# Reversal of Heart Failure: Role of Vascular Recovery

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2022 · $710,878

## Abstract

PROJECT SUMMARY
Heart failure is a major cause of morbidity and mortality worldwide, currently affecting an estimated 6.5 million
adults in the US alone and contributing to $21 billion in health care costs. The aim of this proposal is to understand
the mechanisms of heart failure recovery. We have clinical evidence that heart failure recovery involves a
reduction in interstitial myocardial fibrosis and an increase in microvascular density. Our library of human
samples from Left Ventricular Assist Device (LVAD) implantation/explantation represent a convenience sample
to examine the mechanisms of recovery. In these patients, the LVAD implantation (and unloading of the heart
from hemodynamic forces) promotes some improvement in ventricular function (as assessed by
echocardiography) that is associated with decreased interstitial fibrosis and increased vascular density. Based on
clinical and pre-clinical data, we hypothesize that recovery from heart failure is (at least in part) a vascular
recovery. The vascular recovery may involve mesenchymal-to-endothelial transition (MEndoT), that is, the
transdifferentiation of cardiac fibroblasts (or other mesenchymal cells) into endothelial cells. Furthermore, we
have evidence that MEndoT may require a glycolytic switch that directly affects DNA accessibility and cellular
plasticity. In our first aim, we will characterize the physiological, cellular, and molecular hallmarks of heart failure
recovery in a unique mouse model. In the second aim, transcriptional profiling of disaggregated mouse hearts as
well as human cardiac tissue obtained pre- and post-LVAD implantation will be combined with bioinformatics
analyses to predict novel genes in heart failure recovery. In our third aim, we will confirm the genetic
determinants discovered in the first aim using gain- or loss-of-function studies in vitro and in vivo. In addition,
we will explore the role of the glycolytic switch in cell fate transitions and vascular recovery using bioinformatics
analyses of our RNAseq data, confirmed with cell-specific and conditional gain- or loss-of-function studies of
target genes (e.g. in metabolic pathways) in vitro and in vivo. The intent of this proposal is to generate
fundamental insights regarding heart failure recovery that may lead to a new therapeutic strategy.

## Key facts

- **NIH application ID:** 10397100
- **Project number:** 5R01HL148338-03
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** JOHN P COOKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $710,878
- **Award type:** 5
- **Project period:** 2020-07-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397100

## Citation

> US National Institutes of Health, RePORTER application 10397100, Reversal of Heart Failure: Role of Vascular Recovery (5R01HL148338-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10397100. Licensed CC0.

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