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 #
5R37AG018915-13
Application #
8490257
Study Section
Special Emphasis Panel (NSS)
Program Officer
Zieman, Susan
Project Start
2001-02-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2013
Total Cost
$386,790
Indirect Cost
$114,725
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
Reeves, Gordon R; Whellan, David J; Patel, Mahesh J et al. (2016) Comparison of Frequency of Frailty and Severely Impaired Physical Function in Patients ≥60 Years Hospitalized With Acute Decompensated Heart Failure Versus Chronic Stable Heart Failure With Reduced and Preserved Left Ventricular Ejection Fraction. Am J Cardiol 117:1953-8
Molina, Anthony J A; Bharadwaj, Manish S; Van Horn, Cynthia et al. (2016) Skeletal Muscle Mitochondrial Content, Oxidative Capacity, and Mfn2 Expression Are Reduced in Older Patients With Heart Failure and Preserved Ejection Fraction and Are Related to Exercise Intolerance. JACC Heart Fail 4:636-45
Kitzman, Dalane W; Brubaker, Peter; Morgan, Timothy et al. (2016) Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA 315:36-46
Fleg, Jerome L; Cooper, Lawton S; Borlaug, Barry A et al. (2015) Exercise training as therapy for heart failure: current status and future directions. Circ Heart Fail 8:209-20
Kitzman, Dalane W; Upadhya, Bharthi; Reeves, Gordon (2015) Hospitalizations and Prognosis in Elderly Patients With Heart Failure and Preserved Ejection Fraction: Time to Treat the Whole Patient. JACC Heart Fail 3:442-4
Dardas, Todd; Li, Yanhong; Reed, Shelby D et al. (2015) Incremental and independent value of cardiopulmonary exercise test measures and the Seattle Heart Failure Model for prediction of risk in patients with heart failure. J Heart Lung Transplant 34:1017-23
Upadhya, Bharathi; Haykowsky, Mark J; Eggebeen, Joel et al. (2015) Sarcopenic obesity and the pathogenesis of exercise intolerance in heart failure with preserved ejection fraction. Curr Heart Fail Rep 12:205-14
Andersen, Mousumi M; Kritchevsky, Stephen B; Morgan, Timothy M et al. (2015) Increased cardiovascular stiffness and impaired age-related functional status. J Gerontol A Biol Sci Med Sci 70:545-53
Kitzman, Dalane W; Upadhya, Bharathi; Vasu, Sujethra (2015) What the dead can teach the living: systemic nature of heart failure with preserved ejection fraction. Circulation 131:522-4
Pandey, Ambarish; Parashar, Akhil; Kumbhani, Dharam J et al. (2015) Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circ Heart Fail 8:33-40

Showing the most recent 10 out of 103 publications