. In hypertension, a common precursor to DHF, aldosterone antagonism prevents and reverses myocardial fibrosis and improves concentric LV remodeling and LV diastolic stiffness. In patients with systolic heart failure, aldosterone antagonism improves exercise intolerance and quality of life, as well as mortality, and the improvements are associated with a decrease in serum procollagen markers of myocardial fibrosis. Spironolactone is a generic, inexpensive aldosterone antagonist. In our open-label pilot study of spironolactone in 10 elderly patients with isolated DHF there were significant improvements in exercise tolerance, quality of life, and LV diastolic stiffness. Therefore, the primary aim of this proposal is to conduct a randomized, controlled, blinded trial in order to test the hypothesis that spironolactone will improve exercise tolerance and quality of life in elderly patients with isolated diastolic heart failure. The secondary aim is to determine whether the improvements in exercise tolerance are related to improvements in abnormal concentric LV remodeling, LV diastolic stiffness, and myocardial fibrosis. These results will be important, not only because diastolic heart failure is highly )revalent among the elderly, but also because exercise intolerance is a pivotal outcome that is modifiable, is ndependent of mortality, and is a critical determinant of quality of life and disability among the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG018915-12
Application #
8300881
Study Section
Special Emphasis Panel (NSS)
Program Officer
Zieman, Susan
Project Start
2001-02-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$441,066
Indirect Cost
$131,431
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Kitzman, Dalane W; Nicklas, Barbara; Kraus, William E et al. (2014) Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 306:H1364-70
Li, Yanhong; Levy, Wayne C; Neilson, Matthew P et al. (2014) Associations between seattle heart failure model scores and medical resource use and costs: findings from HF-ACTION. J Card Fail 20:541-7
Haykowsky, Mark J; Kouba, Erik J; Brubaker, Peter H et al. (2014) Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Cardiol 113:1211-6
Patel, Kanan; Fonarow, Gregg C; Ekundayo, O James et al. (2014) Beta-blockers in older patients with heart failure and preserved ejection fraction: class, dosage, and outcomes. Int J Cardiol 173:393-401
Kitzman, Dalane W; Brubaker, Peter H; Herrington, David M et al. (2013) Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. J Am Coll Cardiol 62:584-92
Li, Yanhong; Neilson, Matthew P; Whellan, David J et al. (2013) Associations between Seattle Heart Failure Model scores and health utilities: findings from HF-ACTION. J Card Fail 19:311-6
Haykowsky, Mark J; Brubaker, Peter H; Morgan, Timothy M et al. (2013) Impaired aerobic capacity and physical functional performance in older heart failure patients with preserved ejection fraction: role of lean body mass. J Gerontol A Biol Sci Med Sci 68:968-75
Kitzman, Dalane W; Herrington, David M; Brubaker, Peter H et al. (2013) Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction. Hypertension 61:112-9
Haykowsky, Mark J; Herrington, David M; Brubaker, Peter H et al. (2013) Relationship of flow-mediated arterial dilation and exercise capacity in older patients with heart failure and preserved ejection fraction. J Gerontol A Biol Sci Med Sci 68:161-7
Kitzman, Dalane W (2012) Outcomes in patients with heart failure with preserved ejection fraction: it is more than the heart. J Am Coll Cardiol 59:1006-7

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