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 #
4R37AG018915-09
Application #
7579441
Study Section
Special Emphasis Panel (NSS)
Program Officer
Eldadah, Basil A
Project Start
2001-02-15
Project End
2014-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
9
Fiscal Year
2009
Total Cost
$435,640
Indirect Cost
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; O'Neill 4th, Thomas J; Brubaker, Peter H (2017) Unraveling the Relationship Between Aging and Heart Failure With Preserved Ejection Fraction: The Importance of Exercise and Normative Reference Standards. JACC Heart Fail 5:356-358
Kitzman, Dalane W; Upadhya, Bharathi; Zhao, David (2017) New Concepts in an Old Disease: Exercise Intolerance in Moderate Mitral Stenosis. JACC Cardiovasc Imaging 10:634-636
Upadhya, Bharathi; Hundley, William G; Brubaker, Peter H et al. (2017) Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction. J Am Geriatr Soc 65:2374-2382
Levy, Wayne C; Li, Yanhong; Reed, Shelby D et al. (2017) Does the Implantable Cardioverter-Defibrillator Benefit Vary With the Estimated Proportional Risk of Sudden Death in Heart Failure Patients? JACC Clin Electrophysiol 3:291-298
Kitzman, Dalane W; Lam, Carolyn S P (2017) Obese Heart Failure With Preserved Ejection Fraction Phenotype: From Pariah to Central Player. Circulation 136:20-23
Thompson, Richard B; Pagano, Joseph J; Mathewson, Kory W et al. (2016) Differential Responses of Post-Exercise Recovery of Leg Blood Flow and Oxygen Uptake Kinetics in HFpEF versus HFrEF. PLoS One 11:e0163513
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
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
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
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

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