It is estimated that half of the ~5 million patients in the United States who suffer from heart failure (HF) have HF with preserved ejection fraction (HFpEF), which is also referred to as diastolic heart failure. Hypertension is a major risk factor for the development of HFpEF. Unfortunately, large clinical trials have revealed that standard-of-care HF medications fail to reduce hospitalization rates or improve lifespan in patients with HFpEF. Thus, HFpEF remains a major unmet medical need. Our group has a longstanding interest in elucidating the cardiac functions of a family of enzymes known as histone deacetylases (HDACs), which serve crucial roles as epigenetic regulators of gene expression. Our preliminary data demonstrate remarkable ability of a small molecule HDAC inhibitor to prevent and reverse diastolic cardiac dysfunction in rodent models of systemic hypertension. Surprisingly, HDAC inhibition appears to improve diastolic function of the heart by enhancing relaxation of the contractile units (myofibrils), revealing a non-canonical, non-epigenetic function for HDACs in the control of cardiac relaxation. Three independent specific aims are designed to significantly extend this new field of cardiac research, and test the overall hypothesis that non-genomic actions of HDACs govern relaxation of the heart, and are critically involved in the pathogenesis of HFpEF.

Public Health Relevance

Heart failure is a major health problem and growing economic burden worldwide. With greater than five million heart failure patients in the U.S. alone, treatment of this condition represents an estimated annual cost to the American health care system of over $37 billion. The research outlined in this proposal should provide a foundation for discovery of novel therapeutics to treat patients suffering from heart failure with preserved ejection fraction (HFpEF).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116848-07
Application #
9963040
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2013-08-08
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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