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.

R37AG018915

2001-02-15

2015-03-31