# Myocardial Plasticity in Heart Failure with Preserved Ejection Fraction (HFpEF)

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Abstract
Heart failure (HF) is a leading cause of morbidity, mortality, and escalating health care costs within the
VA. The type of HF that is increasing disproportionately is HF with a preserved ejection fraction
(HFpEF), commonly caused by left ventricular (LV) pressure overload (LVPO). A cornerstone of
HFpEF is LV diastolic dysfunction and extracellular matrix (ECM) remodeling, in which these structural
changes are not readily reversible. A critical pathway for ECM remodeling is post-transcriptional
regulation by the microRNAs (miRs). The guiding hypothesis of this collaborative program is that a
specific and quantifiable shift in a specific miR profile, which regulate key ECM processes and can be
identified in both HFpEF patients and a large animal model of HFpEF, is predictive for exercise
response and attenuation of HFpEF progression and mechanistically directs phenotype
reprogramming of HFpEF myocardial fibroblasts. The integrative project outcomes include
establishing new molecular tools with improved precision to detect onset and attenuate the
progression of HFpEF as well as identify novel therapeutic targets for Veterans suffering from this
devastating HF syndrome. In this project, a large animal model of LVPO induced HFpEF will be utilized
in order to perform functional (LV regional myocardial stiffness) and exercise studies as well as miR
profiling. The guiding hypothesis is that a setpoint shift in a cassette of miRs that regulate the
ECM/fibroblast activation process causes a refractory form of HFpEF, defined by a persistent HFpEF
phenotype despite removal of the LVPO stimulus. In a parallel set of studies, it will be demonstrated that
a standardized exercise regimen will prevent the emergence of this profibrotic miR signature and in turn
refractory HFpEF. These studies will provide the foundation for the development of novel diagnostics
to provide early detection and moreover provide the foundation for a novel therapeutic direction for the
restoration of myocardial plasticity with HFpEF. In this project, the guiding hypothesis is that a key
molecular event in the development of HFpEF is the loss of post-transcriptional control by a specific
cassette of miRs that regulate ECM homeostasis and fibroblast activation, which results in a refractory
form of HFpEF. Integrating a standardized exercise protocol during the progression of HFpEF will
prevent this loss of miR post-transcriptional control, attenuate ECM accumulation and fibroblast
activation, and thereby prevent the development of a refractory HFpEF phenotype.

## Key facts

- **NIH application ID:** 10367549
- **Project number:** 1I01BX005320-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** FRANCIS G SPINALE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367549

## Citation

> US National Institutes of Health, RePORTER application 10367549, Myocardial Plasticity in Heart Failure with Preserved Ejection Fraction (HFpEF) (1I01BX005320-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10367549. Licensed CC0.

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