# Deacetylase-Dependent Control of Diastolic Dysfunction and HFpEF

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $773,007

## Abstract

Project Summary/Abstract
Large clinical outcome trials with inhibitors of excess neurohormonal activity in heart failure (HF) with reduced
ejection fraction (HFrEF) patients have shown significant decreases in mortality. However, the effects of these
same neurohormonal inhibitors in HF with preserved ejection fraction (HFpEF) patients have consistently failed
to reach positive primary outcomes. The dichotomy in the responses of the patients likely results from
differences in HFpEF versus HFrEF pathophysiology, and the absence of experimental HFpEF models that
capture essential characteristics of this syndrome. Our contention, and the approach used in the proposed
work, is that concomitant use of a large animal HFpEF model and a mouse model of diastolic dysfunction with
preserved EF will enable us to document common effects of a putative therapeutic on the HFpEF phenotype,
thus facilitating translation of our findings to the estimated 2.5 million humans currently suffering from HFpEF in
the United States alone.
Within the last year, work by the two PIs of this proposal was the first to illustrate a crucial role for a family of
epigenetic regulatory enzymes, histone deacetylases (HDACs), in the control of diastolic dysfunction and
HFpEF pathogenesis. The McKinsey laboratory showed that a small molecule HDAC inhibitor prevented
diastolic dysfunction in rat and mouse models of diastolic dysfunction with preserved EF triggered by
hypertension or aging. Strikingly, the work was the first to link impairment of myofibril relaxation to the
development of diastolic dysfunction in rodents, as well as in humans with HFpEF. Furthermore, it was shown
that HDAC inhibition improves relaxation of the heart by promoting myofibrillar protein acetylation, thereby
speeding myofibril relaxation rates. The Houser laboratory has recently demonstrated similar beneficial effects
of an HDAC inhibitor in a feline model that recapitulates many elements of HFpEF in humans. The studies
proposed in this application would define a strategy for HDAC inhibition that provides the greatest therapeutic
efficacy, setting the stage for a proof-of-concept Phase 2a clinical trial with an HDAC inhibitor in patients with
HFpEF. Furthermore, the work would define which HDAC isoforms promote diastolic dysfunction, and expand
our understanding of the cellular and molecular mechanisms by which HDAC inhibitors improve relaxation of
the heart. Three independent specific aims are designed to significantly extend this new field of translational
cardiac research, and test the overall hypothesis that increased HDAC activity contributes to the
pathogenesis of HFpEF by promoting diastolic dysfunction via deacetylation of proteins that regulate myofibril
relaxation, cardiac fibrosis and/or sarcoplasmic reticulum calcium uptake.

## Key facts

- **NIH application ID:** 9903434
- **Project number:** 5R01HL147558-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Steven R Houser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $773,007
- **Award type:** 5
- **Project period:** 2019-04-04 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903434

## Citation

> US National Institutes of Health, RePORTER application 9903434, Deacetylase-Dependent Control of Diastolic Dysfunction and HFpEF (5R01HL147558-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9903434. Licensed CC0.

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